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Meeting Coverage

Published: Sep 1, 2013

By Todd Neale, Senior Staff Writer, MedPage Today

Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco

Action Points

AMSTERDAM -- Dabigatran (Pradaxa) increased thromboembolic events and bleeding in patients with mechanical heart valves compared with warfarin, full results of the prematurely halted RE-ALIGN trial confirmed.

In the 12-week dose-validation study, patients treated with dabigatran had higher rates of stroke, myocardial infarction (MI), valve thrombosis, and major bleeding compared with those treated with warfarin, Frans Van de Werf, MD, PhD, of the University of Leuven in Belgium, reported at the European Society of Cardiology meeting here.

The findings -- which were published simultaneously online in the New England Journal of Medicine -- "indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complications in patients who require anticoagulation after the implantation of a prosthetic heart valve," Van de Werf and colleagues wrote.

The trial was stopped last year after enrolling 252 of a planned 405 patients because of the excess risks seen in the dabigatran group, and the FDA followed that up with a warning against using the drug in patients with mechanical heart valves.

The use of dabigatran in these patients is "rightfully prohibited," Elaine Hylek, MD, MPH, of Boston University, wrote in an editorial accompanying the NEJM paper. But she cautioned against giving up on finding alternatives to warfarin in this setting.

"The results of RE-ALIGN are disappointing," she wrote, "but there is a palpable downside as well to potential premature abandonment of research into the use of such drugs in patients with mechanical heart valves."

For patients with severe valvular disease who require a valve replacement, mechanical versus bioprosthetic valves have greater durability but require the patients to take anticoagulants for the rest of their lives. Vitamin K antagonists like warfarin are effective for preventing thromboembolic complications but they have shortcomings, including dietary restrictions, potential interactions with other drugs, and the need for continuous monitoring of anticoagulation.

"Because of the limitations of vitamin K antagonists, many patients opt for a bioprosthesis rather than a mechanical valve, despite the higher risk of premature valve failure requiring repeat valve-replacement surgery with bioprostheses," Van de Werf and colleagues noted.

Dabigatran -- an oral direct thrombin inhibitor approved for use in preventing stroke in patients with atrial fibrillation based on the results of the RE-LY trial -- has been shown to be effective in preventing valve thrombosis in preclinical studies.

To further evaluate its potential in patients with mechanical heart valves, Van de Werf and colleagues initiated the RE-ALIGN trial, a phase II study conducted at 39 centers in 10 countries. It included patients who had undergone replacement of the aortic or mitral valve -- or both -- within the past 7 days and those who had a replacement at least 3 months before randomization to either dabigatran or warfarin.

Patients in the dabigatran group received one of three doses depending on their renal function -- 150, 220, or 300 mg twice daily. The doses were adjusted to achieve a trough plasma level of at least 50 ng/mL, a threshold that was derived using data from the RE-LY trial.

The warfarin dose was adjusted to achieve an INR of 2 to 3 for those with a low thromboembolic risk and of 2.5 to 3.5 for those with a higher risk.

The trial was stopped when it became apparent that dabigatran carried a higher risk of various thromboembolic events, including stroke (5% versus 0%), myocardial infarction (2% versus 0%), and valve thrombosis (3% versus 0%). Most of the events occurred in the patients enrolled within 1 week of having their valve replacement.

There were few deaths -- one with dabigatran and two with warfarin.

Bleeding of any severity was more common with dabigatran (27% versus 12%; HR 2.45, 95% CI 1.23-4.86). All of the patients with major bleeding had pericardial bleeding.

There was no relationship between plasma levels of dabigatran and either thromboembolic events or bleeding.

That's not surprising, Hylek said in her editorial, because of "individual variation in dose and therapeutic response, unmeasured confounders in the recent surgical period, and the interval between trough measurement and event."

Van de Werf and colleagues speculated that the results of the trial "might be explained by the relative inability of dabigatran to suppress activation of coagulation that occurs when blood is exposed to the artificial surfaces of the valve prosthesis."

Hylek pointed out some other possible explanations, "including the use of a fixed dabigatran dose during a period of anticipated wide fluctuations in endogenous and exogenous confounding factors, a trough level predicated on a stasis thrombosis model, and extrapolation of a dosing regimen derived from a different patient population with a different indication."

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