Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial Fibrillation

An Expert Commentary With An Expert Commentary With Clyde W. Yancy, MDClyde W. Yancy, MD

A Clinical Context ReportA Clinical Context Report

Jointly Sponsored by:Jointly Sponsored by:

andand

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationExpert CommentaryExpert Commentary

Supported in part by an educational grant from Supported in part by an educational grant from Ortho-McNeilOrtho-McNeil, Division of Ortho-McNeil-, Division of Ortho-McNeil-

Janssen Pharmaceuticals, Inc., administered by Janssen Pharmaceuticals, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.Ortho-McNeil Janssen Scientific Affairs, LLC.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationExpert CommentaryExpert Commentary

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationClinical Context SeriesClinical Context Series

The goal of this series is to provide up-to-The goal of this series is to provide up-to-date information and multiple perspectives date information and multiple perspectives on the pathogenesis, symptoms, risk on the pathogenesis, symptoms, risk factors, and complications of stroke factors, and complications of stroke prevention in atrial fibrillation as well as prevention in atrial fibrillation as well as current and emerging treatments and best current and emerging treatments and best practices in the management of stroke practices in the management of stroke prevention in atrial fibrillation.prevention in atrial fibrillation.

Stroke Prevention in Atrial FibrillationStroke Prevention in Atrial FibrillationClinical Context SeriesClinical Context Series

Target AudienceTarget Audience

Electrophysiologists, cardiologists, Electrophysiologists, cardiologists, primary care physicians, nurses, nurse primary care physicians, nurses, nurse practitioners, physician assistants, practitioners, physician assistants, pharmacists, and other healthcare pharmacists, and other healthcare professionals involved in the management professionals involved in the management of stroke prevention in atrial fibrillation.of stroke prevention in atrial fibrillation.

Activity Activity Learning ObjectiveLearning Objective

Upon successful completion of this Upon successful completion of this educational program, participants should educational program, participants should be able to:be able to:

Review the relevance and significance of the Review the relevance and significance of the activity in the broader context of clinical careactivity in the broader context of clinical care

CME Information: PhysiciansCME Information: Physicians Statement of AccreditationStatement of Accreditation

This activity has been planned and implemented This activity has been planned and implemented in accordance with the Essential Areas and in accordance with the Essential Areas and Policies of the Accreditation Council for Policies of the Accreditation Council for Continuing Medical Education through the joint Continuing Medical Education through the joint sponsorship of the University of Pennsylvania sponsorship of the University of Pennsylvania School of Medicine and MedPage Today. The School of Medicine and MedPage Today. The University of Pennsylvania School of Medicine is University of Pennsylvania School of Medicine is accredited by the ACCME to provide continuing accredited by the ACCME to provide continuing medical education for physicians. medical education for physicians.

CME InformationCME Information

Credit DesignationCredit Designation

The University of Pennsylvania School of The University of Pennsylvania School of Medicine Office of CME designates this Medicine Office of CME designates this enduring material for a maximum of 1.0 enduring material for a maximum of 1.0 AMA AMA PRA Category 1 Credits.™ PRA Category 1 Credits.™ Physicians Physicians should claim only the credit commensurate should claim only the credit commensurate with the extent of their participation in the with the extent of their participation in the activity.activity.

CME Information: PhysiciansCME Information: Physicians

Credit for Family PhysiciansCredit for Family Physicians

MedPage Today "News-Based CME" has been MedPage Today "News-Based CME" has been reviewed and is acceptable for up to 2098 reviewed and is acceptable for up to 2098 Elective credits by the American Academy of Elective credits by the American Academy of Family Physicians. AAFP accreditation begins Family Physicians. AAFP accreditation begins January 1, 2011. Term of approval is for one January 1, 2011. Term of approval is for one year from this date. Each article is approved year from this date. Each article is approved for 1 Elective credit. Credit may be claimed for for 1 Elective credit. Credit may be claimed for one year from the date of each article. one year from the date of each article.

CE Information: NursesCE Information: Nurses

Statement of AccreditationStatement of Accreditation– Projects In Knowledge, Inc. (PIK) is accredited Projects In Knowledge, Inc. (PIK) is accredited

as a provider of continuing nursing education as a provider of continuing nursing education by the American Nurses Credentialing by the American Nurses Credentialing Center’s Commission on Accreditation.Center’s Commission on Accreditation.

– Projects In Knowledge is also an approved Projects In Knowledge is also an approved provider by the California Board of Registered provider by the California Board of Registered Nursing, Provider Number CEP-15227.Nursing, Provider Number CEP-15227.

– This activity is approved for 0.75 nursing This activity is approved for 0.75 nursing contact hours. contact hours.

DISCLAIMER: Accreditation refers to educational content only and does not imply ANCC, CBRN, or PIK endorsement of any commercial product or service.

CE Information: PharmacistsCE Information: Pharmacists

Projects In KnowledgeProjects In Knowledge®® is accredited by the is accredited by the Accreditation Council for Pharmacy Education Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy (ACPE) as a provider of continuing pharmacy education. This program has been planned and education. This program has been planned and implemented in accordance with the ACPE Criteria implemented in accordance with the ACPE Criteria for Quality and Interpretive Guidelines. This activity for Quality and Interpretive Guidelines. This activity is worth up to 0.75 contact hours (0.075 CEUs). The is worth up to 0.75 contact hours (0.075 CEUs). The ACPE Universal Activity Number assigned to this ACPE Universal Activity Number assigned to this knowledge-type activity is 0052-9999-11-1515-H04-knowledge-type activity is 0052-9999-11-1515-H04-P.P.

Clyde W. Yancy, MD, MSc Magerstadt Professor of Medicine

Northwestern University Feinberg School of Medicine

Chief of CardiologyNorthwestern Memorial Hospital

Chicago, Illinois

DiscussantDiscussant

Disclosure InformationDisclosure Information

Clyde W. Yancy, MD, MSc,

has disclosed that he has no relevant has disclosed that he has no relevant financial relationships or conflicts of financial relationships or conflicts of

interest to report. interest to report.

Disclosure InformationDisclosure InformationMichael Mullen, MD, Clinical Instructor of Vascular Neurology, University of Pennsylvania; Peggy Peck; andand Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner, have disclosed that they have no relevant financial have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity.related directly or indirectly to this educational activity.

The staff of The University of Pennsylvania School of Medicine Office of CME, MedPage Today, andand Projects In Knowledge have no relevant financial relationships or have no relevant financial relationships or conflicts of interest with commercial interests related directly conflicts of interest with commercial interests related directly or indirectly to this educational activity.or indirectly to this educational activity.

Atrial Fibrillation — Profiling Afib

• Atrial fibrillation (Afib) affects about 1% of the population or about 2.3 million people in the United States

• Prevalence increases with age — affecting roughly 10% of population age 80 or older

• Afib is associated with a four- to five-fold increase in risk of stroke

Cardiac Comorbidities Associated With Afib

• Hypertension• Coronary artery disease• Valvular heart disease• Congestive heart failure• Cardiomyopathy• Pericarditis• Congenital heart disease• Cardiac surgery

Source: Clin J Am Nephrol 2010; 5: 173-181

Noncardiac Comorbidities Associated With Afib

• Pulmonary embolism

• Chronic obstructive pulmonary disease (COPD)

• Obstructive sleep apnea

• Hyperthyroidism

• Obesity

Source: Clin J Am Nephrol 2010; 5: 173-181

Atrial Fibrillation and Congestive Heart Failure

• Congestive heart failure affects 15-20 million people worldwide

• CHF is the most important risk factor for afib in developed nations

• Roughly 66% of CHF patients are >65

• Framingham data: CHF increased the risk of AF 4.5-fold in men and 5.9-fold in women

Source: Europace 2004; 5: S5-S19

Warfarin for Prevention of Stroke in Patients With Atrial Fibrillation

• Meta-analysis of 16 trials: 9,874 patients; mean follow-up 1.7 years

• Results: Adjusted-dose warfarin associated with a 62% reduction in the relative risk of stroke; Absolute risk reduction 2.7% per year for primary prevention and 8.4% per year for secondary stroke prevention

Source: Ann Intern Med 1999; 131: 492-501

Source: Baylor University Medical Center Proceedings

Indication INRPrevention of systemic embolism 2.0-3.0

  Tissue heart valves 2.0-3.0

AMI (to prevent systemic embolism)† 2.0-3.0

  Valvular heart disease 2.0-3.0 

Atrial fibrillationAtrial fibrillation 2.0-3.02.0-3.0

*Adapted from Hirsh J, Dalen JE, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D, Brandt JT. “Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range.” Chest 1998; 114(5 Suppl): 445S-469S. †If oral anticoagulant therapy is elected to prevent recurrent myocardial infarction, an INR of 2.5-3.5 is recommended, consistent with recommendations of the Food and Drug Administration.

AMI indicates acute myocardial infarction; INR, international normalized ratio.

Recommended Therapeutic Range for Oral Anticoagulant Therapy*

Home Monitoring: An Option for the Well-Motivated Patient

• The Home INR Study (THINRS) to compare methods among 2,922 warfarin-treated patients at VA centers

• Weekly finger-stick INR associated with nonsignificant decrease in bleeding, stroke, or death compared with clinic monitoring (P=0.10)

Source: Jacobson AK, et al "A Prospective Randomized Controlled Trial of the Impact of Home INR Testing on Clinical Outcomes: The Home INR Study (THINRS)" AHA 2008; Abstract 5217.

Home Monitoring: An Option for the Well-Motivated Patient (cont’d)

• Home monitoring reduced time outside of therapeutic range by 7%

• “Overall, the findings support home testing as an acceptable alternative to high-quality clinic care or even preferable if patients have difficulty getting to the clinic because of disability or distance.”

Source: Jacobson AK, et al "A prospective randomized controlled trial of the impact of home INR testing on clinical outcomes: The Home INR Study (THINRS)" AHA 2008; Abstract 5217.

But Home Monitoring …

• “Over three years of follow-up in the trial, home monitoring did not reduce the primary endpoint of annual rate of first-time major bleeding events, stroke, and death significantly compared with clinic-based monitoring (hazard ratio 0.868, 95% confidence interval 0.733 to 1.026, P=0.10).”

Source: Jacobson AK, et al "A prospective randomized controlled trial of the impact of home INR testing on clinical outcomes: The Home INR Study (THINRS)" AHA 2008; Abstract 5217.

The Real Key: The Anticoagulation Clinic • The researchers studied 104,541 patients

who were treated at 100 Veterans Health Administration Clinics and found that a longer interval between testing was a marker for poor control whether the out-of-range INR result was high or low

Source: Rose A, et al "Prompt repeat testing after out-of-range INR values a quality indicator for anticoagulation care" Circ Cardiovasc Qual Outcomes 2011; published online April 19, 2011.

RE-LY Study Overview

• In a large, randomized trial, two doses of the direct thrombin inhibitor dabigatran were compared with warfarin in patients who had atrial fibrillation and were at risk for stroke

• At 2 years, the 110-mg dose of dabigatran was found to be noninferior, and the 150-mg dose superior, to warfarin with respect to the primary outcome of stroke or systemic embolism

Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group

Connolly SJ, et al. N Engl J Med 2009; 361: 1139-1151.

RE-LY Study Conclusion

• In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage

• Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage

Turning off Warfarin

• “In patients receiving warfarin who have asymptomatic excessive prolongations in their INR results, 1 mg of oral vitamin K reliably reduces the INR to the therapeutic range within 24 h. This therapy is more convenient, less expensive, and might be safer than parenteral vitamin K. Thus, it should be considered in all non-bleeding patients receiving warfarin, who present with INR results of 4.5 to 9.5.”

Source: Thromb Haemost 1998; 79(6): 1116-1118.

Atrial fibrillation affects about 1% of the popu-lation and its prevalence increases with age

Afib is associated with a number of cardiac comorbidities including hypertension, valvular heart disease, coronary artery disease, and congestive heart failure

Noncardiac comorbidities include sleep apnea, obesity, and COPD

Summary

At the end of this activity, participants should understand:

Warfarin has been the leading oral anticoagulant treatment for afib

In a meta-analysis of more of 16 studies, use of warfarin was associated with a significant reduction in the risk of stroke

Warfarin use is also associated with an increased risk of extracranial bleeding

The recommended INR therapeutic range for afib patients treated with warfarin is 2.0-3.0

Summary

In a randomized trial, use of home monitoring decreased the time outside therapeutic range

Anticoagulation clinics are key to the success of warfarin therapy, and recent studies suggest that shorter intervals between INR testing at clinics can improve control

Summary

An alternative to warfarin is dabigatran (Pradaxa), a direct thrombin inhibitor, which is approved for prevention of stroke in patients with afib

Dabigatran requires neither INR testing nor special diets and is approved at doses of 150 mg and 75 mg bid

Unlike warfarin, which has an antidote (vitamin K), dabigatran does not have an antidote

Summary