Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients

NCT02200822 | Completed Phase 4 DMC

• 1 other identifier: ZOL-STOP-CRT
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

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of cardiac resynchronization therapy, device treatment is sufficient and neurohumoral blocker therapy can safely be withdrawn

Conditions

Heart Failure (HF)

Keywords

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

Outcome Measures

Primary Outcomes (1)

• a > 15% increase in left ventricular end systolic volume

  at 12 months

Secondary Outcomes (3)

• - 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

Other Outcomes (10)

• >15% increase in left ventricular end systolic volume

  6 and 24 months

• > 15% decrease in left ventricular ejection fraction

  at 6, 12 and 24 months

• mean blood pressure change

  at 6, 12 and 24 months

Study Arms (4)

non-intervention arm

NO INTERVENTION

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)

withdrawal of beta blockers

ACTIVE COMPARATOR

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

withdrawal of RAAS blockers

ACTIVE COMPARATOR

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

withdrawal of RAAS - and beta blockers

ACTIVE COMPARATOR

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; Drug: RAAS blockers

Interventions

beta blockers DRUG

withdrawal of RAAS - and beta blockers; withdrawal of beta blockers

RAAS blockers DRUG

RAAS blockers (combination of ACE-I/ARB and a mineralocorticoid receptor antagonist)

withdrawal of RAAS - and beta blockers; withdrawal of RAAS blockers

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥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
• euvolemic clinical state and functioning in NYHA class I

You may not qualify if:

• 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%)

Sponsors & Collaborators

• Hasselt University: lead
• Ziekenhuis Oost-Limburg: collaborator

Study Sites (1)

Ziekenhuis Oost Limburg

Genk, Limburg, 3600, Belgium

Location

Related Publications (1)

• Nijst P, Martens P, Dauw J, Tang WHW, Bertrand PB, Penders J, Bruckers L, Voros G, Willems R, Vandervoort PM, Dupont M, Mullens W. Withdrawal of Neurohumoral Blockade After Cardiac Resynchronization Therapy. J Am Coll Cardiol. 2020 Mar 31;75(12):1426-1438. doi: 10.1016/j.jacc.2020.01.040.

  PMID: 32216911 DERIVED

MeSH Terms

Conditions

Heart Failure; Bundle-Branch Block

Interventions

Adrenergic beta-Antagonists

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Heart Block; Arrhythmias, Cardiac; Cardiac Conduction System Disease; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Physiological Effects of Drugs

Study Officials

• Petra Nijst, MD

  Ziekenhuis Oost-Limburg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD PhD

Study Record Dates

• First Submitted: July 24, 2014
• First Posted: July 25, 2014
• Study Start: July 1, 2014
• Primary Completion: February 1, 2019
• Study Completion: February 1, 2019
• Last Updated: August 1, 2019

Record last verified: 2019-07

Locations

BE (1)