Atrial Fibrillation or Pulmonary Embolism, Existent Coronary or Valvular Calcification, or Both and Agatston Score > 50 in at Least One Location, Need of Long Term Oral Anticoagulation Therapy (OAT)
Conditions
Keywords
Coronary or Valvular Calcification, Agatston Score, Rivaroxaban, Coumarin, Oral Anticoagulation Therapy (OAT), Atrial Fibrillation, Pulmonary Embolism
Brief summary
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.
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)
Interventions
DRUGRivaroxaban 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.
Sponsors
Bayer
RWTH Aachen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression of coronary and aortic valve calcification (Agatston, volume & mass score as assessed by cardiac CT) | Cardiac Computertomography (CT) will be performed at screening, after 12 months and at 24 months | 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 |
Secondary
| Measure | Time frame |
|---|---|
| Changes in intima-media thickness of carotid artery (IMT) and flow-mediated vasodilation of brachial artery (FMD) | Baseline, 6, 12 and 24 month FU |
| Serum chemistry including Matrix Gla Protein (MPG) level changes and Fetuin-A (baseline/ follow up) | baseline and 12 month Follow Up |
| 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
| Measure | Time frame |
|---|---|
| Major bleedings | 1 week, 6, 9, 12 and 24 month FU |
| Non- major bleedings | 1week, 1, 6, 9, 12 and 24 month FU |
| Occurrence of major cardiovascular complications (MACE) | 1 week, 1, 6, 9, 12 and 24 month FU |
Countries
Germany
Outcome results
None listed