Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation

Abstract

Objective: To examine the comparative efficacy and safety of antithrombotic treatments (apixaban, dabigatran, edoxaban, rivaroxaban and vitamin K antagonists (VKA) at a standard adjusted dose (target international normalised ratio 2.0-3.0), acetylsalicylic acid (ASA), ASA and clopidogrel) for non-valvular atrial fibrillation and among subpopulations.

Design: Systematic review and network meta-analysis.

Data sources: A systematic literature search strategy was designed and carried out using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and the grey literature including the websites of regulatory agencies and health technology assessment organisations for trials published in English from 1988 to January 2014.

Eligibility criteria for selecting studies: Randomised controlled trials were selected for inclusion if they were published in English, included at least one antithrombotic treatment and involved patients with non-valvular atrial fibrillation eligible to receive anticoagulant therapy.

Results: For stroke or systemic embolism, dabigatran 150 mg and apixaban twice daily were associated with reductions relative to standard adjusted dose VKA, whereas low-dose ASA and the combination of clopidogrel plus low-dose ASA were associated with increases. Absolute risk reductions ranged from 6 fewer events per 1000 patients treated for dabigatran 150 mg twice daily to 15 more events for clopidogrel plus ASA. For major bleeding, edoxaban 30 mg daily, apixaban, edoxaban 60 mg daily and dabigatran 110 mg twice daily were associated with reductions compared to standard adjusted dose VKA. Absolute risk reductions with these agents ranged from 18 fewer per 1000 patients treated each year for edoxaban 30 mg daily to 24 more for medium dose ASA.

Conclusions: Compared with standard adjusted dose VKA, new oral anticoagulants were associated with modest reductions in the absolute risk of stroke and major bleeding. People on antiplatelet drugs experienced more strokes compared with anticoagulant drugs without any reduction in bleeding risk. To fully elucidate the comparative benefits and harms of antithrombotic agents across the various subpopulations, rigorously conducted comparative studies or network meta-regression analyses of patient-level data are required.

Systematic review registration number: PROSPERO registry-CRD42012002721.

Keywords: CARDIOLOGY; EPIDEMIOLOGY.

Figure 1

Evidence network for all-cause stroke or systemic embolism. (Four RCTs, PETRO, WASPO Chung et al and Yamashita et al, were not included in the analysis because they did not report data for this outcome or had zeros in both arms.) The width of the lines is proportional to the number of randomised controlled trials comparing each pair of treatments, and the size of each treatment node is proportional to the number of randomised participants (sample size). A dotted line indicates a three-arm randomised controlled trial and a black node indicates a node included in the analysis but not reported in the main text. ASA, acetylsalicylic acid; RCT, randomised controlled trial; VKA, vitamin K antagonist.

Figure 2

OR for all-cause stroke or systemic embolism (A) and major bleeding (B) in Bayesian network meta-analysis versus standard adjusted dose VKA. CrI, credible interval; VKA, vitamin K antagonist.

Figure 3

OR from network meta-analyses for stroke or systemic embolism and major bleeding for all pairwise comparisons. (Results between individual treatments, especially newer oral anticoagulants, should be interpreted with caution, given the limitations associated with using a fixed-effects model. See online supplementary appendix 9 for additional details.) ORs for recurrence of stroke or systemic embolism are below the diagonal (row-defining treatment vs column-defining treatment) and those for major bleeding are above the diagonal and in blue (column-defining treatment vs row-defining treatment). To obtain ORs for comparisons in the opposite direction, reciprocals should be taken (eg, the OR for standard dose warfarin compared with apixaban 5 mg twice daily for stroke or systemic embolism is 1/0.78=1.28). Significant results are in bold. VKA, vitamin K antagonist.

Figure 4

Icon array illustrating the absolute risks of Stroke or systemic embolism (blue) and major bleeding episodes (red) per 1000 patients treated. (Figures do not reflect uncertainty around effect estimates and there is more uncertainty (ie, wider credible intervals) for low-dose ASA, medium-dose ASA and clopidogrel plus low dose ASA (see online supplementary appendix 8). Underlying studies may also double count haemorrhage stroke.)