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

Sponsor

Hasselt University (Other)

Overall Status

Completed

CT.gov ID

NCT02200822

Collaborator

Ziekenhuis Oost-Limburg (Other)

Enrollment

Location

Arms

55.1

Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

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of cardiac resynchronization therapy, device treatment is sufficient and neurohumoral blocker therapy can safely be withdrawn

Condition or Disease	Intervention/Treatment	Phase
Heart Failure (HF)	Drug: beta blockers Drug: RAAS blockers	Phase 4

Study Design

Study Type:

Interventional

Actual Enrollment :

80 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Jul 1, 2014

Actual Primary Completion Date :

Feb 1, 2019

Actual Study Completion Date :

Feb 1, 2019

Arms and Interventions

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→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 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)

Outcome Measures

Primary Outcome Measures

a > 15% increase in left ventricular end systolic volume [at 12 months]

Secondary Outcome Measures

- 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

>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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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%)