NOACs Particularly Beneficial for Women With A-fib, Study Suggests

Women with atrial fibrillation treated with non-vitamin K antagonist oral anticoagulants (NOACs) may derive even greater benefit from therapy than do men, a real-world analysis from Hong Kong suggests.

Compared with warfarin, treatment with NOACs was associated with lower risks of intracranial hemorrhage (HR 0.16; 95% CI 0.06-0.40) and all-cause mortality (HR 0.55; 95% CI 0.39-0.77) in women, researchers led by Sharon Law, MPharm (University of Hong Kong), report in a study published online ahead of the July 17, 2018, issue of the Journal of the American College of Cardiology.

In contrast, NOAC use was not associated with a reduction in death and ICH in men. Other clinical outcomes, including ischemic stroke/systemic embolism and GI bleeding, did not differ based on type of anticoagulation treatment in either women or men.

“More prospective studies are needed to evaluate the mechanisms responsible for sex-based differences in clinical outcomes with direct oral anticoagulants compared with warfarin and how these may relate to the quality and consistency of anticoagulation control,” the authors write.

Commenting by email for TCTMD, Louise Pilote, MD, PhD (McGill University, Montreal, Canada), indicated that the results are consistent with those from prior observational studies. The sex differences, she said, might be related to platelet function and adherence to drug treatment.

The message to be taken away from this study, however, is that more representative data from clinical trials are needed, she suggested.

“[The US Food and Drug Administration] must demand large enough sample sizes to provide definitive RCT conclusions in both men and women,” Pilote said. “Journals must also have these requirements for publication. Then, pharma will provide enough funds for studies that are large enough to provide evidence in women.”

She added, “A large trial enrolling enough women to look at sex differences is unlikely to happen, but it should.”

ICH Advantage Seen Even vs Well-Controlled Warfarin

Although men have a greater risk of A-fib, women with A-fib have a higher risk of stroke and worse outcomes than their male counterparts, even when treated with warfarin. It remains uncertain whether women treated with NOACs have better outcomes than those treated with warfarin.

To tackle that issue, Law and colleagues turned to the clinical database of the Hospital Authority in Hong Kong. They looked at data on patients newly diagnosed with nonvalvular A-fib and prescribed oral anticoagulation between 2010 and 2015. Propensity score-matching left the researchers with 4,972 men and 4,834 women—half treated with warfarin and half with NOACs—for analysis.

The most commonly used NOAC was dabigatran (63% in both sexes), followed by rivaroxaban (28% of men and 27% of women). Only 41% of men and 32% of women received standard doses of the drugs.

When looking at clinical outcomes through a median follow-up of about 15 months, there was a significant interaction by sex for ICH only (P = 0.037), with NOACs associated with a reduced risk in women only.

In an analysis stratified by the quality of warfarin control, NOACs were still associated with a lower risk of ICH in women when compared with well-controlled warfarin (HR 0.13; 95% CI 0.02-1.00), which was defined as a time in therapeutic range of 60% or more. There were no other differences in clinical outcomes seen between NOACs and well-controlled warfarin in either women or men, although NOAC-treated patients had the advantage over warfarin-treated patients who did not undergo routine INR monitoring for multiple outcomes.

“This finding highlights the importance of regular INR measurements for warfarin patients and is in line with the suggestion that regular INR monitoring plays a major role in achieving better clinical outcomes among warfarin users,” the authors write.

Mechanisms Unknown

Law et al say further studies are needed to better understand the reasons for the observed sex differences. They point out that in the major warfarin trials, only about one-quarter of the participants were women. The NOAC trials did better by enrolling about 40% women, although they were not designed to evaluate differences between men and women, the author note.

“The lack of trial evidence data makes it difficult to optimize oral anticoagulation therapy with respect to the sex of patients in real-world practice,” they write. “Sex-specific analysis is particularly important as women appear to have different utilization patterns and metabolism of anticoagulants when compared with men.”

The mechanisms underlying the differential effects of NOACs versus warfarin between the sexes are unclear, they say, adding that proposed explanations include differences in metabolism of warfarin driven by the lower body mass and hepatic fat content of women or fluctuations in the anticoagulant effects of warfarin.

Agreeing with the need for additional research in this area are Giulia Renda, MD, PhD, and Raffaele De Caterina, MD, PhD (G. d’Annunzio University of Chieti, Italy)

“The main finding from the study by Law et al, as well as from other studies, points to the existence of sex differences in thrombotic and hemorrhagic risk and in the response to anticoagulants,” they write in an accompanying editorial. “This may imply different efficacy and safety profile of the direct oral anticoagulants in patients with atrial fibrillation according to sex, which should be confirmed in further studies.

“Further studies are also needed,” they continue, “to fully elucidate the mechanisms underlying sex differences, eventually to help clinicians to make the best of anticoagulants in general, and of direct oral anticoagulants in particular, also according to sex.”