Rivaroxaban Compared to Vitamin K Antagonist Upon Development of Cardiovascular Calcification

Influence of Rivaroxaban Compared to Vitamin K Antagonist Treatment Upon Development of Cardiovascular Calcification in Patients With Atrial Fibrillation and/ or Pulmonary Embolism (IRIVASC- Trial)

The following trial hypothesis will be proved: In patients with atrial fibrillation and/ or pulmonary embolism standard anticoagulant treatment with coumadin/phenprocoumon is associated with accelerated coronary or valvular calcification as assessed by cardiac computed tomography compared to the new anticoagulant therapy with rivaroxaban.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation or Pulmonary Embolism; Need of Long Term Oral Anticoagulation Therapy (OAT); Existent Coronary or Valvular Calcification, or Both and Agatston Score > 50 in at Least One Location
• Intervention / Treatment: Drug: Rivaroxaban or Marcumar

Detailed Description

A multi center, prospective, controlled, open, randomized, interventional clinical trial blinded concerning outcome measurements with a two- arm parallel group design will be performed to investigate the association of rivaroxaban compared to coumadin/phenprocoumon treatment for OAT in patients with atrial fibrillation and / or pulmonary embolism regarding the development and progression of coronary artery calcification (CAC) and aortic valve calcification (AVC) as assessed by multi-slice spiral computed tomography scanning (MSCT) within one year follow-up.

In total 190 patients (95 patients per treatment arm) with atrial fibrillation and/ or pulmonary embolism with the indication for oral anticoagulation therapy will be enrolled.

After screening first cardiac CT scan will be performed in order to validate if calcium score is >50 which is an inclusion criteria. If the patient matches all other inclusion/exclusion criteria the remaining imaging procedures (Echocardiography, Intima Media Thickness of carotid artery (IMT) and Flow Mediated Vasodilatation (FMD), Electrocardiography (ECG) and blood pressure are executed. Pregnancy strip test will be executed and also serum chemistry, hematology, coagulation and batch analysis will be performed.

Patients will then be randomized to one of the two arms (Rivaroxaban or Marcumar) and will undergo the same examinations and measurements as described above at 1 week, 1, 6, 9 and 12 month Follow- Up (FU). In case of a positive result in respect to the primary endpoint a FU after 2 years will be performed.

Primary outcome measures will be assessed after all active patients will have completed 12-months study visit (interim analysis)

• Study Type: Interventional
• Enrollment (Actual): 192
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Bavaria
    • Coburg, Bavaria, Germany, 96450
      • Hospital Coburg, Med. Clinic II for Internal Medicine and Cardiology
  • North Rhine Westphalia
    • Aachen, North Rhine Westphalia, Germany, 52074
      • University Hospital Aachen, Department of Cardiology
    • Eschweiler, North Rhine Westphalia, Germany, 52249
      • St.-Antonius-Hospital Eschweiler, Internal Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patient aged > 18 years
2. Need for long-term OAT according to current international guidelines for the treatment of atrial fibrillation (ACC/(American Heart Association [AHA]/ European Society of Cardiology [ESC]guidelines) and / or pulmonary embolism (ACCP/ESC guidelines).
3. Existent Coronary or Valvular Calcification, or both and an Agatston Score > 50 in at least one location as assessed by MSCT at Screening
4. The anticipated minimum life expectancy is18 months

Exclusion Criteria:

1. Patient has any clinical condition which does not allow initiation of long-term OAT including all contraindications such as hypersensitivity to active ingredient or other excipients, clinically relevant acute bleedings and all other risk circumstances according to Summary of Medicinal Product (SmPC) in which all warnings and preventive measures and precautions are described and have to be kept.
2. Hypersensitivity to active substances investigated or to any of the excipients
3. Patients had a previous coronary stent implantation in a way which makes coronary artery calcification scoring impossible or unreliable and no Valvular Calcification with Agatston Score > 50
4. Chronic kidney disease (CKD) Stage V (GFR <15 mL)
5. Liver disease with coagulopathy or other bleeding disorders including cirrhotic patients with Child Pugh B and C
6. Acute gastrointestinal diseases
7. Clinically significant active bleeding
8. Alcohol, opioids or drug abuse
9. Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study
10. Patient is unwilling or unable to give informed consent
11. Patient is unlikely to comply with protocol, e.g. uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
12. Participation in a parallel interventional clinical trial
13. Patient has been committed to an institution by legal or regulatory order
14. Pregnant or lactating women
15. Female patient capable of bearing children without highly effective methods of birth control
16. Patient receives concomitant treatment with strong concurrent Cytochrome P 450 3A4 (CYP3A4)- and P- glycoprotein (P-gp)- inhibitors, i.e. azole-antimycotics (ketoconazole, itraconazole) or human immunodeficiency virus (HIV) protease inhibitors
17. Neuraxial Anaesthesia or spinal/epidural puncture
18. Known Endocarditis
19. Known Lactose intolerance

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Rivaroxaban; Arm A: Rivaroxaban (tablet) for patients with atrial fibrillation: with 20 mg once daily for patients with eGFR > 49 ml per minute and 15 mg rivaroxaban once daily for patients with eGFR of 15 to 49 ml. Rivaroxaban (tablet) for patients with pulmonary embolism : 2x a day 15 mg at day 1-21 and 1x 20 mg from day 22 ongoing	Drug: Rivaroxaban or Marcumar; Arm A: Rivaroxaban (tablet) for patients with atrial fibrillation: with 20 mg once daily for patients with eGFR > 49 ml per minute and 15 mg rivaroxaban once daily for patients with eGFR of 15 to 49 ml. Rivaroxaban (tablet) for patients with pulmonary embolism : 2x a day 15 mg at day 1-21 and 1x 20 mg from day 22 ongoing; Arm B: Adjusted dose coumadin/phenprocoumon (tablet) titrated according to target international normalized ratio (INR) with a target range 2.0 to 3.0.; Other Names: Xarelto; Marcumar
ACTIVE_COMPARATOR: Marcumar; Arm B: Adjusted dose coumadin/phenprocoumon (tablet) titrated according to target international normalized ratio (INR) with a target range 2.0 to 3.0.	Drug: Rivaroxaban or Marcumar; Arm A: Rivaroxaban (tablet) for patients with atrial fibrillation: with 20 mg once daily for patients with eGFR > 49 ml per minute and 15 mg rivaroxaban once daily for patients with eGFR of 15 to 49 ml. Rivaroxaban (tablet) for patients with pulmonary embolism : 2x a day 15 mg at day 1-21 and 1x 20 mg from day 22 ongoing; Arm B: Adjusted dose coumadin/phenprocoumon (tablet) titrated according to target international normalized ratio (INR) with a target range 2.0 to 3.0.; Other Names: Xarelto; Marcumar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression of coronary and aortic valve calcification (Agatston, volume & mass score as assessed by cardiac CT)	To investigate the association of rivaroxaban compared to coumadin/phenprocoumon treatment for OAT in patients with atrial fibrillation and / or pulmonary embolism regarding the development and progression of coronary artery calcification (CAC) and aortic valve calcification (AVC) as assessed by multi-slice spiral computed. tomography scanning (MSCT) within one year follow-up	Cardiac Computertomography (CT) will be performed at screening, after 12 months and at 24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Serum chemistry including Matrix Gla Protein (MPG) level changes and Fetuin-A (baseline/ follow up)	baseline and 12 month Follow Up
Changes in intima-media thickness of carotid artery (IMT) and flow-mediated vasodilation of brachial artery (FMD)	Baseline, 6, 12 and 24 month FU
Progression of aortic calcification (aortic Agatston Score)	screening and 12 month FU
Changes in ventricular diastolic function parameters as determined by echocardiography (strain/strain-rate imaging)	baseline, 6, 9, 12 and 24 month FU

Other Outcome Measures

Outcome Measure	Time Frame
Occurrence of major cardiovascular complications (MACE)	1 week, 1, 6, 9, 12 and 24 month FU
Non- major bleedings	1week, 1, 6, 9, 12 and 24 month FU
Major bleedings	1 week, 6, 9, 12 and 24 month FU

Collaborators and Investigators

• Sponsor: RWTH Aachen University
• Collaborators: Bayer

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (ACTUAL): March 1, 2020
• Study Completion (ACTUAL): March 1, 2020

Study Registration Dates

• First Submitted: February 17, 2014
• First Submitted That Met QC Criteria: February 17, 2014
• First Posted (ESTIMATE): February 19, 2014

Study Record Updates

• Last Update Posted (ACTUAL): October 22, 2020
• Last Update Submitted That Met QC Criteria: October 21, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Atrial Fibrillation; Rivaroxaban; Pulmonary Embolism; Agatston Score; Coronary or Valvular Calcification; Coumarin; Oral Anticoagulation Therapy (OAT)
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Arrhythmias, Cardiac; Calcium Metabolism Disorders; Embolism; Atrial Fibrillation; Pulmonary Embolism; Calcinosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Phenprocoumon
• Other Study ID Numbers: 12-001