DOACs May Cut Cranial Bleed Risk, Up Survival in Women With AF

Marlene Busko

July 19, 2018

Among patients with newly diagnosed atrial fibrillation (AF), women may benefit more than men from therapy with a direct oral anticoagulant (DOAC) rather than warfarin, a large observational study hints.

Women — but not men — with new AF had a lower risk for intracranial hemorrhage (ICH) and better 1-year survival if they received a DOAC rather than warfarin.

And women who received a DOAC still had a lower risk for ICH than women with good anticoagulation control on warfarin.  

However, there were no significant differences in the risks for combined ischemic stroke or systemic embolism, or for gastrointestinal bleeding with either therapy choice, among men and women.

The study, by Sharon W.Y. Law, MPharm, University of Hong Kong, and colleagues, was published online July 17 in the Journal of the American College of Cardiology (JACC).

This is "the first observational study using the real-world data" to investigate sex differences in response to anticoagulation in AF, coauthor Wallis C. Y. Lau, PhD, from the University of Hong Kong and University College London School of Pharmacy, United Kingdom, told theheart.org | Medscape Cardiology in an email.

However, before these findings are translated into clinical practice, they "should be confirmed in further prospective epidemiological and mechanistic studies," he cautioned.

Giulia Renda, MD, and Raffaele De Caterina, MD, PhD, from d'Annunzio University of Chieti in Italy, agree in an accompanying editorial comment.

"Further studies are needed to fully elucidate the mechanisms underlying 'potential' sex differences in the efficacy and safety profiles of NOACs [novel oral anticoagulants] in patients with AF, to help clinicians to make the best [choices for] anticoagulants in general, and of NOACs in particular," Renda said in an email to theheart.org | Medscape Cardiology.

We know that "female sex increases the risk of thromboembolism when other thromboembolic risk factors are present," she noted, and perhaps in the future patient sex may be considered "to help inform therapy choices in AF."

For now, clinicians should follow guideline recommendations, regardless of the patient's sex, "taking into account patient characteristics that are known to affect anticoagulant effectiveness and safety."

Sex-Based Differences With DOACs?

Women with AF have a higher risk for stroke than men, which is reflected in the CHA2DS2-VASc score for stroke risk prediction, Law and colleagues note, and this may be partly due to a lower percentage of time in the therapeutic range with warfarin.

To investigate this, researchers analyzed data from the Clinical Data Analysis and Reporting System of health records from hospitals and clinics that serve more than 7 million Hong Kong residents (98% Asian, of whom 92% are Chinese).  

The researchers identified 15,292 adults with a new diagnosis of nonvalvular AF during 2010 to 2015 who were prescribed a DOAC (apixaban, dabigatran, rivaroxaban) or warfarin. About half had been prescribed a DOAC.

Of these, 2486 men who received warfarin and 2486 men who received a DOAC were matched for age, risk scores (including CHA2DS2-VASc and HAS-BLED), comorbidities, inpatient visits, and medication use. And 2417 women who received warfarin were matched with 2417 women who had received a DOAC.

Close to a third of the patients (30%) had had a stroke and 72% were taking an antiplatelet agent. Most DOAC users were taking dabigatran (63%), followed by rivaroxaban (28%) and apixaban (10%).

Compared with men, women were slightly older (mean age, 76 vs 72 years) and had higher CHA2DS2-VASc and HAS-BLED scores. The men and women were followed for a mean of 1.23 years and 1.29 years, respectively.

The primary outcome of ischemic stroke or systemic embolism occurred in 6.1% of warfarin users and 5.6% of DOAC users among men and in 7.9% of warfarin users and 6.3% of DOAC users among women, which was not significantly different in either sex.   

Among women, however, DOAC use was associated with a significantly lower risk for ICH (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.06 - 0.40; P < .001) and all-cause mortality (HR, 0.55; 95% CI, 0.39 - 0.77; P < .001).

Persistent Benefit, Even With INR Control

In further analysis, women who used DOACs still had a lower risk for ICH than women who had good anticoagulation control (60% of the time in the INR therapeutic range) with warfarin (HR, 0.13; 95% CI, 0.02 - 1.00; P = .050).

The editorialists note that there is "inconsistency of published results" from two meta-analyses and two recent observational studies, which is probably related to population and methodologic differences. For example, the current study was in Asians, used electronic medical records, and did not include hemorrhagic stroke."

"But in any case," they conclude, "the main finding from the study by Law et al., as well as from other studies, points to the existence of sex difference in thrombotic and hemorrhagic risk and in the response to anticoagulants."

Part of the biological explanation may be that women have a lower mean body mass and hepatic fat, so warfarin may be metabolized differently by cytochrome P450 enzymes in the liver, the researchers suggest.

In an audio commentary of the study, JACC editor-in-chief Valentin Fuster, MD, Mount Sinai Medical Center, New York City, said, "First, over the last few years we have learned that in patients with atrial fibrillation, the use of the new direct oral anticoagulants are of more benefit than conventional warfarin, and we are just talking about strict endpoints.

"Second, there appear to be gender differences in how men and women respond to the new oral anticoagulants, but the study published in JACC, in a large population of patients with atrial fibrillation, suggests to me that female patients are even better responders than men with such advanced new agents or oral anticoagulants."

Law and Lau have no relevant financial disclosures; the financial disclosures of the other authors are published with the study. Renda has received consultant and speaker fees from Bayer, Boehringer Ingelheim, and Daiichi-Sankyo. De Caterina has received institutional grant support from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, and Daiichi-Sankyo and speaker and consultancy fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Merck, Novartis, Roche, and Portola. Fuster has no relevant financial disclosures.

J Am Coll Cardiol. Published July 17, 2018. Abstract, Editorial

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