Different Anticoagulant Regimens, Mortality, and Bleeding in Hospitalized Patients with COVID-19: A Systematic Review and an Updated Meta-Analysis

Abstract

We conducted a systematic review and a meta-analysis to assess the association of anticoagulants and their dosage with in-hospital all-cause mortality in COVID-19 patients. Articles were retrieved until January 8, 2021, by searching in seven electronic databases. The main outcome was all-cause mortality occurred during hospitalization. Data were combined using the general variance-based method on the effect estimate for each study. Separate meta-analyses according to type of COVID-19 patients (hospitalized or intensive care unit [ICU] patients), anticoagulants (mainly heparin), and regimens (therapeutic or prophylactic) were conducted. A total of 29 articles were selected, but 23 retrospective studies were eligible for quantitative meta-analyses. No clinical trial was retrieved. The majority of studies were of good quality; however, 34% did not distinguish heparin from other anticoagulants. Meta-analysis on 25,719 hospitalized COVID-19 patients showed that anticoagulant use was associated with 50% reduced in-hospital mortality risk (pooled risk ratio [RR]: 0.50, 95% confidence interval [CI]: 0.40–0.62; I 2: 87%). Both anticoagulant regimens (therapeutic and prophylactic) reduced in-hospital all-cause mortality, compared with no anticoagulation. Particularly in ICU patients, the anticoagulant therapeutic regimen was associated with a reduced in-hospital mortality risk (RR: 0.30, 95% CI: 0.15–0.60; I 2: 58%) compared with the prophylactic one. However, the former was also associated with a higher risk of bleeding (RR: 2.53, 95% CI: 1.60–4.00; I 2: 65%). Anticoagulant use, mainly heparin, reduced all-cause mortality in COVID-19 patients during hospitalization. Due to the higher risk of bleeding at therapeutic doses, the use of prophylactic dosages of anticoagulant is probably to be preferred in noncritically ill COVID-19 patients.

High versus Standard Intensity of Thromboprophylaxis in Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis

“…Two relevant meta-analyses have been identified through our literature search [ 46 , 47 ]. Both of them analyzed studies comparing the efficacy and safety of therapeutic versus prophylactic dose of thromboprophylaxis and confirmed a trend towards clinical benefits of therapeutic dose.…”

“…Both of them analyzed studies comparing the efficacy and safety of therapeutic versus prophylactic dose of thromboprophylaxis and confirmed a trend towards clinical benefits of therapeutic dose. However, mixed adjusted and unadjusted estimates were used, rendering these analyses inconclusive [ 46 , 47 ]. In the present meta-analysis, only high-quality studies with adjusted effect size estimates were included.…”

An update on drugs with therapeutic potential for SARS-CoV-2 (COVID-19) treatment

“… Drug No. patients Dose Outcome Effect Ivermectin ( AFMZ et al, 2021 ) 1,788 140 - 400 µg/kg Mortality reduction RR = 0.39 (95% CI: 0.20 - 0.74); p = 0.004 Colchicine ( Golpour et al, 2021 ) 5,901 NA Mortality reduction RR = 0.644 (95% CI: 0.555 – 0.748) Niclosamide ( Abdulamir et al, 2021a ) 150 3 g per day Reduced recovery time p ≤ 0.05 Tofacitinib ( Gunay et al, 2021 ) 289 10 mg twice a day Mortality reduction HR = 0.49 (95% CI: 0.15 to 1.63) Bamlanivimab - Etesevimab ( Dougan et al, 2021 ) 1,035 2.8 g + 2.8 g Hospitalizations or death absolute risk difference = −4.8%; (95% CI − 7.4 - −2.3); RR = 0.3; p < 0.001 Bamlanivimab - Etesevimab ( Gottlieb et al, 2021 ) 577 2.8 g + 2.8 g Viral load Viral load change = - 0.57 (95% CI: −1.00 to −0.14); p = 0.01 Anticoagulants ( Parisi et al, 2021 ) 25,719 therapeutic and prophylactic dose Mortality reduction RR = 0.50 (95% CI: 0.40 - 0.62) ASA ( RECOVERY Collaborative Group, 2021 ) 14,892 150 mg Mortality reduction RR = 0.96 (95% CI 0.89 – 1.04); p = 0.35 …”

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19

“…In addition to these limitations, the risk of bleeding should be assessed on an individualized and continuous basis, especially if higher rather than standard thromboprophylaxis doses are administered, since they are associated with a higher incidence of bleeding [41,42]. A meta-analysis involving 7781 patients hospitalized for COVID-19 showed that standard doses of thromboprophylaxis were not associated with an excess of bleeding compared to no thromboprophylaxis, while the use of therapeutic anticoagulation was associated with more than two-fold increased risk of bleeding than standard thromboprophylaxis [41]. This excess of bleeding events needs to be weighed against any potential benefit of therapeutic anticoagulant doses as a part of COVID-19 treatment.…”