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While randomized trials of 3 novel oral anticoagulants have shown that they are comparable or superior to warfarin for preventing stroke in patients with atrial fibrillation (A-fib), clinicians have had little guidance in choosing among them. Now indirect comparisons of these agents with one another suggest that while they all show similar overall efficacy, some safety differences do exist.

The findings were published in the August 21, 2012, issue of the Journal of the American College of Cardiology.

Trying to Tease Out Differences

Investigators led by Gregory Y. H. Lip, MD, of the University of Birmingham Centre for Cardiovascular Sciences (Birmingham, United Kingdom), used data from 3 randomized trials to perform indirect comparisons of the 3 novel oral anticoagulants: the direct thrombin inhibitor dabigatran (at both 110-mg and 150-mg doses) and the factor Xa inhibitors apixaban and rivaroxaban. All 3 trials used warfarin as a comparator:

• ARISTOTLE: apixaban (5 mg twice daily)
• RE-LY: dabigatran (110 mg or 150 mg twice daily)
• ROCKET AF: rivaroxaban (20 mg)

When data for the 150-mg (but not 110-mg) dose of dabigatran were incorporated into a weighted average effects analysis, overall the 3 new anticoagulants lowered the risk for stroke or systemic embolism, ischemic stroke, hemorrhagic stroke, all-cause mortality, and major and intracranial bleeding compared with warfarin (table 1).

Table 1. Weighted Average Effects of New Oral Anticoagulants^a vs. Warfarin

Abbreviation: ISTH, International Society on Thrombosis and Haemostasis.

^a Dabigatran 150 mg (twice daily), apixaban, rivaroxaban.
^b All P ≤ 0.001.

In individual comparisons, efficacy proved similar between apixaban and dabigatran (at both 110-mg and 150-mg doses) or rivaroxaban, and between rivaroxaban and 110-mg dabigatran. However, some differences did emerge. For example, compared with rivaroxaban, the 150-mg dose of dabigatran reduced stroke and systemic embolism by 26% as well as hemorrhagic stroke by 56% (P = 0.039) and nondisabling stroke by 40% (P = 0.038).

In terms of safety, apixaban lowered major bleeding by 34% (P < 0.001) compared with rivaroxaban and by 26% (P = 0.003) compared with 150-mg dabigatran (no difference was seen vs. 110-mg dabigatran). Apixaban also reduced gastrointestinal bleeding by 41% (P = 0.003) and extracranial bleeding by 26% (P = 0.007) compared with the higher dose of dabigatran. Similarly, 110-mg dabigatran was associated with 23% less major bleeding (P = 0.011) and 54% less intracranial bleeding (P = 0.006) than rivaroxaban.

Indirect comparisons found no differences in the incidence of MI between either dose of dabigatran and apixaban but almost 60% greater risk of MI with dabigatran compared with rivaroxaban.

‘Extreme Caution’ Urged in Drawing Conclusions

In an editorial accompanying the study, Christopher P. Cannon, MD, of Brigham and Women’s Hospital (Boston, MA), and Payal Kohli, MD, of the University of California, San Francisco (San Francisco, CA), welcome the attempt to answer clinicians’ questions about any differences among the drugs but stress that “indirect comparisons can be misleading, and extreme caution should be exercised when using such methods to draw definitive conclusions.”

While the analysis showing an overall advantage in stroke reduction for the new agents is “statistically sound” and supports their use “as a class,” the editorial says, the indirect comparisons between the individual agents are “a bit confusing.”

When it comes to clinical decision making, Drs. Cannon and Kohli say that “the differences [the authors] report on some endpoints are not robust enough to be relied upon for the clinical care of patients. Instead, we would turn to direct evidence from trials and the indications put forth by the US Food and Drug Administration (FDA) to select the appropriate agent, at the dose tested, for use in the patient population studied within the trial.”

In a telephone interview with TCTMD, Michael D. Ezekowitz, MD, PhD, of Thomas Jefferson Medical College (Philadelphia, PA), likewise stressed that indirect comparisons of the individual agents have major limitations. For example, he said, “you make assumptions that the patient populations and the methods of data analysis are similar, which for these 3 trials is not the case.”

That said, Dr. Ezekowitz continued, certain differences can be inferred from the findings of the individual trials. For example, he observed, in RE-LY the 150-mg dose of dabigatran is the only regimen that reduced ischemic stroke compared with well-controlled warfarin while providing a marked reduction in intracerebral bleeding. In ROCKET AF, rivaroxaban showed only noninferiority to less well-controlled warfarin and equivalence in bleeding. And in ARISTOTLE, while most endpoints favored apixaban, interpretation of the trial has been muddied by a request for additional data from the FDA, which is reviewing the drug for approval.

Stroke Prevention, but at What Price?

The point of anticoagulant therapy in A-fib patients is to prevent stroke, Dr. Ezekowitz noted, and the question for physicians is what clinical price they are willing to pay to achieve that goal. “The cost of maximal efficacy seems to be GI bleeding,” he said, and in some cases doctors may accept a level of efficacy equivalent to well-controlled warfarin in order to limit bleeding risk.

Therapeutic decisions always have to be individualized, Dr. Ezekowitz added, taking into consideration drug and patient factors. For example, he noted, dabigatran is associated with dyspepsia. And because 80% of the drug is cleared by the kidneys, renal function may be an issue.

Dr. Ezekowitz commented that direct head-to-head comparisons of the new anticoagulants are unlikely anytime soon given the large sample sizes required due to low event rates. Meanwhile, “we need to wait for the results of the ENGAGE-AF TIMI 48 trial,” which is testing another new factor Xa inhibitor, endoxaban, against warfarin, he said. “Then perhaps we can look at certain subgroups to try to identify which patients would benefit from which drug. Right now we are just scratching the surface.”

Nonetheless, the study’s indirect comparisons represent “an interesting exercise,” Dr. Ezekowitz observed. “They are by no means definitive, but they make people ask questions about [how] to tailor the drugs and the doses to an individual patient. They also help us understand the pharmacology of the drugs and the differences in the patient populations studied.

“Ultimately, physicians will develop their own manner of practicing,” he concluded.

2. Cannon CP, Kohli P. Danger ahead: Watch out for indirect comparisons! J Am Coll Cardiol. 2012;60:747-748.

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• Updated Guidelines Support New Antithrombotics as Warfarin Alternatives in A-fib
• New Oral Anticoagulants Top Warfarin in A-fib Stroke Prevention
• Apixaban Bests Warfarin in Stroke Prevention for Atrial Fib