Dabigatran in AF: RE-LY Shows Similar Benefits in Milder Valve Disease

Marlene Busko

August 15, 2016

PHILADELPHIA, PA — A post hoc analysis of data from the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial of dabigatran (Pradaxa, Boehringer Ingelheim) adds to accumulating evidence that for patients with atrial fibrillation (AF), novel oral anticoagulants (NOACs) confer the same benefits and risks relative to warfarin—for patients with or without less severe valvular heart disease[1].

"The presence of [valvular heart disease] did not influence comparison of dabigatran at either dose with warfarin regarding stroke or systemic embolism, major bleed, death, or intracranial hemorrhage," Dr Michael D Ezekowitz (Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA) and colleagues report in their study, published online August 5, 2016 in Circulation.

Thus, clinicians "can use the approved doses of dabigatran with confidence in patients with valve disease, only excluding those with prosthetic valve disease or patients with hemodynamic significant mitral stenosis," they write.

"Nonvalvular" AF Is a Misnomer

Many patients with AF have valvular heart disease and thus are commonly seen in routine clinical practice, Ezekowitz and colleagues note. However, since the three pivotal clinical trials of NOACs were done in patients with "nonvalvular" AF, this "may cause some clinicians to hesitate before prescribing NOACs to patients with any form of valvular heart disease," they add.

Yet "nonvalvular" is a misnomer, since although the trials specifically excluded patients with prosthetic heart valves and significant mitral stenosis, up to a quarter of the trial patients had other types of valvular heart disease.

The researchers performed a post hoc analysis of RE-LY, to compare outcomes with dabigatran (110 mg twice daily or 150 mg twice daily) vs warfarin in patients with AF with and without valvular heart disease.

Of the 18,113 patients randomized in RE-LY, 22% had valvular heart disease—mostly mitral-valve regurgitation (17%) and less often tricuspid-valve regurgitation (6.5%), aortic-valve regurgitation (4.5%), aortic-valve stenosis (3%), or mild (presumable rheumatic) mitral-valve stenosis (1%).

The patients with heart-valve disease were older (mean age 74 vs 72), more often female (41% vs 35%), and more likely to have congestive heart failure, CAD, and moderate renal impairment.

Compared with other patients, those with valvular heart disease had similar rates of stroke and systemic embolic events, intracranial hemorrhage, and death, but higher rates of major bleeds.

Event Rate and Outcome Risk, With vs Without Valvular Heart Disease

Outcome Valvular heart disease, event rate/y, % No valvular heart disease, event rate/y, % HR (95% CI)* P
Stroke, systemic embolic event 1.61 1.41 1.09 (0.88–1.33) 0.43
Major bleeding 4.36 2.84 1.32 (1.16–1.33) <0.001
Intracranial hemorrhage 0.51 0.41 1.20 (0.83–1.74) 0.32
All-cause mortality 4.45 3.67 1.09 (0.96–1.23) 0.18
*Adjusted using propensity scores

Compared with patients taking warfarin, those who received the higher dose of dabigatran had a significantly lower risk of stroke or systemic embolism and a similar rate of major bleeding—independent of the presence or absence of valvular heart disease.

Patients who received the lower dose of dabigatran had similar rates of stroke or systemic embolism and a significantly lower risk of major bleeding as patients who received warfarin—also irrespective of valvular heart disease.

The rates of intracranial bleeds and mortality were lower with both doses of dabigatran than with warfarin, again, regardless of the presence of valvular heart disease.

It is important to note that similar to RE-LY, 14% of patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial and 26% of patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial had heart-valve disease other than prosthetic valve disease or significant mitral valve stenosis.

Two other post hoc analyses looked at outcomes with rivaroxaban (Xarelto, Bayer/Johnson) vs warfarin in the ROCKET-AF trial and apixaban ( Eliquis, Bristol-Myers Squibb/Pfizer) vs warfarin and in the ARISTOTLE trial—specifically in patients with valvular heart disease.

Taken together, "the evidence regarding the value of NOACs in patients with [valvular heart disease] as defined in the three studies is very strong" and is reflected in the recent European and American guidelines, according to Ezekowitz et al.

This analysis was sponsored by a research grant from Boehringer-Ingelheim Pharmaceuticals. Ezekowitz has served as a consultant for AstraZeneca, Eisai, Pozen, Boehringer Ingelheim, ARYx Therapeutics, Pfizer, Sanofi, Bristol-Myers Squibb, Portola, Daiichi Sankyo, Medtronic, Merck, Johnson & Johnson, Gilead, Janssen Scientific Affairs, and Armetheon. He has received grants from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, and Bristol-Myers Squibb. Disclosures for the coauthors are listed in the article.

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