Clinical trial NCT03405831: Effect of Ivabradine on Exercise Capacity After Heart Transplantation
Official title: The Effect of Ivabradine Treatment on Exercise Capacity in Patients With Cardiac Allograft Vasculopathy After Heart Transplantation
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Cardiac Allograft Vasculopathy
Transplanted Heart Complication
Keywords: Heart transplantation
Exercise capacity
Heart rate
Cardiac allograft vasculopathy
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Danish Heart Foundation
name: Rigshospitalet, Denmark
First posted: 2018-01-23
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: ΔVO2max
timeFrame: The VO2max is assessed at baseline and 12 weeks follow-up.
Secondary outcomes:
measure: ΔHRrest
timeFrame: 12 weeks
measure: ΔHRreserve
timeFrame: 12 weeks
measure: ΔLVmass
timeFrame: 12 weeks
measure: ΔLVEF
timeFrame: 12 weeks
measure: Δmitral deceleration time
timeFrame: 12 weeks
measure: ΔE/é
timeFrame: 12 weeks
measure: ΔE/A ratio
timeFrame: 12 weeks
measure: Δisovolumetric relaxation time
timeFrame: 12 weeks
measure: Δtransmitral flow rate
timeFrame: 12 weeks
measure: Δpulmonary venous flow
timeFrame: 12 weeks
measure: ΔLVEDV
timeFrame: 12 weeks
measure: ΔLVESV
timeFrame: 12 weeks
measure: ΔLV peak filling rate
timeFrame: 12 weeks
measure: Δtime to peak filling
timeFrame: 12 weeks
measure: ΔQOL KCCQ
timeFrame: 12 weeks
measure: ΔQOL EQ-5D-5L
timeFrame: 12 weeks
Other outcomes:
measure: Coronary vessel characterization
timeFrame: Substudy objective is only evaluated at baseline
Locations:
city: Copenhagen
country: Denmark
facility: Department of Cardiology, Copenhagen University Hospital, Rigshospitalet
Study officials:
affiliation: Rigshospitalet, Denmark
name: Lærke Nelson, MD
role: PRINCIPAL_INVESTIGATOR
References: