Real-world Comparative Effectiveness of Stroke Prevention in Patients With Atrial Fibrillation Treated With Factor Xa Non-vitamin-K Oral Anticoagulants (NOACs) vs. Phenprocoumon (ReLoaDeD)

Existing real-world studies have provided evidence that novel oral anticoagulants (NOACs) in general and rivaroxaban in particular are more effective and at least as safe as warfarin in non-valvular atrial fibrillation (NVAF) patients with renal impairment. Nevertheless, it is known that clinicians often hesitate to prescribe NOACs to patients with even moderate renal impairment. Therefore, it is important to investigate effectiveness and safety of rivaroxaban and other NOACs compared to vitamin-K antagonists in NVAF patients with renal dysfunction in real life setting.

The primary objectives of this study are to describe the risk of ischemic stroke (IS)/ systemic embolism (SE) and intracranial hemorrhage (ICH) in patients with non-valvular atrial fibrillation (NVAF) and renal impairment initiating treatment with individual NOACs (rivaroxaban, apixaban, edoxaban) compared to phenprocoumon.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Phenprocoumon; Drug: Apixaban; Drug: Rivaroxaban (Xarelto, BAY59-7939); Drug: Edoxaban

• Study Type: Observational
• Enrollment (Actual): 64920

Contacts and Locations

Study Locations

• Germany
  • Multiple Locations, Germany
    • Many Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The source population of this study will include all insured members of approximately 64 German statutory health insurances (SHIs) contributing data to the InGef database.

Description

Inclusion Criteria:

• First NOAC (rivaroxaban, apixaban, edoxaban) or phenprocoumon prescription (index drug) in the enrollment period between 1st January 2013 to 30th June 2017 (index date).
• Age of at least 18 years at index date.
• Continuous enrollment in the 12 months before the first NOAC (rivaroxaban, apixaban, edoxaban) or phenprocoumon prescription in the enrollment period (baseline period).
• A verified ambulatory or primary/ secondary hospital discharge diagnosis of NVAF in the 12 months before the first NOAC (rivaroxaban, apixaban, edoxaban) or phenprocoumon prescription in the enrollment period (baseline period).

Exclusion Criteria:

• A verified ambulatory or primary/ secondary hospital discharge diagnosis of valvular atrial fibrillation, indicating pregnancy, transient cause of atrial fibrillation or venous thromboembolism (VTE).
• A claim for hip or knee replacement surgery in the 60 days prior to or on the index date.
• A prescription of more than one oral anticoagulant (rivaroxaban, apixaban, edoxaban or phenprocoumon) on the index date.
• A prescription of warfarin or dabigatran in the baseline period or on the index date.
• A verified ambulatory or primary/ secondary hospital discharge diagnosis of end-stage kidney disease or a claim for dialysis in the baseline period.
• Patients receiving an initial dose of rivaroxaban 10 mg/ 2.5 mg or edoxaban 15 mg (these dosages are not indicated for the treatment of NVAF).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Phenprocoumon; Patients with NVAF who initiated the treatment of Phenprocoumon.	Drug: Phenprocoumon; Follow the physician's prescription.
Apixaban; Patients with NVAF who initiated the treatment of Apixaban.	Drug: Apixaban; 2.5 mg or 5 mg, twice daily
Rivaroxaban (Xarelto, BAY59-7939); Patients with NVAF who initiated the treatment of Rivaroxaban.	Drug: Rivaroxaban (Xarelto, BAY59-7939); 15 mg or 20 mg, once daily
Edoxaban; Patients with NVAF who initiated the treatment of Edoxaban.	Drug: Edoxaban; 30 mg or 60 mg, once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk of Ischemic stroke (IS) / Systemic embolism(SE) (as combined endpoint and alone), recurrent IS/SE (as combined endpoint) and severe IS in patients with NVAF and renal impairment determined by inpatient claims based diagnoses	Severe IS will be defined according to an approach proposed by Schubert et al. as hospitalization with a primary hospital discharge diagnosis of IS in combination with an OPS (Operationen und Prozedurenschlüssel) code indicating one of the following: intubation, mechanical ventilation or percutaneous endoscopic gastronomy	Retrospective analysis from January 2012 - December 2017
Risk of intracranial hemorrhage (ICH) in patients with non-valvular atrial fibrillation (NVAF) with renal impairment determined by inpatient claims based diagnoses		Retrospective analysis from January 2012 - December 2017
Healthcare resource consumption in patients with non-valvular atrial fibrillation (NVAF) and renal impairment determined by inpatient claims based diagnoses		Retrospective analysis from January 2012 - December 2017
Overall costs in patients with renal impairment determined by inpatient claims based diagnoses		Retrospective analysis from January 2012 - December 2017
Sector specific costs in patients with renal impairment determined by inpatient claims based diagnoses		Retrospective analysis from January 2012 - December 2017

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Risk of fatal bleeding in patients with NVAF (overall population as well as patients with renal impairment) determined by inpatient claims based diagnoses	Fatal bleeding will be defined as hospitalization with a primary hospital discharge diagnoses for bleeding with documented death as reason for hospital discharge or within 30 days after hospital discharge.	Retrospective analysis from January 2012 - December 2017
Risk of recurrent hospitalizations (in general and for IS/SE)		Retrospective analysis from January 2012 - December 2017
Risk of Kidney failure determined by inpatient claims based diagnoses		Retrospective analysis from January 2012 - December 2017
Risk of Acute kidney injury (AKI) determined by inpatient claims based diagnoses		Retrospective analysis from January 2012 - December 2017
Risk of treatment discontinuation in patients with NVAF (overall population as well as patients with renal impairment) determined by pharmacy claims		Retrospective analysis from January 2012 - December 2017
Risk of IS, SE, Severe IS and recurrent IS/SE in patient with NVAF determined determined by inpatient claims based diagnoses		Retrospective analysis from January 2012 - December 2017

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Click here to find results for studies related to Bayer products.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2018
• Primary Completion (Actual): December 10, 2019
• Study Completion (Actual): December 10, 2019

Study Registration Dates

• First Submitted: June 11, 2018
• First Submitted That Met QC Criteria: June 11, 2018
• First Posted (Actual): June 20, 2018

Study Record Updates

• Last Update Posted (Actual): November 27, 2020
• Last Update Submitted That Met QC Criteria: November 24, 2020
• Last Verified: November 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; Apixaban; Edoxaban; Phenprocoumon
• Other Study ID Numbers: 20031

Drug and device information, study documents

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