Table 2.
Key Details of Included Studies
| Study | Setting | Enrollment Period | Intervention | Comparator | Primary Outcome (Follow-up Period) | Sample Sizea |
|---|---|---|---|---|---|---|
| INSPIRATION [21] | ICU; Iran | Jul 2020–Nov 2020 | Intermediate-dose enoxaparin | Standard low-dose enoxaparin prophylaxis | Composite outcome: symptomatic VTE or ATE, ECMO treatment, or death (30 days)b | 562 |
| REMAP-CAP, ACTIV-4a, and ATTACC (non–critically ill) [23] | Hospitalized, non-ICU; 9 countriesc | Apr 2020–Jan 2021 | Therapeutic enoxaparin or UFH | Usual care thromboprophylaxis (low-dose or intermediate-dose enoxaparin/UFH) | In-hospital death and organ support–free days (21 days) | 2219 |
| REMAP-CAP, ACTIV-4a, and ATTACC (critically ill) [20] | ICU-level support; 9 countriesc | Apr 2020–Jan 2021 | Therapeutic enoxaparin or UFH | Usual care thromboprophylaxis (low-dose or intermediate-dose enoxaparin/UFH) | In-hospital death and organ support–free days (21 days) | 1098 |
| RAPID [25] | Hospitalized, non-ICU with elevated D-dimer; 6 countriesd | May 2020–Apr 2021 | Therapeutic LMWH or UFH | Standard low-dose prophylaxis (LMWH or UFH) | Composite: death, mechanical ventilation, ICU admission (28 days) | 465 |
| HEP-COVID [26] | Hospitalized, requiring oxygen, with elevated D-dimer or coagulopathy (33% in ICU); USA | May 2020–Apr 2021 | Therapeutic enoxaparin | Standard low-dose or intermediate-dose enoxaparin/UFH | ATE, symptomatic or asymptomatic VTE or death (30 ± 2 days)e | 253 |
| ACTIV-4B [27] | Outpatient; USA | Sep 2020–Jun 2021 | Therapeutic apixaban | Prophylactic low-dose apixaban | Composite: Symptomatic VTE or ATE, hospitalization for CVS or pulmonary events, or death (45 days) | 278 |
| ACTION [22] | Hospitalized with elevated D-dimer levels (6% in ICU); Brazil | Jun 2020–Feb 2021 | Therapeutic rivaroxaban or enoxaparin | Standard low-dose prophylaxis with enoxaparin/LMWH | Composite: time to death, duration of hospitalization, or duration of supplemental oxygen (30 days) | 614 |
| Perepu et al [28] | ICU or with laboratory- confirmed coagulopathy; USA | Apr 2020–Jan 2021 | Intermediate-dose enoxaparin | Standard low-dose prophylactic enoxaparin | All-cause mortality (30 days) | 173 |
| HESACOVID [29] | ICU; Brazil | Apr 2020–Jul 2020 | Therapeutic enoxaparin | Standard low-dose prophylactic enoxaparin/UFH | Gas exchange variations (PaO2:FiO2) (baseline, 7 and 14 days)f | 20 |
| BEMICOP [30] | Hospitalized, non-ICU, with elevated D-dimer; Spain | Oct 2020–May 2021 | Therapeutic bemiparin | Standard bemiparin prophylaxis | Composite: death, ICU admission, mechanical ventilation, moderate/severe ARDS, or symptomatic VTE/ATE (30 days)g | 65 |
| Oliynyk et al [31] | ICU with elevated D-dimer, nonventilated; Ukraine | Jul 2020–Mar 2021 | Therapeutic LMWH or UFH | Standard low-dose enoxaparin prophylaxis | Rates of intubation and death (28 days) | 126 |
Abbreviations: ACTION, AntiCoagulaTloncOroNavirus trial; ACTIV, Accelerating COVID-19 Therapeutic Interventions and Vaccines; ARDS, acute respiratory distress syndrome; ATE, arterial thromboembolism; ATTACC, AntithromboticTherapy to Ameliorate Complications of Covid-19; BEMICOP, Comparison of Two Different Doses of Bemiparin in COVID-19; CVS, cardiovascular system; ECMO, extracorporeal membrane oxygenation; HEP-COVID, Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients; ICU, intensive care unit; HESACOVID, Full versus prophylactic heparinization for the treatment of severe forms of SARS-Covid-19; INSPIRATION, Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial; LMWH, low-molecular-weight heparin; PaO2:FiO2, ratio of partial pressure of oxygen in arterial blood to fractional inspired oxygen; RAPID, Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic trial; REMAP-CAP, Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia; UFH, unfractionated heparin; USA, United States of America; VTE, venous thromboembolism.
Intention-to-treat population (denominator all randomized participants who received at least 1 dose of assigned treatment).
The INSPIRATION trial published independent reports on 30- and 90-day outcomes; for the purposes of this review, only 30-day outcomes were included.
USA, Canada, United Kingdom, Brazil, Mexico, Nepal, Australia, The Netherlands, Spain.
Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, USA.
Only trial to specify screening for asymptomatic deep venous thrombosis with Doppler compression ultrasonography at 10 + 4 days or at discharge if sooner and if no symptomatic VTE event prior to this point.
Secondary outcomes: in-hospital mortality and bleeding at 28 days.
Ten-day safety outcomes reported and included in meta-analysis.