The Comparative Safety and Effectiveness of Dabigatran, Versus Rivaroxaban, and Apixaban Utilized in the Department of Defense Non-Valvular Atrial Fibrillation Patient Population: A Retrospective Database Analysis

Safety and Effectiveness Study Comparing Dabigatran, Rivaroxaban & Apixaban in Non-valvular Atrial Fibrillation Patients Enrolled in the US Department of Defense Military Health System

The purpose of this study is to assess the safety and effectiveness of newly initiated dabigatran among patients diagnosed with non valvular atrial fibrillation (NVAF) in comparison to newly initiated rivaroxaban users and newly initiated apixaban users

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Dabigatran vs. Rivaroxaban; Drug: Dabigatran vs. Apixaban

• Study Type: Observational
• Enrollment (Actual): 42534

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Princeton, New Jersey, United States, 08450
      • InVentiv Health

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

NVAF patients, ≥18 years of age, enrolled within the DoD Military Health System, who have newly initiated dabigatran, rivaroxaban, or apixaban. Patients must be treatment naïve from OAC use prior to first (index) NOAC.

Description

Inclusion Criteria:

• Age 18+ on index date
• Patients must have been prescribed either dabigatran, rivaroxaban, or apixaban identified by pharmacy claim during the study period. The first dispensing date of either study drug will be defined as the index date;
• Patients must be treatment naïve from all OAC use prior to the first NOAC prescription, during study period.
• Patients must have at least 12 months of continuous eligibility prior to the index date;
• Patients must have at least one diagnosis code of atrial fibrillation, defined as International Classification of Diseases (ICD)-9-CM diagnosis of 427.31 or ICD-10-CM diagnosis of I48.0, I48.1, I48.2, I48.91 on the index date or during the pre-index period.

Exclusion Criteria:

Less than 12 months of continuous eligibility in the pre-index period Any claim for OAC drug (oral use only) in the pre-index period Diagnosis of hyperthyroidism during the pre-index period

Having at least one claim for alternative indications; orthopedic procedures, Venous thromboembolism (VTE) (includes deep vein thrombosis (DVT ) & PE)) and the index NOAC prescription at the same time, or, the alternative indication for anticoagulant occurring within 3 months prior to index date in pre-period Having at least one claim with any of the following diagnoses or procedure codes in order to exclude patients with "transient" causes of Afib (3 months prior to index date in pre-period):

• Cardiac surgery
• Pericarditis
• Myocarditis Having at least one medical claim with any of the following diagnoses or procedures codes in order to exclude patients with "valvular" Afib (pre-period):
• Mitral stenosis
• Mitral stenosis with insufficiency
• Mitral valve stenosis and aortic valve stenosis
• Mitral valve stenosis and aortic valve insufficiency
• Diseases of other endocardial structures
• Other and unspecified rheumatic heart diseases
• Open heart valvuloplasty without replacement
• Open and other replacement of unspecified heart valve
• Open and other replacement of aortic valve
• Open and other replacement of mitral valve
• Open and other replacement of pulmonary valve
• Open and other replacement of tricuspid valve
• Heart valve replaced by transplant
• Heart valve replaced by a mechanical device/prosthesis
• Atrioventricular valve repair
• Aortic valve valvuloplasty
• Unlisted procedure, cardiac surgery
• Implantation of catheter-delivered prosthetic aortic heart valve; open thoracic approach
• Transthoracic cardiac exposure (e.g., sternotomy, thoracotomy, subxiphoid) for catheter-delivered aortic valve replacement; without cardiopulmonary bypass
• Transthoracic cardiac exposure (e.g., sternotomy, thoracotomy, subxiphoid) for catheter-delivered aortic valve replacement; with cardiopulmonary bypass
• Replacement, aortic valve, with cardiopulmonary bypass; with prosthetic valve other than homograft or stentless valve
• Valvuloplasty, mitral valve, with cardiopulmonary bypass
• Valvuloplasty, mitral valve, with cardiopulmonary bypass; with prosthetic ring
• Valvuloplasty, mitral valve, with cardiopulmonary bypass; radical reconstruction, with or without ring
• Replacement, mitral valve, with cardiopulmonary bypass
• Implantation of catheter-delivered prosthetic pulmonary valve, endovascular approach
• Replacement, pulmonary valve
• Valvectomy, tricuspid valve, with cardiopulmonary bypass
• Valvuloplasty, tricuspid valve; without ring insertion
• Valvuloplasty, tricuspid valve; with ring insertion
• Replacement, tricuspid valve, with cardiopulmonary bypass

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Dabigatran vs. Rivaroxaban; OAC treatment naïve NVAF patients with at least one prescription claim for dabigatran, rivaroxaban (new oral anticoagulant or NOAC).	Drug: Dabigatran vs. Rivaroxaban; observed for 6 years
Dabigatran vs. Apixaban; OAC treatment naïve NVAF patients with at least one prescription claim for dabigatran, or apixaban (new oral anticoagulant or NOAC).	Drug: Dabigatran vs. Apixaban; Observed for 6 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stroke Overall (Hemorrhagic, Ischemic, Uncertain)	The event rate of overall stroke (hemorrhagic, ischemic, uncertain) in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Length of Follow-up: The post-index follow-up period began the day following the NOAC index date and ended on whichever of the following occurred earliest: The day of discontinuation of the index NOAC exposure;; The day before a switch to an anticoagulant different from the index exposure;; The day before a change in dose for the index NOAC;; The end of continuous eligibility of a patient in the health plan (disenrollment);; The end of the study observation period; or; The date of death of the patient.	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Overall Major Bleeding	The event rate of overall Major bleeding (Hemorrhagic Stroke, Major Intracranial Bleeding and Major Extracranial Bleeding) in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first.	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ischemic Stroke	The event rate of ischemic stroke in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Hemorrhagic Stroke	The event rate of Hemorrhagic stroke in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first.	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Major Intracranial Bleeding	The event rate of major intracranial bleeding in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Major Extracranial Bleeding	The event rate of major extracranial bleeding (Major GI bleeding, Major urogenital bleeding and Major other bleeding) in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Major GI Bleeding	The event rate of major GI bleeding (Upper GI Bleeding and Lower GI Bleeding) in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Major Urogenital Bleeding	The event rate of major urogenital bleeding in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first.	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Major Other Bleeding	The event rate of major other bleeding in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Upper GI Bleeding	The event rate of Upper GI Bleeding in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
Lower GI Bleeding	The event rate of Lower GI Bleeding in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
TIA	The event rate of transient ischemic attack (TIA) in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years
All-cause Mortality	The event rate of all-cause mortality in patients matched on propensity scores without index year. Event rates were calculated as the total number of patients in each treatment group who had the outcome during follow-up divided by the total person-years at risk in the cohort. Follow-up time was the time elapsed from the index date to the date of the outcome of interest, disenrollment, end of the observation period (available data), death, discontinuation of the NOAC, or switch to a different NOAC, whichever came first	Baseline (July 1, 2010) until end of the observation period (June 30, 2016), 6 Years

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Collaborators: Health ResearchTx, LLC (HRTX); inVentiv Health Clinical (iVH); United States Department of Defense (DOD)

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 29, 2016
• Primary Completion (ACTUAL): August 23, 2017
• Study Completion (ACTUAL): August 23, 2017

Study Registration Dates

• First Submitted: January 18, 2017
• First Submitted That Met QC Criteria: January 18, 2017
• First Posted (ESTIMATE): January 20, 2017

Study Record Updates

• Last Update Posted (ACTUAL): June 3, 2019
• Last Update Submitted That Met QC Criteria: February 20, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Dabigatran; Apixaban
• Other Study ID Numbers: 1160-0274

Drug and device information, study documents

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