Case: An 82-year-old man presents to the hospital following a transient episode of left visual field changes. His symptoms lasted 20 minutes and resolved spontaneously. He has a normal neurological examination in the emergency department and is admitted to the hospital for a TIA work-up. His past medical history is significant for hypertension. His current medications include daily aspirin and an antihypertensive medication, of which he can t recall the name. On the first night of hospitalization, the telemetry monitor detects that his heart rhythm converted to atrial fibrillation. He is started on a beta-blocker for rate control. His primary care doctor asks for your opinion on anticoagulation for secondary stroke prevention. You calculate his CHADS2 Score to be 4 and estimate his annual risk of stroke to be at least 8.5%. You recommend starting an anticoagulant now, either Heparin bridging to Coumadin or one of the newer anticoagulants that become therapeutic rapidly. Rationale: Atrial fibrillation affects over 2 million people in the United States and causes approximately 70,000 annual strokes. 1, 2 Paroxysmal, persistent, and permanent atrial fibrillation all are associated with an equally increased risk of stroke. Those patients with prior stroke or TIA are at particularly elevated risk and have a 2.5-fold increased risk of stroke over other patients with atrial fibrillation. 1 On average, stroke patients with atrial fibrillation have an estimated 12% per year rate of recurrent stroke. 3 However, this rate is affected by other vascular risk factors, such as coexisting hypertension, congestive heart failure, and diabetes. 4 The CHADS2 score (Figure) is a validated stratification scheme that assigns risk of stroke based on these additional risk factors in patients with atrial fibrillation. 4 Risk Factor CHADS2 Score Annual Stroke Rate without Antithrombotic Therapy Congestive Heart Failure = 1 0 1.9% Hypertension = 1 1 2.8% Age > 75 years = 1 2 4.0% Diabetes = 1 3 5.9% Prior Stroke/TIA = 2 4 8.5% 5 12.5% 6 18.2% Figure. CHAD2 Score 2012 American Academy of Neurology Page 1
While antiplatelet agents have a modest effect on stroke risk reduction, oral anticoagulation is clearly superior at preventing recurrent events. A 2008 Cochrane Review of trials comparing dose adjusted warfarin to antiplatelet therapy reported reductions in both total vascular events (OR = 0.67; 95% CI = 0.50 to 0.91) and recurrent stroke (OR = 0.49; 95% CI = 0.33 to 0.72) in patients with prior stroke/tia treated with anticoagulation. 5 Dual antiplatelet therapy is also inferior to systemic anticoagulation for secondary stroke prevention in patients with atrial fibrillation. The ACTIVE-W trial reported recurrent stroke rates of 5.6% for subjects treated with aspirin plus clopidogrel compared to 3.9% per year for those on warfarin. 6 Major bleeding complications were similar in both groups and occurred in approximately 2% of patients. 6 Elderly patients with atrial fibrillation are often excluded from anticoagulant therapy because of perceived risk of increased complications. The BAFTA trial evaluated older patients with atrial fibrillation (age > 75 years) and revealed a 50% relative risk reduction in all strokes among those treated with warfarin (goal INR 2.0 to 3.0) compared to daily aspirin. 7 Importantly, there was no difference in major hemorrhagic complications between groups. Newer oral anticoagulant medications such as dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, factor Xa inhibitors, are potentially preferable alternatives to dose adjusted warfarin. The RE-LY study evaluated the efficacy of two doses of dabigatran (110 mg or 150 mg twice daily) compared to warfarin (goal INR 2.0 to 3.0) in 18,113 patients with atrial fibrillation, plus an additional risk factor for embolic event. 8 Dabigatran 150 mg twice daily was superior to warfarin in prevention of stroke or systemic embolism [Relative Risk (RR) = 0.66; 95% CI = 0.53 to 0.82] with similar safety profiles. 8 The ROCKET-AF study compared rivaroxaban (20 mg daily) to dose adjusted warfarin (goal INR 2.0 to 3.0) in 14,264 moderate-tohigh risk atrial fibrillation patients. 9 Rivaroxaban was found to be non-inferior to warfarin for prevention of all stroke and systemic embolization [Hazard Ratio (HR) = 0.79; 95% CI = 0.66 to 0.96]. 9 The effects of apixaban in patients with atrial fibrillation has been studied in two clinical trials, ARISTOTLE and AVERROES. 10, 11 The ARISTOTLE trial reported that apixaban was superior to warfarin (HR = 0.79; 95% CI = 0.66 to 0.95) with lower rates of major bleeding. 10 The AVERROES study, which compared apixaban to aspirin in patients with atrial fibrillation deemed poor candidates for anticoagulation, reported significantly lower embolic events (HR = 0.45; 95% CI = 0.32 to 0.62) with equivalent safety. 11 Both dabigatran and rivaroxaban have been approved by the U.S. Food and Drug Administration for prevention or stroke in patients with non-valvular atrial fibrillation. At the time of the writing of this module, apixaban had not yet been FDA approved. Anticoagulation is recommended by the American Heart Association/American Stroke Association and endorsed by the American Academy of Neurology for patients with a CHADS2 Score of 2 or above. 12, 13 Patients with atrial fibrillation should be prescribed an anticoagulant medication at discharge or have a medical reason for not prescribing documented in the medical record. 2012 American Academy of Neurology Page 2
Evidence Base: NeuroPI Case Study: Anticoagulant Therapy The following clinical recommendation statements are quoted verbatim from the referenced clinical guidelines and represent the evidence base for the measure: Administer antithrombotic therapy (oral anticoagulation or aspirin) to all patients with AF, except those with lone AF, to prevent thromboembolism. (ACC/AHA/ESC 1 )(Class I, Level of Evidence: A) It is recommended that clinicians use long-term oral anticoagulation (target INR of 2.5; range, 2.0 to 3.0) for prevention of stroke in atrial fibrillation patients who have suffered a recent stroke or TIA. Oral anticoagulation is also beneficial for prevention of recurrent stroke in patients with several other high-risk cardiac sources. (ACCP 2 ) (Grade 1A) For patients with ischemic stroke or TIA with persistent or paroxysmal AF, anticoagulation with adjusted-dose warfarin (target INR, 2.5; range 2.0 to 3.0) is recommended. (ASA 3 ) (Class I, Level of Evidence: A) Warfarin (Class I; Level of Evidence A), dabigatran (Class I; Level of Evidence B), apixaban (Class I; Level of Evidence B), and rivaroxaban (Class IIa; Level of Evidence B) are all indicated for the prevention of first and recurrent stroke in patients with nonvalvular AF. The selection of an antithrombotic agent should be individualized on the basis of risk factors, cost, tolerability, patient preference, potential for drug interactions, and other clinical characteristics, including time in INR therapeutic range if the patient has been taking warfarin. 4 Dabigatran 150 mg twice daily is an efficacious alternative to warfarin for the prevention of first and recurrent stroke in patients with nonvalvular AF and at least 1 additional risk factor who have CrCl >30 ml/min (Class I; Level of Evidence B). (Furie, 2012) On the basis of pharmacokinetic data, the use of dabigatran 75 mg twice daily in patients with AFand at least 1 additional risk factor who have a low CrCl (15 30 ml/min) may be considered, but its safety and efficacy have not been established (Class IIb; Level of Evidence C). (Furie, 2012) Apixaban 5 mg twice daily is an efficacious alternative to aspirin in patients with nonvalvular AF deemed unsuitable for vitamin K antagonist therapy who have at least 1 additional risk factor and no more than 1 of the following characteristics: Age >80 years, weight <60 kg, or serum creatinine >1.5 mg/dl (Class I; Level of Evidence B). (Furie, 2012) Apixaban 5 mg twice daily is a relatively safe and efficacious alternative to warfarin in patients with nonvalvular AF deemed appropriate for vitamin K antagonist therapy who have at least 1 additional risk factor and no more than 1 of the following characteristics: Age >80 years, weight 2012 American Academy of Neurology Page 3
<60 kg, or serum creatinine >1.5 mg/dl, (Class I; Level of Evidence B). (Furie, 2012) In patients with nonvalvular AF who are at moderate to high risk of stroke (prior history of TIA, stroke, or systemic embolization or >2 additional risk factors), rivaroxaban 20 mg/d is reasonable as an alternative to warfarin (Class IIa; Level of Evidence B). (Furie, 2012) 1. American College of Cardiology, American Heart Association, European Society of Cardiology. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001; 38; 1266i-lxx. 2. Albers GW, Amarenco P, Easton JD, Sacco RL, and Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest 2001;119; 300-320. 3. Sacco RL, Adams R, Albers G, Alberts MJ, et al. Guidelines for Preventions of Stroke in Patients with Ischemic Stroke or Transient Ischemic Attack: A statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke. Stroke 2006;37:577-617. 4. Furie KL, Goldstein LB, Albers GW, et al. Oral Antithrombotic Agents for the Prevention of Stroke in Nonvalvular Atrial Fibrillation: A Science Advisory for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2012;43:3442-3453. References: 1. Furie KL, Kasner SE, Adams RJ, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke 2011;42:227-276. 2. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology 2007;69:546-554. 3. Hart RG, Sherman DG, Easton JD, Cairns JA. Prevention of stroke in patients with nonvalvular atrial fibrillation. Neurology 1998;51:674-681. 4. 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;285:2864-2870. 5. Saxena R, Koudstaal P. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack. 2012 American Academy of Neurology Page 4
Cochrane Database Syst Rev 2004:CD000187. 6. Connolly S, Pogue J, Hart R, 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;367:1903-1912. 7. Mant J, Hobbs FD, 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;370:493-503. 8. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139-1151. 9. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-891. 10. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981-992. 11. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-817. 12. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:517-584. 13. Furie KL, Goldstein LB, Albers GW, et al. Oral Antithrombotic Agents for the Prevention of Stroke in Nonvalvular Atrial Fibrillation: A Science Advisory for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2012;43:3442-3453. 2012 American Academy of Neurology Page 5