The DARE Warfarin CER Study

Study Overview
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Brief Summary
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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.

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

Conditions
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Deep Venous Thrombosis, Pulmonary Embolism

Intervention / Treatment
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* 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)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: 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. 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. No anticoagulant prescription fill in the 365 days prior to index diagnosis date. 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: Any safety outcome between index diagnosis date and index rx date + 90, defined as: intracranial bleed, gastrointestinal bleed, or other major bleed. Any DVT/PE between index diagnosis date and index rx date + 90.

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 |
| --- | --- |
| Continuer at 90 Days: Dabigatran<br> | Drug: Dabigatran: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Continuer at 180 Days: Dabigatran<br> | Drug: Dabigatran: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Continuer at 270 Days: Dabigatran<br> | Drug: Dabigatran: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Continuer at 90 Days: Apixaban<br> | Drug: Apixaban: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Continuer at 180 Days: Apixaban<br> | Drug: Apixaban: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Continuer at 270 Days: Apixaban<br> | Drug: Apixaban: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Continuer at 90 Days: Rivaroxaban<br> | Drug: Rivaroxaban: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Continuer at 180 Days: Rivaroxaban<br> | Drug: Rivaroxaban: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Continuer at 270 Days: Rivaroxaban<br> | Drug: Rivaroxaban: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Continuer at 90 Days: Edoxaban<br> | Drug: Edoxaban: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Continuer at 180 Days: Edoxaban<br> | Drug: Edoxaban: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Continuer at 270 Days: Edoxaban<br> | Drug: Edoxaban: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Continuer at 90 Days: Warfarin<br> | Drug: Warfarin: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Continuer at 180 Days: Warfarin<br> | Drug: Warfarin: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Continuer at 270 Days: Warfarin<br> | Drug: Warfarin: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Discontinuer at 90 Days: Dabigatran<br> | Drug: Dabigatran: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Discontinuer at 180 Days: Dabigatran<br> | Drug: Dabigatran: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Discontinuer at 270 Days: Dabigatran<br> | Drug: Dabigatran: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Discontinuer at 90 Days: Apixaban<br> | Drug: Apixaban: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Discontinuer at 180 Days: Apixaban<br> | Drug: Apixaban: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Discontinuer at 270 Days: Apixaban<br> | Drug: Apixaban: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Discontinuer at 90 Days: Rivaroxaban<br> | Drug: Rivaroxaban: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Discontinuer at 180 Days: Rivaroxaban<br> | Drug: Rivaroxaban: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Discontinuer at 270 Days: Rivaroxaban<br> | Drug: Rivaroxaban: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Discontinuer at 90 Days: Edoxaban<br> | Drug: Edoxaban: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Discontinuer at 180 Days: Edoxaban<br> | Drug: Edoxaban: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Discontinuer at 270 Days: Edoxaban<br> | Drug: Edoxaban: extended treatment (e.g at least 270 days)<br>* 270 days<br>|
| Discontinuer at 90 Days: Warfarin<br> | Drug: Warfarin: extended treatment (e.g at least 90 days)<br>* 90 days<br>|
| Discontinuer at 180 Days: Warfarin<br> | Drug: Warfarin: extended treatment (e.g at least 180 days)<br>* 180 days<br>|
| Discontinuer at 270 Days: Warfarin<br> | Drug: Warfarin: extended treatment (e.g at least 270 days)<br>* 270 days<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dabigatran, warfarin, apixaban, edoxaban, extended treatment, oral anticoagulant, rivaroxaban, comparative safety, comparative effectiveness