Replication of the TRITON-TIMI Antiplatelet Trial in Healthcare Claims Data

Completed

• Conditions: Antiplatelet
• Interventions: Drug: Prasugrel 10mg; Drug: Clopidogrel 75mg

• Registration Number: NCT04237922
• Lead Sponsor: Brigham and Women's Hospital

Brief Summary

Investigators are building an empirical evidence base for real world data through large-scale replication of randomized controlled trials. The investigators' goal is to understand for what types of clinical questions real world data analyses can be conducted with confidence and how to implement such studies.

Detailed Description

This is a non-randomized, non-interventional study that is part of the RCT DUPLICATE initiative (www.rctduplicate.org) of the Brigham and Women's Hospital, Harvard Medical School. It is intended to replicate, as closely as is possible in healthcare insurance claims data, the trial listed below/above. Although many features of the trial cannot be directly replicated in healthcare claims, key design features, including outcomes, exposures, and inclusion/exclusion criteria, were selected to proxy those features from the trial. Randomization is also not replicable in healthcare claims data but was proxied through a statistical balancing of measured covariates according to standard practice. Investigators assume that the RCT provides the reference standard treatment effect estimate and that failure to replicate RCT findings is indicative of the inadequacy of the healthcare claims data for replication for a range of possible reasons and does not provide information on the validity of the original RCT finding.

Study Timeline

• Study Start: 2019-09-22
• Study First Submitted: 2020-01-17
• Study First Submitted QC: 2020-01-17
• Study First Posted: 2020-01-23
• Primary Completion: 2021-02-18
• Study Completion: 2021-02-18
• Status Verified: 2023-07
• Last Update Submitted: 2023-07-25
• Last Update Posted: 2023-07-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 43864

Inclusion Criteria

• 1. Acute coronary syndrome based on the disease diagnostic criteria with planned PCI (ACS definition; one of the following):

  • 1a. Moderate to high risk Unstable angina: A history of chest discomfort or ischemic symptoms of 10 min or longer at rest, 72 h or less before randomization, with persistent or transient ST-segment deviation 1 mm or higher in one or more electrocardiogram (ECG) leads without elevation of creatine kinase-MB (CK-MB) or troponin T or I but with a TIMI risk score 321 or greater

  • 1b. II. Moderate to high-risk NSTEMI. A history of chest discomfort or ischemic symptoms of 10 min or longer at rest, 72 h or less before randomization with no evidence of persistent ST-segment elevation. Subjects must also have CK-MB or troponin T or I greater than the upper limit of normal (ULN) and a TIMI risk score 3 or greater. If CK-MB or troponin is not available, total CK 2 times or greater ULN is acceptable

  • 1c. III. STEMI. A history of chest discomfort or ischemic symptoms of greater than 20 minutes duration at rest, within 14 days or less randomization with one of the following ECG features:

    1. ST-segment elevation 1 mm or higher in 2 or more contiguous ECG leads
    2. New or presumably new left bundle branch block
    3. ST-segment depression 1 mm or greater in 2 anterior precordial leads (V1 through V4) with clinical history and evidence suggestive of true posterior infarction"
• 2. Legal age (and >18 y) and competent mental condition to provide written informed consent
• 3. For women of childbearing potential only, test negative for pregnancy between ACS presentation and enrollment (based on a urine or serum pregnancy test) and agree to use a reliable method of birth control during the study

Exclusion Criteria

• Cardiovascular exclusion criteria

  • 1. Cardiogenic shock at the time of randomization
  • 2. Refractory ventricular arrhythmias
  • 3. New York Heart Association class IV congestive heart failure

• Bleeding risk exclusion criteria

  • 4. Fibrin-specific fibrinolytic therapy less than 24 h before randomization
  • 5. Non-fibrin-specific fibrinolytic therapy less than 48 h before randomization
  • 6. Active internal bleeding or history of bleeding diathesis
  • 7. Clinical findings, in the judgment of the investigator, associated with an increased risk of bleeding

  • 8. Any of the following:

    9. History of hemorrhagic stroke

    10. Intracranial neoplasm, arteriovenous malformation, or aneurysm

    11. Ischemic stroke within 3 months prior to screening

  • 9. International normalized ratio known to be greater than 1.5 at the time of screening
  • 10. Platelet count of less than 100000/mm3 at the time of screening
  • 11. Anemia (hemoglobin b10 g/dL) at the time of screening

• Prior/concomitant therapy exclusion criteria

  • 12. One or more doses of a thienopyridine 5 d or less before PCI
  • 13. Oral anticoagulation or other antiplatelet therapy that cannot be safely discontinued for the duration of the study
  • 14. Daily treatment with nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase-2 inhibitors (COX-2 inhibitors)

• General exclusion criteria

  • 15. Investigative site personnel directly affiliated with the study or immediate family
  • 16. Employed by Eli Lilly and Company; Ube Industries Limited, Daiichi Sankyo Co.; The TIMI Study Group; Quintiles
  • 17. Treatment within the last 30 d with an investigational drug or are presently enrolled in another drug or device study
  • 18. Previously completed or withdrawn from this study or any other study investigating prasugrel
  • 19. Women who are known to be pregnant, have given birth within the past 90 d, or are breast-feeding
  • 20. Concomitant medical illness that in the opinion of the investigator is associated with reduced survival
  • 21. Known severe hepatic dysfunction
  • 22. Any condition associated with poor treatment compliance including alcoholism, mental illness, or drug dependence
  • 23. Intolerance of or allergy to aspirin, tilopidine, or clopidogrel
  • 24. May be unable to cooperate with protocol requirements and follow-up procedures

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Prasugrel 10 mg	Prasugrel 10mg	Exposure group
Clopidogrel 75 mg	Clopidogrel 75mg	Reference group

Primary Outcome Measures

Name	Time	Method
Relative hazard of 3-P MACE (composite outcome of Stroke, MI, and Mortality)	Through study completion (a median of 276-312 days)	Relative hazard of 3-point major adverse cardiovascular events (MACE), i.e., non-fatal myocardial infarction, non-fatal stroke, or all-cause/CV mortality- Please refer to uploaded protocol for full definition due to size limitations.

Secondary Outcome Measures

Name	Time	Method
Relative hazard of Hospital admission for MI	Through study completion (a median of 276-312 days)	Relative hazard of Hospital admission for MI - Please refer to uploaded protocol for full definition due to size limitations.
Relative hazard of Hospital admission for stroke	Through study completion (a median of 276-312 days)	Relative hazard of Hospital admission for stroke - Please refer to uploaded protocol for full definition due to size limitations.
Relative hazard of All-cause mortality/CV mortality	Through study completion (a median of 276-312 days)	Relative hazard of All-cause mortality/CV mortality- Please refer to uploaded protocol for full definition due to size limitations.

Trial Locations

Locations (1)

Brigham And Women's Hospital; 🇺🇸 Boston, Massachusetts, United States