Warfarin Alternative Dabigatran Added to Atrial Fibrillation Guidelines

Takeaway points:

• Results from the RE-LY trial confirm that dabigatran is an alternative to warfarin in patients with atrial fibrillation
• Dabigatran reduced stroke rates and major bleeding risk (at the 110 mg dose) compared to warfarin
• There was no difference in mortality with dabigatran compared with warfarin

The approval of dabigatran etexilate, the first new oral anticoagulant to become available for clinical use in more than 50 years, for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF), together with the publication of results from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, recently led the American College of Cardiology, American Heart Association, and the Heart Rhythm Society to update their guidelines on the use of anti-clotting drugs in the management of patients with AF.

The introduction to the 2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation (Update on Dabigatran): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines notes that the publication of the RE-LY trial results was “considered important enough to prompt a focused update of the ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation.”

The RE-LY trial compared dabigatran with warfarin in more than 18,000 patients with nonvalvular atrial fibrillation who had at least one risk factor for stroke (according to the Focused Update, this included “previous stroke or transient ischemic attack or systemic embolism, left ventricular ejection fraction less than 40% or symptomatic heart failure [New York Heart Association class II or higher in the last six months], hypertension, age greater than or equal to 75 years, or age 65 to 74 years with either diabetes mellitus or coronary artery disease).

RE-LY evaluated two doses of dabigatran (110 mg and 150 mg twice daily). Mean age of trial participants was 71 years, with males making up nearly two-thirds (63.6%) of total enrollment. Half of participants had “prior long-term therapy with vitamin K antagonists;” mean CHADS2 (Congestive heart failure, Hypertension, Age, Diabetes, prior Stroke) risk prediction score was 2.1. Primary outcome was all stroke (ischemic or hemorrhagic) or systemic embolism. Safety outcomes included “bleeding, liver dysfunction, and other adverse events.”

As summarized in the updated guidelines, RE-LY outcomes included:

• Rates for the primary outcome were 1.71% per year in the warfarin group. Dabigatran (150 mg, twice daily) reduced the rate by 34% (to 1.11% per year) with no increase in major bleeding. Dabigatran (110 mg, twice daily) reduced the rate to 1.54% per year, with a 20% reduction in major bleeding risk compared with warfarin.
• Rates of major bleeding were 3.57% per year for patients in the warfarin group, 2.87% per year for patients in the dabigatran 110 mg group, and 3.32% per year for patients in the dabigatran 150 mg group.
• Rates of “life-threatening, intracranial, and total bleeding,” including intracerebral hemorrhage, were 0.38% per year in the warfarin group, 0.12% per year in the dabigatran 110 mg group, and 0.10% per year in the dabigatran 150 mg group.

The investigators also reported that dyspepsia occurred more frequently with dabigatran compared with warfarin, and myocardial infarction was more frequent with dabigatran. Drug discontinuation rates were “slightly higher in the dabigatran groups compared with warfarin.” There was no difference in mortality with dabigatran compared with warfarin

Summarizing these results, the updated guidelines note that “Both dabigatran doses appeared to be noninferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism. In addition, the 150-mg twice–daily dose was superior to warfarin with respect to stroke or systemic embolism, and the 110-mg twice–daily dose was superior to warfarin with respect to major bleeding.”

The guideline authors cautioned that, “because of the twice-daily dosing and greater risk of nonhemorrhagic side effects with dabigatran,” patients already taking warfarin with excellent [goal international normalized ratio] INR control “may have little to gain by switching to dabigatran.” They also recommend that when physicians evaluate whether a patient with atrial fibrillation and at least one additional risk factor for stroke may benefit from treatment with dabigatran as opposed to warfarin, they should “consider individual clinical features, including the ability to comply with twice-daily dosing, availability of an anticoagulation management program to sustain routine monitoring of INR, patient preferences, cost, and other factors.”

A news release distributed by the American Heart Association in conjunction with the publication of the updated guidelines reported the guidelines states that “dabigatran is useful as an alternative to warfarin to prevent stroke and blood clots in patients with either paroxysmal (recurrent episodes that stop after seven days) or permanent (an on-going episode) atrial fibrillation, and with risk factors for stroke or blood clotting who do not have a prosthetic heart valve, significant heart valve disease, severe renal failure or advanced liver disease.”