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Giossi R, Menichelli D, Pani A, et al. A Systematic Review and a Meta-Analysis Comparing Prophylactic and Therapeutic Low Molecular Weight Heparins for Mortality Reduction in 32,688 COVID-19 Patients. Front Pharmacol. 2021 Sep 2;12:698008. doi: 10.3389/fphar.2021.698008. eCollection 2021. (Systematic review)

Background: Antithrombotic treatment, including low molecular weight heparin (LMWH) or unfractionated heparin (UFH), has been proposed as a potential therapy for coronavirus disease 2019 (COVID-19) to lower diffuse intravascular clotting activation. However, it is unclear whether prophylactic or therapeutic doses have similar efficacy in reducing mortality. Methods: We performed a systematic review (PROSPERO registration CRD42020179955) and meta-analysis including observational cohort studies and randomized controlled trials (RCT) evaluating the effectiveness of heparins (either LMWH, UFH, or fondaparinux) in COVID-19 patients. Heparin treatment was compared to no anticoagulation. A subgroup analysis on prophylactic or therapeutic doses compared to no anticoagulation was performed. Prophylactic dose was also compared to full dose anticoagulation. Primary endpoint was all-cause mortality. Secondary endpoints were major bleeding and length of hospital stay (LOS). Results: 33 studies (31 observational, 2 RCT) were included for a total overall population of 32,688 patients. Of these, 21,723 (66.5%) were on heparins. 31 studies reported data on all-cause mortality, showing that both prophylactic and full dose reduced mortality (pooled Hazard Ratio [HR] 0.63, 95% confidence interval [CI] 0.57-0.69 and HR 0.56, 95% CI 0.47-0.66, respectively). However, the full dose was associated with a higher risk of major bleeding (Odds Ratio [OR] 2.01, 95% CI 1.14-3.53) compared to prophylactic dose. Finally, LOS was evaluated in 3 studies; no difference was observed between patients with and without heparins (0.98, -3.87, 5.83 days). Conclusion: Heparin at both full and prophylactic dose is effective in reducing mortality in hospitalized COVID-19 patients, compared to no treatment. However, full dose was associated with an increased risk of bleeding. Systematic Review Registration: https://clinicaltrials.gov/, identifier CRD42020179955.

Discipline Area Score
Hospital Doctor/Hospitalists 7 / 7
Internal Medicine 7 / 7
Infectious Disease 6 / 7
Emergency Medicine 6 / 7
Hemostasis and Thrombosis 5 / 7
Comments from MORE raters

Hemostasis and Thrombosis rater

There were only two RCTs included. Furthermore, the results of the two RCTs did not compare anticoagulation with no anticoagulation. Therefore, the results of the SR still should be confirmed by future high-quality studies.

Hospital Doctor/Hospitalists rater

This meta-analysis included 2 randomized and 31 observational comparisons of prophylactic vs therapeutic dosing with a heparin or fondaparinux in COVID-19 patients, published before 22 June 2021. The authors conclude that prophylactic and full dose treatment both reduced all cause mortality but not length of stay, and that major bleeding was more likely with full dose heparin. The overview is limited by its heavy weighting for observational studies (only 5/31 were 'good quality') and the few randomized trials (n=2). Pubmed lists 4 major randomized trials published since their cut-off date. Conclusions are, therefore, preliminary.

Hospital Doctor/Hospitalists rater

This metanalysis based on the existing evidence so far, (and before two recent RCT) comparing prophylactic versus full dose anticoagulation in hospitalized COVID-19 patients confirms that heparin (mostly LMWH) at both full and prophylactic dose is effective in reducing mortality in this subset of patients. D-dimers were expressed only in a subset of studies. Confounding biases were frequent on most of observational studies included, but not in the 2 RCT. There were 32688 patients evaluated, and 33.5% of the hospitalized did not receive any anticoagulant. Heparin reduced risk of all-cause mortality at 28 days, both on prophylactic and full dose. As other studies that came after this, the data does not support an extensive use of full dose anticoagulation in all hospitalized subjects (significant bleeding risk) except in specific cases. Prophylactic should represent first choice.

Infectious Disease rater

This systematic review includes predominantly observational studies with high risk of bias, but the evidence suggests a robust effect in favour of prophylactic Low Molecular Weight Heparins in terms of mortality.
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