New Oral Anticoagulants Top Warfarin for Afib

Action Points

This meta-analysis reviews data for all four new oral anticoagulants studied in pivotal phase III clinical trials for stroke prevention, or systemic embolic events in patients with atrial fibrillation.

New oral anticoagulants had a favorable risk–benefit profile, with significant reductions in stroke, intracranial hemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding.

As a whole, the new oral anticoagulants improve outcomes versus warfarin in patients with nonvalvular atrial fibrillation, at the expense of more gastrointestinal bleeding, a meta-analysis showed.

The newer drugs also reduced all-cause mortality relative to warfarin during follow-up (RR 0.90, 95% CI 0.85-0.95), but did not affect ischemic stroke or myocardial infarction (MI), the researchers reported online in The Lancet.

Intracranial hemorrhage was less frequent with the new anticoagulants (RR 0.48, 95% CI 0.39-0.59), but there was an increase in gastrointestinal bleeding (RR 1.25, 95% CI 1.01-1.55).

Overall, "the new oral anticoagulants show a favorable balance between efficacy and safety compared with warfarin, which is consistent across a wide range of patients with atrial fibrillation known to be at high risk for both ischemic and bleeding events," Ruff and colleagues wrote.

"Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population."

Up until 2010 -- when dabigatran was approved by the FDA -- warfarin and other vitamin K antagonists dominated stroke prevention in atrial fibrillation. But those drugs require frequent monitoring to ensure that anticoagulation remains within a therapeutic range.

To explore the efficacy and safety of the newer agents relative to warfarin in various patient subgroups, Ruff and colleagues pooled results from the four pivotal trials -- RE-LY (dabigatran), ROCKET AF (rivaroxaban), ARISTOTLE (apixaban), and ENGAGE AF-TIMI 48 (edoxaban). The analysis included 71,683 total patients (mean age 72) followed for a median of 2.2 years.

The primary analysis included the higher doses of dabigatran (150 mg twice daily) and edoxaban (60 mg once daily), as well as the single doses of rivaroxaban (20 mg once daily) and apixaban (5 mg twice daily).

The reduction in stroke of systemic embolism seen with the new agents was consistent across various subgroups defined by age, sex, diabetes status, history of stroke or transient ischemic attack, baseline stroke risk, creatinine clearance, past vitamin K antagonist use, and center-based time in therapeutic range for patients treated with warfarin.

Major bleeding was not significantly reduced overall, although there was an interaction with the center-based time in therapeutic range. The new anticoagulants reduced major bleeding if that value was less than 66% (RR 0.66, 95% CI 0.59-0.81), but not if it was 66% or higher (RR 0.93, 95% CI 0.76-1.13).

In a separate analysis that pooled results from the low-dose regimens of dabigatran (110 mg twice daily) and edoxaban (30 mg once daily), both the new anticoagulants and warfarin performed similarly for reducing stroke or systemic embolism (RR 1.03, 95% CI 0.84-1.27).

"Although indirect comparisons between novel oral anticoagulants have been both criticized and justified, these comparisons suggest that, ultimately, the drug could be fitted to the patient, or the patient to the drug, dependent on a focus on safety or efficacy, and on other patient factors, such as renal function and drug compliance," they wrote. "Indeed, postmarketing safety reports provide some reassurance that these drugs work well, if used correctly."

Larsen has been an investigator for Janssen Scientific Affairs and Boehringer Ingelheim, and served on the speakers' bureau for Bayer, Bristol-Myers Squibb/Pfizer, Janssen Pharmaceuticals, Takeda, Roche Diagnostics, and Boehringer Ingelheim. Lip has served as a consultant for Bayer, Astellas, Merck, Sanofi, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Biotronik, Portola, and Boehringer Ingelheim, and as a speaker for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, and sanofi-aventis.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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