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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Embolism
• Intervention / Treatment: Drug: Rivaroxaban; Drug: Warfarin

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.

• Study Type: Observational
• Enrollment (Actual): 98947

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02120
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This study will involve a new user, parallel group, propensity score-matched, retrospective cohort study design comparing rivaroxaban to warfarin users. The patients will be required to have continuous enrollment during a baseline period of 180 days before initiation of rivaroxaban or warfarin (index date). We will restrict the analyses to patients with a diagnosis of acute symptomatic proximal PE with or without symptomatic DVT.

Description

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]

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Warfarin; Reference group	Drug: Warfarin; Any warfarin dispensing claim is used as the reference group
Rivaroxaban; Exposure group	Drug: Rivaroxaban; Any rivaroxaban dispensing claim is used as the exposure group

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Shirley Wang, PhD, ScM, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2020
• Primary Completion (Actual): June 11, 2021
• Study Completion (Actual): June 11, 2021

Study Registration Dates

• First Submitted: May 4, 2021
• First Submitted That Met QC Criteria: May 6, 2021
• First Posted (Actual): May 10, 2021

Study Record Updates

• Last Update Posted (Actual): July 28, 2023
• Last Update Submitted That Met QC Criteria: July 25, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Warfarin
• Other Study ID Numbers: 2018P002966-DUP-EINSTEIN-PE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No