Design and outcomes of the major RCTs and international multiplatform studies of thromboprophylaxis in COVID-19 disease
| Study . | Study type . | Comparator . | Population . | Sample size, N . | Primary outcome . | Bleeding . | Comment . |
|---|---|---|---|---|---|---|---|
| Sadeghipour et al (INSPIRATION)87 | RCT | Prophylactic vs intermediate intensity enoxaparin (1 mg/kg daily) | ICU | 562 Iran | No significant difference in primary composite outcome (venous or arterial thrombosis, ECMO, or 30-d mortality) | Bleeding events rare. Major bleeding and CRNMB, 6.2% intermediate-dose vs 3.1% prophylactic; P = NS. | Not critically ill ICU population; only 50% of each cohort had invasive or NIV. Median number of days was 7 in both groups |
| Perpepu et al113 | RCT | Prophylactic vs intermediate intensity enoxaparin | ICU or coagulopathy D-dimer ≥1.00 ug/mL | 156 United States | No significant difference in preventing death or thrombosis at 30 d. | Major bleeding occurred in 2% of patients in each arm | ICU and non-ICU patients included |
| Goliger et al (International multiplatform trial)88 | Combined 1 RCT (ACTIV-4a) + 2 studies with response-adaptive randomization (ATTACC and REMAP-CAP) | Prophylactic heparin vs therapeutic dose UFH or LMWH | Critically ill | 1098 | No difference in primary outcome of days free from organ support or survival until hospital discharge, despite decreasing major thrombotic events | Major bleeding, 3.8% therapeutic, 2.3% thromboprophylaxis; not significantly different | Seemingly contradictory outcomes in a non–critically ill population (see text). |
| Lawler et al (International multiplatform trial)92 | Combined 1 RCT (ACTIV-4a) + 2 studies with response-adaptive randomization (ATTACC and REMAP-CAP) | Prophylactic heparin vs therapeutic dose UFH or LMWH | Non–critically ill | 2219 | Reduced organ support–free days to day 21 (primary outcome) | Major bleeding, 1.9% therapeutic, 0.9% thromboprophylaxis | Treatment benefit independent of D-dimer level, although treatment effect greater in patients with higher D-dimer |
| Lopes et al (ACTION)90 | Open-label RCT | Therapeutic Anticoagulation: rivaroxaban 20 mg or enoxaparin 1 mg/kg twice daily for clinically unstable patients (defined similarly to critically unwell/ICU patients in heparin studies) vs SOC enoxaparin or UFH prophylaxis | COVID-19 inpatients D-dimer >ULN 90% non–critically ill | 615 Brazil | No difference in primary outcome of time to death, duration of hospitalization and supplemental oxygen to day 30. No difference in thrombotic outcomes. | Increased major bleeding/CRNMB in 8% vs 2% (RR, 3.43; 95% CI, 1.61-8.27; P = 0.001) with 1 fatal ICH in a clinically unstable patient on therapeutic enoxaparin. | — |
| Sholzberg et al (RAPID)91 | RCT | Prophylactic heparin vs therapeutic dose UFH or LMWH | Non–critically ill D-dimer >ULN | 465 Brazil, Canada, Ireland, Saudi Arabia, UAE and United States | No difference in primary composite outcome (invasive ventilation, ICU, or death). Therapeutic heparin decreased odds of death at 28 d (odds ratio, 0.22; 95% CI, 0.07-0.65) | Major bleeding, 0.9%, therapeutic heparin and 1.7%, prophylactic heparin; P = NS | Underpowered for the analysis of the primary outcome. |
| Spyropoulos AC et al (HEP-COVID)89 | RCT | Prophylactic or intermediate dose UFH or LMWH vs therapeutic dose enoxaparin | COVID-19 inpatients D-dimer >4 × ULN or sepsis induced coagulopathy score ≥4; 67.2% noncritically ill | 253 United States | Reduction in primary composite outcome (VTE, ATE, death) 41.9% “standard-dose” heparins vs 28.7% therapeutic LMWH (RR, 0.68; 95% CI, 0.49-0.96; P = .03). Reduction in thromboembolism 29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P <.001. | Major bleeding 1.6% with standard-dose vs 4.7% therapeutic-dose heparins; P = NS | Treatment effect was not seen in patients in ICU. |
| Marcos-Jubilar et al (BEMICOP)96 | RCT | Prophylactic vs therapeutic dose bemiparin for 10 d | Non–critically ill D-dimer >ULN | 65 Spain | No difference in primary composite outcome (death, ICU, invasive ventilation mod/severe ARDS, VTE or ATE within 10 d). | No major bleeding event, but short duration of study treatment period. | Prespecified interim analysis performed at 40% recruitment; trial halted due to slow recruitment/futility. |
| X-COVID-19114 | RCT | Prophylactic vs intermediate intensity enoxaparin (40 mg twice daily) | Noncritically ill | 189 Italy | Primary efficacy outcome (VTE) occurred in 6 of 92 (6.5%, 0 DVT, 6 PE) once daily dose group and 0 in twice daily. Group. | Two major bleeding events in each arm (1.1%). | Trial halted due to slow recruitment. 189 of 2712 recruited; underpowered and few events. |
| Study . | Study type . | Comparator . | Population . | Sample size, N . | Primary outcome . | Bleeding . | Comment . |
|---|---|---|---|---|---|---|---|
| Sadeghipour et al (INSPIRATION)87 | RCT | Prophylactic vs intermediate intensity enoxaparin (1 mg/kg daily) | ICU | 562 Iran | No significant difference in primary composite outcome (venous or arterial thrombosis, ECMO, or 30-d mortality) | Bleeding events rare. Major bleeding and CRNMB, 6.2% intermediate-dose vs 3.1% prophylactic; P = NS. | Not critically ill ICU population; only 50% of each cohort had invasive or NIV. Median number of days was 7 in both groups |
| Perpepu et al113 | RCT | Prophylactic vs intermediate intensity enoxaparin | ICU or coagulopathy D-dimer ≥1.00 ug/mL | 156 United States | No significant difference in preventing death or thrombosis at 30 d. | Major bleeding occurred in 2% of patients in each arm | ICU and non-ICU patients included |
| Goliger et al (International multiplatform trial)88 | Combined 1 RCT (ACTIV-4a) + 2 studies with response-adaptive randomization (ATTACC and REMAP-CAP) | Prophylactic heparin vs therapeutic dose UFH or LMWH | Critically ill | 1098 | No difference in primary outcome of days free from organ support or survival until hospital discharge, despite decreasing major thrombotic events | Major bleeding, 3.8% therapeutic, 2.3% thromboprophylaxis; not significantly different | Seemingly contradictory outcomes in a non–critically ill population (see text). |
| Lawler et al (International multiplatform trial)92 | Combined 1 RCT (ACTIV-4a) + 2 studies with response-adaptive randomization (ATTACC and REMAP-CAP) | Prophylactic heparin vs therapeutic dose UFH or LMWH | Non–critically ill | 2219 | Reduced organ support–free days to day 21 (primary outcome) | Major bleeding, 1.9% therapeutic, 0.9% thromboprophylaxis | Treatment benefit independent of D-dimer level, although treatment effect greater in patients with higher D-dimer |
| Lopes et al (ACTION)90 | Open-label RCT | Therapeutic Anticoagulation: rivaroxaban 20 mg or enoxaparin 1 mg/kg twice daily for clinically unstable patients (defined similarly to critically unwell/ICU patients in heparin studies) vs SOC enoxaparin or UFH prophylaxis | COVID-19 inpatients D-dimer >ULN 90% non–critically ill | 615 Brazil | No difference in primary outcome of time to death, duration of hospitalization and supplemental oxygen to day 30. No difference in thrombotic outcomes. | Increased major bleeding/CRNMB in 8% vs 2% (RR, 3.43; 95% CI, 1.61-8.27; P = 0.001) with 1 fatal ICH in a clinically unstable patient on therapeutic enoxaparin. | — |
| Sholzberg et al (RAPID)91 | RCT | Prophylactic heparin vs therapeutic dose UFH or LMWH | Non–critically ill D-dimer >ULN | 465 Brazil, Canada, Ireland, Saudi Arabia, UAE and United States | No difference in primary composite outcome (invasive ventilation, ICU, or death). Therapeutic heparin decreased odds of death at 28 d (odds ratio, 0.22; 95% CI, 0.07-0.65) | Major bleeding, 0.9%, therapeutic heparin and 1.7%, prophylactic heparin; P = NS | Underpowered for the analysis of the primary outcome. |
| Spyropoulos AC et al (HEP-COVID)89 | RCT | Prophylactic or intermediate dose UFH or LMWH vs therapeutic dose enoxaparin | COVID-19 inpatients D-dimer >4 × ULN or sepsis induced coagulopathy score ≥4; 67.2% noncritically ill | 253 United States | Reduction in primary composite outcome (VTE, ATE, death) 41.9% “standard-dose” heparins vs 28.7% therapeutic LMWH (RR, 0.68; 95% CI, 0.49-0.96; P = .03). Reduction in thromboembolism 29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P <.001. | Major bleeding 1.6% with standard-dose vs 4.7% therapeutic-dose heparins; P = NS | Treatment effect was not seen in patients in ICU. |
| Marcos-Jubilar et al (BEMICOP)96 | RCT | Prophylactic vs therapeutic dose bemiparin for 10 d | Non–critically ill D-dimer >ULN | 65 Spain | No difference in primary composite outcome (death, ICU, invasive ventilation mod/severe ARDS, VTE or ATE within 10 d). | No major bleeding event, but short duration of study treatment period. | Prespecified interim analysis performed at 40% recruitment; trial halted due to slow recruitment/futility. |
| X-COVID-19114 | RCT | Prophylactic vs intermediate intensity enoxaparin (40 mg twice daily) | Noncritically ill | 189 Italy | Primary efficacy outcome (VTE) occurred in 6 of 92 (6.5%, 0 DVT, 6 PE) once daily dose group and 0 in twice daily. Group. | Two major bleeding events in each arm (1.1%). | Trial halted due to slow recruitment. 189 of 2712 recruited; underpowered and few events. |
ARDS, acute respiratory distress syndrome; CRNMB, clinically relevant non–major bleeding; ECMO, extracorporeal membrane oxygenation; ICH, intracranial hemorrhage; RR, relative risk; SOC, standard of care; ULN upper limit of normal.