Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients - Clinical Trial for Heart Failure (HF) | NCT02200822

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Primary Purpose

Status

Completed

Phase

Phase 4

Locations

Belgium

Study Type

Interventional

Intervention

beta blockers

RAAS blockers

About this trial

This is an interventional treatment trial for Heart Failure (HF) focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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%)

Sites / Locations

Ziekenhuis Oost Limburg

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

No Intervention

Active Comparator

Arm Label

non-intervention arm

withdrawal of beta blockers

withdrawal of RAAS blockers

withdrawal of RAAS - and beta blockers

Arm Description

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)

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

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

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

Outcomes

Primary Outcome Measures

a > 15% increase in left ventricular end systolic volume

Secondary Outcome Measures

- Incidence of HF related hospitalizations defined as admission to hospital / presentation to emergency room with need for parental therapy

All cause mortality

VO2 max change

Full Information

NCT ID

NCT02200822

First Posted

July 24, 2014

Last Updated

July 30, 2019

Sponsor

Hasselt University

Collaborators

Ziekenhuis Oost-Limburg

1. Study Identification

Unique Protocol Identification Number

NCT02200822

Brief Title

Systematic Withdrawal of Neurohumoral Blocker Therapy in Optimally Responding CRT Patients

Acronym

STOP-CRT

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

July 2019

Overall Recruitment Status

Completed

Study Start Date

July 2014 (undefined)

Primary Completion Date

February 2019 (Actual)

Study Completion Date

February 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Hasselt University

Collaborators

Ziekenhuis Oost-Limburg

4. Oversight

Data Monitoring Committee

Yes

5. 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Factorial Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

80 (Actual)

8. Arms, Groups, and Interventions

Arm Title

non-intervention arm

Arm Type

No Intervention

Arm Description

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)

Arm Title

withdrawal of beta blockers

Arm Type

Active Comparator

Arm Description

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

Arm Title

withdrawal of RAAS blockers

Arm Type

Active Comparator

Arm Description

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

Arm Title

withdrawal of RAAS - and beta blockers

Arm Type

Active Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

beta blockers

Intervention Type

Drug

Intervention Name(s)

RAAS blockers

Intervention Description

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

Primary Outcome Measure Information:

Title

a > 15% increase in left ventricular end systolic volume

Time Frame

at 12 months

Secondary Outcome Measure Information:

Title

- Incidence of HF related hospitalizations defined as admission to hospital / presentation to emergency room with need for parental therapy

Time Frame

at 12 months

Title

All cause mortality

Time Frame

at 12 months

Title

VO2 max change

Time Frame

at 12 months

Other Pre-specified Outcome Measures:

Title

>15% increase in left ventricular end systolic volume

Time Frame

6 and 24 months

Title

> 15% decrease in left ventricular ejection fraction

Time Frame

at 6, 12 and 24 months

Title

mean blood pressure change

Time Frame

at 6, 12 and 24 months

Title

HF symptoms change (dyspnea visual analogue scale (VAS), New York Heart Association (NYHA) class, questionnaire "Minnesota living with Heart Failure")

Time Frame

at 6, 12 and 24 months

Title

incidence of heart rhythm events (sustained ventricular tachycardia (VT), atrial fibrillation, ventricular fibrillation)

Time Frame

at 6, 12 and 24 months

Title

heart rate variability

Time Frame

at 6, 12 and 24 months

Title

urinary catecholamine concentration

Time Frame

at 6, 12 and 24 months

Title

change in myocardial contractility (force frequence relationship, left ventricular pre-ejection time, iso-volumetric contraction time, dP/dt)

Time Frame

at 6, 12 and 24 months

Title

change in diastolic filling pattern

Time Frame

at 6, 12 and 24 months

Title

plasma concentrations of plasma renin activity and aldosterone

Time Frame

at 6, 12 and 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

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%)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Petra Nijst, MD

Organizational Affiliation

Ziekenhuis Oost-Limburg

Official's Role

Principal Investigator

Facility Information:

Facility Name

Ziekenhuis Oost Limburg

City

Genk

State/Province

Limburg

ZIP/Postal Code

3600

Country

Belgium

12. IPD Sharing Statement

Citations:

PubMed Identifier

32216911

Citation

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.

Results Reference

derived

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

Heart Failure (HF)

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial