Rapid Fire Review of ACC.17 Late-Breaking Clinical Trials · Study Design Aim: Compare the efficacy...
Transcript of Rapid Fire Review of ACC.17 Late-Breaking Clinical Trials · Study Design Aim: Compare the efficacy...
Rapid Fire Review of ACC.17 Late-Breaking Clinical Trials
Akhil Narang, MDAdvanced Cardiac Imaging Fellow, University of ChicagoImmediate Past Chair, ACC Fellows-in-Training Section
2017 ACC Illinois/Wisconsin Annual MeetingLake Geneva, WIMay 7, 2017
@AkhilNarangMD
Michael J. Reardon, MD
For the SURTAVI Investigators
Transcatheter Aortic Valve Replacement with a Self-Expanding Prosthesis or Surgical Aortic Valve
Replacement in Intermediate-Risk Patients:First Results from the SURTAVI Clinical Trial
• TAVR is is superior in patients at high risk for operative mortality at 30 days.1
• Comparative efficacy of TAVR and SAVR has been less well studied in AS patients at lower surgical risk.
Background
1Adams D, Popma J, Reardon M, et al. New Engl J Med 2014
3
Objective
Assess the safety and efficacy of TAVR with the self-expanding valve vs. surgical AVR in patients
with symptomatic, severe AS at intermediate surgical risk
4
Intermediate Surgical Risk Predicted risk of operative mortality ≥3% and <15%
Heart Team EvaluationAssess inclusion/exclusion
Risk classification
RandomizationStratified by need for revascularization
TAVR SAVR
TAVR + PCI SAVR + CABGTAVR only SAVR only
Baseline neurological assessments
Screening CommitteeConfirmed eligibility
5
Trial Design
• 17 sites in Europe• 5 sites Canada• 65 sites in the
United States
894 patients
796 patients
First patient enrolled June 19, 2012
Primary endpointassessment Dec 2016
CoreValve (n=724) Evolut R (n=139)
2012 2013 2014 2015 2016
Enrollment completed June 30, 2016
Evolut R (US)
CoreValve: 23, 26 and 29 mm (CAN, EU)
CoreValve: 31 mm (US, CAN, EU)
94% TF4% DA2% SCA
6
CoreValve: 23, 26 and 29 mm (US)
April
Study Timeline
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
All-
Cau
se M
ort
alit
y o
r D
isab
ling
Stro
ke
Months Post-ProcedureNo. at Risk796 674 555 407 241
864 755 612 456 272TAVR
SAVR
Primary Endpoint: All-Cause Mortality or Disabling Stroke
24 Months
TAVR SAVR12.6% 14.0%
7
Meetsnoninferiority
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
24 Months
TAVR SAVR95% CI for Difference
11.4% 11.6% -3.8, 3.3
0%
5%
10%
15%
20%
25%
30%
0 6 12 18 24
All-
Cau
se M
ort
alit
y
Months Post-Procedure
TAVR SAVR
No. at Risk796 690 569 414 249
864 762 621 465 280TAVR
SAVR
All-Cause Mortality
30 DaySAVR 1.7% O:E 0.38TAVR 2.2% O:E 0.50
8
0%
2%
4%
6%
8%
10%
0 6 12 18 24
Dis
ablin
g St
roke
Months Post-ProcedureNo. at Risk
796 674 555 407 241
864 755 612 456 272TAVR
SAVR
Disabling Stroke
24 Months
TAVR SAVR95% CI for Difference
2.6% 4.5% -4.0, 0.1
9
• SURTAVI met its primary endpoint: TAVR with a self-expanding CoreValve or Evolut R bioprosthesis is noninferior to SAVR for all-cause mortality or disabling stroke at 24 months.
• TAVR had significantly less 30 day stroke, AKI, atrial fibrillation and transfusion use and a superior quality of life at 30 days.
• TAVR resulted in significantly improved AV hemodynamics with lower mean gradients and larger aortic valve areas than SAVR through 24 months.
• SAVR had less residual aortic regurgitation, major vascular complications and fewer new pacemakers.
• Need for a new pacemaker after TAVR was not associated with increased mortality.
Summary
10
• In SURTAVI, TAVR with the self-expanding valve was safe and effective treatment for patients with symptomatic severe AS at intermediate risk for surgical mortality
Summary
11
Dr. Phil Wells on behalf of the EINSTEIN CHOICE Steering Committee and Investigators
Weitz JI et al. N Engl J Med 2017 (DOI: 10.1056/NEJMoa1700518)
Rivaroxaban or Aspirin for Extended Treatment
of Venous Thromboembolism
NCT02064439
Background
Risk of recurrent VTE is up to 10% in the first year if anticoagulation (AC) is
stopped in patients without reversible risk factors for VTE
ASA has been previously shown to reduced rates of recurrent VTE
Although extended AC prevents recurrent VTE, there is reluctance to extend
treatment beyond 6-12 months due to bleeding
Study Design
Aim: Compare the efficacy and safety of once daily rivaroxaban (20 or 10 mg)
with aspirin (100 mg) in VTE patients who completed 6 to 12 months of
treatment
Randomized, double-blind, active-comparator, event-driven, superiority study
1 month
observation
period
Rivaroxaban 20 mg od (1121 patients)
Rivaroxaban 10 mg od (1127 patients)N=3396Patients with confirmed
symptomatic DVT/PE who completed 6–12 months of anticoagulation
R
Aspirin 100 mg od (1069 patients)
12-month treatment duration
Weitz JI et al. Thromb Haemost 2015;114:645–50
Recurrent VTE – Cumulative Incidence
VTE, Venous thromboembolism; HR, hazard ratio
Aspirin 4.4% (50/1131)
Rivaroxaban 20 mg 1.5% (17/1107)
Rivaroxaban 10 mg 1.2% (13/1127)
Days
0
1
2
3
4
5
Cu
mu
lati
ve
in
cid
en
ce
(%
)
1 30 60 90 120 150 180 210 240 270 300 330 367
Number of patients at risk
Rivaroxaban 20 mg 1107 1102 1095 1090 1084 1079 997 876 872 860 794 718 0
Rivaroxaban 10 mg 1126 1124 1119 1118 1111 1109 1029 890 886 867 812 723 0
Aspirin 1131 1121 1111 1103 1094 1088 1010 859 857 839 776 707 0
Major Bleeding – Cumulative Incidence
Treatment-emergent major bleeding: onset during study treatment up to 2 days after stop of study treatment
Number of patients at risk
Rivaroxaban 20 mg 1107 1081 1063 1048 1036 1024 963 818 801 780 712 642 449 10 0 0 0
Rivaroxaban 10 mg 1126 1103 1080 1070 1058 1046 988 823 812 790 733 653 469 8 0 0 0
Aspirin 1131 1096 1075 1058 1040 1023 970 800 791 768 709 645 445 5 2 2 0
0
1
2
4
5
3
1 30 60 120 150 180 240 270 300 360 390 420 45090 210 330 480Days
Aspirin 0.3% (3/1131)
Rivaroxaban 20 mg 0.5% (6/1107)
Rivaroxaban 10 mg 0.4% (5/1127)
Cu
mu
lati
ve
in
cid
en
ce
(%
)
Summary and Conclusions
In patients with VTE who completed 6 to 12 months of treatment, rivaroxaban
(20 or 10 mg once daily) is superior to ASA for recurrent VTE and are
associated with similar rates of bleeding
Compared with aspirin, NNT to prevent one VTE without increase in bleeding for
rivaroxaban 20 mg QD = 33 and rivaroxaban 10 mg QD = 30
Rivaroxaban 10 mg once daily provides an additional option for extended
VTE treatment
*Number needed to treat (NNT) compared with aspirin for primary efficacy outcome up to 1 year
COMPARE-ACUTE
Randomised trial of
FFR-guided complete revascularization
versus
infarct artery only treatment in
multivessel STEMI patients
On behalf of all COMPARE-ACUTE investigators
Pieter Smits
Maasstad Hospital
Rotterdam, The Netherlands
Introduction
• ~50% of the STEMI patients have multivessel disease at
presentation (≥50% stenosis in ≥1 non-infarct-related
arteries (non-IRAs)
• Management of these non-IRAs lesions an unresolved
clinical dilemma
Trial design
885 stable multivesselSTEMI pts. randomized
295 pts
Acute FFR-guided complete revascularization of non-IRA lesions
590 pts
Infarct related artery only treatment + blinded FFR of non-IRA lesions
1 : 2 randomization
Follow-up at 30 days, 12, 24 and 36 months
45 day treatment window for
elective clinically indicated PCI
Acute STEMI patients
undergoing primary PCI
FFR was
measured
by Pd/Pa in
rest and after
adenosine iv
or ic
Primary outcome
No. at risk
FFR guided complete
295 286 281 264 215
Culprit lesion only 590 512 492 457 371
HR = 0.35 (95% CI 0.22 - 0.55),
p<0.001
Log-rank p<0.001
7.8%
20.5%
Driven by the
decreased need
for subsequent
revascularization
Conclusions
• In multivessel STEMI patients, FFR-guided complete
revascularization of non-IRA in the acute phase reduced
the risk of the composite MACCE outcome compared to
treatment of the IRA only
• This reduction was mainly driven by the decreased need
for subsequent revascularization
DECISION-CTO
Optimal Medical Therapy With or Without
Stenting For Coronary Chronic Total Occlusion
Seung-Jung Park, MD., PhD.
Heart Institute, University of Ulsan College of Medicine
Asan Medical Center, Seoul, Korea
Background
• Benefits of successful CTO-PCI include reduced angina and
improvements in QOL, LVEF, or survival.
• CTO-PCI can lead to procedure-related complications.
• Evidence for CTO-PCI mostly from observational studies,
most of which compared successful and failed CTO-PCI
without a control group receiving optimal medical treatment.
DECISION CTO Trial
• OBJECTIVE: To compare the outcomes of OMT alone with
PCI coupled with OMT in patients with CTO.
• DESIGN: a prospective, open-label, randomized trial
• Inclusion Criteria:
- Silent ischemia, stable angina, or ACS
- De novo CTO located in a proximal to mid epicardial coronary artery with a
reference diameter of ≥2.5 mm
Study Procedures
• Patients who were assigned to PCIs underwent CTO-PCI using DES within 30
days after randomization
• In cases of failed CTO-PCI, additional attempts were allowed within 30 days
after the index procedure.
• Patients were prescribed guideline derived OMT including aspirin, P2Y12
receptor inhibitors (>12months in case of PCI), BB, CCB, nitrate, ACEi/ARB,
and statin.
• Blood pressure and diabetic control, smoking cessation, weight control, and
regular exercise were recommended.
Noninferiority Test for Primary End Point at 3-Year
Prespecified non-inferiority margin: 0.7
Lower 1-sided 97.5% CI
0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5
Event Rate Ratio 1.05
Non-inferiority P=0.008
Estimated 3-year Event Rate OMT: 19.6% PCI: 20.6%
Event Rate Ratio of 3-year MACE rate (PCI/OMT)
ITT Population
Non-inferiority met with ITT (not in as-treated
analysis or in per-protocol analysis)
Primary End Point(Death, MI, Stroke, Any Repeat Revascularization)
ITT Population
No. at Risk
OMT 398 305 246 178 129 72
PCI 417 293 241 175 117 65
Y e a rs S in c e R a n d o m iz a t io n
Pro
ba
bil
ity
(%
)
0 1 2 3 4 5
0
1 0
2 0
3 0
4 0
5 0
6 0
Crude HR 0.95 (95% CI, 0.74-1.22), P=0.67
Adjusted HR 0.91 (95% CI, 0.68-1.23), P=0.54
20.6%
19.6%25.1%
26.3%
PCIOMT
Conclusion
• DECISION-CTO trial is the first RCT to compare the strategy of OMT alone with that of
PCI in patients with coronary CTO.
• The ITT analysis showed that OMT as an initial strategy was non-inferior to PCI with
respect to the primary endpoint of the composite of death, MI, stroke, or any
revascularization at 3 years.
• Quality of life in the OMT and the PCI groups were comparable.
• OMT could be a reasonable initial treatment strategy for coronary CTO compared
with CTO-PCI.
Relationship between highsensitivity Troponin T
measurements and 30-day mortality after noncardiac surgery
PJ Devereaux, MD, PhD
McMaster University
Background• >5 Million Americans >45 years old undergo in-patient noncardiac surgery/year
and 1.3% die in hospital
– Cardiac complications are leading cause
• Myocardial injury after noncardiac surgery (MINS) is
– Defined as myocardial injury caused by ischemia that occurs during or within 30 days after surgery and is independently associated with mortality
• Little is known about relationship between perioperative hsTnT measurements and 30-day mortality and MINS
Design and Methods • Prospective, international, cohort study
• >45 yrs underwent in-patient noncardiac surgery
• Participating countries (23 centers in 13 countries)
• Patients had hsTnT measurements 6-12 hours after surgery and daily for 3 days
– 40.4% had preoperative hsTnT measurement
Results• 21,842 participants
– Mean age 63 years, 49% were female
• Most common types of surgery
– Major orthopedic (16%)
– Major general (20%)
– Low-risk (35%)
• 21,050 (96.4%) completed 30-day follow-up
– 266 patients (1.2%; 95% CI, 1.1-1.4) died within 30 days of surgery
Peak postoperative hsTnT thresholds associated with 30-day mortality
• No interaction b/w postop hsTnT threshold ≥20 ng/L and eGFR or sex (interaction p=0.83 and 0.20)
hsTnT thresholds % of PatientsMortality Rate
(%)aHR (95% CI) p-value
<5 ng/L 24.4 0.1 1.00 -
5 to <14 ng/L 40.1 0.5 3.73 (1.58-8.82) 0.003
14 to <20 ng/L 11.6 1.1 9.11 (3.76-22.09) <0.001
20 to <65 ng/L 18.6 3.0 23.63 (10.32-54.09) <0.001
65 to <1000 ng/L 5.1 9.1 70.34 (30.60-161.71) <0.001
≥1000 ng/L 0.2 29.6 227.01 (87.35-589.92) <0.001
• Among 4385 patients with elevated postop hsTnT
– 481 (11.0%) had non-ischemic (e.g., sepsis) non-MINS hsTnT elevation
– 13.8% of patients with elevated perioperative hsTnT had their peak value before surgery
Conclusions• Elevated postoperative hsTnT measurements strongly associated with 30-
day mortality (regardless of eGFR and sex)
• 13.8% of patients had their peak value before surgery suggests
– Physicians should consider obtaining preoperative hsTnT measurement in patients who they plan to measure hsTnT after surgery
• MINS may explain 24% of perioperative deaths
• 93% of MINS would probably go undetected without troponin monitoring
Subclinical Leaflet Thrombosis in Surgical and
Transcatheter Bioprosthetic Aortic ValvesResults from RESOLVE and SAVORY registries
Raj R. Makkar, MD
On Behalf of RESOLVE and SAVORY Investigators
• Subclinical leaflet thrombosis (reduced leaflet motion on CT) reported in ~10-15% of
patients after TAVR and surgical bioprosthetic AV
– Less common in patients on therapeutic anticoagulation with warfarin and resolves with
initiation of warfarin.
• No data on differences between SAVR and TAVR, impact of NOACs on prevention,
treatment, and outcomes
• Objective: Characterize incidence of leaflet thrombosis in SAVR/TAVR and role of
NOACs in management
Background
Makkar R. et al. NEJM 2015; Pache G. et al. EHJ 2015; Yanagisawa R. et al. JACC: Cardiovascular
Interventions 2016; Hansson NC. et al. JACC 2016; Ruile P. et al. Clin Res Cardiol 2017
Valve types and timing of CTTime from TAVR to CT vs. SAVR to CT: p<0.0001
890 patients with CTs (RESOLVE and SAVORY Registry)
Median time from AVR to CT 83 days (IQR 32-281 days)
752 transcatheter valves
Median time from TAVR to CT
58 days (IQR 32–236 days)
138 surgical valves
Median time from SAVR to CT
162 days (IQR 79–417 days)
Hypoattenuated leaflet thickening assessed using 2D and 3D volume-rendered (VR) imaging. Leaflet motion was assessed using 4D VR imaging.
Reduced leaflet motion was defined as the presence of at least 50% restriction of leaflet motion.
Prevalence of reduced leaflet motionTranscatheter vs. surgical bioprosthetic aortic valves: p=0.001
Reduced leaflet motion was present in 106
(11.9%) patients
Transcatheter valves
13.4% (101 out of 752)
Surgical valves
3.6% (5 out of 138)
Anticoagulation and reduced leaflet motionAnticoagulation vs. no anticoagulation
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
Pre
va
len
ce o
f re
du
ced
lea
flet
mo
tio
n
Anticoagulation NOACs WarfarinNo
anticoagulation
8/224
(3.6%) 3/107
(2.8%)
5/117
(4.3%)
98/666
(14.7%)Anticoagulation vs. no anticoagulation: p<0.0001
NOACs vs. no anticoagulation: p=0.0002
Warfarin vs. no anticoagulation: p=0.001
NOACs vs. warfarin: p=0.72
Anticoagulation and reduced leaflet motionAnticoagulation vs. antiplatelet therapy
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
Pre
va
len
ce o
f re
du
ced
lea
flet
mo
tio
n
Anticoagulation NOACs Warfarin DAPT
8/224
(3.6%) 3/107
(2.8%)
5/117
(4.3%)
31/208
(14.9%)Anticoagulation vs. DAPT: p<0.0001
Anticoagulation vs. monoantiplatelet therapy: p<0.0001
63/405
(15.6%)
Monoantiplatelet
therapy
Impact of initiation of anticoagulation on
reduced leaflet motion
0.0
20.0
40.0
60.0
80.0
100.0
120.0
Pre
va
len
ce o
f re
du
ced
lea
flet
mo
tio
n
Resolution
36/36
(100%) • Resolution in 36 out of
36 patients treated with
anticoagulation
(NOACs, n=12;
warfarin, n=24)
• Persistence/progression
in 20 out of 22 patients
not treated with
anticoagulation
P<0.0001No change or
progressionResolution No change or
progression
0/36
(0%)
2/22
(9.1%)
20/22
(89.1%)
Anticoagulation initiated No anticoagulation initiated
Conclusions
• In a heterogeneous cohort of bioprosthetic AV, reduced leaflet motion occurred 12% on CT.
• SAVR vs TAVR, had lower incidence of reduced leaflet motion (3.6% vs. 12%; p<0.04).
However, SAVR patients younger and fewer comorbidities.
• Anticoagulation with both warfarin and NOACs and not DAPT which is the standard of care
were effective in prevention and treatment of reduced leaflet motion.
• Cases of subclinical leaflet thrombosis diagnosed by CT are hemodynamically silent and hence
missed by TTE
• While the death, MI and stroke rates were not significantly different between the 2 groups,
subclinical leaflet thrombosis was associated with increased rates of TIAs and strokes/TIAs.
Background
• Management of stable coronary disease: optimize risk factors, OMT
– Revascularize those with resistant symptoms and proven ischemia
• FAME & DEFER showed FFR to invasive angiography has
prognostic benefits
• Combination of OMT + FFR-guided revascularization current best
invasive management strategy for patients with stable angina
Optimal Non-Invasive Strategy
• Non-invasive ischemia testing with perfusion imaging accurately
predicts flow-limiting stenosis and outcomes
• CMR perfusion imaging highest accuracy of non-invasive testing
– No radiation
– Gives anatomy, function, and myocardial structure
• Combination of OMT + CMR perfusion current best non-invasive
management strategy for patients with stable angina
Hypothesis
• In patients with stable angina and intermediate to high
risk of CAD, guiding the initial management with OMT
+ CMR-perfusion imaging is non-inferior to OMT +
invasive angiography with FFR
Optimal Medical Therpy
• All patients received OMT
– ASA or Clopidogrel
– Statin (goal LDL <2 mmol/L (77 mg/dL), total chol <4 mmol/L (154 mg/dL))
– ACE-I or ARB (goal BP <130/80)
– Counseling (goal BMI <25, random glucose <6 mmol/L (108 mg/dL), non-
smoking)
918 patients total randomized (groups well matched)-27% with diabetes-13% with known CAD
FFR arm (464)CMR arm (454)
Follow-up 1-year
MACE at 1-year-FFR vs. CMR: 3.9% vs. 3.3%, P=0.62
-Death: 0.22% vs. 0.89%-MI: 1.7% vs. 1.8%-Repeat revasc: 1.9% vs. 0.7%
Conclusions
• CMR-perfusion guided management of stable angina is
noninferior for the MACE endpoint at 1 year compared with
invasive angiography and FFR
• First trial to show that CMR-perfusion imaging could guide
patient management in a high-risk population with the same
effectiveness as invasive angiography with FFR
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
FOURIERFurther cardiovascular OUtcomes
Research with PCSK9 Inhibition in
subjects with Elevated RiskMS Sabatine, RP Giugliano, AC Keech, N Honarpour,
SM Wasserman, PS Sever, and TR Pedersen,
for the FOURIER Steering Committee & Investigators
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Sever P & Mackay J. Br J Cardiol 2014;21:91-3
Giugliano RP, et al. Lancet 2012;380:2007-17
Sabatine MS, et al. NEJM 2015;372:1500-9
Proprotein convertase subtilisin/kexin type 9 (PCSK9)
• Chaperones LDL-R to destruction circulating LDL-C
Evolocumab
• Fully human anti-PCSK9 mAb
• ~60% LDL-C
• Safe & well-tolerated in Ph 2 & 3 studies
• Exploratory data suggested CV events
Objective: In patients with CV disease on statin therapy, test whether
evolocumab reduces incidence of major CV events; long-term safety
Background & Objective
evolocumab
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Trial Design
Evolocumab SC 140 mg Q2W or 420 mg QM
Placebo SCQ2W or QM
LDL-C ≥70 mg/dL or
non-HDL-C ≥100 mg/dL
Follow-up Q 12 weeks
Screening, Lipid Stabilization, and Placebo Run-in
High or moderate intensity statin therapy (± ezetimibe)
27,564 high-risk, stable patients (49 countries) w/ established
CV disease (prior MI, prior stroke, or symptomatic PAD)
RANDOMIZED
DOUBLE BLIND
Sabatine MS et al. Am Heart J 2016;173:94-101
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Lipid Lowering Therapy
& Lipid Levels at BaselineCharacteristic Value
Statin use (%)*
High-intensity 69
Moderate-intensity 30
Ezetimibe use (%) 5
Median lipid measures (IQR) – mg/dL
LDL-C 92 (80-109)
Total cholesterol 168 (151-189)
HDL-C 44 (37-53)
Triglycerides 133 (100-182)
*Per protocol, patients were to be on atorva ≥20 mg/d or equivalent.
1% were on low intensity or intensity data were missing.
Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines.
Pooled data; no differences between treatment arms
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0
10
20
30
40
50
60
70
80
90
100
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168
LD
L C
ho
les
tero
l (m
g/d
l)
Weeks
LDL Cholesterol
Evolocumab
(median 30 mg/dl, IQR 19-46 mg/dl)
Placebo
59% mean reduction (95%CI 58-60), P<0.00001
Absolute reduction: 56 mg/dl (95%CI 55-57)
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
10%
12%
14%
16%
Primary Endpoint
Evolocumab
Placebo
Months from Randomization
CV
Death
, M
I, S
tro
ke,
Ho
sp
fo
r U
A,
or
Co
rR
evasc
0 6 12 18 24 30 36
Hazard ratio 0.85
(95% CI, 0.79-0.92)
P<0.0001 12.6%
14.6%
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Lower LDL-C Is Better
P<0.0001
Patients divided by quartile of baseline LDL-C and by treatment arm
Q4
Q3
Q2
Q1
Q4Q3
Q2
Q1
PlaceboEvolocumab
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
0%
2%
4%
6%
8%
0%
2%
4%
6%
8%
Landmark Analysis
Evolocumab
Placebo
Months from Randomization
CV
Death
, M
I, S
tro
ke
0 3 9 12 24 30 366 12 18
16% RRR
HR 0.84 (95%CI 0.74-0.96)
P=0.008
25% RRR
HR 0.75 (95%CI 0.66-0.85)
P<0.00001
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Summary for Evolocumab
• LDL-C by 59%
– Consistent throughout duration of trial
– Median achieved LDL-C of 30 mg/dl (IQR 19-46 mg/dl)
• CV outcomes in patients already on statin therapy
– 15% broad primary endpoint; 20% CV death, MI, or stroke
– Consistent benefit, incl. in those on high-intensity statin, low LDL-C
– 25% reduction in CV death, MI, or stroke after 1st year
• Safe and well-tolerated
– Similar rates of AEs, incl DM & neurocog events w/ evolocumab & placebo
– Rates of evolocumab discontinuation low and no greater than pbo
– No neutralizing antibodies developed
An Academic Research Organization of
Brigham and Women’s Hospital and Harvard Medical School
Conclusions
In patients with known cardiovascular disease:
1. PCSK9 inhibition with evolocumab significantly &
safely major cardiovascular events when added to
statin therapy
2. Benefit was achieved with lowering LDL cholesterol
well below current targets