Ticagrelor Compared to Clopidogrel in Acute Coronary Syndromes (TC4)

November 1, 2023 updated by: James Brophy, McGill University Health Centre/Research Institute of the McGill University Health Centre

Ticagrelor Compared to Clopidogrel in Acute Coronary Syndromes - the TC4 Comparative Effectiveness Study

The McGill University Health Center (MUHC) Division of Cardiology, with funding from the Canadian Institute of Health Research, is performing this randomized controlled trial to determine which dual antiplatelet therapy (DAPT), ticagrelor + aspirin (T+A) or clopidogrel and aspirin (C+A), is the most effective and safest for our patients. While the PLATO trial reported that T+A was superior, the prespecified group of North American patients (about 1/10 of the total study sample) actually did better with C+A, although this difference was not statistically significant. When the FDA approved T, they also stated: "Lack of Robustness of PLATO Superiority with Failure in the US Makes a Confirmatory Study Mandatory." As no confirmatory study has been done, this TC4 study aims to fill that void.

Study design: A cluster randomization design, so all patients will receive either T+A or C+A, depending on the month they arrive at the MUHC when they start their DAPT. We will follow patients through their electronic health records. The patients have no follow-up visits for this research project.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Acute Coronary Syndrome (ACS) is most often caused by erosion or rupture of an atherosclerotic plaque associated with inflammation, thrombus formation, vasoconstriction, and microembolisation. In unremitting circumstances, thrombosis at the site of plaque rupture or erosion leads to complete compromise of coronary blood flow and ultimately myocardial infarction (MI). Platelet adhesion, activation and aggregation, therefore, play key roles in the transformation of a stable atherosclerotic plaque to an unstable lesion and antiplatelet drugs have become a mainstay in the prevention of recurrent cardiovascular events.

A large multicenter RCT (PLATO) showed a statistically significant decrease in composite CV outcomes with the newer ticagrelor compared to clopidogrel. This has prompted both European and Canadian guideline writers to endorse ticagrelor/aspirin as the DAPT of choice. However residual uncertainties regarding the choice of DAPT are highlighted by the PLATO subgroup analysis that showed an increased risk with ticagrelor in North America (NA) patients. This led to delayed FDA approval, dissenting FDA reviews and a reluctance in US guidelines to recommend the ticagrelor DAPT regime over others.

The main area of uncertainty, at least from the NA perspective, hinges on the small number of NA patients randomized in the PLATO trial and their increased risk with ticagrelor (n=1814, HR 1.25; 95% CI 0.93 - 1.67). The risk in NA patients was statistically significantly different from the benefit seen in the other subgroups (P=0.04) and the crux of the debate is then whether to believe the subgroup analysis or the combined study results (n=18624, HR, 0.84; 95% CI 0.77 to 0.92). The complete study provides maximal information but perhaps at a cost of being less representative of what to expect in NA practice. Conventional statistical paradigms would say that given the pre-specified nature of the geographic subgroup analysis and given the statistically significant interaction observed, one should concentrate on the subgroup results and not the combined results.

The conventional statistical model used in the PLATO analysis subsumes that every patient, regardless of differences in recruitment characteristics or ancillary treatment strategies received in the different regions, is completely identical in their response to the studied intervention. It seems highly unlikely that patients from the 43 PLATO enrolling countries are truly identical in their drug response given recruitment, genetic and background treatment variations.

This project will resolve these uncertainties and address the crucial clinical question of which DAPT regime is best after an ACS? This proposal will double the currently available evidence with a novel research design using inexpensive, electronic data and will provide a feasible answer to this important clinical question.

More information can be found here:

https://brophyj.github.io/index.html

Study Type

Interventional

Enrollment (Actual)

1038

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Quebec
      • Montreal, Quebec, Canada
        • McGill University Health Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Patients that are prescribed a dual-antiplatelet therapy (DAPT) regimen following an acute coronary syndrome (ACS) event.
  • ACS, with or without ST-segment elevation.
  • STEMI and NSTEMI positive biomarkers and appropriate ECG changes will be required.
  • NSTEMI patients with negative biomarkers are generally considered as unstable angina and will also be eligible for study inclusion if their treating physician has determined that DAPT is appropriate.
  • Patients provided written informed consent.

Exclusion Criteria:

  • A decision from the patients attending physician to circumvent randomization and assign the patient a specific dual-antiplatelet therapy regimen.
  • A contraindication to clopidogrel or ticagrelor
  • Patients diagnosed with chronic total occlusion percutaneous coronary intervention (CTO PCI)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ticagrelor 90mg
Ticagrelor: 180 mg loading dose followed by 90 mg BID. Aspirin: 325 loading dose followed by 81 mg daily.
Drug: Ticagrelor 90mg
Ticagrelor tablet
Other Names:
  • Brilinta
Drug: acetylsalicylic acid (ASA) 81mg
acetylsalicylic acid tablet
Other Names:
  • Aspirin
Active Comparator: Clopidogrel 75mg
Clopidogrel: 300 mg loading dose followed by 75 mg daily. Aspirin: 325 loading dose followed by 81 mg daily.
Drug: acetylsalicylic acid (ASA) 81mg
acetylsalicylic acid tablet
Other Names:
  • Aspirin
Drug: Clopidogrel 75mg
Clopidogrel tablet
Other Names:
  • Plavix

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The hazard ratio for the number of participants that develop the outcome, a composite of cardiovascular-related mortality, myocardial infarction (MI), or stroke.
Time Frame: 12 months
ICD-10 Codes
12 months

Secondary Outcome Measures

Outcome Measure
Time Frame
The primary outcome (The hazard ratio for the number of participants that develop the outcome, a composite of cardiovascular-related mortality, myocardial infarction (MI), or stroke) stratified by sex.
Time Frame: 12 months
12 months
The hazard ratio for the number of participants that develop the outcome, a composite of cardiovascular-related mortality, myocardial infarction (MI), or stroke.
Time Frame: 36 months
36 months
The primary outcome (The hazard ratio for the number of participants that develop the outcome, a composite of cardiovascular-related mortality, myocardial infarction (MI), or stroke) stratified by sex
Time Frame: 36 months
36 months
The hazard ratio for the number of participants with any cardiovascular-related mortality event
Time Frame: 12 months
12 months
The hazard ratio for the number of participants with any acute MI event
Time Frame: 12 months
12 months
The hazard ratio for the number of participants with any stroke event
Time Frame: 12 months
12 months
The hazard ratio for the number of participants with any major bleeding requiring hospitalization event
Time Frame: 12 months
12 months
The hazard ratio for the number of participants with any recurrent coronary revascularization(s) event
Time Frame: 12 months
12 months
The hazard ratio for the number of participants with any reported drug side effects
Time Frame: 12 months
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McGill University Health Centre/Research Institute of the McGill University Health Centre

Collaborators

Canadian Institutes of Health Research (CIHR)

Investigators

  • Principal Investigator: James Brophy, MD, PhD, McGill University Health Centre/Research Institute of the McGill University Health Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2018

Primary Completion (Actual)

April 1, 2022

Study Completion (Actual)

April 1, 2023

Study Registration Dates

First Submitted

August 13, 2019

First Submitted That Met QC Criteria

August 13, 2019

First Posted (Actual)

August 15, 2019

Study Record Updates

Last Update Posted (Estimated)

November 3, 2023

Last Update Submitted That Met QC Criteria

November 1, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • TC4/2019-4530

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

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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