Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis

Abstract

Objective: To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism.

Design: Systematic review and network meta-analysis.

Data sources: Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand.

Review methods: Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms.

Results: 12 articles met our inclusion criteria, with 11,999 patients evaluated for efficacy and 12,167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available.

Conclusions: All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding.

Fig 1 Evidence network for recurrence of venous thromboembolism. The width of lines for each connection in the evidence network are proportional to the number of randomised controlled trials (RCTs) comparing each pair of treatments. The size of each treatment node is proportional to the number of randomised participants (sample size). Dotted line=three arm RCT in the evidence network. The analysis includes ximelagatran to improve precision of effect estimates; however, the results are not reported because ximelagatran is not commercially available

Fig 2 Odds ratio (95% credible interval) for recurrent VTE and major bleeding episodes in Bayesian network meta-analysis versus placebo or observation. CrI=credible interval. *Estimates are derived from random effects, Bayesian network meta-analysis, which treats between study variance as an informative prior (log normal distribution). Estimates differ from those reported in frequentist direct meta-analysis in ASPIRE and web appendix 5 (both reported significant differences in favour of ASA) because between study variance is treated as a constant in frequentist analyses. Web appendix 6 reports detailed estimates for the ASA versus placebo comparison. †Only one study investigated rivaroxaban for major bleeding and contained a zero cell (0 of 590 people receiving placebo and four of 598 receiving rivaroxaban), which resulted in uncertain estimates of effect

Fig 3 Odds ratios (95% credible interval) from network meta-analyses for recurrence of VTE and major bleeding for all pairwise comparisons. Odd ratios for recurrence of VTE are below the diagonal line (row defining treatment v column defining treatment); odds ratios for major bleeding are above the diagonal line (column defining treatment v row defining treatment). To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken (for example, the odds ratio for placebo or observation compared with ASA 100 mg daily for recurrence of VTE is 1÷0.65=1.54). Significant results are in bold and underlined. *Estimates are derived from random effects, Bayesian network meta-analysis, which treats between study variance as an informative prior (log normal distribution). Estimates differ from those reported in frequentist direct meta-analysis in ASPIRE and web appendix 5 (both reported significant differences in favour of ASA) because between study variance is treated as a constant in frequentist analyses. Web appendix 6 reports detailed estimates for the ASA versus placebo comparison. †Only one study investigated rivaroxaban for major bleeding and contained a zero cell (0 of 590 people receiving placebo and four of 598 receiving rivaroxaban), which resulted in uncertain estimates of effect

Fig 4 Icon array showing absolute risks of recurrent VTE (blue) and major bleeding episodes (red). *Only one study investigated rivaroxaban for major bleeding and contained a zero cell (0 of 590 people receiving placebo and four of 598 receiving rivaroxaban), which resulted in uncertain estimates of effect