An anticoagulation option for nonvalvular atrial fibrillation

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Applied Evidence

An anticoagulation option for nonvalvular atrial fibrillation

J Fam Pract. 2012 June;61(6):E1-E6

By

Rajesh Kabra, MD

Mazen H. Shaheen, MD

Pranab Das, MD

Santhosh K.G. Koshy, MD

Sunil K. Jha, MD

Patients with a risk of stroke—particularly those taking warfarin with poorly controlled INR—may be candidates for dabigatran.

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References

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PRACTICE RECOMMENDATIONS

• Consider dabigatran as an alternative to warfarin for patients with nonvalvular paroxysmal or permanent atrial fibrillation and risk factors for stroke. A

• Avoid using dabigatran with patients who have a creatinine clearance <15 mL/min, a prosthetic heart valve, or hemodynamically significant valve disease. C

• Withhold dabigatran for at least 24 hours before planned surgery, or for a longer time if there is renal insufficiency or the procedure is high risk. C

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

There are an estimated 2.3 million cases of atrial fibrillation (AF) in the United States, and that number may increase to 5.6 million by the year 2050.¹ The stasis of blood during AF, in addition to proinflammatory factors, predisposes patients to clot formation in the left atrium, especially in the left atrial appendage. In 5% of AF patients each year, such a thrombus dislodges and causes a stroke, a rate 2 to 7 times higher than that of people without AF.^1-3 Patients with paroxysmal or permanent AF have similar risks of stroke.⁴

Stratifying stroke risk aids in treatment decisions. Multiple criteria have been devised to identify AF patients at a higher risk of stroke. The CHADS₂ risk index, used extensively in clinical settings, stratifies risk according to a cumulative score based on a patient’s risk factors (TABLE 1).⁵ A joint 2006 guideline released by the American College of Cardiology, American Heart Association, and European Society of Cardiology,¹ and a separate 2008 guideline by the American College of Chest Physicians⁶ recommend that patients with a CHADS₂ score of ≥2 be treated with a vitamin K antagonist such as warfarin, while patients with a score of 1 may be treated with either antiplatelet or anticoagulant therapy.

The evidence behind the guidelines. These guidelines are based on a number of randomized clinical trials that demonstrated the superiority of dose-adjusted warfarin in preventing stroke compared with placebo: Stroke Prevention in Atrial Fibrillation (SPAF), Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF), Copenhagen Atrial Fibrillation Aspirin Anticoagulation (AFASAK), Canadian Atrial Fibrillation Anticoagulation (CAFA), Stroke Prevention in Nonrheumatic Atrial Fibrillation (SPINAF), and European Atrial Fibrillation Trial (EAFT).^7-12

Further support for anticoagulant therapy. In a meta-analysis conducted after release of the guidelines, dose-adjusted warfarin was associated with a 62% risk reduction for stroke vs placebo, and a 39% risk reduction vs antiplatelet agents.¹³ For high-risk patients in the SPAF III trial, dose-adjusted warfarin led to a 76% risk reduction of stroke and systemic embolism compared with combination therapy of aspirin and low-intensity fixed-dose warfarin.¹⁴ The Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W) trial was stopped prematurely when it demonstrated that, in patients with AF who have one or more risk factors for stroke, warfarin was superior to the combination of aspirin and clopidogrel in preventing a combined end point of stroke, non-CNS systemic embolism, myocardial infarction, and vascular death; secondary outcomes of stroke were also more favorable with warfarin.¹⁵ The results of all 3 studies were noted during a follow-up of 1 to 2 years. In clinical practice, patients must continue antithrombotic agents for a much longer period.

Disadvantages of long-term warfarin use. The main drawback of warfarin therapy is the need for frequent laboratory monitoring. It also interacts unfavorably with other drugs and with certain foods. These factors often lead to patient discontinuation of therapy or to inadequate anticoagulation even when patients are compliant.¹⁶ A meta-analysis of 67 clinical studies showed that, regardless of the setting of anticoagulation management with warfarin, the international normalization ratio (INR) was in the therapeutic range only 64% of the time.¹⁷ These issues with warfarin have increased interest in developing novel oral anticoagulants that have better drug profiles. An oral direct thrombin inhibitor, ximelagatran, was shown to be as effective as warfarin in the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) V trial,¹⁸ but it was associated with hepatotoxicity and did not receive US Food and Drug Administration (FDA) approval.

FAST TRACK

Regardless of the setting of anticoagulation management with warfarin, the INR was in the therapeutic range only 64% of the time.

However, another thrombin inhibitor, dabigatran, was approved by the FDA for anticoagulation in nonvalvular AF, and has been incorporated into the ACCF/AHA/HRS guidelines as a therapeutic option.¹⁹ Since this article was submitted for publication, rivaroxaban, an oral factor Xa inhibitor, was approved by the FDA for anticoagulation in AF, based on results of the study Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF).²⁰