Low Dose Low-Molecular-Weight Heparin for Thrombosis Prophylaxis: Systematic Review with Meta-Analysis and Trial Sequential Analysis

Ruben J Eck, Wouter Bult, Jørn Wetterslev, Reinold O B Gans, Karina Meijer, Iwan C C van der Horst, Frederik Keus, Ruben J Eck, Wouter Bult, Jørn Wetterslev, Reinold O B Gans, Karina Meijer, Iwan C C van der Horst, Frederik Keus

Abstract

International guidelines recommend low-molecular-weight heparin (LMWH) as first-line pharmacological option for the prevention of venous thromboembolism (VTE) in many patient categories. Guidance on the optimal prophylactic dose is lacking. We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials to assess benefits and harms of low-dose LMWH versus placebo or no treatment for thrombosis prophylaxis in patients at risk of VTE. PubMed, Cochrane Library, Web of Science, and Embase were searched up to June 2019. Results were presented as relative risk (RR) with conventional and TSA-adjusted confidence intervals (CI). Forty-four trials with a total of 22,579 participants were included. Six (14%) had overall low risk of bias. Low-dose LMWH was not statistically significantly associated with all-cause mortality (RR 0.99; 95%CI 0.85-1.14; TSA-adjusted CI 0.89-1.16) but did reduce symptomatic VTE (RR 0.62; 95%CI 0.48-0.81; TSA-adjusted CI 0.44-0.89) and any VTE (RR 0.61; 95%CI 0.50-0.75; TSA-adjusted CI 0.49-0.82). Analyses on major bleeding (RR 1.07; 95%CI 0.72-1.59), as well as serious adverse events (SAE) and clinically relevant non-major bleeding were inconclusive. There was very low to moderate-quality evidence that low-dose LMWH for thrombosis prophylaxis did not decrease all-cause mortality but reduced the incidence of symptomatic and asymptomatic VTE, while the analysis of the effects on bleeding and adverse events remained inconclusive.

Keywords: low-molecular-weight heparin; meta-analysis; venous thromboembolism.

Conflict of interest statement

KM reports grants from Bayer, Sanquin, and Pfizer; speaker fees from Bayer, Sanquin, Boehringer Ingelheim, BMS, and Aspen; travel support from Bayer, and consulting fees from Uniqure outside the submitted work; JW is a member of the task force at the Copenhagen Trial Unit to develop theory and software of Trial Sequential Analysis; other authors have disclosed no potential conflicts of interest.

Figures

Figure 1
Figure 1
Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow-chart of study inclusion.
Figure 2
Figure 2
Forest plot of all-cause mortality. Forest plot of all-cause mortality at maximal follow-up of LMWH prophylaxis compared to placebo or no treatment, stratified according to population. The size of the squares reflects the weight of the trial in the pooled analysis. Horizontal bars represent 95% confidence intervals; LMWH, low-molecular-weight heparin; CI, confidence intervals.
Figure 3
Figure 3
Trial sequential analysis of symptomatic venous thromboembolism (VTE). Trial sequential analysis of symptomatic VTE at maximal follow-up of LMWH compared to placebo or no treatment. The required information size was calculated using α = 0.025, β = 0.90, relative risk reduction (RRR) = 20%, diversity (D2) as suggested by trials, and a control event rate of 1.81%. The cumulative Z-curve was constructed using a random-effects model, and each cumulative Z-value was calculated after inclusion of a new trial (represented by black dots). The dotted horizontal lines represent the conventional naïve boundaries for benefit. The etched lines represent the trial sequential boundaries for benefit (positive), harm (negative), or futility (middle triangular area). The cumulative Z-curve crosses the TSA boundary for benefit, indicating future trials are very unlikely to change the conclusions. Note: the two most recent trials were excluded from this TSA because inclusion would result in an incorrect graphical display of the LanDeMets boundary for benefit. The TSA-adjusted confidence interval remained similar.
Figure 4
Figure 4
Forest plot of symptomatic VTE. Forest plot of symptomatic VTE at maximal follow-up of LMWH prophylaxis compared to placebo or no treatment, stratified according to patient type. The size of the squares reflects the weight of the trial in the pooled analysis. Horizontal bars represent 95% confidence intervals.
Figure 5
Figure 5
Forest plot of major bleeding. Forest plot of major bleeding at maximal follow-up of LMWH prophylaxis compared to placebo or no treatment, stratified according to patient type. The size of the squares reflects the weight of the trial in the pooled analysis. Horizontal bars represent 95% confidence intervals.

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