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

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ClinicalTrials.gov Identifier: NCT02200822
Recruitment Status : Unknown
Verified July 2014 by Wilfried Mullens, MD PhD, Hasselt University.
Recruitment status was:  Recruiting
First Posted : July 25, 2014
Last Update Posted : July 25, 2014
Sponsor:
Collaborator:
Ziekenhuis Oost-Limburg
Information provided by (Responsible Party):
Wilfried Mullens, MD PhD, Hasselt University

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of cardiac resynchronization therapy, device treatment is sufficient and neurohumoral blocker therapy can safely be withdrawn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

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : July 2014
Estimated Primary Completion Date : July 2016
Estimated Study Completion Date : July 2017

Resource links provided by the National Library of Medicine


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)




Primary Outcome Measures :
  1. a > 15% increase in left ventricular end systolic volume [ Time Frame: at 12 months ]

Secondary Outcome Measures :
  1. - Incidence of HF related hospitalizations defined as admission to hospital / presentation to emergency room with need for parental therapy [ Time Frame: at 12 months ]
  2. All cause mortality [ Time Frame: at 12 months ]
  3. VO2 max change [ Time Frame: at 12 months ]

Other Outcome Measures:
  1. >15% increase in left ventricular end systolic volume [ Time Frame: 6 and 24 months ]
  2. > 15% decrease in left ventricular ejection fraction [ Time Frame: at 6, 12 and 24 months ]
  3. mean blood pressure change [ Time Frame: at 6, 12 and 24 months ]
  4. 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 ]
  5. incidence of heart rhythm events (sustained ventricular tachycardia (VT), atrial fibrillation, ventricular fibrillation) [ Time Frame: at 6, 12 and 24 months ]
  6. heart rate variability [ Time Frame: at 6, 12 and 24 months ]
  7. urinary catecholamine concentration [ Time Frame: at 6, 12 and 24 months ]
  8. 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 ]
  9. change in diastolic filling pattern [ Time Frame: at 6, 12 and 24 months ]
  10. plasma concentrations of plasma renin activity and aldosterone [ Time Frame: at 6, 12 and 24 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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%)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02200822


Contacts
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Contact: Petra Nijst, MD 3289761525 nijst.petra@gmail.com
Contact: Wilfried Mullens, MD, PhD 3289327110 wilfried.mullens@zol.Be

Locations
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Belgium
Ziekenhuis Oost Limburg Recruiting
Genk, Limburg, Belgium, 3600
Contact: Petra Nijst, MD    3289761525    nijst.petra@gmail.com   
Contact: Wilfried Mullens, MD, PhD    3289327110    wilfried.mullens@zol.Be   
Principal Investigator: Petra Nijst, MD         
Principal Investigator: Frederik Verbrugge, MD         
Principal Investigator: Matthias Dupont, MD         
Principal Investigator: Wilfried Mullens, MD, PhD         
Sponsors and Collaborators
Hasselt University
Ziekenhuis Oost-Limburg
Investigators
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Principal Investigator: Petra Nijst, MD Ziekenhuis Oost-Limburg

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Responsible Party: Wilfried Mullens, MD PhD, MD PhD, Hasselt University
ClinicalTrials.gov Identifier: NCT02200822     History of Changes
Other Study ID Numbers: ZOL-STOP-CRT
First Posted: July 25, 2014    Key Record Dates
Last Update Posted: July 25, 2014
Last Verified: July 2014

Keywords provided by Wilfried Mullens, MD PhD, Hasselt University:
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

Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Spironolactone
Adrenergic beta-Antagonists
Angiotensin-Converting Enzyme Inhibitors
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Diuretics, Potassium Sparing
Diuretics
Natriuretic Agents
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Protease Inhibitors
Enzyme Inhibitors