DANISH-CRT - Does Electric Targeted LV Lead Positioning Improve Outcome in Patients With Heart Failure and Prolonged QRS

Study Overview
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Brief Summary
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Heart failure is a leading cause of morbidity and mortality. Cardiac resynchronization therapy (CRT) is a well-established treatment for patients with symptomatic heart failure in spite of optimised medical treatment (OMT), reduced left ventricular pump function with left ventricular ejection fraction (LVEF) ≤ 35% and prolonged activation of the ventricles (bundle branch block: BBB). CRT is established by implanting an advanced pacemaker system with three leads in the right atrium, right ventricle, and in the coronary sinus (CS) for pacing the left ventricle (LV), and often is combined with an implantable defibrillator (ICD) function. On average, CRT treatment improves longevity, quality of life and functional class, and reduces heart failure symptoms. Thus, at present, CRT is indicated for heart failure patients on OMT with BBB or chronic right ventricular (RV) pacing. It is, however, a significant problem that 30-40% of CRT patients do not benefit measurably - showing symptomatic improvement or improved cardiac pump function - from this therapy (socalled non-responders). LV lead placement is one of the major determinants of beneficial effect from CRT. Observational studies and three randomised trials with small sample sizes indicate that targeted placement of the LV lead towards a late activated segment of the LV may be associated with improved outcome. Based on this literature, some physicians already search for late activation when positioning the LV lead. However, such a strategy was never tested in a controlled trial with a sample size sufficient to investigate important clinical outcomes. Detailed mapping for a late activation may increase operating times and infection risk, result in use of more electrodes and wires, thereby increasing costs, and increase radiation exposure for patient and staff. Placement of the LV lead in late activated areas close to myocardial scar may even result in higher risk of arrhythmia and death. At present, it is completely unsettled whether targeted positioning of the LV lead to the latest electrically activated area of LV is superior to contemporary standard CRT with regard to improving prognosis for patients with heart failure and BBB. The present study aims to test whether targeting the placement of the LV lead towards the latest electrically activated segment in the coronary sinus branches improves outcome as compared with standard LV lead implant in a patient population with heart failure and CRT indication.

Official Title
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Does Targeted LV Lead Positioning Towards Latest Local Electric Activation at CRT Implantation Reduce Incidence of the Combined Endpoint Death or Non-planned Hospitalisation for Heart Failure (HF) in Patients With HF and Prolonged QRS

Conditions
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Heart Failure, Branch Block, Bundle

Intervention / Treatment
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* Device: Implantation of a Cardiac Resynchronisation Therapy (CRT) pacing device with or without Implanted Cardioverter Defibrillator


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Heart Failure, NYHA II, III, outpatient IV LVEF ≤35% measured by echocardiography Optimal medical treatment for heart failure Bundle Branch Block Indication for primary CRT-D or CRT-P implantation or upgrade from RV pacing (pacemaker or ICD) to CRT-D or CRT-P Ischemic heart disease (IHD) or non-IHD Sinus rhythm or atrial fibrillation Life expectancy >2 years Signed informed consent Exclusion Criteria: NYHA class I Acute mycardial infarction (AMI) within the latest 3 months Coronary artery bypass graft (CABG) within the latest 3 months Life expectancy <2 years Participation in another clinical trial of experimental treatment Contraindication for establishing implantable device treatment Previously implanted CRT system Does not wish to participate

Ages Eligible for Study
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Minimum Age: 40 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: Double-blind randomised controlled trial. Patients are included and randomised 1:1 into two groups for implantation of either a CRT-D/P device with the LV lead positioned according to the latest electrical activation in the CS (intervention group) or a CRT-D/P device with the LV lead positioned preferentially in a posterolateral, non-apical position (control group)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control<br>Implantation of a Cardiac Resynchronisation Therapy (CRT) pacing device with or without Implanted Cardioverter Defibrillator with the LV lead positioned preferentially in a posterolateral, non-apical position | Device: Implantation of a Cardiac Resynchronisation Therapy (CRT) pacing device with or without Implanted Cardioverter Defibrillator<br>* Implantation of CRT-P/-D device<br>|
| Experimental: Intervention<br>Implantation of a Cardiac Resynchronisation Therapy (CRT) pacing device with or without Implanted Cardioverter Defibrillator with the LV lead positioned according to the latest electrical activation in the CS | Device: Implantation of a Cardiac Resynchronisation Therapy (CRT) pacing device with or without Implanted Cardioverter Defibrillator<br>* Implantation of CRT-P/-D device<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or first non-planned hospitalisation for heart failure | Time to death or first non-planned hospitalisation for heart failure | All patients will be followed until the last included patient has been followed for two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death | Time to death | All patients will be followed until the last included patient has been followed for two years | 
| Non-planned hospitalisation for heart failure | Time to first non-planned hospitalisation for heart failure | All patients will be followed until the last included patient has been followed for two years | 
| Sudden death | Time to sudden death | All patients will be followed until the last included patient has been followed for two years | 
| Cardiac death | Time to cardiac death | All patients will be followed until the last included patient has been followed for two years | 
| Clinical response | Increase in New York Heart Association (NYHA) class (≥1 class from baseline) or improved walking distance by six-minute walk test (6MWT) (≥10% from baseline) | Follow-up at 3, 6, 12, 24 and 48 months | 
| Quality of Life (QoL) | Changes in score from baseline to follow-up | Follow-up at 6, 12, 24 and 48 months | 
| Patient Reported Outcomes (PROs) | Changes in score from baseline to follow-up | Follow-up at 6, 12, 24 and 48 months | 
| Echocardiographic measures of LV function | Changes from baseline to follow-up in left ventricular ejection fraction (%) | Follow-up at 6, 12, 24 and 48 months | 
| Time to first appropriate ICD Therapy | Time to first appropriate ICD therapy (antitachycardia pacing (ATP) or shock therapy) | All patients will be followed until the last included patient has been followed for two years | 
| Time to first inappropriate ICD Therapy | Time to first inappropriate ICD therapy (antitachycardia pacing (ATP) or shock therapy) | All patients will be followed until the last included patient has been followed for two years | 
| Numbers of appropriate ICD Therapies | Numbers of appropriate ICD therapies (antitachycardia pacing (ATP) or shock therapy) | All patients will be followed until the last included patient has been followed for two years | 
| Numbers of inappropriate ICD Therapies | Numbers of inappropriate ICD therapies (antitachycardia pacing (ATP) or shock therapy) | All patients will be followed until the last included patient has been followed for two years | 
| Ventricular tachycardia (VT)/ventricular fibrillation (VF) | Time to first episode of VT/VF | All patients will be followed until the last included patient has been followed for two years | 
| Persistent atrial fibrillation | Recorded by the implanted device | All patients will be followed until the last included patient has been followed for two years | 
| Any atrial fibrillation | >30 seconds recorded by the implanted device | All patients will be followed until the last included patient has been followed for two years | 
| Implantation time | Procedure time at implantation | 0-6 hours, assessed at completion of implantation procedure | 
| Fluoroscopy time | Fluoroscopy time at implantation in minutes | 0-120 minutes, assessed at completion of implantation procedure | 
| Fluoroscopy dose | Fluoroscopy dose at implantation in mGy | Assessed <24 hours after implantation initiation | 
| Equipment used at implantation | Number of LV leads (0-5) used at implantation | Assessed <24 hours after implantation initiation | 
| Device-related outcomes | Periprocedural: lead re-operation, pneumothorax, hemothorax, pericardial bleeding/tamponade and later (30 days post implantation): LV lead re-operation, device replacement due to battery depletion, and infection requiring extraction | All patients will be followed until the last included patient has been followed for two years | 
| Battery replacements | Number of device replacements during the study period due to battery depletion | All patients will be followed until the last included patient has been followed for two years | 
| Battery longevity estimate | Measured by actual device battery longevity + estimated remaining device battery longevity as reported by the device at last study follow-up | All patients will be followed until the last included patient has been followed for two years | 
| QRS complex width | Changes in the ECG parameter QRS complex width during follow-up | All patients will be followed until the last included patient has been followed for two years | 
| QRS complex morphology | Changes in the ECG parameter QRS complex morphology during follow-up | All patients will be followed until the last included patient has been followed for two years | 
| Predictive value of P-wave | Predictive value of the baseline ECG parameter P-wave on clinical outcome measures in the entire cohort and between the two treatment groups | All patients will be followed until the last included patient has been followed for two years | 
| Predictive value of QRS complex width | Predictive value of the baseline ECG parameter QRS complex width on clinical outcome measures in the entire cohort and between the two treatment groups | All patients will be followed until the last included patient has been followed for two years | 
| Predictive value of QRS complex morphology | Predictive value of the baseline ECG parameter QRS complex morphology on clinical outcome measures in the entire cohort and between the two treatment groups | All patients will be followed until the last included patient has been followed for two years | 
| Changes in cardiac chamber dimensions | Volumes of cardiac chambers (left ventricle, left atrium, right ventricle, right atrium) measured by echocardiography and cardiac CT during follow-up in the entire cohort and between the two treatment groups | All patients will be followed until the last included patient has been followed for two years | 
| Changes in left ventricular ejection fraction LVEF | Changes in cardiac chamber function measured by echocardiography and cardiac CT during follow-up in the entire cohort and between the two treatment groups | All patients will be followed until the last included patient has been followed for two years | 
| Changes in right ventricular ejection fraction RVEF | Changes in cardiac chamber function measured by echocardiography and cardiac CT during follow-up in the entire cohort and between the two treatment groups | All patients will be followed until the last included patient has been followed for two years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Branch Block, Cardiac Resynchronization Therapy