Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients (STOP-CRT)

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

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of cardiac resynchronization therapy, device treatment is sufficient and neurohumoral blocker therapy can safely be withdrawn

Study Overview

• Status: Completed
• Conditions: Heart Failure (HF)
• Intervention / Treatment: Drug: beta blockers; Drug: RAAS blockers

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Limburg
    • Genk, Limburg, Belgium, 3600
      • Ziekenhuis Oost Limburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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%)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: non-intervention arm; 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; 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
Active Comparator: withdrawal of RAAS blockers; 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→stopenalapril: 10 mg bid→5 mg bid→2,5 mg bid→1,25 mg bid→stoplisinopril: 20 mg/d→10 mg/d→5 mg/d→2,5 mg/d→stopramipril: 10 mg/d→5 mg/d→2,5 mg/d→1,25 mg/d→stopcandesartan: 32 mg/d→16 mg/d→8 mg/d→4 m/d→stopvalsartan: 160 mg bid→80 mg bid→40 mg bid→20 mg bid→stop	Drug: RAAS blockers; RAAS blockers (combination of ACE-I/ARB and a mineralocorticoid receptor antagonist)
Active Comparator: withdrawal of RAAS - and beta blockers; 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; RAAS blockers (combination of ACE-I/ARB and a mineralocorticoid receptor antagonist)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Other Outcome Measures

Outcome Measure	Time Frame
>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
HF symptoms change (dyspnea visual analogue scale (VAS), New York Heart Association (NYHA) class, questionnaire "Minnesota living with Heart Failure")	at 6, 12 and 24 months
incidence of heart rhythm events (sustained ventricular tachycardia (VT), atrial fibrillation, ventricular fibrillation)	at 6, 12 and 24 months
heart rate variability	at 6, 12 and 24 months
urinary catecholamine concentration	at 6, 12 and 24 months
change in myocardial contractility (force frequence relationship, left ventricular pre-ejection time, iso-volumetric contraction time, dP/dt)	at 6, 12 and 24 months
change in diastolic filling pattern	at 6, 12 and 24 months
plasma concentrations of plasma renin activity and aldosterone	at 6, 12 and 24 months

Collaborators and Investigators

• Sponsor: Hasselt University
• Collaborators: Ziekenhuis Oost-Limburg
• Investigators: Principal Investigator: Petra Nijst, MD, Ziekenhuis Oost-Limburg

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): February 1, 2019
• Study Completion (Actual): February 1, 2019

Study Registration Dates

• First Submitted: July 24, 2014
• First Submitted That Met QC Criteria: July 24, 2014
• First Posted (Estimate): July 25, 2014

Study Record Updates

• Last Update Posted (Actual): August 1, 2019
• Last Update Submitted That Met QC Criteria: July 30, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: heart failure; spironolactone; beta blocker; left bundle branch block; neurohumoral blocker therapy; renin-angiotensin-aldosterone system (RAAS); RAAS-blocker; angiotensin converting enzyme inhibitor (ACE-I); angiotensin receptor blocker (ARB); cardiac resynchronization therapy (CRT); dyssynchrony
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Adrenergic beta-Antagonists
• Other Study ID Numbers: ZOL-STOP-CRT