A Cochrane review [Abstract] 1 on factor Xa inhibitors versus vitamin K antagonists 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. 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. Treatment with a factor Xa inhibitor also significantly reduced the number of all-cause deaths, the number of major bleedings and the risk of on intracranial haemorrhages (ICH) compared with warfarin (table T1).
| Outcome | OR (95% CI) | Assumed risk (warfarin) | Corresponding risk (Factor Xa inhibitors) | Participants (studies) |
|---|---|---|---|---|
| Stroke and other systemic embolic events | 0.89 (0.82 to 0.97) | 34 per 1000 | 32 per 1000 (33 to 28) | 67 477(13) |
| All strokes | 0.89 (0.81 to 0.97) | 30 per 1000 | 28 per 1000 (29 to 24) | 67 449(13) |
| Major bleeding | 0.78 (0.73 to 0.84) | 51 per 1000 | 41 per 1000 (43 to 38) | 67 396(13) |
| Intracranial haemorrhages | 0.50 (0.42 to 0.59) | 13 per 1000 | 7 per 1000 (8 to 6) | 66 259(12) |
| All-cause deaths | 0.89 (0.83 to 0.95) | 67 per 1000 | 66 per 1000 (67 to 57) | 65 624(10) |
Another Cochrane review [Abstract] 1 compared direct thrombin inhibitors versus vitamin K antagonists and included 8 studies with a total of 27 557 participants with non-valvular atrial fibrillation (AF) and one or more risk factors for stroke; 26 601 of them were assigned to standard doses groups and included in the primary analysis. Dabigatran 110 mg twice daily and 150 mg twice daily, AZD0837 300 mg once per day and ximelagatran 36 mg twice per day were compared with the vitamin K antagonists (VKA) warfarin with target INR 2.0 to 3.0. In the groups assigned to warfarin, the INR was maintained within the therapeutic range between 57% and 71% of the time.
The odds of vascular death and ischaemic events were not significantly different between all direct thrombin inhibitors (DTIs) and warfarin (OR 0.94, 95% CI 0.85 to 1.05; 8 studies, n=26 601). Sensitivity analysis by dose of dabigatran indicated that dabigatran 150 mg twice daily was superior to warfarin although the effect estimate was of borderline statistical significance (OR 0.86, 95% CI 0.75 to 0.99; 3 studies, n=12 448). Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with all DTIs compared with warfarin (OR 0.87, 95% CI 0.78 to 0.97; 8 studies, n=26 601). There was no difference in all-cause mortality between all DTIs or dabigatran and warfarin.
Most data on dabigatran came from the large RE-LY study 3, which compared warfarin (INR 2-3), dabigatran 110 mg x 2, and dabigatran 150 mg x 2. The main results are shown in table T2.
| Outcome | Warfarin (n=6 022) | Dabigatran 110 mg (n=6 015) | Dabigatran 150 mg (n=6 076) | Dabigatran 110 mg vs. warfarinRR (95% CI) | Dabigatran 150 mg vs. warfarinRR (95% CI) |
|---|---|---|---|---|---|
| Stroke or systemic embolism | 1.69% per year | 1.53% per year | 1.11% per year | 0.91(0.74 to 1.11) | 0.66 (0.53 to 0.82) |
| Major bleeding | 3.36% per year | 2.71% per year | 3.11% per year | 0.80 (0.69 to 0.93) | 0.93 (0.81 to 1.07) |
| Gastrointestinal bleeding | 1.02% per year | 1.12% per year | 1.51% per year | 1.10 (0.86 to 1.41) | 1.50 (1.19 to 1.89) |
| Intracranial bleeding | 0.74% per year | 0.23% per year | 0.30% per year | 0.31 (0.20 to 0.47) | 0.40 (0.27 to 0.60) |
| All-cause deaths | 4.13% per year | 3.75% per year | 3.64% per year | 0.91 (0.80 to 1.03) | 0.88 (0.77 to 1.00) |
The studies had many exclusion criteria such as advanced chronic kidney disease, severe heart-valve disorder, a condition that increased the risk of hemorrhage, a creatinine clearance of less than 25 to 30 ml per minute, active liver disease etc. Reported TTR values for warfarin were not optimal in the comparison groups. There are currently no specific antidotes for the new direct anticoagulant agents, and strategies for reversal of the anticoagulant effects are limited.
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