Chapter 83 Anticoagulation in Atrial Arrhythmias
Current Therapy and New Therapeutic Options
Atrial fibrillation (AF) is an independent risk factor for stroke and the direct cause of 15% to 20% of all strokes.1 Anticoagulation reduces the relative risk by 68% and all-cause mortality by 33%.2 In the United States, approximately 500,000 people have strokes each year.3
Economics of Stroke
The economic costs of stroke are from direct costs for stroke-related morbidity and mortality, estimated at $17 billion per year. Indirect costs from lost income are $13 billion.3 Institutional care is the bulk of post-stroke care cost and varies according to the type of stroke and long-term disability.4 The costs of anticoagulation with warfarin therapy include frequent laboratory monitoring and hospitalization for bleeding complications, including the need for blood transfusions.
Risk Factors for Stroke
Risk markers for a first stroke can be classified according to their potential for modification (nonmodifiable, modifiable, or potentially modifiable) and the strength of evidence (well documented or less well documented) for prevention. Nonmodifiable risk factors include age, gender, low birth weight, race or ethnicity, and genetic factors. Well-documented modifiable risk factors include hypertension, exposure to cigarette smoke, diabetes, AF and certain other cardiac conditions, dyslipidemia, carotid artery stenosis, sickle cell disease, postmenopausal hormone therapy, poor diet, physical inactivity, and obesity and body fat distribution. From the Framingham data, Wang et al found obesity—or, more specifically, body mass index—to be a risk factor for the development of AF.5
Stroke Risk Stratification
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
| CHADS2 SCORE | STROKE RISK % (95% CI) | RECOMMENDATION |
|---|---|---|
| 0 | 1.9 (1.2–3.0) | Aspirin therapy (81 or 325 mg daily) |
| 1 | 2.8 (2.0–3.8) | Oral antithrombotic therapy or aspirin therapy |
| 2 | 4.0 (3.1–5.1) | Oral antithrombotic therapy |
| 3 | 5.9 (4.6–7.3) | Oral antithrombotic therapy |
| 4 | 8.5 (6.3–11.1) | Oral antithrombotic therapy |
| 5 | 12.5 (8.2–17.5) | Oral antithrombotic therapy |
| 6 | 18.2 (10.5–27.4) | Oral antithrombotic therapy |
Data from Gage BF, Waterman AD, Shannon W, et al: Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation, JAMA 285(22):2864–2870, 2001.
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).
| CHA2DS2-VASC SCORE | ADJUSTED STROKE RATE (% PER YEAR) | RECOMMENDATION |
|---|---|---|
| 0 | 0 | No therapy (or aspirin) |
| 1 | 1.3 | Oral anticoagulant (or aspirin) |
| 2 | 2.2 | Oral anticoagulant |
| 3 | 3.2 | Oral anticoagulant |
| 4 | 4.0 | Oral anticoagulant |
| 5 | 6.7 | Oral anticoagulant |
| 6 | 9.8 | Oral anticoagulant |
| 7 | 9.6 | Oral anticoagulant |
| 8 | 6.7 | Oral anticoagulant |
| 9 | 15.2 | Oral anticoagulant |
Data from Lip GY, Nieuwlaat R, Pisters R, et al: Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The Euro Heart Survey on atrial fibrillation, Chest 137:263–272, 2010.
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.
Challenges of Anticoagulation
Anticoagulation therapy confers a reduced stroke rate but it has its challenges, including time in therapeutic range (TTR), frequent monitoring of international normalized ratio (INR), and bleeding risk. Interactions with vitamin K antagonist (VKA) therapy drug-drug interactions for competing metabolism in the CYP 2C9, drug-food interactions in vitamin K–containing foods, and genetic mutations that make it a challenge to increase TTR, all occur frequently.9
TTR is essential for the prevention of stroke; the ideal frequency of testing of INR values is determined by multiple factors, such as comorbid conditions, diet changes, medication changes, and variable dose response.10 INR values within therapeutic range increased from 48% to 89% when monitoring occurred every 4 days by point-of-care device versus every 28 days in patients with mechanical valves.11 New therapeutic options boast a longer TTR, offering better protection against stroke.12
Current Therapy
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
