Anticoagulants for thrombosis prophylaxis in acutely ill patients admitted to hospital: systematic review and network meta-analysis

Abstract

Objective: To assess the benefits and harms of different types and doses of anticoagulant drugs for the prevention of venous thromboembolism in patients who are acutely ill and admitted to hospital.

Design: Systematic review and network meta-analysis.

Data sources: Cochrane CENTRAL, PubMed/Medline, Embase, Web of Science, clinical trial registries, and national health authority databases. The search was last updated on 16 November 2021.

Eligibility criteria for selecting studies: Published and unpublished randomised controlled trials that evaluated low or intermediate dose low-molecular-weight heparin, low or intermediate dose unfractionated heparin, direct oral anticoagulants, pentasaccharides, placebo, or no intervention for the prevention of venous thromboembolism in acutely ill adult patients in hospital.

Main outcome measures: Random effects, bayesian network meta-analyses used four co-primary outcomes: all cause mortality, symptomatic venous thromboembolism, major bleeding, and serious adverse events at or closest timing to 90 days. Risk of bias was also assessed using the Cochrane risk-of-bias 2.0 tool. The quality of evidence was graded using the Confidence in Network Meta-Analysis framework.

Results: 44 randomised controlled trials that randomly assigned 90 095 participants were included in the main analysis. Evidence of low to moderate quality suggested none of the interventions reduced all cause mortality compared with placebo. Pentasaccharides (odds ratio 0.32, 95% credible interval 0.08 to 1.07), intermediate dose low-molecular-weight heparin (0.66, 0.46 to 0.93), direct oral anticoagulants (0.68, 0.33 to 1.34), and intermediate dose unfractionated heparin (0.71, 0.43 to 1.19) were most likely to reduce symptomatic venous thromboembolism (very low to low quality evidence). Intermediate dose unfractionated heparin (2.63, 1.00 to 6.21) and direct oral anticoagulants (2.31, 0.82 to 6.47) were most likely to increase major bleeding (low to moderate quality evidence). No conclusive differences were noted between interventions regarding serious adverse events (very low to low quality evidence). When compared with no intervention instead of placebo, all active interventions did more favourably with regard to risk of venous thromboembolism and mortality, and less favourably with regard to risk of major bleeding. The results were robust in prespecified sensitivity and subgroup analyses.

Conclusions: Low-molecular-weight heparin in an intermediate dose appears to confer the best balance of benefits and harms for prevention of venous thromboembolism. Unfractionated heparin, in particular the intermediate dose, and direct oral anticoagulants had the least favourable profile. A systematic discrepancy was noted in intervention effects that depended on whether placebo or no intervention was the reference treatment. Main limitations of this study include the quality of the evidence, which was generally low to moderate due to imprecision and within-study bias, and statistical inconsistency, which was addressed post hoc.

Systematic review registration: PROSPERO CRD42020173088.

Fig 1

Network geometry for each outcome. Network plot is the overview of direct comparisons between interventions. Each circle represents an intervention and is referred to as node. Node size correlates with the number of studies that included the intervention. Lines or edges between nodes represent direct comparisons, and their thickness is proportional to the number of trials contributing to each comparison. The number of trials is also included on the edges. DOAC=direct oral anticoagulant; Int=intermediate dose; low=low dose; LMWH=low-molecular-weight heparin; Pentasach=pentasaccharides; UFH=unfractionated heparin

Fig 2

Head-to-head comparisons of interventions for risk of mortality (upper white fields) and venous thromboembolism (lower shaded fields). Data are odds ratio with 95% credible interval. Figure should be read from left to right: for comparisons of the mortality outcome (upper white fields) odds ratios <1 favour the row defining treatment, whereas for venous thromboembolism (lower shaded fields), odds ratios <1 favour the column defining treatment. For example, LMWH intermediate dose conclusively reduced venous thromboembolism compared with no intervention (odds ratio 0.44; 95% credible interval 0.25 to 0.69), placebo (0.66; 0.46 to 0.93), and UFH low dose (0.63; 0.43 to 0.92), but not to other anticoagulants. To obtain odds ratios for comparisons in the opposite direction, reciprocals should be taken. DOAC=direct oral anticoagulant; int=intermediate dose; LMWH=low-molecular-weight heparin; low=low dose; UFH=unfractionated heparin

Fig 3

Effect estimates of anticoagulants versus placebo or no intervention. Forest plots show effect estimates of each anticoagulant compared with placebo and with no intervention on all four outcomes. Results <1.0 favour the anticoagulant and results >1.0 favour placebo or no intervention. DOAC=direct oral anticoagulant; int=intermediate dose; low=low dose; LMWH=low-molecular-weight heparin; Pentasach=pentasaccharides; UFH=unfractionated heparin

Fig 4

Cumulative ranking curves for all four outcomes. Graphs show the cumulative probability of each intervention ranking, from best (rank 1) to worst (rank 8 or 5 depending on the number of treatments) for each outcome. A rank indicates the probability that an intervention is best, second best, etc. For example, pentasaccharides and intermediate dose LMWH ranked best for preventing venous thromboembolism, whereas no intervention ranked worst. DOAC=direct oral anticoagulant; int=intermediate dose; low=low dose; LMWH=low-molecular-weight heparin; Pentasach=pentasaccharides; UFH=unfractionated heparin. An interactive version of this graphic is available at: https://bit.ly/3nmPgNs

Fig 5

Head-to-head comparisons of interventions for risk of serious adverse events (upper white fields) and major bleeding (lower shaded fields). Data are odds ratio with 95% credible interval. Figure should be read from left to right: for comparisons of the serious adverse event outcome (upper white fields) odds ratios <1 favour the row defining treatment, whereas for major bleeding (lower shaded fields), odds ratios <1 favour the column defining treatment. For example, UFH low dose conclusively increased risk of major bleeding compared with no intervention (odds ratio 2.15; 95% credible interval 1.06 to 5.46), but not to placebo (1.51; 0.68 to 3.86) or other anticoagulants. To obtain odds ratio for comparisons in the opposite direction, reciprocals should be taken. DOAC=direct oral anticoagulant; int=intermediate dose; LMWH=low-molecular-weight heparin; low=low dose; UFH=unfractionated heparin