Replication of the EINSTEIN-PE Anticoagulant 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 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 through 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 EINSTEIN-PE Anticoagulant Trial in Healthcare Claims Data

Conditions
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Pulmonary Embolism

Intervention / Treatment
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* Drug: Rivaroxaban
* Drug: Warfarin


Participation Criteria
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Eligibility Criteria
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Criteria: Please see https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions. Inclusion Criteria: Confirmed acute symptomatic proximal PE with or without symptomatic DVT Exclusion Criteria: Legal lower age limitations [Day 0, Day 0] Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT or PE [Day -14, Day 0] Other indications for VKA than DVT and/or PE [Day -180, Day 0] Creatinine clearance <30 ml/min [Day -180, Day 0] Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALAT>3x ULN [Day -180, Day 0] Bacterial endocarditis [Day -180, Day 0] Life expectancy <3 months [Day -365, Day 0] Active bleeding or high risk for bleeding contraindicating treatment with enoxaparin or VKA [Day -180, Day 0] Systolic blood pressure >180 mgHg or diastolic blood pressure >110mgHg [Day -180, Day 0] Childbearing potential without proper contraceptive measures, pregnancy or breastfeeding [Day -180, Day 0] Concomitant use of strong CYP3A4 inhibitors (e.g. HIV protease inhibitors, systemic ketoconazole) or strong CYP3A4 inducers rifampin [Day -14, Day 0]

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Warfarin<br>Reference group | Drug: Warfarin<br>* Any warfarin dispensing claim is used as the reference group<br>|
| Rivaroxaban<br>Exposure group | Drug: Rivaroxaban<br>* Any rivaroxaban dispensing claim is used as the exposure group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative hazard of recurrent venous thromboembolic events | Claims-based algorithm: see attached protocol for full definition | Through study completion or censoring, up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative hazard of major bleeding | Claims-based algorithm: see attached protocol for full definition | Through study completion or censoring, up to 12 months |