Drug products: Xarelto, Xarelto®
ATC code: B01AF01
Clinical studies show that rivaroxaban reduces the risk of stroke and systemic embolism as effectively in men as in women with atrial fibrillation. The effect of rivaroxaban as initial treatment and as prophylaxis of recurrent venous thromboembolism is similar in men and women.
A lower bleeding risk has been seen in women but not in men treated with rivaroxaban for atrial fibrillation. In patients treated with venous thromboembolism, no sex differences in bleeding risk was seen in clinical studies.
A single-blind, placebo-controlled study in healthy individuals (16 men, 16 women) found no effect of sex on the pharmacokinetics and pharmacodynamics of rivaroxaban 10 mg . No studies with a clinically relevant sex analysis regarding the dosing of rivaroxaban have been found.
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 rivaroxaban
In the pivotal study on rivaroxaban (ROCKET), included in the meta-analyses mentioned above, patients with nonvalvular AF who were at increased risk for stroke received either rivaroxaban 20 mg daily or dose-adjusted warfarin (4300 men and 2831 women on rivaroxaban, 4301 men and 2832 women on warfarin). The efficacy rivaroxaban as prevention of stroke or systemic embolism was similar in both sexes . An analysis of mortality data in the ROCKET study revealed that male sex was one of many independent predictors of increase all-cause mortality. Female sex was among factors associated with lower likelihood of cardiovascular death as well as sudden or unwitnessed death .
The pivotal VTE studies included in the meta-analyses mentioned above (EINSTEIN-DVT AND EINSTEIN-PE) report similar treatment effects of rivaroxaban in men and women [15, 16].
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 rivaroxaban
In the ROCKET trial, included in the meta-analyses mentioned above, women with AF treated with rivaroxaban had a lower risk of major bleeding, while men had a higher risk, when compared to warfarin .
The pivotal studies in VTE patients, included in the meta-analyses mentioned above, report no sex differences in major bleeding [15, 16]. Contrary to this, higher rates of bleedings were reported in females a cohort of younger patients (40 males, 38 females; 14-55 years) treated with rivaroxaban for VTE. The median daily rivaroxaban dose per kilogram body weight were higher in women than men (0.25 mg/kg vs. 0.21 mg/kg, p<0.000) .
Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2019-01-22
Reviewed by: Mia von Euler
Approved by: Karin Schenck-Gustafsson