UC SF. Division of General Internal Medicine UNIVERSITY OF CALIFORNIA SAN FRANCISCO, DIVISION OF HOSPITAL MEDICINE

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1 Updates in the Management of Atrial Fibrillation Margaret C. Fang, MD, MPH Associate Professor of Medicine UCSF Division of Hospital Medicine Medical Director, Anticoagulation Clinic UC SF Division of General Internal Medicine UNIVERSITY OF CALIFORNIA SAN FRANCISCO, DIVISION OF HOSPITAL MEDICINE Atrial Fibrillation Most common clinically significant cardiac arrhythmia Affects ~ 2.2 million people in the US Prevalence will rise as the population ages ~1 in 4 lifetime risk for patients older than 40 years Responsible for 15-20% of strokes Objectives Rate vs. rhythm control Overview of antiarrhythmic strategies Risk stratification for stroke and antithrombotic treatment Newer anticoagulants Goals of Therapy in Patients With AF Prevention of stroke (thromboembolism) Prevention of tachycardia-induced cardiomyopathy Symptom relief Primary prevention of other cardiovascular events 1

2 Treatment Strategies for AF Which of the following is most true? Rate Control Pharmacologic Ca 2+ blockers β-blockers Digitalis Amiodarone Nonpharmacologic Ablate and pace Prevent Remodeling Pharmacologic Antiarrhythmic drugs: Class IA Class IC Class III Maintenance of SR a CCB ACE-I, ARB Statins Nonpharmacologic Catheter ablation Pacing Surgery Implantable devices Stroke Prevention Pharmacologic Aspirin Thrombin inhibitor Nonpharmacologic Removal/isolation LA appendage a Consider for symptomatic patients 1. Rhythm control with antiarrhythmic medications is superior to rate control 2. Rhythm control with cardioversion + antiarrhythmic medications is superior to rate control 3. Rate control is superior to rhythm control 4. Rate control and rhythm control have similar outcomes Prystowsky EN. Am J Cardiol Rate vs. Rhythm Rhythm control not superior to rate control No differences in stroke rates or quality of life Stroke rates: 5.5% with rate control and 7.1% with rhythm control (p=0.79) Does not obviate need for anticoagulation Stroke events occurred mostly in patient off or sub- therapeutic on warfarin, regardless of rhythm Trend towards worse outcomes with rhythm control, probably due to drug toxicity Rate Control Should be part of initial therapy for AF Beta-blockers or nondihydropyridine calcium channel blockers are first-line agents Digoxin may be helpful in those with heart failure, who are sedentary, or as a 2 nd drug AV node ablation can be considered if drug therapy fails AFFIRM Investigators, NEJM

3 Strict vs. Lenient Rate Control Strict rate-control (resting heart rate < 80 bpm) had similar outcomes compared to lenient rate-control (resting heart rate < 110 bpm) No difference in cardiovascular death, heart failure, stroke, bleeding, arrhythmias: 14.9% in strict and 12.9% in lenient Strict rate-control may not be beneficial unless heart rate symptomatic Which of the following is most true? 1. Rhythm control with antiarrhythmic medications is superior to rate control 2. Rhythm control with cardioversion + antiarrhythmic medications is superior to rate control 3. Rate control is superior to rhythm control 4. Rate control and rhythm control have similar outcomes Van Gelder et al, NEJM 2010 Which of the following is most true? 1. Rhythm control with antiarrhythmic medications is superior to rate control 2. Rhythm control with cardioversion + antiarrhythmic medications is superior to rate control 3. Rate control is superior to rhythm control 4. Rate control and rhythm control have similar outcomes Rhythm Control Rhythm control recommended for symptomatic atrial fibrillation Can consider cardioversion with new onset atrial fibrillation Most effective when initiated close to atrial fibrillation onset Antiarrhythmic medications Catheter ablation 3

4 Which of the following antiarrhythmics is considered first-line therapy for patients with AF and heart failure? 1. Flecainide 2. Sotalol 3. Amiodarone 4. Dronedarone Antiarrhythmic Drugs Drug choice depends on clinical comorbidities and side-effect effect profile Class IC agents (flecainide, propafenone) amiodarone, sotalol, and dronedarone can be started as outpatients in patients with minimal underlying heart disease Pill in the pocket approach for paroxysmal atrial fibrillation Amiodarone probably the most effective agent but limited by side-effectseffects Preferred antiarrhythmic in patients with heart failure Dronedarone New antiarrhythmic approved in 2009 Less effective than amiodarone, but may have somewhat fewer side-effectseffects Avoid in patients with heart failure Drug-drug interactions Digoxin, statins QT interval prolongation or CYP3A4 inducers May potentiate nodal blockade when used with beta- blockers/calcium channel blockers Case reports of hepatotoxicity; should monitor LFTs during initiation of therapy Catheter Ablation May be useful for symptomatic atrial fibrillation or if antiarrhythmic medications do not control rhythm Outcomes are not well described for older patients or those with heart failure Many people go back into atrial fibrillation Highest relapse rate is within the first year Piccini et al, JACC 2009; 2011 ACCF/AHA/HRS Guidelines 4

5 Sinus Rhythm after First Catheter Ablation Maintenance of Sinus Rhythm No Heart Disease HTN CAD CHF Patients in Sinus Rhythm (%) Weerasooriya et al. JACC % 29% Amiodarone Dofetilide Dronedarone Flecainide Propafenone Sotalol Catheter Ablation No LVH? Yes Amiodarone Dofetilide Dronedarone Sotalol Amiodarone Dofetilide Catheter Ablation 2011 ACCF/AHA/HRS Practice Guidelines Which of the following antiarrhythmics is considered first-line therapy for patients with AF and heart failure? 1. Flecainide 2. Sotalol 3. Amiodarone 4. Dronedarone Which of the following antiarrhythmics is considered first-line therapy for patients with AF and heart failure? 1. Flecainide 2. Sotalol 3. Amiodarone 4. Dronedarone 5

6 A 70 y/o man presents with atrial fibrillation. He has a history of hypertension, asthma, peripheral arterial disease, and diabetes. What is his CHADS2 stroke risk score? 1. CHADS2 = 1 2. CHADS2 = 2 3. CHADS2 = 3 4. CHADS2 = 4 5. CHADS2 = 5 CHADS 2 Risk Scheme For Stroke Risk Factors Score C Recent congestive heart failure 1 H Hypertension 1 A Age 75 years 1 D Diabetes mellitus 1 S 2 History of stroke or transient ischemic attack (TIA) 2 Gage et al., JAMA 2001 CHADS 2 Risk Score and Stroke Rates CHADS 2 Score Stroke Rate per 100 p-yrs A 70 y/o man presents with atrial fibrillation. He has a history of hypertension, asthma, peripheral arterial disease, and diabetes. What is his CHADS2 stroke risk score? 1. CHADS2 = 1 2. CHADS2 = 2 3. CHADS2 = 3 4. CHADS2 = 4 5. CHADS2 = 5 Gage et al., JAMA, Rates from NRAF Cohort Study 6

7 A 70 y/o man presents with atrial fibrillation. He has a history of hypertension, asthma, peripheral arterial disease, and diabetes. What is his CHADS2 stroke risk score? 1. CHADS2 = 1 2. CHADS2 = 2 3. CHADS2 = 3 4. CHADS2 = 4 5. CHADS2 = 5 Stroke Risk Low (<1%/yr) Intermediate (1-4%/yr) High (>4%/yr) 8 th ACCP Guidelines CHADS2 = 0 CHADS2 = 1 CHADS2 2 Recommended Treatment Aspirin 75 to 325 mg or Aspirin 8 th ACCP Consensus Statement, Chest The most commonly used oral anticoagulant Reduces risk of atrial fibrillation-related related stroke by 64% Recommended International Normalized Ratio (INR) range: works but what about bleeding? Hart et al, Ann Intern Med

8 Falls and Intracranial Hemorrhage Relatively little data on falls and ICH Oldest patients generally excluded from studies Some observational data: Fall Risk ICH Rate Stroke Rate High 2.8% 13.7% Not high 1.1% 6.9% Gage et al, Am J Med Falls and Intracranial Hemorrhage Assessed effect of warfarin on combined outcome of stroke, major hemorrhage, MI in patients at high fall risk CHADS 2 HR [95%CI] Recommended Treatment [ ] Aspirin or none [ ] 0.9] Anticoagulation Moderate and high stroke risk warfarin Gage et al, AJM, You start your patient on warfarin. Over the next 6 months however, his INRs have been difficult to control. He wants to know whether he can stop warfarin. What do you recommend? 1. Stop warfarin and start aspirin 2. Stop warfarin and start aspirin + clopidogrel 3. Stop warfarin and start dabigatran 4. Obtain genetic testing to help figure out his optimal dose and advise him to continue warfarin Genotype-guided Dosing Two haplotypes related to warfarin response CYP2C9 (cytochrome P450 enzyme, which metabolizes warfarin) VKORC1 (Vitamin K epoxide reductase complex, required to regenerate vitamin K) dosing algorithms using genotyping + clinical factors can predict 50-60% of the variability in warfarin dosing However, not yet clear whether incorporating genetic testing significantly improves patient outcomes International Pharmacogenetics Consortium, NEJM

9 Alternatives to? Antiplatelet agents Direct thrombin inhibitors Factor Xa inhibitors Aspirin Compared to placebo, aspirin reduces stroke risk by 22% Considerably less effective than warfarin BAFTA Trial: randomized older patients (mean age 81.5 years) to warfarin vs. aspirin more effective Bleeding rates were similar (1.4% per year on warfarin, 1.6% on aspirin) Hart et al, Ann Intern Med 2007; Mant et al, Lancet 2007 Clopidogrel + Aspirin Less Effective than for Stroke Prevention Aspirin + Clopidogrel More Effective Than Aspirin Alone in Non- Candidates Cumulative Hazard Rates RR = 1.72 ( ) Clopidogrel + aspirin Oral anticoagulation therapy 0.5 Years Cumulative Hazard Rates HR = 0.72 ( ) Aspirin Clopidogrel + aspirin Years ACTIVE-W Trial, Connolly S, et al. Lancet ACTIVE A Trial: Connolly SJ, et al. NEJM

10 New and Investigational Agents for Stroke Prevention in AF Direct thrombin inhibitors Dabigatran (RE-LY): FDA approved for prevention of stroke and blood clots in patients with AF (10/19/10) Direct factor Xa inhibitors Rivaroxaban (ROCKET AF) Apixaban (ARISTOTLE) Edoxaban (ENGAGE-AF) AF) Betrixaban (EXPERT) YM150 (ONYX-2) Indirect Xa inhibitors Idraparinux (BOREALIS-AF) AF) Indirect inhibitors (eg, odiparcil) New and Investigational Agents Mechanisms Intrinsic pathway XII XI IX VIII X V II Fibrinogen Fibrin clot VII Extrinsic pathway Tissue factor Direct FXa inhibitors (rivaroxaban, apixaban) Direct thrombin inhibitors (dabigatran) Newer Anticoagulants Target Time to effect Dabigatran Rivaroxaban Apixaban Thrombin Factor Xa Factor Xa 2 hrs hrs 3 hrs Half-life hrs 9-13 hrs (older pts) Monitoring Administration Not needed Twice daily Not needed Once daily 8-15 hrs Not needed Twice daily Bioavailability 5%-6% 60%-80% 50%-85% Renal excretion 80% 33% 25% Drug interactions PPI and P-gp inhibitors Potent CYP3A4 inhibitors Potent CYP3A4 inhibitors RE-LY Trial: Dabigatran vs. Dabigatran 110 mg (n = 6015) Annual Rate Dabigatran 150 mg (n = 6076) Annual Rate (n = 6022) Annual Rate Stroke 1.4% 1.0% 1.6% Death 3.8% 3.6% 4.1% Dabigatran 110 mg vs RR 95% CI P Value Dabigatran 150 mg vs RR 95% CI P Value < Connolly SJ, et al N Engl J Med

11 Dabigatran vs. Dabigatran 110 mg Annual Rate Dabigatran 150 mg Annual Rate Annual Rate Major Bleeds 2.7% 3.1% 3.4% Intracranial Hemorrhage 0.2% 0.3% 0.7% Myocardial Infarction 0.7% 0.7% 0.5% Dabigatran 110 mg vs Dabigatran 150 mg vs RR 95% CI P Value.003 < RR 95% CI P Value < Dabigatran At least similar in efficacy to warfarin for AF May have lower rates of intracranial hemorrhage Associated with a slight increase in risk of myocardial infarction FDA approved doses: 150mg BID and 75mg BID dosing (for CrCl < 30) More costly than warfarin No way to monitor or reverse anticoagulant effect Connolly SJ, et al N Engl J Med When Should I Prescribe Dabigatran? Patients who have difficulty remaining in a therapeutic INR range on warfarin Do not have renal insufficiency Can be adherent to twice a day dosing Can afford dabigatran ROCKET-AF Trial: Rivaroxaban vs. Vascular death, stroke, embolism Ischemic stroke Intracranial hemorrhage Rivaroxaban 20mg (n = 7081) Annual Rate (n =7090) Annual Rate Major bleeding Rivaroxaban vs. RR 95% CI 0.86 ( ) 0.99) 0.94 ( ) 0.67 ( ) 0.94) 1.04 ( ) P Value Califf R. Presented at: American Heart Association Scientific Sessions

12 Rivaroxaban Similar efficacy and safety compared to warfarin Not yet approved for use in the US Once daily dosing Hepatically-cleared cleared (might be able to use in renal insufficiency) Also no effective way to monitor or reverse anticoagulant effect You start your patient on warfarin. Over the next 6 months however, his INRs have been difficult to control. He wants to know whether he can stop warfarin. What do you recommend? 1. Stop warfarin and start aspirin 2. Stop warfarin and start aspirin + clopidogrel 3. Stop warfarin and start dabigatran 4. Obtain genetic testing to help figure out his optimal dose and advise him to continue warfarin You start your patient on warfarin. Over the next 6 months however, his INRs have been difficult to control. He wants to know whether he can stop warfarin. What do you recommend? 1. Stop warfarin and start aspirin 2. Stop warfarin and start aspirin + clopidogrel 3. Stop warfarin and start dabigatran 4. Obtain genetic testing to help figure out his optimal dose and advise him to continue warfarin Summary Rate control and rhythm control have similar outcomes May not require strict rate control Consider rhythm control for symptomatic patients Choice of therapy depends on patient characteristics and side- effect profile Antithrombotic therapy should be guided by risk stratification is more effective than antiplatelet agents Net benefit of warfarin increases with older patients at higher stroke risk Newer anticoagulants (dabigatran, rivaroxaban) may become viable alternatives to warfarin 12

13 Bibliography Thank you! 1. AFFIRM Investigators: A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation. New England Journal of Medicine 2002; 347(23): Connolly SJ, Ezekowitz MD, Yusuf S, et al.: Dabigatran versus in Patients with Atrial Fibrillation. N Engl J Med 2009; 361: Gage BF, Birman-Deych E, Kerzner R, Radford M, Nilasena DS, Rich MW: Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. American Journal of Medicine 2005; 118: Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ: Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001; 285(22): Hart R, Pearce LA, Aguilar MI: Meta-analysis: analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of Internal Medicine 2007; 146: Hohnloser SH, Crijns HJGM, van Eickels M, et al.: Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation. New England Journal of Medicine 2009; 360(7 ): Mant J, Hobbs R, Fletcher K, et al.: 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): Bibliography Bibliography 8. Piccini JP, Hasselblad V, Peterson ED, Washam JB, Califf RM, Kong DF: Comparative Efficacy of Dronedarone and Amiodarone for the Maintenance of Sinus Rhythm in Patients With Atrial Fibrillation. J Am Coll Cardiol 2009; 54(12): Prystowsky EN: Management of atrial fibrillation: therapeutic options and clinical decisions. American Journal of Cardiology 2000; 85(10, Supplement 1): ROCKET AF Study Investigators: Rivaroxaban-Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: Rationale and Design of the ROCKET AF study. American Heart Journal 2010; 159(3): Singer DE, Albers GW, Dalen JE, et al.: Antithrombotic Therapy in Atrial Fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133(6_suppl): 546S Singer DE, Chang Y, Fang MC, et al.: The Net Clinical Benefit of Anticoagulation in Atrial Fibrillation. Ann Intern Med 2009; 151(5): Singer DE, Chang Y, Fang MC, et al.: Should Patient Characteristics Influence Target Anticoagulation Intensity for Stroke Prevention in Nonvalvular Atrial Fibrillation?: The ATRIA Study. Circ Cardiovasc Qual Outcomes 2009; 2(4): The ACTIVE Investigators: Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation. New England Journal of Medicine 2009; 360(20 ): The ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, et al.: Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367(9526): The International Pharmacogenetics Consortium: Estimation of the Dose with Clinical and Pharmacogenetic Data. New England Journal of Medicine 2009; 360(8 ): Van Gelder IC, Groenveld HF, Crijns HJGM, et al.: Lenient versus Strict Rate Control in Patients with Atrial Fibrillation. New England Journal of Medicine; 362(15 ): Wann LS, Curtis AB, January CT, et al.: 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123(1): Weerasooriya R, Khairy P, Litalien J, et al.: Catheter Ablation for Atrial Fibrillation: Are Results Maintained at 5 Years of Follow-Up? J Am Coll Cardiol 2011; 57(2):