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Semin Thromb Hemost 2019; 45(08): 810-824
DOI: 10.1055/s-0039-1696965
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

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

Ruben J. Eck
1   Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Wouter Bult
2   Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, Groningen, The Netherlands
3   Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Jørn Wetterslev
4   The Copenhagen Trial Unit (CTU), Center for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
,
Reinold O.B. Gans
1   Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Karina Meijer
5   Department of Haematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Frederik Keus
3   Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
,
Iwan C.C. van der Horst
3   Department of Critical Care, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
› Author Affiliations Funding There was no funding source for this study.
Further Information

Publication History

Publication Date:
17 October 2019 (online)

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Abstract

Different doses of low-molecular-weight heparin (LMWH) are registered and used for thrombosis prophylaxis. We assessed benefits and harms of thrombosis prophylaxis with a predefined intermediate-dose LMWH compared with placebo or no treatment in patients at risk of venous thromboembolism (VTE). We performed a systematic review with meta-analyses and trial sequential analyses (TSA) following The Cochrane Handbook for Systematic Reviews of Interventions. Medline, Cochrane CENTRAL, Web of Science, and Embase were searched up to December 2018. Trials were evaluated for risk of bias and quality of evidence was assessed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seventy randomized trials with 34,046 patients were included. Eighteen (26%) had overall low risk of bias. There was a small statistically significant effect of LMWH on all-cause mortality (risk ratio [RR]: 0.96; TSA-adjusted confidence interval [TSA-adjusted CI]: 0.94–0.98) which disappeared in sensitivity analyses excluding ambulatory cancer patients (RR: 0.99; TSA-adjusted CI: 0.84–1.16). There was moderate-quality evidence for a statistically significant beneficial effect on symptomatic VTE (odds ratio [OR]: 0.59; TSA-adjusted CI: 0.53–0.67; number needed to treat [NNT]: 76; 95% CI: 60–106) and a statistically significant harmful effect on major bleeding (Peto OR: 1.66; TSA-adjusted CI: 1.31–2.10; number needed to harm [NNH]: 212; 95% CI: 142–393). There were no significant intervention effects on serious adverse events. The use of intermediate-dose LMWH for thrombosis prophylaxis compared with placebo or no treatment was associated with a small statistically significant reduction of all-cause mortality that disappeared in sensitivity analyses excluding trials that evaluated LMWH for anticancer treatment. Intermediate-dose LMWH provides benefits in terms of VTE prevention while it increases major bleeding.

Keywords

low-molecular-weight heparin - LMWH - thrombosis - systematic review - meta-analysis

Systematic Review Registration

PROSPERO CRD42016036951.


Authors' Contributions

R.J. Eck, W. Bult, and F. Keus had full access to all data in the study and take responsibility for integrity and accuracy of data analysis. All authors contributed to study concept and design. R.J. Eck and W. Bult contributed to acquisition of data. R.J. Eck, J. Wetterslev, and F. Keus did the statistical analysis and interpreted the data. J. Wetterslev, R.O.B. Gans, K. Meijer, F. Keus, and I.C.C. van der Horst provided directions and intellectual content. R.J. Eck and F. Keus drafted the manuscript with critical revisions from all authors. The final version of this manuscript has been read and approved by all authors.


Ethics Committee Approval

No ethics committee approval was required.


Supplementary Material

 

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