Cardiac Allograft Vasculopathy, Transplanted Heart Complication
Conditions
Keywords
Heart transplantation, Exercise capacity, Heart rate, Cardiac allograft vasculopathy
Brief summary
This study evaluates whether treatment with ivabradine compared to placebo can improve exercise capacity in long-term heart transplant recipients with cardiac allograft vasculopathy and elevated heart rate at rest. Patients will receive treatment with either ivabradin or placebo for a period of 12 weeks.
Detailed description
Elevated resting heart rate (HR) is a normal finding after successful heart transplantation (HTx) due to parasympathetic denervation at the operation. Elevated resting HR is generally acknowledged as a negative predictor of outcome in heart disease. The impact in heart transplant recipients is not fully understood, however, it has been associated with increased risk of developing cardiac allograft vasculopathy (CAV) or death. Cardiac allograft vasculopathy is a diffuse vascular disease affecting the entire coronary tree. It is the leading cause of death in patients more than 5 years after HTx and it is well known that patients with CAV have markedly reduced exercise capacity. The association between elevated HR and CAV raises the question whether an intervention to specifically lower HR could improve symptoms and prognosis in heart transplant recipients with CAV and elevated resting HR. Small studies have shown that HR reduction using the If channel blocker ivabradine after HTx is safe. However, none of these studies were randomized or blinded, and as such proof of any efficacy (beyond HR reduction) after HTx is non-existing. Clearly, there is a need to determine if such treatment could improve exercise capacity, graft function and prognosis after HTx.
Interventions
DRUGIvabradine
Ivabradine, oral tablets, 5 mg, coated in gelatine capsules to ensure blinding, 1 capsule twice a day, for a period of 12 weeks
DRUGPlacebo
Placebo, gelatine capsules to ensure blinding, 1 capsule twice daily, for a period of 12 weeks
Sponsors
Danish Heart Foundation
Rigshospitalet, Denmark
Finn Gustafsson
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This is a prospective single-center, double-blinded, placebo controlled, randomized study in long-term heart transplant recipients. Patients who meet the eligibility criteria will be randomized 1:1 at inclusion for one of two treatment groups: (i) treatment with ivabradine 5 mg bid or (ii) treatment with placebo bid for a period of 12 weeks. 35 participants will be enrolled.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Patients \> 1 year post heart transplantation * CAV verified by coronary angiography or intravascular ultrasound * Resting HR \> 80 bpm * Age \> 18 years * Signed informed consent Women, who have not yet entered menopause (defined as no menstrual bleeding in the last 12 months), will be required to provide a negative urine human chorionic gonadotropin (hCG) before entering the study and must use a safe birth control method in the total study period.
Exclusion criteria
* Rejection (\>H1R) \< 3 months * Severe renal failure (estimated glomerular filtration rate (GFR) \< 30 mL/min/1.73 m2) * Inability or contraindication to perform a VO2 max test * Presence of any condition that might per se influence exercise performance * Known contraindication for treatment with ivabradine * Hypersensitivity to the active substance or to any of the excipients of either study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ΔVO2max | The VO2max is assessed at baseline and 12 weeks follow-up. | The change in VO2max (ΔVO2max) (mL/kg/min) from baseline to 12 weeks follow-up. The peak oxygen uptake (VO2max) reflects the maximal ability of a person to take in, transport and use oxygen, and it defines the functional aerobic capacity. It is used to provide an overall assessment of exercise capacity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| ΔHRrest | 12 weeks | Change in resting HR (beats/min) from baseline to 12 weeks follow-up |
| ΔHRreserve | 12 weeks | Change in HR reserve (beats/min) from baseline to 12 weeks follow-up |
| ΔLVmass | 12 weeks | Change in left ventricular (LV) mass (g) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
| ΔLVEF | 12 weeks | Change in left ventricular ejection fraction (LVEF) (%) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
| Δmitral deceleration time | 12 weeks | Change in mitral decelaration time (ms) evaluated by echocardiography from baseline to 12 weeks follow-up |
| ΔE/é | 12 weeks | Change in E/é evaluated by echocardiography from baseline to 12 weeks follow-up |
| ΔE/A ratio | 12 weeks | Change in E/A ratio evaluated by echocardiography from baseline to 12 weeks follow-up |
| Δisovolumetric relaxation time | 12 weeks | Change in isovolumetric relaxation time (ms) evaluated by echocardiography from baseline to 12 weeks follow-up |
| Δpulmonary venous flow | 12 weeks | Change in pulmonary venous flow (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
| ΔLVEDV | 12 weeks | Change in LVEDV (left ventricular end diastolic volume) (ml) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
| ΔLVESV | 12 weeks | Change in LVESV (left ventricular end systolic volume) (ml) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
| ΔLV peak filling rate | 12 weeks | Change in left ventricular (LV) peak filling rate (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
| Δtime to peak filling | 12 weeks | Change in time to peak filling (sec) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
| ΔQOL KCCQ | 12 weeks | Change in QOL score evaluated by Kansas City Cardiomyopathy Questionnaire from baseline to 12 weeks follow-up |
| ΔQOL EQ-5D-5L | 12 weeks | Change in QOL score evaluated by EQ-5D-5L questionnaire from baseline to 12 weeks follow-up |
| Δtransmitral flow rate | 12 weeks | Change in transmitral flow rate (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up |
Other
| Measure | Time frame | Description |
|---|---|---|
| Coronary vessel characterization | Substudy objective is only evaluated at baseline | Substudy objective: To characterize coronary vessels in CAV using new imaging modalities and relating them to functional parameters of cardiac function. Modalities performed at baseline: Intravascular ultrasound (IVUS)/Near-infrared spectroscopy (NIRS), optical coherence tomography (OCT), 82-Rubudium positron emission tomography (PET) scan |
Countries
Denmark
Contacts
Primary ContactFinn Gustafsson, MD PhD DMSc
Backup ContactLærke Nelson, MD
Outcome results
None listed