Effect of Ivabradine on Exercise Capacity After Heart Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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The Effect of Ivabradine Treatment on Exercise Capacity in Patients With Cardiac Allograft Vasculopathy After Heart Transplantation

Conditions
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Cardiac Allograft Vasculopathy, Transplanted Heart Complication

Intervention / Treatment
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* Drug: Ivabradine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ivabradine<br>Study participants in this arm will receive ivabradin 5 mg bid for a period of 12 weeks. | Drug: Ivabradine<br>* Ivabradine, oral tablets, 5 mg, coated in gelatine capsules to ensure blinding, 1 capsule twice a day, for a period of 12 weeks<br>* Other names: Procoralan;|
| Placebo Comparator: Placebo<br>Study participants in this arm will receive placebo bid for a period of 12 weeks. | Drug: Placebo<br>* Placebo, gelatine capsules to ensure blinding, 1 capsule twice daily, for a period of 12 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ΔVO2max | 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. | The VO2max is assessed at baseline and 12 weeks follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ΔHRrest | Change in resting HR (beats/min) from baseline to 12 weeks follow-up | 12 weeks | 
| ΔHRreserve | Change in HR reserve (beats/min) from baseline to 12 weeks follow-up | 12 weeks | 
| ΔLVmass | Change in left ventricular (LV) mass (g) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| ΔLVEF | Change in left ventricular ejection fraction (LVEF) (%) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| Δmitral deceleration time | Change in mitral decelaration time (ms) evaluated by echocardiography from baseline to 12 weeks follow-up | 12 weeks | 
| ΔE/é | Change in E/é evaluated by echocardiography from baseline to 12 weeks follow-up | 12 weeks | 
| ΔE/A ratio | Change in E/A ratio evaluated by echocardiography from baseline to 12 weeks follow-up | 12 weeks | 
| Δisovolumetric relaxation time | Change in isovolumetric relaxation time (ms) evaluated by echocardiography from baseline to 12 weeks follow-up | 12 weeks | 
| Δtransmitral flow rate | Change in transmitral flow rate (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| Δpulmonary venous flow | Change in pulmonary venous flow (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| ΔLVEDV | Change in LVEDV (left ventricular end diastolic volume) (ml) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| ΔLVESV | Change in LVESV (left ventricular end systolic volume) (ml) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| ΔLV peak filling rate | Change in left ventricular (LV) peak filling rate (volume/min) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| Δtime to peak filling | Change in time to peak filling (sec) evaluated by cardiac MRI from baseline to 12 weeks follow-up | 12 weeks | 
| ΔQOL KCCQ | Change in QOL score evaluated by Kansas City Cardiomyopathy Questionnaire from baseline to 12 weeks follow-up | 12 weeks | 
| ΔQOL EQ-5D-5L | Change in QOL score evaluated by EQ-5D-5L questionnaire from baseline to 12 weeks follow-up | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart transplantation, Exercise capacity, Heart rate, Cardiac allograft vasculopathy