Table 2.
Included Studies
| Study Characteristics | mpRCT (critically ill)13 | mpRCT (noncritically ill)12 | ACTION16 | RAPID19 | INSPIRATION18 | HEP-COVID20 | HESACOVID15 | Perepu et al17 |
|---|---|---|---|---|---|---|---|---|
| Design | Adaptive, multinational, open-label RCT | Adaptive, multinational, open-label RCT | Multicenter (Brazil), open-label RCT | Multinational, open-label RCT | Multicenter (Iran), open-label RCT with 2 × 2 factorial designa | Multicenter (US), open-label RCT | Single-center (Brazil), open-label RCT | Multicenter (US), open-label RCT |
| Intervention | Therapeutic dose heparin until discharge or day 14 | Therapeutic dose heparin until discharge or day 14 | Rivaroxaban 20 mg daily for 30 db | Therapeutic dose heparin until discharge or day 28 | Intermediate dose heparin for 30 d | Therapeutic dose heparin until discharge | Therapeutic dose heparin for ≥ 4 to 14 d | Intermediate dose enoxaparin until discharge |
| Comparator | Usual care pharmacologic thromboprophylaxis (up to intermediate dose heparin) until discharge | Usual care pharmacologic thromboprophylaxis (up to intermediate dose heparin) until discharge | BMI-adjusted prophylactic dose heparin until dischargec | BMI-adjusted prophylactic dose heparin until discharge or day 28 | Weight- and BMI-adjusted prophylactic dose heparin for 30 d | Usual care pharmacologic thromboprophylaxis (up to intermediate dose heparin) until discharge | Weight- adjusted prophylactic dose heparin | BMI-adjusted prophylactic dose enoxaparin until discharge |
| Primary outcome | Organ support-free days up to day 21 | Organ support-free days up to day 21 | Hierarchical composite of time to death, duration of hospitalization, or duration of supplemental oxygen use through 30 d | Composite of ICU admission, noninvasive or invasive mechanical ventilation, or death up to 28 d | Composite of acute VTE, arterial thrombosis, treatment with ECMO, or mortality within 30 d | Composite of VTE, ATE, or death from any cause within 30 ± 2 d | Change in Pao2/ Fio2 ratio from baseline to day 14 | Mortality at 30 d |
| Major bleeding criteria | ISTH | ISTH | ISTH | ISTH | BARC (type 3 or 5) | ISTH | TIMI | ISTH |
| Screening ultrasound for DVT | No | No | No | No | No | 10 +4 d or at discharge | No | No |
| Eligibility based on D-dimer | No | No | >ULN | ≥ 2× ULN or > ULN and oxygen saturation ≤ 93% | No | > 4× ULN | > 1,000 μg/L | No |
| No. of randomized participants | 1,207d | 2,244e | 615 | 465 | 598 | 257 | 20 | 176 |
| No. of participants included in primary analysis | 1,103 | 2,219 | 614 | 465 | 562 | 253 | 20 | 173 |
| Age (y) | 61 (mean) | 59 (mean) | 57 (mean) | 60 (mean) | 62 (median) | 67 (mean) | 57 (mean) | 64 (median) |
| Women, No./total No. (%) | 331/1,103 (30) | 921/2,231 (41) | 247/615 (40) | 201/465 (43) | 237/562 (42) | 117/253 (46) | 4/20 (20) | 76/173 (44) |
| BMI ≥ 30 kg/m2, No./total No. (%) | Median 30 kg/m2 | Median 30 kg/m2 | 264/615 (43) | 191/455 (42) | 123/535 (23) | Mean 31 kg/m2 | Mean 34 kg/m2 | 106/173 (61) |
| D-dimer ≥ 2× ULN, No./total No. (%) | 207/433 (48) | 630/1705 (37) | ≥ 3 ULN: 167/615 (27) | 227/465 (49) | 94/188 (50) | 253/253 (100) | NR | NR |
| Oxygen support at baseline | ||||||||
| None | 0 | 279/2,231 (13)f | 155/615 (25) | g | 0 | 9/253 (3.6) | 0 | NRh |
| Low-flow nasal cannula or mask, No./total No. (%) | 15/1,103 (1.4) | 1485/2,231 (67)f | 369/615 (60) | g | 256/562 (46) | 192/253 (76) | 0 | NRh |
| High-flow nasal cannula, No./total No. (%) | 358/1,103 (32) | 53/2231 (2.4) | 48/615 (7.8) | 27/465 (5.8) | 15/562 (2.7) | i | 0 | NRh |
| Noninvasive positive pressure ventilation, No./total No. (%) | 415/1,103 (38) | 45/2,231 (2.0) | 5/615 (0.1) | 0 | 178/562 (32) | i | 0 | NRh |
| Invasive ventilation, No./total No. (%) | 315/1,103 (29) | 0 | 38/615 (6.2) | 0 | 113/562 (20) | 13/253 (5.1) | 20/20 (100) | 40/173 (23) |
| Cotreatment at baseline | ||||||||
| Antiplatelet agent, No./total No. (%) | 75/979 (7.7)j | 259/2153 (12)k | 48/615 (7.8) | 53/465 (11) | 172/562 (31) | 64/253 (25) | 0 | NR |
| Glucocorticoids, No./total No. (%) | 884/1,077 (82) | 894/1,447 (62) | 510/615 (83) | 323/465(69) | 524/562 (93) | 204/250 (82) | 14/20 (70) | 130/173 (75)l |
| Remdesivir, No./total No. (%) | 346/1,096 (32) | 811/2226 (36) | NR | 0 | 338/562 (60) | 178/253 (70) | 0 | 105/173 (61)l |
| Tocilizumab, No./total No. (%) | 20/1,096 (32) | 13/2,148 (0.6) | NR | 0 | 74/562 (13) | NR | 0 | NR |
ATE = arterial thromboembolism; BARC = Bleeding Academic Research Consortium; ECMO = extracorporeal membrane oxygenation; ISTH = International Society on Thrombosis and Haemostasis; mpRCT = multiplatform randomized controlled trial; NR = not reported; RCT = randomized controlled trial; TIMI = Thrombolysis In Myocardial Infarction; ULN = upper limit of normal.
INSPIRATION was an RCT with a 2 × 2 factorial design comparing intermediate dose vs prophylactic dose anticoagulation and statin therapy vs matching placebo.
In patients with a creatinine clearance of 30 to 49 mL/min or those taking azithromycin, rivaroxaban 15 mg daily was used (66 of 280 patients taking rivaroxaban, 24%). Unstable patients received enoxaparin 1 mg/kg subcutaneous bid or therapeutic dose IV unfractionated heparin (30 of 311 patients, 9.6%).
Extended prophylaxis beyond hospital discharge was prescribed in 38 of 304 (13%) patients allocated to the comparator group.
A total of 81 patients were excluded, because they did not have confirmed COVID-19.
A total of 12 patients were excluded, because they did not have confirmed COVID-19.
In REMAP-CAP, levels of oxygen support (including no support) below the level of high-flow nasal cannula were not reported.
Levels of oxygen support below the level of high-flow nasal cannula were not reported.
Levels of oxygen support other than mechanical ventilation were not reported. At baseline, 107 (62%) patients were admitted to an ICU.
A total of 45 of 253 (18%) patients were on either high-flow or noninvasive positive pressure ventilation.
Not listed are 113 patients who were co-enrolled in the REMAP-CAP Antiplatelet Domain (47 in the therapeutic dose anticoagulation group and 66 in the usual care pharmacologic thromboprophylaxis group).
Not listed are 74 patients who were co-enrolled in the REMAP-CAP Antiplatelet Domain (39 in the therapeutic dose anticoagulation group and 35 in the usual-care pharmacologic thromboprophylaxis group).
Treatment during trial period.