A Cochrane review [Abstract] 1 included 13 studies with a total of 67 688 subjects with atrial fibrillation (AF) or atrial flutter. The included studies compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or rivaroxaban. Most data (approximately 90%) was from studies with apixaban, edoxaban, and rivaroxaban. Median duration of follow-up ranged from 12 weeks to 2.8 years. Mean and median ages of randomised participants ranged between 65 and 74 years, and approximately one-third of all randomised participants were women. Reported time-in-therapeutic range (TTR) values for warfarin ranged from 45% to 83% in the included studies but TTR values were not reported in 2 studies.
Treatment with a factor Xa inhibitor significantly decreased the number of strokes and systemic embolic events compared with dose-adjusted warfarin (table T1). The number needed to treat (NNT) were calculated for studies with follow-up periods of one year or more: NNT was 304 per year for apixaban and 376 per year for rivaroxaban. Only a number needed to harm (NNTH) could be calculated for for edoxaban, since the OR was greater than 1 (OR 1.01, 95% CI 0.88 to 1.15); the NNTH was 7 661 per year indicating that 7 661 people need to be treated for one year with edoxaban to cause one more stroke or systemic embolic embolism compared with warfarin. Treatment with a factor Xa inhibitor also significantly reduced the number of all-cause deaths compared with warfarin.
| Outcome | Participants (studies) | Assumed risk (warfarin) | Corresponding risk (Factor Xa inhibitors) | OR (95% CI) |
|---|---|---|---|---|
| Stroke and other systemic embolic events | 67 477(13) | 34 per 1000 | 32 per 1000(33 to 28) | 0.89(0.82 to 0.97) |
| All strokes | 67 449(13) | 30 per 1000 | 28 per 1000(29 to 24) | 0.89(0.81 to 0.97) |
| Major bleedings | 67 396(13) | 51 per 1000 | 41 per 1000(43 to 38) | 0.78(0.73 to 0.84) |
| Intracranial haemorrhages | 66 259(12) | 13 per 1000 | 7 per 1000(8 to 6) | 0.50(0.42 to 0.59) |
| All-cause deaths | 65 624(10) | 67 per 1000 | 66 per 1000(67 to 57) | 0.89(0.83 to 0.95) |
Treatment with a factor Xa inhibitor significantly reduced the number of major bleedings compared with warfarin (table T1). There was, however, statistically significant and high heterogeneity (I² = 83%) and an analysis using a random-effects model did not show a statistically significant decrease in the number of major bleedings (OR 0.88, 95% CI 0.66 to 1.17). Part of the observed heterogeneity can be explained by the increased risk of major bleedings in the factor Xa treatment arm in the single included open-label study, which studied idraparinux. Other heterogeneity might be explained by differences in baseline bleeding risks in the three largest trials, and also partly by differences in the characteristics and bleeding profiles of apixaban, edoxaban and rivaroxaban. Treatment with a factor Xa inhibitor significantly reduced the risk of on intracranial haemorrhages (ICH) compared with warfarin (table T1). Again, statistically significant heterogeneity (I² = 55%) was observed. The pre-specified sensitivity analysis excluding the open-label study showed that treatment with a factor Xa inhibitor significantly reduced the number of ICHs compared with warfarin (OR 0.47, 95% CI 0.40 to 0.56), with low, non-statistically significant heterogeneity (I² = 27%).
Caution is needed when drawing any conclusions for people with a 'very low risk' for thromboembolic events (i.e. low CHA2DS2-VASc scores), people with severe renal failure (creatinine clearance < 30 ml/minute), or people on haemodialysis, as these people were not included in the majority of studies analysed in this review.
There is currently no conclusive evidence to determine which factor Xa inhibitor is more effective and safer for long-term anticoagulant treatment of patients with AF as head-to-head studies of the different factor Xa inhibitors have not yet been performed.
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