Summary of randomized controlled trial of intermediate- and therapeutic-dose anticoagulation or antiplatelet therapy in hospitalized patients with COVID-19
| Trial . | Number of patients analyzed . | Antithrombotic therapies . | Thrombosis . | Bleeding . | Mortality . | Primary outcome . |
|---|---|---|---|---|---|---|
| (A) Inpatient therapeutic- vs prophylactic- or intermediate-dose anticoagulation | ||||||
| Critically ill patients | ||||||
| Multiplatform: REMAP-CAP, ACTIV-4a, and ATTAC30 Trial included only critically ill patients | 1098 | Therapeutic- vs prophylactic- or intermediate-dose enoxaparin (48.9%) or dalteparin (32.3%) | ⇓ Any thrombotic events: 7.2% vs 11.1% Major thrombotic events: 6.4% vs 10.4% | ⇑ Major bleeding: 3.8% vs 2.3%, OR 1.48 (0.75-3.04) | ⇔ Death in-hospital: 37.3% vs 35.5% | ⇔ Organ support-free days: OR 0.83 (0.67-1.03) |
| HEP-COVID33 Trial included patients with D-dimer >4 times ULN (98.4% adherence) with both ICU (32.8%) and non-ICU (67.2%) patients | 83 Overall study included 83 ICU and 170 non-ICU patients | Therapeutic- enoxaparin vs prophylactic- or intermediate-dose enoxaparin | ⇔ Venous and arterial thrombosis: 51.1% vs 55.3%, RR 0.92 (0.62-1.39) | ⇔ Major bleeding: 8.9% vs 0%, RR 7.62 (0.42-137.03) | ⇔ Death, overall study (both ICU and non-ICU patients): 19.4% vs 25.0%, RR 0.78 (0.49-1.23) | ⇔ Thrombosis (see other column) |
| Non–critically ill patients | ||||||
| Multiplatform: REMAP-CAP, ACTIV-4a, and ATTAC29 Trial included only non– critically ill patients | 2219 | Therapeutic- vs prophylactic- or intermediate-dose enoxaparin (69.5%) or dalteparin (7.4%) | ⇓ Major thrombotic events: 1.1% vs 2.1% | ⇑ Major bleeding:1.9% vs 0.9%, OR 1.8 (0.9-3.74) | ⇔ Death in-hospital 7.3% vs 8.2% | ⇔ Organ support-free days: OR 1.27 (1.03-1.58) High D-dimer (≥2 times ULN): OR 1.31 (1.00-1.76) Low D-dimer: OR 1.22 (0.93-1.57) Unknown D-dimer: 1.32 (1.00-1.86) |
| ACTION31 Trial included 93.7% clinically stable and 6.3% clinically unstable (ie, critically ill) patients | 614, including 576 clinically stable and 39 clinically unstable | Therapeutic-dose rivaroxaban vs prophylactic-dose enoxaparin or UFH | ⇔ Venous and arterial thrombosis: 7% vs 10%, RR 0.75 (0.45-1.26) | ⇑ Major and clinically relevant nonmajor bleeding: 8% vs 2%, RR 3.64 (1.61-8.27) | ⇔ Death: 11% vs 8%, RR 1.49 (0.90-2.46) | ⇔ Composite of time to death, duration of hospitalization, and duration of supplemental oxygen use: 34.8% vs 41.3% (win ratio 0.86, 0.59-1.22) |
| RAPID32 Trial included patients with D-dimer >ULN (97.7% adherence) | 443 | Therapeutic- vs prophylactic-dose enoxaparin (79.8%), dalteparin (10.8%), or UFH (3.7%) | ⇔ Venous thrombosis: 0.9% vs 2.5%, OR 0.34 (0.07-1.71) | ⇔ Major bleeding: 0.9% vs 1.7%, OR 0.52 (0.09-2.85) | ⇓ Death from any cause: 1.8% vs 7.6%, OR 0.22 (0.07-0.65) | ⇔ Composite of ICU admission, noninvasive or invasive mechanical ventilation, or death: 16.2% vs 21.9%, OR 0.69 (0.43-1.10) |
⇑ Mean ventilator-free days: 26.5 vs 24.7, OR 1.77 (1.02-3.08) | ||||||
| HEP-COVID33 Trial included patients with D-dimer >4 times ULN (98.4% adherence) with both ICU (32.8%) and non-ICU (67.2%) patients | 170 Overall study included 83 ICU and 170 non-ICU patients | Therapeutic- enoxaparin vs prophylactic- or intermediate-dose enoxaparin | ⇓ Venous and arterial thrombosis: 16.7% vs 36.1%, RR 0.46 (0.27-0.81) | ⇔ Major bleeding: 2.4% vs 2.3%, RR 1.02 (0.15-7.10) | ⇔ Death, overall study (both ICU and non-ICU patients): 19.4% vs 25.0%, RR 0.78 (0.49-1.23) | Thrombosis (see other column) |
| (B) Inpatient intermediate- vs prophylactic-dose anticoagulation | ||||||
| INSPIRATION34 Trial included only critically ill patients | 562 | Intermediate- vs prophylactic-dose enoxaparin | ⇔ Venous thrombosis: 3.3% vs 3.5%, OR 0.93 (0.37-2.32) | ⇔ Major and clinically relevant nonmajor bleeding: 6.2% vs 3.1%, OR 2.02 (0.89-4.61) | ⇔ All-cause mortality: 43.1% vs 40.9%, OR 1.09 (0.78-1.53) | ⇔ Composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality: 45.7% vs 44.1%, OR 1.06 (0.76-1.48) |
| Perepu et al35 Trial included ICU (62.2%) and non-ICU (37.8%) patients | 169 | Intermediate- vs prophylactic-dose enoxaparin | ⇔ Venous thrombosis: 7% vs 8%, OR 1.79 (0.51-6.25) Arterial thrombosis: 3% vs 6%, OR 1.69 (0.39-7.29) | ⇔ Major bleeding: 2% vs 2%, OR 0.99 (0.14-7.14) Minor bleeding: 7% vs 7%, OR 0.99 (0.31-3.23) | ⇔ All-cause mortality: 21% vs 15%, OR 0.66 (0.30-1.45) All-cause mortality adjusted for age, sex, body mass index, and ICU admission: OR 0.53 (0.25-1.13) | ⇔ All-cause mortality (see other column) |
| (C) Postdischarge thromboprophylaxis | ||||||
| MICHELLE36 Trial included ICU (52%) and non-ICU (48%) patients | 318 | Rivaroxaban 10 mg for 35 days initiated at hospital discharge vs no postdischarge thromboprophylaxis | ⇓ Symptomatic or fatal venous thrombosis: 0.63% vs 5.03%, RR 0.13 (0.02-0.99) | ⇔ Major, clinically relevant nonmajor, and other bleeding: 2.51% vs 1.89% | ⇔ 28-day mortality: 17% vs 17%, RR 0.96 (0.89-1.04) | ⇔ Composite outcome of venous or arterial thrombosis or cardiovascular death at day 35 after hospital discharge: 3.14% vs 9.43%, RR 0.33 (0.13-0.90) |
| (D) Inpatient antiplatelet vs no antiplatelet therapy | ||||||
| RECOVERY38 Trial included patients who required no ventilation or simple oxygen (67%), noninvasive ventilation (28.1%), or invasive mechanical ventilation (4.9%) | 14747 | Aspirin 150 mg vs no antiplatelet therapy | ⇓ Venous or arterial thrombotic event: 4.6% vs 5.3%, RR 0.88 (0.76-1.01) | ⇑ Major bleeding: 1.6% vs 1.0%, OR 1.55 (1.16-2.07) | ⇔ 28-day mortality: 17% vs 17%, RR 0.96 (0.89-1.04) | ⇔ 28-day mortality (see other column) |
⇑ Discharge from hospital within 28 days: 75% vs 74%, RR 1.06 (1.02-1.10) | ||||||
| ACTIV-4a39 Trial included patients with D-dimer ≥2 times ULN or age 60-80 years | 562 | Therapeutic-dose UFH + P2Y12 inhibitor (ticagrelor, 63.2%; or clopidogrel, 36.8%) vs therapeutic-dose UFH | ⇓ Any thrombotic event: 3.1% vs 1.9% | ⇔ Major bleeding: 2.0% vs 0.7%, OR 3.31 (0.64-17.2) | ⇔ In-hospital death: 4.4% vs 3.0% | ⇔ Organ support-free days: 21 vs 21, OR 0.83 (0.55-1.25) |
| REMAP-CAP40 Trial enrolled only critically ill patients | 1532 | Aspirin vs P2Y12 inhibitor (clopidogrel, 88.5%; ticagrelor, 1.3%; or prasugrel, 1.3%) vs no antiplatelet therapy | ⇔/⇓ Any thrombotic event: 12.4% vs 9.8% vs 12.7% | ⇑ Major bleeding: 2.0% vs 2.3% vs 0.4% | ⇓ In-hospital death: 28.6% vs 28.4% vs 32.1% | ⇔ Organ support-free days: 563 vs 448 vs 521 |
⇑ Hospital survival: all antiplatelet therapy, OR 1.27 (0.99-1.62) Hospital survival: all antiplatelet therapy with less than therapeutic-dose anticoagulation, OR 1.33 (0.99-1.79) Survival over 90 days: all antiplatelet therapy, HR 1.22 (1.06-1.40) | ||||||
| Trial . | Number of patients analyzed . | Antithrombotic therapies . | Thrombosis . | Bleeding . | Mortality . | Primary outcome . |
|---|---|---|---|---|---|---|
| (A) Inpatient therapeutic- vs prophylactic- or intermediate-dose anticoagulation | ||||||
| Critically ill patients | ||||||
| Multiplatform: REMAP-CAP, ACTIV-4a, and ATTAC30 Trial included only critically ill patients | 1098 | Therapeutic- vs prophylactic- or intermediate-dose enoxaparin (48.9%) or dalteparin (32.3%) | ⇓ Any thrombotic events: 7.2% vs 11.1% Major thrombotic events: 6.4% vs 10.4% | ⇑ Major bleeding: 3.8% vs 2.3%, OR 1.48 (0.75-3.04) | ⇔ Death in-hospital: 37.3% vs 35.5% | ⇔ Organ support-free days: OR 0.83 (0.67-1.03) |
| HEP-COVID33 Trial included patients with D-dimer >4 times ULN (98.4% adherence) with both ICU (32.8%) and non-ICU (67.2%) patients | 83 Overall study included 83 ICU and 170 non-ICU patients | Therapeutic- enoxaparin vs prophylactic- or intermediate-dose enoxaparin | ⇔ Venous and arterial thrombosis: 51.1% vs 55.3%, RR 0.92 (0.62-1.39) | ⇔ Major bleeding: 8.9% vs 0%, RR 7.62 (0.42-137.03) | ⇔ Death, overall study (both ICU and non-ICU patients): 19.4% vs 25.0%, RR 0.78 (0.49-1.23) | ⇔ Thrombosis (see other column) |
| Non–critically ill patients | ||||||
| Multiplatform: REMAP-CAP, ACTIV-4a, and ATTAC29 Trial included only non– critically ill patients | 2219 | Therapeutic- vs prophylactic- or intermediate-dose enoxaparin (69.5%) or dalteparin (7.4%) | ⇓ Major thrombotic events: 1.1% vs 2.1% | ⇑ Major bleeding:1.9% vs 0.9%, OR 1.8 (0.9-3.74) | ⇔ Death in-hospital 7.3% vs 8.2% | ⇔ Organ support-free days: OR 1.27 (1.03-1.58) High D-dimer (≥2 times ULN): OR 1.31 (1.00-1.76) Low D-dimer: OR 1.22 (0.93-1.57) Unknown D-dimer: 1.32 (1.00-1.86) |
| ACTION31 Trial included 93.7% clinically stable and 6.3% clinically unstable (ie, critically ill) patients | 614, including 576 clinically stable and 39 clinically unstable | Therapeutic-dose rivaroxaban vs prophylactic-dose enoxaparin or UFH | ⇔ Venous and arterial thrombosis: 7% vs 10%, RR 0.75 (0.45-1.26) | ⇑ Major and clinically relevant nonmajor bleeding: 8% vs 2%, RR 3.64 (1.61-8.27) | ⇔ Death: 11% vs 8%, RR 1.49 (0.90-2.46) | ⇔ Composite of time to death, duration of hospitalization, and duration of supplemental oxygen use: 34.8% vs 41.3% (win ratio 0.86, 0.59-1.22) |
| RAPID32 Trial included patients with D-dimer >ULN (97.7% adherence) | 443 | Therapeutic- vs prophylactic-dose enoxaparin (79.8%), dalteparin (10.8%), or UFH (3.7%) | ⇔ Venous thrombosis: 0.9% vs 2.5%, OR 0.34 (0.07-1.71) | ⇔ Major bleeding: 0.9% vs 1.7%, OR 0.52 (0.09-2.85) | ⇓ Death from any cause: 1.8% vs 7.6%, OR 0.22 (0.07-0.65) | ⇔ Composite of ICU admission, noninvasive or invasive mechanical ventilation, or death: 16.2% vs 21.9%, OR 0.69 (0.43-1.10) |
⇑ Mean ventilator-free days: 26.5 vs 24.7, OR 1.77 (1.02-3.08) | ||||||
| HEP-COVID33 Trial included patients with D-dimer >4 times ULN (98.4% adherence) with both ICU (32.8%) and non-ICU (67.2%) patients | 170 Overall study included 83 ICU and 170 non-ICU patients | Therapeutic- enoxaparin vs prophylactic- or intermediate-dose enoxaparin | ⇓ Venous and arterial thrombosis: 16.7% vs 36.1%, RR 0.46 (0.27-0.81) | ⇔ Major bleeding: 2.4% vs 2.3%, RR 1.02 (0.15-7.10) | ⇔ Death, overall study (both ICU and non-ICU patients): 19.4% vs 25.0%, RR 0.78 (0.49-1.23) | Thrombosis (see other column) |
| (B) Inpatient intermediate- vs prophylactic-dose anticoagulation | ||||||
| INSPIRATION34 Trial included only critically ill patients | 562 | Intermediate- vs prophylactic-dose enoxaparin | ⇔ Venous thrombosis: 3.3% vs 3.5%, OR 0.93 (0.37-2.32) | ⇔ Major and clinically relevant nonmajor bleeding: 6.2% vs 3.1%, OR 2.02 (0.89-4.61) | ⇔ All-cause mortality: 43.1% vs 40.9%, OR 1.09 (0.78-1.53) | ⇔ Composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or all-cause mortality: 45.7% vs 44.1%, OR 1.06 (0.76-1.48) |
| Perepu et al35 Trial included ICU (62.2%) and non-ICU (37.8%) patients | 169 | Intermediate- vs prophylactic-dose enoxaparin | ⇔ Venous thrombosis: 7% vs 8%, OR 1.79 (0.51-6.25) Arterial thrombosis: 3% vs 6%, OR 1.69 (0.39-7.29) | ⇔ Major bleeding: 2% vs 2%, OR 0.99 (0.14-7.14) Minor bleeding: 7% vs 7%, OR 0.99 (0.31-3.23) | ⇔ All-cause mortality: 21% vs 15%, OR 0.66 (0.30-1.45) All-cause mortality adjusted for age, sex, body mass index, and ICU admission: OR 0.53 (0.25-1.13) | ⇔ All-cause mortality (see other column) |
| (C) Postdischarge thromboprophylaxis | ||||||
| MICHELLE36 Trial included ICU (52%) and non-ICU (48%) patients | 318 | Rivaroxaban 10 mg for 35 days initiated at hospital discharge vs no postdischarge thromboprophylaxis | ⇓ Symptomatic or fatal venous thrombosis: 0.63% vs 5.03%, RR 0.13 (0.02-0.99) | ⇔ Major, clinically relevant nonmajor, and other bleeding: 2.51% vs 1.89% | ⇔ 28-day mortality: 17% vs 17%, RR 0.96 (0.89-1.04) | ⇔ Composite outcome of venous or arterial thrombosis or cardiovascular death at day 35 after hospital discharge: 3.14% vs 9.43%, RR 0.33 (0.13-0.90) |
| (D) Inpatient antiplatelet vs no antiplatelet therapy | ||||||
| RECOVERY38 Trial included patients who required no ventilation or simple oxygen (67%), noninvasive ventilation (28.1%), or invasive mechanical ventilation (4.9%) | 14747 | Aspirin 150 mg vs no antiplatelet therapy | ⇓ Venous or arterial thrombotic event: 4.6% vs 5.3%, RR 0.88 (0.76-1.01) | ⇑ Major bleeding: 1.6% vs 1.0%, OR 1.55 (1.16-2.07) | ⇔ 28-day mortality: 17% vs 17%, RR 0.96 (0.89-1.04) | ⇔ 28-day mortality (see other column) |
⇑ Discharge from hospital within 28 days: 75% vs 74%, RR 1.06 (1.02-1.10) | ||||||
| ACTIV-4a39 Trial included patients with D-dimer ≥2 times ULN or age 60-80 years | 562 | Therapeutic-dose UFH + P2Y12 inhibitor (ticagrelor, 63.2%; or clopidogrel, 36.8%) vs therapeutic-dose UFH | ⇓ Any thrombotic event: 3.1% vs 1.9% | ⇔ Major bleeding: 2.0% vs 0.7%, OR 3.31 (0.64-17.2) | ⇔ In-hospital death: 4.4% vs 3.0% | ⇔ Organ support-free days: 21 vs 21, OR 0.83 (0.55-1.25) |
| REMAP-CAP40 Trial enrolled only critically ill patients | 1532 | Aspirin vs P2Y12 inhibitor (clopidogrel, 88.5%; ticagrelor, 1.3%; or prasugrel, 1.3%) vs no antiplatelet therapy | ⇔/⇓ Any thrombotic event: 12.4% vs 9.8% vs 12.7% | ⇑ Major bleeding: 2.0% vs 2.3% vs 0.4% | ⇓ In-hospital death: 28.6% vs 28.4% vs 32.1% | ⇔ Organ support-free days: 563 vs 448 vs 521 |
⇑ Hospital survival: all antiplatelet therapy, OR 1.27 (0.99-1.62) Hospital survival: all antiplatelet therapy with less than therapeutic-dose anticoagulation, OR 1.33 (0.99-1.79) Survival over 90 days: all antiplatelet therapy, HR 1.22 (1.06-1.40) | ||||||
HR, hazard ratio; ICU, intensive care unit; OR, odds ratio; RR, relative risk; UFH, unfractionated heparin; ULN, upper limit of normal range.