Replication of the ARISTOTLE 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: Atrial Fibrillation
• Intervention / Treatment: Drug: Warfarin; Drug: Apixaban

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 is 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 according to 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): 220518

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: Yes

• Sampling Method: Probability Sample

Study Population

This study will involve a new user, parallel group, cohort study design comparing apixaban to warfarin. The patients will be required to have continuous enrollment during baseline period of 180 days before initiation of apixaban or the comparator drug (cohort entry date). Follow-up for the outcome, begins the day after drug initiation.

Description

Please see: https://drive.google.com/drive/folders/1WD618wrywYjEaXzfLTcuK-VCcnb6b-gV for full code and algorithm definitions.

Eligible cohort entry dates: Market availability of apixaban in the U.S. started on December 28, 1012. For Marketscan: Jan 1, 2013 -Dec 31, 2018 (end of data availability). For Optum: Jan 1, 2013-Dec 31, 2019 (end of data availability). For Medicare: Jan 1, 2013 -Dec 31, 2017.

Inclusion Criteria:

• 1. Age ≥ 18 years

• 2. Atrial fibrillation - either of the following:

  • 2a. In atrial fibrillation or atrial flutter not due to a reversible cause and documented by ECG at the time of enrollment
  • 2b. If not in atrial fibrillation/flutter at the time of enrollment, must have atrial fibrillation/flutter documented on two separate occasions, not due to a reversible cause at least 2 weeks apart in the 12 months prior to enrollment. Atrial fibrillation/flutter may be documented by ECG, or as an episode lasting at least one minute on a rhythm strip, Holter recording, or intracardiac electrogram (from an implanted pacemaker or defibrillator)

• 3. One or more of the following risk factor(s) for stroke:

  • 3a. Age 75 years or older
  • 3b. Prior stroke, TIA, or systemic embolus
  • 3c. Either symptomatic congestive heart failure within 3 months or left ventricular dysfunction with an LV ejection fraction (LVEF) ≤ 40% by echocardiography, radionuclide study or contrast angiography
  • 3d. Diabetes mellitus
  • 3e. Hypertension requiring pharmacological treatment

Exclusion Criteria:

• 2. Clinically significant (moderate or severe) mitral stenosis
• 3. Increased bleeding risk that is believed to be a contraindication to oral anticoagulation (e.g. previous intracranial hemorrhage)
• 4. Conditions other than atrial fibrillation that require chronic anticoagulation (e.g. prosthetic mechanical heart valve)
• 5. Persistent, uncontrolled hypertension (systolic BP > 180 mm Hg, or diastolic BP > 100 mm Hg)
• 6. Active infective endocarditis
• 11. Simultaneous treatment with both aspirin and a thienopyridine (e.g., clopidogrel, ticlopidine)
• 12. Severe comorbid condition with life expectancy of ≤ 1 year
• 13. Active alcohol or drug abuse, or psychosocial reasons that make study participation impractical
• 14. Recent ischemic stroke (within 7 days)
• 15. Severe renal insufficiency (serum creatinine > 2.5 mg/dL or a calculated creatinine clearance < 25 mL/min, See Section 6.3.2.2)
• 17. Platelet count ≤ 100,000/ mm3
• 18. Hemoglobin < 9 g/dL
• 19. Women of child bearing potential (WOCBP) unwilling or unable to use an acceptable method to avoid pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative hazard of composite outcome of Stroke and Systemic Embolism	Relative hazard of composite outcome of Stroke and Systemic Embolism - Please refer to uploaded protocol for full definition due to size limitations.	[Time Frame: Through study completion (a median of 98 days)]

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Investigators: Principal Investigator: Jessica Franklin, PhD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2020
• Primary Completion (Actual): February 18, 2021
• Study Completion (Actual): February 18, 2021

Study Registration Dates

• First Submitted: October 13, 2020
• First Submitted That Met QC Criteria: October 13, 2020
• First Posted (Actual): October 19, 2020

Study Record Updates

• Last Update Posted (Actual): July 27, 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: 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; Apixaban; Warfarin
• Other Study ID Numbers: 2018P002966-DUP-ARISTOTLE

Drug and device information, study documents

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