CHADS₂

The CHADS₂ score is the primary risk stratification scheme and was used for the 2006 American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines for nonvalvular AF.⁶ The following risk factors are allotted values that guide the administration of anticoagulation: congestive heart failure (CHF), 1; hypertension, 1; age 75 years and older, 1; diabetes mellitus, 1; and stroke or transient ischemic attack (TIA), 2. For a score of 0 or 1, which indicates low risk or no risk of stroke (lone AF), aspirin therapy (81 or 325 mg) is recommended. For a score of 1 or 2, which indicates intermediate risk, an oral anticoagulant therapy should be recommended if the patient has no contraindications. A score of 3 or greater indicates a high risk for stroke, and oral anticoagulant therapy is recommended (Table 83-1).

Table 83-1 CHADS₂ Score Stroke Rates and Recommended Therapy

CHA₂DS₂-VASc

The CHA₂DS₂-VASc score, recommended by the 2010 ESC guidelines for use by cardiology professionals for the determination of stroke risk, accounts for major and nonmajor stroke risk factors.⁷ Major risk factors, scored with 2 points, include previous stroke, TIA or systemic embolism, and age 75 years and older. Minor risks, scored with 1 point each, include CHF with impaired left ventricular function (left ventricular ejection fraction [LVEF] <40%), hypertension, diabetes mellitus, vascular disease, female gender, and age 65 to 74 years. A score of 0 indicates very low risk, and either no therapy or aspirin therapy (75 or 325 mg) is recommended. A score of 1 shows a benefit to the use of oral anticoagulant therapy or aspirin therapy. For a score greater than 2, an oral anticoagulant is recommended. Patients with paroxysmal AF should be treated with anticoagulants, as are those with persistent or permanent AF (Table 83-2).

Table 83-2 CHA₂DS₂-VASc Stroke Rate and Recommended Therapy

Transthoracic Echocardiography

Transthoracic echocardiography is used in risk stratification by evaluating left ventricular function as an indicator of stroke risk. For moderate to severe left ventricular dysfunction, the stroke relative risk is 2.5 times greater than in patients with mild or normal function. By analysis with transthoracic echocardiography, 38% of patients determined to be in a low-risk group were re-categorized to a high-risk group on the basis of findings pertaining to left ventricular function.⁸ Transesophageal echocardiography (TEE) is not recommended for risk stratification.

Warfarin

Warfarin, a VKA, has been used for the prevention of stroke in the United States since the 1950s. It is an effective anticoagulant that has been proven to reduce the risk of stroke associated with AF. Warfarin reduces stroke relative risk by 62%.¹² For primary prevention, the absolute risk reduction with dose-adjusted warfarin was 2.7% per year; for secondary prevention, the absolute risk reduction was 8.4% per year. Aspirin reduced stroke rates by 22%, showing warfarin to be superior to aspirin in the reduction of stroke.¹³ Warfarin has been standard of care for stroke prevention until an update of the 2006 ACC/AHA recommendations in February 2011, which recommended the use of dabigatran as an acceptable alternative to warfarin therapy in the prevention of stroke in nonvalvular AF.

Aspirin and Clopidogrel

Antiplatelet therapy with aspirin and clopidogrel were compared with anticoagulant therapy in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W) study to evaluate the efficacy of each therapy for stroke prevention. The study showed oral anticoagulants to be superior to antiplatelet therapy, with a higher annual event rate with aspirin and clopidogrel compared with warfarin (3.93% vs. 5.64%; P < .001). For patients with contraindications for anticoagulant therapy, the ACTIVE A trial showed a reduction in stroke rates with combined aspirin and clopidogrel verses aspirin alone.¹²

Dabigatran

Dabigatran (Pradaxa) is the first new oral anticoagulant in more than 50 years approved by the U.S. Food and Drug Administration for the reduction of stroke risk and systemic thromboembolism in nonvalvular AF. Benefits of dabigatran include prevention of thromboembolism without the need for monitoring. Dabigatran has no food interactions and limited drug interactions. A warning to avoid the use of rifampin, a P-glycoprotein (P-gp) inducer, is included in the FDA label. Interactions with the P-gp inhibitors ketoconazole, amiodarone, verapamil, and quinidine do occur, but no dose adjustments are needed.¹⁴

Dabigatran has been evaluated in two major clinical trials, the Prevention of Embolic and Thrombotic Events in Patients with Persistent Atrial Fibrillation (PETRO) study (and the extension study PETRO-EX) and the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study (and the continuation study RELY-ABLE). In the phase II PETRO study, dabigatran (300 mg, 150 mg, and 50 mg twice daily) was compared with dose-adjusted warfarin or aspirin.¹⁵ Major bleeding events occurred most often in the highest dose (300 mg) group of patients who concurrently took aspirin (stopped during the study), and inadequate thromboembolic prevention was seen in the lowest dose (50 mg) group.¹⁶ This trial proved pivotal in choosing the correct doses for the evaluation of the drug in the definitive phase III trial.

RE-LY showed the 150 mg twice-daily dose to be superior in the prevention of stroke or systemic embolism in patients with nonvalvular AF compared with the warfarin 150 mg twice-daily dose (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.52 to 0.81, P = .0001) and 110 mg twice-daily dose (HR, 0.72; 95% CI, 0.58 vs. 0.90; P = .004).¹⁴ The 150-mg dose of dabigatran had fewer stroke and systemic thromboembolism rates compared with warfarin and lower rates of hemorrhagic stroke compared with warfarin.¹⁴

TEE is not recommended for risk stratification purposes. However, it is useful before cardioversion to evaluate for clots in the left atrial appendage. Anticoagulation is recommended before cardioversion for the prevention of potential complications by thromboembolism. According to the 2010 ESC guidelines, anticoagulation with warfarin is recommended for at least 3 weeks before cardioversion. If no clots are seen in the left atrial appendage on TEE, the time frame can be shortened. Anticoagulation is recommended for 4 weeks to life after cardioversion, depending on stroke risk factors.¹⁷ Eighty percent of thromboembolic events occur within 3 to 10 days after cardioversion. In instable AF, cardioversion should be performed without delay.¹⁷ In the case of emergency cardioversion, low-molecular-weight heparin is not recommended. Unfractionated heparin should be used and should be followed by 4 weeks of post-cardioversion warfarin administration.¹⁸

Use of dabigatran in cardioversion was analyzed from the RE-LY data. The rates of stroke and systemic embolism at 30 days after cardioversion following the recommended 3 weeks of pre-cardioversion anticoagulation were 0.8% (P = .71 vs. warfarin) for the 110-mg dose, 0.3% (P = .40 vs. warfarin) for the 150-mg dose, and 0.6% for warfarin. Major bleeding event rates were similar in the 150-mg group (1.7%) and warfarin group (0.6%), whereas the 110-mg group had more events (0.6%; P = .06 vs. warfarin). Rates of stroke and systemic embolism were low compared with those of warfarin. As Nagarakanti et al have concluded, dabigatran is an alternative to warfarin for cardioversion anticoagulation.¹⁹

RE-LY also evaluated the rates of stroke and systemic embolism in VKA-naïve patients compared with the two dose groups (110 mg twice daily and 150 mg twice daily). Being “VKA naïve” was defined as 62 days or less of lifetime VKA exposure. Stroke and systemic embolism rates per year for the 110-mg, 150-mg, and warfarin groups were 1.57%, 1.07%, and 1.69%, respectively. The 150-mg dose was found to be superior to warfarin (P = .005) and the 110-mg dose similar to warfarin (P = .65). Major bleeding rates in VKA-naïve patients were similar in the dose groups compared with warfarin. Intracranial bleeding rates for the 110-mg, 150-mg, and warfarin groups were 3.11%, 3.34%, and 3.57% per year, respectively, with the 110-mg and 150-mg groups having a lower rate than the warfarin group (P < .001 and P = .005, respectively). In the VKA-experienced 110-mg, 150-mg, and warfarin groups, the stroke and systemic embolism rates were 1.51%, 1.15%, and 1.74% per year, respectively, with 110 mg being similar to warfarin (P = .32) and 150 mg superior (P = .007). Major bleeding rates were lower in the 110-mg group and similar to warfarin in the 150-mg group (P = .003 and P = .41, respectively). Intracranial bleeding rates were lower in both groups of dabigatran compared with the warfarin group (P < .001). RE-LY showed that prior VKA exposure did not alter the benefit of dabigatran.²⁰

Stroke rate, broken down by subtype, either ischemic or hemorrhagic, was evaluated in RE-LY. In the 150-mg twice-daily dose group, the HR, compared with the warfarin group, for all stroke events was 0.64 (95% CI, 0.51 to 0.81), 0.75 (95% CI, 0.58 to 0.97) for ischemic stroke, and 0.26 (95% CI, 0.14 to 0.49) for hemorrhagic stroke. The HR of systemic embolism was 0.61 (95% CI, 0.30 to 1.21) versus warfarin. Dabigatran 150 mg twice daily reduced stroke occurrence compared with warfarin.¹⁴

On the basis of the evidence of the RE-LY trial, the ACC/AHA/Heart Rhythm Society (HRS) published a focused update on management of patients with nonvalvular AF that recommended the use of dabigatran for the prevention of stroke.²¹ Dabigatran is dosed at 150 mg twice daily and 75 mg twice daily for creatinine clearance of 15 to 30 mL/min. It is not approved for patients with creatinine clearance less than 15 mL/min.