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Direct Oral Anticoagulants in Patients With Atrial Fibrillation (DOACs vs Warfarin)

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ClinicalTrials.gov Identifier: NCT03596502
Recruitment Status : Completed
First Posted : July 24, 2018
Last Update Posted : February 8, 2019
Sponsor:
Collaborators:
Drug Safety and Effectiveness Network, Canada
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
Canadian Network for Observational Drug Effect Studies, CNODES

Brief Summary:

The purpose of this study is to assess safety and effectiveness of direct oral anticoagulants (DOACs) and warfarin for stroke prevention in patients with non-valvular atrial fibrillation (AF). The comparison of DOACs versus oral vitamin K antagonists, in particular warfarin, is of interest.

The investigators will carry out separate population-based, matched cohort studies, using health administrative databases in seven Canadian provinces. New users of oral anticoagulants (DOACs or warfarin) for stroke prevention in non-valvular AF will be eligible to enter the cohorts. Follow-up will continue until a hospitalization or emergency department visit for a stroke. The results from the separate sites will be combined by meta-analysis to provide an overall assessment of the safety and effectiveness of the different anticoagulation regimens in stroke prevention in AF.

The investigators hypothesize that DOACs and warfarin will have similar safety and effectiveness profiles.


Condition or disease Intervention/treatment
Atrial Fibrillation Ischemic Stroke Systemic Embolization Major Bleed Myocardial Infarction All-cause Mortality Drug: Direct oral anticoagulants (DOACs) Drug: Warfarin

Detailed Description:

The objective of this study is to assess safety and effectiveness of direct oral anticoagulants (DOACs) and warfarin for stroke prevention in patients with non-valvular atrial fibrillation (AF).

A common-protocol approach will be used to conduct retrospective cohort studies using administrative health care data from seven Canadian provinces (Alberta, British Columbia, Manitoba, Nova Scotia, Ontario, Quebec, Saskatchewan). Briefly, the Canadian databases include population-level data on physician billing, diagnoses and procedures from hospital discharge abstracts, and dispensations for prescription drugs. The data in Alberta, Nova Scotia, and Ontario will be restricted to patients aged 65 years and older, as prescription data are not available for younger patients.

In each jurisdiction, the investigators will assemble a base cohort that includes all patients newly prescribed an oral anticoagulant (DOAC or warfarin) for stroke prevention in AF. Study period will be from the date of the first DOAC approval for stroke prevention in AF at each site to the date of latest data availability at each site. All patients newly dispensed an oral anticoagulant (i.e. with no prescription for any oral anticoagulant in the prior year) with a diagnosis of AF within the 3 years prior to the date of the prescription will be eligible to be included into the study cohorts, given they present no exclusion criteria. The date of study cohort entry will be defined by the dispensation date of the newly prescribed oral anticoagulant. Patients will be censored at the earliest of death, end of healthcare coverage, switch from DOAC to warfarin, switch from warfarin to DOAC, initiation of hemodialysis or heart valve surgery, or the end of the study period, whichever occurs first.

Exposure to a DOAC will be defined as a new prescription for a DOAC (apixaban, dabigatran, rivaroxaban) on the date of cohort entry. Exposure to warfarin will be defined as a new prescription for warfarin on the date of cohort entry. The investigators will use an analysis analogous to an intention-to-treat approach. The primary outcome will be defined as a hospitalization or emergency department visit for ischemic stroke or systemic embolization. The secondary outcomes will be: 1) major bleeding; 2) a composite of stroke (ischemic or hemorrhagic), systemic embolization, major bleeding or all-cause mortality; 3) myocardial infarction; 4) gastrointestinal bleeding; 5) intracranial bleeding; and 6) all-cause mortality.

The study cohort will be analyzed using a matched cohort design, where DOAC users will be matched 1:1 to warfarin users on sex, age, cohort entry date, and propensity score (which will be constructed using a multivariable logistic regression model estimating the odds of being treated with DOACs, while adjusting for a number of pre-identified covariates to account for baseline differences at the time of cohort entry). Cox-proportional hazards regression models will be used to estimate adjusted hazards ratios (HRs) and corresponding 95% confidence intervals (CIs) for ischemic stroke or systemic embolization in the three cohorts. Meta-analyses of the site-specific results will be performed using random effects models. As secondary analyses, the composite outcome will be stratified by age (<85 and ≥85) and sex. In addition, an as treated analysis using inverse probability of censoring weights (IPCW) will be performed to account for non-random censoring.


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Study Type : Observational
Actual Enrollment : 402764 participants
Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Safety and Effectiveness of Direct Oral Anticoagulants for Stroke Prevention in Non-valvular Atrial Fibrillation: a Multi-database Cohort Study With Meta-analysis (DOACs vs Warfarin)
Actual Study Start Date : February 1, 2018
Actual Primary Completion Date : December 1, 2018
Actual Study Completion Date : December 1, 2018

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Direct oral anticoagulants (DOACs)
Patients diagnosed with non-valvular atrial fibrillation who initiated their oral anticoagulation with a DOAC (apixaban, dabigatran or rivaroxaban) at cohort entry date, and did not have a previous prescription for any oral anticoagulant in the prior year.
Drug: Direct oral anticoagulants (DOACs)
Exposure to DOACs will be defined as a new prescription for apixaban (ATC B01AF02), dabigatran (ATC B01AE07), or rivaroxaban (ATC B01AF01) at cohort entry date in patients diagnosed with non-valvular atrial fibrillation.
Other Name: Eliquis, Pradaxa, Xarelto

Warfarin
Patients diagnosed with non-valvular atrial fibrillation who initiated their oral anticoagulation with warfarin at cohort entry date, and did not have a previous prescription for any oral anticoagulant in the prior year.
Drug: Warfarin
Exposure to warfarin will be defined as a new prescription for warfarin (ATC B01AA03) at cohort entry date in patients diagnosed with non-valvular atrial fibrillation.
Other Name: Coumadin




Primary Outcome Measures :
  1. Ischemic stroke (IS) or systemic embolization (SE) [ Time Frame: Patients will be followed from date of first DOAC or warfarin prescription (cohort entry date) until a hospitalization or ED visit for IS or SE, censoring due to death, end of healthcare coverage, or for up to 65 months, whichever occurs first. ]

    Patients hospitalized or visiting the emergency department (ED) for a stroke or a systemic embolization recorded as the most responsible diagnosis in either the discharge abstract or hospitalization record with the following ICD codes:

    Ischemic stroke:

    ICD-9 codes: 434.x; ICD-10 codes: I63.x, I64.x

    Systemic embolization:

    ICD-9 codes: 444.x; ICD-10 codes: I74.x



Secondary Outcome Measures :
  1. Major bleeding [ Time Frame: Patients will be followed from date of first DOAC or warfarin prescription (cohort entry date) until a hospitalization or ED visit for major bleed, censoring due to death, end of healthcare coverage, or for up to 65 months, whichever occurs first. ]

    Patients hospitalized or visiting the emergency department (ED) for a major bleed composite recorded as the most responsible diagnosis in either the discharge abstract or hospitalization record with the following ICD codes:

    Intracranial bleeding (including hemorrhagic stroke):

    ICD-9 codes: 430.x, 431.x, 432.x; ICD-10 codes: I60.x, I61.x, I62.x

    Gastrointestinal bleeding:

    ICD-9 codes: 456.0, 531.0, 531.2, 531.4, 531.6, 532.0, 532.2, 532.4, 532.6, 533.0, 533.2, 533.4, 533.6, 534.0, 534.2, 534.4, 534.6, 569.3, 578.x; ICD-10 codes: I85.0, I98.3, K25.0, K25.2, K25.4, K25.6, K26.0, K26.2, K26.4, K26.6, K27.0, K27.2, K27.4, K27.6, K28.0, K28.2, K28.4, K28.6, K29.0, K55.21, K62.5, K63.81, K92.0, K92.1, K92.2

    Ocular bleeding:

    ICD-9 codes: 362.81, 363.6x, 376.32, 379.23, 377.42; ICD-10 codes: H31.3, H35.6, H43.1, H45.0

    Other bleeding causing ED visit or hospitalization:

    ICD-9 codes: 459.0, 596.7, 599.7, 627.1, 719.1, 729.92, 784.7, 784.8, 786.3; ICD-10 codes: D68.3, K66.1, M25.0x, N02.x


  2. All-cause mortality [ Time Frame: Patients will be followed from date of first DOAC or warfarin prescription (cohort entry date) until death, end of healthcare coverage, or for up to 65 months, whichever occurs first. ]
  3. Myocardial infarction [ Time Frame: Patients will be followed from date of first DOAC or warfarin prescription (cohort entry date) until a hospitalization for a myocardial infarction, censoring due to death, end of healthcare coverage, or for up to 65 months, whichever occurs first. ]

    Patients hospitalized for a myocardial infarction recorded as the most responsible diagnosis in hospitalization record with the following ICD codes:

    ICD-9 codes: 410.x; ICD-10 codes: I21.x




Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
In each jurisdiction, the investigators will assemble a study cohort that includes all patients newly anticoagulated from the date of the first DOAC approval for stroke prevention in AF (in each site) to the date of the latest data availability at each site, that had a diagnosis of AF within the 3 years prior to the date of the prescription.
Criteria

Inclusion Criteria:

  • Patients with a new prescription for an oral anticoagulant that had a diagnosis of atrial fibrillation or atrial flutter within the 3 years prior to the date of the prescription
  • Patients aged 18 years or older (except Alberta, Nova Scotia, and Ontario, where patients will be aged at least 66 years or older)

Exclusion Criteria:

  • Patients with less than one year of data availability prior to cohort entry
  • Patients with a diagnosis of valvular disease (including rheumatic heart disease) or prior cardiac valve surgery
  • Patients with a diagnosis of venous thromboembolic disease in the year prior to cohort entry
  • Patients who underwent hemodialysis in the 90 days prior to cohort entry
  • Patients with a hip, femur, or knee surgery in the 30 days prior to cohort entry
  • Patients with a diagnosis of antiphospholipid syndrome

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03596502


Locations
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Canada, Quebec
Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)
Montréal, Quebec, Canada, H2X 0A9
Sponsors and Collaborators
Canadian Network for Observational Drug Effect Studies, CNODES
Drug Safety and Effectiveness Network, Canada
Canadian Institutes of Health Research (CIHR)
Investigators
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Principal Investigator: Madeleine Durand, MD, MSc, FRCPC Centre de Recherche du Centre Hospitalier de l'Université de Montréal

Additional Information:
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Responsible Party: Canadian Network for Observational Drug Effect Studies, CNODES
ClinicalTrials.gov Identifier: NCT03596502     History of Changes
Other Study ID Numbers: Q16-13B
First Posted: July 24, 2018    Key Record Dates
Last Update Posted: February 8, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Canadian Network for Observational Drug Effect Studies, CNODES:
Direct oral anticoagulants
Safety
Atrial fibrillation
Ischemic stroke
Systemic embolization
Additional relevant MeSH terms:
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Stroke
Atrial Fibrillation
Myocardial Infarction
Infarction
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Arrhythmias, Cardiac
Heart Diseases
Pathologic Processes
Ischemia
Necrosis
Myocardial Ischemia
Warfarin
Anticoagulants