Effect of Ivabradine on Exercise Capacity After Heart Transplantation (VANISH-CAV)

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

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.

Study Overview

• Status: Unknown
• Conditions: Cardiac Allograft Vasculopathy; Transplanted Heart Complication
• Intervention / Treatment: Drug: Ivabradine; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 35
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Recruiting
    • Department of Cardiology, Copenhagen University Hospital, Rigshospitalet
    • Contact: Finn Gustafsson, MD PhD DMSc; Phone Number: +45 3545 9743; Email: finng@dadlnet.dk
    • Contact: Lærke Nelson, MD; Phone Number: +45 3545 9549; Email: laerke.marie.nelson@regionh.dk
    • Principal Investigator: Lærke Nelson, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 96 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Coronary vessel characterization	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	Substudy objective is only evaluated at baseline

Collaborators and Investigators

• Sponsor: Finn Gustafsson
• Collaborators: Rigshospitalet, Denmark; Danish Heart Foundation
• Investigators: Principal Investigator: Lærke Nelson, MD, Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2018
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: January 5, 2018
• First Submitted That Met QC Criteria: January 12, 2018
• First Posted (Actual): January 23, 2018

Study Record Updates

• Last Update Posted (Actual): March 5, 2019
• Last Update Submitted That Met QC Criteria: March 4, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Cardiac allograft vasculopathy; Heart transplantation; Heart rate; Exercise capacity
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases
• Other Study ID Numbers: RH-HJE-LN-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No