Drug products: Eliquis
ATC code: B01AF02
Apixaban reduces the risk of stroke and systemic embolism as effectively in men as in women with atrial fibrillation. The effect of apixaban as initial treatment and as prophylaxis of recurrent venous thromboembolism is similar in men and women. The risk of larger bleeds is similar in men and women.
The exposure of apixaban is reported to be about 18% higher in women than men . However, a study of healthy individuals (40 men, 40 women) receiving a single dose of apixaban 20 mg reported no significant differences between men and women in Cmax and AUC of apixaban . No dose adjustment based on sex is recommended .
New oral anticoagulants
In atrial fibrillation (AF) patients, large meta-analyses of phase III trials have found that NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) are better than warfarin in preventing stroke and systemic embolism in both men and women [1-3]. In contrast, a meta-analysis on data from other phase III trials (in total 18 415 men, 13 094 women) on NOACs (apixaban, dabigatran, ximelagatran), found that men were more protected from stroke or systemic embolism than women . An observational study on AF patients in Hong-Kong (4972 men, 4834 women) showed that use of NOACs (apixaban, dabigatran, rivaroxaban) was associated with lower all-cause mortality in women but not in men, when compared to warfarin . However, risk of stroke and response to thrombolytic therapy may vary between ethnic groups, and a higher risk of bleeding in Asians treated with warfarin has been reported . Similarly, another meta-analysis found a higher risk of stroke and systemic embolism in women treated with NOAC (apixaban, dabigatran, edoxaban, rivaroxaban) .
In venous thromboembolism (VTE) patients, two sex-specific meta-analyses on NOACs (apixaban, dabigatran, edoxaban, rivaroxaban, ximelagatran) have found no sex difference in the rate of VTE recurrence [7, 8].
Specific for apixaban
The pivotal studies in AF patients, ARISTOTLE and AVERROES, show similar treatment effects of apixaban in men and women [14, 15]. In the large ARISTOTLE study (11785 men, 6416 women), patients received either apixaban 5 mg twice daily or dose-adjusted warfarin. Efficacy for apixaban in subgroups, such as age and patient’s sex, were equally consistent with the primary efficacy results for the whole study population [14, 16]. The AVERROES study (3277 men, 2322 women) compared efficacy of apixaban (5 mg twice daily) with aspirin (81-324 mg daily) in the treatment of patients with AF for whom vitamin K antagonist therapy was considered unsuitable. The positive benefit of apixaban was equal in men and women .
The pivotal VTE studies, AMPLIFY and AMPLIFY-EXT, report similar treatment effects of apixaban in men and women [17, 18]. In the AMPLIFY study (3169 men, 2226 women), standard dosing of apixaban was compared with enoxaparin/warfarin in patients with acute VTE. Relative risks of recurrent symptomatic VTE or death related to VTE were similar in men and women . In AMPLIFY-EXT (1424 men, 1058 women), apixaban in two doses (2.5 mg and 5 mg, twice daily) were compared with placebo in patients who had completed participation in the AMPLIFY study or had been treated for 6-12 months with standard anticoagulant therapy. Relative risks of symptomatic recurrent VTE or all-cause death were similar for all doses of apixaban .
New oral anticoagulants
A sex-specific meta-analysis on the risk of bleeding from anticoagulants in patients with AF or VTE (57 043 men, 37 250 women) found a similar bleeding risk in men and women . However, sex differences have been observed when analyzing by indication, as described below.
In AF patients, a worldwide meta-analysis (16 760 men, 9 500 women) found that women treated with NOACs (apixaban, dabigatran, rivaroxaban) had lower risk of major bleeding than men, while women treated with warfarin had similar risk of bleeding as men . Similarly, another meta-analysis found a lower risk of major bleeding in women (apixaban, dabigatran, edoxaban, rivaroxaban) even after omitting the AVERROES study using aspirin as comparator . Contrary to this, another meta-analysis, including the same studies, found no sex differences in major bleeding events from NOACs (apixaban, edoxaban, dabigatran, rivaroxaban), when compared with warfarin . Also, an observational study conducted in Hong-Kong (4972 men, 4834 women) showed that use of NOAC (apixaban, dabigatran, rivaroxaban) was associated with a lower risk of intracranial hemorrhage in women but not in men, when compared with warfarin. The risk of GI bleeding was similar in men and women treated with NOAC, when compared with warfarin .
In VTE patients, a sex-specific meta-analysis (43.7% women) found that women had more bleeding events from NOACs (apixaban, rivaroxaban, ximelagatran) than men . Another sex-specific meta-analysis on VTE (13 139 men, 9814 women) found a higher risk of bleeding in women than in men from both warfarin and NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) . However, another similar meta-analysis of the same studies showed that the sex difference in incidence of bleedings was only significant for edoxaban (RR 0.52) [8, 11].
Specific for apixaban
The pivotal studies of apixaban report that the risks of major bleeding in men and women are consistent with the primary safety results of the whole study populations. In AF patients, the relative risks of major bleeding were similar in men and women .
In VTE patients, the relative risks of major bleeding were 0.38 for men and 0.24 for women in the AMPLIFY study . No sex-divided data of the primary safety outcome major bleeding was presented in AMPLIFY-EXT. The relative risks of secondary safety outcome (composite of major and clinically relevant non-major bleeding) were similar in men and women .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2018-11-12
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson