New Class of Oral Anticoagulants Safer Compared with Warfarin for A-fib

Novel oral anticoagulants are associated with lower rates of death and stroke compared with warfarin in patients with atrial fibrillation (A-fib), according to a large meta-analysis published online, October 15, 2012, ahead of print in Circulation. The findings also suggest a trend toward reduced major bleeding with the newer drugs.

Investigators led by Francesco Dentali, MD, of Ospedale di Circolo (Varese, Italy), analyzed 12 randomized phase II and phase III trials totaling 54,875 patients with A-fib. The studies compared warfarin to dabigatran (n = 3), rivaroxaban (n = 4), apixaban (n = 2), and edoxaban (n = 3).

As a whole, the new class of drugs reduced total mortality, cardiovascular mortality, and stroke or systemic embolism with a trend toward less major bleeding. However, rates of MI were similar between the newer drugs and warfarin (table 1).

Table 1. Clinical Outcomes


Novel Oral Anticoagulants


RR (95% CI)

Total Mortality



0.89 (0.83-0.96)

CV Mortality



0.89 (0.82-0.98)

Stroke or Systemic Embolism



0.77 (0.70-0.86)

Major Bleeding



0.86 (0.72-1.02)

Intracranial Hemorrhage



0.46 (0.39-0.56)




0.99 (0.85-1.15)

In a subgroup analysis examining each new agent separately, apixaban and dabigatran reduced major bleeding events, while rivaroxaban and edoxaban did not.

Another subgroup analysis that included only studies with short-term follow-up found that only the rate of stroke and systemic embolism were reduced in patients randomized to the newer drugs. On the other hand, in studies with long-term follow-up, results were the same as the primary analysis.

‘Diluted’ Results

The findings suggest that the novel anticoagulants are better than warfarin, said Michael D. Ezekowitz, MD, PhD, of Thomas Jefferson Medical College (Philadelphia, PA), in a telephone interview with TCTMD. “One of the newer agents should be very seriously considered for patients with atrial fibrillation,” he added.

Still, Dr. Ezekowitz said, the meta-analysis “doesn’t tell us much new, it just confirms what the individual trials have shown.”

But Renato D. Lopes, MD, PhD, of Duke University Medical Center (Durham, NC), told TCTMD in a telephone interview that he does not “see the clinical importance of these results when we’ve pretty much already gotten consistent results from existing trials.” While the meta-analysis was “well done and carefully performed,” combining “different studies—phase II and phase III—with different agents in different classes in different populations . . . might be diluting the results,” he suggested.

Choosing Among the Novel Agents

According to Greg C. Flaker, MD, of the University of Missouri-Columbia (Columbia, MO), the “big question in clinicians’ minds is should we take a person who’s on warfarin and convert them to the new agents.” The myriad data on the novel agents essentially make it clear that patients should be converted, he said, but the issue is deciding which new drug is best.

“If you’re the clinician you have to [ask yourself] are you afraid of bleeding or are you afraid of stroke” and then figure out which agent is best at preventing the problem, Dr. Flaker said.

Dr. Lopes said the best way to compare the novel anticoagulants would be in a head-to-head comparison “which is very unlikely to happen. So we just need to understand that there are new drugs, and all of them are better than warfarin in one way or another. Clinical practice will make us learn more about these drugs and find out which patients will benefit from 1 drug or the other.”

Dr. Ezekowitz added that clarification also is needed “with respect to the optimal doses for patients who are being prescribed dual antiplatelet therapy.”


Dentali F, Riva N, Crowther M, et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: A systematic review and meta-analysis of the literature. Circulation. 2012;Epub ahead of print.



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  • Dr. Dentali reports no relevant conflicts of interest.
  • Dr. Ezekowitz reports serving as co-principal investigator for the RE-LY trial, on the executive committee for the ENGAGE-AF TIMI 48 trial, and as a consultant for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer.
  • Dr. Flaker reports serving as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, and Sanofi-Aventis.
  • Dr. Lopes reports receiving a research grant from Bristol-Myers Squibb as well as consulting fees from Boehringer Ingelheim and Pfizer.

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