Stroke Prevention in Atrial Fibrillation An Expert Commentary With Clyde W. Yancy, MD A Clinical Context Report

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

Stroke Prevention in Atrial Fibrillation Clinical Context Series Target Audience Electrophysiologists, cardiologists, primary care physicians, nurses, nurse practitioners, physician assistants, pharmacists, and other healthcare professionals involved in the management of stroke prevention in atrial fibrillation.

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Clyde W. Yancy, MD, MSc Magerstadt Professor of Medicine Northwestern University Feinberg School of Medicine Chief of Cardiology Northwestern Memorial Hospital Chicago, Illinois Discussant

Disclosure Information Clyde W. Yancy, MD, MSc, has disclosed that he has no relevant financial relationships or conflicts of interest to report.

Disclosure Information and have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. Michael Mullen, MD, Clinical Instructor of Vascular Neurology, University of Pennsylvania; Peggy Peck; and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner, have disclosed that they have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. and have no relevant financial relationships or conflicts of interest with commercial interests related directly or indirectly to this educational activity. The staff of The University of Pennsylvania School of Medicine Office of CME, MedPage Today, and Projects In Knowledge have no relevant financial relationships or conflicts of interest with commercial interests related directly 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:

Noncardiac Comorbidities Associated With Afib Pulmonary embolism Chronic obstructive pulmonary disease (COPD) Obstructive sleep apnea Hyperthyroidism Obesity Source: Clin J Am Nephrol 2010; 5:

Atrial Fibrillation and Congestive Heart Failure Congestive heart failure affects 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:

Source: Baylor University Medical Center Proceedings IndicationINR Prevention of systemic embolism Tissue heart valves AMI (to prevent systemic embolism) † Valvular heart disease Atrial fibrillation *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 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 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:

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):

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 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