Edoxaban, a direct oral factor Xa inhibitor under development by Daiichi Sankyo, is the latest in the series of new oral anticoagulants seeking to take over the troubled role of warfarin in clinical practice. The results of ENGAGE-AF-TIMI 48 were presented at the American Heart Association meeting in Dallas and published simultaneously in the New England Journal of Medicine. The results of the trial were promising, but edoxaban may have a hard time finding its footing as the fourth new oral anticoagulant to enter the market, following dabigatran (Pradaxa), Boehringer Ingelheim; rivaroxaban (Xarelto), Johnson & Johnson; and apixaban (Eliquis), Pfizer and Bristol-Myers Squibb.
In the trial, more than 21,000 patients with moderate-to-high-risk AF were randomized to one of two regimens of edoxaban or warfarin. Both high-dose and low-dose edoxaban were found to be noninferior to warfarin for the primary endpoint of stroke or systemic embolism. Here are the on-treatment annual rates of stroke or systemic embolism:
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Since its approval in the United States in October 2010 dabigatran (Pradaxa) has been prescribed 3.2 million times to more than 600,000 patients with nonvalvular atrial fibrillation (AF), according to its manufacturer, Boehringer Ingelheim. The company also announced that, based on the pivotal RE-LY trial, the “Clinical Studies” section of the drug’s prescribing information now includes the statement that 150 mg twice daily of dabigatran “was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.”
But the news about dabigatran is not entirely upbeat. According to new data compiled by QuarterWatch (PDF), in 2011 the FDA received more safety reports about dabigatran than any other drug. The data are not entirely unexpected, since the bleeding complications of dabigatran are well known and physicians are more likely to report adverse events associated with new drugs. The drug that dabigatran was designed to replace, warfarin (Coumadin), was the second most reported drug, and has been high on the FDA list for many years.
Dabigatran was the subject of 3,781 serious adverse events reported to the FDA in 2011. This included 542 patient deaths and 2,367 hemorrhages. Warfarin was the subject of 1,106 serious adverse events, including 72 deaths.
QuarterWatch noted that the difference between the two anticoagulants “could be at least partly explained by differences in the reporting rate for an older generic drug with many manufacturers, and a newly launched brand name drug being promoted by a large sales force.” But, according to QuarterWatch:
“What is clear, however, is that the FDA’s system is receiving a strong signal about this safety issue. A large share of dabigatran reports (79%) come from health professionals, suggesting that despite this well-known drug risk the bleeding was unexpected or unusually severe.”
QuarterWatch notes that the rapid uptake of dabigatran is probably due to its ease of use– no frequent INR tests are required– and the lack of drug interactions. One likely source of complications is the use of the standard 150 mg dose in older patients or those with renal dysfunction. The label now recommends that physicians “assess renal function during therapy as clinically indicated” but QuarterWatch wonders “whether this modest language will lead to safer use.”
Click here to read the Boehringer press release…
Here’s a completely personal review of the past year in cardiology. Please write a comment if you strongly agree, disagree, or think something is missing.
Drug of the Year: Rivaroxaban (Xarelto)– Despite a highly negative review from FDA reviewers, rivaroxaban gained FDA approval for the coveted stroke prevention in AF indication. The drug was approved earlier in the year for VTE prevention after surgery. The biggest surprise, though, was rivaroxaban’s success in ACS in the ATLAS ACS TIMI 51 trial, which may well have an important impact on the field for years to come.
Device of the Year: Sapien Transcatheter Heart Valve– TAVI entered the marketplace this year. It will take another few years before its full impact is completely understood.
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