TABLE 1.

Published randomized controlled trials evaluating VTE prophylactic strategies in hospitalized patients with COVID‐19

Clinical trial	Patient population	Interventions	Primary efficacy outcome	Total participants	Follow up	Efficacy results	Thrombotic event rate	Safety results
INSPIRATION 48	ICU	Enoxaparin, 1 mg/kg daily vs enoxaparin, 40 mg daily a	Composite of venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days	600	30 days	Primary outcome occurred in 45.7% (n = 126) of patients who received intermediate‐dose anticoagulation and in 44.1% (n = 126) of those who received standard‐dose prophylaxis (odds ratio, 1.06; 95% CI, 0.76‐1.48; P = .70)	VTE occurred in 3.3% (n = 9) in intermediate dose vs 3.5% (n = 10) in standard dose (odds ratio, 0.93; 95% CI, 0.37‐2.32; P = .87)	Major bleed b occurred in 2.5% (n = 7) in the intermediate‐dose group and in 1.4% (n = 4) in those who received standard prophylaxis (odds ratio, 1.83; 1‐sided 97.5% CI, 0.00‐5.93, not meeting the noninferiority criteria; P for noninferiority 0.99)
Zed 49	Hospitalized with severe COVID defined as ICU admission and/or modified ISTH Overt DIC score ≥3	Enoxaparin, 1 mg/kg daily vs enoxaparin, 40 mg daily c	All‐cause mortality	176	30 days	Primary outcome occurred in 21% (n = 18) of those who received standard dose prophylaxis and in 15% (n = 13) of those who received intermediate dose (odds ratio, 0.66; 95% CI, 0.30‐1.45; P = .31	VTE occurred in 7% (n = 6) in standard dose vs. 8% (n = 7) in intermediate dose (odds ratio, 1.79; 95% CI, 0.51‐6.25; P > .95)	Major bleed d 2% (n = 2) in both arms; minor bleed 7% (n = 6) in both arms; P > .99 for both major and minor bleeding
ATTACC, ACTIV‐4a, and REMAP‐CAP e , 50	ICU‐level respiratory or cardiovascular organ support	Therapeutic‐dose anticoagulation with heparin or LMWH vs pharmacologic thromboprophylaxis in accordance with local usual care	Organ support–free days	1207	21 days	Therapeutic‐dose anticoagulation group’s median value for organ support–free days was 1 (interquartile range, −1 to 16). Those assigned to usual care prophylaxis the median value was 4 (interquartile range, −1 to 16)	Arterial or VTE occurred in 7.2% (n = 38) in therapeutic dose vs 11.1% (n = 62) in usual care prophylaxis	Major bleed d occurred in 3.8% (n = 20) in the therapeutic dose anticoagulation arm vs 2.3% (n = 13) in usual care arm (adjusted odds ratio, 1.48; 95% CI, 0.75‐3.04)
ATTACC, ACTIV‐4a, and REMAP‐CAP 52	Non–critically ill at enrollment	Therapeutic‐dose anticoagulation with heparin or LMWH vspharmacologic thromboprophylaxis in accordance with local usual care	Organ support–free days	2219	21 days	Probability that therapeutic‐dose anticoagulation increased organ support–free days as compared with usual care thromboprophylaxis was 98.6% (adjusted odds ratio, 1.27; 95% credible interval, 1.03‐1.58)	Arterial or VTE occurred in 1.1% (n = 13) in therapeutic dose vs 2.1% (n = 22) in usual care prophylaxis	Major bleeding d occurred in 1.9% (n = 22) of the patients receiving therapeutic‐dose anticoagulation and in 0.9% (n = 9) of those receiving thromboprophylaxis
ACTION 53	Hospitalized with elevated D‐dimer	Therapeutic (rivaroxaban if clinically stable or enoxaparin if clinically unstable) vs prophylactic anticoagulation (UFH or LMWH)	Time to death, duration of hospitalization, or duration of supplemental oxygen	615	30 days	Composite thrombotic outcome and all‐cause death occurred in 15% (n = 46) in the therapeutic anticoagulation group and in 14% (n = 44) in the prophylactic anticoagulation group (RR, 1.04; 95% CI, 0.70‐1.50; P = .91)	VTE occurred in 4% (n = 11) in therapeutic anticoagulation group vs. 6% (n = 18) in prophylactic anticoagulation group (RR, 0.60; 95% CI, 0.29‐1.25; P = .19)	Major bleed or CRNMB d occurred in 8% (n = 26) in the therapeutic anticoagulation group and in 2% (n = 7) in the prophylactic anticoagulation group (RR, 3.64; 95% CI, 1.61‐8.27; P = .001)
HEP‐COVID 12	Hospitalized adult patients with COVID‐19 with D‐dimer levels >4 times the upper limit of normal or sepsis‐induced coagulopathy score of ≥4	Standard prophylactic or intermediate‐dose LMWH or unfractionated heparin vs therapeutic‐dose enoxaparin	Venous thromboembolism, arterial thromboembolism, or death from any cause	257	30 ± 2 days	Primary outcome occurred in 41.9% in the standard‐dose group vs 28.7% in the therapeutic‐dose group. RR, 0.68; 95% CI, 0.49‐0.96); P = .03	thromboembolism (29.0% in standard –dose group vs 10.9% in therapeutic dose group. RR, 0.37 95% CI, 0.21–0.66; p < 0.001)	2 major bleeds (1.6%) in the standard‐dose vs 6 major bleeds (4.7%) in the therapeutic‐dose groups (RR, 2.88; 95% CI, 0.59–14.02; p = 0.17)
RAPID 54	Adults admitted to hospital wards with COVID‐19 and increased D‐dimer levels	Therapeutic‐dose or prophylactic‐dose heparin (low‐molecular‐weight or unfractionated heparin)	Composite of death, invasive mechanical ventilation, noninvasive mechanical ventilation, or admission to an ICU	465	28 days	Primary outcome occurred in 16.2% assigned to therapeutic heparin and in 21.9% assigned to prophylactic heparin (odds ratio, 0.69; 95% CI, 0.43‐1.10; P = .12)	Venous thromboembolism occurred in two patients (0.9%) assigned to therapeutic heparin and six (2.5%) assigned to prophylactic heparin (odds ratio, 0.34; 95% CI, 0.07‐1.71; P = .19)	Major bleeding occurred in two patients (0.9%) assigned to therapeutic heparin and four (1.7%) assigned to prophylactic heparin (odds ratio, 0.52; 95% CI, 0.09‐2.85; P = .69)

Abbreviations: CI, confidence interval; CRNBM, clinically relevant nonmajor bleeding; DIC, disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; LMWH, low‐molecular‐weight heparin; RR, relative risk; UFH, unfractionated heparin; VTE, venous thromboembolism.

^a With modification according to body weight and creatinine clearance.

^b According to the Bleeding Academic Research Consortium.

^c Adjusted for obesity.

^d According to ISTH criteria.

^e Trial was stopped when the prespecified criterion for futility was met for therapeutic‐dose anticoagulation.