A Cochrane review [Abstract] 1 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. The mean age of participants in all studies was over 70 years, and 61% of participants were men. The rate of participants never previously exposed to VKAs was approximately 50% (range 5% to 100%). The average CHADS2 score, if reported, was 2.1 except for one study in which the average score was 3. 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 (table T1). 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.
| Intervention | Relative effect | Control (warfarin) | Intervention (95% CI) | Participants (studies) |
|---|---|---|---|---|
| * Vascular deaths and ischaemic events includes non-fatal ischaemic strokes and TIAs, non-fatal systemic embolic events (any event of acute non-intracerebral or non-coronary vascular origin including deep vein thrombosis and pulmonary embolism), non-fatal myocardial infarction, any death related to a vascular cause not including fatal haemorrhages or cardiovascular deaths (e.g. sudden arrhythmia, pump failure). | ||||
| Direct thrombin inhibitors (all) | OR 0.94 (0.85 to 1.05) | 23 per 1000 | 22 per 1000 (20 to 24) | 26 601 (8 studies) |
| Dabigatran (all doses) | OR 0.92 (0.82 to 1.04) | 74 per 1000 | 68 per 100 (61 to 77) | 18 509 (3 studies) |
| Dabigatran 150 mg twice daily | OR 0.86 (0.75 to 0.99) | 74 per 1000 | 64 per 1000 (56 to 73) | 12 448 (3 studies) |
Fatal and non-fatal major bleeding events, including haemorrhagic strokes, were less frequent with all DTIs compared with warfarin, but no difference was observed between dabigatran 150 mg and warfarin (table T2). Adverse events other than bleeding and ischaemic events that led to treatment discontinuation were significantly more frequent with all DTIs (OR 2.18, 95% CI 1.82 to 2.61; 5 studies, n=19143) and dabigatran (OR 2.12, 95% CI 1.77 to 2.56; 3 studies, n=18 509) compared with warfarin. Serious adverse events were also more frequent with all DTIs (OR 1.31, 95% CI 1.09 to 1.56; 5 studies, n=19 077) and dabigatran (OR 1.35, 95% CI 1.12 to 1.63; 3 studies, n=18 443) than warfarin. There was no difference in all-cause mortality between all DTIs (OR 0.91, 95% CI 0.83 to 1.01; 8 studies, n=26 601), or dabigatran (OR 0.90, 95% CI 0.80 to 1.01; 3 studies, n=18 509) and warfarin.
| Intervention | Relative effect | Control (warfarin) | Intervention (95% CI) | Participants (studies) |
|---|---|---|---|---|
| Direct thrombin inhibitors (all) | OR 0.87 (0.78 to 0.97) | 39 per 1000 | 34 per 1000 (31 to 38) | 26 601 (8 studies) |
| Dabigatran (all doses) | OR 0.92 (0.82 to 1.03) | 79 per 1000 | 73 per 1000 (66 to 81) | 18 509 (3 studies) |
| Dabigatran 150 mg twice daily | OR 1.01 (0.89 to 1.16) | 79 per 1000 | 80 per 1000 (71 to 91) | 12 448 (3 studies) |
People on DTIs should be carefully monitored, as concerns remain with the lack of drug antidote and compliance, given the need for twice daily administration. Several additional factors exist, such as comorbid conditions including reduced renal function, side-effect profile, cost and patient preference. Thus, it is needed to consider the balance of benefit and risk in each individual.
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