A Systematic Review and a Meta-Analysis Comparing Prophylactic and Therapeutic Low Molecular Weight Heparins for Mortality Reduction in 32,688 COVID-19 Patients

• Main Authors: Riccardo Giossi (Author), Danilo Menichelli (Author), Arianna Pani (Author), Elena Tratta (Author), Alessandra Romandini (Author), Rossana Roncato (Author), Alessandro Nani (Author), Paolo Schenardi (Author), Erika Diani (Author), Veronica Andrea Fittipaldo (Author), Alessio Farcomeni (Author), Francesco Scaglione (Author), Daniele Pastori (Author)
• Format: Book
• Published: Frontiers Media S.A., 2021-09-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2021.698008
• Keywords: SARS-CoV2; COVID-19; mortality; heparin; LMWH; bleeding; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 12 (2021)

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