Intermediate-to-therapeutic versus prophylactic anticoagulation for coagulopathy in hospitalized COVID-19 patients: a systemic review and meta-analysis

Abstract

Background Anticoagulation in hospitalized COVID-19 patients has been associated with survival benefit; however, the optimal anticoagulant strategy has not yet been defined. The objective of this meta-analysis was to investigate the effect of intermediate-to-therapeutic versus prophylactic anticoagulation for thromboprophylaxis on the primary outcome of in-hospital mortality and other patient-centered secondary outcomes in COVID-19 patients. Methods MEDLINE, EMBASE, and Cochrane databases were searched from inception to August 10th 2021. Cohort studies and randomized clinical trials that assessed the efficacy and safety of intermediate-to-therapeutic versus prophylactic anticoagulation in hospitalized COVID-19 patients were included. Baseline characteristics and relevant data of each study were extracted in a pre-designed standardized data-collection form. The primary outcome was all-cause in-hospital mortality and the secondary outcomes were incidence of thrombotic events and incidence of any bleeding and major bleeding. Pooled analysis with random effects models yielded relative risk with 95 % CIs. Results This meta-analysis included 42 studies with 28,055 in-hospital COVID-19 patients totally. Our pooled analysis demonstrated that intermediate-to-therapeutic anticoagulation was not associated with lower in-hospital mortality (RR=1.12, 95 %CI 0.99-1.25, p=0.06, I2=77 %) and lower incidence of thrombotic events (RR=1.30, 95 %CI 0.79-2.15, p=0.30, I2=88 %), but increased the risk of any bleeding events (RR=2.16, 95 %CI 1.79-2.60, p<0.01, I2=31 %) and major bleeding events significantly (RR=2.10, 95 %CI 1.77-2.51, p<0.01, I2=11 %) versus prophylactic anticoagulation. Moreover, intermediate-to-therapeutic anticoagulation decreased the incidence of thrombotic events (RR=0.71, 95 %CI 0.56-0.89, p=0.003, I2=0 %) among critically ill COVID-19 patients admitted to intensive care units (ICU), with increased bleeding risk (RR=1.66, 95 %CI 1.37-2.00, p<0.01, I2=0 %) and unchanged in-hospital mortality (RR=0.94, 95 %CI 0.79-1.10, p=0.42, I2=30 %) in such patients. The Grading of Recommendation, Assessment, Development, and Evaluation certainty of evidence ranged from very low to moderate. Conclusions We recommend the use of prophylactic anticoagulation against intermediate-to-therapeutic anticoagulation among unselected hospitalized COVID-19 patients considering insignificant survival benefits but higher risk of bleeding in the escalated thromboprophylaxis strategy. For critically ill COVID-19 patients, the benefits of intermediate-to-therapeutic anticoagulation in reducing thrombotic events should be weighed cautiously because of its association with higher risk of bleeding. Trial registration The protocol was registered at PROSPERO on August 17th 2021 (CRD42021273780). Graphical abstract

Thromboprophylactic low-molecular-weight heparin versus standard of care in unvaccinated, at-risk outpatients with COVID-19 (ETHIC): an open-label, multicentre, randomised, controlled, phase 3b trial

“… 2 A meta-analysis of 42 studies of hospitalised patients with COVID-19 found that higher versus lower doses of anticoagulants did not significantly reduce in-hospital mortality and the incidence of thrombotic events, but significantly increased bleeding events. 19 The optimal dose of heparin for outpatients with COVID-19 remains to be determined, but it seems unlikely that the use of higher doses would have provided better outcomes.…”

Optimal thromboprophylaxis strategies in non-critically ill patients with COVID-19 pneumonia. The PROTHROMCOVID Randomized Controlled Trial

“…A meta-analysis including 49 studies concluded that prophylactic anticoagulation was recommended against intermediate-to-therapeutic anticoagulation, considering insignificant survival benefits but higher risk of bleeding when higher doses were used. (20). The PROTHROMCOVID study confirms the non-superiority of intermediate doses with respect to standard prophylactic LMWH doses; consequently, the accumulated evidence suggests that this strategy should be abandoned.…”

Acute Necrotizing Pancreatitis Complicated by Multiple Splanchnic Venous Thromboses and Bilateral Renal Infarctions in a Patient With Recent COVID-19 Infection: A Case Report

“…Thus, it is recommended that hospitalized COVID-19 patients receive prophylactic anticoagulation to reduce all-cause mortality [17,18]. In critically ill patients, the risk of thrombotic events should be weighed against the risk of haemorrhagic complications before anticoagulation is initiated [17,18]. Unfortunately, there are no similar studies conducted on patients with recent COVID-19 infection who are hospitalized for other reasons, such as our patient.…”

“…In addition, COVID-19 patients who suffer thromboembolic events are at a higher risk of death compared to those without thromboembolic events [14,15]. Thus, it is recommended that hospitalized COVID-19 patients receive prophylactic anticoagulation to reduce all-cause mortality [17,18]. In critically ill patients, the risk of thrombotic events should be weighed against the risk of haemorrhagic complications before anticoagulation is initiated [17,18].…”