DOACs in Patients With Mitral Stenosis and A-fib: Analysis Suggests a Benefit

Patients with mitral stenosis and A-fib appear to do better when they receive direct oral anticoagulants (DOACs) instead of warfarin, an observational analysis suggests. The data, while not randomized, offer insight into an important patient group, one which was largely excluded from the trials that first brought DOACs to market, experts say.

In the study, DOAC therapy was associated with significantly lower risks of stroke or systemic embolism (adjusted HR 0.28; 95% CI 0.18-0.45) and all-cause mortality (adjusted HR 0.41; 95% CI 0.30-0.56) compared with warfarin therapy through a mean follow-up of 27 months, according to researchers led by Ju Youn Kim, MD (Uijeongbu St. Mary’s Hospital, South Korea).

The risk of intracranial hemorrhage was numerically—but not significantly—lower in the DOAC group (adjusted HR 0.53; 95% CI 0.22-1.26), they report in a study published online ahead of the March 19, 2019, issue of the Journal of the American College of Cardiology.

“Our observation supports that DOAC use appears reasonable in patients with mitral stenosis with atrial fibrillation,” they write. “Based on this consideration, a clinical trial evaluation of the superiority of DOACs in moderate-to-severe mitral stenosis would be justified.”

Commenting for TCTMD, Sarah Anderson, PharmD (University of Colorado School of Pharmacy, Aurora), agreed, pointing out that DOACs have several advantages over warfarin, including more consistent anticoagulation, a reduced need for monitoring (aside from occasional checks of kidney function), and lower bleeding risks.

“For all of those reasons, if we can show that there’s that same level of efficacy and safety within an even broader population, I think that makes management of those patients even more optimized,” Anderson said. “But I think given this current study and given the data to date, we can’t jump to that conclusion just yet, that DOACs are okay for all cases of mitral stenosis and A-fib.”

Patients with A-fib commonly have valvular heart disease and this combination can carry a high risk for stroke. Mitral stenosis in particular, when combined with atrial fibrillation, increases that risk more than 20-fold.

The standard treatment for patients with mitral stenosis who require oral anticoagulation for stroke prevention in A-fib is warfarin. Currently, guidelines and regulatory bodies do not support the use of DOACs in this setting, since all of the pivotal DOAC trials excluded patients with moderate-to-severe or hemodynamically significant mitral stenosis.

Anderson noted, however, that other forms of valvular heart disease were allowed in the trials. She said that might have influenced the 2019 update to the US A-fib guidelines, which provided more clarity as to what is considered valvular heart disease and stated that DOACs should be preferred over warfarin except in patients with moderate-to-severe mitral stenosis or a mechanical heart valve. That means, Anderson said, that other patients with valvular heart disease should be considered candidates for DOAC therapy. “It actually has been huge because it opens up the door for a lot of patients that we traditionally couldn’t or didn’t use DOACs in to now be indicated,” she said, adding, however, that “there’s still some concern about patients with mitral stenosis and whether DOACs can safely be used and whether they’re efficacious in this population.”

As pointed out by study co-author Sung-Hwan Kim, MD (Seoul St. Mary’s Hospital, South Korea), in an email to TCTMD, “Our study is the first one which addresses the results of DOAC [therapy] in patients with atrial fibrillation and mitral stenosis. There is a paucity of data even for warfarin in patients with atrial fibrillation and mitral stenosis.”

Warfarin Lags Behind

The current analysis included information from the national health insurance database in South Korea on 7,357 patients who had mitral stenosis and A-fib and received oral anticoagulation between February 2008 and January 2017; patients with a history of mitral valve surgery were excluded.

Roughly one-quarter of patients (26.1%) received a DOAC in an off-label fashion and the rest received warfarin. Rivaroxaban (Xarelto; Bayer/Janssen) was the most commonly used DOAC (42.3%), followed by dabigatran (Pradaxa; Boehringer Ingelheim) in 32.9%, apixaban (Eliquis; Bristol-Myers Squibb) in 17.2%, and edoxaban (Savaysa; Daiichi Sankyo) in 7.5%.

Propensity-score matching resulted in 1,115 pairs of patients (mean age 70; 69% women) treated with either a DOAC or warfarin. The mean CHA2DS2-VASc score was 5.2.

The primary efficacy endpoint was a composite of ischemic stroke or systemic embolism, and that occurred at a lower rate in the DOAC group (2.22% vs 4.19% per year). All-cause mortality was also less frequent with DOAC therapy (3.45% vs 8.08% per year).

In terms of safety, the rate of intracranial hemorrhage was low in both groups, with a nonsignificantly lower rate in the DOAC group (0.49% vs 0.93% per year).

In an accompanying editorial, Robert Giugliano, MD, and Patrick O’Gara, MD (both Brigham and Women’s Hospital, Boston, MA), say, “Given the paucity of information regarding the use of DOACs in patients with mitral stenosis, these observational data are welcome and should be viewed as hypothesis-generating.”

They note that the differences observed in ischemic stroke/systemic embolism and mortality “appear overly optimistic,” with a likely contribution from residual confounding. They also provide cautionary notes on the large number of patients with mitral stenosis and A-fib who were excluded from the analysis, including those who were not anticoagulated and those who had undergone mitral valve surgery, as well as the lack of information on the quality of warfarin management, which has been shown to be subpar in Korean studies.

“Thus, one should also be cautious about extrapolating these results to patients who achieve a high level of time-in-therapeutic range with a vitamin K antagonist or who have had prior mitral valve surgery,” they write.

Even so, the findings warrant confirmation in a future trial, Giugliano and O’Gara say.

“Given the evolving demographics of rheumatic heart disease, a large RCT in patients with mitral stenosis would need to involve patients from regions of the world (eg, Africa, South and Central Asia, Oceania, Latin America, and the Caribbean) where clinical research is challenged and DOACs have not generally been studied and/or have limited availability,” they write. “Nevertheless, we agree with the authors and others that the time has come to answer this question with an adequately powered RCT with significant implications for the health of vulnerable populations.”