Replication of the EINSTEIN-DVT Anticoagulant Trial in Healthcare Claims Data

Study Overview
=================
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 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
-----------------
Replication of the EINSTEIN-DVT Anticoagulant Trial in Healthcare Claims Data

Conditions
-----------------
Venous Thromboembolism

Intervention / Treatment
-----------------
* Drug: Rivaroxaban
* Drug: Warfarin


Participation Criteria
=================
Eligibility Criteria
-----------------
Criteria: Please see https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions. Inclusion Criteria: - Confirmed acute symptomatic proximal DVT without symptomatic PE Exclusion Criteria: Age ≤ 18 Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT or PE two weeks prior to and including day of enrollment Other indications for VKA than DVT and/or PE six months prior to and including day of enrollment Any of the following six months prior to and including day of enrollment: Creatine clearance < 30 ml/min Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or ALAT>3 ULN Bacterial endocarditis Active bleeding or high risk for bleeding contraindicating treatment with enoxaparin or VKA Systolic blood pressure > 180 mgHg or diastolic blood pressure > 110 mgHg Childbearing potential without proper contraceptive measures, pregnancy, or breastfeeding Life expectancy < 3 months in the last year prior to and including day of enrollment Concomitant use of strong CYP3A4 inhibitors (e.g. HIV protease inhibitors, systemic ketoconazole) or strong CYP3A4 inducers two weeks prior to and including day of enrollment Symptomatic pulmonary embolism two weeks prior to and including day of enrollment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

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

What is the study measuring?
-----------------
Primary Outcome Measures

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

Secondary Outcome Measures

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