A Nationwide Observational Study Looking at Effectiveness and Bleeding Complications of NOACs vs. VKA in Non-valvular Atrial Fibrillation Patients. (PROTECT-AF)

A Post-marketing Retrospective Non-interventional Study Using Nationwide Registries and Electronic Medical Records to Investigate the Real-life Effectiveness and Major Bleeding Complications of Oral Anticoagulants in Norwegian Non-valvular Atrial Fibrillation Patients

Using mandatory nationwide registries and possibly hospital electronic medical records in Norway, the researchers want to understand how well a group of drugs called "non-vitamin K antagonist oral anticoagulants" (rivaroxaban - Xarelto; apixaban - Eliquis; dabigatran - Pradaxa) works in patients with non-valvular atrial fibrillation (this is a condition when the heart beats irregularly) compared to another older drug, a vitamin K antagonist oral anticoagulants (warfarin) and how safe these drugs are. The primary objective of the study is to assess the occurence of an ischemic stroke (a condition when an artery that brings blood to the brain is blocked) and intracranial hemorrhage (a serious condition when a diseased blood vessel within the brain bursts).

Study Overview

• Status: Terminated
• Conditions: Non-valvular Atrial Fibrillation
• Intervention / Treatment: Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Apixaban (Eliquis); Drug: Dabigatran etexilate (Pradaxa); Drug: Warfarin (Marevan)

• Study Type: Observational
• Enrollment (Actual): 70000

Contacts and Locations

Study Locations

• Norway
  • Multiple Locations, Norway
    • Many Locations

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

The study population will comprise all adult OAC naïve NVAF patients in Norway who filled a prescription for an OAC (rivaroxaban, apixaban, dabigatran, warfarin) in the study period, defined as from 1 January 2014 to 30 June 2018 (or later depending on availability of data) and followed until outcome of interest, the end of the study period or death. This initiation of an OAC is the index event and requires that there is no previous prescription dispensed for an OAC in the preceding 365 days (from end date of OAC supply to date of new OAC dispensation).

Description

Inclusion Criteria:

Registry cohort (Cohort 1)

Cohort 1a:

• Age ≥18 at the date of first OAC (Oral Anti-Coagulants) dispensation (index date)
• Diagnosed with atrial fibrillation or flutter in the period 5-year pre-index period. Defined as ICD10 codes; I480 (paroxysmal AF), I481 (persisting AF), I482 (chronic AF), I483 (typical AF), I484 (atypical AF) or I489 (unspecified atrial fibrillation or flutter) as given by either NPR (Norwegian Patient Register) or as a OAC (warfarin, dabigatran, rivaroxaban or apixaban) dispensed on the reimbursement code for AF in NorPD (Norwegian Prescription Database) (ICD10 I48 or ICPC-2 K78)
• Dispensation of a first-time prescription for an OAC during the study period 1 January 2014 to 31 May 2018. This initiation of an OAC is the index event and requires that there is no previous prescription for any OAC in the preceding 365 days (counted from the date of the first dispensation backward to the end of OAC supply).

Cohort 1b:

• Age ≥18 at the beginning of the study period (1 January 2014).
• Diagnosed with atrial fibrillation or flutter prior or during the study period. Defined as ICD10 codes; I480 (paroxysmal AF), I481 (persisting AF), I482 (chronic AF), I483 (typical AF), I484 (atypical AF) or I489 (unspecified atrial fibrillation or flutter) as given by NPR.
• No dispensation of a prescription for an OAC (warfarin, dabigatran, rivaroxaban or apixaban) during the study period 1 January 2014 to 30 June 2018. The index event will be the beginning of the study period (1 January 2014) and requires that there is no previous prescription for an OAC in the preceding 365 days.

EMR cohort (Cohort 2):

• Age ≥18 at the date of first OAC dispensation (index date).
• Diagnosed with atrial fibrillation or flutter in the 5-year pre-index period defined as one of the following ICD10 codes in the EMRs obtained from the hospitals in the South-Eastern Health Region; I480 (paroxysmal AF), I481 (persisting AF), I482 (chronic AF), I483 (typical AF), I484 (atypical AF) or I489 (unspecified atrial fibrillation or flutter).
• Dispensation of a first-time prescription for an OAC (warfarin, dabigatran, rivaroxaban or apixaban) during the study period 1 January 2014 to 31 May 2018. This initiation of an OAC is the index event and requires that there is no previous prescription of any OAC in the preceding 365 days (counted from the date of the first dispensation backward to the end of OAC supply).

Exclusion Criteria:

• Valvular atrial fibrillation defined as presence of ICD10 codes in NPR; I05.2 mitral stenosis with insufficiency, I05.8 other mitral valve diseases (mitral (valve) failure), I342 (non-rheumatic mitral valve stenosis), Z952 (presence of prosthetic heart valve) and procedure codes FKD (prosthetic replacement of mitral valve), FKA (Repair of mitral valve for stenosis), FKB (Annuloplasty of mitral valve for insufficiency), FKC (Repair of mitral valve for insufficiency), FKW (Other operations on mitral valve) and FMD (replacement of aortic valve).
• Deep Venous Thrombosis (DVT) as defined by ICD10 codes I80 (Phlebitis and thrombophlebitis), Pulmonary Embolism (PE) as defined by ICD10 code I26 or I82 (other venous embolism and thrombosis), Other venous embolism and thrombosis within last 6 months before index date.
• Knee and/or hip replacement surgery (NCSP (Nordic Classification of Surgical Procedures) procedure codes; NGB, NGC, NFB or NFC) 5 weeks before index date.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Registry cohort; Registries in Norway are nation-wide and provision of the information is mandatory, which eliminates the risk of both selection and re-call bias. The large and detailed dataset also makes it possible to adjust for other risk factors on which information is available.	Drug: Rivaroxaban (Xarelto, BAY59-7939); Administration according to clinical practice; Drug: Apixaban (Eliquis); Administration according to clinical practice; Drug: Dabigatran etexilate (Pradaxa); Administration according to clinical practice; Drug: Warfarin (Marevan); Administration according to clinical practice
Electronic Medical Records (EMR) cohort; Patients with NVAF diagnosis will be identified through extraction of patient-level data from EMRs from a number of hospitals in Norway, in order to describe these patients more closely regarding their clinical characteristics that are not available in nation-wide registers (e.g., in-patient treatments, anthropometric data and laboratory test results).	Drug: Rivaroxaban (Xarelto, BAY59-7939); Administration according to clinical practice; Drug: Apixaban (Eliquis); Administration according to clinical practice; Drug: Dabigatran etexilate (Pradaxa); Administration according to clinical practice; Drug: Warfarin (Marevan); Administration according to clinical practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ischemic stroke	Ischemic stroke is defined by the following ICD10 (International Classification of Diseases) codes: I63x: Cerebral infarction	Retrospective analysis from 1 January 2014 to 30 June 2018
Intracranial hemorrhage	Intracranial haemorrhage (ICH) is defined by the following ICD10 codes: I60x Subarachnoid haemorrhage I61x Intracerebral haemorrhage I62x Other non-traumatic intracranial haemorrhage	Retrospective analysis from 1 January 2014 to 30 June 2018

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall stroke	Overall stroke is defined by the following ICD10 codes: I60x: Subarachnoid haemorrhage I61x: Intracerebral haemorrhage I62x: Other nontraumatic intracranial haemorrhage I63x: Cerebral infarction I64x: Stroke, not specified as haemorrhage or infarction	Retrospective analysis from 1 January 2014 to 30 June 2018
Systemic embolism	Systemic embolism is defined by the following ICD10 codes: I74x: Arterial embolism and thrombosis	Retrospective analysis from 1 January 2014 to 30 June 2018
Myocardial infarction	Myocardial infarction is defined by the following ICD10 codes: I21x: Acute myocardial infarction I22x: Subsequent myocardial infarction	Retrospective analysis from 1 January 2014 to 30 June 2018
All-cause mortality		Retrospective analysis from 1 January 2014 to 30 June 2018
Major bleeding	As defined by Cunningham algorithm and Internation Society of Thrombosis and Hemostasis (ISTH) for EMR cohort.	Retrospective analysis from 1 January 2014 to 30 June 2018
Demographic characteristics		Retrospective analysis from 1 January 2014 to 30 June 2018
Clinical characteristics	Age, gender, CHA2DS2-VASc and HAS-BLED score, bleeding history, concomitant medications and co-morbidities	Retrospective analysis from 1 January 2014 to 30 June 2018
Drug utilization patterns		Retrospective analysis from 1 January 2014 to 30 June 2018

Collaborators and Investigators

• Sponsor: Bayer
• Collaborators: Janssen Research & Development, LLC

Study record dates

Study Major Dates

• Study Start (ACTUAL): October 31, 2018
• Primary Completion (ACTUAL): January 20, 2020
• Study Completion (ACTUAL): January 20, 2020

Study Registration Dates

• First Submitted: October 19, 2018
• First Submitted That Met QC Criteria: October 19, 2018
• First Posted (ACTUAL): October 23, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 10, 2020
• Last Update Submitted That Met QC Criteria: December 9, 2020
• Last Verified: December 1, 2020

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; Warfarin
• Other Study ID Numbers: 19468

Drug and device information, study documents

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