Randomized trials of therapeutic heparin for COVID-19: A meta-analysis

Abstract

Background: Pulmonary endothelial injury and microcirculatory thromboses likely contribute to hypoxemic respiratory failure, the most common cause of death, in patients with COVID-19. Randomized controlled trials (RCTs) suggest differences in the effect of therapeutic heparin between moderately and severely ill patients with COVID-19. We did a systematic review and meta-analysis of RCTs to determine the effects of therapeutic heparin in hospitalized patients with COVID-19.

Methods: We searched PubMed, Embase, Web of Science, medRxiv, and medical conference proceedings for RCTs comparing therapeutic heparin with usual care, excluding trials that used oral anticoagulation or intermediate doses of heparin in the experimental arm. Mantel-Haenszel fixed-effect meta-analysis was used to combine odds ratios (ORs).

Results and conclusions: There were 3 RCTs that compared therapeutic heparin to lower doses of heparin in 2854 moderately ill ward patients, and 3 RCTs in 1191 severely ill patients receiving critical care. In moderately ill patients, there was a nonsignificant reduction in all-cause death (OR, 0.76; 95% CI, 0.57-1.02), but significant reductions in the composite of death or invasive mechanical ventilation (OR, 0.77; 95% CI, 0.60 0.98), and death or any thrombotic event (OR, 0.58; 95% CI, 0.45-0.77). Organ support-free days alive (OR, 1.29; 95% CI, 1.07-1.57) were significantly increased with therapeutic heparin. There was a nonsignificant increase in major bleeding. In severely ill patients, there was no evidence for benefit of therapeutic heparin, with significant treatment-by-subgroup interactions with illness severity for all-cause death (P = .034). In conclusion, therapeutic heparin is beneficial in moderately ill patients but not in severely ill patients hospitalized with COVID-19.

Keywords: COVID‐19; anticoagulation; clinical trials; heparin; meta‐analysis.

FIGURE 1

Preferred Reporting for Systematic Reviews and Meta‐Analyses diagram

FIGURE 2

Meta‐analyses of effectiveness and safety outcomes in randomised trials comparing therapeutic heparin with usual care in moderately ill ward patients with COVID‐19. Mantel‐Haenszel fixed‐effect meta‐analyses of the RAPID trial, the multiplatform trial and HEP‐COVID trial in moderately ill ward patients., , Squares and horizontal lines show treatment effects and their 95% confidence intervals in each trial. The area of each square is proportional to the weight the trial received in the meta‐analysis. Diamonds show estimated treatment effects and 95% confidence intervals from meta‐analyses. Odds ratios for ventilator‐free and organ support–‐free days alive are from ordinal logistic regression in both trials; death was assigned the worst outcome (a value of −1). Absolute values were not available for all‐cause death from the multiplatform trial. Major thrombotic events were defined as the composite of myocardial infarction, pulmonary embolism, ischemic stroke or systemic arterial embolism; any thrombotic events were defined as a major thrombotic event or deep vein thrombosis; major bleeding defined by the ISTH Scientific and Standardization Committee. The observation time for the outcomes in the trials were 28 days for the multiplatform trial (with the exception of organ support–free days, which was calculated for an observation time of 21 days), 28 days for the RAPID trial, and 30 days for HEP‐COVID trial, ,

FIGURE 3

Meta‐analyses of effectiveness and safety outcomes in randomised trials comparing therapeutic heparin with usual care in severely ill intensive care unit (ICU) patients with COVID‐19. Mantel‐Haenszel fixed‐effect meta‐analyses of the multiplatform trial, HESACOVID and HEP‐COVID in severely ill ICU patients., , Squares and horizontal lines show treatment effects and their 95% confidence intervals in each trial. The area of each square is proportional to the weight the trial received in the meta‐analysis. Diamonds show estimated treatment effects and 95% confidence intervals from meta‐analyses. Odds ratios for organ support–free days alive are from ordinal logistic regression; death was assigned the worst outcome (a value of −1). Major thrombotic events were defined as the composite of myocardial infarction, pulmonary embolism, ischemic stroke, or systemic arterial embolism; any thrombotic events were defined as a major thrombotic event or deep vein thrombosis; major bleeding defined by the ISTH Scientific and Standardization Committee. The observation time for the outcomes in the trials were 28 days for the multiplatform trial (with the exception of organ support–free days, which was calculated for an observation time of 21 days), and 30 days for HEP‐COVID trial,

FIGURE 4

Analyses of the interaction between treatment effect and severity of illness of therapeutic heparin versus usual care in patients with COVID‐19. The analysis is based on Mantel‐Haenszel fixed‐effect meta‐analyses of the RAPID trial, HEP‐COVID trial, and the multiplatform trial in moderately ill ward patients,, , and results of the multiplatform trial, HESACOVID, and HEP‐COVID trial in severely ill ICU patients., , Squares and horizontal lines show treatment effects and their 95% confidence intervals in each subgroup. The area of each square is proportional to the inverse of the variance in the subgroup. Odds ratios for organ support‐free days alive are from ordinal logistic regression in all trials; death up to 28 days was assigned the worst outcome (a value of −1) in all trials. The P values for interaction are for the comparison of treatment effects between moderately and severely ill patients and were derived from a chi‐squared test. Major thrombotic events were defined as the composite of myocardial infarction, pulmonary embolism, ischemic stroke, or systemic arterial embolism; any thrombotic events were defined as a major thrombotic event or deep vein thrombosis; major bleeding defined by the ISTH Scientific and Standardization Committee. The observation time for the outcomes in the trials were 28 days for the multiplatform trials (with the exception of organ support free days which was calculated for an observation time of 21 days), 28 days for the RAPID trial and 30 days for the HEP‐COVID trial, ,