Clinical trial NCT04237935: Replication of the PLATO Antiplatelet Trial in Healthcare Claims Data
Official title: Replication of the PLATO Antiplatelet Trial in Healthcare Claims Data
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Antiplatelet
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
First posted: 2020-01-23
Enrollment: 27960
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study will involve a new user, parallel group, cohort study design comparing ticagrelor 90mg twice daily to clopidogrel 75mg daily. The patients will be required to have continuous enrollment during the baseline period of 180 days before initiation of ticagrelor 90mg or the comparator drug (cohort entry date). Follow-up for the outcome (3P-MACE), begins the day after drug initiation.

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.

Eligibility criteria: Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Market availability of ticagrelor in the U.S. started on 2011-07-20.

* For Marketscan: 2011-07-20 to 2017-12-31 (end of data availability).
* For Optum: 2011-07-20 to 2019-03-31 (end of data availability).

Inclusion Criteria:

* 1-4 ALL REQUIRED

  * 1. Hospitalized for potential ST-segment elevation or non-ST-segment elevation ACS, with onset during the previous 24 hours, documented by cardiac ischemic symptoms due to atherosclerosis of ≥10 minutes' duration at rest
  * 2. ≥18 years of age
  * 3. Not pregnant. Urinary and/or blood pregnancy tests are to be performed in women of child-bearing potential and repeated at least every 6 months. Women of child-bearing potential must be using ≥2 forms of reliable contraception, including one barrier method.
  * 4. With informed consent 1-4 AND 5A OR 5B
* 5A. ≥2 of the following:

  * 1. ST-segment changes on ECG indicating ischemia. ST-segment depression or transient elevation ≥ 1 mm in two or more 2 contiguous leads"
  * 2. Positive biomarker indicating myocardial necrosis. Troponin I or T or CK-MB greater than the upper limit of normal
  * 3. One of the following:

    1. ≥60 y of age
    2. Previous MI or CABG
    3. CAD with ≥50% stenosis in ≥2 vessels
    4. Previous ischemic stroke, TIA (hospital-based diagnosis), carotid stenosis (≥50%), or cerebral revascularization
    5. Diabetes mellitus
    6. Peripheral artery disease
    7. Chronic renal dysfunction
* OR
* 5B. Persistent ST-segment elevation ≥1 mm (not known to be preexisting or due to a coexisting disorder) in ≥2 contiguous leads or new LBBB plus primary PCI planned.

Exclusion Criteria:

* Drug related

  * 1. Contraindication to clopidogrel or other reason that study drug should not be administered (eg, hypersensitivity, moderate or severe liver disease, active bleeding or bleeding history, major surgery within 30 days)"
  * 2. Oral anticoagulation therapy that cannot be stopped
  * 3. Fibrinolytic therapy planned or within the previous 24 h
  * 4. Concomitant oral or IV therapy with strong CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, grapefruit juice N1 L/d), CYP3A substrates with narrow therapeutic indices (cyclosporine, quinidine), or strong CYP3A inducers (rifampin/rifampicin, phenytoin, carbamazepine)
* Treatment related

  * 1. Index event is an acute complication of PCI
  * 2. PCI after index event and before first study dose
* Medical

  * 1. Increased risk of bradycardiac events
  * 2. Dialysis required
  * 3. Known clinically important thrombocytopenia
  * 4. Known clinically important anemia
  * 5. Any other condition that may put the patient at risk or influence study results in the investigators' opinion (eg, cardiogenic shock, severe hemodynamic instability, active cancer)
* General

  * 1. Participant in another investigational drug or device study within 30 days
  * 2. Pregnancy or lactation
  * 3. Any condition that increases the risk for noncompliance or being lost to follow-up
  * 4. Involvement in the planning or conduct of the study
  * 5. Previous enrollment or randomization in this study

Primary outcomes:
measure: Relative hazard of 3-P MACE (composite outcome of Stroke, MI, and Mortality)
timeFrame: Through study completion (a median of 163-219 days)
Secondary outcomes:
measure: Relative hazard of Hospital admission for MI
timeFrame: Through study completion (a median of 163-219 days)
measure: Relative hazard of Hospital admission for stroke
timeFrame: Through study completion (a median of 163-219 days)
measure: Relative hazard of All-cause mortality/CV mortality
timeFrame: Through study completion (a median of 163-219 days)
Other outcomes:
measure: Relative hazard of Major bleeding (Control outcome)
timeFrame: Through study completion (a median of 163-219 days)
measure: Relative hazard of Pneumonia (Control outcome)
timeFrame: Through study completion (a median of 163-219 days)
Locations:
city: Boston
country: United States
facility: Brigham And Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Hospital
name: Shirley Wang, PhD, ScM
role: PRINCIPAL_INVESTIGATOR
References:
citation: Franklin JM, Patorno E, Desai RJ, Glynn RJ, Martin D, Quinto K, Pawar A, Bessette LG, Lee H, Garry EM, Gautam N, Schneeweiss S. Emulating Randomized Clinical Trials With Nonrandomized Real-World Evidence Studies: First Results From the RCT DUPLICATE Initiative. Circulation. 2021 Mar 9;143(10):1002-1013. doi: 10.1161/CIRCULATIONAHA.120.051718. Epub 2020 Dec 17.