Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients

Study Overview
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Brief Summary
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The primary objective of this study is to demonstrate that in patients with recuperated/normalized left ventricular function, defined as an ejection fraction (EF) ≥ 50%, after implantation of cardiac resynchronization therapy, device treatment is sufficient and neurohumoral blocker therapy can safely be withdrawn

Official Title
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Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding Patients to Cardiac Resynchronization Therapy: the STOP-CRT Trial

Conditions
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Heart Failure (HF)

Intervention / Treatment
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* Drug: beta blockers
* Drug: RAAS blockers


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years CRT implantation based on class I recommendations of ESC (European society of CArdiology) guidelines: Left bundle branch block (LBBB) with QRS duration >150 ms and left ventricular ejection fraction (LVEF) ≤35% who remained NYHA functional class II, III and ambulatory IV despite adequate medical treatment LBBB with QRS duration 120-150 ms and LVEF ≤ 35% who remain in NYHA functional class II, III and ambulatory IV despite adequate medical treatment At the moment of inclusion: ≥ 6 months after implantation At the moment of inclusion: normalised LVEF (≥ 50%), LVIDD/BSA (left ventricular internal diastolic diameter indexed to body surface area) ≤3.2 cm/m²(woman) en ≤3.1 cm/m² (men) or LVDV/BSA (left ventricular diastolic volume indexed to body surface area) ≤75 ml/m² (women) or ≤75 ml/m² (men) euvolemic clinical state and functioning in NYHA class I Exclusion Criteria: contraindication for withdrawal of ACE-I/ARB such as diabetic nephropathy and proteinuria > 1g / 24 h severe ventricular arrythmia (sustained VT or ventricular fibrillation) occuring at the time LV function was normalized ischemic cardiomyopathy with evidence of scarring (scarring on MRI or severe hypokinesia/akinesia in >1 LV wall segment on echocardiography) known severe coronary atherosclerosis (stenosis ≥ 80%)

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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: non-intervention arm<br>continuation of neurohumoral blocker therapy based on maximum tolerated guideline recommended dose (this group is the control arm for as well withdrawal of beta blocker therapy as withdrawal of RAAS blocker therapy) | |
| Active Comparator: withdrawal of beta blockers<br>Intervention arm with systematic withdrawal of beta blocker therapy at a reverse sequence of guideline recommended uptitration. (this group is the experimental arm for beta blocker withdrawal. This group receives no intervention with regards to the withdrawal of RAAS blockade). Per 2 weeks: bisoprolol: 10mg/d → 5 mg/d → 2,5 mg/d → 1,25 mg/d stop metoprolol: 200 mg/d → 100 mg/d → 50 mg/d → 25 mg/d → stop nebivolol: 10mg/d → 5 mg/d → 2,5 mg/d → 1,25 mg/d stop carvedilol: 50 mg bid → 25 mg bid → 12,5 mg bid → 6,25 mg bid → stop | Drug: beta blockers<br> <br> |
| Active Comparator: withdrawal of RAAS blockers<br>intervention arm with systematic withdrawal of spironolactone followed by withdrawal of ACE-I/ARB at a reverse sequence of guideline recommended uptitration (this group receives no intervention regarding the withdrawal of beta blockers. This group is the experimental arm for withdrawal of RAAS blockers) first spironolactone/eplerenone: per two weeks: 25 mg/d→12,5 mg/d → stop after 2 weeks stop spironolactone/eplerenone start withdrawal of ACE-I/ARB per two weeks: captopril: 50 mg tid→25 mg tid→12,5 mg tid→6,25 mg tid→stop enalapril: 10 mg bid→5 mg bid→2,5 mg bid→1,25 mg bid→stop lisinopril: 20 mg/d→10 mg/d→5 mg/d→2,5 mg/d→stop ramipril: 10 mg/d→5 mg/d→2,5 mg/d→1,25 mg/d→stop candesartan: 32 mg/d→16 mg/d→8 mg/d→4 m/d→stop valsartan: 160 mg bid→80 mg bid→40 mg bid→20 mg bid→stop | Drug: RAAS blockers<br>* RAAS blockers (combination of ACE-I/ARB and a mineralocorticoid receptor antagonist)<br>|
| Active Comparator: withdrawal of RAAS - and beta blockers<br>intervention arm with systematic withdrawal of spironolactone, secondly ACE-I/ARB and finally beta blockers. (this group is the experimental group for both study interventions (withdrawal of beta blockers and RAAS blockers) First: spironolactone/eplerenone cfr reduction schedule supra After 2 weeks of stop spironolactone withdrawal of ACE-I or ARB cfr reduction schedule supra After 2 weeks of stop ACE-I/ARB withdrawal of beta blocker cfr reduction schedule supra | Drug: beta blockers<br> <br> Drug: RAAS blockers<br>* RAAS blockers (combination of ACE-I/ARB and a mineralocorticoid receptor antagonist)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| a > 15% increase in left ventricular end systolic volume |  | at 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| - Incidence of HF related hospitalizations defined as admission to hospital / presentation to emergency room with need for parental therapy |  | at 12 months | 
| All cause mortality |  | at 12 months | 
| VO2 max change |  | at 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neurohumoral blocker therapy, renin-angiotensin-aldosterone system (RAAS), RAAS-blocker, beta blocker, spironolactone, angiotensin converting enzyme inhibitor (ACE-I), angiotensin receptor blocker (ARB), cardiac resynchronization therapy (CRT), heart failure, dyssynchrony, left bundle branch block