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

A Multicenter, Randomized-Controlled Trial to Evaluate the Efficacy and Safety of Antithrombotic Therapy for Prevention of Arterial and Venous Thrombotic Complications in Critically-Ill COVID-19 Patients

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.

Study Overview

• Status: Completed
• Conditions: COVID-19; Venous Thromboembolism; Arterial Thrombosis
• Intervention / Treatment: Drug: Unfractionated Heparin IV; Drug: Enoxaparin 1 mg/kg; Drug: Clopidogrel; Drug: Unfractionated heparin SC; Drug: Enoxaparin 40 mg SC

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

• Study Type: Interventional
• Enrollment (Actual): 390
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02459
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Key Exclusion Criteria:

1. Ongoing (>48 hours) or planned full-dose (therapeutic) anticoagulation for any indication
2. Ongoing or planned treatment with dual antiplatelet therapy

3. 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
4. History of heparin-induced thrombocytopenia
5. 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):

1. Ongoing or planned antiplatelet therapy, including aspirin monotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Full-dose anticoagulation (FDAC); 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	Drug: Unfractionated Heparin IV; Unfractionated heparin (UFH) administered intravenously with a nomogram targeting an aPTT of 1.5-2.5 times the control as per institutional therapeutic target for treatment of VTE; Drug: Enoxaparin 1 mg/kg; Enoxaparin 1 mg/kg administered subcutaneously (SC) every 12 hours; Other Names: Lovenox; Drug: Clopidogrel; Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily orally on subsequent days; Other Names: Plavix
Active Comparator: Standard-dose prophylactic anticoagulation (SDPAC); 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	Drug: Clopidogrel; Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily orally on subsequent days; Other Names: Plavix; Drug: Unfractionated heparin SC; Heparin 5,000 units administered subcutaneous three times daily; Drug: Enoxaparin 40 mg SC; Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if CrCl<30 ml/min); Other Names: Lovenox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation	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.	28 days or until hospital discharge, whichever earlier
Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy	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.	28 days or until hospital discharge, whichever earlier

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation	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.	28 days or until hospital discharge, whichever earlier
Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy	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.	28 days or until hospital discharge, whichever earlier

Collaborators and Investigators

• Sponsor: The TIMI Study Group
• Investigators: Study Chair: Marc S Sabatine, MD, MPH, TIMI Study Group; Principal Investigator: David A Morrow, MD, MPH, TIMI Study Group

Publications and helpful links

General Publications

• Lee CK, Merriam LT, Pearson JC, Lipnick MS, McKleroy W, Kim EY. Treating COVID-19: Evolving approaches to evidence in a pandemic. Cell Rep Med. 2022 Feb 9;3(3):100533. doi: 10.1016/j.xcrm.2022.100533. eCollection 2022 Mar 15.
• Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
• Bohula EA, Berg DD, Lopes MS, Connors JM, Babar I, Barnett CF, Chaudhry SP, Chopra A, Ginete W, Ieong MH, Katz JN, Kim EY, Kuder JF, Mazza E, McLean D, Mosier JM, Moskowitz A, Murphy SA, O'Donoghue ML, Park JG, Prasad R, Ruff CT, Shahrour MN, Sinha SS, Wiviott SD, Van Diepen S, Zainea M, Baird-Zars V, Sabatine MS, Morrow DA; COVID-PACT Investigators. Anticoagulation and Antiplatelet Therapy for Prevention of Venous and Arterial Thrombotic Events in Critically Ill Patients With COVID-19: COVID-PACT. Circulation. 2022 Nov;146(18):1344-1356. doi: 10.1161/CIRCULATIONAHA.122.061533. Epub 2022 Aug 29.

Study record dates

Study Major Dates

• Study Start (Actual): August 5, 2020
• Primary Completion (Actual): March 10, 2022
• Study Completion (Actual): March 10, 2022

Study Registration Dates

• First Submitted: May 28, 2020
• First Submitted That Met QC Criteria: May 28, 2020
• First Posted (Actual): June 1, 2020

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: December 22, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Embolism and Thrombosis; COVID-19; Thrombosis; Thromboembolism; Venous Thromboembolism; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Anticoagulants; Clopidogrel; Heparin; Enoxaparin; Calcium heparin; Enoxaparin sodium
• Other Study ID Numbers: CCCTN/TIMI COVID-PACT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No