ENGAGE AF-TIMI 48: Once-Daily Edoxaban Noninferior to Warfarin in AF for Stroke Prevention, Cuts Bleeding Risks

November 19, 2013

DALLAS, TX (updated) — Once-daily therapy with the oral factor Xa inhibitor edoxaban (Lixiana, Daiichi-Sankyo) at either of two dosages was noninferior to warfarin for preventing stroke or systemic embolism in a randomized atrial-fibrillation (AF) trial—a behemoth at >20 000 patients[1].

Both edoxaban daily dosages, 60 mg and 30 mg, were associated with significantly less major bleeding than the vitamin-K antagonist in the trial, called  Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48).

The newer agent's success in the trial came in a match against fairly high-quality warfarin management. Among those who took the venerable oral anticoagulant, the median time of exposure to the drug was 907 days, during which patients spent a median of 68.4% of the time in the INR therapeutic range of 2.0 to 3.0.

"The high-dose edoxaban regimen tended to be more effective than warfarin," write the authors of the study's publication, led by Dr Robert P Giugliano (Brigham and Women's Hospital, Boston, MA). "The rate of ischemic stroke was similar with high-dose edoxaban and warfarin but was higher with the low-dose edoxaban regimen." Hemorrhagic strokes and CV mortality were both significantly lower on both factor Xa inhibitor regimens than on warfarin.

Dr Robert P Giugliano

ENGAGE AF-TIMI 48 is published today in the New England Journal of Medicine to coincide with Giugliano's scheduled formal presentation of the trial here at the American Heart Association 2013 Scientific Sessions .

Edoxaban, which is investigational in the US, was recently shown to be as effective as warfarin for preventing recurrences in patients with acute venous thromboembolism and associated with fewer of some types of bleeding complications, in the Hokusai-VTE Study , as reported by heartwire .

Others in the wave of modern oral anticoagulants had already demonstrated their prowess for stroke prevention in AF trials, including the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim) in RE-LY and the factor Xa inhibitors apixaban (Eliquis, Pfizer/Bristol-Myers Squibb) and rivaroxaban (Xarelto, Bayer) in the ARISTOTLE and ROCKET-AF trials, respectively—all as covered by heartwire .

Dr Elaine M Hylek (Boston University Medical Center, MA), the assigned discussant following Giugliano's formal presentation of the trial, referred to the consistency across trials for the new oral anticoagulants in their ability cut the risk of a particularly nasty complication of the drugs. The current trial, she said, provides "very important confirmation, for another oral factor Xa inhibitor, that indeed we are seeing a dramatic reduction in intracerebral hemorrhage."

Indeed, in ENGAGE AF-TIMI 48, the risk of hemorrhagic stroke went down 46% for high-dose edoxaban and 53% for low-dose edoxaban compared with warfarin (p<0.001 for both differences). But for ischemic stroke, it was a wash for high-dose edoxaban compared with warfarin (p=0.97), and the risk went up 41% with low-dose edoxaban vs warfarin (p<0.001).

Hylek was also intrigued by what she called the trial's innovation of dynamic dosage adjustment, which called for edoxaban dosage reductions by 50% in patients with certain features that enhance blood levels of the drug. Those features were renal dysfunction, low body weight, or concomitant treatment with P-glycoprotein-inhibiting drugs like verapamil or quinidine.

About one-fourth of patients needed such adjustments at randomization, according to Giugliano, and almost 10% of the rest had dosage modification after randomization. Speaking to the news media, Guiliano said, "The dosage reduction worked in that it maintained similar efficacy [compared with] if you hadn't [needed to be] dose-reduced." And patients with dosage modifications did better on the trial's measures of safety.

ENGAGE AF-TIMI 48 randomized 21 105 patients with moderate- to high-risk AF to undergo either the high-dose or low-dose edoxaban regimens or to go on warfarin; patients were followed a mean of 2.8 years. They were treated at 1393 centers in 46 countries.

Hazard Ratio (97.5% CI) for Stroke or Systemic Embolic Events (Primary Efficacy End Point)

Regimen vs warfarin HR (97.5% CI) p for noninferiority/superiority
High-dose edoxaban 0.79 (0.63–0.99) <0.001/0.02
Low-dose edoxaban 1.07 (0.87–1.31) 0.005/0.44


Hazard Ratio (95% CI) for Major Bleeding (Principal Safety End Point)

Regimen vs warfarin HR (95% CI) p
High-dose edoxaban 0.80 (0.71–0.91) <0.001
Low-dose edoxaban 0.47 (0.41–0.55) <0.001

At every forum at the AHA sessions where the ENGAGE AF-TIMI 48 was discussed, a common question—given edoxaban's strong performance in the trial and apparent expectation that it will be approved for stroke prevention in AF, joining apixaban, rivaroxaban, and dabigatran: how are clinicians to choose among the new oral anticoagulants?

Speaking at the media briefing, Dr Mark S Link (Tufts Medical Center, Boston, MA) said the four agents "are more similar than different, and when they're compared with warfarin [they] look better than warfarin. It's hard to compare—in fact, it's impossible to compare the drugs because [they haven't been] compared head to head. [So one will] look for certain patient characteristics that will favor one drug over the other—[such as] once-a-day dosing, renal failure, and age."

Dr Patrick T Ellinor (Massachusetts General Hospital, Boston, MA), also speaking to the press, said all four of the agents appear safer than warfarin but proposed that the choice of agent may come down to "the relationship between cost and [how each suits] individual patients more so than whether they are safe or not."

The trial was funded by Daiichi Sankyo. Giugliano discloses receiving consulting fees from Daiichi-Sankyo, Janssen Pharmceuticals, and Merck; lecture fees from Bristol-Myers Squibb, Daiichi-Sankyo, Merck, and Sanofi; and grant support through his center from Daiichi-Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Disclosures for the coauthors are listed in the paper.

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