Supplementary appendix - The Lancet€¦ · Supplementary appendix ... Lumin Sheeba, Shantha Kumar...

Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Vinereanu D, Lopes RD, Bahit MC, et al, on behalf of the IMPACT-AF investigators. A multifaceted intervention to improve treatment with oral anticoagulants in atrial fibrillation (IMPACT-AF): an international, cluster-randomised trial. Lancet 2017; published online Aug 28. http://dx.doi.org/10.1016/S0140-6736(17)32165-7.

Supplemental Appendix

Baseline risk factors used in the adjusted models Supplemental figure: Pre-specified subgroup analyses for the primary outcome, as odds

ratios representing the proportional increase in anticoagulation use from baseline to one year in the intervention group compared with the control group

IMPACT-AF investigators CME monograph: “Approaching the Patient with Atrial Fibrillation: Clinical Information

for Physicians” Webinars:

o Webinar #1: Atrial Fibrillation: Patient identification and risk stratification o Webinar #2: Atrial Fibrillation: Managing anticoagulation o Webinar #3: Atrial Fibrillation: How to change care

Baseline factors used in the adjusted models:

1. Age (≥65 vs. <65 years) 2. Sex (male vs. female) 3. Education level (≤10 vs. >10 years) 4. Residence (urban/city vs. rural/village) 5. Medical payment type (insurance vs. self/family) 6. Living alone (yes vs. no) 7. New or recent (<3 months) diagnosis of atrial fibrillation (yes vs. no) 8. History of rheumatic valvular heart disease (yes vs. no) 9. Prior major bleeding (yes vs. no) 10. History of falls (yes vs. no) 11. Patient able to complete all activities of daily life (yes vs. no) 12. Signs or prior diagnosis of cognitive impairment (yes vs. no) 13. Prior stroke or transient ischemic attack (yes vs. no) 14. Hypertension requiring treatment (yes vs. no) 15. Uncontrolled (systolic blood pressure >160 mmHg) hypertension (yes vs. no) 16. Congestive heart failure and/or ejection fraction ≤40% (yes vs. no) 17. History of diabetes (yes vs. no) 18. Creatinine (≤1.5 vs. >1.5 mg/dL) 19. Creatinine clearance (≥80 vs. <80 mL/min) 20. History of liver diseases (yes vs. no) 21. Prior or ongoing alcohol abuse (yes vs. no) 22. History of peptic ulcer disease (yes vs. no) 23. History of anemia requiring transfusion (yes vs. no) 24. Prior deep vein thrombosis or pulmonary embolism (yes vs. no) 25. Vascular disease (yes vs. no) 26. Prior myocardial infarction (yes vs. no) 27. Prior coronary revascularization (yes vs. no)

p-valueOdds Ratio (95% CI)n/N (%)n/N (%)PatientsGroupInteractionControlInterventionNo. of

0.48

0.98

0.23

0.01

0.71

0.95

0.92

3.28 (1.67, 6.44)

2.50 (1.41, 4.41)

3.40 (1.61, 7.21)

2.91 (1.44, 5.85)

2.89 (1.62, 5.15)

2.94 (1.57, 5.51)

2.62 (1.38, 4.99)

5.07 (2.09, 12.28)

1.83 (1.12, 2.98)

2.23 (1.21, 4.11)

3.32 (1.66, 6.63)

2.45 (0.96, 6.25)

2.80 (1.64, 4.77)

1.92 (0.99, 3.72)

2.94 (1.64, 5.27)

0.5 1 2 4 8

better better<-Control- -Intervention->

732 / 1092 (67.0%)

515 / 772 (66.7%)

217 / 320 (67.8%)

329 / 506 (65.0%)

403 / 586 (68.8%)

184 / 351 (52.4%)

542 / 734 (73.8%)

126 / 350 (36.0%)

606 / 742 (81.7%)

375 / 563 (66.6%)

357 /529 (67.5%)

193 / 315 (61.3%)

538 / 776 (69.3%)

214 / 325 (65.9%)

515 / 762 (67.6%)

943 / 1184 (79.6%)

651 / 843 (77.2%)

292 / 341 (85.6%)

452 / 569 (79.4%)

491 / 615 (79.8%)

266 / 351 (75.8%)

661 / 815 (81.1%)

203 / 328 (61.9%)

740 / 856 (86.5%)

417 / 545 (76.5%)

526 / 639 (82.3%)

244 / 297 (82.1%)

691 / 879 (78.6%)

161 / 230 (70.0%)

776 / 946 (82.0%)

2276

1615

661

1075

1201

703

1553

678

1598

1108

1168

612

1655

555

1708

Overall

Age

>=65y

<65y

Sex

Female

Male

New or recent AF

Yes

No

On aspirin

Yes

No

CHA2DS2 VASc

>3

<=3

Diabetes

Yes

No

Prior MI

Yes

No

md141

Typewritten Text

Figure. Pre-specified subgroup analyses for the primary outcome, as odds ratios representing the proportional increase in anticoagulation use from baseline to one year in the intervention group compared with the control group

IMPACT-AF Investigators: Argentina, Brazil, China, India, and Romania

Argentina: Justo Carbajales, Javier Neri Ceferino Gómez, Mario Bruno Principato, María Alejandra Von Wulffen (Clínica Modelo de Lanús); Jorge Galperín Rafael Salvador Acunzo, Ricardo Renato Bonato, Natalia Ciampi (Hospital General de Agudos "José María Ramos Mejía"); Alberto Babil Marani, Cristian Gustavo Panigadi, Silvia Gabriela Pastura (Hospital Interzonal General de Agudos "Dr. Diego Paroissien"); Leonardo Martín Onetto, Cecilia Rafaela Moya, Nadia Budassi, Marisol Valle (Hospital Interzonal General de Agudos “Dr. José Penna”); Daniel Camerini, Enrique Monjes, Federico Zabala, Juan Pablo Ricart, Luis Medesani (Hospital Interzonal General de Agudos “General José de San Martín” de La Plata); Eduardo Noe Ortuño Campos, Fabián Ferroni, Mariana Foa Torres (Hospital Universitario Austral); Daniel Omar Fassi, Fernando Javier Díaz Bosio, Gabriel Edgardo Pérez Baztarrica, Teresa Zúñiga Infantas (Hospital Universitario de la Universidad Abierta Interamericana); Daniela Perlo, Celso Fernando García, Rubén García Durán, Luisina García Durán (Instituto de Investigaciones Clínicas San Nicolás); Cecilia Alejandra Pettinari, Marisa Liliana Vico, Paulina Virginia Lanchiotti, Mariela Soledad Gómez (Instituto de Investigaciones Clínicas Zárate); Carlos Alberto Poy, Franco Sebastián Grazziani, Marcela Julieta Laspina, María Laura Poy (Sanatorio Parque de Rosario); María Cecilia Bahit (Grupo Argentino Colaborativo en Investigación Clínica / INECO Neurociencias / Argentine Clinical Research Group [ACRG]); Carlos Tajer (Hospital de Alta Complejidad El Cruce); Marilia García (Argentine Clinical Research Group [ACRG])Grupo Argentino Colaborativo en Investigación Clínica).

Brazil: Renato D. Lopes, Pedro Gabriel Melo de Barros e Silva, Otavio Berwanger, Flávia Egydio, Elissa Restelli, Anelise Kawakami, Tamara Colaiácovo Soares, Mayara Vioto Valois, Tauane Bello Duarte, Lilian Mazza Barbosa (National Coordinating Center, Brazilian Clinical Research Institute [BCRI]); Angelo Amato Vicenzo de Paola, Thiago Librelon Pimenta, Gabriela Dal Moro Jeronimo, Bruna S. Fernandes da Costa, Enia Lucia Coutinho, Andressa Zulmira A. Guerrero (Universidade Federal de São Paulo - UNIFESP/Hospital São Paulo); Lilia Nigro Maia, Marcelo Arruda Nakazone, Maria Angelica Teixeira Lemos, Osana Maria Coelho Costa, Ana Paula Demore, Roberta Parra Brito, Camila Dal Bon Melo, Nadielly Codonho Góes, Osvaldo Lorenço, Luiz Otavio Maia Gonçalves, Kátia Nishiama, Tiago Aparecido Maschio de Lima (Hospital de Base de São José do Rio Preto); Luciano Marcelo Backes, Keyla Liliana Alves de Lima Deucher, Milena Pozzatto Rodrigues, Dunnia Monisa Baldissera, José Basileu Caos Reolão, Tais Alves dos Santos, Fernanda Michel Birck Freisleben, Níncia Lucca da Silveira Kaross, Jéssika Tzervieczenski Montovani, Maiara Cantarelli, Aline Lucion, Luciano do Amarante, Priscila Foscarini (Hospital São Vicente de Paulo); Claudia de Mello Perez, Fernanda Ribeiro França, Lisa Fialho, Helena Cramer Veiga Rey (Instituto Nacional de Cardiologia [INC]); Epotamenides Maria Good God (Hospital Socor); Estêvão Lanna Figueiredo, Gustavo Fonseca Werner, Jose Carlos de Faria Garcia, Bruna Azevedo (Hospital Lifecenter); Luiz Carlos Vianna Barbosa, Ernaldo Pardi, Márcia Domingos Oliveira, Toshie Martinelli, Roseli Gomes Cavalini, Michele Santos Montoni de Moraes (Hospital das Clínicas Luzia de Pinho Melo); Adalberto Menezes Lorga Filho, Eduardo Palmegiani, Thiago Baccilli Cury Megid, Clotildes S. P. Queirantes, Thamyres Santini Arroyo Cruz (Instituto de Moléstias Cardiovasculares [IMC]).

China: Pengkang He, Xiaolan Zhou, Na Zhou (Peking University First Hospital); Mingzhong Zhao, Juan Yu, Yong Cheng (Zhengzhou Ninth People's Hospital); Lijun Wang, Lili Liu (Shijiazhuang The Third Hospital); Shuwang Liu, Lei Li (Peking University Third Hospital); Aihua Li, Xiaochen Yuan, Guangwei Xia (Yangzhou First People's Hospital); Zhirong Wang, Chengzong Li, Wensu Chen (The Affiliated Hospital of Xuzhou Medical College); Qiang Tang, Qunzhong Tang (Peking University Shougang Hospital); Weiting Xu, Xinyi Zhu (The Second Affiliated Hospital of Soochow University); Bin Hou, Wenjian Ma (Tengzhou Central People's Hospital); Chongquan Wang, Qiaoyun Jin (Tai He Hospital); Jianan Wang, Xiaojie Xie (The Second Affiliated Hospital of Zhejiang University School of Medicine).

India: Johny Joseph, Deepak Davidson, Joby K. Thomas, Tony V. Kunjumon, Tibin Stephen (Caritas Hospital); Kamlesh Fatania, Gaurav Rathi, Kinjal Garala, Dhruval Doshi (Rathi Hospital); Kiron Varghese, Srilakshmi M A, Lumin Sheeba, Shantha Kumar (St.John's Medical College & Hospital); Malipeddi Bhaskara Rao, Kodem Damodara Rao, Anjan Kumar Vuriya, Mandula Padma Kumari (My Cure Hospitals); Bidita Khandelwal, Mona Dhakal, Nitin Srivastava, Dheeraj Khatri, Shova Moktan (Sikkim Manipal Institute of Medical Sciences); Rajeev Gupta, Sanjeeb Roy, Kapil Kumawat, Mukesh Sharma, K.K. Sharma (Fortis Escorts Hospital); Narendra Jathappa,

Lokesh B.H., Shilpa Kariyappa, Leela A.C, Someshwara K.C (Nanjappa Life Care); Soaham Desai, Devangi Desai, Kunj Patel, Sujal Patel, Maulik Bhartiya (Shree Krishna Hospital and Medical Research Centre); Bhupendra Narayan Mahanta, Dibya Jyoti Dutta, Ghanashyam Rajkonwer (Assam Medical College); Sandeep Kumar Gupta, Ashok Kumar Mishra, Akansha Singh, Naveen Kesarwani, Shivendra Kumar (M.V Hospital & Research Centre).

Romania: Ovidiu Chioncel, Adriana Balan, Nicolae Carstea (National Institute Prof. C C Iliescu); Gabriel Tatu Chitoiu, Stelian Cornaciu (Cardiomed SRL); Mircea Cinteza, Roxana C. Rimbas (University and Emergency Hospital Bucharest; University of Medicine and Pharmacy Carol Davila); Doina Dimulescu (Clinical Emergency Hospital Elias; University of Medicine and Pharmacy Carol Davila); Luminita Ionescu (Clinical Emergency Hospital Elias); Ana Fruntelata, Nicoleta Dumitru (Monza Hospital); Dan Gaita, Roxana Pleava (University of Medicine and Pharmacy Victor Babes); Adriana Iliesiu, Gabriela Uscoiu (Clinical Hospital Theodor Burghele; University of Medicine and Pharmacy Carol Davila); Daniel Lighezan, Roxana Buzas (University of Medicine and Pharmacy Victor Babes); Crina J. Sinescu, Ana-Maria Avram (Clinical Emergency Hospital Bagdazar-Arseni; University of Medicine and Pharmacy Carol Davila); Sorina Baldea (University and Emergency Hospita; University of Medicine and Pharmacy Carol Davila); Ruxandra Dragoi Galrinho, Stefania L. Magda, Lavinia Matei (University and Emergency Hospital Bucharest).

IMPACT-AF Data Monitoring Committee: Bernard J. Gersh (Mayo Clinic, Rochester, Minnesota, USA) and Jeff Healey (McMaster University, Hamilton, Ontario, Canada).

IMPACT AF

Sponsored by

Approaching the Patient with Atrial Fibrillation:Clinical Information for Physicians

CME Monograph

Contributing AuthorMeena Rao, MDDuke Clinical Research InstituteDuke University Medical CenterDurham, NC 27701

Activity Medical Director Christopher Granger, MDProfessor of MedicineDuke Clinical Research InstituteDuke University Medical CenterDurham, NC 27701

Release date: April 7, 2014Expiration date: April 6, 2015Estimated time to complete: 1 hour

Dear Colleague,

We are pleased to bring you “Approaching the Patient with Atrial Fibrillation.”

This is an exciting and important time for these patients. With the development of novel anticoagulants, we have the opportunity to identify patients who are at high risk for ischemic stroke and start anticoagulation, thereby decreasing rates of preventable stroke. To achieve this, clinicians must familiarize themselves on how to identify high-risk patients, appropriately dose anticoagulants, and understand barriers to adherence to treatment plans.

We hope you enjoy reading this material.

Christopher Granger, MDDuke Clinical Research Institute

IMPACT AF

Table of ContentsCME information 1–2

Introduction 3

Case study 3

Evaluating risk of stroke 4–5

Treatment considerations 6–8

Guiding patients to manage their condition 9

Assisting patients in adhering to treatment plans 10–13

Summary 14

Post-test questions 15

1Approaching the Patient with Atrial Fibrillation

Target AudienceThis activity is designed for primary care physicians, general practitioners, and other relevant healthcare professionals involved in the care of patients with atrial fibrillation.

Statement of NeedPatients with atrial fibrillation have increased risk for ischemic stroke. The risk for each patient is unique and can be determined by the number of risk factors the patient has. For some, the risk of stroke is elevated enough to require lifelong anticoagulation to reduce this risk. Prescribed medications for anticoagulation, including vitamin K antagonists and the novel agents (rivaroxaban, dabigatran, and apixaban), reduce the risk of stroke but pose additional risk due to bleeding. This monograph presents strategies for healthcare professionals to facilitate safe management of guideline-based medications and to improve the likelihood of patient engagement in successful self-management of atrial fibrillation through shared goal setting.

Educational Learning ObjectivesAt the conclusion of this activity, participants should be able to: • Increasetheirawarenessoftheroleandimpactof oral anticoagulants• Identifytherightpatientforanticoagulants•Recognizetheadvantagesandrisksinvolvedin treating patients using anticoagulants•Providemethodsforidentifyingandaddressing potential adherence issues

Accreditation StatementThe Duke University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education (CME) for physicians.

Credit DesignationThe Duke University School of Medicine designates this live activity for a maximum of 1.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. FacultyActivity Medical DirectorChristopher Granger, MDProfessor of MedicineDuke Clinical Research InstituteDuke University Medical CenterDurham, NC 27701

Contributing AuthorMeena Rao, MDDuke Clinical Research InstituteDuke University Medical CenterDurham, NC 27701

Staff and Content Validation Reviewer DisclosureThe staff involved with this activity and any content validation reviewers of this activity have reported no relevant financial relationships with commercial interests. Resolution of Conflicts of InterestIn accordance with the ACCME Standards for Commercial Support of CME, the Duke University School of Medicine implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

CME Information


Planning Committee/Faculty DisclosureThe following speakers and/or planning committee members have indicated that they have no relationships with industry to disclose relative to the content of this CME activity: Meena Rao, MD.

The following speakers and/or planning committee members have indicated that they have relationships with industry to disclose:

Christopher Granger, MD, has indicated that he serves as a speaker for AstraZeneca and a principal investigator for BI, BMS, GSK, Hoffmann-La Roche, Medtronic Foundation, Merck & Company, Pfizer, sanofi-aventis,Takeda, and The Medicines Company. He serves as a consultant to Takeda, The Medicines Company, Daiichi Sankyo, sanofi-aventis, Pfizer, Eli Lilly, GSK, and BMS.

This CME activity is supported by an unrestricted educationalgrantfromBMS-Pfizer.

Unapproved Use DisclosureDuke School of Medicine requires CME faculty (speakers) to disclose to attendees when products or procedures being discussed are off-label, unlabeled, experimental, and/or investigational (not approved by the U.S. Food and Drug Administration), and any limitations on the information that is presented, such as data that are preliminary or that represent ongoing research, interim analyses, and/or unsupported opinion. This information is intended solely for CME and is not intended to promote off-label use of these medications. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information. Faculty will not be discussing information about pharmaceutical agents that is outside of U.S. Food and Drug Administration approved labeling.

DisclaimerThe information provided at this activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.

Performance Assessment In order to successfully complete this activity for AMA PRA Category 1 CreditTM, learners must demonstrate performance by achieving a minimum of 80% on the post-test.

Instructions on How to Receive CreditReview the CME information and complete the activity. Complete the post-test, scoring 80% or above in order to receive credit. ContactIf you have questions about this activity, please contact DukeCME at 919-401-1200 or [email protected].

CME Information


Atrial fibrillation is the most common form of sustained arrhythmia. In 2012, more than 6 million Europeans and an estimated 2.3 million people in the United States were affected with atrial fibrillation. Prevalence of atrial fibrillation in other countries has not been well described. In 2012, a systematic review of atrial fibrillation globally reported a global prevalence of atrial fibrillation outside North America and Europe ranging from 0.1–4% for community-based studies and 2.8-14% for hospital-based studies (1). The incidence of atrial fibrillation increases with age and is associated with approximately 15% of all strokes (1). Strokes due to atrial fibrillation have worse outcomes than strokes due to other causes. Over two thirds of these strokes can be prevented with oral anticoagulation (2). A 2007 meta-analysis of antithrombotic therapy use for the prevention of stroke in patients with atrial fibrillation found that treatment with adjusted-dose warfarin reduced stroke risk by 62% and demonstrated low rates of major hemorrhage (3). The newer oral anticoagulants (dabigatran, rivaroxaban, apixaban) are at least as good as warfarin at preventing stroke, with half the rate of intracranial hemorrhage.

Despite the effectiveness of anticoagulation, recent literature documents that current practice does not follow published guidelines, resulting in substantial occurrence of preventable ischemic stroke (4). Underuse of anticoagulation appears to be due, at least in part, to the concern of increased risk of bleeding, especially in the elderly. Since rates of stroke in persons aged 70 years and older are higher than in the younger population, those who need anticoagulation the most may be the least likely to receive it.

While it is true that the risk of bleeding increases with age, the risk of hemorrhage is associated with the intensity of anticoagulation and is highest in the first 3 months of treatment. This highlights the importance of appropriate patient selection, appropriate intensity of anticoagulation, and close monitoring during the initiation of therapy (5,6,7).

In addition to appropriate patient selection, understanding the role of novel anticoagulant therapies may also affect initiation of therapy in certain patients. Novel therapies that are safe, effective, and require less monitoring are now available; however, physicians may be reluctant to change practice patterns due to unfamiliarity with these medications.

Understanding underuse of anticoagulation is complex and multifaceted. While identifying appropriate patients and choice of anticoagulants is important, even when anticoagulation is appropriately started, patients often stop therapy by the end of the first year. Poor adherence to therapy may relate to cost of the medication, limited access to drugs, lack of infrastructure to provide long-term care, or lack of education regarding the importance of therapy. Understanding these factors and guiding patients to manage their therapy is important for providers taking care of patients with atrial fibrillation.

Case StudyDawn, a 79-year-old female with past medical history including hypertension, hyperlipidemia, and diabetes, presents with a chief complaint of 3 months of fatigue. On exam it is found that she has an irregular pulse. A 12-lead EKG is done in the office and is significant for atrial fibrillation. She is hemodynamically stable and without signs of heart failure. Her heart rate is 115 beats per minute and irregular.

Initial management goals are to rule out acute reversible causes of atrial fibrillation, control her heart rate, consider cardioversion to sinus rhythm, and determine whether stroke prevention is appropriate.

Introduction


The two clinical prediction tools used to predict the risk of stroke in patients with atrial fibrillation are the CHADS2 score and the CHA2DS2 VASC score (8,9). This section outlines how to use these risk scores to identify patients who are eligible for anticoagulation.

CHADS2 score: To estimate stroke risk, use the scoring table (Table 1) below to add together the points that correspond to the conditions that are present for the patient. According to the findings of the initial validation study, the risk of stroke as a percentage per year is shown in Table 2 below. If the patient has a CHADS2 score of 2 and above, anticoagulation is recommended. If the score is 0–1, other stroke risk modifiers could be considered by calculating the CHA2DS2 VASC score.

CHA2DS2 VASC score: When the CHADS2 score is 0–1, it is helpful to consider additional stroke risk factors. As with the CHADS2 score, refer to Table 3 below to add together the points that correspond to the conditions present. If the score is 2 or more, anticoagulation is recommended. If there is one risk factor, anticoagulation is recommended; however, aspirin is also a consideration based on patient values and preferences. If the score is 0, the patient is low risk and the recommendation is aspirin or no anticoagulation.

Evaluating Risk of Stroke

Table 1: CHADS2 scoring table

Condition Points

C Congestive heart failure 1

HHypertension: Blood pressure >140/90 mmHg (or treated on one medication)

1

A Age ≥ 75 years old 1

D Diabetes mellitus 1

S2

Prior stroke or TIA or thromboembolism 2

Table 2: CHADS2 annual stroke risk

CHADS2 score

Stroke risk % 95% CI

0 1.9 1.2–3.0

1 2.8 2.0–3.8

2 4.0 3.1–5.1

3 5.9 4.6–7.3

4 8.5 6.3–11.1

5 12.5 8.2–17.5

6 18.2 10.5–27.4

Table 3: CHA2DS2 VASC scoring system

Condition Points

C Congestive heart failure 1

H Hypertension: blood pressure >140/90 mmHg (or treated on one medication) 1

A2 Age ≥ 75 years old 2

D Diabetes mellitus 1

S2 Prior stroke or TIA or thromboembolism 2

VVascular Disease (e.g., peripheral artery disease, myocardial infarction, aortic plaque)

1

A Age 65–74 years old 1

SC Female gender 1

Table 4: CHA2DS2 VASC annual stroke risk

CHA2DS2 VASC score Stroke risk %

0 0

1 1.3

2 2.2

3 3.2

4 4.0

5 6.7

6 9.8

7 9.6

8 6.7

9 15.2


Stroke risk assessment should be considered with bleeding risk. Quantification of bleeding risk can be done with the HAS-BLED score (10). As done on the previous page, use the scoring table below (Table 5) to add together the points that correspond to the conditions that are present to estimate bleeding risk (Table 6).

Evaluating Risk of Stroke

Table 5: HAS-BLED scoring system

Condition Points

HHypertension (uncontrolled): systolic BP > 160 mmHg

1

AAbnormal renal function: Dialysis, Cr >2.6 mg/dl

1

Abnormal liver function: cirrhosis, bilirubin >2x normal, AST/ALT >3x normal

1

S Stroke history 1

BBleeding: prior major bleed (requiringhospitalization,intracranial,Hgb decrease >2 g/L, transfusion)

1

L Labile INR 1

E Elderly: age ≥65 years 1

D Drug/alcohol use 1

Table 6: HAS-BLED risk for bleeding on anticoagulation

Bleed risk per 100 patient years

HAS-BLED score Bleed risk Risk %

0 1.13 0.90

1 1.02 3.40

2 1.88 4.10

3 3.74 5.80

4 8.7 8.90

5 12.5 9.10

Returning to the Case…Dawn is started on 25 mg of metoprolol twice daily and now has a heart rate that is 75 beats per minute. Because her CHADS2 score is 3, she is started on rivaroxaban for anticoagulation. After reviewing the novel agents, she preferred rivaroxaban because it is a single daily dose. After 2 months, she returns to clinic. An EKG confirms that she is still in atrial fibrillation, and she continues to complain of fatigue. She is referred for cardioversion to normal sinus rhythm.


Vitamin K antagonist: WarfarinTarget INR 2.0–3.0Dosage: 5 mg daily for the first 3 days, then assess INRIf age >65 years, debilitated, congestive heart failure or liver disease, then 2.5 mg daily for 3 days and assess INR.Appropriate initial dose and close monitoring of anticoagulation status are of particular importance due to delayed response in INR and drug-drug interactions.

Dose adjustment algorithm based on INR levels can be found online at www.warfarindosing.org. An algorithm used at Duke University for the target INR goal of 2.0–3.0 is found below. TWD is total weekly dose.

Treatment Considerations

INR monitoring frequency*

Dose adjustment INR reassessment (return to clinic)

New starts3 to 4 days after initiation (3–4 daily doses),

then weekly thereafter until therapeutic

Increase 10–20% or decrease > 15% Within 1 week

Increase 5–10% 2–3 weeks

No change / stable 4–6 weeks

Decrease 5–15% 1–2 weeks

* Peak anticoagulant effect of warfarin usually occurs in 72 to 96 hours

Warfarin dosing algorithm for target INR 2.0–3.0

INR result Day 1 adjustment Weekly adjustment Return

1.1–1.4 Add 10–20% of TWD Increase TWD by 10–20% 1 week

1.5–1.9 Add 5–10% of TWD Increase TWD by 5–10% 2–3 weeks

2.0–3.0 No change No change 4–6 weeks

3.1–4.0 Decrease by 5–15% TWD Decrease by 5–15% 1–2 weeks


Management of elevated INR with or without bleeding:

Enoxaparin: Not indicated for new onset atrial fibrillation

Novel Oral Anticoagulants:Indication: patients with non-valvular atrial fibrillation requiring anticoagulation (CHADS2 score >1)Suitable candidates for treatment: patients with unstable INRs, complicated drug regimens, high risk for intracranial bleeding, difficulty in having INRs monitored regularlyExclusion criteria:•Endstagerenaldiseaseorsevererenalimpairment•Prostheticheartvalve•Acutestroke(within14daysordisablingstrokewithin6months)• Infectiveendocarditis•Acuteliverdisease(LFTs>2xupperlimitofnormal)•ConcomitantP-glycoproteininducers(rifampin,St.John’swort)•ActivepathologicbleedorGIbleedingwithinpastyearorrecurrentGIbleed•Pregnancy• Inabilitytoswallowcapsules(capsulesmaynotbeopenedorcrushed)


INR adjustment for elevated INR

INR range No bleeding Suspected bleeding

> target range but < 5.0

Lower or omit next dose

Refer for medical evaluation

Resume at lower maintenance dose unless cause of bleeding is identified and resolved, in which case dose

adjustment is not needed

Check INR in 7–10 days

>5.0 but <9.0

If risk factors for bleeding are present, omit next dose and give vitamin K 2.5 mg orally

Refer for medical evaluationIf no risk factors for bleeding, omit next dose

and evaluate INR in 24-48 hours

Resume maintenance dose when INR <5.0 and reevaluate in 3-5 days

> 9.0

Refer patient for medical evaluation and administration of vitamin K

Hold warfarin therapy until INR <5.0 then resume maintenance dose and recheck INR in 3-5 days


Dabigatran: direct thrombin inhibitor (11)Dosage: CrCl > 30 ml/min: 150 mg twice dailyCrCl 15–30 ml/min: 75 mg twice dailyCrCl <15: do not use

Apixaban: direct factor Xa inhibitor (12)Dosage:5 mg twice daily2.5 mg twice daily if two of the following are present: age >80 years, body weight < 60 kg, creatinine > 1.5 mg/dl.

Rivaroxaban: direct factor Xa inhibitor (13)Dosage:CrCl>50 ml/min: 20 mg dailyCrCl 15–50 ml/min: 15 mg daily

For more information, including switching between anticoagulant regimens, drug-drug interactions, management with bleeding, and surgical considerations, please follow the link to the European Heart Rhythm Association’s Practical Guide on the use of new oral anticoagulants: http://eurheartj.oxfordjournals.org/content/early/2013/04/25/eurheartj.eht134


Returning to the Case…After cardioversion, Dawn returns to clinic and is feeling better. She has more energy and has been more active. She has no problems taking her rivaroxaban and has had no trouble with bleeding. A month later, she is seen in the hospital after she tripped over her grandchild’s toy and fell. She has a large ecchymosis on her right cheek as well as her right elbow and hip. Her anticoagulation was held in the emergency department given concerns of bleeding. A CT scan showed no acute bleeding, and laboratory tests did not show acute anemia. Her anticoagulation was restarted, and she was discharged home.


The following steps are taken from the American Medical Association’s Healthier Life Steps physician tools and modified for patients with atrial fibrillation.

1. Arrange for screening at check-in Provide a questionnaire to assess the level of knowledge that the patients have regarding their chronic condition at check-in. Patients can complete the questionnaire during their wait time. For example, ask the patients: Did your doctor ever tell you that you have atrial fibrillation? What is atrial fibrillation? What risks do you have with atrial fibrillation?

2. Encourage patients to develop action plans At the end of the visit, have patients identify and write down specific goals and actions in an area that they would like to target.

3. Offer brief provider intervention Ask patients what they already know about their chronic condition or review the questionnaire the patients filled out at check-in. This is your opportunity to educate the patients regarding their condition and develop a treatment plan with them. If patients indicate that they need more information, make sure to provide the action plan that lists resources along with information you may already have available. If patients indicate they are ready to take action, make sure they have completed an action plan. Check the patients’ confidence level and make sure they have chosen steps they believe they can achieve. Always offer words of encouragement.

4. Chart it and follow up Make a note in the patient’s chart of the action plan and record the amount of time spent counseling. The note will be a reminder of the patient’s action plan at the next visit

5. Commit to your program Justasyourpatientswillhavetocommittoactionstepplans,youwillneedtomakeacommitmenttoinclude this program in your practice. Designate one staff person as the office coordinator to ensure you have sufficient copies of the program materials and that the system is working. Begin with a few patients to see how the program works in terms of flow and logistics. Assess what worked and make adjustments accordingly. Once you are comfortable with the flow, set a goal to provide the patient questionnaire to every adult with atrial fibrillation at check-in. This can be done by identifying a staff person who can review the list of patients to be seen in clinic that day and ensure that the patients with a diagnosis of atrial fibrillation are given a questionnaire at check-in.

Guiding Patients to Manage their Condition


Reasons for non-adherence or misuse of therapies are complex. They include but are not limited to lack of knowledge about the medication, side effects/adverse effects, forgetfulness, lack of social support, cultural/religious beliefs, denial, financial barriers, poor relationships with clinicians, and lack of health literacy. A 2009 study by Oyekan et al outlines a multifaceted approach that they call the B-SMART (Barriers, Solutions, Motivation, Adherence tools, Relationships, and Triage) Appropriate Medication Use process (14). Please see the study publication for more details. Below we present a chart to help facilitate understanding barriers to adherence. The chart lists possible barriers, questions/tools for better understanding the associated barrier, and potential solutions.

Assisting Patients in Adhering to Treatment Plans

Understanding barriers to appropriate medication use and adherence

BarriersQuestions/tools for

better understandingSolutions

PATIENT-RELATED BARRIERS

Forgetfulness

Do you ever have difficulty in taking your medications?What gets in the way of taking your medications on some days? See Morisky Medication Adherence Scale (15) on page 12

Suggestuseofpillorganizersandreminders, linking medications to daily habits, and close follow-up

Lack of knowledge about the medication and its use

What did your doctor tell you this medication is for?

Provide information in terms of benefit to the patient using visual aids and teach-back method

Cultural, health, and/or religious beliefs about the medication

Why do you have difficulty taking the medication?

Listen with empathy, explore and understand the patient’s beliefs, acknowledge and discuss similarities and differences, recommend treatment and finally negotiate an agreement

Denial or ambivalence regarding conditions

Explore readiness to accept the disease condition

Educate about the condition and benefits of medication therapy, and close follow-up

Financial challenges

Prescribe generic drugs, find mail-order discount programs and look into pharmaceutical company programs

Lack of health literacy

Provide patient information at the fourth-grade reading level, use non-medical language, speak slowly, use visual aids and teach-back method, and provide interpreter services for those who do not speak your language

Lack of social support Provide information for patient groups

DepressionScreen for depression using available tools (e.g. Beck Depression Inventory)

Refer for therapy

Lack of motivation

Assess readiness to change using the Readiness Assessment Ruler (14) on page 12

Educate, empower patients to take care of their own health by assisting them to set goals and create action plans



Understanding barriers to appropriate medication use and adherence

BarriersQuestions/tools for

better understandingSolutions

MEDICATION-RELATED BARRIERS

Complex medication regimens

Consideroptimizingfrequencyanddosage when able, provide adherence tools, prescribe combination pills when available, and link medications with daily habits

Side effects or adverse effects from the medication

Provide information on what side effects to expect,howtominimizesideeffects,and alternative therapies

Taking multiple medications at the same time

Provide adherence tools or prescribe combination pills when available

PROVIDER-RELATED BARRIERS

Poor relationship with the provider

Poor communication with the provider Cultural, health, and/or religious beliefs disparity between provider and patient

Lack of feedback and ongoing reinforcement from provider

Consider referring the patient to another provider


Morisky Medication Adherence Scale (15):This scale consists of 7 yes or no questions for which a yes answer confers a point value of 1 and a no answer 0 points. The 8th question has 5 possible answers, all of which are assigned a point value as shown below. The points are added up at the end of the questionnaire. A score of 0 indicates high adherence, 1–2 indicates medium adherence, and >2 indicates low adherence.

1. Do you sometimes forget to take your medicine? Yes = 1 No = 0 2. People sometimes miss taking their medicines for reasons other than forgetting. Thinking over the past 2 weeks, were there any days when you did not take your medicine? 3. Have you ever cut back or stopped taking your medicine without telling your doctor because you felt worse when you took it? 4. When you travel or leave home, do you sometimes forget to bring along your medicine? 5. Did you take all your medicine yesterday? 6. When you feel like your symptoms are under control, do you sometimes stop taking your medicine? 7. Taking medicine every day is a real inconvenience for some people. Do you ever feel hassled about sticking to your treatment plan? 8. How often do you have difficulty remembering to take all your medicine? a. Never/Rarely = 0 b. Once in a while = 1 c. Sometimes = 1 d. Usually = 1 e. All of the time = 1

Beck Depression Inventory: A series of 21 questions for which each answer is given a score from 0–3. At the end, the total score determines a category from normal to extreme depression. A persistent score of 17 or higher may indicate that medical therapy is required. This depression inventory is available online.

Readiness Assessment Ruler (14):The ruler creates a scale of 0–10 that is used as a tool to measure how a patient feels about taking a medication for a long period of time. If a patient scores 0–3 on the ruler, he or she is not ready for change, a score of 4–6 indicates the patient is considering change but is not sure, and 7–10 indicates readiness to take action.


READINESS ASSESSMENT RULERCircle one answer for each type of drug

Types of medications

Readiness StagesI do not use this type

of medicationNot ready UnsureReady to

take action

0 1 2 3 4 5 6 7 8 9 10

Medication A 0 1 2 3 4 5 6 7 8 9 10 Don’t use

Medication B 0 1 2 3 4 5 6 7 8 9 10 Don’t use

Medication C 0 1 2 3 4 5 6 7 8 9 10 Don’t use

Medication D 0 1 2 3 4 5 6 7 8 9 10 Don’t use



ADHERENCE TOOLS

Follow-up and reminder phone calls •AsamplescriptforacallisavailableattheAgencyforHealthcareResearchandQuality(AHRQ) website: http://www.ahrq.gov/professionals/systems/hospital/red/callscript.html

Devices: pillboxes, calendars, diaries

Written information on atrial fibrillation•SomepatientinformationcanbefoundontheHeartRhythmSocietywebsiteunderpatient resources: http://www.hrsonline.org/Patient-Resources/

Visual aids: pictures, medication charts, and instruction labels•PicturescanbefoundonthepatientresourcestaboftheHeartRhythmSocietywebsite:http://www.hrsonline.org/Patient-Resources/Heart-Diseases-Disorders#axzz2d6I5sRr7

Teach-back method: explain the concept as the patient repeats it back

Newsletters and letters: mail reminders

Coaches and care managers: help change behavior of patients by listening, supporting, and advising patients about medical choices, treatment plans, prevention, and overcoming barriers

Handbook and self-care resources

Clinician follow-up management

RELATIONSHIPS AND ROLES OF THE HEALTHCARE TEAM

Identify the team and the roles of each person

Patient’s role: active involvement in decisions regarding treatment plan

Clinician’s role: develop a relationship with the patient and foster patient-clinician communication

Outpatient Pharmacist’s role: helps with adherence and simplifying medication regimens

Pharmacist or Nurse Care Manager’s role: review adherence and identify barriers and potential solutions

Medical Assistant/Support Coordinator/Technician’s role: clarify visits, provide tools, remind patients about follow-up appointments and medications

TRIAGE

Coordinate the treatment plan with broader healthcare management services such as community-based programs or providing web-based tools


Anticoagulation in patients with atrial fibrillation is an effective and important therapy to decrease the risk of ischemic stroke. Despite the effectiveness of anticoagulation, current practice does not follow published guidelines, resulting in preventable ischemic stroke. Underuse of anticoagulation is multifactorial, involving both the clinical team and the patient.

References

1. Lip GY, Brechin CM, Lane DA. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside of North America and Europe. Chest. 2012;142(6):1489--1498

2. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2011;57(11):e101-198

3. Mittal MK, Rabinstein AA. Anticoagulation-related intracranial hemorrhages. Curr Atheroscler Rep. 2012;14(4):351-359

4. Ogilvie IM, Newton N, Welner SA, et al. Underuse of oral anticoagulants in atrial fibrillation: a systematic review. Am J Med. 2010;123(7):638-645

5. DiMarco JP, Flaker G, Waldo AL, et al. Factors affecting bleeding risk during anticoagulant therapy in patients with atrial fibrillation: Observations from the AFFIRM Study. Am Heart J. 2005;149(4):650-656 6. Mant J, Hobbs FDR, Fletcher K, et al. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007;370(9586):493–503 7. Hylek EM, Evans-Molina C, Shea C, et al. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21): 2689–2696

8. Gage BF, van Walraven C, Pearce L, et al. Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation. 2004;110(16):2287-2292

9. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the Euro Heart Survey on atrial fibrillation. Chest. 2010;137(2):263-272

10. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-1100

11. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151

12. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–992

13. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–891

14. Oyekan E, Nimalasuriya A, Martin J, Scott R, Dudi RJ, Green K. The B-SMART Appropriate Medication-Use Process: A guide for clinicans to help patients–part 1: barriers, solutions, and motivation. Perm J. 2009;13(1):62-69

15. Morisky DE, Ang A, Krousel-Wood M, Ward H. Predictive validity of a medication adherence measure for hypertension control in an outpatient setting. J Clin Hypertens. 2008; 10(5):348-354

Summary


Georgiana is a 75-year-old female with past medical history of coronary artery disease, diabetes, chronic kidney disease on hemodialysis, and hypertension. She presents to your clinic with shortness of breath and fatigue. On physical exam, her blood pressure is 147/83 with normal oxygen saturation. She appears to be euvolemic but her pulse is irregular. An EKG confirms the diagnosis of atrial fibrillation with a heart rate of 125 beats per minute.

Question #1: What is the next step for this patient?a. Start Lasix for diuresisb. Start a rate control strategyc. Determine risk of stroke and start anticoagulation if appropriated. Order an echocardiogram as the patient appears to have heart failuree. a and b f. c and d Question #2: What is his CHADS2 Score?a. 0b. 1c. 2d. 3e. 4

Question #3: If you were to start an anticoagulant, which of the following agents would you start?a. Apixabanb. Dabigatranc. Rivaroxaband. Warfarin

Case continued: She is discharged home and returns to clinic for follow-up. She was started on Warfarin for anticoagulation, and her INR is 1.2.

Question #4: What is the most appropriate next step?a. Explore patient-related barriersb. Explore medication-related barriersc. Educate the patient on the importance of anticoagulationd. All of the above

Case continued: You identify her barriers to be poor health literacy and a complicated medical regimen. You simplify her medication regimen, provide education including visual aids, and provide adherence tools including a pillbox. At her next follow-up visit, her INR is 4.5.

Question #5: What is the most appropriate next step?a. Stop Warfarin and give 2.5 mg of vitamin K orallyb. Stop Warfarin and assess for bleeding; if no signs of bleeding, restart maintenance dose when INR is <3.0c. Continue maintenance dose as prescribed and adjust dietd. Switch to another anticoagulant

Post-Test Questions

DCRI COMMUNICATIONS • APRIL 2014

Webinar #1

Atrial Fibrillation:Patient identification and

risk stratification

Learning Objectives

Who are the right patients for therapy?– Patient identification– Risk Stratification

• Stroke• Bleeding

Case PresentationEmergency Department 75 year old female Past medical history: Hypertension Presents with fatigue and palpitations

Social History: denies smoking, alcohol or IV drug use

Past Surgical History: prior cesarean section

Medications: Hydrochlorothiazide 25mg daily

Case Presentation

Patient Identification

Fast & chaotic atrial activity (400-600 bpm) Leads to irregularly irregular ventricular

beats


Atrial Fibrillation

Normal Sinus Rhythm

Atrial Fibrillation: Mechanism

‘Reversible’ causes– Thyroid disease (hyperthyroidism)– Pulmonary embolism– After cardiac surgery– Other, rare causes

More commonly…


Hypertension Cardiovascular disease Heart failure (class II‐IV) Diabetes Older age Sleep apnea Alcohol and/or tobacco use Obesity

Clinical Risk Factors

Atrial Fibrillation: Risk

Rate‐related cardiomyopathy Shortness of breath, weakness, palpitations and reduced quality of life AF increases risk of stroke

Risk: Stroke

15-20% of all strokes are due to AF– Strokes in patients with AF

are worse

Stroke is a leading cause of death and disability

Projected to be leading cause of death and disability after myocardial infarction in 2020

World Health Organization atlas of burden of disease and disability

Risk: Stroke

The CHADS2 Score

Congestive Heart failure 1 32Hypertension 1 65Age > 75 years 1 28Diabetes mellitus 1 18Stroke or TIA 2 10

Moderate-High risk >2 50-60Low risk 0-1 40-50

VanWalraven C, et al. Arch Intern Med 2003; 163:936.* Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).

Prevalence (%)*Score (points)

Risk: Stroke

The CHADS2 ScoreStroke Risk Threshold Favoring Anticoagulation

Van Walraven C, et al. Arch Intern Med 2003; 163:936.Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.

0 1.9

1 2.8

2 4.03 5.94 8.55 12.56 18.2

Risk of Stroke (%/year)Score (points)

3%/yearApproximateRisk Threshold forAnticoagulation

Risk: Stroke

Risk: StrokeScore Annual stroke

rate, %n 1084 73 538

0 0 0.781 1.3 2.012 2.2 3.713 3.2 5.924 4.0 9.275 6.7 15.266 9.8 19.787 9.6 21.508 6.7 22.389 15.2 23.64

CHF/ LV dysfunction 1Hypertension 1Age 75 2Diabetes mellitus 1Stroke/TIA/TE 2

Vascular disease 1Age 65‐74 1Sex category (female) 1

Score 0 – 9Validated in 1084 NVAF patients not on OAC with known TE status at 1 year in Euro Heart Survey

Lip GYH, et al. Chest 2009

Olesen JB et al. BMJ 2011;342:124

CHA2DS2-VASc

Recommendations Class Level

In patients with a CHA2DS2‐VASc score of 0 (i.e., aged <65 years with lone AF) who are at low risk, with none of therisk factors, no antithrombotic therapy is recommended.

I B

In patients with a CHA2DS2‐VASc score ≥2, OAC therapy with:• adjusted‐dose VKA (INR 2–3); or• a direct thrombin inhibitor (dabigatran); or• an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban

.… is recommended, unless contraindicated.

I A

In patients with a CHA2DS2‐VASc score of 1, OAC therapy with: • adjusted‐dose VKA (INR 2–3); or• a direct thrombin inhibitor (dabigatran); or• an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d

…. should be considered, based upon an assessment of the risk of bleeding complications and patient preferences.

IIa A

European Heart Journal 2012 ‐ doi:10.1093/eurheartj/ehs253

Anticoagulation – according to CHADS‐VASc

Risk: Stroke

100% 50% 0% -50% -100%

AFASAK-1 SPAF

BAATAF

CAFA

SPINAF

EAFT

ALL Trials

Favors Warfarin Favors Placebo or Control

Hart R, et al. Ann Intern Med. 2007;146:857-867.

Warfarin vs. Placebo

64%

Risk: Stroke

Risk: Stroke vs Bleeding

Predicting Bleeding Risk with WarfarinHAS‐BLED Risk Score

HAS‐BLED– Uncontrolled hypertension– Abnormal renal/liver function (1 pt for each)

– Stroke– Bleeding hx or prone– Labile INR– Elderly (>65)– Drugs/alcohol (1 pt for each)

c‐index 0.72

Pisters R. Chest. 2010 Mar 18.

Risk: Bleeding

Risk: Major Bleeding

HAS‐ BLED score CHADS2 score CHA2DS2 VASc score0‐1 2 >3 1 2 >3 1 2 >3

Percentage of p

atient events

Lopes R. online Lancet 2012

Risk: Bleeding

• Apropriate dosing of warfarin: www.warfarindosing.org

• Look for potential drug‐drug interactions on patients medication list

• Use proton pump inhibitors• Avoid non‐steroidal anti‐inflammatory medications

• Avoid aspirin use when possible

Choice of Anticoagulant

Atrial fibrillation

Valvular AF*

VKANo antithrombotic therapy NOAC

Assess risk of stroke (CHA2DS2-VASc score)

1** ≥2

Yes

No

Yes

No (i.e. non-valvular AF)

0

Oral anticoagulant therapy

Assess bleeding risk

Consider patient values and preferences

< 65 years and lone AF (including females)

* Includes moderate to severe mitral stenosis and mechanical valves

** Antiplatelet therapy with aspirin plus clopidogrel, or – less effectively –aspirin only, may be considered in patients who refuse any OAC


Treatment Algorithm

Case Revisited

75 year old female with Hypertension • CHA2DS2 VASc Score = 4• Stroke rate is 4% per year• HAS BLED score = 2• Bleeding rate is 1.88% per year

Would you put this patient on oral anticoagulation?

• Labs: all normal• Echo: normal

Conclusion

Patient Identification– Mechanism of atrial fibrillation– EKG diagnosis

Risk Stratification– Stroke risk

• CHA2DS2‐VASc score– Bleeding risk

• HAS‐BLED score, but recognize high bleeding risk usually also means high stroke risk and thus is not a reason to withhold anticoagulation

Summary Question #1

Stroke is the most serious complication of atrial fibrillation (AF). Compared to patients without AF, patients with AF have stroke that are generally:

A. More severeB. Less severeC. The same

A 55 year old man presents to clinic complaining of palpitations when playing golf. The episodes are brief, spontaneously terminate and are not associated with other symptoms. He has no past medical history and is not on any medications. What is the next step?

A. Given his symptoms assume he has atrial fibrillation and give him an anticoagulant

B. Refer for cardioversionC. Prescribe aspirin therapyD. Undergo additional diagnostic evaluation with portable

ECG monitoring

Summary Question #2

70 year old female with past medical history of hypertension, diabetes and heart failure presents in clinic with shortness of breath. An EKG done in clinic shows atrial fibrillation. What is her CHA2DS2 VASc Score?

A. 0B. 3C. 5D. 7

Summary Question #3

A 60 year old female presents with occasional palpitations and is found on a holter monitor to have paroxysmal atrial fibrillation. She has a past medical history of lung cancer which was resected without signs of recurrence. She currently takes a proton pump inhibitor for reflux symptoms with good control. In clinic, she is in normal sinus rhythm. What is the next most appropriate step?

A. Refer for immediate cardioversionB. Have a discussion regarding anticoagulation and take

patient preference into account before starting therapyC. Recommend against anticoagulation given her history of

lung cancer

Summary Question #4

Summary Question #5

A 75 year old male with a history of atrial fibrillation on warfarin therapy has had difficulty controlling his INRs. His last three INRs have been >3.5. He has noticed that he bleeds easily. He ambulates with a cane due to gait instability and has difficulty getting transport to INR clinic. He is unable to afford any novel anticoagulants, what is the next step?

A. Stop anticoagulation until he is able to get reliable transportation to INR clinic

B. Continue anticoagulationC. None of the above

Webinar #2

Atrial Fibrillation:Managing anticoagulation

Learning Objectives

How to choose which anticoagulant to prescribe Patient specific considerations

Transitioning from a vitamin K antagonist to a novel anticoagulant Management of anticoagulation around procedures Management with bleeding

Case PresentationOutpatient clinic• 85 year old female • Past medical history:

– Atrial fibrillation on warfarin for 5 years, stable INRs– Moderate aortic regurgitation– Creatinine 1.3 (CrCl 24ml/min)

• Recently has had some dyspepsia and was started on naproxen for arthritis

• Presents to clinic and is tired of having her INRs checked

Case Presentation

Next step?• Continue warfarin• Dabigatran 110 mg twice daily• Rivaroxaban 15 mg once daily• Apixaban 2.5 mg twice daily

Choice of Anti‐coagulant

Atrial fibrillation

Valvular AF*

VKANo antithrombotic therapy NOAC

Assess risk of stroke (CHA2DS2-VASc score)

1** ≥2

Yes

No

Yes

No (i.e. non-valvular AF)

0

Oral anticoagulant therapy

Assess bleeding risk

Consider patient values and preferences

< 65 years and lone AF (including females)

* Includes moderate to severe mitral stenosis and mechanical heart valves

** Antiplatelet therapy with aspirin plus clopidogrel, or – less effectively –aspirin only, may be considered in patients who refuse any OAC


Anticoagulation

NOACsRecommendations for prevention of thromboembolism in non‐valvular AF ‐

NOACs

Recommendations Class LevelWhen adjusted‐dose VKA (INR 2–3) cannot be used in a patient with AF where an OAC is recommended, due to difficulties in keeping within therapeutic anticoagulation, experiencing side effects of VKAs, or inability to attend or undertake INR monitoring, one of the NOACs, either:• a direct thrombin inhibitor (dabigatran); or• an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d… is recommended.

I B

Where OAC is recommended, one of the NOACs, either:• a direct thrombin inhibitor (dabigatran); or• an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban)d… should be considered rather than adjusted‐dose VKA (INR 2–3) for most patients with non‐valvular AF, based on their net clinical benefit.

IIa A


Anticoagulation

Trials Designs Comparing New Anticoagulants with Warfarin in Atrial Fibrillation

Dabigatran Rivaroxaban Apixaban EdoxabanTrial Name RELY ROCKET-AF ARISTOTLE ENGAGE-AF

Population CHADS ≥ 1 CHADS ≥ 2-3 CHADS ≥ 1 CHADS ≥ 2

Sample Size 18,000 14,000 18,000 21,000

ComparatorQuality

Median TTR = 67%

Median TTR = 57%

Median TTR = 66%

Median TTR=

68%Dosing 110 mg BID

150 mg BID 20 mg daily 5 mg BID 30 mg daily

60 mg daily

Dose modification

None Randomization Randomization Randomization During Trial

Blinding PROBE Blinded Blinded Blinded

Endpoint Stroke / SE Stroke / SE Stroke / SE Stroke / SE

Primary Analysis

Non-inferiorityIntention-to-treat

Non-inferiorityOn treatment

Non-inferiorityIntention-to-treat

Non-inferiority

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011; Giugliano RP et alNEJM 2013

New anticoagulants compared to warfarinStroke or systemic embolism

Abixaban 5 mg b.i.d.

Rivaroxaban 20 mg o.d.

Dabigatran 110 mg b.i.d.


0.5 1 2

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger CB et al NEJM 2011

New anticoagulants compared to warfarinMajor bleeding





0.5 1 2


New anticoagulants compared to warfarinIntracranial hemorrhage





0.1 1 2


New anticoagulants compared to warfarin All‐cause mortality





0.5 1 2


Patient specific considerations

Chronic kidney disease History of GI bleed Elderly patients Patients on aspirin and antiplatelet therapy (Triple therapy) Valvular heart disease Medication list

Patient specific: Renal Disease

• CrCl < 25 to 30 ml/min– Recommend warfarin therapy

• CrCl 30‐49ml/min– Rivaroxaban 15mg daily– Apixaban 5mg twice daily Use 2.5 mg twice daily if two of the following are present: age >80 years, body weight < 60kg, creatinine > 1.5mg/dl

• CrCl >50ml/min– All choices are appropriate

0

0.5

1

1.5

2

2.5

dabigatran 150 rivaroxaban apixaban

% /year w

ith major GI b

leed

NOAC

Warfarin

HR 1.49*HR 1.61*

HR .89

*statistically significant

Desai J. Gastrointest Endosc. 2013;78:227

Patient specific: History of GI bleed

Patient specific: Elderly

CHADS2 score ATRIA bleeding score

Warfarin

use (%

)

Hess et al American Heart Journal 2012

0

5

10

15

20

25

30

35

40

45

50

0 1 >2 0‐3 4 5‐10

65‐79 years>80 years

Elderly

Stroke or systemic embolismHR (95% CI)

Major and clinicallyrelevant non major bleeding: HR (95% CI)

ARISTOTLE Major bleeding

Age>75 years 0.71 (0.53‐0.95) 0.64 (0.52‐0.79)

Age 65‐<75 0.72 (0.54‐0.96) 0.71 (0.56‐0.89)

Age <65 1.16 (0.77‐1.73) 0.78 (0.55‐1.11)RE‐LYdabigatran 150mg BID Age>75 years 0.67 (0.49‐0.90) 1.18 (0.98‐1.42)

Age<75 years 0.63 (0.46‐0.86) 0.70 (0.57‐0.86)dabigatran 110mg BID Age>75 years 0.88 (0.66‐1.17) 1.01 (0.83‐1.23)

Age<75 years 0.93 (0.70‐1.23) 0.62 (0.50‐0.77)

ROCKET‐AF Major bleeding

Age>75 years 0.80 (0.63‐1.02) 1.11 (0.92‐1.34)

Age<75 years 0.95 (0.76‐1.19) 0.96 (0.78‐1.19)

Patient specific: Elderly

Connolly S et al NEJM 2009; Patel M et al NEJM 2011; Granger C et al NEJM 2011

Patient Specific: Triple therapy

Use warfarin for anticoagulation Use triple therapy for minimum necessary time Use clopidogrel rather than prasugrel or ticagrelor

Consider Proton Pump Inhibitor during therapy

Patient specific: Valvular heart disease• 4808 (26.4%) patients in ARISTOTLE had a history of moderate or

severe valve abnormalities at baseline

Any VHD* 4,808 100.0%

Any mitral valve disease 3,578 74.4%

Mitral regurgitation 3,526 73.3%

Mitral stenosis 131 2.7%

Any aortic valve disease 1,150 23.9%

Aortic stenosis 887 18.4%

Aortic regurgitation 384 8.0%

Tricuspid regurgitation 2,124 44.2%

Prior valve surgery 251 5.2%*Patients may be included in more than one category.

Avezum A, et al. Eur Heart J 2013;34(Abst_Suppl):809.

Efficacy outcomes: Treatment effect by valvular heart disease status)

Avezum A, et al. Eur Heart J 2013;34(Abst_Suppl):809.

Patient specific: Valvular heart disease

Patient Specific: MedicationsEffect on NOAC levels from drug‐drug interactions

Adapted from Heidbuchel H.Eur Heart J. 2013;34:2094-106

via Dabigatran Apixaban Edoxaban Rivaroxaban

KetoconazoleP‐gpstrong CYP3A4

1.5x 2x Increased 2.5x

Digoxin P‐gp no effect no data no effect no effect

VerapamilP‐gpweak CYP3A4

+12‐180%reduce dose take together

no data +53% (SR)reduce dose

minor effectuse with caution

if CrCL: 15‐50ml/min

DiltiazemP‐gpweak CYP3A4

no effect +40% no dataminor effect

use with cautionif CrCL: 15‐50ml/min

Quinidine P‐gp +50% no data +80%reduce dose +50%

Amiodarone P‐gp +12‐60% no data no effectminor effect

use with cautionif CrCL: 15‐50ml/min

DronedaroneP‐gpweak CYP3A4

+70‐100% no data +88% reduce dose No data yet

Not recommended/contraindicated Reduce doseReduce dose if 2 factors or more No data yet

CYP = cytochrome; CrCl = creatinine clearance; NOAC = novel oral anticoagulant; P-gp = P-glycoprotein

Warfarin‐ Food and Drug Interactions (USPI)

USPI = United States product insert

Transition from warfarin Dabigatran Stop warfarin, and when INR < 2.0, start dabigatran

Rivaroxaban Stop warfarin, and when INR < 3.0, start rivaroxaban(but 6X higher bleeding in first 7d in start of ROCKET‐AF in both warfarin exp. and naïve#)

Apixaban Stop warfarin, and when INR < 2.0, start apixaban

#Mahaffey KM Ann Intern Med. 2013 18;158(12):861‐8* Not yet approved

.

Procedures

For procedures with low bleeding risk, stop 2‐3 half lives before procedure (1‐2 days) For procedures with high bleeding risk, stop 4‐5 half lives before procedure (2‐3 days, longer with dabigatran and CrCL < 50) • Consider checking coagulation level (aPTT for dabigatran, PT for rivaroxaban) prior to procedure

Resume after allowing full hemostasis

Adapted from Circulation. 2012;126:343‐348

Procedures: Cardioversion Comparable outcomes compared to warfarin More data would be helpful, and in meantime same guidelines as with warfarin reasonable –three weeks pretreatment with ≤ 1 missed dose TEE if concerned over high risk of thromboembolism

Managing bleeding

Novel OACs have less fatal bleeding than warfarin No specific antidote

Guide to the Management ofBleeding in Patients Taking NOAC

Hankey GJ and Eikelboom JW. Circulation. 2011; 123: 1436-1450

Patients with bleeding on NOAC therapy

Mild bleeding Moderate-Severebleeding

Life-threateningbleeding

• Delay next dose or discontinue treatment as appropriate

• Mechanical compression• Surgical intervention• Fluid replacement and

hemodynamic support• Blood product transfusion• Oral charcoal • Hemodialysis• ? Prothrombin Complex

Concentrate?(Circulation 2011; 2011: 124: 1573-9)

• Consideration of rFVIIa or PCC

• Charcoal filtration• ? Prothrombin Complex

Concentrate(Circulation 2011; 2011: 124: 1573-9)

Case Conclusion

• 85 year old: ok for novel agent• Aortic Regurgitation: ok for novel agent• CrCl 24ml/min: Would recommend warfarin therapy

Conclusions

How to choose an anticoagulant for a patient Patient specific considerations

Transitioning from a vitamin K antagonist to a novel anticoagulant Management of anticoagulation around procedures Management with bleeding

Summary Question #1

• Which antithrombotic strategy is not an acceptable alternative to warfarin for atrial fibrillation?A. ApixabanB. DabigatranC. RivaroxabanD. Low‐dose warfarin plus aspirin

70 year old male with history of atrial fibrillation on rivaroxaban for anticoagulation is being referred for colonoscopy. What is the best way to manage his anticoagulant for this procedure?

A. Stop rivaroxaban 2‐3 half lives (1‐2 days) prior to this low bleeding risk procedure

B. Admit for bridge therapy with iv heparinC. Continue anticoagulation without stopping

Summary Question #2

80 year old patient with history of atrial fibrillation on dabigatran for anticoagulation presents with tarry black stools and weakness. His stool is positive for occult blood. What is the best next step in management?

A. Hemodynamic assessment with supportive care and transfusions as needed

B. Give oral activated charcoalC. Hold dabigatran until source of bleeding is

determinedD. All of the above

Summary Question #3

72 year old female with history of transient ischemic attack, diabetes and atrial fibrillation on apixaban for anticoagulation presents with chest pain to the ED and found to have a STEMI. She is taken emergently to the cardiac catheterization lab and receives a bare metal stent. Which antithrombotic strategy is most appropriate?

A. Indefinite warfarin plus clopidogrelB. Aspirin, clopidogrel and warfarin for at least one monthC. Warfarin monotherapyD. Apixaban, aspirin and prasugrel

Summary Question #4

Valvular atrial fibrillation refers to which of the following valve abnormality in a patient with atrial fibrillation?

A. Aortic StenosisB. Moderate to Severe mitral stenosisC. Tricuspid regurgitationD. Aortic RegurgitationE. All of the above

Summary Question #5

Webinar #3

Atrial Fibrillation:How to change care

Learning objectives

Define the scope of underuse of anticoagulation Reasons for underuse of anticoagulation Understanding a systematic approach for change IMPACT AF trial

• Specific Aims• Study design

Case presentation

75 year old male presents with palpitations and found to have atrial fibrillation Past medical history: hypertension, prior stroke, prior GI bleed 10 years ago CHA2DS2 VASc score = 5 A discussion of anticoagulation was had with the patient and he was started on apixaban

Case presentation8 months later he presents to the Emergency Room with a stroke, he was no longer taking his apixaban What are possible explanations?

– He couldn’t afford the medication– His friend started bleeding on that medication so he didn’t want to take it

– He missed his follow up appointment and stopped taking the medication because of a side effect

– He didn’t understand the need for the medication and did not feel badly without it

Subtherapeutic INR 29%

INR in range10%

No warfarin61%

Preventable Strokes

AF Patients with Stroke with no Known Contraindication to Anticoagulation

Gladston, DJ, et al. Stroke2009;40:235-40

Preventable strokes per year

3,000,000 in the US have diagnosed/detected AF Half (1,500,000) not anticoagulated Of these, 5% stroke per year (75,000) Of these, 75% are preventable >50,000 preventable strokes per year in US

World‐wide at least 10 million with AF, more than half not treated, and well over 200,000 preventable strokes per year

Atrial Fibrillation

65

46

65

44

55

13

39

0

25

50

75

100

GWTG‐HF Medicare NRAF II UHSC ATRIA NSTEMI STEMI

Percen

t

Warfarin Use in AF Patients with an Indication: How are we doing in practice?

Piccini JP, Lopes RD, Mahaffey KW .Curr Opin Cardiol. 2010;25:312-20.

Risk: Stroke

Healey JS. The RE‐LY AF Registry. ESC 2012 Congress; August 29, 2012; Munich, Germany. http://spo.escardio.org/eslides/view.aspx?eevtid=48&fp=1355

CHADS2

GARFIELD Registry: Cohort 1 (n = 10,614).

Kakkar AK et al. Risk Profiles and Antithrombotic Treatment of Patients Newly Diagnosed with Atrial Fibrillation at Risk of Stroke: Perspectives from the International, Observational, Prospective GARFIELD Registry. PLoS ONE 2013;8(5): e63479.

Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479

GARFIELD: Underuse of Oral Anticoagulation

(n=10,607) (n=305) (n=1,345) (n=2,903) (n=2,471) (n=2,180) (n=1,311) (n=902)

Patie

nts,

N (

%)

Kakkar AK, et al. PLoS One. 2013 May 21;8(5):e63479

Reasons For Not Using Anticoagulants: GARFIELD

Reasons for Failing to Anticoagulate Patients with CHADS2>2 [n=2,302] (n, %)

Alcohol misuse 11 (0.5)

Already taking antiplatelet drug for another condition 117 (5.1)

Patient refusal 165 (7.2)

Previous bleeding event 55 (2.4)

Taking medication contraindicated/cautioned for use with vitamin K antagonists 16 (0.7)

Other 239 (10.4)

Physicians choice 1,112 (48.3)

Bleeding risk 170 (7.4)

Concern over patient compliance 121 (5.3)

Guideline recommendation 32 (1.4)

Fall risk 150 (6.5)

Low risk of stroke 95 (4.1)

Other 544 (23.6)

INR could not or unlikely to be measured 43%at appropriate intervals

Patient refusal 38%(as only reason) 15%

CHADS2 of 1 and VKA not recommended 22%(as only reason) 12%

INR not maintained in target range 17%Uncertainty of patients ability to adhere 15%Serious bleeding on VKA 3%

Multiple reasons 52%

Reasons for Unsuitability for VKA in AVERROES

Connolly S. N Engl J Med 2011; 364:806‐817

Risk: Stroke

Adherence: The problem

20‐30% of prescriptions are never filled

When filled, less than 80% of doses are taken

50% of patients prematurely discontinue chronic medications during first year

Bosworth HB. Exp rev pharm out res. 2012;12:133‐135

Contributing factors for non‐adherence

Forgetfulness

Prescription not collected or not dispensed

Purpose of treatment not clear

Perceived lack of effect

Real or perceived side‐effects

Instructions for administration not clear

Complicated regimen

Cost of drugs

Interventions Shown to Improve Adherence

More thorough patient instructions, counseling Pill organizers or packaging Reminders (including telephone follow‐up) Close follow‐up Supervised self‐monitoring Reduced out‐of‐pocket expenses Rewards for success Family or couple‐focused therapy Psychological and behavioral support

Haynes RB. 2008. Cochrane ReviewViswanathan M. Ann Intern Med. 2012;157:785‐795.

System level change

Adherence is like everything else…

If you do not measure it, you can not improve it

Steps to Building a Regional System: STEMI Care

IMPACT‐AF Cluster Randomized Trial Argentina, Brazil, China, India, Romania

Argentina Cecilia Bahit INECO Rosario Brazil Renato Lopes Federal University Sao PauloIndia Denis Xavier St. John’s BangaloreChina Huo Yong Peking University BeijingRomania Dragos Vinereanu Carol Davila Bucharest

IMPACT AF: Study Aims• To determine if a multi-faceted intervention aimed

at physicians and patients will increase the proportion of eligible patients treated with oral anticoagulation

• Increase patient adherence and persistence to therapy

• Assess country specific perceptions, system challenges and barriers

• Create a model that can be implemented in other networks

ControlIntervention

Primary outcome: difference in percentage change of patents taking oral anticoagulants from baseline to one year

Baseline oral anticoagulant use of 60%, post‐intervention 70%

Collect Baseline Data

Randomize 50 centers

Patients (40-70 per center)Atrial fibrillation CHADS ≥ 1, CHADSVaSC ≥ 2StableNo clear contraindication to oral anticoagulationAble to give consentAble to have 1 year follow-up

One year follow‐up

• High volume centers with ability to collect and feed back data

• 2 page baseline data form• One year follow‐up• Multifaceted educational and

systems improvement intervention

IMPACT‐AF Cluster Randomized Trial50 Centers in Argentina, Brazil, China, India, Romania

Challenges for a healthcare system Plan:

• Identify patients with atrial fibrillation• Define risk and need for anticoagulation• Define contraindications• Categorize reasons for non‐treatment

Do: Each country will create a country specific interventions

Study Interventions that work Act: Establish performance measures for anticoagulation in atrial fibrillation

Keys to success

1. Review in detail each and every patient who is not on an oral anticoagulantAnd take measures to assure that those patients are treated if at all possible

2. Take measures to improve adherence and persistence for patients on oral anticoagulantsEducation, patient and family engagement, measurement, tools, including for both warfarin and novel drugs

Study TimelineStudy Timeline

B 1mo 3mo 6mo 9mo 12mo

Site

Info

rmat

ion

&P

atie

ntS

cree

ning

Site

mat

chin

g

RPatient

Inclusion(50-70 per site)

3 months Control Sites

Intervention Sites✔ ✔ ✔ ✔ ✔

✔ ✔ ✔

★

1 month telephone call, 3, 6, 9 and 12 monthvisits: assessment of anticoagulation treatmentcontinuation 6 and 12 month visits: clinical event assessment

6 and 12 month visits: Clinical event assessment

Site Randomization

Case conclusion

Reasons for underuse of anticoagulation are complex To improve rates of anticoagulation a systematic approach to change care is needed

Conclusion

Define the scope of underuse of anticoagulation Reasons for underuse of anticoagulation Understanding a systematic approach for change IMPACT AF trial

• Specific Aims• Study design

Summary Question #1

Worldwide there are millions of patients with atrial fibrillation and risk factors for stroke and less than half are treated with oral anticoagulation. This translates into how many preventable strokes per year?

A. 1,000B. 10,000C. 100,000D. >100,000

Reasons for underuse of anticoagulants include system level reasons, provider level reasons and patient level reasons.

A. TrueB. False

Summary Question #2

In order to create change that will last, a systems based approach will be implemented using which of the following models?

A. Lewin’s Change Management ModelB. Kotter’s 8‐step Change ModelC. Plan‐Study‐Do‐Act (PDSA) cycle

Summary Question #3

Which of the following is true regarding the intervention in IMPACT‐AF?

A. It is country specificB. It targets the system, provider and the patientC. It is based on a PDSA model for changeD. All of the aboveE. None of the above

Summary Question #4

An 80 year old patient with atrial fibrillation presents to clinic with a normal INRs despite being prescribed warfarin for anticoagulation. He states he filled his medicine but then was unable to get reliable transport to INR clinic so stopped taking it because he couldn’t get his levels checked. He is unable to afford the novel agents. Which of the following level of intervention would help this patient?

A. System level: easier access to INR clinicsB. System level: decreasing cost of medications to

increase accessC. A and B

Summary Question #5

An 76 year old woman with atrial fibrillation presents to clinic on aspirin and no oral anticoagulant. She had vaginal bleeding on warfarin and aspirin years ago and it was stopped. Which of the following interventions is the most likely to be successful?

A. Patient level: review with patient the risks and benefits of oral anticoagulants and why you think switching to OAC is important

B. Provider level: educate providers in this clinic that warfarin alone has 30‐50% less bleeding than warfarin plus aspirin

C. System level: assure that there is a protocol in place to review each such patient and make attempts to reestablish OAC

D. All of the above

Summary Question #6

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