NOACs Seem to Perform Just Fine in Patients With A-fib and Most Types of Valvular Disease

The efficacy and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) relative to warfarin do not substantially differ based on the presence of valvular heart disease, data from pivotal trials of the newer agents indicate.

Those trials consistently excluded patients with moderate-to-severe mitral stenosis or mechanical heart valves but allowed most patients with other types of valvular disease to participate. Although the presence of valve disease was associated with higher risks of death and major bleeding overall, it did not modify treatment effects on a variety of outcomes, according to a meta-analysis by Giulia Renda, MD, PhD (G. d’Annunzio University, Chieti, Italy), and colleagues.

Compared with warfarin-treated patients, those receiving NOACs had a similar risk of major bleeding and significantly lower risks of stroke or systemic embolism and intracranial hemorrhage.

The meta-analysis included previously published data from the RE-LY, ARISTOTLE, and ROCKET AF trials, as well as from a new analysis of the ENGAGE AF-TIMI 48 trial led by Raffaele De Caterina, MD, PhD (G. d’Annunzio University, Chieti, Italy). Both that latter study and the meta-analysis are being published in the March 21, 2017, issue of the Journal of the American College of Cardiology.

“There was no signal of loss of efficacy or worse safety with the NOACs compared with warfarin, which is consistent with what we’ve been thinking all along, that it’s just the mechanical heart valve patients and the mitral stenosis patients that one needs more data on and for the moment ought to avoid the NOACs,” Robert Giugliano, MD (Brigham and Women’s Hospital, Boston), a coauthor on both papers, told TCTMD.

This is an area that has created confusion among clinicians stemming from use of the term “nonvalvular A-fib” to describe patients included in the clinical trials of the NOACs, Giugliano said, pointing out that some prescribing physicians have assumed that any degree of valvular disease precludes NOAC therapy.

That’s not the case, as 19% of patients pooled for the meta-analysis had some type of valvular disorder, most commonly moderate-to-severe mitral regurgitation.

Giugliano said he supports doing away with the term “nonvalvular A-fib” and instead using MARM-AF (mechanical and rheumatic mitral valvular AF)—which was coined by De Caterina and John Camm, MD (St. George’s University of London, England)—to distinguish patients who should receive warfarin or another vitamin K antagonist over a NOAC, at least until further research is conducted in those groups.

The most recent European A-fib guidelines stopped using the term nonvalvular A-fib, and Giugliano would like to see a similar change made when the US guidelines are updated. “I think that it ought to be eliminated because even if you were to redefine it, it would be confusing,” he said, adding that he thinks the US Food and Drug Administration should revise prescribing information for oral anticoagulants, as well.

Evidence Gap Starting to Fill

Prior analyses of the RE-LY, ROCKET AF, and ARISTOTLE trials supported the idea that the performance of dabigatran (Pradaxa; Boehringer Ingelheim), rivaroxaban (Xarelto; Janssen Pharmaceuticals), apixaban (Eliquis; Bristol-Myers Squibb), respectively, compared with that of warfarin was generally the same in patients with and without valve conditions. The new analysis of the ENGAGE AF-TIMI 48 trial of edoxaban (Savaysa; Daiichi Sankyo) yielded similar results.

There were some differences across trials in terms of design and inclusion/exclusion criteria, so Renda et al performed a meta-analysis to further explore the potential impact of valvular disease. The trials included a total of 71,683 patients, of whom 13,585 had valvular disease. Moderate-to-severe mitral regurgitation accounted for 73.3% to 87.7% of valve disease, but some patients had aortic regurgitation or stenosis, tricuspid regurgitation, mild mitral stenosis, or a history of valve surgery.

The main analysis evaluated the effects of the higher NOAC doses when multiple doses were used for a particular drug, although a secondary analysis that incorporated all doses produced similar findings.

The presence of valvular disease did not modify treatment effects (P > 0.05 for all interactions) for stroke or systemic embolism, major bleeding, or intracranial hemorrhage. There was an interaction regarding all-cause death (P = 0.03), which was reduced with NOACs versus warfarin in patients without valve disease but not in those with valve disease.

That finding “may be spurious, or alternatively related to a different sensitivity of some components of death to the effect of NOACs versus warfarin in [valvular heart disease] patients. However, the small number of death events may also have caused a type I error,” the authors say. They add that there was no indication of harm with NOAC therapy.

The findings “[suggest] that NOACs can be safely used in patients without moderate-to-severe mitral stenosis or mechanical valves,” the authors say. “Future trials should specifically address patients with bioprosthetic heart valves and valve repair surgery who were relatively underrepresented in trials performed to date.”

Commenting for TCTMD, Dan Atar, MD (Oslo University Hospital, Norway), a coauthor of the 2016 European A-fib guidelines, said there is a gap in evidence regarding the utility of NOACs in patients with valvular heart disease that is starting to be filled with analyses like those by Renda et al and De Caterina et al.

It is becoming clearer that clinicians should not be discouraged from using NOACs in patients with certain types of valvular disease, he said. “There is no reason to suspect that the favorable results of NOACs versus warfarin in the A-fib trials would not be reflected in an A-fib patient who also has a certain valvular component in his heart disease,” said Atar, a former vice president of the European Society of Cardiology. He added, however, “We must nevertheless be aware that we do not have good data and good evidence in this field.”

Next Steps

Atar said more trials should be done to explore the efficacy and safety of NOACs in patients with various types of valvular disease. “We would like to have solid evidence to show that if you have severe aortic stenosis or severe mitral insufficiency, for example, NOACs are still good to use,” he said.

Giugliano agreed that further study in patients with aortic stenosis would be useful, particularly because interventions in that area—including TAVR and implantation of a new mechanical heart valve called On-X (CryoLife)—are evolving so rapidly.

Another group of patients that would be a prime target for future studies would be those with a recent valve surgery. In that situation, Giugliano said, many cardiac surgeons like to use short-term anticoagulation therapy.

It would also be worth exploring the utility of NOACs in patients with moderate-to-severe mitral stenosis, he said, but conducting such trials is challenging because the disease is becoming rarer in North America and Europe.

While awaiting additional trials, clinicians “should continue to choose warfarin or another vitamin K antagonist . . . in patients with mechanical heart valves or moderate-to-severe mitral stenosis,” Giugliano said, adding that current data “provide support to use the NOACs instead of warfarin in all the other types of valvular disease, excepting those who are within 3 months of surgery.”