Prevention of Arteriovenous Thrombotic Events in Critically-Ill COVID-19 Patients Trial

Phase 4

Completed

Conditions: COVID-19
Arterial Thrombosis
Venous Thromboembolism

Interventions: Drug: Unfractionated Heparin IV
Drug: Clopidogrel
Drug: Enoxaparin 1 mg/kg
Drug: Unfractionated heparin SC
Drug: Enoxaparin 40 mg SC

Registration Number: NCT04409834

Lead Sponsor: The TIMI Study Group

Brief Summary: The researchers wanted to learn how to help sick patients who are in the hospital because of COVID-19. They are trying to find out the best way that is safe to stop blood clots that could be dangerous from forming in patients with COVID-19. This research study happened at 34 hospitals.

All patients in the study took medicines that help prevent blood clots. These medicines are called blood thinners or anticoagulants. Patients got different amounts of blood thinners to see what works better and is safer. Researchers randomly chose some patients to get more and some to get less.

The researchers also wanted to know if another medicine called clopidogrel can safely help stop blood clots from forming. This kind of medicine helps keep parts of the blood, called platelets, from sticking together. In some patients who did not have other reasons to take a platelet-blocker the researchers randomly chose the patient to take clopidogrel or not. This type of medicine is also called an antiplatelet.

Detailed Description: This is a multicenter, open-label, randomized-controlled trial in critically-ill patients with novel coronavirus disease 2019 (COVID-19) evaluating the efficacy and safety of full-dose vs. standard prophylactic dose anticoagulation and of antiplatelet vs. no antiplatelet therapy (in a nested second randomization) for prevention of venous and arterial thrombotic events. In a subcohort without an ongoing indication for antiplatelet therapy at screening, the second randomization is performed to either antiplatelet or no antiplatelet therapy

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 390

Inclusion Criteria

Age ≥18 years (male or female)
Acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)
Currently admitted to an intensive care unit (ICU)

Key

Exclusion Criteria

Ongoing (>48 hours) or planned full-dose (therapeutic) anticoagulation for any indication
Ongoing or planned treatment with dual antiplatelet therapy
Contraindication to antithrombotic therapy or high risk of bleeding due to conditions including, but not limited to, any of the following:
1. History of intracranial hemorrhage, known central nervous system (CNS) tumor or CNS vascular abnormality
2. Active or recent major bleeding within the past 30 days with untreated source
3. Platelet count <70,000 or known functional platelet disorder
4. Fibrinogen <200 mg/dL
5. International normalized ratio (INR) >1.9
History of heparin-induced thrombocytopenia
Ischemic stroke within the past 2 weeks

Patients who meet the following criterion are excluded from the second randomization (antiplatelet therapy vs. no antiplatelet therapy):

Ongoing or planned antiplatelet therapy, including aspirin monotherapy

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Full-dose anticoagulation (FDAC)	Enoxaparin 1 mg/kg	* Unfractionated heparin (UFH) administered intravenously with a nomogram targeting an activated partial thromboplastin time (aPTT) of 1.5-2.5 times the control as per institutional therapeutic target for treatment of venous thrombotic events (VTE) * Enoxaparin 1 mg/kg administered subcutaneously (SC) every 12 hours * With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days
Full-dose anticoagulation (FDAC)	Unfractionated Heparin IV	* Unfractionated heparin (UFH) administered intravenously with a nomogram targeting an activated partial thromboplastin time (aPTT) of 1.5-2.5 times the control as per institutional therapeutic target for treatment of venous thrombotic events (VTE) * Enoxaparin 1 mg/kg administered subcutaneously (SC) every 12 hours * With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days
Standard-dose prophylactic anticoagulation (SDPAC)	Unfractionated heparin SC	* Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if creatinine clearance CrCl \<30 ml/min) * Heparin 5,000 units administered subcutaneous three times daily * With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days
Standard-dose prophylactic anticoagulation (SDPAC)	Clopidogrel	* Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if creatinine clearance CrCl \<30 ml/min) * Heparin 5,000 units administered subcutaneous three times daily * With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days
Standard-dose prophylactic anticoagulation (SDPAC)	Enoxaparin 40 mg SC	* Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if creatinine clearance CrCl \<30 ml/min) * Heparin 5,000 units administered subcutaneous three times daily * With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days
Full-dose anticoagulation (FDAC)	Clopidogrel	* Unfractionated heparin (UFH) administered intravenously with a nomogram targeting an activated partial thromboplastin time (aPTT) of 1.5-2.5 times the control as per institutional therapeutic target for treatment of venous thrombotic events (VTE) * Enoxaparin 1 mg/kg administered subcutaneously (SC) every 12 hours * With or without anti-platelet therapy: Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily on subsequent days

Primary Outcome Measures

Name	Time	Method
Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation	28 days or until hospital discharge, whichever earlier	The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the FDAC (Full-dose anticoagulation) arm to every patient in the SDPAC (Standard dose prophylactic anticoagulation) arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT.
Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy	28 days or until hospital discharge, whichever earlier	The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the Anti-platelet group to every patient in the No Anti-platelet group arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia, or clinically silent DVT.

Secondary Outcome Measures

Name	Time	Method
Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy	28 days or until hospital discharge, whichever earlier	The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the Anti-platelet group to every patient in the No Anti-platelet group arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia.
Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation	28 days or until hospital discharge, whichever earlier	The efficacy of these interventions was analyzed using an unmatched win ratio. * The number of wins was found by comparing every patient in the FDAC (Full-dose anticoagulation) arm to every patient in the SDPAC (Standard dose prophylactic anticoagulation) arm to determine a 'win' and totaling up the number of wins in each arm. * A 'win' is a point in the favor of the arm it is given to. For each comparison of one patient in full dose arm compared to one patient in the standard dose arm, a 'win' is given to arm with the patient who had a component of the composite endpoint either lower in the hierarchy than the paired patient, or if the patient did not have any component of the composite while the paired patient did experience a component event of the composite. * Hierarchical composite: Death due to venous or arterial thrombosis, pulmonary embolism, clinically evident DVT, type 1 MI, ischemic stroke, systemic embolism or acute limb ischemia.