Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care

Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04362085

Enrollment

465

Registered

2020-04-24

Start date

2020-05-11

Completion date

2021-10-14

Last updated

2025-01-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

COVID-19

Keywords

coagulopathy, anticoagulation

Brief summary

Coagulopathy of COVID-19 afflicts approximately 20% of patients with severe COVID-19 and is associated with need for critical care and death. COVID-19 coagulopathy is characterized by elevated D-dimer, an indicator of fibrin formation and clot lysis, and a mildly prolonged prothrombin time, suggestive of coagulation consumption. To date, it seems that COVID-19 coagulopathy manifests with thromboembolism, thus anticoagulation may be of benefit. We propose to conduct a parallel pragmatic multi-centre open-label randomized controlled trial to determine the effect of therapeutic anticoagulation compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer.

Detailed description

2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation, with low molecular weight heparin or unfractionated heparin (high dose nomogram), compared to standard care in hospitalized patients with COVID-19 and an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Eligible participants will be randomized to one of two treatment regimens, receiving either therapeutic anticoagulation or standard care until discharged from hospital, death or day 28. The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days. Key secondary outcomes between study arms up to day 28 include: 1. All-cause death 2. Composite outcome of ICU admission or all-cause death 3. Composite outcome of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation 5. Number of participants who received red blood cell transfusion (≥1 unit) 6. Number of participants with transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate 7. Renal replacement therapy; 8. Number of hospital-free days alive 9. Number of ICU-free days alive 10. Number of ventilator-free days alive 11. Number of organ support-free days alive 12. Number of participants with venous thromboembolism 13. Number of participants with arterial thromboembolism 14. Number of participants with heparin induced thrombocytopenia 15. Changes in D-dimer up to day 3 The treatment arm is therapeutic anticoagulation with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin, or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to the center-specific protocol. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement. The standard care arm is the administration of LMWH, UFH or fondaparinux at thromboprophylactic doses in the absence of contraindication. No study specific bloodwork will be ordered aside from a single D-dimer test (if not collected through standard of care) up to and including day 3 after randomization for all participants in both study arms. In those on the active treatment arm who are receiving UFH, the aPTT or UFH anti-Xa will be drawn according to local institutional UFH nomogram protocol guidance. All laboratory results will be collected from standard of care from admission to hospital discharge, death or 28 days, where available. An optional biobanking component will collect blood at baseline and 2 follow up time points. This study will immediately impact the clinical care of patients with severe COVID-19 internationally, whether the findings are positive or negative, as COVID-19 coagulopathy is a highly prevalent complication of severe COVID-19 and may precede the respiratory manifestations that characterize it.

Interventions

DRUGTherapeutic Anticoagulation

The choice of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to center-specific institutional protocol.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Masking description

Blinding of participants, clinical research staff, and clinicians is not possible due to the nature of the intervention. However, the biostatisticians will be blinded at the data analysis phase.

Intervention model description

This study is a 2-arm, parallel, pragmatic, multi-centre, open-label randomized controlled trial to determine the effect of therapeutic anticoagulation on the composite outcome of ICU admission, mechanical ventilation and/or death in hospitalized patients with COVID-19.

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

The inclusion criteria are: 1. laboratory confirmed diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification.Positive test prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2. admitted to hospital for COVID-19; 3. one D-dimer value above ULN (5 days (i.e. 120 hours) of hospital admission) and either: a) D-Dimer ≥2 times ULN; or b) D-dimer above ULN and oxygen saturation ≤ 93% on room air; 4. ≥18 years of age; 5. informed consent from the patient (or legally authorized substitute decision maker). The

Exclusion criteria

are: 1. pregnancy; 2. hemoglobin \<80 g/L in the last 72 hours; 3. platelet count \<50 x 10\^9/L in the last 72 hours; 4. known fibrinogen \<1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5. known INR \>1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6. patient already on intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7. patient already on therapeutic anticoagulation at the time of screening (low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban); 8. patient on dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9. known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10. known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11. known history of heparin-induced thrombocytopenia; 12. known allergy to UFH or LMWH; 13. admitted to the intensive care unit at the time of screening; 14. treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening (of note: high flow oxygen delivery via nasal cannula is acceptable and is not an exclusion criterion). 15. imminent death according to the judgement of the most responsible physician 16. enrollment in another clinical trial of antithrombotic therapy involving pre-intensive care unit hospitalized patients

Design outcomes

Primary

Measure	Time frame	Description
Composite Outcome of ICU Admission, Non-invasive Positive Pressure Ventilation, Invasive Mechanical Ventilation, or All-cause Death up to 28 Days.	Up to 28 days	Composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation, or all-cause death up to 28 days.

Secondary

Measure	Time frame	Description
Composite Outcome of ICU Admission or All-cause Death	Up to 28 days	Composite outcome of ICU admission or all-cause death
Composite Outcome of Mechanical Ventilation or All-cause Death	Up to 28 days	Composite outcome of mechanical ventilation or all-cause death
Major Bleeding	Up to 28 days	Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation
Red Blood Cell Transfusion	Up to 28 days	Red Blood Cell transfusion (greater than or equal to 1 unit)
Transfusion of Platelets, Frozen Plasma, Prothrombin Complex Concentrate, Cryoprecipiate and/or Fibrinogen Concentrate	Up to 28 days	Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipiate and/or fibrinogen concentrate
Renal Replacement Therapy	Up to 28 days	Renal replacement therapy defined as continuous renal replacement therapy or intermittent hemodialysis
Hospital-free Days Alive up to Day 28	Up to 28 days	Hospital-free days alive up to day 28
All-cause Death	Up to 28 days	All-cause death
Ventilator-free Days Alive up to Day 28	Up to 28 days	Ventilator-free days alive up to day 28
Organ Support-free Days Alive up to Day 28	Up to 28 days	Organ support-free days alive up to day 28
Venous Thromboembolism	Up to 28 days	Venous thromboembolism
Arterial Thromboembolism	Up to 28 days	Arterial thromboembolism
Heparin Induced Thrombocytopenia	Up to 28 days	Heparin induced thrombocytopenia
Changes in D-dimer	Up to day 3	Geometric mean ratio defined as ratio of geometric means of D-dimer ratios (D-dimer×ULN) of day 2 ±24 hours post-randomisation, adjusted for baseline geometric means of D-dimer ratios using analysis of covariance.
ICU-free Days Alive up to Day 28	Up to 28 days	ICU-free days alive up to day 28

Countries

Canada

Participant flow

Participants by arm

Arm	Count
Therapeutic Anticoagulation Therapeutic anticoagulation with LMWH or UFH (high dose nomogram). The choice of LMWH versus UFH will be at the clinician's discretion and dependent on local institutional supply. Therapeutic anticoagulation will be administered until discharged from hospital, 28 days or death. If the patient is admitted to the ICU or requiring ventilatory support, we recommend continuation of the allocated treatment as long as the treating physician is in agreement. Therapeutic Anticoagulation: The choice of low molecular weight heparin (LMWH) versus unfractionated heparin (UFH) will be at the clinician's discretion. LMWH options include: Tinzaparin, Enoxaparin or Dalteparin. UFH will be administered using a weight-based nomogram with titration according to center-specific institutional protocol.	228
Standard Care Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is considered standard care.	237
Total	465

Baseline characteristics

Characteristic	Therapeutic Anticoagulation	Standard Care	Total
Age, Continuous	60.4 years STANDARD_DEVIATION 14.1	59.6 years STANDARD_DEVIATION 15.5	60.0 years STANDARD_DEVIATION 14.8
Race/Ethnicity, Customized American Indian, Alaska Native, First Nations, Indigenous/Aboriginal, Metis	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Asian	27 Participants	38 Participants	65 Participants
Race/Ethnicity, Customized Black or African American	18 Participants	23 Participants	41 Participants
Race/Ethnicity, Customized European	97 Participants	96 Participants	193 Participants
Race/Ethnicity, Customized Hispanic or Latino	14 Participants	10 Participants	24 Participants
Race/Ethnicity, Customized Middle Eastern, North African	65 Participants	67 Participants	132 Participants
Race/Ethnicity, Customized Missing Data	6 Participants	2 Participants	8 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants	0 Participants	1 Participants
Sex: Female, Male Female	105 Participants	96 Participants	201 Participants
Sex: Female, Male Male	123 Participants	141 Participants	264 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	4 / 228	18 / 237
other Total, other adverse events	228 / 228	237 / 237
serious Total, serious adverse events	228 / 228	237 / 237

Arm	Measure	Value (MEAN)	Dispersion
Therapeutic Anticoagulation	Ventilator-free Days Alive up to Day 28	26.5 days	Standard Deviation 5.6
Standard Care	Ventilator-free Days Alive up to Day 28	24.7 days	Standard Deviation 8.5

Source: ClinicalTrials.gov · Data processed: Feb 23, 2026

Coagulopathy of COVID-19: A Pragmatic Randomized Controlled Trial of Therapeutic Anticoagulation Versus Standard Care

Conditions

Keywords

Brief summary

Detailed description

Related papers

Interventions

Sponsors

Study design

Masking description

Intervention model description

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Participants by arm

Baseline characteristics

Adverse events

Outcome results

Composite Outcome of ICU Admission, Non-invasive Positive Pressure Ventilation, Invasive Mechanical Ventilation, or All-cause Death up to 28 Days.

All-cause Death

Arterial Thromboembolism

Changes in D-dimer

Composite Outcome of ICU Admission or All-cause Death

Composite Outcome of Mechanical Ventilation or All-cause Death

Heparin Induced Thrombocytopenia

Hospital-free Days Alive up to Day 28

ICU-free Days Alive up to Day 28

Major Bleeding

Organ Support-free Days Alive up to Day 28

Red Blood Cell Transfusion

Renal Replacement Therapy

Transfusion of Platelets, Frozen Plasma, Prothrombin Complex Concentrate, Cryoprecipiate and/or Fibrinogen Concentrate

Venous Thromboembolism

Ventilator-free Days Alive up to Day 28