Ticagrelor Compared to Clopidogrel in Acute Coronary Syndromes

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Acute Coronary Syndrome

Intervention / Treatment
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* Drug: Ticagrelor 90mg
* Drug: Clopidogrel 75mg
* Drug: acetylsalicylic acid (ASA) 81mg


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ticagrelor 90mg<br>Ticagrelor: 180 mg loading dose followed by 90 mg BID. Aspirin: 325 loading dose followed by 81 mg daily. | Drug: Ticagrelor 90mg<br>* Ticagrelor tablet<br>* Other names: Brilinta;Drug: acetylsalicylic acid (ASA) 81mg<br>* acetylsalicylic acid tablet<br>* Other names: Aspirin;|
| Active Comparator: Clopidogrel 75mg<br>Clopidogrel: 300 mg loading dose followed by 75 mg daily. Aspirin: 325 loading dose followed by 81 mg daily. | Drug: Clopidogrel 75mg<br>* Clopidogrel tablet<br>* Other names: Plavix;Drug: acetylsalicylic acid (ASA) 81mg<br>* acetylsalicylic acid tablet<br>* Other names: Aspirin;|

What is the study measuring?
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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. | ICD-10 Codes | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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. |  | 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. |  | 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 |  | 36 months | 
| The hazard ratio for the number of participants with any cardiovascular-related mortality event |  | 12 months | 
| The hazard ratio for the number of participants with any acute MI event |  | 12 months | 
| The hazard ratio for the number of participants with any stroke event |  | 12 months | 
| The hazard ratio for the number of participants with any major bleeding requiring hospitalization event |  | 12 months | 
| The hazard ratio for the number of participants with any recurrent coronary revascularization(s) event |  | 12 months | 
| The hazard ratio for the number of participants with any reported drug side effects |  | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cardiovascular disease, Myocardial Infarction, Stroke, Clopidogrel, Ticagrelor, Platelet Aggregation Inhibitors, Pragmatic Trial