Post on 20-Jun-2022
Protocol
This trial protocol has been provided by the authors to give readers additional information about their
work.
Protocol for: Yong Liu, Yong Huo, Shiqun Chen, et al. Aggressive hydration and contrast induced acute
kidney injury following primary angioplasty.
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Context
APPENIX A The following individuals participated in the ATTEMPT study
APPENIX B ATTEMEPT Clinical Trial Protocol Version 1.0
APPENIX C ATTEMEPT Clinical Trial Protocol Version 3.0
APPENIX D Changes to ATTEMPT Protocol
APPENIX E ATTEMEPT Clinical Trial Case Report Form
APPENIX F ATTEMEPT Clinical Trial Statistical Analysis Plan Version 1.0
APPENIX G ATTEMEPT Clinical Trial Statistical Analysis Plan Version 3.0
APPENIX H Changes to ATTEMPT Statistical Analysis Plan
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Appendix A
The following individuals participated in the
ATTEMPT study:
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Title: Aggressive Hydration and Contrast Induced Acute Kidney InjuryFollowing Primary Angioplasty
Acronym: ATTEMPT
The following individuals participated in the ATTEMPT study:
PIDr. Jiyan ChenGuangdong Cardiovascular Institute,Guangdong Provincial Key Laboratory ofCoronary Disease, Guangdong ProvincialPeople’s Hospital, Guangzhou, Guangdong,China
Executive directorDr. Yong LiuGuangdong Cardiovascular Institute,Guangdong Provincial Key Laboratory ofCoronary Disease, Guangdong ProvincialPeople’s Hospital, Guangzhou, Guangdong,China
CO-PIProf. Yong HuoPeking University First Hospital,Beijing, China
Site PIProf. Jun-Bo GeZhongshan Hospital, Fudan University,Shanghai Institute of CardiovascularDiseases, Shanghai, China
Prof. Yun-Dai ChenChinese PLA General Hospital,Beijing, China
Dr. Keng WuThe Affiliated Hospital, Guangdong MedicalUniversity,Zhanjiang, Guangdong, China
Dr. Gui-Fu WuThe Eighth Affiliated Hospital, Sun Yat-senUniversity, Shenzhen, Guangdong, China
Dr. Kai-Hong ChenLongyan First Affiliated Hospital of FujianMedical University, Longyan, Fujian, China
Dr. Jian-Feng YeDongguan TCM Hospital, Dongguan,Guangdong, China
Dr. Yan LiangMaoming People's Hospital, Maoming,Guangdong, China
Dr. Xin-Wu FengFirst People’s Hospital of Zhaoqing City,Zhaoqing, Guangdong, China
Dr. Shao-Hong DongShenzhen People's Hospital, Shenzhen,518020, China
Dr. Qi-Ming WuBeijing Ditan Hospital, Capital MedicalUniversity, Beijing, China
Dr. Xian-Hua YeHangzhou First People’s Hospital,Hangzhou, China
Dr. He-Song ZengTongji Hospital, Tongji Medical College,Huazhong University of Science andTechnology, Wuhan, China
Dr. Min-Zhou ZhangGuangdong Provincial Hospital of ChineseMedicine, Guangzhou, Guangdong, China
Dr. Min DaiMianyang Central Hospital, Mianyang City,Sichuan, China
Data Monitoring CommitteeDr. ChunWangPeking university Shenzhen Hospital
Dr. Chun-Quan OuSouthern Medical University
Dr. Xiao-Qi LiuGuangdong Provincial People’s Hospital
Clinical Event CommitteeDr. Zhi-Min DuThe First Affiliated Hospital, Sun Yat-senUniversity
Dr. Hong TanGuangdong Provincial People’s Hospital
Dr. Xue-Ping YangGuangdong Provincial People’s Hospital
Dr. Hao WangSichuan Provincial People’s Hospital
Dr. Yan Xuethe people's hospital of Guangxi Zhuangautonomous region
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Trial Steering Committee members:Dr. Ying XianDuke Clinical Research Institute, Durham, NC, 27705, USA
Investigators and Coordinators
1. Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key
Laboratory of Coronary Disease, Guangdong Provincial People’s Hospital, Affaliated
Guangdong Provincial People’s Hospital of South China University of Technology,
Guangzhou 510100, China: Ning Tan, Ying-Ling Zhou, Jian-Fang Luo, Shi-Qun Chen,
Dan-Qing Yu, Li-Wen Li, Zhu-Jun Chen, Guang Li, Bin Zhang, Li-Jun Jin, Hong Yan, Tai-Ming
Dong, Yuan Liu, Wen-Hui Huang, Jun-Qing Yang, Peng-Cheng He, Nian-Jin Xie,Yong-Quan
Yang, Jing-Ru Deng, Xiao-Yu Huang;
2. Department of Cardiology, the First Medical center, Chinese PLA General Hospital, Beijing,
100853, China: Xiang-Zhu Dong, Ye Zhang, Geng Qian, Dan-Dan Li;
3. Department of Cardiology, The Affiliated Hospital, Guangdong Medical University,Zhanjiang,
Guangdong Province, 524001, P.R. China: Hai-Liang Mo;
4. The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518033, P.R. China:
Wen-Bin Wei, Xing-Rui Fang;
5. Department of Cardiology, Longyan First Affiliated Hospital of Fujian Medical University,
Longyan, Fujian 364000, P.R. China: Li-Ling Chen;
6. Department of Cardiology, Dongguan TCM Hospital, Dongguan, 523209, China: Shao-Hui Su;
7. Department of Cardiology, Maoming People's Hospital, Maoming, 525000, China: Cong Chen;
8. Department of Cardiology, First People’s Hospital of Zhaoqing City, Zhaoqing City,
Guangdong Province, 526000, P.R. China:Rong-Bin Su;
9. The Department of Cardiology, Shenzhen People's Hospital, Shenzhen, 518020, China:
Hua-Dong Liu, Qian Mou, Rui-Jing Chen, Chuan-Shou Zhang;
10. Department of Cardiology, Beijing Ditan Hospital, Capital Medical University, Beijing 100070,
China: Yu-Qing Song, Qian Dong, Li Fu, Wen-Jing Xu, Wang-Jiang Wei, Chang Ma, Qian Wang,
Yong-Fu Chen, Da-Wei Tan;
11. Department of Cardiology, Hangzhou First People’s Hospital, Hangzhou, 310006, China:
Jian-Min Yang;
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12. Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical
College, Huazhong University of Science and Technology, Wuhan, 430030, China:Qiang
Zhou;
13. Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, 510120, China: Li-Heng
Guo, Lei Wang, Yong-Jie Kong, Huang Ma, Guang-Ping Wu, Shuai Mao;
14. Department of Cardiology, Mianyang Central Hospital, Changjia Alley 12, Fucheng district,
Mianyang City, 621000, Sichuan, China: Yu Li, Min Wang.
15. State Key Laboratory of Organ Failure Research, Department of Biostatistics, Guangdong
Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern
Medical University, Guangzhou, 510515, China: Chong-Yang Duan;
16. Department of Emergency and Critical Care Medicine, Guangdong Provincial People’s
Hospital and Guangdong Academy of Medical Sciences, Guangzhou, 510080, P.R. China:
Fei-er Song;
17. Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of
Cardiovascular Diseases, Shanghai, 200032, China:Shu-Fu Chang, Hao Lu, Li-Li Xu;
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 1.0
Appendix B
ATTEMEPT Clinical Trial Protocol Version 1.0
(Appendix independently paginated)
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 1.0
AGGRESSIVE HYDRATION AND CONTRAST INDUCED ACUTE KIDNEY INJURYFOLLOWING PRIMARY ANGIOPLASTY (ATTEMPT):
CONTENTS
RESEARCH CENTERS
EXECUTIVE SUMMARY........................................................................................................1
ABBREVIATIONS................................................................................................................... 3
INTRODUCTION......................................................................................................................5
BACKGROUND....................................................................................................................6
SIGNIFICANCE OF THE PROPOSED RESEARCH...................................................19
STUDY DESIGN....................................................................................................................20
STUDY HYPOTHESES AND OBJECTIVES.................................................................20
OVERVIEW OF STUDY DESIGN...................................................................................21
METHOD.................................................................................................................................28
STUDY POPULATION AND PATIENT RECRUITMENT............................................28
STUDY PROCEDURES...................................................................................................30
POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS................................51
FEASIBILITY OF RECRUITMENT...............................................................................555
ANTICIPATED BARRIERS TO RECRUITMENT.......................................................566
PROPOSED ANCILLARY STUDY............................................................................... 577
HUMAN SUBJECTS....................................................................................................... 588
DATA MANAGEMENT......................................................................................................60
QUALITY CONTROL......................................................................................................722
GOOD CLINICAL PRACTICE.......................................................................................822
RESEARCH MONITORING AND AUDIT PLANS........................................................83
RESULT..................................................................................................................................90
BIOSTATISTICAL CONSIDERATIONS.........................................................................90
STUDY ORGANIZATION AND ADMINISTRATION..................................................944
PUBLICATIONS...............................................................................................................977
REFERENCES.................................................................................................................988
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 1.0
Research centers
No. Study Site
01 Guangdong Provincial People’s Hospital
02 Peking University First Hospital
03 Zhongshan Hospital, Fudan University
04 Chinese PLA General Hospital
05 The Affiliated Hospital, Guangdong Medical University
06 The people’s Hospital of Baoan Shenzhen
07 The Eighth Affiliated Hospital, Sun Yat‐sen University
08 Longyan First Affiliated Hospital of Fujian Medical University
09 First People’s Hospital of Zhaoqing City
10 Dongguan TCM Hospital
11 Maoming People's Hospital
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 1.0
1
EXECUTIVE SUMMARY
The intravascular administration of iodinated contrast agent for coronary
angiography (CAG) or percutaneous coronary intervention (PCI) is a common
cause of acute kidney injury (AKI) and a leading cause of iatrogenic renal
disease. Multiple studies have determined that contrast-induced AKI (CI-AKI)
is associated with prolonged hospitalization, increased medical economic
burden, and adverse long-term prognosis.
Patients with ST-elevation myocardial infarction (STEMI) have a higher risk of
CI-AKI, which is a potentially serious complication of angiographic procedures
that are associated with increased mortality, morbidity, and health care use in
patients undergoing PCI. According to guidelines for the management of
STEMI, saline hydration is widely recommended. However, optimal saline
hydration strategy has not been well established in this high-risk population.
The Induced Diuresis With Matched Hydration Compared to Standard
Hydration for Contrast Induced Nephropathy Prevention (MYTHOS) study
found that a loading dose (125/250mL) of isotonic saline matched with
furosemide-induced high urine output significantly reduces the risk of CI-AKI
and might be associated with improved clinical outcomes in patients with
chronic kidney disease (CKD). QIAN G et al suggested that CVP-guided fluid
administration can be safely and effectively reduce the risk of CI-AKI in
patients with CKD and chronic heart failure and substantially reduce composite
major adverse events for these high-risk patients. The Prevention of Contrast
Renal Injury with Different Hydration Strategies (POSEIDON) trial suggested
that intravenous (IV) administration of normal saline guided by the left
ventricular end diastolic pressure (LVEDP) is well tolerated and could
substantially reduce the incidence of CI-AKI and major adverse clinical events
in patients with combined CKD and one or more of several risk factors
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2
undergoing cardiac catheterization. Three clinical trials above consistently
demonstrated that saline hydration based on certain guiding strategies was
more effective than general hydration in preventing CI-AKI and reducing the
risk of adverse prognosis.
Patients with STEMI are likely to present with hypotension or even shock, a
large volume of contrast agent, and inability to start a kidney prophylactic
therapy, all of which are associated with an increased risk of CI-AKI. In
previous studies, cardiologists were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; The main
reason is lacking of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a definite
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Therefore, flexible
and individualized hydration therapy based on certain guiding strategy needed
to maintain renal perfusion, given that perioperative IV volume expansion
could potentially compensate for reduced cardiac output, hypotension, and
depletion of intravascular volume in patients with STEMI.
Given these previous data, we designed the ATTEMPT trial to examine the
efficacy of a preprocedural loading dose and postprocedural aggressive
hydration with normal saline guided by LVEDP as compared with general
hydration(Figure A1). We hypothesize that aggressive hydration strategy
reduces the risk of CI-AKI and improves the clinical outcomes in STEMI
patients undergoing primary PCI. The ATTEMPT study is a multicenter,
open-label, investigator-driven, randomized controlled trial in China.
Approximately 560 patients with STEMI undergoing primary PCI will be
randomized (1:1) to receive either periprocedural general hydration (control
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3
group) or aggressive hydration (intervention group). Patients in the control
group receive periprocedural general hydration with ≤500 mL normal saline
(within 6 hours) at a normal rate (0.5 or 1 mL/kg*h). Patients in the intervention
group receive a preprocedural loading dose (125/250 mL) of normal saline
within 30 minutes and intravenous hydration at a normal rate until LVEDP is
available, followed by postprocedural aggressive hydration guided by LVEDP
for 4 hours and then continuous intravascular hydration at the normal rate until
24 hours after PCI. The primary endpoint is CI-AKI, defined as a >25% or
0.5-mg/dL increase in serum creatinine from baseline during the first 48 to 72
hours after the procedure. The ATTEMPT study has the potential to identify
optimal hydration regimens for STEMI patients undergoing primary PCI.
ABBREVIATIONS
AKI Acute kidney injury
ACS Acute coronary syndrome
AHF Acute heart failure
AMI Acute myocardial infarction
ACEI Angiotensin-Converting Enzyme Inhibitors
ARB Angiotensin Receptor Blockers
BMI Body Mass Index
pPCI Primary Percutaneous Cornary Intervention
RR Risk Ratio
ARR Absolute Risk Ratio
SCr Serum creatinine
DSMB Data and safety monitoring committee
CCU Cardiac care unit
CEC Clinical Event Committee
CI Confidence Interval
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CI-AKI Contrast-induced Acute Kidney Injury
CK Creatine kinase
CK-MB Creatine kinase-MB
CKD Chronic kidney disease
CAG Coronary Angiography
CEC Clinical Event Committee
CVD Cardiovascular disease
CRA Clinical Research Associate
CT Computed Tomography
DM Diabetes Mellitus
DMC Data Monitoring Committee
DVP Data Validation Plan
EDC Electronic Data Capture
eGFR estimated Glomerular Filtration Rate
ESRD End-stage Renal Disease
GCP Good Clinical Practice
HF Heart Failure
HR Hazard Ratio
HCT Hematocrit
ICH International technical committee
IEC Independent Ethics Committee
ITT Intention-to-treat
IABP Intra-aortic Ballon Pump
LVEDP Left Ventricular end-diastolic Pressure
LVEF Left Ventricular Ejection Fraction
MACE Major Adverse Cardiovascular Events
MDRD Modification of Diet in Renal Disease formula
OR Odd Ratio
PCI Percutaneous Coronary Intervention
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PM Project Manager
PLT Platelets
NT-proBNP N-terminal pro-brain natriuretic peptide
NNT Number needed to treat
NYHA New York Heart Association
STEMI Stsegment Elevation Myocardial Infarction
RR Risk Ratio
WBC White Blood Cell
DCF Data Challenge Form
INTRODUCTION
Contrast-induced acute kidney injury (CI-AKI) is a common complication of
coronary angiography and/or percutaneous coronary intervention (CAG/PCI).
Patients with ST-elevation myocardial infarction (STEMI) undergoing primary
percutaneous coronary intervention (pPCI) have a higher risk of CI-AKI.
Previous trials failed to find out the efficacy of sodium bicarbonate and
acetylcysteine in prevention of CI-AKI and outcomes following pPCI or
angiography. Although previous studies suggested the benefit of intravenous
hydration (vs. no hydration) in reducing risk of CI-AKI following pPCI, recent
systematic review suggested that the most effective regimen of intravenous
hydration has not been determined. According to the guideline for the
management of STEMI, timely reperfusion with shortest delay was the most
important for clinical outcomes, while adequate hydration is also
recommended for CI-AKI prevention in patients undergoing pPCI. Therefore,
adequate preventive hydration including pre-procedural long-term duration
conflicts shortest delay before pPCI among patients with STEMI.
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MYTHOS study suggested that a loading dose (125/250 mL in short half an
hour) of isotonic saline matched with furosemide-induced high urine output
significantly reduces the risk of CI-AKI, more effective among patients
undergoing emergent PCI, without increased risk of acute heart failure.
POSEIDON trial showed that left ventricular end-diastolic pressure (LVEDP)
guided intensive hydration in short time (4 hours) could substantially reduce
the incidence of CI-AKI and was well safety tolerated. Therefore, our
hypothesis was that aggressive intravenous hydration, including above short
intensive regimen (loading dose, post-reperfusion LVEDP guide) and
long-term maintenance, might be suitable for the special emergent condition
among STEMI patients undergoing pPCI. We designed the Aggressive
hydraTion in patients with ST-Elevation Myocardial infarction undergoing
Primary percutaneous coronary intervention to prevenT Contrast-Induced
Nephropathy (ATTEMPT) trial to investigate the efficacy and safety of the
aggressive hydration strategy in high-risk patients with STEMI undergoing
pPCI.
1. BACKGROUND
1.1 Definition, incidence, and risk factors for CI-AKI in STEMI patients
CI-AKI is defined as a decrease in kidney function following the exposure of
contrast agent1,2. Although the diagnostic criteria of CI-AKI varies in different
studies, the widely accepted definition of CI-AKI is an increase in the serum
creatinine concentration (SCr) of at least 0.5 mg/dL and/or 25% within 2-3
days of intravascular administration of contrast agent3-5.
The previous study found that CI-AKI occurred in 8.5% of with eGFR >60
ml/min/1.73 m2 undergoing non-urgent coronary angiography and 13.2% of
clinically stable Veterans with eGFR <60 ml/min/1.73 m2 undergoing
non-urgent, non-coronary angiography6. Other studies showed that up to 33%
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of extremely high-risk patients develop this condition following
contrast-enhanced procedures7.
We have made a system review which has illuminated the pivotal risk factors
for CI-AKI in STEMI patients (Figure A1). Renal insufficiency is recognized as
the principal risk factor for the development of CI-AKI, with increasing levels of
kidney dysfunction associated with incremental degree of risk8. Combined with
diabetes mellitus substantially increase the risk for CI-AKI in patients with
chronic kidney disease8-10. Patients with hypovolemia are also vulnerable to
kidney dysfunction due to iodized contrast media, as are patients with
advanced heart failure8. In both clinical states, hypovolemia and reduced renal
perfusion induced renal vasoconstriction after intravascular contrast media
administration. The risk of CI-AKI increases with the administration of contrast
agents in large quantities11, 12. It is also believed that the risk of CI-AKI after
intra-arterial contrast agent administration is greater than that of intravenous
administration. Recognition of these major risk factors helps clinicians to more
accurately determine which patients are most likely to develop CI-AKI, and
studies has been conducted to assess the effectiveness of preventive
interventions for this disease.
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Figure A1-Major risk factors for CI-AKI in STEMI patients
1.2 Association of CI-AKI with mortality
Observational studies have shown a correlation between CI-AKI (defined by
small absolute and/or relative changes in SCr) and increased short-term
mortality13-20. In a retrospective study, Levy et al. CI-AKI was found to be an
important predictor of in-hospital mortality (OR = 5.5, P < 0.001) in 183
hospitalized patients (an increase of 25% from SCr to at least 2.0 mg/dL).
Follow-up studies by McCullough et al. Among the 1,826 patients receiving
PCI, CI-AKI was found to be related with an in-hospital mortality rate of 7.1%,
compared with 1.1% in patients with no such change in SCr. (p < 0.0001)21.
Among CI-AKI patients who needed renal replacement therapy, the hospital
mortality rate was 35.7%. Many other studies reported an independent
association between CI-AKI and short-term mortality13-15, 17-19. although there is
a close relationship between small changes in SCr and short-term mortality,
most of them are retrospective analysis. Therefore, there may be deterministic
bias in assessing postoperative SCr, and there may be missing potential
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problem data13, 14, 17-19, 21. However, prospective studies confirm these findings
in the clinical study of Marenzi et al. The study found that the in-hospital
mortality of patients with CI-AKI was significantly higher than that of patients
without renal dysfunction (26% vs. 1.4%, P < 0.001)22. Maioli et al. conducted
several studies that have shown that in-hospital mortality in patients with
CI-AKI is significantly higher than that in patients without complications (11.1%
vs. 0.2%, P = 0.001)23. Therefore, data from observational studies and
randomized trials support the association between postoperative decline of
kidney function and short-term mortality.
In addition to increased short-term complications, CI-AKI has also been linked
with long-term mortality in recent studies17, 24-28. Solomon et al. demonstrated
that CI-AKI was associated with a greater than 3-fold increased risk of major
adverse outcomes (death, stroke, myocardial infarction, end-stage renal
disease requiring renal replacement therapy) at 1-year of follow up28. Four
additional studies found an independent association of CI-AKI with long-term
mortality, although the study by Roghi et al. demonstrated a trend toward
increased long-term mortality that did not reach statistical significance in
multivariable analyses17, 24, 25, 27. Collectively, these findings indicate that
CI-AKI, defined by small decrements in renal function, is associated with
adverse long-term outcomes and more compromised renal function over time.
Despite the abundance of epidemiological and experimental data associating
small changes in SCr with adverse renal and extra-renal outcomes, the
evidence remains inadequate to warrant the use of small changes in SCr as a
surrogate primary endpoint in large transformative clinical trials. Although
serious events following angiography occur as a consequence of CI-AKI, they
may also develop independent of this intermediate event, as many of the
clinical conditions that predispose patients to the development of CI-AKI (e.g.,
CKD, diabetes mellitus, heart failure) are also independently associated with
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mortality and other adverse outcomes (Figure A2). In addition, not all episodes
of CI-AKI lead to clinically consequential sequelae. For this reason, we believe
that it is most appropriate for a definitive trial of interventions for the prevention
of CI-AKI to demonstrate effectiveness in reducing serious, adverse,
patient-centered outcomes rather than merely focusing on the amelioration of
small changes in SCr. In our ATTEMPT study, the primary end point is CI-AKI,
defined as a >25% or 0.5-mg/dL increase in serum creatinine from baseline
during the first 48 to 72 hours after the procedure. Secondary end points are
as follows: (1) CI-AKI48h, defined as a >50% or 0.3-mg/dL absolute increase in
serum creatinine from baseline during the first 48 hours after the procedure; (2)
CI-AKIcysc, defined as a >10% or 0.3-mg/dL absolute increase in serum
cystatin C during the first 24 hours after the procedure; (3) contrast induced
persistence kidney injury (CI-PKI), defined as residual impairment of renal
function indicated by >25% reduction in creatinine clearance at 3 months in
comparison with baseline; (4) major adverse cardiovascular events, including
all-cause mortality, target vascular revascularization, and nonfatal myocardial
infarction; (5) post-procedural acute heart failure during hospitalization; (6)
major post-procedure in-hospital adverse clinical events, including acute
pulmonary edema, cardiogenic shock, stroke, clinically significant arrhythmias,
and bleeding within the first year; and (7) total hospitalization costs and length
of stay.
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Figure A2 – Development process of clinical adverse events exposure to
contrast agent
1.3 Prolonged hospitalization and increased costs associated with
CI-AKI
Multiple retrospective studies also focus on clarifying an association of CI-AKI
with economic benefits of health13,19,29-32. In the analysis of over 27,000
patients who underwent CAG, a rise in SCr of 0.25 - 0.5 mg/dL was associated
with prolonged hospitalization after adjusting for underlying severity of illness19.
The length of hospitalization extended with the increase of SCr gradually.
Bartholomew found that patients who developed CI-AKI after PCI were 15
times more likely to extend length of hospitalization more than four days13. In a
clinical trial comparing IV fluids for the prevention of CI-AKI, Adolph found that
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patients with a postoperative increase in SCr of ≥25% or ≥0.5 mg/dL was
associated with a mean of two days longer than patients without obvious
change of SCr29. Prolonged hospitalization results in increased healthcare
expenditures as documented in an observational study32. In the analysis of 598
diabetics with CKD undergoing CAG, CI-AKI was independently associated
with a 2-fold increase in healthcare expenditures32. Subramanian et al used a
decision analytic model to show that CI-AKI results in an average increase in
hospital-related costs of more than $10,300 and 1-year costs in excess of
$11,80031. Based on the number of CHD and cardiac catheterization
performed across the China, there may be approximately 940,000 cases of
CI-AKI nationwide. In general, these data indicate that CI-AKI is associated
with prolonged hospitalization and huge expenditure on health economics.
1.4 Pathophysiology and prevention strategies of CI-AKI in STEMI
patients
Although the pathophysiological mechanism of renal injury induced by contrast
agents has not been fully elucidated, the following mechanisms are generally
accepted: direct and indirect renal injury induced by contrast agents, and
disturbance of hemodynamic stability (Figure A3)33. Firstly, intravascular
exposure of contrast agents leads to transient systemic vasodilation, followed
by intense contractions of the renal vascular bed. Outside the vasoconstriction
in the renal medulla have particularly low baseline oxygen tension, cause the
oxygen supply and demand do not match, leading to ischemic renal tubular
damage33, 34. Secondly, direct toxic on renal tubular epithelial cells caused by
contrast agents33, 35. Thirdly, the use of contrast agents lead to reactive oxygen
species (ROS) generation, this will accelerate renal tubular cell injury33,36-38.
Patients with STEMI are likely to present with hypotension or even shock, a
large volume of contrast agent, and inability to start a kidney prophylactic
therapy, all of which are associated with an increased risk of CI-AKI. Patients
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with STEMI also commonly have other risk factors for CI-AKI such as reduced
cardiac output or hypotension due to myocardial infarction or depletion of
intravascular volume caused by vomiting, diaphoresis, or decreased oral
intake. Despite a considerable prevalence of risk factors, including reduced
LVEF, renal insufficiency, and diabetes mellitus, in patients needing adequate
hydration, cardiologists in previous studies were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; this was
related to a lack of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a certain
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Through the
understanding of the above pathogenesis, it is helpful to explore the prevention
and treatment strategy of CI-AKI in STEMI patients.
Figure A3 - Pathophysiology of CI-AKI in STEMI patients
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Renal injury induced by contrast agents may be preventable. Patients at
increased risk of CI-AKI are easily identified by the presence of known clinical
risk factors. Past efforts to find effective prevention strategies for CI-AKI have
focused on three recommendations39: 1) risk factors assessment of CI-AKI; 2)
minimization and preference of low-osmolar or iso-osmolar contrast media; 3)
adequate hydration. The incidence of CI-AKI has decreased due to the change
in the type of contrast agent over time and risk factors of CI-AKI are gradually
clarified. Recently, Jurado-Román et al40 suggested that the risk of CI-AKI after
IV administration of normal saline is 48% lower than with no IV hydration in
patients with STEMI, which is rarely performed in actual practice, when
following the guideline for the management of STEMI41. However, we still have
to be soberly aware that the optimal saline hydration strategy still remain
controversial9, 42-44.
1.5 Characteristics of randomized clinical trials on prevention of CI-AKI
under different hydration strategies of IV isotonic saline
Previous studies have focused on the optimal composition of hydration therapy.
With the publication of PRESERVE results, acetylcysteine as a component of
hydrated liquids has no obvious benefit for the prevention of CI-AKI. Therefore,
the preferred position of isotonic saline hydration in the prevention strategy of
CI-AKI hydration has been gradually consolidated. At present, the optimal
hydration strategy for the prevention of CI-AKI in high-risk patients still remain
inconclusive. We systematically review the RCT articles published in the past
few years on the prevention of CI-AKI by hydration of isotonic saline under
different guiding strategies. Nine studies were included20,40,45-51. Eight of them
showed that the hydration guidance strategy of the intervention group was
better than that of the control group without special hydration strategy. One
study showed that isotonic saline hydration had no significant benefit in
preventing CI-AKI (Table A1). The different results of nine studies suggest that
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the optimal hydration strategy of saline is still uncertain, and for high-risk
patients such as STEMI, we lack relevant research evidence. In particular, we
need to focus not only on the different effects of individualized isotonic saline
hydration strategies on preventing CI-AKI, but also to explore the optimal
isotonic saline hydration strategy that can reduce the short-term and long-term
adverse prognosis among high-risk patients such as STEMI.
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Table A1- Characteristics of randomized clinical trials on prevention of CI-AKI under different hydration strategies of IV isotonic saline
Authors Number
of
patients
Procedure Baseline renal function Definition of
CI-AKI
Hydration strategy of IV isotonic saline Frequency of
CI-AKI in isotonic
saline group
Dialysis Death
WEISBORD S
D et al
4993 Elective CAG ↑ SCr >0.5mg/dL or >25%
within 3-5 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
During 1-12h before angiography:1-3ml/kg/h; during angiography:1-1.5ml/kg/h ,
during a period of 2-12h after angiography:1-3ml/kg/h. hydration speed will be
adjusted if overweight.
8.3% 1.2% 2.7%
TRIVEDI H S et
al
53 Elective CAG/PCI ↑ SCr >0.5mg/dL within 2 days
of contrast exposure
↑
SCr >0.5mg/dL
1ml/kg/h, 12h before CAG/PCI for total 24h. 3.7% NA NA
BRAR S S et al 396 Elective CAG/PCI ↑ SCr >0.5mg/dL or ≥25%
within 1-4 days of contrast
exposure
↑
SCr >0.5mg/dL
or ≥25%
A: LVEDP-guided volume expansion
B: Standard fluid administration protocol.
6.7%/16.3% 0.5%/2.0% 0.5%/4.0
%
JURADO-ROM
AN A et al
408 Primary CAG/PCI ↑ SCr >0.5mg/dL or >25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
1 ml/kg/h since the beginning of CAG/PCI for total 24 hours. 11% 0% 2.8%
LUO Y et al 216 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
1mL/kg/h for 12 hours after CAG/PCI., the rate was reduced to 0.5 mL/kg/h in
patients with LVEF≤30% or a Killip class 2 or 3 status.
20.4% 0.93% 2.78%
MARENZI G et
al
450 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
1mL/kg/h for 12 hours immediately after CAG/PCI, rate was reduced to 0.5 mL/kg/h in
patients with LVEF≤40% or NYHA III–IV.
22.7% 0.93% 2.78%
MAIOLI M et al 170 Elective CAG ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
A: Furosemide with matched hydration group(FMH)
B: 1 ml/kg/h (0.5ml/kg/h in case of LVEF<40%) for at least 12 h before and 12 h after
the CAG.
4.6%/18% 1.1%/4% 1.1%/4%
QIAN G et al 264 Elective CAG/PCI ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
↑
SCr >0.5mg/dL
A: CVP-guided hydration group
B: standard hydration group.
15.9%/29.5% 3.0%/9.8% 1.1%/4%
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exposure or ≥25%
NIJSSEN E C
et al
660 Elective CAG ↑ SCr >0.5mg/dL or ≥25%
within 2-6 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
A: 3–4mL/kg/h during 4 h before and 4 h after contrast administration;
B: 1mL/kg/h during 12 h before and 12 h after contrast administration/No hydration
group.
2.7%/2.6% 0%/0% 0%/0.9%
CI-AKI denotes contrast induced acute kedney injury, CAG denotes coronary angiogram, NA denotes not assessed, PCI denotes percutaneous coronary intervention.
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1.6 Summary of limitations of randomized clinical trials on prevention of
CI-AKI under different hydration strategies of IV isotonic saline
AMACING study has the following limitations: Firstly, it is a single center study.
Secondly, the final number of patients participating in this study were less than
half of the planned number of patients, and the overall incidence of CI-AKI was
low. Patients with eGFR<30 mL/min/1.73 m2 were excluded. Therefore, the
efficacy of hydration therapy for the prevention of CI-AKI in high-risk patients
cannot be generalized. The main limitation of the POSEIDON study is the
exclusion of STEMI patients. Therefore, the most effective hydration strategy
for preventing CI-AKI among STEMI patients with high risk of adverse events
after PCI is still inconclusive. The PRESERVE study did not focus on the
discussion of different isotonic saline hydration strategies. In addition to
AMACING, POSEIDON and PRESERVE studies, other studies characterized
in (Table A1) were limited by being single center, unblinded and without clearly
defined allocation concealment mechanisms. Furthermore there was
inconsistent reporting of cross-over between allocated groups and the volume
of fluid received by the control arm was not reported in any study. It is also not
possible to define the most effective hydration strategy as all these studies
used different starting times, rates and durations of hydration. Further
information is expected from the ATTEMPT study evaluating the efficacy of
aggressive hydration therapy guided by LVEDP compared with general
hydration (≤500 mL) for CI-AKI following primary PCI.
1.7 Summary
CI-AKI is a common complication after exposure to iodine-contrast agents,
especially in high risk patients such as STEMI, which is closely associated with
short-term adverse events in hospital and long-term prognosis after discharge.
Isotonic saline hydration strategy has been accepted as an effective strategy
for preventing CI-AKI. After a systematic review of the existing articles
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comparing different isotonic saline hydration strategy, subject-related articles
are scarce and the starting and ending time of hydration, hydration rate and
total amount of hydration fluid remain great difference. For STEMI patients, the
optimal isotonic saline hydration strategy is still inconclusive. Combined with
the above lack of clinical evidence, we urgently need to design a clinical trial to
solve this complex but extremely important clinical problem. ATTEMPT is the
first multicenter, randomized controlled clinical trial that compare the effect of
saline aggressive hydration guided by LVEDP with general hydration on
CI-AKI among STEMI patients undergoing primary PCI. It aims to provide
reliable evidence to guide the optimal hydration strategy for STEMI patients
undergoing primary PCI. If our hypothesis is supported by the results, the
aggressive hydration protocol could be easily adopted in most cardiac
intervention laboratories in China and benefiting the vast number of STEMI
patients.
2. SIGNIFICANCE OF THE PROPOSED RESEARCH
According to the latest data, the number of CHD in worldwide is about 150
million52. China has about 11 million CHD patients. Although the global
mortality rate of CHD is declining, the mortality rate of CHD in China is still
increasing year by year, especially among STEMI population. As an important
measure of diagnosis and treatment, the number of PCI in China increased to
915,256. PCI/CT consumes about 80 million contrast agents per year
worldwide and 20 million contrast agents per year in China, with an annual
increase of 20-30%. The burden of STEMI in China has become increasingly
serious and has become a major public health problem53. CI-AKI is associated
with poorer outcomes for patients, including prolongation of hospital stay and
higher mortality54. The results of our research group’s previous meta-analysis
showed that the global incidence of CI-AKI was about 8.6%. The risk in
patients with STEMI undergoing primary PCI is even greater55, with increased
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incidence of CI-AKI about 29% and increased risk of death by 4.75 times.
Despite a considerable prevalence of risk factors, including reduced LVEF,
renal insufficiency, and diabetes mellitus, in patients needing adequate
hydration, cardiologists in previous studies were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; this was
related to a lack of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a certain
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Therefore, a flexible
and individualized hydration therapy based on certain guiding strategy is
urgently needed. By determining the effectiveness of aggressive hydration with
normal saline guided by LVEDP on CI-AKI and important clinical outcomes in
patients post-STEMI comparing with general hydration, the findings of this
clinical trial will provide reliable evidence to guide the optimal hydration
strategy for STEMI patients undergoing primary PCI. What’s more, the
aggressive hydration protocol could be easily adopted in most cardiac
intervention laboratories in China and benefiting the vast number of STEMI
patients.
STUDY DESIGN
3. STUDY HYPOTHESES AND OBJECTIVES
3.1 Study hypotheses
Compared to general hydration strategy, aggressive hydration (ie,
pre-procedural IV loading plus post-procedural hemodynamic-guided [LVEDP]
fluid administration) will reduce the risk of CI-AKI and long-term clinical
adverse events in STEMI patients undergoing primary PCI.
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3.2 Study objectives
To assess the effectiveness of preprocedural loading dose and
postprocedural aggressive hydration with normal saline guided by LVEDP as
compared with general hydration for prevention of CI-AKI and reduction of
long-term adverse events. CI-AKI is defined as a > 25% or 0.5-mg/dL
increase in serum creatinine from baseline during the first 48 to 72 hours after
PCI. Long-term adverse events includes: all-cause mortality, target vascular
revascularization, nonfatal myocardial infarction; acute pulmonary edema,
cardiogenic shock, stroke, clinically significant arrhythmias, bleeding within the
first year, total hospitalization costs and length of stay. Our ultimate objective is
to identify optimal hydration strategy for high-risk patients with STEMI
undergoing primary PCI.
4. OVERVIEW OF STUDY DESIGN
ATTEMPT (trial registration: ClinicalTrials.gov NCT02067195) is an
investigator-initiated, multicenter, open-label, randomized controlled trial
conducted in the departments of cardiology from 15 hospitals in China. The
institutional ethics review board approved the study's design.
The study population will consist of 560 patients 18 years or older with STEMI
who undergo primary PCI and provide written informed consent for this study.
The time limit of the study is May 2014 - June 2016. Patients are excluded for
the following reasons: contrast medium administration within the previous 7
days; end-stage renal failure or renal transplantation; Inferior and/or right
ventricle myocardial infarction combined with hypotension (defined as systolic
pressure ≤90 mmHg) on admission; Preprocedural renal insufficiency (history
of chronic kidney disease or eGFR ≤60 mL/min/1.73 m2 was calculated using
the level-modified Modification of Diet in Renal Disease formula [MDRD]);
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cardiogenic shock or NYHA IV; acute kidney injury defined as an absolute
serum creatinine increase of 0.5 mg/dL from baseline obtained in the previous
24 hours; lactation; pregnancy; malignant tumor or life expectancy <1 year;
allergy to contrast; periprocedural administration of nonsteroidal
anti-inflammatory drugs; aminoglycosides, cyclosporine, or cisplatin in the
previous 48 hours or during the study period; planned renal catheterization; or
heart valve surgery.
Eligible patients are randomized using computer generated random numbers
and a 1:1 ratio to receive either general hydration (control group) or
intervention hydration with isotonic saline. Randomization is stratified by age
(<60 years, 60-75 years,>75 years), sex (male or female), and myocardial
infarction location (anterior or not anterior). After screening for eligibility based
on the criteria, the patients who have agreed to undergo the procedure in the
emergency department or catheter laboratory are asked to provide consent
and are randomized before the primary PCI. Then, the fluid-loading dose is
administered before the procedure and continued for 30 minutes during the
procedure, if necessary; we do not wait 30 minutes to start the procedure to
avoid a delay in revascularization of the target vessel. General hydration for
the control group consists of a periprocedural continuous IV infusion of ≤500
mL isotonic saline within 6 hours. Aggressive hydration consists of a 250-mL
loading dose of isotonic saline (125 mL for patients with congestive heart
failure, Killip II/III or NYHA III) over a 30-minutes period prior to the procedure48,
followed by IV hydration at a rate of 1 mL/kg/h (0.5 mL/kg/h for patients with
congestive heart failure, Killip II/III or NYHA III) until the LVEDP measurement.
Therefore, in the intervention group, LVEDP is measured after the primary PCI
to guide the hydration. Hydration on a sliding scale is used 4 hours after the
procedure: 5mL/kg d h for LVEDP <13 mm Hg, 3 mL/kg d h for LVEDP 13-18
mm Hg, 1.5mL/kg d h for LVEDP >18mmHg, and 0.5mL/kg d h for LVEDP >20
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mm Hg. Then, hydration is continued at the normal rate until 24 hours after the
procedure45. When the LVEDP value does not agree with the heart function as
evaluated by the clinical doctors, the rate and duration of hydration are based
on the clinical evaluation for heart function and at the discretion of the
cardiologists.
Blood serum creatinine, cystatin C, C-reactive protein, and serum electrolytes
are evaluated at baseline; before the coronary angiography; at 24 ± 4, 48 ± 4,
and 72 ± 4 hours after the procedure; and at hospital discharge. The time
between symptom onset and reperfusion, including the time at the beginning
and end of the procedure; urine output; and oral hydration volume (waterl in
milliliters) during the 24 hours after the procedure are recorded. Periprocedural
intervention (ie, fluid mixed with medications and normal saline or glucose
injection, furosemide, or statins), PCI technique, contrast agent (nonionic,
low-osmolality, or isotonic), and contrast dose are at the discretion of the
cardiologists in charge of the patient routine and procedure management,
following current practice guidelines56. Patients will be excluded if they receive
contrast again within 72 hours after the procedure57 and undergo CAG but no
PCI or dead during the procedure. All of this information is carefully collected
by the research staff.
The primary end point is CI-AKI, defined as a >25% or 0.5 mg/dL increase in
serum creatinine from baseline during the first 48 to 72 hours after the
procedure58. Secondary end points are as follows: (1) CI-AKI48h, defined as
a >50% or 0.3-mg/dL absolute increase in serum creatinine from baseline
during the first 48 hours after the procedure; (2) CI-AKIcys-c, defined as a >10%
or 0.3-mg/dL absolute increase in serum cystatin C during the first 24 hours
after the procedure59; (3) CI-PKI, defined as residual impairment of renal
function indicated by a >25% reduction in creatinine clearance at 3 months in
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safety, study conduct and progress, and, when appropriate, efficacy and will
make recommendations to the principal investigators concerning the
continuation, modification of enrollment, or termination of the trial. Details of
any protocol violations (eg, descriptions, reasons, and resolution) will be
reported by the investigators and clinical research associates to the primary
investigators, the Central Event Adjudication committee, and Data and Safety
Monitoring Board, if necessary. In addition, training will be provided to the
researchers, and the study procedure will be supervised, with particular
attention to the reasons for bias and data verification to avoid recurrence of
protocol violations.
Finally, intention-to-treat analysis will be used for the patients with protocol
violations instead of the per-protocol analysis. The sample size calculation was
based on our previous findings60, and a CI-AKI incidence of 23% was
estimated for the control group, and a CI-AKI incidence of 11.5% was
assumed for the intervention group (50% relative reduction). Using nQuery +
nTerim 3.0 (Statistical Solutions Ltd, Farmer's Cross, Cork, Ireland) with a
2-sided χ2 test, a significance level of 0.05, a power of 90%, and a dropout
rate <20%, 280 patients are required in each group, for a total sample size of
560. The primary outcome, that is, rate of CI-AKI, will be compared between 2
groups using χ2 tests, and the 95% CI of the rate difference will be calculated
using the method described by Altman et al (reported in Newcombe61) and
recommended by the Food and Drug Administration and Clinical and
Laboratory Standards Institute. Multivariable logistic regression models will be
developed to adjust for clinical characteristics (eg, age, sex, creatinine
clearance, and left ventricular ejection fraction [LVEF]), and the Mehran risk
score will be calculated62. Odds ratios will be reported with their corresponding
95% CIs. Comparisons between normally distributed continuous variables,
expressed as mean ± SD, will be performed using 2-sample t tests;
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nonnormally distributed continuous variables, presented as median and
interquartile range, will be analyzed using Wilcoxon rank sum tests. Pearson
χ2 or Fisher exact tests will be used, as appropriate, for categorical data,
which will be expressed as percentages. The primary and secondary end
points will be analyzed based on the intention-to-treat principle. All tests will be
2 tailed, and a P value <.05 will be considered statistically significant. All data
analyses will be performed using SAS version 9.4 (SAS Institute, Cary, NC).
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Table A2 Timetable of visits and procedures
Visits5 Screening visit1
Operative day
1 daysafter
operation
2 daysafter
operation
3 daysafter
operation2
7 daysafter
operation
90±14daysafter
operation4
360±14daysafter
operation
Informedconsent √
Inclusion/Exclusion criteria √
Baseline √
Routine bloodtest √
Liver function √
Renal function √ √ √ √ √ √3 √
Characteristicsof coronaryintervention
√
Entry audit √
Randomization √
Record drugs √ √ √
Record AEs √ √ √ √ √3 √ √Study directorreviews medicalrecords
√
CRA reviewsmedical records √
Medical recordentry database √
EDC √
Medical recordreturn and filing √
1 Screening and random observation (1 day before direct coronary intervention)
2 Items must be checked on the 3rd day after coronary intervention
3 The renal function included cystatin C from the 4th to 7th day after PCI (daily evaluation: for
patients whose serum creatinine value (SCR) in 48-72 hours after PCI was higher than or equal to
0.3mg/dl than the baseline absolute value).
4.90±14 days.
5.HCG-Items to be tested for women who were likely to be become pregnant.
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METHOD
5. STUDY POPULATION AND PATIENT RECRUITMENT
5.1 Study population
The study population will consist of 560 patients, aged ≥18 years with STEMI
who provided written informed consent for this study. Since a major risk factor
for subsequent adverse clinical events following STEMI is the delay of PCI, we
will only enroll patients underwent primary PCI.41, 63
Inclusion Criteria:
All consecutive patients with STEMI, age at least 18 years, who were
candidates for primary PCI were considered for enrollment.
STEMI was defined as the onset of chest pain or chest distress lasting
for at least 30 minutes with electrocardiography(ECG) ST-segment
elevation of at least 0.2 mV in two or more contiguous leads and/or the
development of new left bundle-branch block associated with elevation
in the levels of creatinine kinase or its MB isozyme to at least two times
that of normal.46
STEMI patients who were candidates for primary PCI should meet at
least one of the following conditions: 1. Ischemic symptoms <12 h; 2.
Ischemic symptoms <12 h and contraindications to fibrinolytic therapy
irrespective of time delay from FMC; 3. Cardiogenic shock or acute
severe HF irrespective of time delay from MI onset.41
Exclusion Criteria:
Contrast medium administration within the previous 14 days or follow 72
hours,
End-stage renal failure or renal transplantation, and refuse PCI or dead
during the procedure,
Heart failure of cardiac shock or New York Heart Association class IV, (we
are excluding these patients because IV fluid administration may be
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contraindicated):
Recent acute kidney injury defined as an absolute increase of 0.5 mg/dl in
serum creatinine over baseline in the past 24h.
The presence of lactation, pregnancy,
Malignant tumor or life expectancy less than 1 year,
Allergy to contrast medium, peri-procedural receipt of metformin or
non-steroidal anti-inflammatory drugs in the past 48h and during the study
period,
Planned renal catheterization or heart valvular surgery.
5.2 Screening and patient recruitment
All the potentially eligible patients will be screened out by the chief resident of
the department of cardiology. Then, the chief resident will dial the “ATTEMPT
phone” to report the initial situation of the patient to the ATTEMPT research
personnel on-duty, who must arrive within 15 minutes (for those who are
unable to arrive in time, he/she must contact other members to follow up).
Researchers will contact potentially eligible subjects to describe the study and
complete the screening process. Based on our past experience, almost all the
patients intended to undergo primary PCI will have a SCr measured as part of
routine care before angiography. However due to the urgency, we are unable
to get the result of pre-procedure renal function before angiography. In such
situation, for the majority of patients who do not have a SCr measured before,
we can only exclude them after PCI if they were proven to suffer end-stage
renal failure. Patients with no peri-operative creatinine were found to be
excluded after randomization. We will also require that potentially eligible
female subjects who are able to be pregnant (not considered post-menopausal
[had a menstrual period within previous 12 months], not had tubal ligation, a
hysterectomy or bilateral oophorectomy) and are sexually active, have a
negative pregnancy test before being enrolled in the research. No adult patient
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(age ≥18 years) will be excluded from participating based on age, gender, race,
ethnicity, or sexual preference.
6. STUDY PROCEDURES
6.1 Assessment of pre-procedural laboratory examinations
Eligible patients will have their SCr measured before angiography, which will
serve as their baseline SCr. At present, the methods for detecting SCr mainly
include basic picric acid method (Jaffe assay) and enzymatic assay. The
enzymatic assay avoids the poor specificity of the Jaffe assay and has a strong
anti-interference ability. Therefore, it is widely accepted as the most reliable
assay in the clinical laboratories. All laboratories in our study are consistently
adopting this methodology to reliably and accurately assess the development
of CI-AKI. The timing of the pre-procedure study SCr (baseline SCr) testing
used to assess the outcomes is also important as the administration of IV fluids
may lead to hemodilution and artifactual lowering of SCr. In addition, variation
in intravascular volume status affects renal function, particularly in patients
with underlying CKD. Therefore, we will standardize the timing of assessment
of the baseline SCr for endpoint ascertainment. This blood sample will be drew
at the same time of patient enrollment and immediately prior to the beginning
of study IV fluids to avoid any potential influence of study interventions on the
baseline SCr level. Although STEMI patients will have some basic laboratory
examinations as soon as they reach the emergency department or a few
minutes after the chest pain onset if it happens in hospital, some examinations
are not routine for such patients, such as cystatin C, hypersensitive C-reactive
protein and so on. For these variables, to make sure that they are not affected
by the interventions, the research personnel needs to check whether the
relevant blood tests of the patient had been done before the intervention
(cystatin C, hypersensitive C-reactive protein, cardiac enzyme, emergency
biochemistry, blood routine). If there is any omission of these tests, the
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research personnel needs to make a prescription and asks the nurse
completes the blood draw before the intervention begins.
6.2 Randomization procedures
All patients meeting eligibility criteria and providing informed consent will be
randomized to each of the two study groups [general hydration (control group)
versus aggressive hydration with isotonic saline (intervention group)]. Qualified
patients are randomized using computer-generated random numbers at a 1:1
ratio. Randomization will be accomplished using a block random method with 8
units in each group. Some offset or variability will be inserted to prevent
anticipation of the next treatment. Randomization will be stratified by sex, age
and anterior myocardial infarction. Study coordinators at each site will be
responsible for obtaining a randomized treatment assignment for each eligible
patient. A web-based randomization program will be provided to study sites for
this purpose. This web-based program will be tested at each site prior to the
start of the trial and will be reviewed, as per Center guidelines, by the Key
Laboratory of Coronary Heart Disease. At the time of subject enrollment,
research personnel will enter the Subject ID number, sex, age and anterior
myocardial infarction into the randomization program. The program will check
that all eligibility criteria are met. If met, the program will select the first unused
entry from the pre-specified list of random treatment assignments for the
particular site. The lists are stored on a secure server at Southern Medical
University, Department of Biostatistics, Clinical Research Management
System. If the electronic system fails, the random envelope method will be
adopted. The random envelope method is to store a random grouping scheme
of a numbered research object in a sealed and opaque envelope, which is
performed in two steps:1) verifying whether the patient meets the criteria for
inclusion and exclusion, signing informed consent, and giving the case number;
2) Disassemble the random envelopes of the corresponding numbers in order,
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determine the grouping of a patient according to the distribution plan in the
envelope, and carry out corresponding interventions. Since this is an
open-label study, we do not have the procedure of blinding.
6.3 Study interventions
In this study, patients will receive either general hydration (control group) or
aggressive hydration with isotonic saline guided by LVEDP (intervention
group)
Control group:
The general hydration for the control group is a peri-procedural continuous
intravenous infusion of ≤500 mL isotonic saline within 6h.
Intervention group:
The aggressive hydration consists of a 250mL loading dose of isotonic saline
(125 mL for patients with congestive heart failure, Killip II/III) over 30 min prior
to procedure,48 followed by IV hydration at the rate of 1 mL/kg/h (0.5 mL/kg/h
for patients with congestive heart failure, Killip II/III) until the LVEDP
measurement, which were performed after the coronary revascularization.
Hydration on a sliding-scale is used 4 h after the procedure: 5 mL/kg·h for
LVEDP <13 mmHg, 3 mL/kg·h for LVEDP 13–18 mmHg, 1.5 mL/kg·h for
LVEDP >18 mmHg, and 0.5 mL/kg·h for LVEDP >20 mmHg. Then, hydration
is continued at the normal rate until the 24 h after the procedure reaches.45
When the LVEDP value does not agree with the heart function as evaluated by
the clinical doctors, the rate and duration of hydration is based on the clinical
evaluation for heart function and at the discretion of the cardiologists.
In the intervention group, we will use LVEDP to guide hydration within 4 hours
after the procedure. At the end of the procedure, the research personnel will
remind the operators to make an LVEDP measurement before the catheter is
withdrawn. Although LVEDP is a more objective indicator of left ventricular
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volume, it cannot be used to diagnose whether a patient has heart failure or
not.64 Therefore, when the LVEDP value does not agree with the heart function
as evaluated by the clinical doctors, the rate and duration of hydration is based
on the clinical evaluation for heart function and at the discretion of the
cardiologists. In addition, some sub-centers may not be able to measure
LVEDP for several reasons. In this case, we allow the clinicians to estimate
LVEDP based on the patient's situation and to determine the hydration
strategy within 4 hours after the procedure. We chose this flexible approach
rather than a strict protocol for IV fluid administration for several reasons. First,
though there is a general belief that “more fluid” may be dangerous for HF
patients, the optimal rate, duration, and volume of IV fluid to prevent CI-AKI
and other adverse outcomes for HF patients have not been conclusively
determined. Therefore, the rate and duration of hydration is based on the
clinical evaluation for heart function and at the discretion of the cardiologists.
Second, since LVEDP have not been determined as a golden standard for
making hydration strategy, requiring that IV fluids be administered strictly
based on LVEDP could significantly limit other medical workers` willingness to
help. In clinical practice, the volume and duration of pre and post-procedure IV
fluid often vary based on the clinical setting and individual patient
circumstances. We do not believe that using this flexible approach will
compromise our ability to determine differences in study outcomes between
two groups.
6.4 Peri-procedural management issues
Drug prescription and blood collection time points are strictly in accordance
with the protocol, clinical guidelines and clinical reality. Though all contrast
media may cause potential clinical complications, the osmolality of the contrast
agent is proven to potentially impact the risk for CI-AKI. Previous conclusively
demonstrate that high osmolality (>1200 mOsm/kg) agents pose a greater risk
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for CI-AKI than low osmolality (500-860 mOsm/kg) agents in high-risk
patients.65, 66 However, data on the comparative incidence of CI-AKI with
low-osmolal contrast and iso-osmolal are on dept and inconclusive. To provide
care that is consistent with prior guidelines issued by the American College of
Cardiology/American Heart Association for the use of iodinated contrast, all
patients in this trial will receive either iso-osmolal contrast media (i.e., iodixanol)
or non-ionic, low-osmolal contrast media.67 Usage of the specific contrast
agent and the volume of contrast media administered will be at the discretion
of the operator as there is no current guideline or consensus on the least
nephrotoxic contrast agent.
Accompanying medications and invasive treatment device, for example IABP,
are also source of potentially nephrotoxicity.68 Aminoglycosides or any other
drugs with significant nephrotoxicity are strictly prohibited. Patients are
recommended to have statin therapy preoperatively. The implication of
perioperative platelet glycoprotein IIb/IIIa receptor antagonists--Ikat (Iroko
Cardio Australia Pty Ltd), the use of loop diuretics and other drugs that are not
prohibited in this study will be at the discretion of the treating provider
according to the condition and treatment routine. We will also defer decisions
on the discontinuation of angiotensin converting enzyme inhibitors or
angiotensin receptor blockers to the treating provider(s) because there are no
conclusive data on the optimal approach to the management of these
medications in patients with STEMI undergoing angiography.
6.5 Post-procedure management issues
Drug prescription and blood collection time points are strictly in accordance
with the protocol, clinical guidelines and clinical reality. Following angiography,
research personnel will follow the patient to cardiac care unit (CCU) and reset
the hydration speed to routine level 4 hours after the procedure. Research
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personnel are also required to communicate with the patient's responsible
nurse and ask he/she to record the patient's postoperative liquid intake
(including oral and intravenous) as well as the liquid output (mainly urine
volume) in detail (time and volume). Following angiography and prior to
discharge from the hospital, research personnel will also arrange the
participant`s blood specimen collection at 24, 48 and 72 ± 4 hours following
their angiography.
6.6 Study Outcomes
6.6.1Primary study outcome
The primary endpoint consist of:
CI-AKI, defined as a ≥ 25% or 0.5 mg/dL absolute increase in serum
creatinine from baseline during the first 48-72 h post-procedure.
a 10% or 0.3 mg/dL increase in cystatin-C during the first 24h post-procedure.
6.6.2 Secondary study outcomes
The secondary outcomes consist of:
1) CI-AKI48h, defined as a >50% or 0.3-mg/dL absolute increase in serum
creatinine from baseline during the first 48 h post-procedure;
2) CI-AKIcysc, defined as a >10% or 0.3-mg/dL absolute increase in serum
cystatin-C during the first 24 h post-procedure; 58
3) Persistent renal damage, defined as residual impairment of renal function
indicated by a >25% reduction in creatinine clearance at 3 months in
comparison with baseline;59
4) Composite major adverse cardiovascular events, including all-cause
mortality, target vascular revascularization, and non-fatal myocardial infarction;
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Table A3 - Definitions of components of MACEs
Term Definition
All-cause mortality All cause mortality, defined as any death recorded between
the date of interview and the end of data.
Target vascular
revascularization (TVR)
TVR is defined as any revascularization procedure (PCI or
CABG) involving the vessel treated during the index PCI
procedure for STEMI.
Non-fatal myocardial
infarction
Recurrent MI will be subdivided into MI within the first 24 h of
randomization, between 24 h and 7 d after randomization,
and >7 d after randomization.
MI occurring
between 24 h
and 7 d of
randomization
Recurrent ischemic symptoms >20 min with
new ST elevation >0.1 mV in ≥2 contiguous
leads not due to changes from evolution of
the index MI. Ischemic symptoms >20 min
and either 1) elevation or re-elevation of
cardiac biomarkers(CK-MB or troponin)
greater than twice the upper limit of normal
(ULN) and if already elevated, then further
elevations >50% above a previous value
that was decreasing or 2) new ST-segment
elevation or new significant Q waves in ≥2
contiguous leads, which are separate from
the baseline MI.
MI occurring
after 7 d of
randomization
Typical rise and fall of biochemical markers
of myocardial necrosis to greater than twice
the ULN or if markers were already
elevated, further elevation of a marker
to >50% of a previous value that was
decreasing and >2× ULN, with ≥ 1 of the
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following: 1) ischemic symptoms, 2)
development of new pathologic Q waves, or
3) ECG changes of new ischemia or (iv)
pathologic evidence of MI.
MI occurring
within 24 h
after nonindex
PCI that is
performed >24
h after
randomization
Cardiac biomarker (creatine kinase-MB
[CK-MB] or troponin) >3× the ULN or
increased by 50% from the preprocedural
valley level and ≥3 times ULN in patients
with already elevated enzymes or new
ST-segment elevation or development of
significant Q waves in ≥2 contiguous leads,
which are discrete from baseline MI.
Within 24 h
post-CABG
CK-MB (or total CK, if CK-MB is
unavailable) ≥5× ULN and increased 50%
from the preprocedural valley level and N
5× ULN in patients with already elevated
enzymes and development new pathologic
Q waves in ≥2 contiguous leads or CK-MB
value ≥10 times ULN without new
pathologic Q waves.
5) Major post-procedure in-hospital adverse clinical events, including acute
pulmonary edema, cardiogenic shock, stroke, clinically significant arrhythmias,
and bleeding.
Table A4 - Definitions of components of major post-procedure in-hospital
adverse clinical events
Term Definition
Acute pulmonary edema Acute pulmonary edema, defined as arterial partial pressure
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of oxygen (PaO2)/inspired oxygen fraction (FiO2) ratio <300
for arterial blood gas, and pulmonary edema or bilateral
infiltrates on chest radiograph as read by radiologists, both
within 24 h.
Cardiogenic shock Cardiogenic shock is defined as systolic blood pressure <90
mmHg not responsive to fluid resuscitation and/or heart rate
correction for ≥1 h or need for vas opressor/inotropic therapy
to maintain systolic blood pressure >90 mm Hg for ≥1 h and
believed to be secondary to cardiac dysfunction and
associated with ≥1 of the following: 1) signs of pulmonary
edema, 2) signs of hypoperfusion (cool clammy skin, oliguria,
or altered sensiorium), or 3) cardiac index <2.2 L/min.
In patients presenting with cardiogenic shock at the time of
randomization, they must have a ≥24 h period with complete
resolution of shock and a new cardiogenic shock event (ie,
due to new stent thrombosis) for this event to be eligible as a
primary outcome event.
Stroke Any stroke is defined as the presence of a new focal
neurologic deficit thought to be vascular in origin, with signs
or symptoms lasting >24 h. It is strongly recommended (but
not required) that an imaging procedure such as a computed
tomography or magnetic resonance imaging be performed.
Clinically significant
arrhythmias
Clinically significant arrhythmias (SA) were defined as 1 or
more of the following: more than 100 VPC or APC (including
VPC2/3 or APC2/3) per 24 h (equalling a rate of 4.17/h) or any
presence of RT, VT, or AT.
Bleeding Major bleeding or vascular events (bleeding requiring
transfusion of hemoglobin drop ≥3 g/dL or need for vascular
surgery).
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6.7 Data collection
6.7.1 Assessment of baseline demographic and clinical characteristics
Following patient enrollment, research personnel will make a comprehensive
review of the electronic medical record and/or interview the subject and his/her
families to abstract the following data elements:
Demographic characteristics including date of birth, gender and ethnicity
Admission information including
Time of symptoms onset
Time of first medical contact (FMC)
Time of admission
Time of entering catheterization laboratory
Did thrombolytic therapy be used in this case? (If it did, then the time of
thrombolytic therapy should be recorded)
Did cardiac arrest happen in this case? (If it did, then the time should
be recorded)
Did heart failure happen in this case?
Heart function (Killip class)
Use of vasoactive drugs
Use of IABP
Administration of any IV fluid and prior to the initiation of study
Pre-procedure laboratory parameters obtained as part of routine clinical care
including date of test (most proximate to and within the 7 days preceding the
angiogram:
ɸ CK, CKMB, troponin T, troponin I, hsCRP, NT-proBNP or BNP, WBC, Hb,
PLT, Hct, Neut%, SCr, Cystatin C, serum glucose, sodium, potassium, blood
urea nitrogen and pregnancy examination (if available)
medical history:
ɸ Hypertension, diabetes, hyperlipidemia, coronary artery disease (CAD),
myocardial infarction (if available, the happening time should be record),
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congestive heart failure, peripheral vascular disease, chronic kidney disease,
stroke and chronic pulmonary disease. Standard procedures and definitions
will be developed to systematically evaluate patients records for each of these
conditions.
Family history of CAD
Smoking history
Physical examination, including:
1) Height in centimeter and weight in kilograms. The recommended
method of obtaining the patient`s height and weight will be for research
personnel to measure them. In the event this is not possible, the most recent
measurement (usually at the time of admission) found in the patients medical
record will be recorded. Finally, if there is no measurement in the medical
record, this information will be collected via subject report.
2) Blood pressure and heart rate at the time of admission.
3) Physical examination record on chest (including heart and lung),
abdomen, nervous system, limbs and spinal.
Pre-procedure ECG and cardiac ultrasound (if available)
Names and doses of all pre-procedure medications, including those
prescribed by physicians outside the research centers, regularly taken by
the subject within the 14 days preceding the angiogram.
6.7.2 Collection of oral hydration and urine volume within 24h post-procedure
Research personnel will communicate with and hand over a specially designed
chart to the patient's responsible nurse and ask he/she to record the patient's
postoperative liquid intake (oral) as well as the liquid output (mainly urine
volume) in detail (time and volume) within 24h post-procedure. We will collect
the chart later.
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6.7.3 Evaluation of procedure-related data
Subsequent to the angiogram, research personnel will review the electronic
medical record and angiogram procedure report to determine:
Primary PCI or not;
The beginning and ending time of procedure;
The time of balloon dilation
Type and volume of contrast administered (Iodixanol, Iopromide,
Iopamidol or iohexol)
The use of GPIIb/IIIa Inhibitors
The implication of thrombus aspiration
The implication of IABP
Post-procedure LVEDP
Coronary artery lesions and performance of percutaneous intervention
Complications during the procedure including:
Hypotension or cardiac shock necessitating the administration of
additional non-study IV fluid including the type of non-study IV fluid
administered
Hypotension or cardiac shock necessitating the insertion of an
intra-aortic balloon pump and/or the administration of vasopressor
therapy
Arrhythmia
Death
Any new accompany medications
Assessment of procedure-related complications will ensure that we capture all
events that could impact on the development of our primary and secondary
outcomes. To clarify and confirm all of these procedure-related data, research
personnel will also organized a brief interview with the angiography operators.
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6.7.4 Evaluation of study IV fluid administration
Research personnel will track and record from the electronic medical record
the speed, total volume and total duration of study IV fluid administered
pre-procedure, intra-procedure, and post-procedure.
6.7.5 Evaluation of post-procedure course (within 24 ± 4 hours post procedure)
Research personnel will review the electronic record and collect the following
data elements:
Vital signs within 6h and at 24 hours post-procedure;
Renal function assessment and blood electrolytes and the date of test (If
the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72
hours post-procedure, the renal function of the subjects was monitored
until 1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Performance of additional contrast exposure including coronary or
non-coronary angiography or computed tomography with intravascular
iodinated contrast;
6.7.6 Evaluation of post-procedure course (48 ± 4 hours post procedure)
Research personnel will review the electronic record and collect the following
data elements:
Vital signs at 48 hours post-procedure;
Renal function assessment, hsCRP and blood electrolytes and the date of
test (If the serum creatinine (SCr) increased by more than 0.3 mg/dL within
72 hours post-procedure, the renal function of the subjects was monitored
until 1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Performance of additional contrast exposure including coronary or
non-coronary angiography or computed tomography with intravascular
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iodinated contrast;
Cardiac and Carotid Ultrasound and the date of test (if available);
Any new accompany medications
6.7.7 Evaluation of post-procedure course (72 ± 4 hours post procedure)
Research personnel will review the electronic record and collect the following
data elements:
Vital signs at 72 hours post-procedure;
Renal function assessment, hsCRP and blood electrolytes and the date of
test (If the serum creatinine (SCr) increased by more than 0.3 mg/dL within
72 hours post-procedure, the renal function of the subjects was monitored
until 1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Performance of additional contrast exposure including coronary or
non-coronary angiography or computed tomography with intravascular
iodinated contrast;
Any new accompany medications
Since this creatinine determination is essential to the determined of primary
end-point, it is very important that the blood collection be done within the 72
hours after angiography. We recognize that unforeseen circumstances may
hinder collection within this window. Under such circumstances the blood
should be collected as soon as possible and most proximate to 72 hours and a
protocol deviation should be noted.
6.7.8 Evaluation of post-procedure hospitalization course (4 – 7 days post
procedure and the day of discharge)
Research personnel will review the electronic record on a daily basis for
patients who remain in the hospital following their angiography procedure and
collect the following data elements:
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Vital signs have collected for once among 4-7 days post-procedure;
Renal function assessment, hsCRP and blood electrolytes and the date of
test (If the serum creatinine (SCr) increased by more than 0.3 mg/dL within
72 hours post-procedure, the renal function of the subjects was monitored
until 1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Any new accompany medications
Date of discharge and total hospitalization expenses
Generally speaking, subjects will only have one examination during this period.
For those who have vital signs or renal assessment for many times, we will
record the highest level of each day.
6.9.9 Day 30 post procedure assessment (30 days post angiography,
allowable range 23-37 days post angiography)
Thirty days following the angiography, clinical doctors will review the electronic
medical record (if available) and perform a telephone interview with the patient
to inquire about any adverse events they experienced related to study
participation. The electronic medical record review and telephone interview will
specifically focus on assessing the renal function and the development of any
of the following adverse outcome within the research sites system.
Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
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Bleeding
Heart broken
The 30-day telephone interview with the patient will be a supplement to the
electronic medical record review. This telephone interview will verify data
abstracted from the electronic medical record and enable research personnel
to inquire about death, re-hospitalizations at non-research sites and other
MACEs that would not have been captured in the electronic medical record.
For any patients who were hospitalized outside the research centers, the
research personnel will obtain the hospitalization information from the patient
or his/her families.
To ensure the follow-up quality, before the first time of telephone interviews,
research personnel assistants will help researchers to arrange the follow-up
method and time.
During the telephone interview:
Recording and judgment of events
In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in
details. And then, they will submit the record to the research personnel who will
make the judgment later.
Quality control
After the start of follow-up, the quality control team needs to check the
follow-up form and EDC regularly (not less than two times a week). Research
personnel assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
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We recommend that this contact should be made at 30 days after angiography,
with an allowable range of 30±7 days. We recognize that sometimes it may be
difficult to contact with a patient within this window. However, it is important to
collect the required data, which should be done even if done after the
recommended time frame has elapsed. It will not be considered a protocol
deviation as long as the required data are collected and there is progress note
documenting the attempt to schedule the data collection during the
recommended time frame.
6.7.10 Day 90 post procedure assessment (90 days post angiography,
allowable range 90 ± 14 days post angiography)
Ninety days following the angiography, research personnel assistants will
review the electronic medical record (if available) and perform a telephone
interview with the patient to inquire about any adverse events they
experienced related to study participation. The electronic medical record
review and telephone interview will specifically focus on assessing the renal
function and the development of any of the following adverse outcome within
the research sites system.
Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
Bleeding
Heart broken
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The 90-day telephone interview with the patient will be a complement to the
electronic medical record review. This telephone interview will verify data that
was abstracted from the electronic medical record and enable research
personnel to inquire about death, re-hospitalizations at non-research sites and
other MACEs that would not have been captured in the electronic medical
record. For any patients who were hospitalized outside the research centers,
the research personnel will obtain the hospitalization information from the
patient or his/her family.
During the telephone interview:
Recording and judgment of events
In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in
details. And then, they will submit the record to the research personnel who will
make the judgment later.
Quality control
After the start of follow-up, the quality control team needs to check the
follow-up form and EDC regularly (not less than two times a week). Research
personnel assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
We recommend that this contact should be made at 90 days after angiography,
with an allowable range of 90 ± 14 days. We recognize that sometimes it may
be difficult to contact with a patient within this window. However, it is important
to collect the required data, which should be done even if done after the
recommended time frame has elapsed. It will not be considered a protocol
deviation as long as the required data are collected and there is progress note
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documenting the attempt to schedule the data collection during the
recommended time frame.
6.7.11 Day 180 post procedure assessment (180 days post angiography,
allowable range 180±14 days post angiography)
180 days following the angiography, research personnel assistants will review
the electronic medical record (if available) and perform a telephone interview
with the patient to inquire about any adverse events they experienced related
to study participation. The electronic medical record review and telephone
interview will specifically focus on assessing the renal function and the
development of any of the following adverse outcome within the research sites
system.
Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
Bleeding
Heart broken
The 180-day telephone interview with the patient will be a complement to the
electronic medical record review. This telephone interview will verify data that
was abstracted from the electronic medical record and enable research
personnel to inquire about death, re-hospitalizations at non-research sites and
other MACEs that would not have been captured in the electronic medical
record. For any patients who were hospitalized outside the research centers,
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the research personnel will obtain the hospitalization information from the
patient or his/her family.
During the telephone interview:
Recording and judgment of events
In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in
details. And then, they will submit the record to the research personnel who will
make the judgment later.
Quality control
After the start of follow-up, the quality control team needs to check the
follow-up form and EDC regularly (not less than two times a week). Research
personnel assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
We recommend that this contact should be made at 180 days after
angiography, with an allowable range of 180±14 days. We recognize that
sometimes it may be difficult to contact with a patient within this window.
However, it is important to collect the required data, which should be done
even if done after the recommended time frame has elapsed. It will not be
considered a protocol deviation as long as the required data are collected and
there is progress note documenting the attempt to schedule the data collection
during the recommended time frame.
6.7.12 1 year post procedure assessment (1 year post angiography, allowable
range 1 year ±14 days post angiography)
1 year following the angiography, research personnel assistants will review the
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electronic medical record (if available) and perform a telephone interview with
the patient to inquire about any adverse events they experienced related to
study participation. The electronic medical record review will specifically focus
on assessing the renal function and the development of any of the following
adverse outcome within the research sites system.
Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
Bleeding
Heart broken
The 1-year telephone interview with the patient will be a complement to the
electronic medical record review. This telephone interview will verify data that
was abstracted from the electronic medical record and enable research
personnel to inquire about death, re-hospitalizations at non-research sites and
other MACEs that would not have been captured in the electronic medical
record. For any patients who were hospitalized outside the research centers,
the research personnel will obtain the hospitalization information from the
patient or his/her family.
During the telephone interview:
Recording and judgment of events
In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in
details. And then, they will submit the record to the research personnel who will
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make the judgment later.
Quality control
After the start of follow-up, the quality control team needs to check the
follow-up form and EDC regularly (not less than two times a week). Research
personnel assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
We recommend that this contact should be made at 1 year after angiography,
with an allowable range of 1 year ±14 days. We recognize that sometimes it
may be difficult to contact with a patient within this window. However, it is
important to collect the required data, which should be done even if done after
the recommended time frame has elapsed. It will not be considered a protocol
deviation as long as the required data are collected and there is progress note
documenting the attempt to schedule the data collection during the
recommended time frame.
7. POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS
7.1 Study Population
Most past studies of CI-AKI have focused on all patients undergoing coronary
angiography. We propose enrolling STEMI patients only. Patients with STEMI
are likely to present with hypotension or even shock, a large volume of contrast
agent, and inability to start a kidney prophylactic therapy, all of which are
associated with an increased risk of CI-AKI. Patients with STEMI also
commonly have other risk factors for CI-AKI such as reduced cardiac output or
hypotension due to myocardial infarction or depletion of intravascular volume
caused by vomiting, diaphoresis, or decreased oral intake. Despite a
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considerable prevalence of risk factors, including reduced LVEF, renal
insufficiency, and diabetes mellitus, in patients needing adequate hydration,
cardiologists in previous studies were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; this was
related to a lack of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a certain
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Therefore, a flexible
and individualized hydration therapy based on certain guiding strategy is
urgently needed. While limiting the enrollment to STEMI patients will restrict
the number of patients available for recruitment and the generalizability of the
study findings, it will increase the homogeneity, find out the optimal hydration
administration regimen in these high-risk patients69 and fill in gaps in
guidelines.
7.2 Study interventions
7.2.1 Fluid administration
There is no consensus among experts on the optimal rate and duration of IV
fluid administration for the prevention of CI-AKI or single protocol for the
administration of IV fluid that has been shown to be the most effective.
Nowadays, in CHINA, most PCI center do not pay attention to CI-AKI, and
prescribe hydration with no regimen but a bag of 500ml saline which is exactly
used to maintain the venous channel. Generally speaking, it is well-accepted
that hydration is effective in preventing CI-AKI but there is no consensus on
how to make hydration.70 Therefore, we conduct a comparison between
aggressive hydration and the reality to find out a more suitable regimen in
these high-risk patients.
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7.2.2 Complications of fluid administration
We anticipate that some patients will develop volume overload/pulmonary
edema during angiography. In such instances, providers performing
angiography may discontinue post-procedure IV fluids resulting in patients
failing to receive the planned hydration regimen following the angiogram. It is
likely that this event will occur in a small proportion of patients and be equally
distributed across treatment arms. While the volume of study IV fluid
administered pre, during and post-procedure will be carefully recorded for all
patients, given the importance of patient safety, we believe it would be
inappropriate to require the administration of post-procedure study IV fluid in
such instances. Since all analyses will be based on the intent-to-treat principle,
these patients will not be excluded from the study analyses.
7.3 Ascertainment of baseline kidney function
In order to ascertain a change in kidney function, it is critical to standardize the
definition of baseline kidney function. SCr often fluctuates over time because
of activities, variations in volume status, protein and salt intake, and drift in the
calibration of laboratory instruments. The timing of the SCr testing used to
screen patients is less critical than the value used to define the baseline SCr
for endpoint ascertainment. For practical purposes, we propose to screen
patients based on a SCr obtained as part of routine clinical care performed by
the doctor as soon as the subject enter the emergency department or cardiac
catheterization laboratory. The SCr was sent for examination after PCI. This
will also be the same pre-angiography study SCr (baseline SCr) that will be
used to assess the development of CI-AKI (a primary endpoint).
7.4 Assessment of primary and secondary outcomes
7.4.1 Assessment of CI-AKI
Most patients who develop CI-AKI will have their SCr increased within 48 to 72
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hours following contrast exposure. However, previous studies demonstrate
that some patients who develop CI-AKI may not be identified by a single SCr
assessment at 48 hours.43 The optimal timing of assessment of SCr following
the angiogram to determine the development of CI-AKI in our trial was
carefully discussed by the committee members. Finally, though complicated, it
was agreed that multiple SCr assessments (e.g., at 24, 48 and 72 hours)
would ensure the identification of all patients who developed CI-AKI. This
decision is based on several reasons. First, some patients who develop CI-AKI
may manifest an increase in SCr at 24-48 hours following angiography.
Second, multiple SCr assessments may describe the trend of SCr after
contrast exposure. Finally, the planning committee feel that measuring SCr at
multiple time points may be of help in finding the most suitable definition of
CI-AKI.
7.4.2 Assessment of cardiovascular outcomes and clinical events
We acknowledge the potential limitations of using administrative data/medical
records for the assessment of cardiovascular outcomes and clinical events,
including all-cause mortality, target vascular revascularization (TVR), non-fatal
MI, acute pulmonary edema, cardiogenic shock, stroke, clinically significant
arrhythmias and bleeding. Therefore, we will also assess these outcomes by
reviewing the hospital discharge summary for documentation of any of the
events that comprise the secondary outcomes. We have considered the
possibility of adjudicating the secondary outcomes using more comprehensive
medical record review. However, we believe that while this would be a more
robust approach, the additional time, effort and cost required to adjudicate
these secondary outcomes using a comprehensive review of the medical
record was not justified.
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7.5 Secular trends in the prevention and incidence of CI-AKI
We acknowledge that there will be novel viewpoints gained and changes in
clinical practices related to the prevention of CI-AKI and serious adverse
outcomes following angiography during the conduct of the current trial. A
comparison between the incidence of CI-AKI reported in studies conducted in
the 1980s and the incidence described in recent studies reveals a trend that
fewer patients are suffering this iatrogenic complication. However, much of this
trend is likely related to the transition from the more nephrotoxic high-osmolal
contrast media to low and iso-osmolal contrast media. Over the past decade,
there is no evidence of a continued decline in the incidence of CI-AKI or
attenuation in the relationship between CI-AKI and serious, adverse outcomes.
This can be illustrated by a recent study of over 1,100 hospitalized subjects
who underwent contrast-enhanced procedures that demonstrated that CI-AKI
developed in over 40% of patients and was associated with a 2-fold increase in
hospital duration and a 10-fold increase in mortality.18
8. FEASIBILITY OF RECRUITMENT
While our inclusion and exclusion criteria are strict, there are multiple important
factors that support the feasibility of recruiting this large number of patients.
First, all the 11 research centers involved in this project are the regional central
hospitals. The Guangdong Cardiovascular Institute/Guangdong Provincial
People's Hospital, which is in charge of this study, is the most influential
research and prevention centers of cardiovascular diseases in South China. It
is one of the leading coronary intervention therapy centers in China with about
971 primary PCI finished last year. It also participates in the compilation of
“Expert Consensus of STEMI Treatment in China”. Second, patients
undergoing primary coronary angiography are easily identifiable. All of these
procedures are started under the coordination of the chief resident of the
department of cardiology, which greatly facilitates identification and screening
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of potential study subjects. Third, unlike trials that recruit from a diverse array
of patient settings (e.g., primary care offices, hospital wards, specialty clinics),
our trial mostly recruit patients from only one hospital venues: emergency
department. This greatly simplifies the process of identifying and locating
potentials participants. Fourth, we have set up a special project management
team, which is directly in charge of the project.
The full-time academic secretary coordinates the management of assets, data
and research results in the process of project implementation. Finally, patient
burden in this study is quite limited since there is no need to return to the
hospital for study visits. Follow up data collection will be performed using
telephone calls. Therefore, patients are unlikely to view participation as unduly
burdensome. All in all, we are highly confident in our capacity to successfully
recruit the number of patients needed to meet our enrollment targets.
9. ANTICIPATED BARRIERS TO RECRUITMENT ANDSTRATEGIES TO ADDRESS POTENTIAL UNDERENROLLMENT
9.1 Development of comprehensive organizational structure
Despite the feasibility of recruitment as outlined above, successful enrollment
of the number of patients we hope to enroll and compliance with the study
protocol will depend on the interest and willingness of chief residents and
interventional cardiologists. We recognize that these practitioners may not be
focused on or necessarily prioritize the prevention of CI-AKI and its associated
outcomes, especially since they are often not involved in the longitudinal care
of patients and may not be notified of delayed complications of angiography.
We believe that comprehensive organizational structure at each site will ease
providers’ burden and optimize the potential for successful subject enrollment
and implication. What is more, we believe that the flexibility built into the
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protocol for study IV fluid administration rates, volumes, and duration will be
attractive to providers performing angiography and will increase their interest
and willingness to have their patients participate in the study.
9.2 Strategies to address under-recruitment of study subjects
Given the relatively large size of our study and the critical importance of
adequate patient recruitment, we anticipate using a number of strategies to
address under-recruitment should it occur. First, during the process of
calculating the sample size, we have taken into account these relevant
problems and enlarged the target number by 20%. Second, in addition to
Guangdong Provincial People`s Hospital, which conduct nearly 400 primary
PCI yearly, we also include another 14 study sites that mostly are the regional
central hospitals. We believe that having these two strategies to address
potential under-enrollment will help ensure the attainment of the target sample
size without compromising the scientific integrity of the study.
10. PROPOSED ANCILLARY STUDY
In addition to the primary study, we are also proposing to conduct an ancillary
study to follow patients for up to 10 years to track renal and cardiovascular
outcomes and mortality.
The specific aims of the proposed study are as follows:
Specific aim 1: To generate and track long-term clinical outcomes in a
matched cohort of patients participating in the ATTEMPT trial with and without
CIN.
Specific aim 2: To assess whether the development of CIN following
angiography is independently associated with serious, adverse, long-term
renal outcomes (i.e., accelerated rate of decline in kidney function and
development of end-stage renal disease), cardiovascular outcomes (i.e.,
cardiac, cerebrovascular, peripheral arterial events) and mortality.
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11. HUMAN SUBJECTS
11.1 Informed consent
Potentially eligible patients will be identified by chief residents and research
personnel at each site. After the study is introduced to the patient by an
individual participating in their care, research personnel will contact potentially
eligible subjects and their legal agent to describe the study and present
him/her with the detailed informed consent form and supplementary material to
read and review.
The general purpose of the study will be delineated and the treatment
comparisons will be clearly described. The process of randomization will be
discussed and a clear explanation of what will be expected of the patient will
also be described. The risks associated with treatments and procedures will
also be addressed. The importance of patient confidentiality will be stressed,
including a description of the process for maintaining patient confidentiality.
Research personnel will ensure that the patient understands every aspect of
the trial, including its risks and benefits, prior to signing the informed consent. If
the patient agrees, his/her consent to participate in the study will be
documented. The original will be placed in the patient's medical record.
Informed consent requires that the patient understand the details of the study
and agree, without coercion, to participate in the study. To obtain informed
consent, the following information shall be provided to each subject:
Name of the study
Name of the Principal or Site Investigator(s)
Explanation that the study involves research
Explanation of the purpose of the study
Explanation of the treatment procedures
Description of randomization
Description of the risks and benefits of participation in the study
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Explanation that all records will be kept confidential
Whom to contact for questions about the research and about subjects'
rights
A statement that participation in the study is voluntary and that a decision
not to participate or to withdraw from the study after initially agreeing involves
no penalty, loss of benefits, or reduction in access to medical care.
A statement that the examinations and treatments provided as part of this
study are mostly clinical routine and will be paid by subject himself.
Merely obtaining signed consent from the patient does not constitute informed
consent. However, the use of a standardized consent form aids in assuring
that subjects receive adequate and consistent information about the trial and
that they have consented to participate.
11.2 Risks and benefits
Any procedure/intervention has potential risks. The interventions used in this
study may cause all, some, or none of the risks and side effects listed. There is
also the potential for rare or unknown risks to occur. Active study participants
will be informed of any information that becomes known during the course of
the study regarding risks of the interventions that might affect their willingness
to continue to participate.
11.2.1 Side effects associated with infusion of intravenous fluids
Reactions due to solution or technique of administration: febrile response,
infection at the site of injection, venous thrombosis or phlebitis extending from
the site of injection, and extravasation of fluids
11.2.2 Side effects associated with infusion of sodium chloride
Cardiovascular: heart failure (aggravated), edema Endocrine and metabolic:
hypernatremia, hyperosmolarity, hypokalemia, metabolic acidosis Respiratory:
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pulmonary edema
Possible benefits of this study include a reduced risk of serious adverse
outcomes, including death, need for acute dialysis, and persistent decline in
kidney function among subjects receiving aggressive hydration.
12. DATA MANAGEMENT
12.1 Source file management
Source documents comprise of source data, include hospital records, clinical
and office charts, laboratory notes, memoranda, subjects diaries or evaluation
checklists, recorded data from automated instruments, microfiches,
photographic negatives, microfilm or magnetic media, x-rays, subject files, and
records kept at the laboratories, and at medico-technical departments involved
in the clinical trial, including certified copies or transcripts. Source files can be
paper and/or electronic. The original document in the clinical trial refers to the
document that records the clinical observation for the first time, such as the
written record of the trial process, the therapy prescribed by the researcher,
the informed consent form, etc.; or the file contains the laboratory examination
and the image examination data, such as Blood routine examination report, CT,
etc. There are paper and electronic forms or other available forms. When the
original is unfavorable for preservation, inconvenient to obtain or lost, a verified
copy (identical to the original recorded information and produced with a dated
signature or a verifiable procedure, shall be reasonable to explain) would be
saved as a source file.
12.2 Data collection
12.2.1 The source data were recorded and modified according to categories
(objective data and subjective data) during the implementation process.
Objective data is usually generated directly from the testing equipment,
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instruments or other tools. When the test sample is read by the instrument or
device, the result data or images, such as blood routine examination, blood
biochemistry, electrocardiogram, test atlas, pathological image, photographs
of the body lesions, body temperature, X-ray film, CT film or electronic images,
etc.
Subjective data refers to data for artificial observation and evaluation, including
data judged and recorded by the investigator, or data generated by the
subject's own records, such as a history review (eg, part of medical history,
medication history which cannot trace back by investigator are recorded
according to the subject's statement), oral hydration table, urine table, subject
log record, oral medication record, etc. Prior to the trial enrollment, proper
training or guidance are provided to the recorder, records should be timely,
and indicate the signature and date to avoid recall bias; ensure that the
collection and recording of such data is real and standardized.
Researchers and sponsors should take effective measures to ensure the
quality of data generation and recording, which shall be completed by
qualified personnel according to study protocol. As for correction, the original
content should be retained and marked with strikeout, new content and the
name of the modified person, the reason and the date of the modification shall
be annotated beside. The modification of the electronic document should
ensure that the audit track is kept in the backstage for future reference, and
keep relevant records and explanation of data modification.
12.2.2 Methods of data collection will be listed during the study, such as
paper or electronic CRF (eCRF), name and version of the data
acquisition/management system, Describe the permission control plan of the
system user, or provide corresponding information in the form of attachments,
including permission definition, allocation, monitoring, and measures or
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methods to prevent unauthorized operations, authority revocation, and so on.
The data acquisition/management system should have the functions of audit
trail, security management, authority control and data backup, and pass the
complete system verification.
12.2.3 CRF record
When filling in the CRF, the person who fills in does the self-examination with
out additional verification. The clinical research associate verify the source
data at the research center to ensure the accuracy of the clinical research data
originally. Proper training will be provided to the investigator or research
coordinator before the study begins. To help the staff at research center fill in
the CRF or eCRF with real, standardized, complete, and accurate data, the
data manager must provide a guidance document that help filling in the CRF
(usually referred as the CRF Completion Guide).
12.2.4 Staff training
After the study is approved, the main research center and the Key Laboratory
of Coronary Heart Disease will prepare the Investigator's Operation Manual,
CRF Guideline, eCRF Entry Guideline, and Training Schedule to guide the site
staff's operation and management, including data collection, data entry, etc.
The training will be conducted at the Investigator Initiative to train all research
fellows and clinical research coordinators to ensure data collection, data entry
consistency, traceability, completeness, and accuracy.
During the research period, all the data management will be trained by the
subject matter expert (SME), including external resource experts (software
developer engineers, training consultants, etc). The content and method of the
training are approved by the research conductor, and the accuracy of the
content must be approved by the SME. The research training is perform by
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means of centralized training, online training and on-the-job training. All
training shall be tested afterward to understand the effectiveness of training
timely, so that to identify and rectify problems in the training. After the training,
the training conductor shall centrally archive the content, time, place of the
training, trainee list and the signature records.
12.3 Electronic data entry
After the data management department receives the paper CRF from the
researcher, the necessary signature and registration record shall be made.
The primary task of data management is to enter the CRF data into the
database as soon as possible. As for the training of data entry staff, make sure
to familiarize themselves with the data entry system, entering screen settings
and schedules, and also enter test data to ensure their work is accurate and
reliable before the official data entry.
Prior to electronic data entry, a well-trained professional will perform manual
verification to identify abnormal data on paper CRF, including unclear writing,
non-compliance with research protocols, missing data, medically
unreasonable data, and inconsistent data. Once a problem is found, it should
immediately contact the investigator and ask for clarification. Specifically the
verification content include but not limited to:
1) Check if the received CRF uses the latest version.
2) Check the CRF for missing pages
3) Check if the CRF has a subject code.
4) Check if the CRF is filled in with the required ink and whether it is clearly
visible.
5) Check if CRF is damaged.
6) Check if all CRFs have the researcher signature and date.
Electronic data entry and management is the responsibility of the data
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manager of the statistical department in Key Laboratory of Coronary Heart
Disease. EDC database is adopted for electronic data entry. Electronic data is
entered by trained specialist. If problems or unexpected situations are found
during the entry process, they should be recorded and reported to the project's
data administrator for prompt solution. As for the unidentified data, data
managers(statisticians and data administrators) discuss each other and
require researchers to clarify with queries when data is cleaned up.
Quality control will be taken during electronic data entry:
1) Strengthen training: In order to improve the quality of data entry, it is
necessary to strengthen the training of data entry personnel.
2) Data quality control: Quality control of the entered data ensures that the
entered data is at an acceptable level.
3) Identify problems in time: If problems are found during the entry process,
they should be recorded and reported timely.
4)Establish a quality inspection system: After the data entry is completed,
some CRFs are randomly or irregularly checked to understand the quality of
the entry, analyze and deal with the problems of data entry. Electronic data
Entry is generally completed within 2 weeks since the CRF check.
12.4 Data Verification and Query
Before the data verification, a detailed Data Validation Plan (DVP) should be
made to clarify the content, method and verification requirements of the data
verification. Data verification is completed by data manager, auditors, medical
personnel and statisticians together.
The abnormal data is generally found through source data monitor, manual
inspection before entry, logic check by computer system, database check, and
analysis report of summary statistical analysis. The main content of data
verification is to check the CRF filling quality, check the data validity, integrity,
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logic and compliance of the data. The methods of data review include manual
review and computer review.
1) Manual review is mainly used to check abnormal data that is not easily
checked by computer programs, such as CRF fill quality, CRF header
information (such as subject code or CRF page number).
2) Computer review, mainly use the data logic check performed by the
computer system.
The following review methods will be used in accordance with the content of
the research data reviewed: source data verification, database data verification
(including logic verification), summary statistics, and CRF-database
verification. The problems found in the research data review are mainly
through internal and external solutions. The internal solution is mainly based
on comparing the data of other parts of the CRF to make a judgment, and
finally solve the problem, mainly by the internal data administrator. The
external solution to the "problem" is mainly solved by the data administrator in
the form of DCF (Data Challenge Form) to obtain the difference data.
For issues with universality found in data review, specific issues such as
revisions to research protocols, revisions to CRF completion guidelines, or
enhanced training for researchers should be addressed. Research centers that
violate research programs should strengthen audits and recommend
improvements within a limited time. When the aggregated descriptive statistics
reveal significant differences between the data of a research center and other
units (such as reporting too many or too few adverse events), audits of
research centers and researchers should also be strengthened.
The problem data that the data administrator cannot solve through the internal
problem needs to be solved in an external way in time, that is, the problem is
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solved by sending the data clarification table or the data challenge table to the
researcher (following ICH GCP [5.5.3(b)] The requester answers or interprets
the question on the challenge form and returns the DCF to the data
administrator. The challenge form is hand-made by the data administrator, and
each question table has its own unique identity. It is convenient to check the
status of the question list to prevent the missing.
After the challenge table is generated, the data administrator needs to
compare the data on the CRF table with the data in the database again to
determine whether the challenge table is reasonable and valid. If the problem
data of the challenge form is reasonable, send the research center/investigator
to clarify. If the problem data on the challenge form is an error caused by data
entry, or if the logic check program is improperly set, the question form is not
required to be sent to the research center/investigator.
After receiving the question form issued by the Data Management Center of
the Key Laboratory of Coronary Heart Disease, the researcher should reply to
the question and sign the question according to the question on the question
form and check the original data, such as the inpatient medical record and the
laboratory test record. And the date of signing. After the photocopy of the
question form is saved with the CRF in the file file of the research center, the
original is returned to the data management center.
After the challenge form is returned to the data management center, the
recipient needs to record the date received on the challenge form and forward
it to the project data administrator. The data administrator will solve the
problem based on the information provided by the researcher on the challenge
form, if the researcher replies. If you are reasonably satisfied, close the
challenge. If the researcher's answer is unreasonable or leads to the
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generation of additional problem data, the data administrator needs to raise
another question and ask the researcher to clarify again until the problem is
solved. Regardless of the form in which the question form is generated, the
data management center should have a means of recording and tracking the
challenge form.
12.5 EDC design and Establish
For this study, the EDC designer will create a research-specific database and
design and define the CRF table through the user interface to facilitate data
entry, cleanup, review, export, and reporting. The database will be designed
with the following main considerations in mind:
1) Must comply with the research program process to facilitate data entry.
2) The data export style is comprehensive and complete, easy to analyze
statistically and meet the requirements of statisticians or programmers.
3) The data can be relatively inspected in the data management system to
find the “problem” data in time.
4) Should conform to the database creation theory.
5) Should meet the requirements of the database application software.
The research database will adopt a standardized database structure to store
data, ensuring that the fields in the data table are the most basic elements.
From a database perspective, data types involve numeric data types, date and
time data types, and character data types.
The database needs to support the establishment of logic verification (subject
to the development process of the computer program: logic inspection
requirements, development, testing, production environment application and
change control, etc.), check the entered data to find the "problem" data, so that
Data administrators or auditors review and clean up to improve data quality.
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12.6 Research Database environment and operation requirement
The system should be installed in a safe physical environment. The security of
the physical environment can generally be guaranteed by the following
measures: restriction, recording and monitoring of the contact person of the
carrier; dual power supply or UPS; shockproof, fireproof, waterproof, heatproof
and moisture proof ( Non-subjective); vandalism, anti-theft (subjective), etc.
The network environment of the system, that is, the environment in which the
electronic network for data transmission (such as the Internet or local area
network) is located, should also be secured. Generally, it can be guaranteed
by the following measures: establishing a firewall or other hardware and
software to prevent viruses, Trojans, hackers, etc. Spyware intrusion.
System servers and their databases should prioritize remote or offsite backups
to ensure system continuity and data security. When this is not possible, you
should use an offline backup device to periodically back up and take away the
physical environment of the online backup. If the EDC system is interrupted
due to force majeure or uncontrollable factors, the EDC supplier shall have a
corresponding emergency plan and return the normal operation of the EDC
system in the shortest time according to the server and database backup.
At present, the system adopts dual hot security backup to ensure the absolute
information security of all projects, independently run the hard disk and the
backup hard disk, and synchronize the data in real time to ensure
uninterrupted data access. Use Linux system scripts to back up the latest data
in time to ensure data is absolutely secure. The latest backup hard disk data,
daily incremental synchronization of local data, so that data is foolproof.
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12.7 Research data assess authority
The EDC system should have user management, role management and rights
management function modules. All users of the EDC system must have a
unique username and password combination. The password must be stored
encrypted in the system. Both the service provider and the user of the EDC
system should establish an SOP to manage EDC services, operations and
maintenance, and follow the SOP in actual use and management. All records
of the execution or implementation of the SOP are archived for reference.
Access to study data is limited to individuals who have been approved by key
laboratories for coronary heart disease. Individuals must have appropriately
qualified researchers and be compliant with information security awareness
training and confidentiality agreements. All personnel who need access to
research data are required to receive SOP training on the management and
use of their authority. In addition, the permissions of the electronic system are
structured, and users in a single research center can only see data from their
research participants and cannot view or access data from other clinical
research centers or other participants.
When a user no longer needs a certain permission, this permission should be
revoked in time. When the account is changed, the reason for the change and
the process and requirements of the change should be stated. When the user
forgets the password, the process of requesting a new password is recorded
and explained. When the user leaves the research center, all the user's
permissions are revoked, but the user name, inspection traces and other
information are still retained. Once the username is disabled, it should not be
used again.
To ensure system security and monitoring, the following measures will be
taken:
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1) The system automatically logs out after 10 minutes when the user has
no activity.
2) Unauthorized access is recorded in the system log, which is checked
periodically by the system administrator.
3) The user must keep the password and cannot share it.
4) Users cannot log in or work with other users.
5) Check of expired/disabled accounts.
12.8 Data safety strategy
The clinical research data of this study belongs to the property of the
cooperative research project. It may not be sent outside the research center
without the written permission of the person in charge of the key laboratory of
coronary heart disease. It will strictly abide by the main research unit, key
laboratory for coronary heart disease, cooperative research projects and
various research. All data transmission and data security policies of the Center.
The head of the Key Laboratory of Coronary Heart Disease will work with the
research centers in accordance with the signed agreements to ensure proper
handling of data security and data transmission.
12.9 Data Storage and archive
In the course of this study, regardless of the collection method, clinical
research data will enter the research database, so ensuring the security,
integrity and accessibility of data is the main purpose of data preservation. The
principle of preservation of raw data and original documents (such as case
report forms and electronic documents) is that their safety must be guaranteed.
Paper documents and electronic documents should be kept in a secure room
or file cabinet and have strict access control rights to prevent unauthorized
access. After receiving the paper documents, they should be scanned and
saved the electronic files as much as possible. The backup files should be kept
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in different places. The electronic data of the research is mainly stored in the
database server, and its security (such as the firewall of the computer) should
also be guaranteed.
The preservation and archiving of clinical data are for different periods of
clinical research, but their purpose is the same, that is, to ensure the security,
accuracy, completeness and accessibility of data/files.
Article 49 of the State Food and Drug Administration General Administration of
Quality Control of Drug Clinical Trials stipulates that the materials in clinical
trials shall be kept and managed as required. The investigator should save the
clinical trial data until five years after the termination of the clinical trial. The
ICH GCP requires at least two years of storage. This study will comply with the
above requirements and will also follow the basic requirements of the following
archives:
1) The archiving of research data needs to be planned and arranged.
2) The content and format of the research data should meet the
requirements of industry standards and regulatory agencies.
3) Archived data should be secure during the specified data retention
period to prevent damage.
4) The responsibility for the archiving work, the division of labor and the
archiving procedures should be clear.
5) The saved records are periodically checked after archiving to ensure
their accuracy, completeness, accessibility and durability.
6) The archived data should have a central directory.
7) After the important upgrade of the clinical research data
acquisition/management system, the archived electronic data accessibility
should be tested.
8) The original data (such as CRF with the signature and signature date of
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the researcher, CRF correction documents, etc.) should be archived in the
research documents of the key laboratory of coronary heart disease or kept in
an off-site archive.
9) The archive of the research document should indicate the hardware,
software and its version used.
In addition, clinical research data is archived to ensure that archiving meets
the requirements of the main research unit, research organization, and
regulatory requirements. The research data key laboratory of coronary heart
disease will completely retain the database until the primary and secondary
analysis is completed. After the analysis is completed, the research data will
be de-identified and stored indefinitely. The research records of the local
research center may not be destroyed without the written permission of the
Key Laboratory of Coronary Heart Disease.
13. QUALITY CONTROL
13.1 Qualified Measurement/Confirmation
This study will, as far as possible, harmonize the qualifications, qualifications,
clinical work experience, etc. of the physicians involved in the treatment to
ensure the consistency of their research methods. Before the start of the study,
the research center researchers and clinical research coordinators will hold a
meeting review,especially the standard of TCM syndrome classification should
be unified. Research procedures and training in research data collection.
Before starting the meeting, send the research plan, implementation plan, and
execution SOP to each research center and related personnel, collect opinions
from all parties, and confirm the modifications, and organize all participants of
the research center (main researcher, researcher, and research coordinator). ,
research inspectors) accept research programs, research data collection
training; training is conducted during the start-up meeting of each center
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research, for research doctors, clinical research coordinators, etc. to obtain
and maintain preservation source documents, and complete research
evaluation, CRF fill out , EDC entry and other content training, strict
confirmation of the entry criteria, through oral or written feedback and
discussion, to ensure that the research doctors and clinical research
coordinators understand and clarify the research assessment, the meeting
also on the relevant variables, laboratory tests normal range, each The
implementation characteristics of the Center were thoroughly reviewed and
discussed, and training was strengthened to develop operational reference
guides for each center.
Before the start of the study, the laboratory qualification certificates of each
center and the normal range of laboratory tests were reviewed and confirmed
to prevent research bias.
13.2 Patients Management
For the subjects of the project, the investigator of each clinical research and
testing center will be responsible for the management of the subjects enrolled,
keeping the patient's personal information confidential, and paying attention to
the patient's health during the study, in the informed consent form. The
researcher's contact information corresponding to each sub-center is attached,
and the patient can contact the researcher at any time to make the patient's
safety secure. For patients who are unable to return to the original center for
follow-up and blood samples, the participants of the participating centers will
conduct telephone follow-ups and answer questions about the patients'
questions. They should try to adapt to the patient's schedule and safety issues.
13.3 Protocol deviation
Any program deviations need to be recorded, and the Key Laboratory of
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Coronary Heart Disease will create a program deviation table to ensure that
events are tracked correctly. The deviation from the program will be evaluated
by the Key Laboratory of Coronary Heart Disease and the effectiveness of the
deviation basis will be determined. Any medical center or subject who has a
program deviation in the absence of a valid reason, and after training in
remedial training, is recommended to terminate it to the Data Monitoring
Committee (DMC) if any member of the DMC or the Inspectorate believes If
the compliance program will impair the health of the subject, the subject's
rights should be prioritized and the subject should be withdrawn from the study
after consultation with the Executive Committee and the program will be
reported to the main research unit IRB as required.
13.4 Randomized control of study treatment
This clinical study is a multicenter, randomized, controlled trial that requires the
necessary uniform standard treatment of routine clinical interventions at
participating centers to rule out confounding due to inconsistent intervention
criteria. Randomized system of the Department of Statistics of Southern
Medical University to ensure random objectivity and reduce selection bias.
13.5 Monitoring and quality control
In order to ensure the uniform and high quality of multi-center participants, the
clinical monitoring group will conduct quality control on the research according
to the audit plan formulated by the Guangdong Provincial Key Laboratory of
Coronary Heart Disease, including but not limited to:
1) Monitoring frequency and report
The first audit was conducted within one week after the first subject was
enrolled;
In the enrollment and follow-up phase (refers to the first case of the center
to be screened to all subjects in the center), the audit is conducted once a
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month, and the window period of the two allowed audits is within ±60 days.
That is, the last audit date is January 1, 2016, and the next audit can be
scheduled from February 28, 2016 to March 3, 2016. The actual visit date of
the audit report must be the same as the registration date in the central visit
registration form. For centers that are concentrated in the group and faster in
the group, the CRA and PM applications can adjust the monitoring frequency
to 2 weeks in the concentration stage of the group;
The frequency of the audit can be adjusted based on the speed of the center's
entry or the problems found in the center. If the audit plan is changed, please
explain it in the audit report.
The trial initiation visit must be performed prior to screening the patient
The last time the audit activity must be before the data is locked; if there
are any remaining problems before the data lock library, all problems must be
resolved before the audit can be terminated;
End of trial visit will be performed after the data is locked.
2) Monitoring visit report and project management report
Monitoring visit report:
All problems found in the audit and not resolved and their action plans must be
reflected in the audit report; the audit report must be sent to the project
execution leader within 7 working days after the audit occurs;
Site visit report:
The center enrollment stage (the center enrollment stage means that the first
subject of the center is screened to complete the enrollment of all subjects in
the center), and the auditor reports the basic information and progress of the
study to the project execution leader every week;
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Central treatment stage (central treatment stage refers to completion of all
subjects in the center to complete completion of treatment of all subjects in the
center) and central follow-up stage (central follow-up stage to all subjects in
the center after completion of treatment after follow-up period to this All
subjects in the center are grouped and reported to the project executive
responsible every 4 weeks.
Project team internal project meeting
Project enrollment stage (refers to the first subject of the project to screen all
subjects of the project to complete the group completion): The auditor holds a
conference call with the project execution leader every 4 weeks; the specific
time is notified by the project team;
During the project follow-up phase (the project follow-up phase means that all
subjects in the project are completed in the group until all subjects in the
project are out of the group): the internal meetings of the project team are held
monthly;
For the project in the center according to the program development and the
subject's rights and interests, the auditor needs to promptly feedback to the
project team. For issues that have significant impact, it needs to be reported to
the project executive person within 1 working day after the knowledge is
obtained.
3) Staff training
Auditor training:
Initial training
The training of the project team will be arranged before the start of the
research center, including training in programs, systems and processes, which
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will ensure the smooth start of the project;
A team member's training was conducted prior to the conference, including
research background, program introduction, ICF management, verification
considerations, project management and entry plan, data management and
EDC profile
Training during the research process
According to the EDC verification situation, the DM summarizes the EDC
entry and common questioning common problems, and the project manager
will share the training of the project team at the project meeting.
According to the audit of the sponsor, etc., the project team summarizes
the problems found, and the project supervisors share the training of the
project team at the project meeting.
For newly joined project team members, the project will arrange relevant
content such as program and process training before undertaking the project
task. Training is generally conducted on-site or on a conference call.
Personnel handover occurred in the project. The project manager handed
over the SOP according to the project team to ensure the smooth handover of
personnel, and systematic training of the new CRA before the handover. The
training was generally conducted by on-site training or conference call.
Add additional training as appropriate.
Research Center Staff Training:
The auditor responsible for each center will provide training to the staff of
the research center at the start-up meeting, CRF filling and testing procedures.
When the first subject is screened or enrolled, the CRA needs to assist
and confirm that the research is familiar with the research process, such as
timely training and reminders.
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4) eCRF fill in / enter
The CRF is filled in/entered by the designated personnel of the research
center according to the filling instructions. All patients enrolled need to
complete CRF, including rejection of the patient.
Even if you withdraw from the case, you will need to complete the “Completion
Study Page”.
Each case with signed informed consent needs to be registered in the
screening and enrollment form, including screening for losers.
All subjects need to retain their original medical records
5) Verification of original data (SDV plan)
Part 1: Important parameters
100% raw data verification for all patients with the following parameters:
1) Informed consent form
Whether the patient's signature and date appear on the informed consent
form;
Whether the patient signature date is before the start of any research
procedure;
Whether the name and date of the doctor who informed the informed
consent are signed;
The researcher's contact number must be a telephone that can be
contacted 24 hours a day;
Whether the date of signing by the researcher is the same day as the
patient;
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Ensure that the version of the informed consent form signed by the subject
is correct;
It is recommended that the pen used by the doctor's signature be as
different as possible from the patient;
Informed consent forms for screening losers must also be kept;
- Record on the original record when the patient has signed an informed
consent form and obtained an original.
Part II: Initial Quality Control
1) After the first 5 patients are enrolled, the rest of the SDV needs to be done in
addition to the above, in order to ensure that the original record is complete,
the program is followed, and the eCRF is correctly filled in/entered.
2) In addition to the content mentioned in the first section, the following should
be verified at each visit:
Is the follow-up time recorded on the CRF consistent with the original
medical record?
Changes in vital signs and laboratory tests after baseline
The laboratory tests required in each program are completed; and any
clinical test abnormalities are recorded and explained in the CRF.
Patient diary (hydration table)
Part III: Quality Control in Progress
100% SDV is required during the trial.
If the investigator is replaced during the trial, the auditor will then review
the data of the first two patients enrolled by the new investigator.
If many problems are found in the trial, discuss it with the investigator and
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not resolve it.
Part IV: Screening failure
The original medical records failed to reflect the reasons for the screening
failure, and the original records must be saved.
Part V: Original Data Verification Record
The researcher must keep all original medical records in the research
center.
The auditor needs to record the important findings of SDV, how to solve it
and the next steps in the audit report. At the same time, feedback these
findings to the researchers and let them correct them in time.
13.6 Participation Center trial/terminate
The research chair and the key laboratory for coronary heart disease will
assess the participation in the hospital. Only hospitals that meet the
corresponding indicators can participate in the study:
1) The hospital has the relevant equipment and technology needed for the
project:
2) Have sufficient patient source that meets the criteria for entry and exit:
meet at least 10 patients with acute myocardial infarction each month;
3) Have sufficient human resources in line with standards: have doctors who
can qualify for such diseases, and receive training for the project. More than
2 doctors are responsible for this project;
During the implementation process, the recruitment rate and operational
aspects of the study are continuously monitored. If the research center is in the
trial stage, it will face the following reasons including but not limited to violation
of the program, violation of GCP or related regulations, and project quality
requirements.
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The risk of terminating the study.
1) Recruitment rate: divide the number of randomized patients by the
expected number of patients, calculate the recruitment rate, and continuously
monitor the indicator during the research. If the recruitment process is slow, if
there is no randomization in February, the center will receive remediation and
reassess. If the plan is not included in the plan, it will enter the probation period
and be evaluated every 2 months.
2) Follow-up rate: The number of patients in any follow-up window was
divided by the number of patients expected to follow the window, and the
follow-up rate was calculated. Both the numerator and the denominator were
delayed for 4 weeks to schedule a visit to the corresponding follow-up window
and complete the form. Study centers with a cumulative follow-up rate of less
than 90% will enter the probationary period and will be assessed every 2
months.
3) Form Completion Rate: The table completion rate is calculated by
dividing the number of completed forms by the number of expected forms,
where the expected number of forms will be sent out as a "not collected" form.
The table completion rate will be calculated according to the patient and the
form. Research centers with a cumulative follow-up rate of less than 90% will
enter the probationary period and will be assessed every 2 months.
Once the research center enters the probationary period, failure to meet
the requirements of the end of the probationary period will result in the
proposed termination of the study. In addition, those that do not meet the
above requirements, or one of which will not meet the standard after
rectification and remediation, will face the termination of the trial. In addition,
after the relevant performance evaluation of the research center in the key
laboratory of coronary heart disease, if it is considered unsuitable for
continuing research, the research center can be terminated without a formal
trial period.
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14.GOOD CLINICAL PRACTICE AND RESEARCH CENTERSREVIEW PROJECTS
This study will be conducted in accordance with the Good Clinical Practice
(GCP) for Drug Clinical Trials. During the study period, the research centers
participating in the research will be monitored according to the monitoring plan.
The Research Center Monitoring Team will visit all participating research
centers at least once in accordance with the GCP. The purpose of these visits
is to ensure that trials are performed, documented, and reported in accordance
with research protocols, standard operating procedures (SOPs), clinical trial
quality management practices (GCP), and applicable regulatory requirements.
The auditor will examine the patient study files, including x-rays,
electrocardiograms, and other source files. Particular attention is paid to
patient informed consent, protocol compliance, ethics committee approval, and
researcher folders. After the interview, the monitoring visit report is prepared
and forwarded to the research center researcher and research leader.
In addition to the review visits scheduled by the sponsors, an independent,
comprehensive research center audit can be conducted at any time, as
required by the research management or research center.
All in all, the audit team will do the following:
1) Provide comprehensive research execution tools to the research center,
including important research requirements in the folder catalog, templates, and
source files to help the research center better implement the research program
and meet the requirements of the GCP regulations.
2) Regular visits to participating research centers and provide GCP
training and enhancement at the kick-off meeting.
3) Conduct a review visit to each participating center at least annually to
monitor the compliance, program compliance, and overall research design
performed by the investigator.
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4) A comprehensive review of the final year of the study to ensure that all
research tasks and related documentation are completed.
15. RESEARCH MONITORING AND AUDIT PLANS
Protecting patients' rights and benefits is a major concern for key coronary
heart disease laboratories. This study will be conducted in accordance with the
local laws of the ICH-GCP, the Helsinki Declaration and the quality
management practices for drug clinical trials.
15.1 Monitoring agency
The study will oversee the scientific and ethical nature of the research through
four external agencies, including the Data Monitoring Committee (DMC), the
Ethics Committee (IRB), the Independent Incidents Committee (CEC), and the
Clinical Monitoring Agency.
15.1.1 Data monitoring committee
The Data Monitoring Board (DMC) will independently monitor and make
recommendations on clinical research processes, safety data, and progress.
(DMC) consists of members of the relevant professional field (meteologists,
cardiology, and clinical research specialists) who regularly evaluate cumulative
data from ongoing clinical trials, including those who have participated or who
will be recruited into the trial. The safety of the tester, the study implementation,
scientific and the integrity of the research data. The DMC will assess the
progress of the enrollment of the subject and make recommendations to the
sponsor, proceeding as planned, continuing or terminating or suspending trials
in one or all of the groups. In the future, it can be adjusted according to the
actual rate of the experiment and the incidence of the event.
15.1.2 Ethics Committee
The Ethics Committee (IEC) provides expert ethics and scientific review of
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multi-center projects while ensuring solve local problems in each research
center. The Key Laboratory Center for Coronary Heart Diseases conducts a
comprehensive, rapid and ongoing review, and the investigator (PI) first
submits applications, including research protocols, informed consent, and so
on. Once approved, the application materials will be sent to all possible
research centers, and the local research center researchers (LSI) will submit
the application to the ethics committee. After approval, a copy of the research
center approval document will be provided to the key laboratory for coronary
heart disease for backup. During the study period, communication between the
participating centers and the IEC shall be recorded or documented. All
participating centers in the study conducted an annual ethical review.
15.1.3 Clinical Events Committee
The Clinical Event Committee (CEC) will be responsible for determining the
endpoints in clinical studies and avoiding deviations in event determination
between centers and centers in order to achieve a more accurate assessment
of test results. CEC is an independent committee of three research field
experts independent of research sponsors and researchers. Its primary
responsibility is to combine clinical expertise and protocols based on uniform
definition criteria for all endpoint events in the study. In the relevant content,
the objective judgment of the end point event is made to see if it meets the
definition criteria. The frequency of this study review will be determined based
on the incidence of enrollment plans and endpoint events.
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Suspected
endpoint
Researcher
evaluation
Audit - source
file collection
Source file
submitted to CEC
CEC regular
evaluation Evaluation result
CECquery data
confirm
Data verification and
analysis
Consistency
comparisoneCRF data
collection
Submit to data
department
Figure A5 - CEC review process
The CEC Secretariat will be responsible for the production and regular
updating and maintenance of the CEC Review Folder. The CEC Review
Folder will store all documents related to CEC content, including CEC member
information, confidentiality agreements, review source files and review results.
15.1.4 Clinical monitoring team
Clinical monitors will ensure that trials are performed, documented, and
reported in accordance with research protocols, standard operating
procedures (SOPs), clinical trial quality management practices (GCP), and
applicable regulatory requirements. The audit is usually scheduled by the
monitor and the investigator and/or other participants prior to the first patient
enrollment. According to the research project, the inspection is usually carried
out every four to six weeks, but the interval between inspections can be
extended or shortened due to the difference in research period and schedule.
The clinical monitor will ensure that the submitted data is accurate and
consistent with the source document; verify that the subject's informed consent
has been correctly obtained and recorded; that the study participants in the
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enrolled study meet the inclusion and exclusion criteria; and that the drug is
ensured. All basic documentation guidelines required by the clinical trial quality
management practices are properly documented.
The auditor will conduct a visit to the research center before the study begins.
At the time of the visit, they will discuss the way the subjects/patients are
recruited, the completion of the case report form and the next management
procedures. In addition, it should be discussed and agreed to: the
investigator's assessment of the program's understanding, his or her
obligations during the study period, and possible recruitment rates. Other
circumstances, such as confirmation of data obtained in the study, should also
be discussed. In addition, they will ensure that appropriate research related
documents exist.
At the end of the study, a study closure visit, the final audit, should be
performed, usually within four to six weeks of the end of the last follow-up of
the last subject in the study center. The preparations and procedures for the
study of closed visits are generally the same as for a regular supervisory visit.
15.2 Monitoring adverse events (AEs) and serious adverse events (SAE)
It should report safety information in a timely and complete manner, assisting
research management in identifying any adverse medical events, ensuring:
protecting the safety of research patients, better understanding the overall
safety characteristics of research interventions and treatment modalities, and
appropriately modifying research protocols Improve research design and
compliance with regulatory requirements.
The participating research centers will be responsible for the AE and SAE
reporting requirements described in this scenario, as described below:
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1) The subjects were closely monitored for new AE and SAE during the
study.
2) Review the accuracy and completeness of all AE and SAE in the report.
3) Report all SAEs to the research centers IEC within 72 hours of the
event.
4) Compliance with the research center IRB policy on AE and SAE
reporting.
5) In order to address security issues, an implementation plan for the study
group and the executive committee may be developed.
15.2.1 Adverse event
The International Conference on Harmonization (ICH) Clinical Safety Data
Management (ICH2A) defines adverse events (AEs) as “any adverse medical
event that occurs in a clinical study subject and accepts one of the research
interventions that do not necessarily have a causal relationship with the
intervention” . The CFDA of the State Food and Drug Administration defines an
adverse event (AE) as an adverse medical event that occurs after a patient or
clinical trial subject receives a drug, but does not necessarily have a causal
relationship with the treatment. Therefore, the AE will include (any adverse
signs, changes in function (symptoms) that occur during the observation, as
well as other tests (assay, ECG, X-ray, etc.).
Researchers at participating research centers are responsible for collecting AE
information from subjects in the research center with the assistance of the
clinical research coordinator. When an adverse event occurs, both during
hospitalization and during follow-up, the usual principles of recording are as
follows: Fill in the adverse event record form, including the name of the
adverse event, the time of occurrence, the end time, the severity, the
measures taken and the outcome and the corresponding evaluation. Adverse
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events with serious adverse events (defined below) will be reported as follows
and followed up to regression or stabilization.
15.2.2 Severe adverse event
Serious adverse events (SAEs) are a subset of adverse events defined by
(ICH) Clinical Safety Data Management (ICH2A) as any of the following
adverse medical events that occur during clinical trials:
1) Lead to death.
2) Crisis life.
3) Need hospitalization or extend hospital stay.
4) Lead to persistent or severe disability or loss of energy.
5) Congenital malformations / birth defects.
6) According to medical judgment, any condition that may harm the subject
and require medication or surgery to prevent one of the above outcomes.
The study will collect all SAEs regardless of whether they are considered
relevant to the study intervention. SAEs that have a reasonable causal
relationship with research interventions and related drugs will be reported as
“relevant.” There is no need to establish a clear causal relationship.
Researchers at participating research centers are responsible for collecting
SAE information from subjects in the research center with the assistance of a
clinical research coordinator.
When a serious adverse event occurs, the researcher is required to report to
the relevant department within 24 hours of obtaining a serious adverse event.
The usual principles of treatment are as follows:
First, the subject should be guaranteed timely and appropriate clinical
diagnosis and treatment;
Secondly collect relevant information, such as medical records and
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inspection results, in order to accurately and timely fill out the Serious Adverse
Event Report and report it to relevant departments.
Ensure that the report is consistent with the original record, CRF, and other
test records. Ensure that the start and end dates and major event descriptions
of serious adverse events are consistent with CRF and other test documents.
Don't delay submitting reports even if the information may be incomplete or
uncertain. When more information is available, it can be supplemented or
revised in the form of follow-up reports. Relevant information should be
collected and recorded continuously until the end of the reporting period.
Reporting forms and reporting procedures for serious adverse events may
have different requirements in different programs and research institutions.
These requirements should be clearly written into the test plan or SOP and
fully trained before the study begins, so that the researcher can follow the
implementation.
During the entire study period, the SAE will be monitored by the Data
Monitoring Committee and all AE and SAE reports will be summarized in
accordance with the time schedule set by the DMC to review the entire study
adverse event data and whether to continue research or Safety reasons stop
the study and give advice. We believe that an independent DMC can
effectively monitor the safety of the trial as it will periodically review all outcome
endpoints based on treatment assignments and will also receive statistical
support to determine the significance of any observed differences.
RESULT
16.BIOSTATISTICAL CONSIDERATIONS
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A.Overview of design
1. The analytic model
There is one primary hypothesis that will be tested: 1) aggressive hydration
(i.e., preprocedural IV loading plus postprocedural hemodynamic-guided
[LVEDP] fluid administration) reduces the risks of CI-AKI and clinical adverse
events in acute myocardial infarction patients undergoing primary PCI.
The study will enroll 560 subjects over 5 years and evaluate each subject 72
hours after the intervention. Within each site, subjects will be randomly
assigned to one of two study interventions:
1) Aggressive hydration,
2) Control (general hydration).
The rates of primary and key second outcomes were compared by Pearson χ2
or Fisher exact tests.We used relative risk (RR) and absolute risk difference
with their corresponding 95% confidence interval (CI) to describe the
intervention effect. Number needed to treat(NNT) for preventing one CI-AKI
event was caculate by inverse of the absolute risk difference. We used logistic
regression with interaction testing to assess whether the recorded treatment
effect was consistent across prespecified subgroups. All tests will be 2 tailed,
and P value less than 0.05 will be considered statistically significant difference.
All data analyses will be performed using SAS version 9.4 (SAS Institute, Cary,
NC).
Relative risk can be estimated from a 2x2 contingency table:
Group
Intervention (I) Control (C)
Events (E) IE CE
Non-events (N) IN CN
The point estimate of the relative risk is
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2. Incidence of the CI-AKI and effects of our interventions
CI-AKI, defined as a >25% or 0.5mg/dL increase in serum creatinine from
baseline during the first 48 to 72 hours after the procedure. Based on our
previous findings, a CI-AKI incidence of 23% was estimated for the control
group, and a CI-AKI incidence of 11.5% was assumed for the intervention
group (50% relative reduction). Using nQuery + nTerim 3.0 (Statistical
Solutions Ltd, Farmer's Cross, Cork, Ireland) with a 2-sided χ2 test, a
significance level of .05, a power of 90%, and a dropout rate <20%, 280
patients are required in each group, for a total sample size of 560.
Model
Aggressive
hydration
Control Overall event
rate
11.5% 23.0% 17.3%
Therefore, we postulate that:
Under control conditions, the rate for our primary outcome CI-AKI is 23.0%
The intervention will prevent 50% of these events
Under the intervention condition, the rate is 11.5%
The absolute effect of the intervention will be an 11.5% reduction in CI-AKI.
We have one primary hypothesis. We will, and therefore assign the type I error
of 5% to the intervention. No interim analysis will be carried out according to
the statistical design.
B. Primary end-point
We fully describe the aggressive hydration versus control (general hydration)
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intervention and the CI-AKI outcome. The null hypothesis is that the two
groups (aggressive hydration and control) do not differ in terms of the
proportion of subjects who experience CI-AKI. The alternative hypothesis is
that the absolute difference in the incidence of CI-AKI between the intervention
group and the control group is 5% or more.
The formal statement of the null hypothesis
Under the null hypothesis:
The proportion of CI-AKI for patients administered aggressive hydration is
23.0%
Under the alternative hypothesis, the proportion of CI-AKI for patients
administered general hydration is 23.0%.
The formal hypothesis test is two-sided allowing for aggressive hydration to be
either more or less effective than control (general hydration). However, the
study of aggressive hydration will only be viewed as more successful if
subjects treated with aggressive hydration have a significantly lower proportion
of CI-AKI than patients who receive general hydration. We will test this
hypothesis with one model that contains main clinical characteristics (e.g., age,
sex, eGFR, HV/W), and the Mehran risk score will be calculated.
C. Secondary end-points
Our secondary objectives will be tested using χ2 tests, and the 95% CI of the
rate difference will be calculated using the method described by Altman et al
(reported in Newcombe and recommended by the Food and Drug
Administration and Clinical and Laboratory Standards Institute. The secondary
end-points will be analyzed based on the intention-to-treat principle. These
objectives are:
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Losses to follow up and missing data
We conservatively estimate that up to 20% of subjects may be lost to follow up
before 72 hours. The site coordinators will make every effort to locate such
subjects including at least two laboratory test of serum creatinine after primary
PCI. If such efforts fail and we have no information indicating the outcome for
these subjects, then we will exclude them from the primary analysis and then
carry out a worst-case analysis to confirm the result of the primary analysis.
Definition of Intention to Treat Sample
All consented and randomized subjects will be accounted for and reported in
the CONSORT diagram for the study, however, only those randomized
subjects who initiated either IV intervention or have finished test a least once
for SCr on preoperation and postoperation (i.e., did not drop out or withdraw
prior to start of the allocated intervention), will be considered as an intention to
treat (ITT) subject to be included in the Data Monitoring Committee (DMC)
reports and primary efficacy analysis.
17. STUDY ORGANIZATION AND ADMINISTRATION
The research group and monitor group will be set up in the Central Office of
the Guangdong Provincial Key Laboratory of Coronary Heart Disease. The
research group is responsible for all operation/implementation procedures of
this study, and the monitor group is responsible for the quality control of this
study. The research team will conduct a face-to-face meeting prior to the start
of the study and thereafter at least once a year (online or offline). Except for
the executive committee (including research center investigators, research
clinicians, and members from academic management centers) will be
responsible for internal progress of research. The research management
structure is shown in the figure below (Figure A6).
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Figure A6 – Study management structure
17.1 Central Office of Guangdong Provincial Key Laboratory of
Coronary Heart Disease
The Central Office of Guangdong Provincial Key Laboratory of Coronary Heart
Disease organizes relevant personnel through the Executive Committee,
Operation Management Center and Academic Management Center to
formulate management systems and standard operating procedures
applicable to all the research in due course.
17.2 Executive Committee
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The Executive Committee will monitor the progress of the study, the operation
of the participating centers, and the quality of the data collected. The
committee will also monitor compliance with the study protocol. Except for the
Executive Committee, a publication plan will be developed for the study and
the display of all data will be monitored. Before relevant data is used for
display or publication, it must be approved by the Executive Committee. The
committee members will be selected by the research chair from the operation
and academic center. The Executive Committee may hold a conference call on
a quarterly or annual basis and, if necessary, hold the meeting in person.
C. Research Operation Management Center
The Research Operation Management Center will conduct daily scientific and
management coordination of research. This will include the development of
research protocol, the preparation of operational manuals and source
document worksheets, ensuring appropriate support for participating centers,
organizing meetings, answering programme queries, regularly publishing
research progress briefs, preparing interim and final reports, and the archiving
of research data at the end of the study. Coordinating research involves the
relationship of relevant departments, quality management of the research
projects (including monitor of patient recruitment and data quality), and
ensuring the smooth progress of study.
17.3 Research Academic Management Center
The Research Academic Management Center will assume the overall design
of the entire study, responsible for the design, supervision and management of
clinical study, and is responsible for various monitor organized by the drug
regulatory authorities, such as monitor, audits, on-site inspections, institutional
qualifications or reviews, etc. Work preparation, coordination and participation
in the audit of the sponsor organization. Provide clinical biometric consultation,
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responsible for DME/evidence-based medicine teaching tasks for medical
graduate students, and provide advice and consultation on academic related
issues during the study.
18. PUBLICATIONS
It is the policy of the DVP that outcome data will not be revealed to the
participating investigators until the data collection phase of the study is
completed. This policy safeguards against possible biases affecting the data
collection. The regular and ex-officio members of the DMC will be monitoring
the outcome results to ensure that the study is stopped if a definitive answer is
reached earlier than the scheduled end of the study. All presentations and
publications from this study will be done in accordance with current DVP
guidelines. The presentation or publication of any or all data collected by
participating investigators on patients entered into the ATTEMPT study is
under the direct control of the study's Executive Committee. This policy is
applicable whether the publication or presentation is concerned with the
results of the principal undertaking or is associated with the study in some
other way. No individual participating investigator has any inherent right to
perform analyses or interpretations or to make public presentations or seek
publication of any or all of the data other than under the auspices and approval
of the Executive Committee.
The Executive Committee has the authority to establish one or more
publication committees, usually made up of sub-groups of participating
investigators and some members of the Executive Committee, for the purpose
of producing manuscripts for presentation and publication. Any presentation or
publication, when formulated by the Executive Committee or its authorized
representatives, should be circulated to all investigators participating in
manuscript prepation for their review, comments, and suggestions at least four
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weeks prior to submission of the manuscript to the presenting or publication
body. All publications must give proper recognition to the study's funding
source, including the Department of SME, and should list all investigators in
the study. If an investigator's major salary support and/or commitment is from
the SME, it is obligatory for the investigator to list the SME as his/her primary
institutional affiliation. Submission of manuscripts or abstracts must follow the
current DVP policy. Since all publications should state that it is a publication
from ATTEMPT study, ideally, a sub-title is used stating, "ATTEMPT study."
The SME contributions to the research project should be acknowledged in all
written and oral presentations of the research results, including scientific
articles, news releases, news conferences, public lectures, and media
interviews. All clinical study reports and journal manuscripts must be reviewed
and approved by IEC prior to submission for publication.
19. REFERENCES
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3. McCullough PA. Contrast-induced acute kidney injury. Journal of the AmericanCollege of Cardiology. 2008;51:1419-28.
4. Mehran R and Nikolsky E. Contrast-induced nephropathy: definition, epidemiology,and patients at risk. Kidney international Supplement. 2006:S11-5.
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Appendix C
ATTEMEPT Clinical Trial Protocol Version 3.0
(Appendix independently paginated)
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AGGRESSIVE HYDRATION AND CONTRAST INDUCED ACUTE KIDNEY INJURYFOLLOWING PRIMARY ANGIOPLASTY (ATTEMPT):
CONTENTS
RESEARCH CENTERS
EXECUTIVE SUMMARY........................................................................................................1
ABBREVIATIONS................................................................................................................... 3
INTRODUCTION......................................................................................................................5
BACKGROUND....................................................................................................................6
SIGNIFICANCE OF THE PROPOSED RESEARCH...................................................19
STUDY DESIGN....................................................................................................................20
STUDY HYPOTHESES AND OBJECTIVES.................................................................20
OVERVIEW OF STUDY DESIGN...................................................................................21
METHOD.................................................................................................................................27
STUDY POPULATION AND PATIENT RECRUITMENT............................................27
STUDY PROCEDURES...................................................................................................29
POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS................................49
FEASIBILITY OF RECRUITMENT...............................................................................553
ANTICIPATED BARRIERS TO RECRUITMENT.......................................................564
PROPOSED ANCILLARY STUDY............................................................................... 575
HUMAN SUBJECTS....................................................................................................... 586
DATA MANAGEMENT......................................................................................................58
QUALITY CONTROL......................................................................................................720
GOOD CLINICAL PRACTICE......................................................................................... 79
RESEARCH MONITORING AND AUDIT PLANS........................................................80
RESULT..................................................................................................................................86
BIOSTATISTICAL CONSIDERATIONS.........................................................................86
STUDY ORGANIZATION AND ADMINISTRATION..................................................941
PUBLICATIONS...............................................................................................................974
REFERENCES.................................................................................................................986
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Research centers
No. Study Site
01 Guangdong Provincial People’s Hospital
03 Zhongshan Hospital, Fudan University
04 Chinese PLA General Hospital
05 The Affiliated Hospital, Guangdong Medical University
07 The Eighth Affiliated Hospital, Sun Yat‐sen University
08 Longyan First Affiliated Hospital of Fujian Medical University
09 First People’s Hospital of Zhaoqing City
10 Dongguan TCM Hospital
11 Maoming People's Hospital
12 Shenzhen People's Hospital
13 Beijing Ditan Hospital
14 Hangzhou First People’s Hospital
15 Tongji Hospital, Tongji Medical College, Huazhong University of Science and
Technology
16 Guangdong Provincial Hospital of Chinese Medicine
17 Mianyang Central Hospital
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1
EXECUTIVE SUMMARY
The intravascular administration of iodinated contrast agent for coronary
angiography (CAG) or percutaneous coronary intervention (PCI) is a common
cause of acute kidney injury (AKI) and a leading cause of iatrogenic renal
disease. Multiple studies have determined that contrast-induced AKI (CI-AKI)
is associated with prolonged hospitalization, increased medical economic
burden, and adverse long-term prognosis.
Patients with ST-elevation myocardial infarction (STEMI) have a higher risk of
CI-AKI, which is a potentially serious complication of angiographic procedures
that are associated with increased mortality, morbidity, and health care use in
patients undergoing PCI. According to guidelines for the management of
STEMI, saline hydration is widely recommended. However, optimal saline
hydration strategy has not been well established in this high-risk population.
The Induced Diuresis With Matched Hydration Compared to Standard
Hydration for Contrast Induced Nephropathy Prevention (MYTHOS) study
found that a loading dose (125/250mL) of isotonic saline matched with
furosemide-induced high urine output significantly reduces the risk of CI-AKI
and might be associated with improved clinical outcomes in patients with
chronic kidney disease (CKD). QIAN G et al suggested that CVP-guided fluid
administration can be safely and effectively reduce the risk of CI-AKI in
patients with CKD and chronic heart failure and substantially reduce composite
major adverse events for these high-risk patients. The Prevention of Contrast
Renal Injury with Different Hydration Strategies (POSEIDON) trial suggested
that intravenous (IV) administration of normal saline guided by the left
ventricular end diastolic pressure (LVEDP) is well tolerated and could
substantially reduce the incidence of CI-AKI and major adverse clinical events
in patients with combined CKD and one or more of several risk factors
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2
undergoing cardiac catheterization. Three clinical trials above consistently
demonstrated that saline hydration based on certain guiding strategies was
more effective than general hydration in preventing CI-AKI and reducing the
risk of adverse prognosis.
Patients with STEMI are likely to present with hypotension or even shock, a
large volume of contrast agent, and inability to start a kidney prophylactic
therapy, all of which are associated with an increased risk of CI-AKI. In
previous studies, cardiologists were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; The main
reason is lacking of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a definite
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Therefore, flexible
and individualized hydration therapy based on certain guiding strategy needed
to maintain renal perfusion, given that perioperative IV volume expansion
could potentially compensate for reduced cardiac output, hypotension, and
depletion of intravascular volume in patients with STEMI.
Given these previous data, we designed the ATTEMPT trial to examine the
efficacy of a preprocedural loading dose and postprocedural aggressive
hydration with normal saline guided by LVEDP as compared with general
hydration(Figure A1). We hypothesize that aggressive hydration strategy
reduces the risk of CI-AKI and improves the clinical outcomes in STEMI
patients undergoing primary PCI. The ATTEMPT study is a multicenter,
open-label, investigator-driven, randomized controlled trial in China.
Approximately 560 patients with STEMI undergoing primary PCI will be
randomized (1:1) to receive either periprocedural general hydration (control
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3
group) or aggressive hydration (treatment group). Patients in the control group
receive periprocedural general hydration with ≤500 mL normal saline (within 6
hours) at a normal rate (0.5 or 1 mL/kg*h). Patients in the treatment group
receive a preprocedural loading dose (125/250 mL) of normal saline within 30
minutes and intravenous hydration at a normal rate until LVEDP is available,
followed by postprocedural aggressive hydration guided by LVEDP for 4 hours
and then continuous intravascular hydration at the normal rate until 24 hours
after PCI. The primary endpoint is CI-AKI, defined as a >25% or 0.5-mg/dL
increase in serum creatinine from baseline during the first 48 to 72 hours after
the procedure. The ATTEMPT study has the potential to identify optimal
hydration regimens for STEMI patients undergoing primary PCI.
ABBREVIATIONS
AKI Acute kidney injury
ACS Acute coronary syndrome
AHF Acute heart failure
AMI Acute myocardial infarction
ACEI Angiotensin-Converting Enzyme Inhibitors
ARB Angiotensin Receptor Blockers
BMI Body Mass Index
pPCI Primary Percutaneous Cornary Intervention
RR Risk Ratio
ARR Absolute Risk Ratio
SCr Serum creatinine
DSMB Data and safety monitoring committee
CCU Cardiac care unit
CEC Clinical Event Committee
CI Confidence Interval
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CI-AKI Contrast-induced Acute Kidney Injury
CK Creatine kinase
CK-MB Creatine kinase-MB
CKD Chronic kidney disease
CAG Coronary Angiography
CEC Clinical Event Committee
CVD Cardiovascular disease
CRA Clinical Research Associate
CT Computed Tomography
DM Diabetes Mellitus
DMC Data Monitoring Committee
DVP Data Validation Plan
EDC Electronic Data Capture
eGFR estimated Glomerular Filtration Rate
ESRD End-stage Renal Disease
GCP Good Clinical Practice
HF Heart Failure
HR Hazard Ratio
HCT Hematocrit
ICH International technical committee
IEC Independent Ethics Committee
ITT Intention-to-treat;
IABP Intra-aortic Ballon Pump
LVEDP Left Ventricular end-diastolic Pressure
LVEF Left Ventricular Ejection Fraction
MACE Major Adverse Cardiovascular Events
MDRD Modification of Diet in Renal Disease formula
OR Odd Ratio
PCI Percutaneous Coronary Intervention
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PM Project Manager
PLT Platelets
NT-proBNP N-terminal pro-brain natriuretic peptide
NNT Number needed to treat
NYHA New York Heart Association
STEMI Stsegment Elevation Myocardial Infarction
RR Risk Ratio
WBC White Blood Cell
DCF Data Challenge Form
INTRODUCTION
Contrast-induced acute kidney injury (CI-AKI) is a common complication of
coronary angiography and/or percutaneous coronary intervention (CAG/PCI).
Patients with ST-elevation myocardial infarction (STEMI) undergoing primary
percutaneous coronary intervention (pPCI) have a higher risk of CI-AKI.
Previous trials failed to find out the efficacy of sodium bicarbonate and
acetylcysteine in prevention of CI-AKI and outcomes following pPCI or
angiography. Although previous studies suggested the benefit of intravenous
hydration (vs. no hydration) in reducing risk of CI-AKI following pPCI, recent
systematic review suggested that the most effective regimen of intravenous
hydration has not been determined. According to the guideline for the
management of STEMI, timely reperfusion with shortest delay was the most
important for clinical outcomes, while adequate hydration is also
recommended for CI-AKI prevention in patients undergoing pPCI. Therefore,
adequate preventive hydration including pre-procedural long-term duration
conflicts shortest delay before pPCI among patients with STEMI.
MYTHOS study suggested that a loading dose (125/250 mL in short half an
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hour) of isotonic saline matched with furosemide-induced high urine output
significantly reduces the risk of CI-AKI, more effective among patients
undergoing emergent PCI, without increased risk of acute heart failure.
POSEIDON trial showed that left ventricular end-diastolic pressure (LVEDP)
guided intensive hydration in short time (4 hours) could substantially reduce
the incidence of CI-AKI and was well safety tolerated. Therefore, our
hypothesis was that aggressive intravenous hydration, including above short
intensive regimen (loading dose, post-reperfusion LVEDP guide) and
long-term maintenance, might be suitable for the special emergent condition
among STEMI patients undergoing pPCI. We designed the Aggressive
hydraTion in patients with ST-Elevation Myocardial infarction undergoing
Primary percutaneous coronary intervention to prevenT Contrast-Induced
Nephropathy (ATTEMPT) trial to investigate the efficacy and safety of the
aggressive hydration strategy in high-risk patients with STEMI undergoing
pPCI.
1. BACKGROUND
1.1 Definition, incidence, and risk factors for CI-AKI in STEMI patients
CI-AKI is defined as a decrease in kidney function following the exposure of
contrast agent1,2. Although the diagnostic criteria of CI-AKI varies in different
studies, the widely accepted definition of CI-AKI is an increase in the serum
creatinine concentration (SCr) of at least 0.5 mg/dL and/or 25% within 2-3
days of intravascular administration of contrast agent3-5.
The previous study found that CI-AKI occurred in 8.5% of with eGFR >60
ml/min/1.73 m2 undergoing non-urgent coronary angiography and 13.2% of
clinically stable Veterans with eGFR <60 ml/min/1.73 m2 undergoing
non-urgent, non-coronary angiography6. Other studies showed that up to 33%
of extremely high-risk patients develop this condition following
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contrast-enhanced procedures7.
We have made a system review which has illuminated the pivotal risk factors
for CI-AKI in STEMI patients (Figure A1). Renal insufficiency is recognized as
the principal risk factor for the development of CI-AKI, with increasing levels of
kidney dysfunction associated with incremental degree of risk8. Combined with
diabetes mellitus substantially increase the risk for CI-AKI in patients with
chronic kidney disease8-10. Patients with hypovolemia are also vulnerable to
kidney dysfunction due to iodized contrast media, as are patients with
advanced heart failure8. In both clinical states, hypovolemia and reduced renal
perfusion induced renal vasoconstriction after intravascular contrast media
administration. The risk of CI-AKI increases with the administration of contrast
agents in large quantities11, 12. It is also believed that the risk of CI-AKI after
intra-arterial contrast agent administration is greater than that of intravenous
administration. Recognition of these major risk factors helps clinicians to more
accurately determine which patients are most likely to develop CI-AKI, and
studies has been conducted to assess the effectiveness of preventive
interventions for this disease.
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Figure A1-Major risk factors for CI-AKI in STEMI patients
1.2 Association of CI-AKI with mortality
Observational studies have shown a correlation between CI-AKI (defined by
small absolute and/or relative changes in SCr) and increased short-term
mortality13-20. In a retrospective study, Levy et al. CI-AKI was found to be an
important predictor of in-hospital mortality (OR = 5.5, P < 0.001) in 183
hospitalized patients (an increase of 25% from SCr to at least 2.0 mg/dL).
Follow-up studies by McCullough et al. Among the 1,826 patients receiving
PCI, CI-AKI was found to be related with an in-hospital mortality rate of 7.1%,
compared with 1.1% in patients with no such change in SCr. (p < 0.0001)21.
Among CI-AKI patients who needed renal replacement therapy, the hospital
mortality rate was 35.7%. Many other studies reported an independent
association between CI-AKI and short-term mortality13-15, 17-19. although there is
a close relationship between small changes in SCr and short-term mortality,
most of them are retrospective analysis. Therefore, there may be deterministic
bias in assessing postoperative SCr, and there may be missing potential
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problem data13, 14, 17-19, 21. However, prospective studies confirm these findings
in the clinical study of Marenzi et al. The study found that the in-hospital
mortality of patients with CI-AKI was significantly higher than that of patients
without renal dysfunction (26% vs. 1.4%, P < 0.001)22. Maioli et al. conducted
several studies that have shown that in-hospital mortality in patients with
CI-AKI is significantly higher than that in patients without complications (11.1%
vs. 0.2%, P = 0.001)23. Therefore, data from observational studies and
randomized trials support the association between postoperative decline of
kidney function and short-term mortality.
In addition to increased short-term complications, CI-AKI has also been linked
with long-term mortality in recent studies17, 24-28. Solomon et al. demonstrated
that CI-AKI was associated with a greater than 3-fold increased risk of major
adverse outcomes (death, stroke, myocardial infarction, end-stage renal
disease requiring renal replacement therapy) at 1-year of follow up28. Four
additional studies found an independent association of CI-AKI with long-term
mortality, although the study by Roghi et al. demonstrated a trend toward
increased long-term mortality that did not reach statistical significance in
multivariable analyses17, 24, 25, 27. Collectively, these findings indicate that
CI-AKI, defined by small decrements in renal function, is associated with
adverse long-term outcomes and more compromised renal function over time.
Despite the abundance of epidemiological and experimental data associating
small changes in SCr with adverse renal and extra-renal outcomes, the
evidence remains inadequate to warrant the use of small changes in SCr as a
surrogate primary endpoint in large transformative clinical trials. Although
serious events following angiography occur as a consequence of CI-AKI, they
may also develop independent of this intermediate event, as many of the
clinical conditions that predispose patients to the development of CI-AKI (e.g.,
CKD, diabetes mellitus, heart failure) are also independently associated with
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mortality and other adverse outcomes (Figure A2). In addition, not all episodes
of CI-AKI lead to clinically consequential sequelae. For this reason, we believe
that it is most appropriate for a definitive trial of interventions for the prevention
of CI-AKI to demonstrate effectiveness in reducing serious, adverse,
patient-centered outcomes rather than merely focusing on the amelioration of
small changes in SCr. In our ATTEMPT study, the primary end point is CI-AKI,
defined as a >25% or 0.5-mg/dL increase in serum creatinine from baseline
during the first 48 to 72 hours after the procedure. Secondary end points are
as follows: (1) CI-AKI48h, defined as a >50% or 0.3-mg/dL absolute increase in
serum creatinine from baseline during the first 48 hours after the procedure; (2)
CI-AKIcysc, defined as a >10% or 0.3-mg/dL absolute increase in serum
cystatin C during the first 24 hours after the procedure; (3) contrast induced
persistence kidney injury (CI-PKI), defined as residual impairment of renal
function indicated by >25% reduction in creatinine clearance at 3 months in
comparison with baseline; (4) major adverse cardiovascular events, including
all-cause mortality, target vascular revascularization, and nonfatal myocardial
infarction; (5) post-procedural acute heart failure during hospitalization; (6)
major post-procedure in-hospital adverse clinical events, including acute
pulmonary edema, cardiogenic shock, stroke, clinically significant arrhythmias,
and bleeding within the first year; and (7) total hospitalization costs and length
of stay.
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Figure A2 – Development process of clinical adverse events exposure to
contrast agent
1.3 Prolonged hospitalization and increased costs associated with
CI-AKI
Multiple retrospective studies also focus on clarifying an association of CI-AKI
with economic benefits of health13,19,29-32. In the analysis of over 27,000
patients who underwent CAG, a rise in SCr of 0.25 - 0.5 mg/dL was associated
with prolonged hospitalization after adjusting for underlying severity of illness19.
The length of hospitalization extended with the increase of SCr gradually.
Bartholomew found that patients who developed CI-AKI after PCI were 15
times more likely to extend length of hospitalization more than four days13. In a
clinical trial comparing IV fluids for the prevention of CI-AKI, Adolph found that
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patients with a postoperative increase in SCr of ≥25% or ≥0.5 mg/dL was
associated with a mean of two days longer than patients without obvious
change of SCr29. Prolonged hospitalization results in increased healthcare
expenditures as documented in an observational study32. In the analysis of 598
diabetics with CKD undergoing CAG, CI-AKI was independently associated
with a 2-fold increase in healthcare expenditures32. Subramanian et al used a
decision analytic model to show that CI-AKI results in an average increase in
hospital-related costs of more than $10,300 and 1-year costs in excess of
$11,80031. Based on the number of CHD and cardiac catheterization
performed across the China, there may be approximately 940,000 cases of
CI-AKI nationwide. In general, these data indicate that CI-AKI is associated
with prolonged hospitalization and huge expenditure on health economics.
1.4 Pathophysiology and prevention strategies of CI-AKI in STEMI
patients
Although the pathophysiological mechanism of renal injury induced by contrast
agents has not been fully elucidated, the following mechanisms are generally
accepted: direct and indirect renal injury induced by contrast agents, and
disturbance of hemodynamic stability (Figure A3)33. Firstly, intravascular
exposure of contrast agents leads to transient systemic vasodilation, followed
by intense contractions of the renal vascular bed. Outside the vasoconstriction
in the renal medulla have particularly low baseline oxygen tension, cause the
oxygen supply and demand do not match, leading to ischemic renal tubular
damage33, 34. Secondly, direct toxic on renal tubular epithelial cells caused by
contrast agents33, 35. Thirdly, the use of contrast agents lead to reactive oxygen
species (ROS) generation, this will accelerate renal tubular cell injury33,36-38.
Patients with STEMI are likely to present with hypotension or even shock, a
large volume of contrast agent, and inability to start a kidney prophylactic
therapy, all of which are associated with an increased risk of CI-AKI. Patients
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with STEMI also commonly have other risk factors for CI-AKI such as reduced
cardiac output or hypotension due to myocardial infarction or depletion of
intravascular volume caused by vomiting, diaphoresis, or decreased oral
intake. Despite a considerable prevalence of risk factors, including reduced
LVEF, renal insufficiency, and diabetes mellitus, in patients needing adequate
hydration, cardiologists in previous studies were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; this was
related to a lack of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a certain
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Through the
understanding of the above pathogenesis, it is helpful to explore the prevention
and treatment strategy of CI-AKI in STEMI patients.
Figure A3 - Pathophysiology of CI-AKI in STEMI patients
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Renal injury induced by contrast agents may be preventable. Patients at
increased risk of CI-AKI are easily identified by the presence of known clinical
risk factors. Past efforts to find effective prevention strategies for CI-AKI have
focused on three recommendations39: 1) risk factors assessment of CI-AKI; 2)
minimization and preference of low-osmolar or iso-osmolar contrast media; 3)
adequate hydration. The incidence of CI-AKI has decreased due to the change
in the type of contrast agent over time and risk factors of CI-AKI are gradually
clarified. Recently, Jurado-Román et al40 suggested that the risk of CI-AKI after
IV administration of normal saline is 48% lower than with no IV hydration in
patients with STEMI, which is rarely performed in actual practice, when
following the guideline for the management of STEMI41. However, we still have
to be soberly aware that the optimal saline hydration strategy still remain
controversial9, 42-44.
1.5 Characteristics of randomized clinical trials on prevention of CI-AKI
under different hydration strategies of IV isotonic saline
Previous studies have focused on the optimal composition of hydration therapy.
With the publication of PRESERVE results, acetylcysteine as a component of
hydrated liquids has no obvious benefit for the prevention of CI-AKI. Therefore,
the preferred position of isotonic saline hydration in the prevention strategy of
CI-AKI hydration has been gradually consolidated. At present, the optimal
hydration strategy for the prevention of CI-AKI in high-risk patients still remain
inconclusive. We systematically review the RCT articles published in the past
few years on the prevention of CI-AKI by hydration of isotonic saline under
different guiding strategies. Nine studies were included20,40,45-51. Eight of them
showed that the hydration guidance strategy of the treatment group was better
than that of the control group without special hydration strategy. One study
showed that isotonic saline hydration had no significant benefit in preventing
CI-AKI (Table A1). The different results of nine studies suggest that the optimal
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hydration strategy of saline is still uncertain, and for high-risk patients such as
STEMI, we lack relevant research evidence. In particular, we need to focus not
only on the different effects of individualized isotonic saline hydration
strategies on preventing CI-AKI, but also to explore the optimal isotonic saline
hydration strategy that can reduce the short-term and long-term adverse
prognosis among high-risk patients such as STEMI.
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Table A1- Characteristics of randomized clinical trials on prevention of CI-AKI under different hydration strategies of IV isotonic saline
Authors Number
of
patients
Procedure Baseline renal function Definition of
CI-AKI
Hydration strategy of IV isotonic saline Frequency of
CI-AKI in isotonic
saline group
Dialysis Death
WEISBORD S
D et al
4993 Elective CAG ↑ SCr >0.5mg/dL or ≥25%
within 3-5 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
During 1-12h before angiography:1-3ml/kg/h; during angiography:1-1.5ml/kg/h ,
during a period of 2-12h after angiography:1-3ml/kg/h. hydration speed will be
adjusted if overweight.
8.3% 1.2% 2.7%
TRIVEDI H S et
al
53 Elective CAG/PCI ↑ SCr >0.5mg/dL within 2 days
of contrast exposure
↑
SCr >0.5mg/dL
1ml/kg/h, 12h before CAG/PCI for total 24h. 3.7% NA NA
BRAR S S et al 396 Elective CAG/PCI ↑ SCr ≥0.5mg/dL or ≤25%
within 1-4 days of contrast
exposure
↑ SCr
≥0.5mg/dL or
≥25%
A: LVEDP-guided volume expansion
B: Standard fluid administration protocol.
6.7%/16.3% 0.5%/2.0% 0.5%/4.0
%
JURADO-ROM
AN A et al
408 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
1 ml/kg/h since the beginning of CAG/PCI for total 24 hours. 11% 0% 2.8%
LUO Y et al 216 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
1mL/kg/h for 12 hours after CAG/PCI., the rate was reduced to 0.5 mL/kg/h in
patients with LVEF≤30% or a Killip class 2 or 3 status.
20.4% 0.93% 2.78%
MARENZI G et
al
450 Primary CAG/PCI ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
1mL/kg/h for 12 hours immediately after CAG/PCI, rate was reduced to 0.5 mL/kg/h in
patients with LVEF≤40% or NYHA III–IV.
22.7% 0.93% 2.78%
MAIOLI M et al 170 Elective CAG ↑ SCr >0.5mg/dL or ≥25%
within 3 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
A: Furosemide with matched hydration group(FMH)
B: 1 ml/kg/h (0.5ml/kg/h in case of LVEF<40%) for at least 12 h before and 12 h after
the CAG.
4.6%/18% 1.1%/4% 1.1%/4%
QIAN G et al 264 Elective CAG/PCI ↑ SCr >0.5mg/dL or >25%
within 3 days of contrast
↑
SCr >0.5mg/dL
A: CVP-guided hydration group
B: standard hydration group.
15.9%/29.5% 3.0%/9.8% 1.1%/4%
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exposure or ≥25%
NIJSSEN E C
et al
660 Elective CAG ↑ SCr >0.5mg/dL or >25%
within 2-6 days of contrast
exposure
↑
SCr >0.5mg/dL
or >25%
A: 3–4mL/kg/h during 4 h before and 4 h after contrast administration;
B: 1mL/kg/h during 12 h before and 12 h after contrast administration/No hydration
group.
2.7%/2.6% 0%/0% 0%/0.9%
CI-AKI denotes contrast induced acute kedney injury, CAG denotes coronary angiogram, NA denotes not assessed, PCI denotes percutaneous coronary intervention.
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1.6 Summary of limitations of randomized clinical trials on prevention of
CI-AKI under different hydration strategies of IV isotonic saline
AMACING study has the following limitations: Firstly, it is a single center study.
Secondly, the final number of patients participating in this study were less than
half of the planned number of patients, and the overall incidence of CI-AKI was
low. Patients with eGFR<30 mL/min/1.73 m2 were excluded. Therefore, the
efficacy of hydration therapy for the prevention of CI-AKI in high-risk patients
cannot be generalized. The main limitation of the POSEIDON study is the
exclusion of STEMI patients. Therefore, the most effective hydration strategy
for preventing CI-AKI among STEMI patients with high risk of adverse events
after PCI is still inconclusive. The PRESERVE study did not focus on the
discussion of different isotonic saline hydration strategies. In addition to
AMACING, POSEIDON and PRESERVE studies, other studies characterized
in (Table A1) were limited by being single center, unblinded and without clearly
defined allocation concealment mechanisms. Furthermore there was
inconsistent reporting of cross-over between allocated groups and the volume
of fluid received by the control arm was not reported in any study. It is also not
possible to define the most effective hydration strategy as all these studies
used different starting times, rates and durations of hydration. Further
information is expected from the ATTEMPT study evaluating the efficacy of
aggressive hydration therapy guided by LVEDP compared with general
hydration (≤500 mL) for CI-AKI following primary PCI.
1.7 Summary
CI-AKI is a common complication after exposure to iodine-contrast agents,
especially in high risk patients such as STEMI, which is closely associated with
short-term adverse events in hospital and long-term prognosis after discharge.
Isotonic saline hydration strategy has been accepted as an effective strategy for
preventing CI-AKI. After a systematic review of the existing articles comparing
different isotonic saline hydration strategy, subject-related articles are scarce
and the starting and ending time of hydration, hydration rate and total amount of
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hydration fluid remain great difference. For STEMI patients, the optimal isotonic
saline hydration strategy is still inconclusive. Combined with the above lack of
clinical evidence, we urgently need to design a clinical trial to solve this complex
but extremely important clinical problem. ATTEMPT is the first multicenter,
randomized controlled clinical trial that compare the effect of saline aggressive
hydration guided by LVEDP with general hydration on CI-AKI among STEMI
patients undergoing primary PCI. It aims to provide reliable evidence to guide
the optimal hydration strategy for STEMI patients undergoing primary PCI. If
our hypothesis is supported by the results, the aggressive hydration protocol
could be easily adopted in most cardiac intervention laboratories in China and
benefiting the vast number of STEMI patients.
2. SIGNIFICANCE OF THE PROPOSED RESEARCH
According to the latest data, the number of CHD in worldwide is about 150
million52. China has about 11 million CHD patients. Although the global mortality
rate of CHD is declining, the mortality rate of CHD in China is still increasing
year by year, especially among STEMI population. As an important measure of
diagnosis and treatment, the number of PCI in China increased to 915,256.
PCI/CT consumes about 80 million contrast agents per year worldwide and 20
million contrast agents per year in China, with an annual increase of 20-30%.
The burden of STEMI in China has become increasingly serious and has
become a major public health problem53. CI-AKI is associated with poorer
outcomes for patients, including prolongation of hospital stay and higher
mortality54. The results of our research group’s previous meta-analysis showed
that the global incidence of CI-AKI was about 8.6%. The risk in patients with
STEMI undergoing primary PCI is even greater55, with increased incidence of
CI-AKI about 29% and increased risk of death by 4.75 times. Despite a
considerable prevalence of risk factors, including reduced LVEF, renal
insufficiency, and diabetes mellitus, in patients needing adequate hydration,
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cardiologists in previous studies were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; this was
related to a lack of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a certain
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Therefore, a flexible
and individualized hydration therapy based on certain guiding strategy is
urgently needed. By determining the effectiveness of aggressive hydration with
normal saline guided by LVEDP on CI-AKI and important clinical outcomes in
patients post-STEMI comparing with general hydration, the findings of this
clinical trial will provide reliable evidence to guide the optimal hydration strategy
for STEMI patients undergoing primary PCI. What’s more, the aggressive
hydration protocol could be easily adopted in most cardiac intervention
laboratories in China and benefiting the vast number of STEMI patients.
STUDY DESIGN
3. STUDY HYPOTHESES AND OBJECTIVES
3.1 Study hypotheses
Compared to general hydration strategy, aggressive hydration (ie,
pre-procedural IV loading plus post-procedural hemodynamic-guided [LVEDP]
fluid administration) will reduce the risk of CI-AKI and long-term clinical adverse
events in STEMI patients undergoing primary PCI.
3.2 Study objectives
To assess the effectiveness of preprocedural loading dose and
postprocedural aggressive hydration with normal saline guided by LVEDP as
compared with general hydration for prevention of CI-AKI and reduction of
long-term adverse events. CI-AKI is defined as a >25% or 0.5-mg/dL increase
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in serum creatinine from baseline during the first 48 to 72 hours after PCI.
Long-term adverse events includes: all-cause mortality, target vascular
revascularization, nonfatal myocardial infarction; acute pulmonary edema,
cardiogenic shock, stroke, clinically significant arrhythmias, bleeding within the
first year, total hospitalization costs and length of stay. Our ultimate objective is
to identify optimal hydration strategy for high-risk patients with STEMI
undergoing primary PCI.
4. OVERVIEW OF STUDY DESIGN
ATTEMPT (trial registration: ClinicalTrials.gov NCT02067195) is an
investigator-initiated, multicenter, open-label, randomized controlled trial
conducted in the departments of cardiology from 15 hospitals in China. The
institutional ethics review board approved the study's design.
The study population will consist of 560 patients 18 years or older with STEMI
who undergo primary PCI and provide written informed consent for this study.
The time limit of the study is June 2014 - June 2016.Patients are excluded for
the following reasons: contrast medium administration within the previous 7
days; end-stage renal failure or renal transplantation; Inferior and/or right
ventricle myocardial infarction combined with hypotension (defined as systolic
pressure ≤90 mmHg) on admission; Preprocedural renal insufficiency (history
of chronic kidney disease or eGFR ≤60 mL/min/1.73 m2 was calculated using
the level-modified Modification of Diet in Renal Disease formula [MDRD]);
cardiogenic shock or NYHA IV; acute kidney injury defined as an absolute
serum creatinine increase of 0.5 mg/dL from baseline obtained in the previous
24 hours; lactation; pregnancy; malignant tumor or life expectancy <1 year;
allergy to contrast; periprocedural administration of nonsteroidal
anti-inflammatory drugs; aminoglycosides, cyclosporine, or cisplatin in the
previous 48 hours or during the study period; planned renal catheterization; or
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heart valve surgery.
Eligible patients are randomized using computergenerated random numbers
and a 1:1 ratio to receive either general hydration (control group) or aggressive
hydration with isotonic saline. Randomization is stratified by age (<60 years,
60-75 years,>75 years), sex (male or female), and myocardial infarction
location (anterior or not anterior). After screening for eligibility based on the
criteria, the patients who have agreed to undergo the procedure in the
emergency department or catheter laboratory are asked to provide consent and
are randomized before the primary PCI. Then, the fluid-loading dose is
administered before the procedure and continued for 30 minutes during the
procedure, if necessary; we do not wait 30 minutes to start the procedure to
avoid a delay in revascularization of the target vessel. General hydration for the
control group consists of a periprocedural continuous IV infusion of ≤500 mL
isotonic saline within 6 hours. Aggressive hydration consists of a 250-mL
loading dose of isotonic saline (125 mL for patients with congestive heart failure,
Killip II/III or NYHA III) over a 30-minutes period prior to the procedure48,
followed by IV hydration at a rate of 1 mL/kg/h (0.5 mL/kg/h for patients with
congestive heart failure, Killip II/III or NYHA III) until the LVEDP measurement.
Therefore, in the treatment group, LVEDP is measured after the primary PCI to
guide the hydration. Hydration on a sliding scale is used 4 hours after the
procedure: 5mL/kg d h for LVEDP <13 mm Hg, 3 mL/kg d h for LVEDP 13-18
mm Hg, 1.5mL/kg d h for LVEDP >18mmHg, and 0.5mL/kg d h for LVEDP >20
mm Hg. Then, hydration is continued at the normal rate until 24 hours after the
procedure45. When the LVEDP value does not agree with the heart function as
evaluated by the clinical doctors, the rate and duration of hydration are based
on the clinical evaluation for heart function and at the discretion of the
cardiologists.
Blood serum creatinine, cystatin C, C-reactive protein, and serum electrolytes
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are evaluated at baseline; before the coronary angiography; at 24 ± 4, 48 ± 4,
and 72 ± 4 hours after the procedure; and at hospital discharge. The time
between symptom onset and reperfusion, including the time at the beginning
and end of the procedure; urine output; and oral hydration volume (waterl in
milliliters) during the 24 hours after the procedure are recorded. Periprocedural
intervention (ie, fluid mixed with medications and normal saline or glucose
injection, furosemide, or statins), PCI technique, contrast agent (nonionic,
low-osmolality, or isotonic), and contrast dose are at the discretion of the
cardiologists in charge of the patient routine and procedure management,
following current practice guidelines56. Patients will be excluded if they receive
contrast again within 72 hours after the procedure57 and undergo CAG but no
PCI or dead during the procedure. All of this information is carefully collected by
the research staff.
The primary end point is CI-AKI, defined as a >25% or 0.5 mg/dL increase in
serum creatinine from baseline during the first 48 to 72 hours after the
procedure58. Secondary end points are as follows: (1) CI-AKI48h, defined as
a >50% or 0.3-mg/dL absolute increase in serum creatinine from baseline
during the first 48 hours after the procedure; (2) CI-AKIcys-c, defined as a >10%
or 0.3-mg/dL absolute increase in serum cystatin C during the first 24 hours
after the procedure59; (3) CI-PKI, defined as residual impairment of renal
function indicated by a >25% reduction in creatinine clearance at 3 months in
comparison with baseline59; (4)major adverse cardiovascular events, including
all-cause mortality, target vascular
revascularization, and nonfatal myocardial infarction; (5) major post-procedure
in-hospital adverse clinical events, including acute pulmonary edema,
cardiogenic shock, stroke, clinically significant arrhythmias, and bleeding within
the first year; (6) AHF and (7) total hospitalization costs and length of stay. A
committee of clinicians, chaired by Zhi-ming Du, MD, who are blinded to the
treatment allocation, will adjudicate all components of the primary outcome
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(CI-AKI), stent thrombosis, transient ischemic attack, stroke, target vessel
revascularization, and major bleeding.
FIGURE A4. OVERVIEW OF STUDY DESIGN
A committee of clinicians and a biostatistician, chaired by Chun Wang, MD, and
Chun-quan Ou, MS, who are blinded to the treatment allocation, will periodically
review and evaluate the accumulated study data for participant safety, study
conduct and progress, and, when appropriate, efficacy and will make
recommendations to the principal investigators concerning the continuation,
modification of enrollment, or termination of the trial. Details of any protocol
violations (eg, descriptions, reasons, and resolution) will be reported by the
investigators and clinical research associates to the primary investigators, the
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Central Event Adjudication committee, and Data and Safety Monitoring Board,
if necessary. In addition, training will be provided to the researchers, and the
study procedure will be supervised, with particular attention to the reasons for
bias and data verification to avoid recurrence of protocol violations.
Finally, intention-to-treat analysis will be used for the patients with protocol
violations instead of the per-protocol analysis. The sample size calculation was
based on our previous findings60, and a CI-AKI incidence of 23% was estimated
for the control group, and a CI-AKI incidence of 11.5% was assumed for the
treatment group (50% relative reduction). Using nQuery + nTerim 3.0
(Statistical Solutions Ltd, Farmer's Cross, Cork, Ireland) with a 2-sided χ2 test,
a significance level of 0.05, a power of 90%, and a dropout rate <20%, 280
patients are required in each group, for a total sample size of 560. The primary
outcome, that is, rate of CI-AKI, will be compared between 2 groups using χ2
tests, and the 95% CI of the rate difference will be calculated using the method
described by Altman et al (reported in Newcombe61) and recommended by the
Food and Drug Administration and Clinical and Laboratory Standards Institute.
Multivariable logistic regression models will be developed to adjust for clinical
characteristics (eg, age, sex, creatinine clearance, and left ventricular ejection
fraction [LVEF]), and the Mehran risk score will be calculated62. Odds ratios will
be reported with their corresponding 95% CIs. Comparisons between normally
distributed continuous variables, expressed as mean ± SD, will be performed
using 2-sample t tests; nonnormally distributed continuous variables, presented
as median and interquartile range, will be analyzed using Wilcoxon rank sum
tests. Pearson χ2 or Fisher exact tests will be used, as appropriate, for
categorical data, which will be expressed as percentages. The primary and
secondary end points will be analyzed based on the intention-to-treat principle.
All tests will be 2 tailed, and a P value <.05 will be considered statistically
significant. All data analyses will be performed using SAS version 9.4 (SAS
Institute, Cary, NC).
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Table A2 Timetable of visits and procedures
VisitsScreeningvisit1
Operative day
1 daysafteroperation
2 daysafteroperation
3 daysafteroperation
4-7daysafteroperation
30 ±7daysafteroperation
90 ±14daysafteroperation
180±14daysafteroperation
360±14 daysafteroperation
Informedconsent √
Inclusion/Exclusion criteria √
Baseline √
Routine bloodtest √
Liverfunction √
Renalfunction √ √ √ √ √ √3 √
Pregnancytest2 √
Characteristicsof coronaryintervention
√
Entry audit √
Randomization √
Record drugs √ √ √ √ √ √
Record AEs √ √ √ √ √3 √ √ √ √Study directorreviewsmedicalrecords
√
CRA reviewsmedicalrecords
√
Medical recordentry database √
EDC √
Medical recordreturn andfiling
√
1 Screening and random observation (1 day before direct coronary intervention)
2 Items to be tested for women of childbearing age
3 The renal function included cystatin C from the 4th to 7th day after PCI (daily evaluation: for
patients whose serum creatinine value (SCR) in 48-72 hours after PCI was higher than or equal to
0.3mg/dl than the baseline absolute value)
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METHOD
5. STUDY POPULATION AND PATIENT RECRUITMENT
5.1 Study population
The study population will consist of 560 patients, aged ≥18 years with STEMI
who provided written informed consent for this study. Since a major risk factor
for subsequent adverse clinical events following STEMI is the delay of PCI, we
will only enroll patients underwent primary PCI.41, 63
Inclusion Criteria:
All consecutive patients with STEMI, age at least 18 years, who were
candidates for primary PCI were considered for enrollment.
STEMI was defined as the onset of chest pain or chest distress lasting
for at least 30 minutes with electrocardiography(ECG) ST-segment
elevation of at least 0.2 mV in two or more contiguous leads and/or the
development of new left bundle-branch block associated with elevation
in the levels of creatinine kinase or its MB isozyme to at least two times
that of normal.46
STEMI patients who were candidates for primary PCI should meet at
least one of the following conditions: 1. Ischemic symptoms <12 h; 2.
Ischemic symptoms <12 h and contraindications to fibrinolytic therapy
irrespective of time delay from FMC; 3. Cardiogenic shock or acute
severe HF irrespective of time delay from MI onset.41
Exclusion Criteria:
Contrast medium administration within the previous 14 days or follow 72
hours,
End-stage renal failure or renal transplantation, and refuse PCI or dead
during the procedure,
Heart failure of cardiac shock or New York Heart Association class IV, (we
are excluding these patients because IV fluid administration may be
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contraindicated):
Recent acute kidney injury defined as an absolute increase of 0.5 mg/dl in
serum creatinine over baseline in the past 24h.
The presence of lactation, pregnancy,
Malignant tumor or life expectancy less than 1 year,
Allergy to contrast medium, peri-procedural receipt of metformin or
non-steroidal anti-inflammatory drugs in the past 48h and during the study
period,
Planned renal catheterization or heart valvular surgery.
5.2 Screening and patient recruitment
All the potentially eligible patients will be screened out by the chief resident of
the department of cardiology. Then, the chief resident will dial the “ATTEMPT
phone” to report the initial situation of the patient to the ATTEMPT research
personnel on-duty, who must arrive within 15 minutes (for those who are unable
to arrive in time, he/she must contact other members to follow up). Researchers
will contact potentially eligible subjects to describe the study and complete the
screening process. Based on our past experience, almost all the patients
intended to undergo primary PCI will have a SCr measured as part of routine
care before angiography. However due to the urgency, we are unable to get the
result of pre-procedure renal function before angiography. In such situation, for
the majority of patients who do not have a SCr measured before, we can only
exclude them after PCI if they were proven to suffer end-stage renal failure.
Patients with no peri-operative creatinine were found to be excluded after
randomization. We will also require that potentially eligible female subjects who
are able to be pregnant (not considered post-menopausal [had a menstrual
period within previous 12 months], not had tubal ligation, a hysterectomy or
bilateral oophorectomy) and are sexually active, have a negative pregnancy
test before being enrolled in the research. No adult patient (age ≥18 years) will
be excluded from participating based on age, gender, race, ethnicity, or sexual
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preference.
6. STUDY PROCEDURES
6.1 Assessment of pre-procedural laboratory examinations
Eligible patients will have their SCr measured before angiography, which will
serve as their baseline SCr. At present, the methods for detecting SCr mainly
include basic picric acid method (Jaffe assay) and enzymatic assay. The
enzymatic assay avoids the poor specificity of the Jaffe assay and has a strong
anti-interference ability. Therefore, it is widely accepted as the most reliable
assay in the clinical laboratories. All laboratories in our study are consistently
adopting this methodology to reliably and accurately assess the development of
CI-AKI. The timing of the pre-procedure study SCr (baseline SCr) testing used
to assess the outcomes is also important as the administration of IV fluids may
lead to hemodilution and artifactual lowering of SCr. In addition, variation in
intravascular volume status affects renal function, particularly in patients with
underlying CKD. Therefore, we will standardize the timing of assessment of the
baseline SCr for endpoint ascertainment. This blood sample will be drew at the
same time of patient enrollment and immediately prior to the beginning of study
IV fluids to avoid any potential influence of study interventions on the baseline
SCr level. Although STEMI patients will have some basic laboratory
examinations as soon as they reach the emergency department or a few
minutes after the chest pain onset if it happens in hospital, some examinations
are not routine for such patients, such as cystatin C, hypersensitive C-reactive
protein and so on. For these variables, to make sure that they are not affected
by the interventions, the research personnel needs to check whether the
relevant blood tests of the patient had been done before the intervention
(cystatin C, hypersensitive C-reactive protein, cardiac enzyme, emergency
biochemistry, blood routine). If there is any omission of these tests, the
research personnel needs to make a prescription and asks the nurse completes
the blood draw before the intervention begins.
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6.2 Randomization procedures
All patients meeting eligibility criteria and providing informed consent will be
randomized to each of the two study groups [general hydration (control group)
versus aggressive hydration with isotonic saline (treatment group)]. Qualified
patients are randomized using computer-generated random numbers at a 1:1
ratio. Randomization will be accomplished using a block random method with 8
units in each group. Some offset or variability will be inserted to prevent
anticipation of the next treatment. Randomization will be stratified by sex, age
and anterior myocardial infarction. Study coordinators at each site will be
responsible for obtaining a randomized treatment assignment for each eligible
patient. A web-based randomization program will be provided to study sites for
this purpose. This web-based program will be tested at each site prior to the
start of the trial and will be reviewed, as per Center guidelines, by the Key
Laboratory of Coronary Heart Disease. At the time of subject enrollment,
research personnel will enter the Subject ID number, sex, age and anterior
myocardial infarction into the randomization program. The program will check
that all eligibility criteria are met. If met, the program will select the first unused
entry from the pre-specified list of random treatment assignments for the
particular site. The lists are stored on a secure server at Southern Medical
University, Department of Biostatistics, Clinical Research Management System.
If the electronic system fails, the random envelope method will be adopted. The
random envelope method is to store a random grouping scheme of a numbered
research object in a sealed and opaque envelope, which is performed in two
steps:1) verifying whether the patient meets the criteria for inclusion and
exclusion, signing informed consent, and giving the case number; 2)
Disassemble the random envelopes of the corresponding numbers in order,
determine the grouping of a patient according to the distribution plan in the
envelope, and carry out corresponding interventions. Since this is an open-label
study, we do not have the procedure of blinding.
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6.3 Study interventions
In this study, patients will receive either general hydration (control group) or
aggressive hydration with isotonic saline guided by LVEDP (intervention group)
Control group:
The general hydration for the control group is a peri-procedural continuous
intravenous infusion of ≤500 mL isotonic saline within 6h.
Treatment group:
The aggressive hydration consists of a 250mL loading dose of isotonic saline
(125 mL for patients with congestive heart failure, Killip II/III) over 30 min prior
to procedure,48 followed by IV hydration at the rate of 1 mL/kg/h (0.5 mL/kg/h for
patients with congestive heart failure, Killip II/III) until the LVEDP measurement,
which were performed after the coronary revascularization. Hydration on a
sliding-scale is used 4 h after the procedure: 5 mL/kg·h for LVEDP <13 mmHg,
3 mL/kg·h for LVEDP 13–18 mmHg, 1.5 mL/kg·h for LVEDP >18 mmHg, and
0.5 mL/kg·h for LVEDP >20 mmHg. Then, hydration is continued at the normal
rate until the 24 h after the procedure reaches.45 When the LVEDP value does
not agree with the heart function as evaluated by the clinical doctors, the rate
and duration of hydration is based on the clinical evaluation for heart function
and at the discretion of the cardiologists.
In the treatment group, we will use LVEDP to guide hydration within 4 hours
after the procedure. At the end of the procedure, the research personnel will
remind the operators to make an LVEDP measurement before the catheter is
withdrawn. Although LVEDP is a more objective indicator of left ventricular
volume, it cannot be used to diagnose whether a patient has heart failure or
not.64 Therefore, when the LVEDP value does not agree with the heart function
as evaluated by the clinical doctors, the rate and duration of hydration is based
on the clinical evaluation for heart function and at the discretion of the
cardiologists. In addition, some sub-centers may not be able to measure
LVEDP for several reasons. In this case, we allow the clinicians to estimate
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LVEDP based on the patient's situation and to determine the hydration strategy
within 4 hours after the procedure. We chose this flexible approach rather than
a strict protocol for IV fluid administration for several reasons. First, though
there is a general belief that “more fluid” may be dangerous for HF patients, the
optimal rate, duration, and volume of IV fluid to prevent CI-AKI and other
adverse outcomes for HF patients have not been conclusively determined.
Therefore, the rate and duration of hydration is based on the clinical evaluation
for heart function and at the discretion of the cardiologists. Second, since
LVEDP have not been determined as a golden standard for making hydration
strategy, requiring that IV fluids be administered strictly based on LVEDP could
significantly limit other medical workers` willingness to help. In clinical practice,
the volume and duration of pre and post-procedure IV fluid often vary based on
the clinical setting and individual patient circumstances. We do not believe that
using this flexible approach will compromise our ability to determine differences
in study outcomes between two groups.
6.4 Peri-procedural management issues
Drug prescription and blood collection time points are strictly in accordance with
the protocol, clinical guidelines and clinical reality. Though all contrast media
may cause potential clinical complications, the osmolality of the contrast agent
is proven to potentially impact the risk for CI-AKI. Previous conclusively
demonstrate that high osmolality (>1200 mOsm/kg) agents pose a greater risk
for CI-AKI than low osmolality (500-860 mOsm/kg) agents in high-risk
patients.65, 66 However, data on the comparative incidence of CI-AKI with
low-osmolal contrast and iso-osmolal are on dept and inconclusive. To provide
care that is consistent with prior guidelines issued by the American College of
Cardiology/American Heart Association for the use of iodinated contrast, all
patients in this trial will receive either iso-osmolal contrast media (i.e., iodixanol)
or non-ionic, low-osmolal contrast media.67 Usage of the specific contrast agent
and the volume of contrast media administered will be at the discretion of the
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operator as there is no current guideline or consensus on the least nephrotoxic
contrast agent.
Accompanying medications and invasive treatment device, for example IABP,
are also source of potentially nephrotoxicity.68 Aminoglycosides or any other
drugs with significant nephrotoxicity are strictly prohibited. Patients are
recommended to have statin therapy preoperatively. The implication of
perioperative platelet glycoprotein IIb/IIIa receptor antagonists--Ikat (Iroko
Cardio Australia Pty Ltd), the use of loop diuretics and other drugs that are not
prohibited in this study will be at the discretion of the treating provider according
to the condition and treatment routine. We will also defer decisions on the
discontinuation of angiotensin converting enzyme inhibitors or angiotensin
receptor blockers to the treating provider(s) because there are no conclusive
data on the optimal approach to the management of these medications in
patients with STEMI undergoing angiography.
6.5 Post-procedure management issues
Drug prescription and blood collection time points are strictly in accordance with
the protocol, clinical guidelines and clinical reality. Following angiography,
research personnel will follow the patient to cardiac care unit (CCU) and reset
the hydration speed to routine level 4 hours after the procedure. Research
personnel are also required to communicate with the patient's responsible
nurse and ask he/she to record the patient's postoperative liquid intake
(including oral and intravenous) as well as the liquid output (mainly urine
volume) in detail (time and volume). Following angiography and prior to
discharge from the hospital, research personnel will also arrange the
participant`s blood specimen collection at 24, 48 and 72 ± 4 hours following
their angiography.
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6.6 Study Outcomes
6.6.1Primary study outcome
The primary endpoint is CI-AKI, defined as a ≥ 25% or 0.5 mg/dL absolute
increase in serum creatinine from baseline during the first 48-72 h
post-procedure.
6.6.2 Secondary study outcomes
The secondary outcomes consist of:
1) CI-AKI, defined as a >50% or 0.3-mg/dL absolute increase in serum
creatinine from baseline during the first 48 h post-procedure;
2) CI-AKI, defined as a 0.3-mg/dL absolute increase in serum creatinine from
baseline during the first 48 h post-procedure and a 10% increase in cystatin-C
during the first 24h post-procedure; 58
3) Persistent renal damage, defined as residual impairment of renal function
indicated by a >25% reduction in creatinine clearance at 3 months in
comparison with baseline;59
4) Major adverse cardiovascular events, including all-cause mortality, target
vascular revascularization, and non-fatal myocardial infarction;
Table A3 - Definitions of components of MACEs
Term Definition
All-cause mortality All cause mortality, defined as any death recorded between
the date of interview and the end of data.
Target vascular
revascularization (TVR)
TVR is defined as any revascularization procedure (PCI or
CABG) involving the vessel treated during the index PCI
procedure for STEMI.
Non-fatal myocardial
infarction
Recurrent MI will be subdivided into MI within the first 24 h of
randomization, between 24 h and 7 d after randomization,
and >7 d after randomization.
MI occurring
between 24 h
Recurrent ischemic symptoms >20 min with
new ST elevation >0.1 mV in ≥2 contiguous
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and 7 d of
randomization
leads not due to changes from evolution of
the index MI. Ischemic symptoms >20 min
and either 1) elevation or re-elevation of
cardiac biomarkers(CK-MB or troponin)
greater than twice the upper limit of normal
(ULN) and if already elevated, then further
elevations >50% above a previous value
that was decreasing or 2) new ST-segment
elevation or new significant Q waves in ≥2
contiguous leads, which are separate from
the baseline MI.
MI occurring
after 7 d of
randomization
Typical rise and fall of biochemical markers
of myocardial necrosis to greater than twice
the ULN or if markers were already
elevated, further elevation of a marker
to >50% of a previous value that was
decreasing and >2× ULN, with ≥ 1 of the
following: 1) ischemic symptoms, 2)
development of new pathologic Q waves, or
3) ECG changes of new ischemia or (iv)
pathologic evidence of MI.
MI occurring
within 24 h
after nonindex
PCI that is
performed >24
h after
randomization
Cardiac biomarker (creatine kinase-MB
[CK-MB] or troponin) >3× the ULN or
increased by 50% from the preprocedural
valley level and ≥3 times ULN in patients
with already elevated enzymes or new
ST-segment elevation or development of
significant Q waves in ≥2 contiguous leads,
which are discrete from baseline MI.
Within 24 h CK-MB (or total CK, if CK-MB is
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post-CABG unavailable) ≥5× ULN and increased 50%
from the preprocedural valley level and N
5× ULN in patients with already elevated
enzymes and development new pathologic
Q waves in ≥2 contiguous leads or CK-MB
value ≥10 times ULN without new
pathologic Q waves.
6) Major post-procedure in-hospital adverse clinical events, including acute
pulmonary edema, cardiogenic shock, stroke, clinically significant arrhythmias,
and bleeding.
Table A4 - Definitions of components of major post-procedure in-hospital
adverse clinical events
Term Definition
Acute pulmonary edema Acute pulmonary edema, defined as arterial partial pressure
of oxygen (PaO2)/inspired oxygen fraction (FiO2) ratio <300
for arterial blood gas, and pulmonary edema or bilateral
infiltrates on chest radiograph as read by radiologists, both
within 24 h.
Cardiogenic shock Cardiogenic shock is defined as systolic blood pressure <90
mmHg not responsive to fluid resuscitation and/or heart rate
correction for ≥1 h or need for vas opressor/inotropic therapy
to maintain systolic blood pressure >90 mm Hg for ≥1 h and
believed to be secondary to cardiac dysfunction and
associated with ≥1 of the following: 1) signs of pulmonary
edema, 2) signs of hypoperfusion (cool clammy skin, oliguria,
or altered sensiorium), or 3) cardiac index <2.2 L/min.
In patients presenting with cardiogenic shock at the time of
randomization, they must have a ≥24 h period with complete
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resolution of shock and a new cardiogenic shock event (ie,
due to new stent thrombosis) for this event to be eligible as a
primary outcome event.
Stroke Any stroke is defined as the presence of a new focal
neurologic deficit thought to be vascular in origin, with signs
or symptoms lasting >24 h. It is strongly recommended (but
not required) that an imaging procedure such as a computed
tomography or magnetic resonance imaging be performed.
Clinically significant
arrhythmias
Clinically significant arrhythmias (SA) were defined as 1 or
more of the following: more than 100 VPC or APC (including
VPC2/3 or APC2/3) per 24 h (equalling a rate of 4.17/h) or any
presence of RT, VT, or AT.
Bleeding Major bleeding or vascular events (bleeding requiring
transfusion of hemoglobin drop ≥3 g/dL or need for vascular
surgery).
6.7 Data collection
6.7.1 Assessment of baseline demographic and clinical characteristics
Following patient enrollment, research personnel will make a comprehensive
review of the electronic medical record and/or interview the subject and his/her
families to abstract the following data elements:
Demographic characteristics including date of birth, gender and ethnicity
Admission information including
Time of symptoms onset
Time of first medical contact (FMC)
Time of admission
Time of entering catheterization laboratory
Did thrombolytic therapy be used in this case? (If it did, then the time of
thrombolytic therapy should be recorded)
Did cardiac arrest happen in this case? (If it did, then the time should be
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recorded)
Did heart failure happen in this case?
Heart function (Killip class)
Use of vasoactive drugs
Use of IABP
Administration of any IV fluid and prior to the initiation of study
Pre-procedure laboratory parameters obtained as part of routine clinical care
including date of test (most proximate to and within the 7 days preceding the
angiogram:
ɸ CK, CKMB, troponin T, troponin I, hsCRP, NT-proBNP or BNP, WBC, Hb,
PLT, Hct, Neut%, SCr, Cystatin C, serum glucose, sodium, potassium, blood
urea nitrogen and pregnancy examination (if available)
medical history:
ɸ Hypertension, diabetes, hyperlipidemia, coronary artery disease (CAD),
myocardial infarction (if available, the happening time should be record),
congestive heart failure, peripheral vascular disease, chronic kidney disease,
stroke and chronic pulmonary disease. Standard procedures and definitions will
be developed to systematically evaluate patients records for each of these
conditions.
Family history of CAD
Smoking history
Physical examination, including:
1) Height in centimeter and weight in kilograms. The recommended
method of obtaining the patient`s height and weight will be for research
personnel to measure them. In the event this is not possible, the most recent
measurement (usually at the time of admission) found in the patients medical
record will be recorded. Finally, if there is no measurement in the medical
record, this information will be collected via subject report.
2) Blood pressure and heart rate at the time of admission.
3) Physical examination record on chest (including heart and lung),
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abdomen, nervous system, limbs and spinal.
Pre-procedure ECG and cardiac ultrasound (if available)
Names and doses of all pre-procedure medications, including those
prescribed by physicians outside the research centers, regularly taken by
the subject within the 14 days preceding the angiogram.
6.7.2 Collection of oral hydration and urine volume within 24h post-procedure
Research personnel will communicate with and hand over a specially designed
chart to the patient's responsible nurse and ask he/she to record the patient's
postoperative liquid intake (oral) as well as the liquid output (mainly urine
volume) in detail (time and volume) within 24h post-procedure. We will collect
the chart later.
6.7.3 Evaluation of procedure-related data
Subsequent to the angiogram, research personnel will review the electronic
medical record and angiogram procedure report to determine:
Primary PCI or not;
The beginning and ending time of procedure;
The time of balloon dilation
Type and volume of contrast administered (Iodixanol, Iopromide, Iopamidol
or iohexol)
The use of GPIIb/IIIa Inhibitors
The implication of thrombus aspiration
The implication of IABP
Post-procedure LVEDP
Coronary artery lesions and performance of percutaneous intervention
Complications during the procedure including:
Hypotension or cardiac shock necessitating the administration of
additional non-study IV fluid including the type of non-study IV fluid
administered
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Hypotension or cardiac shock necessitating the insertion of an
intra-aortic balloon pump and/or the administration of vasopressor
therapy
Arrhythmia
Death
Any new accompany medications
Assessment of procedure-related complications will ensure that we capture all
events that could impact on the development of our primary and secondary
outcomes. To clarify and confirm all of these procedure-related data, research
personnel will also organized a brief interview with the angiography operators.
6.7.4 Evaluation of study IV fluid administration
Research personnel will track and record from the electronic medical record the
speed, total volume and total duration of study IV fluid administered
pre-procedure, intra-procedure, and post-procedure.
6.7.5 Evaluation of post-procedure course (within 24 ± 4 hours post procedure)
Research personnel will review the electronic record and collect the following
data elements:
Vital signs within 6h and at 24 hours post-procedure;
Renal function assessment and blood electrolytes and the date of test (If
the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72
hours post-procedure, the renal function of the subjects was monitored until
1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Performance of additional contrast exposure including coronary or
non-coronary angiography or computed tomography with intravascular
iodinated contrast;
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6.7.6 Evaluation of post-procedure course (48 ± 4 hours post procedure)
Research personnel will review the electronic record and collect the following
data elements:
Vital signs at 48 hours post-procedure;
Renal function assessment, hsCRP and blood electrolytes and the date of
test (If the serum creatinine (SCr) increased by more than 0.3 mg/dL within
72 hours post-procedure, the renal function of the subjects was monitored
until 1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Performance of additional contrast exposure including coronary or
non-coronary angiography or computed tomography with intravascular
iodinated contrast;
Cardiac and Carotid Ultrasound and the date of test (if available);
Any new accompany medications
6.7.7 Evaluation of post-procedure course (72 ± 4 hours post procedure)
Research personnel will review the electronic record and collect the following
data elements:
Vital signs at 72 hours post-procedure;
Renal function assessment, hsCRP and blood electrolytes and the date of
test (If the serum creatinine (SCr) increased by more than 0.3 mg/dL within
72 hours post-procedure, the renal function of the subjects was monitored
until 1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Performance of additional contrast exposure including coronary or
non-coronary angiography or computed tomography with intravascular
iodinated contrast;
Any new accompany medications
Since this creatinine determination is essential to the determined of primary
end-point, it is very important that the blood collection be done within the 72
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hours after angiography. We recognize that unforeseen circumstances may
hinder collection within this window. Under such circumstances the blood
should be collected as soon as possible and most proximate to 72 hours and a
protocol deviation should be noted.
6.7.8 Evaluation of post-procedure hospitalization course (4 – 7 days post
procedure and the day of discharge)
Research personnel will review the electronic record on a daily basis for
patients who remain in the hospital following their angiography procedure and
collect the following data elements:
Vital signs have collected for once among 4-7 days post-procedure;
Renal function assessment, hsCRP and blood electrolytes and the date of
test (If the serum creatinine (SCr) increased by more than 0.3 mg/dL within
72 hours post-procedure, the renal function of the subjects was monitored
until 1 week after operation);
Episodes of primary end point or any major adverse cardiovascular events;
Any new accompany medications
Date of discharge and total hospitalization expenses
Generally speaking, subjects will only have one examination during this period.
For those who have vital signs or renal assessment for many times, we will
record the highest level of each day.
6.9.9 Day 30 post procedure assessment (30 days post angiography, allowable
range 23-37 days post angiography)
Thirty days following the angiography, clinical doctors will review the electronic
medical record (if available) and perform a telephone interview with the patient
to inquire about any adverse events they experienced related to study
participation. The electronic medical record review and telephone interview will
specifically focus on assessing the renal function and the development of any of
the following adverse outcome within the research sites system.
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Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
Bleeding
Heart broken
The 30-day telephone interview with the patient will be a supplement to the
electronic medical record review. This telephone interview will verify data
abstracted from the electronic medical record and enable research personnel to
inquire about death, re-hospitalizations at non-research sites and other MACEs
that would not have been captured in the electronic medical record. For any
patients who were hospitalized outside the research centers, the research
personnel will obtain the hospitalization information from the patient or his/her
families.
To ensure the follow-up quality, before the first time of telephone interviews,
research personnel assistants will help researchers to arrange the follow-up
method and time.
During the telephone interview:
Recording and judgment of events
In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in details.
And then, they will submit the record to the research personnel who will make
the judgment later.
Quality control
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After the start of follow-up, the quality control team needs to check the follow-up
form and EDC regularly (not less than two times a week). Research personnel
assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
We recommend that this contact should be made at 30 days after angiography,
with an allowable range of 30±7 days. We recognize that sometimes it may be
difficult to contact with a patient within this window. However, it is important to
collect the required data, which should be done even if done after the
recommended time frame has elapsed. It will not be considered a protocol
deviation as long as the required data are collected and there is progress note
documenting the attempt to schedule the data collection during the
recommended time frame.
6.7.10 Day 90 post procedure assessment (90 days post angiography,
allowable range 90 ± 14 days post angiography)
Ninety days following the angiography, research personnel assistants will
review the electronic medical record (if available) and perform a telephone
interview with the patient to inquire about any adverse events they experienced
related to study participation. The electronic medical record review and
telephone interview will specifically focus on assessing the renal function and
the development of any of the following adverse outcome within the research
sites system.
Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
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Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
Bleeding
Heart broken
The 90-day telephone interview with the patient will be a complement to the
electronic medical record review. This telephone interview will verify data that
was abstracted from the electronic medical record and enable research
personnel to inquire about death, re-hospitalizations at non-research sites and
other MACEs that would not have been captured in the electronic medical
record. For any patients who were hospitalized outside the research centers,
the research personnel will obtain the hospitalization information from the
patient or his/her family.
During the telephone interview:
Recording and judgment of events
In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in details.
And then, they will submit the record to the research personnel who will make
the judgment later.
Quality control
After the start of follow-up, the quality control team needs to check the follow-up
form and EDC regularly (not less than two times a week). Research personnel
assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
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We recommend that this contact should be made at 90 days after angiography,
with an allowable range of 90 ± 14 days. We recognize that sometimes it may
be difficult to contact with a patient within this window. However, it is important
to collect the required data, which should be done even if done after the
recommended time frame has elapsed. It will not be considered a protocol
deviation as long as the required data are collected and there is progress note
documenting the attempt to schedule the data collection during the
recommended time frame.
6.7.11 Day 180 post procedure assessment (180 days post angiography,
allowable range 180±14 days post angiography)
180 days following the angiography, research personnel assistants will review
the electronic medical record (if available) and perform a telephone interview
with the patient to inquire about any adverse events they experienced related to
study participation. The electronic medical record review and telephone
interview will specifically focus on assessing the renal function and the
development of any of the following adverse outcome within the research sites
system.
Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
Bleeding
Heart broken
The 180-day telephone interview with the patient will be a complement to the
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electronic medical record review. This telephone interview will verify data that
was abstracted from the electronic medical record and enable research
personnel to inquire about death, re-hospitalizations at non-research sites and
other MACEs that would not have been captured in the electronic medical
record. For any patients who were hospitalized outside the research centers,
the research personnel will obtain the hospitalization information from the
patient or his/her family.
During the telephone interview:
Recording and judgment of events
In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in details.
And then, they will submit the record to the research personnel who will make
the judgment later.
Quality control
After the start of follow-up, the quality control team needs to check the follow-up
form and EDC regularly (not less than two times a week). Research personnel
assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
We recommend that this contact should be made at 180 days after angiography,
with an allowable range of 180±14 days. We recognize that sometimes it may
be difficult to contact with a patient within this window. However, it is important
to collect the required data, which should be done even if done after the
recommended time frame has elapsed. It will not be considered a protocol
deviation as long as the required data are collected and there is progress note
documenting the attempt to schedule the data collection during the
recommended time frame.
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6.7.12 1 year post procedure assessment (1 year post angiography, allowable
range 1 year ±14 days post angiography)
1 year following the angiography, research personnel assistants will review the
electronic medical record (if available) and perform a telephone interview with
the patient to inquire about any adverse events they experienced related to
study participation. The electronic medical record review will specifically focus
on assessing the renal function and the development of any of the following
adverse outcome within the research sites system.
Vital signs and renal function assessment (if available)
Renal replacement therapy
All-cause mortality
Target vascular revascularization
Non-fatal myocardial infarction
Acute heart failure
Cardiogenic shock
Stroke
Clinically significant arrhythmias
Bleeding
Heart broken
The 1-year telephone interview with the patient will be a complement to the
electronic medical record review. This telephone interview will verify data that
was abstracted from the electronic medical record and enable research
personnel to inquire about death, re-hospitalizations at non-research sites and
other MACEs that would not have been captured in the electronic medical
record. For any patients who were hospitalized outside the research centers,
the research personnel will obtain the hospitalization information from the
patient or his/her family.
During the telephone interview:
Recording and judgment of events
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In the course of follow-up, once considering the events probably occur to the
subjects, research personnel assistants will record the relevant events in details.
And then, they will submit the record to the research personnel who will make
the judgment later.
Quality control
After the start of follow-up, the quality control team needs to check the follow-up
form and EDC regularly (not less than two times a week). Research personnel
assistants who fail to reach the standard will repeat the training and
assessment work, and those who fail three times will be replaced by more
suitable personnel.
Lost to follow-up control
We will control the number of missing calls by dialing the lost calls again,
inquiring the hospital system or the public security system, etc.
We recommend that this contact should be made at 1 year after angiography,
with an allowable range of 1 year ±14 days. We recognize that sometimes it
may be difficult to contact with a patient within this window. However, it is
important to collect the required data, which should be done even if done after
the recommended time frame has elapsed. It will not be considered a protocol
deviation as long as the required data are collected and there is progress note
documenting the attempt to schedule the data collection during the
recommended time frame.
7. POTENTIAL RISKS AND ALTERNATIVE CONSIDERATIONS
7.1 Study Population
Most past studies of CI-AKI have focused on all patients undergoing coronary
angiography. We propose enrolling STEMI patients only. Patients with STEMI
are likely to present with hypotension or even shock, a large volume of contrast
agent, and inability to start a kidney prophylactic therapy, all of which are
associated with an increased risk of CI-AKI. Patients with STEMI also
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commonly have other risk factors for CI-AKI such as reduced cardiac output or
hypotension due to myocardial infarction or depletion of intravascular volume
caused by vomiting, diaphoresis, or decreased oral intake. Despite a
considerable prevalence of risk factors, including reduced LVEF, renal
insufficiency, and diabetes mellitus, in patients needing adequate hydration,
cardiologists in previous studies were primarily concerned with rapid
revascularization for occluded culprit arteries instead of adequate
preprocedural hydration to prevent CI-AKI in patients with STEMI; this was
related to a lack of information regarding baseline kidney function and related
medical history. Conversely, excessive hydration of saline without a certain
guiding strategy may exceed the impaired cardiac tolerance in STEMI patients,
thus increasing the risk of cardiac function deterioration. Therefore, a flexible
and individualized hydration therapy based on certain guiding strategy is
urgently needed. While limiting the enrollment to STEMI patients will restrict the
number of patients available for recruitment and the generalizability of the study
findings, it will increase the homogeneity, find out the optimal hydration
administration regimen in these high-risk patients69 and fill in gaps in guidelines.
7.2 Study interventions
7.2.1 Fluid administration
There is no consensus among experts on the optimal rate and duration of IV
fluid administration for the prevention of CI-AKI or single protocol for the
administration of IV fluid that has been shown to be the most effective.
Nowadays, in CHINA, most PCI center do not pay attention to CI-AKI, and
prescribe hydration with no regimen but a bag of 500ml saline which is exactly
used to maintain the venous channel. Generally speaking, it is well-accepted
that hydration is effective in preventing CI-AKI but there is no consensus on
how to make hydration.70 Therefore, we conduct a comparison between
aggressive hydration and the reality to find out a more suitable regimen in these
high-risk patients.
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7.2.2 Complications of fluid administration
We anticipate that some patients will develop volume overload/pulmonary
edema during angiography. In such instances, providers performing
angiography may discontinue post-procedure IV fluids resulting in patients
failing to receive the planned hydration regimen following the angiogram. It is
likely that this event will occur in a small proportion of patients and be equally
distributed across treatment arms. While the volume of study IV fluid
administered pre, during and post-procedure will be carefully recorded for all
patients, given the importance of patient safety, we believe it would be
inappropriate to require the administration of post-procedure study IV fluid in
such instances. Since all analyses will be based on the intent-to-treat principle,
these patients will not be excluded from the study analyses.
7.3 Ascertainment of baseline kidney function
In order to ascertain a change in kidney function, it is critical to standardize the
definition of baseline kidney function. SCr often fluctuates over time because of
activities, variations in volume status, protein and salt intake, and drift in the
calibration of laboratory instruments. The timing of the SCr testing used to
screen patients is less critical than the value used to define the baseline SCr for
endpoint ascertainment. For practical purposes, we propose to screen patients
based on a SCr obtained as part of routine clinical care performed by the doctor
as soon as the subject enter the emergency department or cardiac
catheterization laboratory. The SCr was sent for examination after PCI. This will
also be the same pre-angiography study SCr (baseline SCr) that will be used to
assess the development of CI-AKI (a primary endpoint).
7.4 Assessment of primary and secondary outcomes
7.4.1 Assessment of CI-AKI
Most patients who develop CI-AKI will have their SCr increased within 48 to 72
hours following contrast exposure. However, previous studies demonstrate that
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some patients who develop CI-AKI may not be identified by a single SCr
assessment at 48 hours.43 The optimal timing of assessment of SCr following
the angiogram to determine the development of CI-AKI in our trial was carefully
discussed by the committee members. Finally, though complicated, it was
agreed that multiple SCr assessments (e.g., at 24, 48 and 72 hours) would
ensure the identification of all patients who developed CI-AKI. This decision is
based on several reasons. First, some patients who develop CI-AKI may
manifest an increase in SCr at 24-48 hours following angiography. Second,
multiple SCr assessments may describe the trend of SCr after contrast
exposure. Finally, the planning committee feel that measuring SCr at multiple
time points may be of help in finding the most suitable definition of CI-AKI.
7.4.2 Assessment of cardiovascular outcomes and clinical events
We acknowledge the potential limitations of using administrative data/medical
records for the assessment of cardiovascular outcomes and clinical events,
including all-cause mortality, target vascular revascularization (TVR), non-fatal
MI, acute pulmonary edema, cardiogenic shock, stroke, clinically significant
arrhythmias and bleeding. Therefore, we will also assess these outcomes by
reviewing the hospital discharge summary for documentation of any of the
events that comprise the secondary outcomes. We have considered the
possibility of adjudicating the secondary outcomes using more comprehensive
medical record review. However, we believe that while this would be a more
robust approach, the additional time, effort and cost required to adjudicate
these secondary outcomes using a comprehensive review of the medical
record was not justified.
7.5 Secular trends in the prevention and incidence of CI-AKI
We acknowledge that there will be novel viewpoints gained and changes in
clinical practices related to the prevention of CI-AKI and serious adverse
outcomes following angiography during the conduct of the current trial. A
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comparison between the incidence of CI-AKI reported in studies conducted in
the 1980s and the incidence described in recent studies reveals a trend that
fewer patients are suffering this iatrogenic complication. However, much of this
trend is likely related to the transition from the more nephrotoxic high-osmolal
contrast media to low and iso-osmolal contrast media. Over the past decade,
there is no evidence of a continued decline in the incidence of CI-AKI or
attenuation in the relationship between CI-AKI and serious, adverse outcomes.
This can be illustrated by a recent study of over 1,100 hospitalized subjects who
underwent contrast-enhanced procedures that demonstrated that CI-AKI
developed in over 40% of patients and was associated with a 2-fold increase in
hospital duration and a 10-fold increase in mortality.18
8. FEASIBILITY OF RECRUITMENT
While our inclusion and exclusion criteria are strict, there are multiple important
factors that support the feasibility of recruiting this large number of patients.
First, all the 15 research centers involved in this project are the regional central
hospitals. The Guangdong Cardiovascular Institute/Guangdong Provincial
People's Hospital, which is in charge of this study, is the most influential
research and prevention centers of cardiovascular diseases in South China. It
is one of the leading coronary intervention therapy centers in China with about
971 primary PCI finished last year. It also participates in the compilation of
“Expert Consensus of STEMI Treatment in China”. Second, patients
undergoing primary coronary angiography are easily identifiable. All of these
procedures are started under the coordination of the chief resident of the
department of cardiology, which greatly facilitates identification and screening
of potential study subjects. Third, unlike trials that recruit from a diverse array of
patient settings (e.g., primary care offices, hospital wards, specialty clinics), our
trial mostly recruit patients from only one hospital venues: emergency
department. This greatly simplifies the process of identifying and locating
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potentials participants. Fourth, we have set up a special project management
team, which is directly in charge of the project.
The full-time academic secretary coordinates the management of assets, data
and research results in the process of project implementation. Finally, patient
burden in this study is quite limited since there is no need to return to the
hospital for study visits. Follow up data collection will be performed using
telephone calls. Therefore, patients are unlikely to view participation as unduly
burdensome. All in all, we are highly confident in our capacity to successfully
recruit the number of patients needed to meet our enrollment targets.
9. ANTICIPATED BARRIERS TO RECRUITMENT ANDSTRATEGIES TO ADDRESS POTENTIAL UNDERENROLLMENT
9.1 Development of comprehensive organizational structure
Despite the feasibility of recruitment as outlined above, successful enrollment of
the number of patients we hope to enroll and compliance with the study protocol
will depend on the interest and willingness of chief residents and interventional
cardiologists. We recognize that these practitioners may not be focused on or
necessarily prioritize the prevention of CI-AKI and its associated outcomes,
especially since they are often not involved in the longitudinal care of patients
and may not be notified of delayed complications of angiography. We believe
that comprehensive organizational structure at each site will ease providers’
burden and optimize the potential for successful subject enrollment and
implication. What is more, we believe that the flexibility built into the protocol for
study IV fluid administration rates, volumes, and duration will be attractive to
providers performing angiography and will increase their interest and
willingness to have their patients participate in the study.
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9.2 Strategies to address under-recruitment of study subjects
Given the relatively large size of our study and the critical importance of
adequate patient recruitment, we anticipate using a number of strategies to
address under-recruitment should it occur. First, during the process of
calculating the sample size, we have taken into account these relevant
problems and enlarged the target number by 20%. Second, in addition to
Guangdong Provincial People`s Hospital, which conduct nearly 400 primary
PCI yearly, we also include another 14 study sites that mostly are the regional
central hospitals. We believe that having these two strategies to address
potential under-enrollment will help ensure the attainment of the target sample
size without compromising the scientific integrity of the study.
10. PROPOSED ANCILLARY STUDY
In addition to the primary study, we are also proposing to conduct an ancillary
study to follow patients for up to 10 years to track renal and cardiovascular
outcomes and mortality.
The specific aims of the proposed study are as follows:
Specific aim 1: To generate and track long-term clinical outcomes in a
matched cohort of patients participating in the ATTEMPT trial with and without
CIN.
Specific aim 2: To assess whether the development of CIN following
angiography is independently associated with serious, adverse, long-term renal
outcomes (i.e., accelerated rate of decline in kidney function and development
of end-stage renal disease), cardiovascular outcomes (i.e., cardiac,
cerebrovascular, peripheral arterial events) and mortality.
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11. HUMAN SUBJECTS
11.1 Informed consent
Potentially eligible patients will be identified by chief residents and research
personnel at each site. After the study is introduced to the patient by an
individual participating in their care, research personnel will contact potentially
eligible subjects and their legal agent to describe the study and present him/her
with the detailed informed consent form and supplementary material to read
and review.
The general purpose of the study will be delineated and the treatment
comparisons will be clearly described. The process of randomization will be
discussed and a clear explanation of what will be expected of the patient will
also be described. The risks associated with treatments and procedures will
also be addressed. The importance of patient confidentiality will be stressed,
including a description of the process for maintaining patient confidentiality.
Research personnel will ensure that the patient understands every aspect of
the trial, including its risks and benefits, prior to signing the informed consent. If
the patient agrees, his/her consent to participate in the study will be
documented. The original will be placed in the patient's medical record.
Informed consent requires that the patient understand the details of the study
and agree, without coercion, to participate in the study. To obtain informed
consent, the following information shall be provided to each subject:
Name of the study
Name of the Principal or Site Investigator(s)
Explanation that the study involves research
Explanation of the purpose of the study
Explanation of the treatment procedures
Description of randomization
Description of the risks and benefits of participation in the study
Explanation that all records will be kept confidential
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Whom to contact for questions about the research and about subjects' rights
A statement that participation in the study is voluntary and that a decision
not to participate or to withdraw from the study after initially agreeing involves
no penalty, loss of benefits, or reduction in access to medical care.
A statement that the examinations and treatments provided as part of this
study are mostly clinical routine and will be paid by subject himself.
Merely obtaining signed consent from the patient does not constitute informed
consent. However, the use of a standardized consent form aids in assuring that
subjects receive adequate and consistent information about the trial and that
they have consented to participate.
11.2 Risks and benefits
Any procedure/intervention has potential risks. The interventions used in this
study may cause all, some, or none of the risks and side effects listed. There is
also the potential for rare or unknown risks to occur. Active study participants
will be informed of any information that becomes known during the course of
the study regarding risks of the interventions that might affect their willingness
to continue to participate.
11.2.1 Side effects associated with infusion of intravenous fluids
Reactions due to solution or technique of administration: febrile response,
infection at the site of injection, venous thrombosis or phlebitis extending from
the site of injection, and extravasation of fluids
11.2.2 Side effects associated with infusion of sodium chloride
Cardiovascular: heart failure (aggravated), edema Endocrine and metabolic:
hypernatremia, hyperosmolarity, hypokalemia, metabolic acidosis Respiratory:
pulmonary edema
Possible benefits of this study include a reduced risk of serious adverse
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outcomes, including death, need for acute dialysis, and persistent decline in
kidney function among subjects receiving aggressive hydration.
12. DATA MANAGEMENT
12.1 Source file management
Source documents comprise of source data, include hospital records, clinical
and office charts, laboratory notes, memoranda, subjects diaries or evaluation
checklists, recorded data from automated instruments, microfiches,
photographic negatives, microfilm or magnetic media, x-rays, subject files, and
records kept at the laboratories, and at medico-technical departments involved
in the clinical trial, including certified copies or transcripts. Source files can be
paper and/or electronic. The original document in the clinical trial refers to the
document that records the clinical observation for the first time, such as the
written record of the trial process, the therapy prescribed by the researcher, the
informed consent form, etc.; or the file contains the laboratory examination and
the image examination data, such as Blood routine examination report, CT, etc.
There are paper and electronic forms or other available forms. When the
original is unfavorable for preservation, inconvenient to obtain or lost, a verified
copy (identical to the original recorded information and produced with a dated
signature or a verifiable procedure, shall be reasonable to explain) would be
saved as a source file.
12.2 Data collection
12.2.1 The source data were recorded and modified according to categories
(objective data and subjective data) during the implementation process.
Objective data is usually generated directly from the testing equipment,
instruments or other tools. When the test sample is read by the instrument or
device, the result data or images, such as blood routine examination, blood
biochemistry, electrocardiogram, test atlas, pathological image, photographs of
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the body lesions, body temperature, X-ray film, CT film or electronic images,
etc.
Subjective data refers to data for artificial observation and evaluation, including
data judged and recorded by the investigator, or data generated by the
subject's own records, such as a history review (eg, part of medical history,
medication history which cannot trace back by investigator are recorded
according to the subject's statement), oral hydration table, urine table, subject
log record, oral medication record, etc. Prior to the trial enrollment, proper
training or guidance are provided to the recorder, records should be timely, and
indicate the signature and date to avoid recall bias; ensure that the collection
and recording of such data is real and standardized.
Researchers and sponsors should take effective measures to ensure the
quality of data generation and recording, which shall be completed by
qualified personnel according to study protocol. As for correction, the original
content should be retained and marked with strikeout, new content and the
name of the modified person, the reason and the date of the modification shall
be annotated beside. The modification of the electronic document should
ensure that the audit track is kept in the backstage for future reference, and
keep relevant records and explanation of data modification.
12.2.2 Methods of data collection will be listed during the study, such as paper
or electronic CRF (eCRF), name and version of the data
acquisition/management system, Describe the permission control plan of the
system user, or provide corresponding information in the form of attachments,
including permission definition, allocation, monitoring, and measures or
methods to prevent unauthorized operations, authority revocation, and so on.
The data acquisition/management system should have the functions of audit
trail, security management, authority control and data backup, and pass the
complete system verification.
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12.2.3 CRF record
When filling in the CRF, the person who fills in does the self-examination with
out additional verification. The clinical research associate verify the source data
at the research center to ensure the accuracy of the clinical research data
originally. Proper training will be provided to the investigator or research
coordinator before the study begins. To help the staff at research center fill in
the CRF or eCRF with real, standardized, complete, and accurate data, the
data manager must provide a guidance document that help filling in the CRF
(usually referred as the CRF Completion Guide).
12.2.4 Staff training
After the study is approved, the main research center and the Key Laboratory of
Coronary Heart Disease will prepare the Investigator's Operation Manual, CRF
Guideline, eCRF Entry Guideline, and Training Schedule to guide the site staff's
operation and management, including data collection, data entry, etc. The
training will be conducted at the Investigator Initiative to train all research
fellows and clinical research coordinators to ensure data collection, data entry
consistency, traceability, completeness, and accuracy.
During the research period, all the data management will be trained by the
subject matter expert (SME), including external resource experts (software
developer engineers, training consultants, etc). The content and method of the
training are approved by the research conductor, and the accuracy of the
content must be approved by the SME. The research training is perform by
means of centralized training, online training and on-the-job training. All training
shall be tested afterward to understand the effectiveness of training timely, so
that to identify and rectify problems in the training. After the training, the training
conductor shall centrally archive the content, time, place of the training, trainee
list and the signature records.
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12.3 Electronic data entry
After the data management department receives the paper CRF from the
researcher, the necessary signature and registration record shall be made. The
primary task of data management is to enter the CRF data into the database as
soon as possible. As for the training of data entry staff, make sure to familiarize
themselves with the data entry system, entering screen settings and schedules,
and also enter test data to ensure their work is accurate and reliable before the
official data entry.
Prior to electronic data entry, a well-trained professional will perform manual
verification to identify abnormal data on paper CRF, including unclear writing,
non-compliance with research protocols, missing data, medically unreasonable
data, and inconsistent data. Once a problem is found, it should immediately
contact the investigator and ask for clarification. Specifically the verification
content include but not limited to:
1) Check if the received CRF uses the latest version.
2) Check the CRF for missing pages
3) Check if the CRF has a subject code.
4) Check if the CRF is filled in with the required ink and whether it is clearly
visible.
5) Check if CRF is damaged.
6) Check if all CRFs have the researcher signature and date.
Electronic data entry and management is the responsibility of the data manager
of the statistical department in Key Laboratory of Coronary Heart Disease. EDC
database is adopted for electronic data entry. Electronic data is entered by
trained specialist. If problems or unexpected situations are found during the
entry process, they should be recorded and reported to the project's data
administrator for prompt solution. As for the unidentified data, data
managers(statisticians and data administrators) discuss each other and require
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researchers to clarify with queries when data is cleaned up.
Quality control will be taken during electronic data entry:
1) Strengthen training: In order to improve the quality of data entry, it is
necessary to strengthen the training of data entry personnel.
2) Data quality control: Quality control of the entered data ensures that the
entered data is at an acceptable level.
3) Identify problems in time: If problems are found during the entry process,
they should be recorded and reported timely.
4)Establish a quality inspection system: After the data entry is completed,
some CRFs are randomly or irregularly checked to understand the quality of
the entry, analyze and deal with the problems of data entry. Electronic data
Entry is generally completed within 2 weeks since the CRF check.
12.4 Data Verification and Query
Before the data verification, a detailed Data Validation Plan (DVP) should be
made to clarify the content, method and verification requirements of the data
verification. Data verification is completed by data manager, auditors, medical
personnel and statisticians together.
The abnormal data is generally found through source data monitor, manual
inspection before entry, logic check by computer system, database check, and
analysis report of summary statistical analysis. The main content of data
verification is to check the CRF filling quality, check the data validity, integrity,
logic and compliance of the data. The methods of data review include manual
review and computer review.
1) Manual review is mainly used to check abnormal data that is not easily
checked by computer programs, such as CRF fill quality, CRF header
information (such as subject code or CRF page number).
2) Computer review, mainly use the data logic check performed by the
computer system.
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The following review methods will be used in accordance with the content of the
research data reviewed: source data verification, database data verification
(including logic verification), summary statistics, and CRF-database verification.
The problems found in the research data review are mainly through internal and
external solutions. The internal solution is mainly based on comparing the data
of other parts of the CRF to make a judgment, and finally solve the problem,
mainly by the internal data administrator. The external solution to the "problem"
is mainly solved by the data administrator in the form of DCF (Data Challenge
Form) to obtain the difference data.
For issues with universality found in data review, specific issues such as
revisions to research protocols, revisions to CRF completion guidelines, or
enhanced training for researchers should be addressed. Research centers that
violate research programs should strengthen audits and recommend
improvements within a limited time. When the aggregated descriptive statistics
reveal significant differences between the data of a research center and other
units (such as reporting too many or too few adverse events), audits of research
centers and researchers should also be strengthened.
The problem data that the data administrator cannot solve through the internal
problem needs to be solved in an external way in time, that is, the problem is
solved by sending the data clarification table or the data challenge table to the
researcher (following ICH GCP [5.5.3(b)] The requester answers or interprets
the question on the challenge form and returns the DCF to the data
administrator. The challenge form is hand-made by the data administrator, and
each question table has its own unique identity. It is convenient to check the
status of the question list to prevent the missing.
After the challenge table is generated, the data administrator needs to compare
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the data on the CRF table with the data in the database again to determine
whether the challenge table is reasonable and valid. If the problem data of the
challenge form is reasonable, send the research center/investigator to clarify. If
the problem data on the challenge form is an error caused by data entry, or if
the logic check program is improperly set, the question form is not required to
be sent to the research center/investigator.
After receiving the question form issued by the Data Management Center of the
Key Laboratory of Coronary Heart Disease, the researcher should reply to the
question and sign the question according to the question on the question form
and check the original data, such as the inpatient medical record and the
laboratory test record. And the date of signing. After the photocopy of the
question form is saved with the CRF in the file file of the research center, the
original is returned to the data management center.
After the challenge form is returned to the data management center, the
recipient needs to record the date received on the challenge form and forward it
to the project data administrator. The data administrator will solve the problem
based on the information provided by the researcher on the challenge form, if
the researcher replies. If you are reasonably satisfied, close the challenge. If
the researcher's answer is unreasonable or leads to the generation of additional
problem data, the data administrator needs to raise another question and ask
the researcher to clarify again until the problem is solved. Regardless of the
form in which the question form is generated, the data management center
should have a means of recording and tracking the challenge form.
12.5 EDC design and Establish
For this study, the EDC designer will create a research-specific database and
design and define the CRF table through the user interface to facilitate data
entry, cleanup, review, export, and reporting. The database will be designed
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with the following main considerations in mind:
1) Must comply with the research program process to facilitate data entry.
2) The data export style is comprehensive and complete, easy to analyze
statistically and meet the requirements of statisticians or programmers.
3) The data can be relatively inspected in the data management system to
find the “problem” data in time.
4) Should conform to the database creation theory.
5) Should meet the requirements of the database application software.
The research database will adopt a standardized database structure to store
data, ensuring that the fields in the data table are the most basic elements.
From a database perspective, data types involve numeric data types, date and
time data types, and character data types.
The database needs to support the establishment of logic verification (subject
to the development process of the computer program: logic inspection
requirements, development, testing, production environment application and
change control, etc.), check the entered data to find the "problem" data, so that
Data administrators or auditors review and clean up to improve data quality.
12.6 Research Database environment and operation requirement
The system should be installed in a safe physical environment. The security of
the physical environment can generally be guaranteed by the following
measures: restriction, recording and monitoring of the contact person of the
carrier; dual power supply or UPS; shockproof, fireproof, waterproof, heatproof
and moisture proof ( Non-subjective); vandalism, anti-theft (subjective), etc. The
network environment of the system, that is, the environment in which the
electronic network for data transmission (such as the Internet or local area
network) is located, should also be secured. Generally, it can be guaranteed by
the following measures: establishing a firewall or other hardware and software
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to prevent viruses, Trojans, hackers, etc. Spyware intrusion.
System servers and their databases should prioritize remote or offsite backups
to ensure system continuity and data security. When this is not possible, you
should use an offline backup device to periodically back up and take away the
physical environment of the online backup. If the EDC system is interrupted due
to force majeure or uncontrollable factors, the EDC supplier shall have a
corresponding emergency plan and return the normal operation of the EDC
system in the shortest time according to the server and database backup.
At present, the system adopts dual hot security backup to ensure the absolute
information security of all projects, independently run the hard disk and the
backup hard disk, and synchronize the data in real time to ensure uninterrupted
data access. Use Linux system scripts to back up the latest data in time to
ensure data is absolutely secure. The latest backup hard disk data, daily
incremental synchronization of local data, so that data is foolproof.
12.7 Research data assess authority
The EDC system should have user management, role management and rights
management function modules. All users of the EDC system must have a
unique username and password combination. The password must be stored
encrypted in the system. Both the service provider and the user of the EDC
system should establish an SOP to manage EDC services, operations and
maintenance, and follow the SOP in actual use and management. All records of
the execution or implementation of the SOP are archived for reference.
Access to study data is limited to individuals who have been approved by key
laboratories for coronary heart disease. Individuals must have appropriately
qualified researchers and be compliant with information security awareness
training and confidentiality agreements. All personnel who need access to
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research data are required to receive SOP training on the management and
use of their authority. In addition, the permissions of the electronic system are
structured, and users in a single research center can only see data from their
research participants and cannot view or access data from other clinical
research centers or other participants.
When a user no longer needs a certain permission, this permission should be
revoked in time. When the account is changed, the reason for the change and
the process and requirements of the change should be stated. When the user
forgets the password, the process of requesting a new password is recorded
and explained. When the user leaves the research center, all the user's
permissions are revoked, but the user name, inspection traces and other
information are still retained. Once the username is disabled, it should not be
used again.
To ensure system security and monitoring, the following measures will be
taken:
1) The system automatically logs out after 10 minutes when the user has no
activity.
2) Unauthorized access is recorded in the system log, which is checked
periodically by the system administrator.
3) The user must keep the password and cannot share it.
4) Users cannot log in or work with other users.
5) Check of expired/disabled accounts.
12.8 Data safety strategy
The clinical research data of this study belongs to the property of the
cooperative research project. It may not be sent outside the research center
without the written permission of the person in charge of the key laboratory of
coronary heart disease. It will strictly abide by the main research unit, key
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laboratory for coronary heart disease, cooperative research projects and
various research. All data transmission and data security policies of the Center.
The head of the Key Laboratory of Coronary Heart Disease will work with the
research centers in accordance with the signed agreements to ensure proper
handling of data security and data transmission.
12.9 Data Storage and archive
In the course of this study, regardless of the collection method, clinical
research data will enter the research database, so ensuring the security,
integrity and accessibility of data is the main purpose of data preservation. The
principle of preservation of raw data and original documents (such as case
report forms and electronic documents) is that their safety must be guaranteed.
Paper documents and electronic documents should be kept in a secure room or
file cabinet and have strict access control rights to prevent unauthorized access.
After receiving the paper documents, they should be scanned and saved the
electronic files as much as possible. The backup files should be kept in different
places. The electronic data of the research is mainly stored in the database
server, and its security (such as the firewall of the computer) should also be
guaranteed.
The preservation and archiving of clinical data are for different periods of
clinical research, but their purpose is the same, that is, to ensure the security,
accuracy, completeness and accessibility of data/files.
Article 49 of the State Food and Drug Administration General Administration of
Quality Control of Drug Clinical Trials stipulates that the materials in clinical
trials shall be kept and managed as required. The investigator should save the
clinical trial data until five years after the termination of the clinical trial. The ICH
GCP requires at least two years of storage. This study will comply with the
above requirements and will also follow the basic requirements of the following
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archives:
1) The archiving of research data needs to be planned and arranged.
2) The content and format of the research data should meet the
requirements of industry standards and regulatory agencies.
3) Archived data should be secure during the specified data retention
period to prevent damage.
4) The responsibility for the archiving work, the division of labor and the
archiving procedures should be clear.
5) The saved records are periodically checked after archiving to ensure
their accuracy, completeness, accessibility and durability.
6) The archived data should have a central directory.
7) After the important upgrade of the clinical research data
acquisition/management system, the archived electronic data accessibility
should be tested.
8) The original data (such as CRF with the signature and signature date of
the researcher, CRF correction documents, etc.) should be archived in the
research documents of the key laboratory of coronary heart disease or kept in
an off-site archive.
9) The archive of the research document should indicate the hardware,
software and its version used.
In addition, clinical research data is archived to ensure that archiving meets the
requirements of the main research unit, research organization, and regulatory
requirements. The research data key laboratory of coronary heart disease will
completely retain the database until the primary and secondary analysis is
completed. After the analysis is completed, the research data will be
de-identified and stored indefinitely. The research records of the local research
center may not be destroyed without the written permission of the Key
Laboratory of Coronary Heart Disease.
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13. QUALITY CONTROL
13.1 Qualified Measurement/Confirmation
This study will, as far as possible, harmonize the qualifications, qualifications,
clinical work experience, etc. of the physicians involved in the treatment to
ensure the consistency of their research methods. Before the start of the study,
the research center researchers and clinical research coordinators will hold a
meeting review. Research procedures and training in research data collection.
Before starting the meeting, send the research plan, implementation plan, and
execution SOP to each research center and related personnel, collect opinions
from all parties, and confirm the modifications, and organize all participants of
the research center (main researcher, researcher, and research coordinator). ,
research inspectors) accept research programs, research data collection
training; training is conducted during the start-up meeting of each center
research, for research doctors, clinical research coordinators, etc. to obtain and
maintain preservation source documents, and complete research evaluation,
CRF fill out , EDC entry and other content training, strict confirmation of the
entry criteria, through oral or written feedback and discussion, to ensure that
the research doctors and clinical research coordinators understand and clarify
the research assessment, the meeting also on the relevant variables, laboratory
tests normal range, each The implementation characteristics of the Center were
thoroughly reviewed and discussed, and training was strengthened to develop
operational reference guides for each center.
Before the start of the study, the laboratory qualification certificates of each
center and the normal range of laboratory tests were reviewed and confirmed to
prevent research bias.
13.2 Patients Management
For the subjects of the project, the investigator of each clinical research and
testing center will be responsible for the management of the subjects enrolled,
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keeping the patient's personal information confidential, and paying attention to
the patient's health during the study, in the informed consent form. The
researcher's contact information corresponding to each sub-center is attached,
and the patient can contact the researcher at any time to make the patient's
safety secure. For patients who are unable to return to the original center for
follow-up and blood samples, the participants of the participating centers will
conduct telephone follow-ups and answer questions about the patients'
questions. They should try to adapt to the patient's schedule and safety issues.
13.3 Protocol deviation
Any program deviations need to be recorded, and the Key Laboratory of
Coronary Heart Disease will create a program deviation table to ensure that
events are tracked correctly. The deviation from the program will be evaluated
by the Key Laboratory of Coronary Heart Disease and the effectiveness of the
deviation basis will be determined. Any medical center or subject who has a
program deviation in the absence of a valid reason, and after training in
remedial training, is recommended to terminate it to the Data Monitoring
Committee (DMC) if any member of the DMC or the Inspectorate believes If the
compliance program will impair the health of the subject, the subject's rights
should be prioritized and the subject should be withdrawn from the study after
consultation with the Executive Committee and the program will be reported to
the main research unit IRB as required.
13.4 Randomized control of study treatment
This clinical study is a multicenter, randomized, controlled trial that requires the
necessary uniform standard treatment of routine clinical interventions at
participating centers to rule out confounding due to inconsistent intervention
criteria. Randomized system of the Department of Statistics of Southern
Medical University to ensure random objectivity and reduce selection bias.
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13.5 Monitoring and quality control
In order to ensure the uniform and high quality of multi-center participants, the
clinical monitoring group will conduct quality control on the research according
to the audit plan formulated by the Guangdong Provincial Key Laboratory of
Coronary Heart Disease, including but not limited to:
1) Monitoring frequency and report
The first audit was conducted within one week after the first subject was
enrolled;
In the enrollment and follow-up phase (refers to the first case of the center
to be screened to all subjects in the center), the audit is conducted once a
month, and the window period of the two allowed audits is within ±60 days. That
is, the last audit date is January 1, 2016, and the next audit can be scheduled
from February 28, 2016 to March 3, 2016. The actual visit date of the audit
report must be the same as the registration date in the central visit registration
form. For centers that are concentrated in the group and faster in the group, the
CRA and PM applications can adjust the monitoring frequency to 2 weeks in the
concentration stage of the group;
The frequency of the audit can be adjusted based on the speed of the center's
entry or the problems found in the center. If the audit plan is changed, please
explain it in the audit report.
The trial initiation visit must be performed prior to screening the patient
The last time the audit activity must be before the data is locked; if there are
any remaining problems before the data lock library, all problems must be
resolved before the audit can be terminated;
End of trial visit will be performed after the data is locked.
2) Monitoring visit report and project management report
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Monitoring visit report:
All problems found in the audit and not resolved and their action plans must be
reflected in the audit report; the audit report must be sent to the project
execution leader within 7 working days after the audit occurs;
Site visit report:
The center enrollment stage (the center enrollment stage means that the first
subject of the center is screened to complete the enrollment of all subjects in
the center), and the auditor reports the basic information and progress of the
study to the project execution leader every week;
Central treatment stage (central treatment stage refers to completion of all
subjects in the center to complete completion of treatment of all subjects in the
center) and central follow-up stage (central follow-up stage to all subjects in the
center after completion of treatment after follow-up period to this All subjects in
the center are grouped and reported to the project executive responsible every
4 weeks.
Project team internal project meeting
Project enrollment stage (refers to the first subject of the project to screen all
subjects of the project to complete the group completion): The auditor holds a
conference call with the project execution leader every 4 weeks; the specific
time is notified by the project team;
During the project follow-up phase (the project follow-up phase means that all
subjects in the project are completed in the group until all subjects in the project
are out of the group): the internal meetings of the project team are held
monthly;
For the project in the center according to the program development and the
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subject's rights and interests, the auditor needs to promptly feedback to the
project team. For issues that have significant impact, it needs to be reported to
the project executive person within 1 working day after the knowledge is
obtained.
3) Staff training
Auditor training:
Initial training
The training of the project team will be arranged before the start of the
research center, including training in programs, systems and processes, which
will ensure the smooth start of the project;
A team member's training was conducted prior to the conference, including
research background, program introduction, ICF management, verification
considerations, project management and entry plan, data management and
EDC profile
Training during the research process
According to the EDC verification situation, the DM summarizes the EDC
entry and common questioning common problems, and the project manager will
share the training of the project team at the project meeting.
According to the audit of the sponsor, etc., the project team summarizes the
problems found, and the project supervisors share the training of the project
team at the project meeting.
For newly joined project team members, the project will arrange relevant
content such as program and process training before undertaking the project
task. Training is generally conducted on-site or on a conference call.
Personnel handover occurred in the project. The project manager handed
over the SOP according to the project team to ensure the smooth handover of
personnel, and systematic training of the new CRA before the handover. The
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training was generally conducted by on-site training or conference call.
Add additional training as appropriate.
Research Center Staff Training:
The auditor responsible for each center will provide training to the staff of
the research center at the start-up meeting, CRF filling and testing procedures.
When the first subject is screened or enrolled, the CRA needs to assist and
confirm that the research is familiar with the research process, such as timely
training and reminders.
4) eCRF fill in / enter
The CRF is filled in/entered by the designated personnel of the research
center according to the filling instructions. All patients enrolled need to complete
CRF, including rejection of the patient.
Even if you withdraw from the case, you will need to complete the “Completion
Study Page”.
Each case with signed informed consent needs to be registered in the
screening and enrollment form, including screening for losers.
5) Verification of original data (SDV plan)
Part 1: Important parameters
100% raw data verification for all patients with the following parameters:
1) Informed consent form
Whether the patient's signature and date appear on the informed consent
form;
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Whether the patient signature date is before the start of any research
procedure;
Whether the name and date of the doctor who informed the informed
consent are signed;
The researcher's contact number must be a telephone that can be
contacted 24 hours a day;
Whether the date of signing by the researcher is the same day as the
patient;
Ensure that the version of the informed consent form signed by the subject
is correct;
It is recommended that the pen used by the doctor's signature be as
different as possible from the patient;
Informed consent forms for screening losers must also be kept;
- Record on the original record when the patient has signed an informed
consent form and obtained an original.
Part II: Initial Quality Control
1) After the first 5 patients are enrolled, the rest of the SDV needs to be done in
addition to the above, in order to ensure that the original record is complete, the
program is followed, and the eCRF is correctly filled in/entered.
2) In addition to the content mentioned in the first section, the following should
be verified at each visit:
Is the follow-up time recorded on the CRF consistent with the original
medical record?
Changes in vital signs and laboratory tests after baseline
The laboratory tests required in each program are completed; and any
clinical test abnormalities are recorded and explained in the CRF.
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Patient diary (hydration table)
Part III: Quality Control in Progress
100% SDV is required during the trial.
If the investigator is replaced during the trial, the auditor will then review the
data of the first two patients enrolled by the new investigator.
If many problems are found in the trial, discuss it with the investigator and
not resolve it.
Part IV: Screening failure
The original medical records failed to reflect the reasons for the screening
failure, and the original records must be saved.
Part V: Original Data Verification Record
The researcher must keep all original medical records in the research
center.
The auditor needs to record the important findings of SDV, how to solve it
and the next steps in the audit report. At the same time, feedback these findings
to the researchers and let them correct them in time.
13.6 Participation Center trial/terminate
The research chair and the key laboratory for coronary heart disease will
assess the participation in the hospital. Only hospitals that meet the
corresponding indicators can participate in the study:
1) The hospital has the relevant equipment and technology needed for the
project:
2) Have sufficient patient source that meets the criteria for entry and exit:
meet at least 10 patients with acute myocardial infarction each month;
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3) Have sufficient human resources in line with standards: have doctors who
can qualify for such diseases, and receive training for the project. More than 2
doctors are responsible for this project;
During the implementation process, the recruitment rate and operational
aspects of the study are continuously monitored. If the research center is in the
trial stage, it will face the following reasons including but not limited to violation
of the program, violation of GCP or related regulations, and project quality
requirements.
The risk of terminating the study.
1) Recruitment rate: divide the number of randomized patients by the
expected number of patients, calculate the recruitment rate, and continuously
monitor the indicator during the research. If the recruitment process is slow, if
there is no randomization in February, the center will receive remediation and
reassess. If the plan is not included in the plan, it will enter the probation period
and be evaluated every 2 months.
2) Follow-up rate: The number of patients in any follow-up window was
divided by the number of patients expected to follow the window, and the
follow-up rate was calculated. Both the numerator and the denominator were
delayed for 4 weeks to schedule a visit to the corresponding follow-up window
and complete the form. Study centers with a cumulative follow-up rate of less
than 90% will enter the probationary period and will be assessed every 2
months.
3) Form Completion Rate: The table completion rate is calculated by
dividing the number of completed forms by the number of expected forms,
where the expected number of forms will be sent out as a "not collected" form.
The table completion rate will be calculated according to the patient and the
form. Research centers with a cumulative follow-up rate of less than 90% will
enter the probationary period and will be assessed every 2 months.
Once the research center enters the probationary period, failure to meet the
requirements of the end of the probationary period will result in the proposed
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termination of the study. In addition, those that do not meet the above
requirements, or one of which will not meet the standard after rectification and
remediation, will face the termination of the trial. In addition, after the relevant
performance evaluation of the research center in the key laboratory of coronary
heart disease, if it is considered unsuitable for continuing research, the
research center can be terminated without a formal trial period.
14.GOOD CLINICAL PRACTICE AND RESEARCH CENTERSREVIEW PROJECTS
This study will be conducted in accordance with the Good Clinical Practice
(GCP) for Drug Clinical Trials. During the study period, the research centers
participating in the research will be monitored according to the monitoring plan.
The Research Center Monitoring Team will visit all participating research
centers at least once in accordance with the GCP. The purpose of these visits
is to ensure that trials are performed, documented, and reported in accordance
with research protocols, standard operating procedures (SOPs), clinical trial
quality management practices (GCP), and applicable regulatory requirements.
The auditor will examine the patient study files, including x-rays,
electrocardiograms, and other source files. Particular attention is paid to patient
informed consent, protocol compliance, ethics committee approval, and
researcher folders. After the interview, the monitoring visit report is prepared
and forwarded to the research center researcher and research leader.
In addition to the review visits scheduled by the sponsors, an independent,
comprehensive research center audit can be conducted at any time, as
required by the research management or research center.
All in all, the audit team will do the following:
1) Provide comprehensive research execution tools to the research center,
including important research requirements in the folder catalog, templates, and
source files to help the research center better implement the research program
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and meet the requirements of the GCP regulations.
2) Regular visits to participating research centers and provide GCP training
and enhancement at the kick-off meeting.
3) Conduct a review visit to each participating center at least annually to
monitor the compliance, program compliance, and overall research design
performed by the investigator.
4) A comprehensive review of the final year of the study to ensure that all
research tasks and related documentation are completed.
15. RESEARCH MONITORING AND AUDIT PLANS
Protecting patients' rights and benefits is a major concern for key coronary
heart disease laboratories. This study will be conducted in accordance with the
local laws of the ICH-GCP, the Helsinki Declaration and the quality
management practices for drug clinical trials.
15.1 Monitoring agency
The study will oversee the scientific and ethical nature of the research through
four external agencies, including the Data Monitoring Committee (DMC), the
Ethics Committee (IRB), the Independent Incidents Committee (CEC), and the
Clinical Monitoring Agency.
15.1.1 Data monitoring committee
The Data Monitoring Board (DMC) will independently monitor and make
recommendations on clinical research processes, safety data, and progress.
(DMC) consists of members of the relevant professional field (meteologists,
cardiology, and clinical research specialists) who regularly evaluate cumulative
data from ongoing clinical trials, including those who have participated or who
will be recruited into the trial. The safety of the tester, the study implementation,
scientific and the integrity of the research data. The DMC will assess the
progress of the enrollment of the subject and make recommendations to the
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sponsor, proceeding as planned, continuing or terminating or suspending trials
in one or all of the groups. In the future, it can be adjusted according to the
actual rate of the experiment and the incidence of the event.
15.1.2 Ethics Committee
The Ethics Committee (IEC) provides expert ethics and scientific review of
multi-center projects while ensuring solve local problems in each research
center. The Key Laboratory Center for Coronary Heart Diseases conducts a
comprehensive, rapid and ongoing review, and the investigator (PI) first
submits applications, including research protocols, informed consent, and so on.
Once approved, the application materials will be sent to all possible research
centers, and the local research center researchers (LSI) will submit the
application to the ethics committee. After approval, a copy of the research
center approval document will be provided to the key laboratory for coronary
heart disease for backup. During the study period, communication between the
participating centers and the IEC shall be recorded or documented. All
participating centers in the study conducted an annual ethical review.
15.1.3 Clinical Events Committee
The Clinical Event Committee (CEC) will be responsible for determining the
endpoints in clinical studies and avoiding deviations in event determination
between centers and centers in order to achieve a more accurate assessment
of test results. CEC is an independent committee of three research field experts
independent of research sponsors and researchers. Its primary responsibility is
to combine clinical expertise and protocols based on uniform definition criteria
for all endpoint events in the study. In the relevant content, the objective
judgment of the end point event is made to see if it meets the definition criteria.
The frequency of this study review will be determined based on the incidence of
enrollment plans and endpoint events.
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Suspected
endpoint
Researcher
evaluation
Audit - source
file collection
Source file
submitted to CEC
CEC regular
evaluation Evaluation result
CECquery data
confirm
Data verification and
analysis
Consistency
comparisoneCRF data
collection
Submit to data
department
Figure A5 - CEC review process
The CEC Secretariat will be responsible for the production and regular updating
and maintenance of the CEC Review Folder. The CEC Review Folder will store
all documents related to CEC content, including CEC member information,
confidentiality agreements, review source files and review results.
15.1.4 Clinical monitoring team
Clinical monitors will ensure that trials are performed, documented, and
reported in accordance with research protocols, standard operating procedures
(SOPs), clinical trial quality management practices (GCP), and applicable
regulatory requirements. The audit is usually scheduled by the monitor and the
investigator and/or other participants prior to the first patient enrollment.
According to the research project, the inspection is usually carried out every
four to six weeks, but the interval between inspections can be extended or
shortened due to the difference in research period and schedule. The clinical
monitor will ensure that the submitted data is accurate and consistent with the
source document; verify that the subject's informed consent has been correctly
obtained and recorded; that the study participants in the enrolled study meet
the inclusion and exclusion criteria; and that the drug is ensured. All basic
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documentation guidelines required by the clinical trial quality management
practices are properly documented.
The auditor will conduct a visit to the research center before the study begins.
At the time of the visit, they will discuss the way the subjects/patients are
recruited, the completion of the case report form and the next management
procedures. In addition, it should be discussed and agreed to: the investigator's
assessment of the program's understanding, his or her obligations during the
study period, and possible recruitment rates. Other circumstances, such as
confirmation of data obtained in the study, should also be discussed. In addition,
they will ensure that appropriate research related documents exist.
At the end of the study, a study closure visit, the final audit, should be
performed, usually within four to six weeks of the end of the last follow-up of the
last subject in the study center. The preparations and procedures for the study
of closed visits are generally the same as for a regular supervisory visit.
15.2 Monitoring adverse events (AEs) and serious adverse events (SAE)
It should report safety information in a timely and complete manner, assisting
research management in identifying any adverse medical events, ensuring:
protecting the safety of research patients, better understanding the overall
safety characteristics of research interventions and treatment modalities, and
appropriately modifying research protocols Improve research design and
compliance with regulatory requirements.
The participating research centers will be responsible for the AE and SAE
reporting requirements described in this scenario, as described below:
1) The subjects were closely monitored for new AE and SAE during the
study.
2) Review the accuracy and completeness of all AE and SAE in the report.
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3) Report all SAEs to the research centers IEC within 72 hours of the event.
4) Compliance with the research center IRB policy on AE and SAE
reporting.
5) In order to address security issues, an implementation plan for the study
group and the executive committee may be developed.
15.2.1 Adverse event
The International Conference on Harmonization (ICH) Clinical Safety Data
Management (ICH2A) defines adverse events (AEs) as “any adverse medical
event that occurs in a clinical study subject and accepts one of the research
interventions that do not necessarily have a causal relationship with the
intervention” . The CFDA of the State Food and Drug Administration defines an
adverse event (AE) as an adverse medical event that occurs after a patient or
clinical trial subject receives a drug, but does not necessarily have a causal
relationship with the treatment. Therefore, the AE will include (any adverse
signs, changes in function (symptoms) that occur during the observation, as
well as other tests (assay, ECG, X-ray, etc.).
Researchers at participating research centers are responsible for collecting AE
information from subjects in the research center with the assistance of the
clinical research coordinator. When an adverse event occurs, both during
hospitalization and during follow-up, the usual principles of recording are as
follows: Fill in the adverse event record form, including the name of the adverse
event, the time of occurrence, the end time, the severity, the measures taken
and the outcome and the corresponding evaluation. Adverse events with
serious adverse events (defined below) will be reported as follows and followed
up to regression or stabilization.
15.2.2 Severe adverse event
Serious adverse events (SAEs) are a subset of adverse events defined by (ICH)
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Clinical Safety Data Management (ICH2A) as any of the following adverse
medical events that occur during clinical trials:
1) Lead to death.
2) Crisis life.
3) Need hospitalization or extend hospital stay.
4) Lead to persistent or severe disability or loss of energy.
5) Congenital malformations / birth defects.
6) According to medical judgment, any condition that may harm the subject
and require medication or surgery to prevent one of the above outcomes.
The study will collect all SAEs regardless of whether they are considered
relevant to the study intervention. SAEs that have a reasonable causal
relationship with research interventions and related drugs will be reported as
“relevant.” There is no need to establish a clear causal relationship.
Researchers at participating research centers are responsible for collecting
SAE information from subjects in the research center with the assistance of a
clinical research coordinator.
When a serious adverse event occurs, the researcher is required to report to
the relevant department within 24 hours of obtaining a serious adverse event.
The usual principles of treatment are as follows:
First, the subject should be guaranteed timely and appropriate clinical
diagnosis and treatment;
Secondly collect relevant information, such as medical records and inspection
results, in order to accurately and timely fill out the Serious Adverse Event
Report and report it to relevant departments.
Ensure that the report is consistent with the original record, CRF, and other
test records. Ensure that the start and end dates and major event descriptions
of serious adverse events are consistent with CRF and other test documents.
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Don't delay submitting reports even if the information may be incomplete or
uncertain. When more information is available, it can be supplemented or
revised in the form of follow-up reports. Relevant information should be
collected and recorded continuously until the end of the reporting period.
Reporting forms and reporting procedures for serious adverse events may
have different requirements in different programs and research institutions.
These requirements should be clearly written into the test plan or SOP and fully
trained before the study begins, so that the researcher can follow the
implementation.
During the entire study period, the SAE will be monitored by the Data
Monitoring Committee and all AE and SAE reports will be summarized in
accordance with the time schedule set by the DMC to review the entire study
adverse event data and whether to continue research or Safety reasons stop
the study and give advice. We believe that an independent DMC can effectively
monitor the safety of the trial as it will periodically review all outcome endpoints
based on treatment assignments and will also receive statistical support to
determine the significance of any observed differences.
RESULT
16.BIOSTATISTICAL CONSIDERATIONS
A.Overview of design
1. The analytic model
There is one primary hypothesis that will be tested: 1) aggressive hydration (i.e.,
preprocedural IV loading plus postprocedural hemodynamic-guided [LVEDP]
fluid administration) reduces the risks of CI-AKI and clinical adverse events in
acute myocardial infarction patients undergoing primary PCI.
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(50% relative reduction). Using nQuery + nTerim 3.0 (Statistical Solutions Ltd,
Farmer's Cross, Cork, Ireland) with a 2-sided χ2 test, a significance level of .05,
a power of 90%, and a dropout rate <20%, 280 patients are required in each
group, for a total sample size of 560.
Model
Aggressive
hydration
Control Overall event
rate
11.5% 23.0% 17.3%
Therefore, we postulate that:
Under control conditions, the rate for our primary outcome CI-AKI is 23.0%
The intervention will prevent 50% of these events
Under the intervention condition, the rate is 11.5%
The absolute effect of the intervention will be an 11.5% reduction in CI-AKI.
We have one primary hypothesis. We will, and therefore assign the type I error
of 5% to the intervention. No interim analysis will be carried out according to the
statistical design.
B. Primary end-point
We fully describe the aggressive hydration versus control (general hydration)
intervention and the CI-AKI outcome. The null hypothesis is that the two groups
(aggressive hydration and control) do not differ in terms of the proportion of
subjects who experience CI-AKI. The alternative hypothesis is that the absolute
difference in the incidence of CI-AKI between the treatment group and the
control group is 5% or more.
The formal statement of the null hypothesis
Under the null hypothesis:
The proportion of CI-AKI for patients administered aggressive hydration is
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23.0%
Under the alternative hypothesis, the proportion of CI-AKI for patients
administered general hydration is 23.0%.
The formal hypothesis test is two-sided allowing for aggressive hydration to be
either more or less effective than control (general hydration). However, the
study of aggressive hydration will only be viewed as more successful if subjects
treated with aggressive hydration have a significantly lower proportion of CI-AKI
than patients who receive general hydration. We will test this hypothesis with
one model that contains main clinical characteristics (e.g., age, sex, eGFR,
HV/W), and the Mehran risk score will be calculated.
C. Secondary end-points
Our secondary objectives will be tested using χ2 tests, and the 95% CI of the
rate difference will be calculated using the method described by Altman et al
(reported in Newcombe and recommended by the Food and Drug
Administration and Clinical and Laboratory Standards Institute. The secondary
end-points will be analyzed based on the intention-to-treat principle. These
objectives are:
Losses to follow up and missing data
We conservatively estimate that up to 20% of subjects may be lost to follow up
before 72 hours. The site coordinators will make every effort to locate such
subjects including at least two laboratory test of serum creatinine after primary
PCI. If such efforts fail and we have no information indicating the outcome for
these subjects, then we will exclude them from the primary analysis and then
carry out a worst-case analysis to confirm the result of the primary analysis.
Definition of Intention to Treat Sample
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All consented and randomized subjects will be accounted for and reported in
the CONSORT diagram for the study, however, only those randomized subjects
who initiated either IV intervention or have finished test a least once for SCr on
preoperation and postoperation (i.e., did not drop out or withdraw prior to start
of the allocated intervention), will be considered as an intention to treat (ITT)
subject to be included in the Data Monitoring Committee (DMC) reports and
primary efficacy analysis.
17. STUDY ORGANIZATION AND ADMINISTRATION
The research group and monitor group will be set up in the Central Office of the
Guangdong Provincial Key Laboratory of Coronary Heart Disease. The
research group is responsible for all operation/implementation procedures of
this study, and the monitor group is responsible for the quality control of this
study. The research team will conduct a face-to-face meeting prior to the start
of the study and thereafter at least once a year (online or offline). Except for the
executive committee (including research center investigators, research
clinicians, and members from academic management centers) will be
responsible for internal progress of research. The research management
structure is shown in the figure below (Figure A6).
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Figure A6 – Study management structure
17.1 Central Office of Guangdong Provincial Key Laboratory of
Coronary Heart Disease
The Central Office of Guangdong Provincial Key Laboratory of Coronary Heart
Disease organizes relevant personnel through the Executive Committee,
Operation Management Center and Academic Management Center to
formulate management systems and standard operating procedures applicable
to all the research in due course.
17.2 Executive Committee
The Executive Committee will monitor the progress of the study, the operation
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of the participating centers, and the quality of the data collected. The committee
will also monitor compliance with the study protocol. Except for the Executive
Committee, a publication plan will be developed for the study and the display of
all data will be monitored. Before relevant data is used for display or publication,
it must be approved by the Executive Committee. The committee members will
be selected by the research chair from the operation and academic center. The
Executive Committee may hold a conference call on a quarterly or annual basis
and, if necessary, hold the meeting in person.
C. Research Operation Management Center
The Research Operation Management Center will conduct daily scientific and
management coordination of research. This will include the development of
research protocol, the preparation of operational manuals and source
document worksheets, ensuring appropriate support for participating centers,
organizing meetings, answering programme queries, regularly publishing
research progress briefs, preparing interim and final reports, and the archiving
of research data at the end of the study. Coordinating research involves the
relationship of relevant departments, quality management of the research
projects (including monitor of patient recruitment and data quality), and
ensuring the smooth progress of study.
17.3 Research Academic Management Center
The Research Academic Management Center will assume the overall design of
the entire study, responsible for the design, supervision and management of
clinical study, and is responsible for various monitor organized by the drug
regulatory authorities, such as monitor, audits, on-site inspections, institutional
qualifications or reviews, etc. Work preparation, coordination and participation
in the audit of the sponsor organization. Provide clinical biometric consultation,
responsible for DME/evidence-based medicine teaching tasks for medical
graduate students, and provide advice and consultation on academic related
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issues during the study.
18. PUBLICATIONS
It is the policy of the DVP that outcome data will not be revealed to the
participating investigators until the data collection phase of the study is
completed. This policy safeguards against possible biases affecting the data
collection. The regular and ex-officio members of the DMC will be monitoring
the outcome results to ensure that the study is stopped if a definitive answer is
reached earlier than the scheduled end of the study. All presentations and
publications from this study will be done in accordance with current DVP
guidelines. The presentation or publication of any or all data collected by
participating investigators on patients entered into the ATTEMPT study is under
the direct control of the study's Executive Committee. This policy is applicable
whether the publication or presentation is concerned with the results of the
principal undertaking or is associated with the study in some other way. No
individual participating investigator has any inherent right to perform analyses
or interpretations or to make public presentations or seek publication of any or
all of the data other than under the auspices and approval of the Executive
Committee.
The Executive Committee has the authority to establish one or more publication
committees, usually made up of sub-groups of participating investigators and
some members of the Executive Committee, for the purpose of producing
manuscripts for presentation and publication. Any presentation or publication,
when formulated by the Executive Committee or its authorized representatives,
should be circulated to all investigators participating in manuscript prepation for
their review, comments, and suggestions at least four weeks prior to
submission of the manuscript to the presenting or publication body. All
publications must give proper recognition to the study's funding source,
including the Department of SME, and should list all investigators in the study. If
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an investigator's major salary support and/or commitment is from the SME, it is
obligatory for the investigator to list the SME as his/her primary institutional
affiliation. Submission of manuscripts or abstracts must follow the current DVP
policy. Since all publications should state that it is a publication from ATTEMPT
study, ideally, a sub-title is used stating, "ATTEMPT study." The SME
contributions to the research project should be acknowledged in all written and
oral presentations of the research results, including scientific articles, news
releases, news conferences, public lectures, and media interviews. All clinical
study reports and journal manuscripts must be reviewed and approved by IEC
prior to submission for publication.
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 3.0
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65. Barrett BJ and Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- andlow-osmolality iodinated contrast media. Radiology. 1993;188:171-8.
66. Rudnick MR, Goldfarb S, Wexler L, Ludbrook PA, Murphy MJ, Halpern EF, Hill JA,Winniford M, Cohen MB and VanFossen DB. Nephrotoxicity of ionic and nonionic contrastmedia in 1196 patients: a randomized trial. The Iohexol Cooperative Study. Kidneyinternational. 1995;47:254-61.
67. Kushner FG, Hand M, Smith SC, Jr., King SB, 3rd, Anderson JL, Antman EM, Bailey SR,Bates ER, Blankenship JC, Casey DE, Jr., Green LA, Hochman JS, Jacobs AK, KrumholzHM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL andWilliams DO. 2009 focused updates: ACC/AHA guidelines for the management of patientswith ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focusedupdate) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updatingthe 2005 guideline and 2007 focused update) a report of the American College ofCardiology Foundation/American Heart Association Task Force on Practice Guidelines.Journal of the American College of Cardiology. 2009;54:2205-41.
68. Sun G, Chen P, Wang K, Li H, Chen S, Liu J, He Y, Song F, Liu Y and Chen JY.Contrast-Induced Nephropathy and Long-Term Mortality After Percutaneous CoronaryIntervention in Patients With Acute Myocardial Infarction. Angiology.2018:3319718803677.
69. Zeng JF, Chen SQ, Ye JF, Chen Y, Lei L, Liu XQ, Liu Y, Wang Y, Lin JJ and Chen JY. Asimple risk score model for predicting contrast-induced nephropathy after coronaryangiography in patients with diabetes. Clinical and experimental nephrology.2019;23:969-981.
70. Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA,Collet JP, Falk V, Head SJ, Juni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, RichterDJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R and Zembala MO.[2018 ESC/EACTS Guidelines on myocardial revascularization]. Kardiologia polska.2018;76:1585-1664.
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 3.0
103
Appendix D
Changes to ATTEMPT protocol
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TableA5. Changes to ATTEMPT protocolOriginalProtocolVersionNumber
NewProtocolVersionNumber
Description of Change Justification forChange
2.0 3.0
Update of cover. The version ofthe program was changed from "2.0,June 11, 2014" to "3.0, February 04,2015".The list of participating units wasdeleted, and the main research unitsand main researchers were added.
These changes do notaffect the safety, data quality orscope of the participants, so theresearch leader held a researchmeeting on February 3, 2015and obtained the consent of theresearch team.
2.0 3.0
Update of scheme summary. Thenumber of test center has beenincreased, such as Shenzhen People'sHospital, Beijing Ditan Hospital, etc.
Since more test centerswished to participate in thestudy during the study, theyparticipated and added to theresearch program. The sponsorselects the institution andinvestigator of the clinicaltrial ,and approves qualificationsas well as conditions to ensurethe completion of the trial.
2.0 3.0The statement of intervention
group was changed to the treatmentgroup.
Standardize statements toensure clear language
2.0 3.0The study deadline was revised
from "May 2014-October 2016" to"June 2014-October 2016"
The study was conductedin June 2014, so the studydeadline was revised.
2.0 3.0
Updated research procedure: 7days after surgery was changed to 4-7days after surgery;the two follow-upsincluding 30±7 days after operationand ±14 days after operation wereadded.
For patients receiving directPCI, the number of hospitalstays is variable. If we need toknow more relevant test itemsafter surgery, the visit timeshould be relaxed to 4-7 days;At the same time, in order toensure the integrity of theresearch data to assess theprogress of contrastnephropathy better, An increaseof two visits of 30 ± 7 days aftersurger and 6 months ± 14 daysafter surgery will reduce thenumber of patients missing themain outcome of this part.
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2.0 3.0Update the Timetable of visits and
proceduresUpdated according to new
research process
2.0 3.0
The main endpoint of observationwas to retain only"contrast-inducednephropathy: Serum creatinine (SCr)increased by more than 0.5 mg/dL or25% in 48-72 hours after direct PCIcompared with baseline absolutevalue", and "Contrast-induced acutekidney injury: 10% or 0.3 mg/dL ofCystatin-C increased within 24 hoursafter PCI" was deleted.
Correction of main endpointcriteria was made according toclinical practice.
2.0 3.0
Delete the word " composite " ofthe "secondary endpoint: compositemajor cardiac adverse events:all-cause death, nonfatal myocardialinfarction, target vesselrevascularization".
Correction of secondaryendpoint criteria was madeaccording to clinical practice.
2.0 3.0Correct the 5.1 Study population
sub-heading from the rejection criteriato the exclusion criteria
4.3.2 standard is anexclusion criterion, which is anerror.
2.0 3.0
11.2 Research training, delete the"especially the standard of TCMsyndrome classification should beunified".
This study does not requireresearchers to have a unifiedunderstanding of the criteria forTCM syndrome classification.
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Appendix E
ATTEMEPT Clinical Trial Case Report Form
(Appendix independently paginated)
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Yong Liu:ATTEMPT Clincal Trial Case Reprot Form Version 3.0
1
1.Inclusion criteria
Items Yes No
a. Age ≥ 18 years. □ □
b. Patients with STEMI were likely to undergo primary PCI. □ □
c. Written informed consent. □ □
Any of item above is“no”,the participant is not allowed to enroll.
2.Exclusion criteria
Items Yes No
a. Did not undergo pPCI or die during the procedure. □ □
b. Severe Heart failure (Cardiac shock or NYHA IV). □ □
c. patients with end-stage renal failure or after renal transplantation. □ □
d. An increase > 0.5mg/dl of Scr within 24 h before the procedure compared to
the baseline value.□ □
e. Intravascular administration of a contrast medium within 1 week before thepPCI or 72 h after pPCI,or has a history of acute infections disease.
□ □
f. Allergic to contrast medium. □ □
g. Pregnancy, lactation, or malignant tumoror life expectancy< 1 year. □ □
h. The use of non-steroidal anti-inflammatory drugs, aminoglycoside drugs,
cyclosporine, cisplatin etc renal toxicity drugs within 48 h before cardiac
catheter surgery and the whole process of the research.
□ □
i. Likely to undergo renal artery intervention or surgical valve replacement in
patients with rheumatic heart disease.□ □
j. Inferior and/or right ventricle myocardial infraction combined with
hypotension on admission (systolic pressure ≤90 mmHg).□ □
k. Pre-procedural renal insufficiency eGFR ≤60 mL/min/1.73 m2. □ □
Any of item above is“yes”,the participant is not allowed to enroll.
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Yong Liu:ATTEMPT Clincal Trial Case Reprot Form Version 3.0
2
1.Random check
a. Did the subjects meet all the inclusion criteria and none of the exclusion criteria?
□yes
□no
2.Random allocation
a. Subject group
□Intervention group (aggressive hydration)
□control group (general hydration)
b. Subject random number □□□□□
c. Date of randomization □□h□□min on□□day□□month□□□□year
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 0
(-7~0 d)□□ □□□□ □□□□
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Yong Liu:ATTEMPT Clincal Trial Case Reprot Form Version 3.0
3
1.Screening data
a. Date of written informed consent □□day□□month□□□□year
b. Date of screening □□day□□month□□□□year
2.Demographics
a. Date of birth □□day□□month□□□□year
b. Gender □male □female
c. Nationality □Han nationality □other
3.Hospital admission information
a. Time of symptoms onset □□h□□min on□□day□□month□□□□year
b. Time of first medical contact (FMC) □□h□□min on□□day□□month□□□□year
c. Time of admission □□h□□min on□□day□□month□□□□year
d. Time of entering catheterization laboratory □□h□□min on□□day□□month□□□□year
e. Did thrombolytic therapy be used in this case? □yes □no
If it did, then the time of thrombolytic therapy □□h□□min on□□day□□month□□□□year
f. Did cardiac arrest happen in this case? □yes □no
If it did, then the time of cardiac arrest □□h□□min on□□day□□month□□□□year
g. Did heart failure happen in this case? □yes □no
h. Heart function (Killip class) □Ⅰ □Ⅱ □Ⅲ □Ⅳ
i. Use of IABP □yes □no
j. Use of vasoactive drugs □yes □no
k. Were intravenous fluids administered before the randomization? □yes □no
If it were,then Specific amount of intravenous fluids □□ml □unknown
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 0
(-7~0 d)□□ □□□□ □□□□
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4
4.Past medical history and family history
a. Hypertension □yes □no
b. Diabetes mellitus □yes □no
c. Hyperlipidemia □yes □no
d. Coronary artery disease □yes □no
e. Acute myocardial infarction □yes □no
Time of onset-treatment:
f. Congestive heart failure □yes □no
g. Chronic kidney diseases □yes □no
h. History of smoking □yes □no
i. Peripheral arterial disease □yes □no
j. Smoke □yes □no
k. Chronic obstructive pulmonary disease □yes □no
l. Previous family history of coronary heart disease □yes □no
5.Physical examination
a. Height □□□.□cm b. weight □□□.□kg
c. Blood pressure □□□/□□□mm Hg d.Heart beat □□□b.p.m
Items Normal
AbnormalDescribe the abnormal
situation in detailunknownDon’t exsist
clinical valueExsist
clinical value
e. Heart □ □ □ □
f. Lung □ □ □ □
g. Abdomen □ □ □ □
h. Nervous
system
□ □ □ □
i. Limbs □ □ □ □
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 0
(-7~0 d)□□ □□□□ □□□□
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5
6.1Echocardiogram tests(ECG)
a. Whether to conduct electrocardiogram examination during the screening period □yes □no
b. Time of conduct electrocardiogram examination □□h□□min on□□day□□month□□□□year
c. Results with electrocardiogram
□ normal ECG
□ ST-segment elevation,specific lead:
□ non-ST-segment elevation
□ arrhythmia
□ Q wave,specific lead:
□ other
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 0
(-7~0 d)□□ □□□□ □□□□
6.2Heart ultrasound examination Interview date:□□day□□month201□year
Echocardiography was performed during the screening period □yes □no(if no,then turn to 7)
LVDd □□mm LVDs □□mm LVEF □□%
ventricular
aneurysm
□yes □no
regional wall motion abnormality□yes □no
location(multiple):□anterior □anteroseptal □ministry of ventricular septal apex
□cardiac apex □inside wall □Paries posterior □inferior □interval □right
ventricle □unknown
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6
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 0
(-7~0 d)□□ □□□□ □□□□
7.cardiac markers
Item Result Unit unknownClinical significance
determination#1 2 3
a. CK U/L □ □ □ □
b. CK-MB U/L □ □ □ □
c. troponinT(quantitative)
ng/L □ □ □ □
d. troponinI(quantitative)
ng/L □ □ □ □
e. high-sensitivitytroponin
pg/ml □ □ □ □
f. NT-proBNP pg/ml □ □ □ □
g. BNP pg/ml □ □ □ □
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7
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 0
(-7~0 d)□□ □□□□ □□□□
8.routine blood test
Item Result Unit unknownClinical significance
determination#1 2 3
a. white blood cell ×109/L □ □ □ □
b. hemoglobin g/L □ □ □ □
c. platelet count ×109/L □ □ □ □
d. hematocrit % □ □ □ □
e. NEU% % □ □ □ □
9.Biochemical examination
Item Result Unit unknownClinical significance
determination#1 2 3
a. serum creatinine µmol/L □ □ □ □
b. Serum cystatin C mg/L □ □ □ □
c. Serum urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. Instant BloodGlucose
mmol/L □ □ □ □
10.Other examination
Item Result Unit unknownClinical significance
determination#1 2 3
a. hs-CRP mg/L □ □ □ □
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8
11.pregnancy check
ItemResult
unknown UnapplicablePositive Negative
a. pregnancy check* □ □ □ □
*test for the women likely to be pregnant.
Signature of investigator:________________ date: □□day□□month□□□□year
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 0
(-7~0 d)□□ □□□□ □□□□
12.concomitant medication
Fill the use of drugs 14 days before screening in “ record of concomitant medication”
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9
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 1
(24±4h after procedure)□□ □□□□ □□□□
Peri-procedural oral hydration
Oral distilled water hydration:□no □yes
coronary diagnostic and intervention within 24 h after procedure
Duration of hydration:□□h□□min □no dataOral fluid volume
□□□□mlStart time:□□h□□min on□□day□□month□□□□year □unknown
End time:□□h□□min on□□day□□month□□□□year □unkonwn
Peri-procedural urine volume
coronary diagnostic and intervention within 24 h after procedure urine volume□□□□ml
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10
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 1
(24±4h after procedure)□□ □□□□ □□□□
1.Primary PCI
a. Primary PCI or not □yes □no
b. The beginning time of procedure:□□h□□min on□□day□□month□□□□year
c. The endning time of procedure:□□h□□min on□□day□□month□□□□year
d. The time of balloon dilation:□□h□□min on□□day□□month□□□□year
e. Type of ontrast:□iodixanol □iopromide □iopamidol □iohexol
f. Contrast volume(Accurate to one digit):
g. The use of GPIIb/IIIa Inhibitors □yes □no
h. The use of thrombus aspiration □yes □no
i. The use of IABP □yes □no
j. Post-procedure LVEDP □□mmHg
2.Coronary lesion and interventional treatment
a. LAD:
lesion:□yes □no interventional treatment:□yes □no
interventional measure:□PTCA □PCI □thrombus aspiration
TIMI before intervention □0 □Ⅰ □Ⅱ □Ⅲ
TIMI after intervention □0 □Ⅰ □Ⅱ □Ⅲ
Bailout- stenting:□ no □DES □BMS
Number of stents:□,length of stents□□mm
b. LCX:
lesion:□yes □no interventional treatment:□yes □no
interventional measure:□PTCA □PCI □thrombus aspiration
TIMI before intervention □0 □Ⅰ □Ⅱ □Ⅲ
TIMI after intervention □0 □Ⅰ □Ⅱ □Ⅲ
Bailout- stenting:□ no □DES □BMS
Number of stents:□,length of stents□□mm
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11
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 1
(24±4h after procedure)□□ □□□□ □□□□
c. RCA:
lesion:□yes □no interventional treatment:□yes □no
interventional measure:□PTCA □PCI □thrombus aspiration
TIMI before intervention □0 □Ⅰ □Ⅱ □ⅢTIMI after intervention □0 □Ⅰ □Ⅱ □ⅢBailout- stenting:□ no □DES □BMS
Number of stents:□,length of stents□□mm
d. LM:
lesion:□yes □no interventional treatment:□yes □no
interventional measure:□PTCA □PCI □thrombus aspiration
TIMI before intervention □0 □Ⅰ □Ⅱ □ⅢTIMI after intervention □0 □Ⅰ □Ⅱ □ⅢBailout- stenting:□ no □DES □BMS
Number of stents:□,length of stents□□mm
e. coronary bypass grafts
lesion:□yes □no interventional treatment:□yes □no
interventional measure:□PTCA □PCI □thrombus aspiration
TIMI before intervention □0 □Ⅰ □Ⅱ □ⅢTIMI after intervention □0 □Ⅰ □Ⅱ □ⅢBailout- stenting:□ no □DES □BMS
Number of stents:□,length of stents□□mm
f. Culprit lesion:□LAD □LCX □RCA □LM □coronary bypass grafts □unknown
g.CTO:□yes □no location:□LAD □LCX □RCA □LM □coronary bypass grafts
3.Clinical events
All new clinical events should be recorded in clinical events record form
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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12
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 2
(48±4h after procedure)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
1.Vital signs
a. Blood pressure 1 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
b. Blood pressure 2 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
c. Blood pressure 3 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
d. Blood pressure 4 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
e. Blood pressure 5 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
f. Blood pressure 6 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
g. Blood pressure 24 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
2.Renal function(24±4h after procedure)
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
If the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72 hours post-procedure, the
renal function of the subjects was monitored until 1 week after operation.
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Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 2
(48±4h after procedure)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
3.Other examination
The date of blood collection:□□day□□month□□□□year
Item Result Unit unknownClinical significance
determination#1 2 3
a. ALT U/L □ □ □ □
b. AST U/L □ □ □ □
c. Total cholesterol mmol/L □ □ □ □
d. triglyceride mmol/L □ □ □ □
e. LDL-C mmol/L □ □ □ □
f. HDL-C mmol/L □ □ □ □
g. apolipoproteina mmol/L □ □ □ □
h. serum total bilirubin μmol/L □ □ □ □
i.serum direct bilirubin μmol/L □ □ □ □
j. Serum albumin g/L □ □ □ □
k.CK U/L □ □ □ □
l. CKMB U/L □ □ □ □
m. hs-CRP mg/L □ □ □ □
n. Uric acid μmol/L □ □ □ □
o. HbAlc mmol/L □ □ □ □
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Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 2
(48±4h after procedure)□□ □□□□ □□□□
Signature of investigator:________________ date: □□day□□month□□□□year
4.Heart and carotid ultrasound examination
Interview date:□□day□□month201□year
Echocardiography on addmision □yes □no
LVDd □□mm LVDs □□mm LVEF □□%
ventricular
aneurysm
□yes □no
regional wall motion abnormality□yes □no
location(multiple):□anterior □anteroseptal □ministry of ventricular septal apex
□cardiac apex □inside wall □Paries posterior □inferior □interval □right
ventricle □unknown
carotid ultrasound examination on addmision □yes □no
carotid plaque
□no □yes
stenosis:□yes □no Max stenosis:left side□□%, right side□□%
Carotid intimal thickening:□yes □no, IMT thickening :left side □.□mm,right
side□.□mm
5.Clinical events
All new clinical events should be recorded in 《clinical events record form》
6.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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15
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 3
(72±4h after procedure)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Signature of investigator:________________ date: □□day□□month□□□□year
Interview date: □□day□□month□□□□year
1.Vital signs
a. Blood pressure 48 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
2.Renal function(48±4h after procedure)
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. hs-CRP mg/L □ □ □ □
If the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72 hours post-procedure, the
renal function of the subjects was monitored until 1 week after operation.
3.Clinical events
All new clinical events should be recorded in 《clinical events record form》
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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16
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 4
(4 days after procedure)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Signature of investigator:________________ date: □□day□□month□□□□year
Interview date: □□day□□month□□□□year
1.Vital signs
a. Blood pressure 72 h after post-procedure:□□□/□□□mmHg Heart beat: □□□b.p.m
2.Renal function(72±4h after procedure)
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. hs-CRP mg/L □ □ □ □
If the serum creatinine (SCr) increased by more than 0.3 mg/dL within 72 hours post-procedure, the
renal function of the subjects was monitored until 1 week after operation.
3.Clinical events
All new clinical events should be recorded in 《clinical events record form》
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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17
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 5
(4-7 days after procedure)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Signature of investigator:________________ date: □□day□□month□□□□year
Interview date: □□day□□month□□□□year
1.Vital signs
a. Blood pressure:□□□/□□□mmHg Heart beat: □□□b.p.m
2.Renal function
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. hs-CRP mg/L □ □ □ □
3.Clinical events
All new clinical events should be recorded in 《clinical events record form》
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
5.Date of discharge and total hospitalization expenses
Date of discharge:□□day□□month□□□□year total hospitalization expenses:□□□□yuan
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18
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 6
(1 month after PCI)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Signature of investigator:________________ date: □□day□□month□□□□year
Interview date: □□day□□month□□□□year
1.Vital signs(optional)
a. Blood pressure:□□□/□□□mmHg Heart beat: □□□b.p.m
b. weight:□□□.□kg
2.Renal function(optional)
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. hs-CRP mg/L □ □ □ □
3.Clinical events
All new clinical events should be recorded in 《clinical events record form》
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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19
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 7
(3 month after PCI)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Signature of investigator:________________ date: □□day□□month□□□□year
Interview date: □□day□□month□□□□year
1.Vital signs
a. Blood pressure:□□□/□□□mmHg Heart beat: □□□b.p.m
b. weight:□□□.□kg
2.Renal function
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. hs-CRP mg/L □ □ □ □
3.Clinical events
All new clinical events should be recorded in 《clinical events record form》
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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20
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 8
(6 month after PCI)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Signature of investigator:________________ date: □□day□□month□□□□year
Interview date: □□day□□month□□□□year
1.Vital signs(optional)
a. Blood pressure:□□□/□□□mmHg Heart beat: □□□b.p.m
b. weight:□□□.□kg
2.Renal function(optional)
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. hs-CRP mg/L □ □ □ □
3.Clinical events
All new clinical events should be recorded in 《clinical events record form》
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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21
Center number Participant numberAbbreviation of phoneticize
spell of participant’s nameInterview 9
(1 year after PCI)□□ □□□□ □□□□
#Clinical significance determination:1=normal;2=abnormal without clinical significance;3= abnormal with clinical
significance
Interview date: □□day□□month□□□□year
1.Vital signs
a. Blood pressure:□□□/□□□mmHg Heart beat: □□□b.p.m
b. weight:□□□.□kg
2.Renal function
The date of blood collection:□□day□□month□□□□year
item result unit unknownClinical significance
determination#1 2 3
a. SCr µmol/L □ □ □ □
b. cystatin C mg/L □ □ □ □
c. urea nitrogen mmol/L □ □ □ □
d. Na mmol/L □ □ □ □
e. K mmol/L □ □ □ □
f. hs-CRP mg/L □ □ □ □
3.Clinical events
All new clinical events should be recorded in 《clinical events record form》
4.concomitant medicationAll new use of drugs should be recorded in 《Combined Medication Record Form》
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Yong Liu:ATTEMPT Clincal Trial Case Reprot Form Version 3.0
22
Center number Participant number Abbreviation of phoneticize spell of participant’s nameconcomitant medication / page
□□ □□□□ □□□□
Combined Medication Record FormRecord the subject's medication from 14 days before the operation to the completion or suspension of the study.
No.Drug name
(common name)Dose Unit
Route ofadministration
Start date The drug is still used at Visit7 (if yes:□ marked with “×”)
Reason formedicationEnd date
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
Note: route of administration (1 = po; 2 =ih; 3 = im; 4 = iv; 5 = local topical; 6 = other)
Investigator Signature:__________________________Data:□□day□□month□□□□year
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23
Center number Participant number Abbreviation of phoneticize spell of participant’s nameconcomitant medication / page
□□ □□□□ □□□□
Combined Medication Record FormRecord the subject's medication from 14 days before the operation to the completion or suspension of the study.
No.Drug name
(common name)Dose Unit
Route ofadministration
Start date The drug is still used at Visit7 (if yes:□ marked with “×”)
Reason formedicationEnd date
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
Note: route of administration (1 = po; 2 =ih; 3 = im; 4 = iv; 5 = local topical; 6 = other)
Investigator Signature:__________________________Data:□□day□□month□□□□year
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24
Center number Participant number Abbreviation of phoneticize spell of participant’s nameconcomitant medication / page
□□ □□□□ □□□□
Combined Medication Record FormRecord the subject's medication from 14 days before the operation to the completion or suspension of the study.
No.Drug name
(common name)Dose Unit
Route ofadministration
Start date The drug is still used at Visit7 (if yes:□ marked with “×”)
Reason formedicationEnd date
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
Note: route of administration (1 = po; 2 =ih; 3 = im; 4 = iv; 5 = local topical; 6 = other)
Investigator Signature:__________________________Data:□□day□□month□□□□year
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25
Center number Participant number Abbreviation of phoneticize spell of participant’s nameconcomitant medication / page
□□ □□□□ □□□□
Combined Medication Record FormRecord the subject's medication from 14 days before the operation to the completion or suspension of the study.
No.Drug name
(common name)Dose Unit
Route ofadministration
Start date The drug is still used at Visit7 (if yes:□ marked with “×”)
Reason formedicationEnd date
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
□□day□□month□□□□year□
□□day□□month□□□□year
Note: route of administration (1 = po; 2 =ih; 3 = im; 4 = iv; 5 = local topical; 6 = other)
Investigator Signature:__________________________Data:□□day□□month□□□□year
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26
Center number Participant number Abbreviation of phoneticize spell of participant’s nameTable of hydration schemes
□□ □□□□ □□□□
1. Random allocation
a. Which group is the subject randomly assigned to? □Intervention group □Control group
2.Intervention group hydration scheme
a. □No need to fill in (if you are in the control group, □mark with “×”)
Whether the hydration planis adjusted: 1. Yes, 2. No
Reasons foradjustment ofhydration plan
Dose(ml/kg/h)
Hydration start Hydration end
Date (year / month / day) Time (hour: minute) Date (year / month / day) Time (hour: minute)
Note: route of administration (1 = po; 2 =ih; 3 = im; 4 = iv; 5 = local topical; 6 = other)
Investigator Signature:__________________________Data:□□day□□month□□□□year
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27
Center number Participant number Abbreviation of phoneticize spell of participant’s nameTable of hydration schemes
□□ □□□□ □□□□
3.Control group hydration scheme
a. □No need to fill in (if you are in the experimental group, □mark with “×”)
b. Whether the patient is hydrated ? □Yes □No (if not, the following form is not required)
Whether the hydration planis adjusted: 1. Yes, 2. No
Reasons foradjustment ofhydration plan
Dose(ml/kg/h)
Hydration start Hydration end
Date (year / month / day) Time (hour: minute) Date (year / month / day) Time (hour: minute)
Investigator Signature:__________________________Data:□□day□□month□□□□year
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28
Center number Participant number Abbreviation of phoneticize spell of participant’s nameclinical events record form__/__Page
□□ □□□□ □□□□
Clinical event table
Adverseevent
Occurrence date(year / month / day)
SeverityMeasures taken for
hydrationCausal relationship to
hydration
Action takenwith adverse
eventReturn of adverse event
Was thisEventSerious?
Resolution date(year / month / day)
1. Light2. Medium3. Heavy4. Unknown
1. Continue to hydrate2. Reduce dose3. Resume afterhydration pause4. Disable hydration
1. Definite (clearly related)2. Probable (likely related)3. Unlikely (doubtfullyrelated)4. Unrelated (clearly notrelated)5. Unable to judge
1.Yes2.None
1. Symptoms disappear2. Symptoms disappearwith sequelae3. Symptoms persist4. Death5. Unable to judge
1.Yes2.No
1
2
3
Investigator Signature:__________________________Data:□□day□□month□□□□year
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29
Center number Participant numberAbbreviation of phoneticize
spell of participant’s name
Research Summary
Principal Investigator
statement□□ □□□□ □□□□
Research Summary
The date of completion/withdrawal of participant in the study
Whether the participant finish the whole clinical study according to the project
□yes
□no,the main reason for withdrawal(Individual):
□withdrawal of informed consent/ the participant insist on withdrawing the
trial
□the participant had adverse events
□the participant had serious adverse events
□the participant had taken the drugs forbidden in this study
□Principal investigator consider it ok
□lost to follow-up
□other:
Principal Investigator statement
All the data collected in CRF have been reviewed,the accuracy and completeness of the
information shall be ensured,which bring into correspondence with the original file.
Signature of investigator:________________ date:
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30
Record of oral hydration and urine volume ofpatients undergoing coronary intervention
Name: Bed room: AD: Height: cm Weight: kg
In order to facilitate the doctor to understand the patient's access, so as to minimize the risk ofcontrast nephropathy, please carefully fill in the following form!
Pre-procedure water intake(calculate from 22:00 the night before theprocedure)
Pre-procedure urinary output(calculatefrom 22:00 the night before theprocedure)
date time waterintake(ml)
brand date time urinaryoutput(ml)
Date of procedure: Time of return to ward after peocedure:
Post-procedure water intake(calculate from 24hafter the procedure)
Post-procedure urinary output(calculatefrom 24h after the procedure)
date time waterintake(ml)
brand date time urinaryoutput(ml)
Illustrate:1,the recorded water including the corresponding time period only after drinking water,pure water, mineral water, the latter two need to specify the brand, such as: "Kang Huaqing purewater", etc.,please record in the corresponding Spaces in time and water amount, urine output,for example: "22:00 400 ml.
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Yong Liu:ATTEMPT Clincal Trial Statistical Analysis Plan Version 1.0
Appendix E
ATTEMEPT Clinical Trial Statistical Analysis Plan
Version 1.0
(Appendix independently paginated)
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Yong Liu:ATTEMPT Clincal Trial Statistical Analysis Plan Version 1.0
1
Statistical analysis plan for aggressive hydraTion in patients with ST-elevation
myocardial infarction undergoing primary percutaneous coronary intervention
to prevenT contrast-induced nephropathy (ATTEMPT) study
Abbreviations
SAP = statistical analysis plan;
STEMI = ST-elevation myocardial infarction;
CI-AKI = contrast-induced acute kidney injury;
pPCI = primary percutaneous coronary intervention;
LVEDP = Left ventricular end-diastolic pressure;
LVEF = Left ventricular ejection fraction;
CEC = Clinical Event Committee;
RR = Risk ratio; ARD = Absolute;
NNT = Number needed to treat;
SCr = Serum creatinine;
ITT = intention-to-treat;
DSMB = Data and safety monitoring committee.
1. Introduction
Patients who have ST-segment elevation myocardial infarction (STEMI) carry a
high-risk of contrast-induced acute kidney injury (CI-AKI) following primary
percutaneous coronary intervention (pPCI)1. However, for this high-risk group, the
extent of the effects of optimal hydration strategy is yet to be fully established2,3. The
aggressive hydraTion in patients with ST-Elevation Myocardial infarction undergoing
Primary percutaneous coronary intervention to prevenT contrast-induced nephropathy
(ATTEMPT) study is the first study to evaluate the peri-procedural aggressive
hydration in STEMI patients undergoing pPCI4. Here, we describe the statistical
analysis plan (SAP) for the ATTEMPT study, prior to patient enrollment being
completed (this was completed in June 2018) and the locking of the database for
analysis.
This SAP was written by the study statistician and the principal investigator, both
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Yong Liu:ATTEMPT Clincal Trial Statistical Analysis Plan Version 1.0
2
of whom were kept blind to the course of treatment allocated to the patients. We
prospectively defined each analysis described in this SAP.
2. Methods
2.1 Overview of design
The ATTEMPT study is a multicenter, randomized controlled trial which is
investigator-based and open label in nature. A total of 560 patients with STEMI
undergoing pPCI will be randomized (1:1) to undergo treatment either by
peri-procedural aggressive hydration (treatment group) or general hydration (control
group). The ATTEMPT study could prove valuable for the possible identification of
optimal hydration regimens for STEMI patients undergoing pPCI4.
2.2 Inclusion & Exclusion criteria
Inclusion criteria: All consecutive patients with STEMI who were at least 18
years of age and were prepared for pPCI were taken into consideration for enrollment
in the study.
Exclusion criteria:
Contrast medium administration within the 2 weeks prior to the procedure or the
following 3 days;
End-stage renal failure or renal transplantation, and refusal of pPCI or death
while the procedure is taking place;
Heart failure-induced cardiac shock or New York Heart Association class IV
(these patients were excluded because intravenous hydration administration could
potentially prove harmful);
A recent acute kidney injury, which was considered to be an absolute increase of
0.5 mg/dL in serum creatinine (SCr) over baseline in the 24 hours prior;
The existence of lactation, pregnancy;
A tumor of a malignant nature or a predicted life expectancy of 1 year or less;
An allergic reaction induced by contrast medium, peri-procedural receipt of
metformin, or non-steroidal anti-inflammatory drugs in the 2 days prior and while
the study is taking place;
Planned renal catheterization or heart valvular surgery.
2.3 Randomization
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All patients meeting the eligibility criteria and provided informed consent will be
randomized into two study groups. A computer will carry out randomization of
eligible patients by producing numbers at random at a 1:1 ratio. Randomization will
be accomplished with using a block random method with 8 units in each group. Some
offset or variability will be inserted to prevent anticipation of the next treatment.
Randomization will be stratified based on age (<60, 60–75, >75 years), sex (male or
female), and STEMI location (anterior wall or no-anterior wall). Study coordinators at
each site will be responsible for obtaining a randomized treatment assignment for
each eligible patient. Study sites will be provided with a web-based randomization
program for this purpose. This web-based http://crdms.echobelt.org program will be
tested at each site prior to the start of the trial and will be reviewed. Since this is an
open-label study, the procedure of blinding will not take place.
2.4 Sample size
The total sample size of 560 patients was calculated based on our previous
findings. The incidence of primary end point was estimated to decrease to 11.5%
(50% relative reduction) in the aggressive hydration group from 23% in the control
group with general hydration5. We established a sample size according to nQuery +
nTerim 3.0 (Statistical Solutions Ltd, Ireland) by employing a 2-sided χ2 test, a power
of 90%, a significance level of 0.05, and a dropout rate <20%.
2.5 The formal statement of the null hypothesis
We fully describe the CI-AKI outcome based on the aggressive hydration versus
general hydration intervention. The null hypothesis is that the two treatment groups
(aggressive hydration and control) do not differ in terms of the proportion of subjects
who experience CI-AKI. The alternative hypothesis is that the absolute difference in
the incidence of CI-AKI between the aggressive hydration group and the control
group.
2.6 Intervention
A pre-procedural loading dose 250 mL of normal saline for 30 minutes (125 mL
for patients with congestive heart failure, Killip II/III or NYHA III) will be
administered to the patients in the treatment group in an emergency department or
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cardiac catheterization lab over 30-minutes prior to the pPCI. After this, the patients
will receive intravenous hydration at a general rate (1 or 0.5 mL/kg/h for patients with
congestive heart failure, Killip II/III or NYHA III) until LVEDP measurement.
Patients will then undergo 4 hours of post-procedural aggressive hydration guided
by LVEDP [5 mL/kg/h (LVEDP <13 mmHg), 3 mL/kg/h (LVEDP 13–18 mmHg),
1.5mL/kg/h (LVEDP >18 mmHg), and 0.5 mL/kg/h (LVEDP >20 mmHg)] and
continuous intravascular hydration at the normal rate for the 24 hours following PCI.
Control group patients will receive peri-procedural general hydration with ≤500 mL
normal saline (within 6 hours) at a normal rate (0.5 or 1 mL/kg/h).
2.7 Interim analysis
According to the study design, interim analysis to determine if either intervention
shows a substantial beneficial effect will not be carried out.
2.8 Timing of analysis
At the end of the study, the final audit should be performed usually within four to
six weeks of the end of the last follow-up of the last subject in the study center. The
preparations and procedures for the study of closed visits are generally the same as for
a regular supervisory visit. The last patient was enrolled on 10th June 2018 (Table 1).
Table 1 Analysis timing of measurement for endpointsEndpoint Analysis timing
Primary endpoint
CI-AKI 48 to 72 hours after the procedure
Secondary endpoint
CI-AKI48 h 48 hours after the procedure
CI-AKICysC 24 hours after the procedure
Major adverse cardiovascular events Within the first year after enrollment
Major adverse clinical events Within the first year after enrollment
CI-PKI requiring dialysis Within the 3-month after enrollment
Total hospitalization costs Discharge from hospital
Length of stay Discharge from hospital
Safety endpoint
Acute heart failure Within the hospitalization after enrollment
CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent
renal damage.
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2.9 Analysis principles
Analysis is to be conducted based on adjusted intention-to-treat (ITT)
(randomization must be finished before emergency surgery, and we will not
include the patients who need to be excluded from the final analysis).
We will not impute missing values, unless specified. The number of subjects
included in an analysis will be reported if there is a substantial amount of missing
data. The last observations will not be carried forward. Multiple imputation will
be used if >5% of patients have missing data on the primary outcome.
Each of the tests will be two-tailed, and a P value of less than 0.05 will be
considered to be statistically significant.
Only analyses conducted up to 1 year after randomization will feature in this
analysis plan and in the primary manuscript.
Pre-specified subgroup analyses will be conducted whether or not a statistically
significant treatment effect on the primary outcome is seen across the total
sample.
We use the t-test for normally distributed continuous variables and expressed as
mean ± SD, and the Wilcoxon rank-sum test was used in non-normal distribution
variables and presented as median and interquartile range.
For categorical variables, we used Pearson χ2 or Fisher’s exact tests to compare
baseline characteristics and study’s endpoints between the aggressive and general
hydration groups; these will be expressed as percentages.
Multivariable logistic regression models will be developed to adjust for clinical
characteristics (eg, age, sex, creatinine clearance, and left ventricular ejection
fraction [LVEF]), and the Mehran risk score will be calculated. Odds ratios will
be reported alongside their related 95% CIs.
2.9.1 Analysis of primary outcome
The primary analysis will be based on adjusted intention to treat principles. Since
the intervention is given and the primary outcome is observed for a very short
duration (72 hours), we expect only a few dropouts or crossovers.
As ATTEMPT study’s protocol pointed out primary outcome would use
multivariable logistic regression with (age, sex, creatinine clearance, and left
ventricular ejection fraction). The analysis for each variable will be performed by OR
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with their corresponding 95% CIs to describe the intervention effect. All tests will be
two-tailed, and a P value less than 0.05 will be considered statistically significant.
All consented and randomized subjects will be accounted for and reported in the
CONSORT diagram for the study; however, only those randomized subjects who
have finished test for SCr at least once on pre-procedure and 72 hours post-procedure
(i.e., did not drop out or withdraw prior to the start of the allocated intervention) will
be considered as an adjusted ITT subject to be included in the DMC reports and
primary efficacy analysis.
2.9.2 Subgroup analyses
We will undertake analysis of five pre-specified subgroups defined by the
following baseline criteria: age (<60, 60–75, >75 years), gender (Male or female),
STEMI location (anterior wall or no-anterior wall), and LVEF (≥40% or <40%),
eGFR (≥90 or <90 mL/minute/1.73 m2).
eGFR formula (Modified relative dose response)= [186 × SCr (mg/dL) ]^− 1.154 × age
^− 0.203 × (multiply by 0.742 for women).
Within each subgroup, summary measures will include raw counts and
percentages within each treatment arm. The analysis for each subgroup will be
performed by RR with their corresponding 95% CIs to describe the interaction effect.
The results will be shown on a forest plot including the P-value for heterogeneity
corresponding to the interaction term between the intervention and the subgroup
variable.
2.9.3 Analysis of secondary outcomes
Our secondary objectives will be tested using χ2 tests, and the 95% CI of the rate
difference of RR and ARD will be calculated using the method described by Altman
et al (reported in Newcombe and recommended by the Food and Drug Administration
and Clinical and Laboratory Standards Institute. The secondary end-points will be
analyzed based on the adjusted ITT principle.
2.9.4 Sensitive analyses
To evaluate the stability of primary outcome, we will use logistic regression to
analyze the influence of compliance. It will be performed by OR with their
corresponding 95% CIs. All tests will be two-tailed, and a P value less than 0.05 will
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be considered statistically significant.
For patients: the volumes of urine and oral hydration (water in milliliters) in the
24 hours following the procedure will be recorded.
For medical staff: intravenous hydration information will be gathered in the 24
hours following the procedure. A preoperative renal function test and details on
postoperative SCr, failure to hydrate according to protocol, and the absence of SCr
will be obtained in the follow-up. All of this information, laboratory tests and vital
signs will be carefully collected by the research staff.
2.9.5 Central effect analysis
To evaluate the central effect, we will use Generalized mixed linear analysis of
primary outcome with different centers. We describe the central effect by P value and
less than 0.05 will be considered statistically significant.
2.9.6 Analysis of safety outcomes
One of the important adverse reactions to aggressive hydration is the increased
risk of heart failure. We will record all information relating to acute heart failure:
acute pulmonary edema, cardiogenic shock, and further auxiliary examination such as
ECG, chest X-ray, laboratory assessment (with specific biomarkers), and
echocardiography.
The Clinical Event Committee (CEC) will be responsible for determining the
endpoints in clinical studies and avoiding deviations in event determination between
centers in order to achieve a more accurate assessment of the test results. We will use
RR and ARD with their corresponding 95% CIs to describe the safety endpoint.
2.9.7 Treatment of missing data
We conservatively estimate that up to 20% of subjects may be lost to follow-up
SCr within 72 hours and exclusive patients. The site coordinators will make every
effort to identify such subjects including at least two laboratory tests of SCr after
pPCI. Multiple imputation will be used if >5% of patients have missing data on the
primary outcome.
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PCI, percutaneous coronary intervention; eGFR, estimate glomerular filtration rate.
Table S2 Proposed format of data tables and figures for main results publication
hPeri-procedural receipt of NSAIDs,aminoglycosides, cyclosporine or cisplatinin the past 48 h and during the studyperiod
xxx (xx) xxx (xx)
Inferior and/or right ventricle myocardialinfraction combined with hypotension onadmission (systolic pressure ≤90 mmHg)
xxx (xx) xxx (xx)
Pre-procedural renal insufficiency eGFR≤60 mL/min/1.73 m2
xxx (xx) xxx (xx)
Characteristic Aggressive group (N=xxx) Control group (N=xxx)Age, yr xxx (xx) xxx (xx)Age >75 yr, no. (%) xxx (xx) xxx (xx)Sex (male), no. (%) xxx (xx) xxx (xx)Weight (kg) xxx (xx) xxx (xx)Anterior myocardial infarction, no. (%) xxx (xx) xxx (xx)Killip class >1, no. (%) xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Serum creatinine, μmol/L xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2
xxx (xx) xxx (xx)
Estimate glomerular filtration rate <90mL/min/1.73 m2, no. (%)
xxx (xx) xxx (xx)
Cystatin C, mg/L xxx (xx) xxx (xx)LVEF, % xxx (xx) xxx (xx)LVEF <40%, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)ACEI/ARB, no. (%) xxx (xx) xxx (xx)Beta-Blockers, no. (%) xxx (xx) xxx (xx)Statin, no. (%) xxx (xx) xxx (xx)Abciximab, no. (%) xxx (xx) xxx (xx)Diuretic, no. (%) xxx (xx) xxx (xx)Volume of contrast medium, mL xxx (xx) xxx (xx)Time from diagnosis to reperfusion, min xxx (xx) xxx (xx)Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores† xxx (xx) xxx (xx)Peri-procedures Intravenous Hydrationvolume—ml
xxx (xx) xxx (xx)
Pre-angiography xxx (xx) xxx (xx)Procedure xxx (xx) xxx (xx)0-4 hours Post-angiography xxx (xx) xxx (xx)4-24 hours Post-angiography xxx (xx) xxx (xx)Post-procedures Oral Hydration volume— xxx (xx) xxx (xx)
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LVEF, left ventricular ejection fraction; ACEI/ARB, angiotension-converting enzyme
inhibitor/angiotension receptor blocker.
Table S3 Baseline characteristics
LVEF, left ventricular ejection fraction.
Table S4 Hydration information
mlPost-procedures Urine volume—ml xxx (xx) xxx (xx)
Demographic Aggressive group (N=xx) Control group (N=xx)Smoke, no. (%) xxx (xx) xxx (xx)Clinical xxx (xx) xxx (xx)Killip class, no. (%) xxx (xx) xxx (xx)I xxx (xx) xxx (xx)II xxx (xx) xxx (xx)III xxx (xx) xxx (xx)
Pre-angiography renal function xxx (xx) xxx (xx)Serum creatinine, μmol/L* xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2*
xxx (xx) xxx (xx)
Estimate glomerular filtration rate <90mL/min/1.73 m2, no. (%)
xxx (xx) xxx (xx)
Cystatin C, mg/L* xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Hematocrit, % * xxx (xx) xxx (xx)Hbalc, % * xxx (xx) xxx (xx)LVEF, %* xxx (xx) xxx (xx)LVEF <40, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)Previous myocardial infarction, no. (%) xxx (xx) xxx (xx)Contrast type, no. (%) xxx (xx) xxx (xx)Iodixanol xxx (xx) xxx (xx)Iopromide xxx (xx) xxx (xx)Iopamidol xxx (xx) xxx (xx)
Other low osmolal agents xxx (xx) xxx (xx)Contrast media volume, total (mmHg)* xxx (xx) xxx (xx)Left ventricular end-diastolic pressure, no./total(mmHg)*
xxx (xx) xxx (xx)
Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores xxx (xx) xxx (xx)
Hydration information Aggressive group (N=xx) Control group (N=xx)Pre-procedure’s hydrationadjustment —no.
xxx (xx) xxx (xx)
Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive
hydrationxxx (xx) xxx (xx)
Did not undergo general hydration xxx (xx) xxx (xx)
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3.3 Study outcomes
The primary endpoint is CI-AKI, which is considered to be a >25% or 0.5 mg/dL
increase in SCr from baseline in the 48–72 hours immediately following the
procedure (Table 1, Supplementary Table S5-6)9.
Table S5 Primary and secondary endpoints
CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent renal
damage.
Table S6 Clinical events
In-procedure‘s hydration adjustment—no.
xxx (xx) xxx (xx)
Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive
hydrationxxx (xx) xxx (xx)
Post-procedure’s hydrationadjustment —no.
xxx (xx) xxx (xx)
Intense hydration for hypotension xxx (xx) xxx (xx)
EndpointAggressivegroup(N=xx)
Controlgroup(N=xx)
Relativeratio (95%CI)
Absolutely riskdifference(95% CI)
P value
Primary endpoint, (%)CI-AKI xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx
Secondary endpoint, (%)CI-AKI 48h xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xxCI-AKICysC xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xxMajor adverse cardiovascular
event, (%) xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx
Major adverse clinical event,(%) xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx
CI-PKI (%) xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xxTotal hospitalization costs, $† xxx xxx — — xxLength of stay, d xxx xxx — — xxSafety endpoint, (%)Acute heart failure xxx (xx) xxx (xx) xxx (xx-xx)xxx (xx-xx) xx
Variable name Aggressive group (N=xx) Control group (N=xx)Total events, no. (%) xxx (xx) xxx (xx)CI-AKI xxx (xx) xxx (xx)CI-AKI48 h xxx (xx) xxx (xx)CI-AKICysC xxx (xx) xxx (xx)Death xxx (xx) xxx (xx)
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CI-AKI, contrast-induced acute kidney injury.
The secondary outcomes consist of: (I) CI-AKI, defined as a >50% or 0.3-mg/dL
absolute increase in SCr from baseline in the 48 hours immediately after the
procedure; (II) CI-AKI, defined as a >10% or 0.3-mg/dL absolute increase in serum
cystatin-C during the 24 hours immediately following the procedure9; (III) persistent
renal damage, which is considered to be residual impairment of renal function
demonstrated by a >25% reduction in creatinine clearance at 3 months compared with
baseline10; (IV) major adverse cardiovascular events, which include all-cause
mortality, target vascular revascularization, and non-fatal myocardial infarction; (V)
major adverse clinical events which take place in hospital following the procedure,
including acute pulmonary edema, cardiogenic shock, stroke, clinically significant
arrhythmias, and bleeding; (VI) total hospitalization costs; (VII) length of stay.
The safe outcome is Acute heart failure (AHF) during hospitalization, defined as
signs/symptoms of heart congestion and/or hypoperfusion by physical examination
and further auxiliary examination such as ECG, chest X-ray, laboratory assessment
(with specific biomarkers), and echocardiography11.
3.4 Primary outcome analysis
All consented and randomized subjects will be accounted for and reported in the
CONSORT diagram for the study; however, only those randomized subjects who
have started either intravenous hydration intervention or have finished test for SCr at
least once on pre-procedure and 72 hours post-procedure (i.e., did not drop out or
withdraw prior to the start of the allocated intervention) will be considered as an
adjusted ITT subject to be included in the DMC reports and primary efficacy analysis.
Target vascular revascularization xxx (xx) xxx (xx)Nonfatal myocardial infarction xxx (xx) xxx (xx)Dialysis xxx (xx) xxx (xx)Acute heart failure xxx (xx) xxx (xx)Cardiac shock xxx (xx) xxx (xx)Stroke xxx (xx) xxx (xx)Bleeding xxx (xx) xxx (xx)Arrhythmias xxx (xx) xxx (xx)Infection xxx (xx) xxx (xx)
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4. Conclusions
The ATTEMPT study will investigate the efficacy and safety of adequate
hydration during the perioperative period among patients who require pPCI treatment.
This SAP is intended to minimize the analysis bias of the study.
References
1. Narula A, Mehran R, Weisz G, et al. Contrast-induced acute kidney injury after
primary percutaneous coronary intervention: results from the HORIZONS-AMI
substudy. Eur Heart J 2014;35:1533-40.
2. Mehran R, Dangas GD, Weisbord SD. Contrast-Associated Acute Kidney Injury.
N Engl J Med 2019;380:2146-55.
3. Liu Y, Hong D, Wang AY, et al. Effects of intravenous hydration on risk of
contrast induced nephropathy and in-hospital mortality in STEMI patients
undergoing primary percutaneous coronary intervention: a systematic review and
meta-analysis of randomized controlled trials. BMC Cardiovasc Disord
2019;19:87.
4. Liu Y, Chen JY, Huo Y, et al. Aggressive hydraTion in patients with
ST-Elevation Myocardial infarction undergoing Primary percutaneous coronary
intervention to prevenT contrast-induced nephropathy (ATTEMPT): Study design
and protocol for the randomized, controlled trial, the ATTEMPT, RESCIND 1
(First study for REduction of contraSt-induCed nephropathy followINg carDiac
catheterization) trial. Am Heart J 2016;172:88-95.
5. Tan N, Liu Y, Chen JY, et al. Use of the contrast volume or grams of
iodine-to-creatinine clearance ratio to predict mortality after percutaneous
coronary intervention. Am Heart J 2013;165:600-8.
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recommendations for improving the quality of reports of parallel-group
randomized trials. JAMA 2001;285:1987-91.
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8. Moher D, Hopewell S, Schulz KF et al. CONSORT 2010 explanation and
elaboration: updated guidelines for reporting parallel group randomised trials.
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BMJ 2010;340:c869.
9. Briguori C, Visconti G, Rivera NV, et al. Cystatin C and contrast-induced acute
kidney injury. Circulation 2010;121:2117-22.
10. Maioli M, Toso A, Leoncini M, et al. Persistent renal damage after
contrast-induced acute kidney injury: incidence, evolution, risk factors, and
prognosis. Circulation 2012;125:3099-107.
11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the
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doi: 10.1136/heartjnl-2021-319716–8.:10 2021;Heart, et al. Liu Y
Yong Liu:ATTEMPT Clincal Trial Statistical Analysis Plan Version 2.0
Appendix E
ATTEMEPT Clinical Trial Statistical Analysis Plan
Version 2.0
(Appendix independently paginated)
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 3.0
Statistical analysis plan for aggressive hydraTion in patients with ST-elevation
myocardial infarction undergoing primary percutaneous coronary intervention
to prevenT contrast-induced nephropathy (ATTEMPT) study
1. Introduction
Patients who have ST-segment elevation myocardial infarction (STEMI) carry a
high-risk of contrast-induced acute kidney injury (CI-AKI) following primary
percutaneous coronary intervention (pPCI)1. However, for this high-risk group, the
extent of the effects of optimal hydration strategy is yet to be fully established2,3. The
aggressive hydraTion in patients with ST-Elevation Myocardial infarction undergoing
Primary percutaneous coronary intervention to prevenT contrast-induced nephropathy
(ATTEMPT) study is the first study to evaluate the peri-procedural aggressive
hydration in STEMI patients undergoing pPCI4. Here, we describe the statistical
analysis plan (SAP) for the ATTEMPT study, prior to patient enrollment being
completed (this was completed in June 2018) and the locking of the database for
analysis.
This SAP was written by the study statistician and the principal investigator, both
of whom were kept blind to the course of treatment allocated to the patients. We
prospectively defined each analysis described in this SAP.
2. Methods
2.1 Overview of design
The ATTEMPT study is a multicenter, randomized controlled trial which is
investigator-based and open label in nature. A total of 560 patients with STEMI
undergoing pPCI will be randomized (1:1) to undergo treatment either by
peri-procedural aggressive hydration (treatment group) or general hydration (control
group). The ATTEMPT study could prove valuable for the possible identification of
optimal hydration regimens for STEMI patients undergoing pPCI4.
2.2 Inclusion & Exclusion criteria
Inclusion criteria: All consecutive patients with STEMI who were at least 18
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years of age and were prepared for pPCI were taken into consideration for enrollment
in the study.
Exclusion criteria:
Contrast medium administration within the 2 weeks prior to the procedure or the
following 3 days;
End-stage renal failure or renal transplantation, and refusal of pPCI or death
while the procedure is taking place;
Heart failure-induced cardiac shock or New York Heart Association class IV
(these patients were excluded because intravenous hydration administration could
potentially prove harmful);
A recent acute kidney injury, which was considered to be an absolute increase of
0.5 mg/dL in serum creatinine (SCr) over baseline in the 24 hours prior;
The existence of lactation, pregnancy;
A tumor of a malignant nature or a predicted life expectancy of 1 year or less;
An allergic reaction induced by contrast medium, peri-procedural receipt of
metformin, or non-steroidal anti-inflammatory drugs in the 2 days prior and while
the study is taking place;
Planned renal catheterization or heart valvular surgery.
2.3 Randomization
All patients meeting the eligibility criteria and provided informed consent will be
randomized into two study groups. A computer will carry out randomization of
eligible patients by producing numbers at random at a 1:1 ratio. Randomization will
be accomplished with using a block random method with 8 units in each group. Some
offset or variability will be inserted to prevent anticipation of the next treatment.
Randomization will be stratified based on age (<60, 60–75, >75 years), sex (male or
female), and STEMI location (anterior wall or no-anterior wall). Study coordinators at
each site will be responsible for obtaining a randomized treatment assignment for
each eligible patient. Study sites will be provided with a web-based randomization
program for this purpose. This web-based http://crdms.echobelt.org program will be
tested at each site prior to the start of the trial and will be reviewed. Since this is an
open-label study, the procedure of blinding will not take place.
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2.4 Sample size
The total sample size of 560 patients was calculated based on our previous
findings. The incidence of primary end point was estimated to decrease to 11.5%
(50% relative reduction) in the aggressive hydration group from 23% in the control
group with general hydration5. We established a sample size according to nQuery +
nTerim 3.0 (Statistical Solutions Ltd, Ireland) by employing a 2-sided χ2 test, a power
of 90%, a significance level of 0.05, and a dropout rate <20%.
2.5 The formal statement of the null hypothesis
We fully describe the CI-AKI outcome based on the aggressive hydration versus
general hydration intervention. The null hypothesis is that the two treatment groups
(aggressive hydration and control) do not differ in terms of the proportion of subjects
who experience CI-AKI. The alternative hypothesis is that the absolute difference in
the incidence of CI-AKI between the aggressive hydration group and the control
group.
2.6 Intervention
A pre-procedural loading dose 250 mL of normal saline for 30 minutes (125 mL
for patients with congestive heart failure, Killip II/III or NYHA III) will be
administered to the patients in the treatment group in an emergency department or
cardiac catheterization lab over 30-minutes prior to the pPCI. After this, the patients
will receive intravenous hydration at a general rate (1 or 0.5 mL/kg/h for patients with
congestive heart failure, Killip II/III or NYHA III) until LVEDP measurement.
Patients will then undergo 4 hours of post-procedural aggressive hydration guided
by LVEDP [5 mL/kg/h (LVEDP <13 mmHg), 3 mL/kg/h (LVEDP 13–18 mmHg),
1.5mL/kg/h (LVEDP >18 mmHg), and 0.5 mL/kg/h (LVEDP >20 mmHg)] and
continuous intravascular hydration at the normal rate for the 24 hours following PCI.
Control group patients will receive peri-procedural general hydration with ≤500 mL
normal saline (within 6 hours) at a normal rate (0.5 or 1 mL/kg/h).
2.7 Interim analysis
According to the study design, interim analysis to determine if either intervention
shows a substantial beneficial effect will not be carried out.
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2.8 Timing of analysis
At the end of the study, the final audit should be performed usually within four to
six weeks of the end of the last follow-up of the last subject in the study center. The
preparations and procedures for the study of closed visits are generally the same as for
a regular supervisory visit. The last patient was enrolled on 10th June 2018 (Table 1).
Table 1 Analysis timing of measurement for endpointsEndpoint Analysis timing
Primary endpoint
CI-AKI 48 to 72 hours after the procedure
Secondary endpoint
CI-AKI48 h 48 hours after the procedure
CI-AKICysC 24 hours after the procedure
Major adverse cardiovascular events Within the first year after enrollment
Major adverse clinical events Within the first year after enrollment
CI-PKI requiring dialysis Within the 3-month after enrollment
Total hospitalization costs Discharge from hospital
Length of stay Discharge from hospital
Safety endpoint
Acute heart failure Within the hospitalization after enrollment
CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent
renal damage.
2.9 Analysis principles
Analysis is to be conducted based on adjusted intention-to-treat (ITT)
(randomization must be finished before emergency surgery, and we will not
include the patients who need to be excluded from the final analysis).
We will not impute missing values, unless specified. The number of subjects
included in an analysis will be reported if there is a substantial amount of missing
data. The last observations will not be carried forward. Multiple imputation will
be used if >5% of patients have missing data on the primary outcome.
Each of the tests will be two-tailed, and a P value of less than 0.05 will be
considered to be statistically significant.
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Only analyses conducted up to 1 year after randomization will feature in this
analysis plan and in the primary manuscript.
Pre-specified subgroup analyses will be conducted whether or not a statistically
significant treatment effect on the primary outcome is seen across the total
sample.
We use the t-test for normally distributed continuous variables and expressed as
mean ± SD, and the Wilcoxon rank-sum test was used in non-normal distribution
variables and presented as median and interquartile range.
For categorical variables, we used Pearson χ2 or Fisher’s exact tests to compare
baseline characteristics and study’s endpoints between the aggressive and general
hydration groups; these will be expressed as percentages.
Logistic regression testing to assess whether the recorded treatment effect was
consistent across random stratified variable [age, gender, STEMI location]. Odds
ratios will be reported alongside their related 95% CIs.
Risk ratio (RR) and absolute risk difference (ARD) with their corresponding 95%
confidence interval (CIs) are used to describe the interaction effect (primary,
second, and safe events). The number needed to treat (NNT) for preventing one
CI-AKI-related event was calculated by inverse of the ARD.
2.9.1 Analysis of primary outcome
The primary analysis will be based on adjusted intention to treat principles. Since
the intervention is given and the primary outcome is observed for a very short
duration (72 hours), we expect only a few dropouts or crossovers.
As ATTEMPT study’s protocol pointed out primary outcome would use
multivariable logistic regression with (age, sex, creatinine clearance, and left
ventricular ejection fraction). However, basic on principal component analysis, we
have changed to use multivariable logistic regression to evaluate the intervention
effect with random stratified variable [e.g. age(<60, 60–75, >75 years), gender,
STEMI location]. The analysis for each variable will be performed by OR with their
corresponding 95% CIs to describe the intervention effect. All tests will be two-tailed,
and a P value less than 0.05 will be considered statistically significant.
All consented and randomized subjects will be accounted for and reported in the
CONSORT diagram for the study; however, only those randomized subjects who
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have finished test for SCr at least once on pre-procedure and 72 hours post-procedure
(i.e., did not drop out or withdraw prior to the start of the allocated intervention) will
be considered as an adjusted ITT subject to be included in the DMC reports and
primary efficacy analysis.
2.9.2 Subgroup analyses
We will undertake analysis of five pre-specified subgroups defined by the
following baseline criteria: age (<60, 60–75, >75 years), gender (Male or female),
STEMI location (anterior wall or no-anterior wall), and LVEF (≥40% or <40%),
eGFR (≥90 or <90 mL/minute/1.73 m2).
eGFR formula (Modified relative dose response)= [186 × SCr (mg/dL) ]^− 1.154 × age
^− 0.203 × (multiply by 0.742 for women).
Within each subgroup, summary measures will include raw counts and
percentages within each treatment arm. The analysis for each subgroup will be
performed by RR with their corresponding 95% CIs to describe the interaction effect.
The results will be shown on a forest plot including the P-value for heterogeneity
corresponding to the interaction term between the intervention and the subgroup
variable.
2.9.3 Analysis of secondary outcomes
Our secondary objectives will be tested using χ2 tests, and the 95% CI of the rate
difference of RR and ARD will be calculated using the method described by Altman
et al (reported in Newcombe and recommended by the Food and Drug Administration
and Clinical and Laboratory Standards Institute. The secondary end-points will be
analyzed based on the adjusted ITT principle.
2.9.4 Sensitive analyses
To evaluate the stability of primary outcome, we will use logistic regression to
analyze the influence of compliance and use baseline value comparison to assess the
differences between the two groups of excluded cases. It will be performed by
adjusted with [age(<60, 60–75, >75 years), gender, STEMI location]. All tests will
be two-tailed, and a P value less than 0.05 will be considered statistically significant.
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For patients: the volumes of urine and oral hydration (water in milliliters) in the
24 hours following the procedure will be recorded.
For medical staff: intravenous hydration information will be gathered in the 24
hours following the procedure. A preoperative renal function test and details on
postoperative SCr, failure to hydrate according to protocol, and the absence of SCr
will be obtained in the follow-up. All of this information, laboratory tests and vital
signs will be carefully collected by the research staff.
2.9.5 Central effect analysis
To evaluate the central effect, we will use Generalized mixed linear analysis of
primary outcome with different centers. We describe the central effect by P value and
less than 0.05 will be considered statistically significant.
2.9.6 Analysis of safety outcomes
One of the important adverse reactions to aggressive hydration is the increased
risk of heart failure. We will record all information relating to acute heart failure:
acute pulmonary edema, cardiogenic shock, and further auxiliary examination such as
ECG, chest X-ray, laboratory assessment (with specific biomarkers), and
echocardiography.
The Clinical Event Committee (CEC) will be responsible for determining the
endpoints in clinical studies and avoiding deviations in event determination between
centers in order to achieve a more accurate assessment of the test results. We will use
RR and ARD with their corresponding 95% CIs to describe the safety endpoint.
2.9.7 Treatment of missing data
We conservatively estimate that up to 20% of subjects may be lost to follow-up
SCr within 72 hours and exclusive patients. The site coordinators will make every
effort to identify such subjects including at least two laboratory tests of SCr after
pPCI. Multiple imputation will be used if >5% of patients have missing data on the
primary outcome.
2.9.8 Statistical software
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PCI, percutaneous coronary intervention; eGFR, estimate glomerular filtration rate.
Table S2 Proposed format of data tables and figures for main results publication
LVEF, left ventricular ejection fraction; ACEI/ARB, angiotension-converting enzyme
inhibitor/angiotension receptor blocker.
Inferior and/or right ventricle myocardial infractioncombined with hypotension on admission (systolicpressure ≤90 mmHg)
xxx (xx) xxx (xx)
Pre-procedural renal insufficiency eGFR ≤60mL/min/1.73 m2
xxx (xx) xxx (xx)
Characteristic Aggressive group (N=xxx) Control group (N=xxx)Age, yr xxx (xx) xxx (xx)Age >75 yr, no. (%) xxx (xx) xxx (xx)Sex (male), no. (%) xxx (xx) xxx (xx)Weight (kg) xxx (xx) xxx (xx)Anterior myocardial infarction, no. (%) xxx (xx) xxx (xx)Killip class >1, no. (%) xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Serum creatinine, μmol/L xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2
xxx (xx) xxx (xx)
Estimate glomerular filtration rate <90mL/min/1.73 m2, no. (%)
xxx (xx) xxx (xx)
Cystatin C, mg/L xxx (xx) xxx (xx)LVEF, % xxx (xx) xxx (xx)LVEF <40%, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)ACEI/ARB, no. (%) xxx (xx) xxx (xx)Beta-Blockers, no. (%) xxx (xx) xxx (xx)Statin, no. (%) xxx (xx) xxx (xx)Abciximab, no. (%) xxx (xx) xxx (xx)Diuretic, no. (%) xxx (xx) xxx (xx)Volume of contrast medium, mL xxx (xx) xxx (xx)Time from diagnosis to reperfusion, min xxx (xx) xxx (xx)Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores† xxx (xx) xxx (xx)Peri-procedures Intravenous Hydrationvolume—ml
xxx (xx) xxx (xx)
Pre-angiography xxx (xx) xxx (xx)Procedure xxx (xx) xxx (xx)0-4 hours Post-angiography xxx (xx) xxx (xx)4-24 hours Post-angiography xxx (xx) xxx (xx)Post-procedures Oral Hydration volume—ml
xxx (xx) xxx (xx)
Post-procedures Urine volume—ml xxx (xx) xxx (xx)
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Table S3 Baseline characteristics
LVEF, left ventricular ejection fraction.
Table S4 Hydration information
Demographic Aggressive group (N=xx) Control group (N=xx)Smoke, no. (%) xxx (xx) xxx (xx)Clinical xxx (xx) xxx (xx)Killip class, no. (%) xxx (xx) xxx (xx)I xxx (xx) xxx (xx)II xxx (xx) xxx (xx)III xxx (xx) xxx (xx)
Pre-angiography renal function xxx (xx) xxx (xx)Serum creatinine, μmol/L* xxx (xx) xxx (xx)Estimate glomerular filtration rate,mL/min/1.73 m2*
xxx (xx) xxx (xx)
Estimate glomerular filtration rate <90mL/min/1.73 m2, no. (%)
xxx (xx) xxx (xx)
Cystatin C, mg/L* xxx (xx) xxx (xx)Creatine kinase MB, U/L† xxx (xx) xxx (xx)Hematocrit, % * xxx (xx) xxx (xx)Hbalc, % * xxx (xx) xxx (xx)LVEF, %* xxx (xx) xxx (xx)LVEF <40, no. (%) xxx (xx) xxx (xx)Hypertension, no. (%) xxx (xx) xxx (xx)Diabetes mellitus, no. (%) xxx (xx) xxx (xx)Previous myocardial infarction, no. (%) xxx (xx) xxx (xx)Contrast type, no. (%) xxx (xx) xxx (xx)Iodixanol xxx (xx) xxx (xx)Iopromide xxx (xx) xxx (xx)Iopamidol xxx (xx) xxx (xx)
Other low osmolal agents xxx (xx) xxx (xx)Contrast media volume, total (mmHg)* xxx (xx) xxx (xx)Left ventricular end-diastolic pressure, no./total(mmHg)*
xxx (xx) xxx (xx)
Intra-aortic balloon pump, no. (%) xxx (xx) xxx (xx)Mehran scores xxx (xx) xxx (xx)
Hydration information Aggressive group (N=xx) Control group (N=xx)Pre-procedure’s hydration adjustment —no. xxx (xx) xxx (xx)
Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive hydration xxx (xx) xxx (xx)Did not undergo general hydration xxx (xx) xxx (xx)
In-procedure‘s hydration adjustment —no. xxx (xx) xxx (xx)Intense hydration for hypotension xxx (xx) xxx (xx)Did not undergo aggressive hydration xxx (xx) xxx (xx)
Post-procedure’s hydration adjustment —no. xxx (xx) xxx (xx)Intense hydration for hypotension xxx (xx) xxx (xx)
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3.3 Study outcomes
The primary endpoint is CI-AKI, which is considered to be a >25% or 0.5 mg/dL
increase in SCr from baseline in the 48–72 hours immediately following the
procedure (Table 1, Supplementary Table S5-6)9.
Table S5 Primary and secondary endpoints
CI-AKI, contrast-induced acute kidney injury; CI-PKI, contrast-induced persistent renal
damage.
Table S6 Clinical events
CI-AKI, contrast-induced acute kidney injury.
Endpoint Aggressivegroup (N=xx)
Control group(N=xx)
Relative ratio(95% CI)
Absolutely riskdifference (95%CI)
P value
Primary endpoint, (%)CI-AKI xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx
Secondary endpoint, (%)CI-AKI 48h xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xxCI-AKICysC xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xxMajor adverse cardiovascular event,
(%) xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx
Major adverse clinical event, (%) xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xxCI-PKI (%) xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx
Total hospitalization costs, $† xxx xxx — — xxLength of stay, d xxx xxx — — xxSafety endpoint, (%)Acute heart failure xxx (xx) xxx (xx) xxx (xx-xx) xxx (xx-xx) xx
Variable name Aggressive group (N=xx) Control group (N=xx)Total events, no. (%) xxx (xx) xxx (xx)CI-AKI xxx (xx) xxx (xx)CI-AKI48 h xxx (xx) xxx (xx)CI-AKICysC xxx (xx) xxx (xx)Death xxx (xx) xxx (xx)Target vascular revascularization xxx (xx) xxx (xx)Nonfatal myocardial infarction xxx (xx) xxx (xx)Dialysis xxx (xx) xxx (xx)Acute heart failure xxx (xx) xxx (xx)Cardiac shock xxx (xx) xxx (xx)Stroke xxx (xx) xxx (xx)Bleeding xxx (xx) xxx (xx)Arrhythmias xxx (xx) xxx (xx)Infection xxx (xx) xxx (xx)
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The secondary outcomes consist of: (I) CI-AKI, defined as a >50% or 0.3-mg/dL
absolute increase in SCr from baseline in the 48 hours immediately after the
procedure; (II) CI-AKI, defined as a >10% or 0.3-mg/dL absolute increase in serum
cystatin-C during the 24 hours immediately following the procedure9; (III) persistent
renal damage, which is considered to be residual impairment of renal function
demonstrated by a >25% reduction in creatinine clearance at 3 months compared with
baseline10; (IV) major adverse cardiovascular events, which include all-cause
mortality, target vascular revascularization, and non-fatal myocardial infarction; (V)
major adverse clinical events which take place in hospital following the procedure,
including acute pulmonary edema, cardiogenic shock, stroke, clinically significant
arrhythmias, and bleeding; (VI) total hospitalization costs; (VII) length of stay.
The safe outcome is Acute heart failure (AHF) during hospitalization, defined as
signs/symptoms of heart congestion and/or hypoperfusion by physical examination
and further auxiliary examination such as ECG, chest X-ray, laboratory assessment
(with specific biomarkers), and echocardiography11.
1. Narula A, Mehran R, Weisz G, et al. Contrast-induced acute kidney injury after
primary percutaneous coronary intervention: results from the HORIZONS-AMI
substudy. Eur Heart J 2014;35:1533-40.
2. Mehran R, Dangas GD, Weisbord SD. Contrast-Associated Acute Kidney Injury.
N Engl J Med 2019;380:2146-55.
3. Liu Y, Hong D, Wang AY, et al. Effects of intravenous hydration on risk of
contrast induced nephropathy and in-hospital mortality in STEMI patients
undergoing primary percutaneous coronary intervention: a systematic review and
meta-analysis of randomized controlled trials. BMC Cardiovasc Disord
2019;19:87.
4. Liu Y, Chen JY, Huo Y, et al. Aggressive hydraTion in patients with
ST-Elevation Myocardial infarction undergoing Primary percutaneous coronary
intervention to prevenT contrast-induced nephropathy (ATTEMPT): Study design
and protocol for the randomized, controlled trial, the ATTEMPT, RESCIND 1
(First study for REduction of contraSt-induCed nephropathy followINg carDiac
catheterization) trial. Am Heart J 2016;172:88-95.
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Youg Liu: ATTEMPT Cinical Trial Protocol Version 3.0
5. Tan N, Liu Y, Chen JY, et al. Use of the contrast volume or grams of
iodine-to-creatinine clearance ratio to predict mortality after percutaneous
coronary intervention. Am Heart J 2013;165:600-8.
6. Moher D, Schulz KF, Altman D. The CONSORT statement: revised
recommendations for improving the quality of reports of parallel-group
randomized trials. JAMA 2001;285:1987-91.
7. Kahan BC, Morris TP. Improper analysis of trials randomised using stratified
blocks or minimisation. Stat Med 2012;31:328-40.
8. Moher D, Hopewell S, Schulz KF et al. CONSORT 2010 explanation and
elaboration: updated guidelines for reporting parallel group randomised trials.
BMJ 2010;340:c869.
9. Briguori C, Visconti G, Rivera NV, et al. Cystatin C and contrast-induced acute
kidney injury. Circulation 2010;121:2117-22.
10. Maioli M, Toso A, Leoncini M, et al. Persistent renal damage after
contrast-induced acute kidney injury: incidence, evolution, risk factors, and
prognosis. Circulation 2012;125:3099-107.
11. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the
diagnosis and treatment of acute and chronic heart failure: The Task Force for the
diagnosis and treatment of acute and chronic heart failure of the European
Society of Cardiology (ESC)Developed with the special contribution of the Heart
Failure Association (HFA) of the ESC. Eur Heart J 2016;37:2129-200.
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Appendix D
Changes to ATTEMPT Statistical Analysis Plan
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Table S7. Changes to ATTEMPT SAP
OriginalVersionNumber
NewVersionNumber
Description of Change Justification for Change
1.0 2.0
Analysis principles:
“Multivariable logisticregression models will bedeveloped to adjust for clinicalcharacteristics (eg, age, sex,creatinine clearance, and leftventricular ejection fraction[LVEF])”
Change into “Logisticregression testing to assesswhether the recorded treatmenteffect was consistent acrossrandom stratified variable (age,gender, STEMI location).
”
Because of the age, gender, andSTEMI location are randomstratified variables. To evaluate themain outcome, we need to adjust theintervention method with randomstratified variables.
1.0 2.0
Analysis principles:Add the “Risk ratio (RR) and
absolute risk difference (ARD)with their corresponding 95%confidence interval (CIs) are usedto describe the interaction effect(primary, second, and safeevents). The number needed totreat (NNT) for preventing oneCI-AKI-related event wascalculated by inverse of theARD.”
RR, ARD, and NNT value areimportant intervention effect’sevaluation index.
1.0 2.0
Analysis of soft-ware
Add the “R soft-ware(version 3.6.1; R Core Team,Vienna, Austria)”
R soft-ware is good to drawnsome statistical figures.
1.0 2.0
Analysis of primary outcome
As ATTEMPT study’sprotocol pointed out primaryoutcome would usemultivariable logistic
To evaluate the primaryoutcome, we need to adjust theintervention effect with randomstratified variables.
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regression with (age, sex,creatinine clearance, and leftventricular ejection fraction).
Change into “However,basic on principal componentanalysis, we have changed to usemultivariable logistic regressionto evaluate the intervention effectwith random stratified variable(e.g. age(<60, 60–75, >75 years),gender, STEMI location).”
1.0 2.0
Sensitive analyses
To evaluate the stability ofprimary outcome, we will uselogistic regression to analyze theinfluence of compliance. It will beperformed by OR with theircorresponding 95% CIs.
Add the “and use baselinevalue comparison to assess thedifferences between the twogroups of excluded cases. It willbe performed by adjusted with[age(<60, 60–75, >75 years],gender, STEMI location). ”
To evaluate the sensitive ofintervention effect, it still need toadjust with random stratifiedvariables.
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Table of Contents
Appendix B/CFigure A1. Major risk factors for CI-AKI in STEMI patients.Figure A2. Development process of clinical adverse events exposure to contrastagent.Figure A3. Pathophysiology of CI-AKI in STEMI patients.Figure A4. Overview of study design.Figure A5. CEC review process.Figure A6. Study management structure.Figure A7. Enrollment by Site.Figure A8. Incidence of CI-AKI among different level of center.
Table A1. Characteristics of randomized clinical trials on prevention of CI-AKI underdifferent hydration strategies of IV isotonic saline.Table A2. Timetable of visits and procedures.Table A3. Definitions of components of MACEs.Table A4. Definitions of components of major post-procedure in-hospital adverseclinical events.Table A5.
Appendix D/EFigure 1. Consort flowchartFigure 2. Consent details
Table S1. Inclusion and exclusion criteria.Table S2. Proposed format of data tables and figures for main results publication.Table S3. Baseline characteristicsTable S4. Hydration informationTable S5. Primary and secondary endpointsTable S6. Clinical eventsTable S7. Changes to ATTEMPT Statistical Analysis Plan
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