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

• ClinicalTrials.gov Identifier: NCT04736420
• Recruitment Status: Completed
• First Posted: February 3, 2021
• Last Update Posted: May 10, 2021
• Sponsor: Brigham and Women's Hospital
• Information provided by (Responsible Party): Jessica Franklin, Brigham and Women's Hospital

Study Description

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.

Condition or disease	Intervention/treatment
Venous Thromboembolism	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 Design

• Study Type: Observational
• Actual Enrollment: 78605 participants
• Observational Model: Cohort
• Time Perspective: Retrospective
• Official Title: Replication of the EINSTEIN-DVT Anticoagulant Trial in Healthcare Claims Data
• Actual Study Start Date: September 22, 2020
• Actual Primary Completion Date: February 18, 2021
• Actual Study Completion Date: February 18, 2021

Groups and Cohorts

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

Outcome Measures

Primary Outcome Measures :

1. Relative hazard of venous thromboembolism [ Time Frame: Through study completion or point of censoring, up to 12 months ]
   Claims-based algorithm: see attached protocol for full definition

Secondary Outcome Measures :

1. Relative hazard of a major bleeding event [ Time Frame: Through study completion or point of censoring, up to 12 months ]
   Claims-based algorithm: see attached protocol for full definition

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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 proximal DVT without symptomatic PE.

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

Contacts and Locations

Locations

United States, Massachusetts

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02120

Sponsors and Collaborators

Brigham and Women's Hospital

Investigators

• Principal Investigator: Jessica Franklin, PhD; Brigham and Women's Hospital
• Principal Investigator: Shirley Wang, PhD, ScM; Brigham and Women's Hospital

  Study Documents (Full-Text)

Documents provided by Jessica Franklin, Brigham and Women's Hospital:

Study Protocol  [PDF] January 25, 2021

More Information

• Responsible Party: Jessica Franklin, Associate Professor of Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT04736420
• Other Study ID Numbers: DUPLICATE-EINSTEIN-DVT
• First Posted: February 3, 2021
• Last Update Posted: May 10, 2021
• Last Verified: May 2021

• 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

Additional relevant MeSH terms:

Thromboembolism; Venous Thromboembolism; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Warfarin; Rivaroxaban; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action