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.
Highlights
Venous thromboembolism (VTE) is a common cause of morbidity and mortality in hospitalized and non-hospitalized patients [1]
Preceding systematic reviews on thrombosis prophylaxis have not assessed benefits and harms associated with different low-molecular-weight heparin (LMWH) doses [4,5,6,7,8,9,10]
There is no generally accepted definition of different prophylactic LMWH dose categories, which is why we previously categorized LMWH thrombosis prophylaxis regimens as either ‘low-dose’ or ‘intermediate-dose’, based on different registered doses in summaries of product characteristics (SPCs) worldwide [11]. Using this approach in a previous meta-analysis, we found that intermediate-dose LMWH, compared with placebo or no treatment, was associated with a significant decrease in symptomatic VTE, at the cost of an increase in major bleeding [11]
Summary
Venous thromboembolism (VTE) is a common cause of morbidity and mortality in hospitalized and non-hospitalized patients [1]. The American Society of Hematology and American College of Chest Physicians guidelines recommend low-molecular-weight heparin (LMWH) as a first-line pharmacological option for most patients at risk of VTE [2,3]. Several prophylactic doses and types of LMWH are used worldwide, which is reflected by differences in national summaries of product characteristics (SPCs) and dosing regimens of randomized controlled trials (RCTs). Preceding systematic reviews on thrombosis prophylaxis have not assessed benefits and harms associated with different LMWH doses [4,5,6,7,8,9,10]. There have been very few direct comparisons of prophylactic LMWH dose regimens, and indirect evidence could provide a ‘second best’ estimate of benefits and harms
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