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

NCT04409834 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: CCCTN/TIMI COVID-PACT
• Study Type: interventional
• Target: 390
• Locations: 1 country
• Sites: 1

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.

Conditions

COVID-19; Venous Thromboembolism; Arterial Thrombosis

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (2)

• Clinically Evident Venous or Arterial Thrombotic Events: Full-dose Anticoagulation Versus Standard-dose Prophylactic Anticoagulation

  28 days or until hospital discharge, whichever earlier

• Clinically Evident Venous or Arterial Thrombotic Events: Anti-platelet Therapy Versus No Anti-platelet Therapy

  28 days or until hospital discharge, whichever earlier

Study Arms (2)

Full-dose anticoagulation (FDAC)

EXPERIMENTAL

* 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; Drug: Enoxaparin 1 mg/kg; Drug: Clopidogrel

Standard-dose prophylactic anticoagulation (SDPAC)

ACTIVE COMPARATOR

* 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; Drug: Unfractionated heparin SC; Drug: Enoxaparin 40 mg SC

Interventions

Unfractionated Heparin IV DRUG

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

Full-dose anticoagulation (FDAC)

Enoxaparin 1 mg/kg DRUG

Enoxaparin 1 mg/kg administered subcutaneously (SC) every 12 hours

Also known as: Lovenox

Full-dose anticoagulation (FDAC)

Clopidogrel DRUG

Clopidogrel 300 mg administered once orally on the day of randomization, followed by 75 mg administered once daily orally on subsequent days

Also known as: Plavix

Full-dose anticoagulation (FDAC); Standard-dose prophylactic anticoagulation (SDPAC)

Unfractionated heparin SC DRUG

Heparin 5,000 units administered subcutaneous three times daily

Standard-dose prophylactic anticoagulation (SDPAC)

Enoxaparin 40 mg SC DRUG

Enoxaparin 40 mg administered subcutaneously (SC) once daily (reduce to 30 mg if CrCl\<30 ml/min)

Also known as: Lovenox

Standard-dose prophylactic anticoagulation (SDPAC)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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:
• History of intracranial hemorrhage, known central nervous system (CNS) tumor or CNS vascular abnormality
• Active or recent major bleeding within the past 30 days with untreated source
• Platelet count \<70,000 or known functional platelet disorder
• Fibrinogen \<200 mg/dL
• 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

Sponsors & Collaborators

• The TIMI Study Group: lead

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02459, United States

Location

Related Publications (4)

• 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.

  PMID: 36036760 RESULT

• Fischer AL, Messer S, Riera R, Martimbianco ALC, Stegemann M, Estcourt LJ, Weibel S, Monsef I, Andreas M, Pacheco RL, Skoetz N. Antiplatelet agents for the treatment of adults with COVID-19. Cochrane Database Syst Rev. 2023 Jul 25;7(7):CD015078. doi: 10.1002/14651858.CD015078.

  PMID: 37489818 DERIVED

• 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.

  PMID: 35474746 DERIVED

• 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.

  PMID: 35244208 DERIVED

MeSH Terms

Conditions

COVID-19; Venous Thromboembolism

Interventions

Enoxaparin; Clopidogrel

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates; Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: COVID-PACT Project Manager
• Organization: Brigham and Women's Hospital

covid-pact@bwh.harvard.edu

(617) 278-0145

Study Officials

• Marc S Sabatine, MD, MPH

  The TIMI Study Group

  STUDY CHAIR

• David A Morrow, MD, MPH

  The TIMI Study Group

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized-controlled trial - 1) full-dose anticoagulation (FDAC) versus standard-dose prophylactic anticoagulation (SDPAC) (pooled across antiplatelet regimens) and in a subset of patients 2) antiplatelet (AP) versus no AP therapy (pooled across anticoagulant regimens)

Study Record Dates

• First Submitted: May 28, 2020
• First Posted: June 1, 2020
• Study Start: August 5, 2020
• Primary Completion: March 10, 2022
• Study Completion: March 10, 2022
• Last Updated: January 19, 2024
• Results First Posted: January 19, 2024

Record last verified: 2023-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)