Mechanical Dyssynchrony as Selection Criterion for CRT (AMEND-CRT)

Previous experience with cardiac resynchronization therapy (CRT) candidates suggests that selection of these patients can be improved. Current clinical guideline approaches are mainly too unspecific and lead to a high non-responder rate of 30-40%, which causes a burden on health care systems and puts patients at risk of an unnecessary treatment who might benefit more from a conservative approach. Previous work indicated that using the assessment of mechanical dyssynchrony on echocardiography can lower the non-responder rate at least by 50% without compromising sensitivity for detecting amendable patients. The current prospective, randomized, multi-center trial was therefore designed to prove that the characterization of the mechanical properties of the left ventricle can improve patient selection for CRT. Patients will be randomized into one of two study arms: a control study arm with treatment recommendation based on clinical guidelines criteria, or an experimental study arm with treatment recommendation based on the presence of mechanical dyssynchrony. All patients will receive a CRT implantation. In the control study arm, bi-ventricular pacing will be turned on. In the experimental study arm, bi-ventricular pacing will be turned on or off, depending on the presence or absence of mechanical dyssynchrony, respectively. The primary endpoint will be non-inferiority in outcome of a treatment recommendation based on mechanical dyssynchrony, achieved with a lower number of CRT devices implanted, effectively leading to a lower number needed to treat. Outcome measures are the average relative change in continuously measured LVESV per arm and the percentage 'worsened' according to the Packer Clinical Composite Score per arm after 1 year follow-up.

Left Ventricular Dyssynchrony, Heart Failure, Cardiomyopathy, Dilated, Cardiac Remodeling, Ventricular

Cardiac resynchronization therapy, Heart failure, Mechanical dyssynchrony, Echocardiography, Apical rocking, Septal flash, Left ventricle

Treatment of the patient assigned to this arm will be based on the current guidelines for CRT implantation, as issued by the European Society of Cardiology. All patients will receive CRT implantation, with bi-ventricular pacing ON.

Treatment of the patients assigned to this arm will be based on the presence of mechanical dyssynchrony. All patients will receive CRT implantation. Bi-ventricular pacing will be either turned ON or OFF, based on respectively the presence or absence of mechanical dyssynchrony.

Non-inferiority in outcome of a treatment recommendation based on mechanical dyssynchrony, achieved with a lower number of CRT devices implanted, effectively leading to a lower number needed to treat. Outcome measures are the average relative change in continuously measured left ventricular end-systolic volume per arm and the percentage 'worsened' according to the Packer Clinical Composite Score per arm after 12 months follow-up

≥ 10% difference in relative change in left ventricular ejection fraction and/or ≥1.5% difference in absolute change in global longitudinal strain and/or improvement in myocardial work from baseline to month 12

Difference in quality of life as measured by the Minnesota Living with Heart Failure questionnaire score and EuroQol 5D index score in both arms

≥ 5 points difference in change on the Minnesota Living with Heart Failure questionnaire score and/or ≥0.08 points difference in change on the EuroQol 5D index score from baseline to month 12

≥15% relative reduction in left ventricular end-systolic volume from baseline to month 12 will be considered as a response

Cox's proportional hazards model: At 1 year for 'worsened' PCCS At 3 and 5 years for cardiovascular mortality and heart failure hospitalization

Kaplan Meier survival analysis for heart failure hospitalization Kaplan Meier survival analysis for cardiovascular mortality Kaplan Meier survival analysis for combined heart failure hospitalization and cardiovascular mortality Kaplan Meier survival analysis for all-cause mortality

Inclusion Criteria: The proposed inclusion criteria represent the minimum recommendations for CRT implantation in heart failure patients according to the ESC 2016 guidelines. In addition: Patient has a LVEF ≤ 35% Patient has a LVEDD ≥ 55mm Patient has been in a stable medical condition for ≥ 1 month prior inclusion Patient receives Optimal Medical Treatment (OMT) Patient underwent complete revascularization in case of ischemia Patients is able to understand and willing to provide a written informed consent Patient is 18 years or older Exclusion Criteria: Patients who meet any of the following criteria will not participate in the study: Patient suffers from ventricular arrhythmias which do not allow to acquire 3 consecutive regular beats during echocardiography (e.g. frequent VES, bigemini, …) Patient suffers from severe MR, or otherwise more than moderate valvular disease Patient suffers from unstable angina Patient suffers from pulmonary hypertension, other than secondary to left heart disease Patient has a life expectancy of less than 1 year Patient is pregnant or breastfeeding Patient has either no pacemaker / ICD or has a right ventricular pacing of < 40%, and any of the following: Atrial fibrillation PR duration > 250ms Second or third degree atrioventricular block Intrinsic QRS duration < 130ms Patient has a right ventricular pacing of > 40% and any of the following Sensed AV delay > 250ms Paced AV delay > 280ms