Replication of the ONTARGET Antihypertensive Trial in Healthcare Claims Data

Study Overview
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Brief Summary
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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
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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.

Official Title
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Replication of the ONTARGET Antihypertensive Trial in Healthcare Claims Data

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Ramipril
* Drug: Telmisartan


Participation Criteria
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Eligibility Criteria
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Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions. Eligible cohort entry dates: Market availability of telmistartan in the U.S. started on November 10, 1998, however, the Marketscan and Optum data are available at BWH only from Jan 1, 2003 and Jan 1, 2004, respectively. For Marketscan: Jan 1, 2003 -Dec 2017 (end of data availability). For Optum: Jan 1, 2004-June 30, 2019 (end of data availability). Inclusion Criteria: Individuals 55 years of age with 1 of the following: 1. Coronary artery disease 1a. Previous myocardial infraction ( > 2 days post uncomplicated MI) 1b. Stable angina or unstable angina > 30 days before informed consent and with documented evidence of multivessel coronary artery disease 1c. Multi-vessel PTCA >30 days before informed consent 1d. Multi-vessel CABG surgery > 4 years before informed consent, or with recurrent angina following surgery 2. Peripheral artery disease 2a. Previous limb bypass surgery or Previous limb bypass surgery or angioplasty 2b. Previous limb or foot amputation 2c. Intermittent claudication, with ankle:arm BP ratio =< 0.80 on at least 1 side 2d. Significant peripheral artery stenosis ( > 50%) documented by angiography or non-invasive testing 3. Cerebrovascular disease 3a. Previous stroke 3b. Transient ischemic attacks >7 days and <1 year before informed consent 4. Diabetus mellitus 4a. Diabetes mellitus High-risk diabetics with evidence of endorgan damage Exclusion Criteria: 1. Medication use 1a. Inability to discontinue ACE inhibitors or ARB 1b. Known hypersensitivity or intolerance to ACE inhibitors or ARB (patient intolerant of ACE inhibitor can be enrolled in TRANSCEND) 2. Cardiovascular disease (HF) 2a. Symptomatic congestive heart failure 2b. Hemodynamically significant primary valvular or outflow tract obstruction 2c. Constrictive pericarditis 2d. Complex congenital heart disease 2e. Syncopal episodes of unknown etiology <3 months before informed consent 2f. Planned cardiac surgery or PTCA <3 months of informed consent 2g. Uncontrolled hypertension on treatment (eg, BP >160/100 mm Hg) 2f. Heart transplant recipient 2g. Stroke due to subarachnoid hemorrhage 3. Other conditions 3a. Significant renal artery disease 3b. Hepatic dysfunction 3c. Uncorrected volume or sodium depletion 3d. Primary hyperaldosteronism 3e. Hereditary fructose intolerance 3f. Other major noncardiac illness expected to reduce life expectancy or interfere with study participation 3g. Simultaneously taking another experimental drug 3h. Significant disability precluding regular follow-up visits 3I. Unable or unwilling to provide written informed consent

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Ramipril<br>Reference group | Drug: Ramipril<br>* Ramipril dispensing claim is used as the reference<br>|
| Telmisartan<br>Exposure group | Drug: Telmisartan<br>* Telmisartan dispensing claim is used as the exposure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative hazard of composite outcome of Heart Failure, Stroke, MI, and Mortality | Relative hazard of composite outcome of Heart Failure, Stroke, MI, and Mortality - Please refer to uploaded protocol for full definition due to size limitations. | [Time Frame: Through study completion (a median of ***118-123**** days)] |