Sex differences exist in effectiveness, dose use, and safety for the novel oral anticoagulant (NOAC) dabigatran (Pradaxa, Boehringer Ingelheim) for patients with atrial fibrillation (AF), suggests new research.
A population-based cohort study of more than 63,000 Canadian patients with AF showed that women had a higher risk of stroke at baseline and a lower bleeding risk vs men. Although the male dabigatran users had a significantly lower risk of bleeding vs the men who used warfarin, based on propensity scoring (P for interaction=0.008), this dabigatran-vs-warfarin association was not significant in the women.
The women who used dabigatran at 150 mg twice daily did have a trend toward lower stroke risk vs the women who used warfarin (HR 0.79, 95% CI 0.56–1.04). However, 65% of the female dabigatran users filled their prescriptions at a lower dose (110 mg twice daily).
“In Canada, these two doses of dabigatran are approved,” principal investigator Dr Louise Pilote (McGill University Health Center, Montreal, Quebec) said. Although the 150-mg dose has been approved by the US Food and Drug Administration, the 110-mg dose has not.
“At least in Canada, we’re saying that the 150-mg dose should be prescribed as much as possible in women because it offers better protection for stroke prevention with similar bleeding risk,” she said. “Also, although previous literature has discussed a higher MI risk for dabigatran compared with warfarin, that’s not something we found in our work, which is reassuring.”
The findings were published online October 27, 2015 in Circulation: Cardiovascular Quality and Outcomes.
Women-Specific Results Needed
The investigators note it has been shown that women over the age of 75 with AF are at higher risk of stroke than men. The RE-LY study showed that dabigatran 150 mg given twice a day is more effective at preventing stroke than warfarin, while dabigatran 110 mg twice daily has a lower risk of bleeding.
“However, in the RE-LY trial, there were fewer females enrolled than male (37%), which raises the question as to whether results obtained in a randomized clinical trial of mainly men can be generalizable and applicable to women,” write the researchers.
“Unfortunately, we have little information on women-specific results in terms of drug safety and efficacy. We tend to assume that results found in men will be the same in women, but that’s an assumption,” added Pilote.
For this study, the investigators examined administrative data on 63,110 patients (50.4% women) from Quebec who had been discharged from hospitalization for AF or a major comorbid diagnosis between 1999 and 2013. They found 15,918 users of dabigatran at doses of either 150 or 110 mg twice daily and matched them at a 1:3 ratio with warfarin users (n=47,192). The mean follow-up was 1.3 years.
Significantly more female than male participants had a history of stroke at baseline (12.2% vs 10.5%, P<0.001) and a lower baseline bleeding risk, based on modified mean HAS-BLED score (2.5 vs 2.6, respectively, P=0.02).
Interestingly, all patients who received dabigatran at 150 mg had a lower baseline bleeding rate vs those receiving the medication at 110 mg.
There was no significant difference in dabigatran prescriptions for the higher or lower doses among the men (51.8% vs 48.2%, respectively). Women younger than 75 years were more likely than their male counterparts to fill prescriptions for dabigatran 110 mg twice daily (22.8% vs 18.5%, respectively, P<0.001), as were the women older than 75 (83.5% vs 76%, P<0.001).
After adjustment for age, other treatments, and comorbidities, the overall group of dabigatran women were still significantly more likely to fill their prescriptions at the lower dose (odds ratio [OR] 1.35, 95% CI 1.24–1.48).
Women Perceived as Frailer?
There were no significant differences between the men and women for stroke incidence for the higher dabigatran dose (1.74 events per 100 person-years vs 1.76, respectively) or for the lower dose (2.83 vs 3.05, respectively).
The female lower-dose dabigatran users did have lower crude rates of bleeding vs the men (6.38 vs 7.47, P=0.04), and the women taking the higher dose had lower rates of MI (0.54 vs 1.06, P=0.01).
Although the female warfarin users had significantly lower rates of bleeding than the men (6.56 vs 8.43, P<0.001), they had higher crude rates of stroke (2.95 vs 2.43, P<0.001).
There were no significant between–treatment-group differences in MI risk for the men or for the women.
“In everyday practice, women with [AF] are mainly treated with the dabigatran 110-mg twice-daily dose; however, they tend to gain more stroke protection with the higher dose,” write the investigators, adding that this practice is puzzling.
“It is possible that clinicians perceive women as frailer patients than men, so they tend to be more concerned about safety and therefore prescribe women with a lower dose, compromising efficacy.”
They point out that more studies are now needed — especially those that enroll more women. “Sex represents an important modifier of the cardiovascular system and should be recognized as an important factor in both basic science and clinical research.”
Pilote said that the overall take-home message is that “when we have sufficient number of men and women to compare, there are sex differences in efficacy and safety. And the higher dose of dabigatran appears better in women for lower stroke rate.”
The study was funded by a grant from the Canadian Institutes of Health Research. The authors report no relevant financial relationships.
Source: Tsadok MA, Jackevicious CA, Rahme E, et al. Sex differences in dabigatran use, safety, and effectiveness in a population-based cohort of patients with atrial fibrillation. Circ Cardiovasc Qual Outcomes 2015; DOI:10.1161/CIRCOUTCOMES.114.001398. Abstract