The DARE Warfarin CER Study

The Dabigatran, Apixaban, Rivaroxaban, Edoxaban, Warfarin Comparative Effectiveness Research Study

Approximately half a million Americans annually experience venous thromboembolic disease, including deep venous thrombosis (DVT) and pulmonary embolism (PE). Since 2010, four new oral anticoagulants have been approved for marketing in addition to the vitamin K antagonist warfarin. Very limited head-to-head data exists comparing these treatment options, leaving patients, clinicians, and other stakeholders with little guidance for selecting the best strategy that balances recurrence reduction with risk of bleeding. In the DARE Warfarin CER Study, the researchers compare all five currently available oral anticoagulant agents for the extended treatment of DVT and PE, as well as no extended treatment. This study also aims to evaluate whether treatment heterogeneity exists for specific populations, such as older patients or those with renal dysfunction. In a secondary aim, the study will also leverage a database of linked electronic health record-insurance claims to validate diagnosis definitions and account for potential residual confounding by factors unmeasured in claims data. As the patient population includes all Medicare novel anticoagulant users and large numbers of commercially insured and Medicaid patients, the results will likely be transportable to the majority of US patients experiencing a DVT or PE. Pursuant to the objectives of the Patient-Centered Outcomes Research Institute, a study advisory committee consisting of key stakeholders will be actively involved in the study design and dissemination of results.

Study Overview

• Status: Enrolling by invitation
• Conditions: Pulmonary Embolism; Deep Venous Thrombosis
• Intervention / Treatment: Drug: Dabigatran: extended treatment (e.g at least 90 days); Drug: Dabigatran: extended treatment (e.g at least 180 days); Drug: Dabigatran: extended treatment (e.g at least 270 days); Drug: Apixaban: extended treatment (e.g at least 90 days); Drug: Apixaban: extended treatment (e.g at least 180 days); Drug: Apixaban: extended treatment (e.g at least 270 days); Drug: Rivaroxaban: extended treatment (e.g at least 90 days); Drug: Rivaroxaban: extended treatment (e.g at least 180 days); Drug: Rivaroxaban: extended treatment (e.g at least 270 days); Drug: Edoxaban: extended treatment (e.g at least 90 days); Drug: Edoxaban: extended treatment (e.g at least 180 days); Drug: Edoxaban: extended treatment (e.g at least 270 days); Drug: Warfarin: extended treatment (e.g at least 90 days); Drug: Warfarin: extended treatment (e.g at least 180 days); Drug: Warfarin: extended treatment (e.g at least 270 days)

• Study Type: Observational
• Enrollment (Anticipated): 416000

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
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Cohort derived from a commercial database, MarketScan, and Medicare Research Identifiable Files using data from 2009-2015. Cohort data will be updated as new data come in through 2019.

Description

Inclusion criteria:

1. Inpatient stay with diagnosis code of DVT/PE (see Appendix A), 1/1/2010 - 9/30/2015 for which the patient has at least 365 days continuous medical and pharmacy eligibility prior and no other inpatient stays with DVT/PE diagnosis. Set discharge date as index diagnosis date. Take only the first eligible episode for a patient, if multiple.
2. Prescription fill for an anticoagulant [generic name=dabigatran (150mg), apixaban (2.5mg, 5mg, 10mg), rivaroxaban (15mg, 20mg), edoxaban (30mg, 60mg), or warfarin] within 30 days of and including index diagnosis date. Set earliest anticoagulant prescription as index generic and date as index rx date.
3. No anticoagulant prescription fill in the 365 days prior to index diagnosis date.
4. Continuous enrollment and use of an anticoagulant for the first 90 days including and following the index rx date, defined as no gaps in therapy >7 days. For each patient, assign a variable to indicate whether the patient filled an anticoagulant with a different generic name as index during this period.

Exclusion Criteria:

1. Any safety outcome between index diagnosis date and index rx date + 90, defined as: intracranial bleed, gastrointestinal bleed, or other major bleed.
2. Any DVT/PE between index diagnosis date and index rx date + 90.

Study Plan

How is the study designed?

Number of groups / cohorts

30

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Continuer at 90 Days: Dabigatran	Drug: Dabigatran: extended treatment (e.g at least 90 days); 90 days
Continuer at 180 Days: Dabigatran	Drug: Dabigatran: extended treatment (e.g at least 180 days); 180 days
Continuer at 270 Days: Dabigatran	Drug: Dabigatran: extended treatment (e.g at least 270 days); 270 days
Continuer at 90 Days: Apixaban	Drug: Apixaban: extended treatment (e.g at least 90 days); 90 days
Continuer at 180 Days: Apixaban	Drug: Apixaban: extended treatment (e.g at least 180 days); 180 days
Continuer at 270 Days: Apixaban	Drug: Apixaban: extended treatment (e.g at least 270 days); 270 days
Continuer at 90 Days: Rivaroxaban	Drug: Rivaroxaban: extended treatment (e.g at least 90 days); 90 days
Continuer at 180 Days: Rivaroxaban	Drug: Rivaroxaban: extended treatment (e.g at least 180 days); 180 days
Continuer at 270 Days: Rivaroxaban	Drug: Rivaroxaban: extended treatment (e.g at least 270 days); 270 days
Continuer at 90 Days: Edoxaban	Drug: Edoxaban: extended treatment (e.g at least 90 days); 90 days
Continuer at 180 Days: Edoxaban	Drug: Edoxaban: extended treatment (e.g at least 180 days); 180 days
Continuer at 270 Days: Edoxaban	Drug: Edoxaban: extended treatment (e.g at least 270 days); 270 days
Continuer at 90 Days: Warfarin	Drug: Warfarin: extended treatment (e.g at least 90 days); 90 days
Continuer at 180 Days: Warfarin	Drug: Warfarin: extended treatment (e.g at least 180 days); 180 days
Continuer at 270 Days: Warfarin	Drug: Warfarin: extended treatment (e.g at least 270 days); 270 days
Discontinuer at 90 Days: Dabigatran	Drug: Dabigatran: extended treatment (e.g at least 90 days); 90 days
Discontinuer at 180 Days: Dabigatran	Drug: Dabigatran: extended treatment (e.g at least 180 days); 180 days
Discontinuer at 270 Days: Dabigatran	Drug: Dabigatran: extended treatment (e.g at least 270 days); 270 days
Discontinuer at 90 Days: Apixaban	Drug: Apixaban: extended treatment (e.g at least 90 days); 90 days
Discontinuer at 180 Days: Apixaban	Drug: Apixaban: extended treatment (e.g at least 180 days); 180 days
Discontinuer at 270 Days: Apixaban	Drug: Apixaban: extended treatment (e.g at least 270 days); 270 days
Discontinuer at 90 Days: Rivaroxaban	Drug: Rivaroxaban: extended treatment (e.g at least 90 days); 90 days
Discontinuer at 180 Days: Rivaroxaban	Drug: Rivaroxaban: extended treatment (e.g at least 180 days); 180 days
Discontinuer at 270 Days: Rivaroxaban	Drug: Rivaroxaban: extended treatment (e.g at least 270 days); 270 days
Discontinuer at 90 Days: Edoxaban	Drug: Edoxaban: extended treatment (e.g at least 90 days); 90 days
Discontinuer at 180 Days: Edoxaban	Drug: Edoxaban: extended treatment (e.g at least 180 days); 180 days
Discontinuer at 270 Days: Edoxaban	Drug: Edoxaban: extended treatment (e.g at least 270 days); 270 days
Discontinuer at 90 Days: Warfarin	Drug: Warfarin: extended treatment (e.g at least 90 days); 90 days
Discontinuer at 180 Days: Warfarin	Drug: Warfarin: extended treatment (e.g at least 180 days); 180 days
Discontinuer at 270 Days: Warfarin	Drug: Warfarin: extended treatment (e.g at least 270 days); 270 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Safety Outcome: Intracranial bleed, Gastrointestinal bleed, Other Major bleed	Defined as a new episode of either Intracranial bleed, Gastrointestinal bleed or another Major bleed event during follow-up.	1-2 Years
Composite Effectiveness Outcome: Deep Venous Thrombosis, Pulmonary Embolism	Defined as a new episode of either Deep Venous Thrombosis or Pulmonary Embolism during follow-up.	1-2 Years
Death	Measured after index prescription date + 90 days and on date on which the event occurred and defined as hospitalization with discharge status code of: 20, 22-29, 40-42	1-2 Years
Composite safety and effectiveness outcome	defined as earlier of safety or DVT/PE outcomes	1-2 years
Composite safety and effectiveness outcome, including death	Measured after index prescription date + 90 days and on date on which the event occurred and defined as hospitalization with discharge status code of: 20, 22-29, 40-42	1-2 years

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Harvard Medical School (HMS and HSDM); Patient-Centered Outcomes Research Institute

Publications and helpful links

General Publications

• Krumme AA, Pawar A, Schneeweiss S, Glynn RJ, Choudhry NK, Kulldorff M, Ortiz AS, Avorn J, Gagne JJ. Study protocol for the dabigatran, apixaban, rivaroxaban, edoxaban, warfarin comparative effectiveness research study. J Comp Eff Res. 2018 Jan;7(1):57-66. doi: 10.2217/cer-2017-0053. Epub 2017 Dec 21.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2017
• Primary Completion (Anticipated): October 30, 2021
• Study Completion (Anticipated): October 30, 2021

Study Registration Dates

• First Submitted: August 24, 2017
• First Submitted That Met QC Criteria: August 31, 2017
• First Posted (Actual): September 5, 2017

Study Record Updates

• Last Update Posted (Actual): June 23, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: warfarin; comparative effectiveness; rivaroxaban; apixaban; edoxaban; oral anticoagulant; dabigatran; extended treatment; comparative safety
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Thrombosis; Venous Thrombosis; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Dabigatran; Apixaban; Edoxaban; Warfarin
• Other Study ID Numbers: 2017P000215

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No