Re-evaluation of Optimal Re-synchronisation Therapy in Patients With Chronic Heart Failure

Study Overview
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Brief Summary
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The objective of the study is to demonstrate that in patients with chronic heart failure who receive optimal medical treatment for this condition and have indication for Cardiac Resynchronisation Therapy, the implantation of a pacemaker (index group) is not inferior to defibrillator (control group) with respect to all-cause mortality.

Detailed Description
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Heart failure is a leading cause of death, hospitalisation, impaired quality of life and health expenditure. Symptoms and survival can be significantly improved by implantation of a device for Cardiac Resynchronisation Therapy (CRT). CRT devices are available as biventricular pacemakers (CRT-P) or as significantly more complex and cost-intensive biventricular defibrillators (CRT-D). In patients who have previously experienced a life-threatening arrhythmia, the choice of the CRT-D (and not the CRT-P) is imperative but these are a small minority of patients. For the vast majority of patients receiving CRT therapy, there is currently considerable uncertainty as to whether the defibrillator function is needed and whether its benefits outweigh its risks. The defibrillator function may protect patients from sudden cardiac death. On the other hand, device-associated complications such as device infections appear to be increased; furthermore the defibrillator comes along with specific adverse events, particularly inappropriate shocks. These shocks are common and not only traumatic to patients (potentially leading to post-traumatic stress syndrome, anxiety disorders and depression), they also are negatively associated with overall survival. The objective of the trial is to demonstrate that in patients with chronic heart failure who receive optimal medical treatment for this condition and have indication for CRT, the implantation of a CRT-P (index group) is not inferior to CRT-D (control group) with respect to all-cause mortality. Patients with an indication for CRT will be randomised to CRT-P or CRT-D. RESET-CRT is an event-driven trial with a planned number of randomised and treated patients of at least n=1,356 (maximum of 2,004) and of 361 primary endpoints within an estimated median follow-up period of about 29 to 40 months. No investigational medical product is defined to be used within RESET-CRT since only the therapeutic strategy (CRT-D versus CRT-P) is a pre-defined study treatment and allocated by random group (Proof of Strategy Trial). The devices to be implanted will be decided by the treating physician on the basis of the situation of the individual study patient and in line with local policies in routine clinical care. Duration of study period: Enrolment of 1,356 patients is expected to be completed within 52 months after inclusion of the first patient, i.e., by 31 December 2022. With an overall annual event rate between 9.0% and 12.5%, 361 primary endpoints will have occurred within 9 to 20 months of randomisation of the last patient (between 30 September 2023 and 31 August 2024). Under these circumstances, the total study duration will be between 62 and 73 months. The Steering Committee of the study might prolong the recruitment period, for instance by 12 months, in the event of an unexpected slower recruitment rate or an overall event rate < 9.0% for the primary endpoint. For individual patients, the expected median follow-up time is between 29 and 40 months, with a minimum between 9 and 20 months and a maximum between 61 and 72 months. Follow-up may be prolonged by 12 months in the event of a prolonged recruitment period.

Official Title
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Re-evaluation of Optimal Re-synchronisation Therapy in Patients With Chronic Heart Failure - An Investigator-initiated, Event-driven, Prospective, Parallel-group, Randomised, Open, Blinded Outcome Assessment (PROBE), Multi-centre Trial Without Investigational Medical Products (Proof of Strategy Trial)

Conditions
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Chronic Heart Failure

Intervention / Treatment
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* Procedure: CRT-P implantation
* Procedure: CRT-D implantation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years. Symptomatic chronic heart failure due to ischemic or non-ischemic cardiomyopathy with NYHA class II, III or ambulatory IV. Reduced left ventricular ejection fraction ≤35% in transthoracic echocardiography (TTE) or cardiac magnetic resonance imaging (MRI) assessed verifiably within 4 weeks prior to or on the day of enrolment. On Optimal Medical Therapy (OMT) for at least 3 months prior to enrolment. Class I or IIa indication for implantation of a device for cardiac resynchronisation therapy (according to 2016 Guidelines of the European Society of Cardiology for the diagnosis and treatment of acute and chronic heart failure). Signed informed consent. Exclusion criteria: Class I or IIa indication for implantation of an ICD for secondary prevention of sudden cardiac death and ventricular tachycardia (according to the 2015 Guidelines of the European Society of Cardiology for the management of patients with ven-tricular arrhythmias and the prevention of sudden cardiac death). Violation of Instruction For Use of the selected device by at least one of the random group treatments. Ventricular tachycardia induced in an electrophysiological study. Carrying any implanted cardiac pacemaker, defibrillator or CRT device. Unexplained syncope. Hospitalised with unstable heart failure with NYHA class IV within 1 month prior to enrolment. Acute coronary syndrome or cardiac revascularization therapy by coronary angioplasty or coronary artery bypass grafting within 6 weeks prior to enrolment. Cardiac valve surgery or percutaneous cardiac valvular intervention such as transcatheter aortic valve replacement or transcatheter mitral valve repair performed within 3 months prior to enrolment. Reversible non-ischemic cardiomyopathy such as acute viral myocarditis or discontinuation of alcohol in alcohol-induced heart disease. On the waiting list for heart transplant. Any disease that limits life expectancy to less than 2 years. Severe chronic renal disease (GFR<15 ml/min and/or the need for dialysis) Participation in another clinical trial, either within the past 3 months or still ongoing (participation in sub-studies connected to this trial and participation in observational studies permitted). Previous participation in RESET-CRT. Pregnant women or women of childbearing potential not on adequate birth control. Drug abuse or clinically manifest alcohol abuse.

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CRT-P group<br>Intervention: CRT-P implantation | Procedure: CRT-P implantation<br>* Patients will be treated according to Optimal Medical Therapy defined by ESC Guidelines for treatment of patients with heart failure and will receive on top a CRT-P device.<br>|
| Active Comparator: CRT-D group<br>Intervention: CRT-D implantation | Procedure: CRT-D implantation<br>* Patients will be treated according to Optimal Medical Therapy defined by ESC Guidelines for treatment of patients with heart failure and will receive on top a CRT-D device.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomisation to the occurrence of all-cause death | Time from randomisation to the occurrence of all-cause death | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from randomisation to death from cardiac causes | Time from randomisation to death from cardiac causes | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 
| Time from randomisation to sudden cardiac death | Time from randomisation to sudden cardiac death | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 
| Time from randomisation to life-threatening arrhythmias | Time from randomisation to life-threatening arrhythmias | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 
| Time from randomisation to first composite of Major Adverse Cardiac Event (MACE) | Time from randomisation to first composite of Major Adverse Cardiac Event (MACE) | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 
| Time from randomisation to first hospitalisation for cardiovascular reasons | Time from randomisation to first hospitalisation for cardiovascular reasons | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 
| Nights spent in hospital for cardiovascular reasons per year of follow-up | Number of nights spent in hospital is calculated as time difference in days from hospital discharge to hospital admission. All hospital stays are serious adverse event by definition and will be assessed by an independent Endpoint Review Committee. The Endpoint Review Committee will also evaluate if a hospital stay for cardiovascular reasons is given. Per year of follow-up refers to a calculated number related to total follow-up duration of each patient normalised to years of follow-up. | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 
| Number of hospital readmissions for cardiovascular reasons after randomisation | Number of hospital readmissions for cardiovascular reasons after randomisation | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) | 
| Changes in quality of life (EQ-5D) comparing inclusion/enrolment with 12 and 24 months | Quality of life will be measured using the European Quality of life 5 Dimension (EQ5D) questionnaire including its visual-analogue scale (Scores range from 0-100 where 0 is the worst score). | at baseline, 12 and 24 months after randomisation | 
| Total cost of treatment as compound endpoint of MACEs, number of hospital days for cardiovascular reasons and ambulatory visits for cardiovascular reasons | otal cost of treatment as compound endpoint of MACEs, number of hospital days for cardiovascular reasons and ambulatory visits for cardiovascular reasons | Randomization to end of study (event-driven, expected about 9 to 20 months after last patient in) |