Table 3.
Ongoing multicenter prospective clinical trials evaluating heparins in adults with COVID-19.
| Heparin | Patients | Study Design | Primary Endpoint | Study Acronym / ClinicalTrials.gov Identifier |
|---|---|---|---|---|
| Enoxaparin 40 mg subcut daily for 14 days versus no treatment | Ambulatory, never hospitalized COVID-19 | Randomized, controlled, open-label | 30-day hospitalizations, 30-day all-cause mortality | OVID / NCT04400799 |
| Enoxaparin 40 mg subcut daily < 100 kg or 40 mg subcut twice daily if ≥ 100 kg for 21 days versus no treatment | Ambulatory symptomatic never hospitalized COVID-19 age ≥ 55 years with at least two of the following additional risk factors: age ≥ 70 years body mass index > 25 kg/m2, COPD, DM, CVD or corticosteroid use | Open-label randomized, Phase IIIb | Hospital admission at 21, 51 and 90 days for ICU, ECMO or Mechanical ventilation | ETHIC / NCT04492254 |
| Observational cohort: enoxaparin 40 mg subcut daily for 14 days Prospective cohort: enoxaparin 60 subcutaneous daily 45 to 60 kg or 80 mg subcut daily 61 to 100 kg or 100 mg subcut daily >100 kg for 14 days | Hospitalized moderate- to severe COVID-19 | 2 parts: a phase II single-arm interventional prospective study; observational prospective cohort study including all patients screened for receiving the study drug but not included in the phase II study. | All-cause mortality at 30 and 90 days | NCT04427098 |
| Enoxaparin 40 mg subcut daily versus enoxaparin 70 mg twice daily | Hospitalized, severe COVID-19 with coagulopathy | Randomized, controlled, open-label | Clinical worsening during hospitalization: death or MI or objectively confirmed arterial TE or VTE, or need for CPAP or noninvasive or mechanical ventilation | NCT04408235 |
| Therapeutic dose anticoagulation with either enoxaparin 1mg/kg subcut twice daily for CrCl ≥ 30ml/min or enoxaparin 0.5mg/kg subcut twice daily for CrCl ≥ 15 ml/min and < 30 ml/min versus institutional standard of care prophylaxis with LMWH or UFH | Hospitalized severe COVID-19, randomized within 72 hours of hospitalization, have a need for supplemental oxygen, and either a D- Dimer > 4 x ULN or sepsis-induced coagulopathy (SIC) score of ≥4 | Open-label (pseudoblinding- site PIs blinded), randomized, active control | Composite outcome of arterial TE, VTE, and all-cause mortality at Day 30 ± 2 days. | HEP-COVID/ NCT04401293 |
| Therapeutic dose anticoagulation with LMWH (enoxaparin preferred over other LMWHs; preferred over UFH) or adjusted-dose UFH (target aPTT or anti-Xa) | Hospitalized < 72 hrs COVID-19 | Randomized, open-label | Ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation, or death | ATTACC / NCT04372589 |
| Therapeutic dose anticoagulation (LMWH or UFH at any dose above prophylactic dose) versus prophylactic dose anticoagulation (LMWH or UFH) | Hospitalized < 72 hrs COVID-19 | Open-label, randomized, masked adjudicators | Number of organ support free days (free of Noninvasive or mechanical ventilation or vasopressors) through day 21 ISTH major bleeding | ACTIV-4 Inpatient/ NCT04505774 |
| Therapeutic tinzaparin 175 IU/kg every 24 hours if CrCl ≥ 20 mL/min or UFH (target anti-Xa) if CrCl < 20 mL/min versus prophylaxis standard of care (LMWH or UFH) for 14 days | Hospitalized COVID-19 Group 1: patients not requiring ICU at admission with mild disease to severe pneumopathy according to The Who Criteria of severity of COVID pneumopathy, and with symptom onset before 14 days, with need for oxygen but NIV or high flow Group 2: Respiratory failure and requiring mechanical ventilation, WHO progression scale ≥ 6, no do-not-resuscitate order (DNR order) | Randomized, 2 parallel arms, stratified for disease severity (ventilated or not) | 14-day survival without ventilation (group 1), 28-day ventilator free survival (Group 2) | CORIMMUNO-COAG / NCT04344756 |
| Therapeutic anticoagulation (enoxaparin preferred with UFH for renal insufficiency or morbid obesity) versus standard anticoagulant prophylaxis (enoxaparin preferred) | Hospitalized with COVID-19 and elevated D-Dimer (>1500 mg/L) without severe ARDS | Randomized, open-label | Composite endpoint of death, cardiac arrest, symptomatic VTE, arterial TE, MI, or hemodynamic shock at day 21 | NCT04377997 |
| Standard dose LMWH versus weight-adjusted LMWH (e.g. enoxaparin 40 mg twice daily <50 kg, 50 mg twice daily 50-70 kg, 60 mg twice daily 70-100kg, 70 mg twice daily > 100kg) | Hospitalized COVID-19 | Randomized, open-label controlled, stratified (ICU or not) | Symptomatic VTE at day 28 | COVI-DOSE / NCT04373707 |
| Standard prophylaxis with enoxaparin versus intermediate-dose prophylaxis with enoxaparin (atorvastatin 20 mg versus placebo) | Hospitalized within 7 days to ICU | Randomized, controlled, open-label, 2 × 2 factorial design | Composite of incident VTE, undergoing ECMO, and all-cause mortality at 30 days, composite of objectively-confirmed VTE, undergoing ECMO, or death from any cause | INSPIRATION / NCT04486508[93] |
| Therapeutic anticoagulation with enoxaparin 1 mg/kg subcut twice daily or UFH (aPTT 1.5-2 x control) versus standard prophylaxis (enoxaparin 40 mg subcut daily or UFH 5000 units three times daily) (Clopidogrel 300 mg followed by 75 mg daily versus placebo) | Hospitalized ICU COVID-19 | Randomized, controlled, open-label, 2 × 2 factorial design | VTE at day 28 or hospital discharge whichever sooner Hierarchical composite: death due to VTE, arterial thrombosis, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT | COVID PACT / NCT04409834 |
| Therapeutic anticoagulation with either: oral rivaroxaban 20 mg daily (15 mg daily if CrCl 30-49 mL/min and/or concomitant use of azithromycin) or enoxaparin 1 mg/kg every 12 hours or UFH (preferred if DIC) versus usual anticoagulant prophylaxis standard of care for 30 days | Hospitalized COVID-19 with D-dimer > 3 x ULN | Randomized, controlled, open-label | Composite endpoint: mortality, number of days alive, number of days in the hospital and number of days with oxygen therapy at the end of 30 days (win ratio) | ACTION / NCT04394377 |
| Therapeutic anticoagulation (either treatment dose enoxaparin or UFH infusion per weight-based nomogram) administered until discharged or 28 days versus standard of care | Hospitalized COVID-19 with D-dimer > 2 x ULN within 72 hours of admission | Randomized, controlled, open-label | ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days | NCT04362085 |
| Therapeutic dose bemiparin (115 IU/kg subcut daily) versus prophylaxis dose bemiparin (3500 IU/kg subcut daily) for 10 days | Hospitalized COVID-19 with D-dimer > 500 ng/mL | Randomized, single-blind | Composite endpoint (worsening): death, ICU admission, need for either non-invasive or invasive mechanical ventilation, progression to moderate / severe respiratory distress syndrome according to objective criteria (Berlin definition), VTE, MI, or stroke | NCT04420299 |
| FREEDOM Trial Prophylaxis enoxaparin (40 mg subcut daily or 30 mg subcut daily for CrCl <30 mL/min) versus Therapeutic dose enoxaparin (1 mg/kg subcut every 12 hours or 1 mg/kg subcut daily for CrCl <30 mL/min) and Therapeutic dose apixaban (5 mg PO every 12 hrs or 2.5 mg every 12 hours for patients with at least two of three of age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5 mg/dL) | Hospitalized COVID-19 but not yet intubated | Randomized, controlled, open-labelled | The time to first event rate within 30 days of randomization of the composite of all-cause mortality, intubation requiring mechanical ventilation, systemic VTE confirmed by imaging or requiring surgical intervention OR ischemic stroke confirmed by imaging Number of in-hospital rate of BARC 3 or 5 bleeding | NCT04512079 |
| COVID-HEP Therapeutic anticoagulation with UFH or enoxaparin versus prophylaxis dose UFH or enoxaparin (augmented prophylaxis dose if in ICU) from admission to end of hospital stay | Hospitalized COVID-19 | Randomized, parallel, open-label, single masked | 30-day composite outcome arterial or venous thrombosis, DIC and all-cause mortality ISTH major bleeding | NCT04345848 |
| Rivaroxaban 10 mg PO daily x 35 days versus placebo | Medically ill outpatients with symptomatic COVID-19 | Randomized, double-blind, placebo-controlled | 35-day composite outcome of symptomatic VTE, MI, ischemic stroke, acute limb ischemia, non-CNS systemic embolization, all-cause hospitalization and all-cause mortality | PREVENT-HD / NCT04508023 |
| Apixaban 2.5 mg PO twice daily versus apixaban 5 mg PO twice daily versus aspirin 81 mg PO daily versus placebo for 45 days | Adults > age 40 and < 80 years found to be COVID-19 positive with elevated D-dimer and hsCRP who do not require hospitalization due to stable COVID-19 related symptoms status. | Randomized, double-blind, placebo-controlled | 45-day composite endpoint of need for hospitalization for cardiovascular/pulmonary events, symptomatic VTE, MI, ischemic stroke, and all-cause mortality | ACTIV Outpatient / NCT04498273 |
| Standard prophylactic dose enoxaparin (40 mg subcut daily or 30 or 40 mg subcut twice daily if BMI ≥30kg/m2; standard of care arm) versus intermediate-dose enoxaparin (1 mg/kg subcut daily or 0.5 mg/kg subcut twice daily if BMI≥30kg/m2; intervention arm) | Hospitalized with COVID-19 | Randomized, open-label, controlled | 30-day all-cause mortality ISTH major bleeding | NCT04360824 |
| Therapeutic dose UFH or LMWH versus standard prophylaxis according to local standard | Hospitalized with COVID-19 | Randomized, open-label, parallel | 30-day ordinal endpoint with three possible outcomes based on the worst status of each patient through day 30: no requirement for invasive mechanical ventilation, invasive mechanical ventilation, or death. | ATTACC / NCT04372589 |
aPTT, activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; CrCl, creatinine clearance; CVD, cardiovascular disease; DIC, disseminated intravascular coagulation; DM, diabetes mellitus; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; ISTH, International Thrombosis and Haemostasis; LMWH, low-molecular-weight heparin; MI, myocardial infarction; NIV, noninvasive ventilation; SIC, sepsis induced coagulopathy; subcut, subcutaneous; TE, thromboembolism; UFH, unfractionated heparin; VTE, venous thromboembolism; WHO, World Health Organization.