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Cardiac Resynchronisation Therapy Versus Rate-responsive Pacing in Heart Failure With Preserved Ejection Fraction (PREFECTUS)

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ClinicalTrials.gov Identifier: NCT03338374
Recruitment Status : Recruiting
First Posted : November 9, 2017
Last Update Posted : January 18, 2020
Sponsor:
Collaborators:
Abbott
Cardiff Metropolitan University
Information provided by (Responsible Party):
Freya Lodge, Cardiff and Vale University Health Board

Brief Summary:

Half of patients with heart failure have normal heart pumping function (Heart failure with Preserved Ejection Fraction, HFpEF), most commonly characterised by breathlessness on exercise. A number of mechanisms are responsible, but frequently patients are unable to raise their heart rate on exercise. This can be treated by a 'rate-responsive pacemaker' (RRP), which detects exercise and increases the heart rate accordingly. Some beneficial effects on echocardiographic parameters have been reported with exercise programmes. However, evidence based treatment options are limited in this group and therapy mainly relies on water tablets and treatment of blood pressure.

Cardiac resynchronisation therapy (CRT) is a technique using specialised 'biventricular' pacemakers that is well established in heart failure with reduced pump function. Patients who respond to this treatment have lower risk of death and hospitalisation and usually feel better. CRT is not currently used in HFpEF. The PROSPECT trial showed that some patients with relatively preserved heart function exhibited similar benefits to those with poor pump function, but this has not been formally tested. CRT aims to make the heart beat in a more synchronised way. Patients with HFpEF commonly have evidence of reduced heart synchronisation.

The investigators plan to assess the feasibility of using a prospective cohort study to assess the incremental benefit of CRT over and above RRP in patients with HFpEF. 10 patients with HFpEF and insufficient heart rate will be recruited and will undergo exercise testing, heart scanning and symptom questionnaires. A biventricular pacemaker will be implanted and programmed to RRP for 12 weeks before repeating the tests. After this, the investigators will non-invasively programme the pacemaker to CRT for 12 weeks and repeat the functional tests. If incremental benefit is shown with CRT the echocardiograms will be analysed in detail to determine the mechanism of change. The study participants will be invited to continue their involvement in a study extension. This will involve non-invasively programming the pacemakers to optimise their function guided by the results of the echocardiograms in the first two phases of the study. After a further 12 weeks, the functional assessments will be repeated. If no benefit is seen with CRT after initial analysis, the participant involvement will end.


Condition or disease Intervention/treatment Phase
Diastolic Heart Failure Device: Biventricular pacemaker Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Exploratory single-centre, open label, non-randomised, prospective cohort study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Heart Failure With Preserved Ejection Fraction Treated by Cardiac Resynchronisation Therapy Versus Rate Responsive Pacing: A Mechanistic Study
Actual Study Start Date : November 27, 2017
Estimated Primary Completion Date : May 1, 2020
Estimated Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Experimental: Biventricular Pacemaker
All subjects to be in a single study group experiencing all interventions.
Device: Biventricular pacemaker
All subjects will receive a biventricular pacemaker at implantation. Programming will initially be to dual-chamber, dual-function rate-responsive pacing for 12 weeks; following reassessment, device will be reprogrammed to biventricular pacing for a further 12 weeks. Optional study extension: if incremental benefit is shown for biventricular pacing above dual chamber, the mechanism will be sought using echocardiographic evidence and the devices will be optimised according to this mechanism of action to see whether further benefit can be achieved.
Other Name: Rate responsive pacing




Primary Outcome Measures :
  1. Diastolic reserve index [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    The change in e' between rest and exercise, as measured by tissue Doppler in the septal and/or lateral left ventricular walls on echocardiography. To be expressed using the formula: [change in e'] x [1-(1/e' at rest)]. e' is the peak diastolic velocity of the myocardium during passive left ventricular filling.

  2. Systolic reserve index [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    The change in s' between rest and exercise, as measured by tissue Doppler in the septal and/or lateral left ventricular walls on echocardiography. To be expressed using the formula: [change in s'] x [1-(1/s' at rest)]. s' is the peak systolic velocity of the myocardium.


Secondary Outcome Measures :
  1. Global longitudinal strain [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    Peak systolic strain of 6 myocardial segments measured on echocardiography by speckle tracking, measured both at rest and on exercise

  2. Left ventricular torsion [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    The twisting movement of the heart can be quantified with echocardiography using speckle tracking at rest and on exercise.

  3. Exercise duration [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    Cardiopulmonary exercise testing will be used with standard local protocols to evaluate exercise duration.

  4. Oxygen carrying capacity [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    Measurement of peak ventilatory capacity (VO2 max) using cardiopulmonary exercise testing with standard local protocols, ensuring a respiratory exchange ratio of greater than 1.1 to guarantee near-maximal exercise achieved. This will be assessed using expired gas analysis, which is a standard technique.

  5. Distance walked in a six-minute walk test [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    Subjects walk down a pre-measured course, usually a hallway or corridor, and their distance achieved after six minutes is recorded.

  6. New York Heart Association Function Class [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    Standard measure of heart failure severity that correlates with outcomes. Assessed using measures of impairment in activities of daily living, such as dressing, walking.

  7. Minnesota Living with Heart Failure Quality of Life Score [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    Change in Minnesota living with heart failure questionnaire score. This questionnaire asks 21 questions relating to daily tasks of living, hobbies, social life and well-being in relation to heart failure symptoms and ascribes greater points to more severe symptoms; a higher score is therefore indicative of a lower quality of life. Scores may range between 0 and 105.

  8. Prognostic biomarkers [ Time Frame: After 12 weeks of rate responsive pacing and again after 12 weeks of biventricular pacing; study extension: after 6 weeks of optimised pacing ]
    Measurement of serum N-terminal pro-B-type Natriuretic Peptide, a commonly used marker of ventricular wall stretch that correlates with heart failure severity and is adversely associated with prognosis.


Other Outcome Measures:
  1. Drop-out rate [ Time Frame: At 24 weeks (or if study extension used, then following completion of this 6-week extension) ]
    A measure of the number of participants who fail to complete the study processes, to inform further studies using a similar design



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:

  • Confirmed HFpEF as described above
  • Chronotropic incompetence as described above
  • Ongoing exertional breathlessness of NYHA Grade II or worse
  • Ability to understand and sign written consent form
  • Males and females, age >18 years
  • Ability to participate in follow-up appointments at 3 and 6 months post-implantation
  • Ability to complete a cardiopulmonary exercise test

Exclusion Criteria:

  • Any contraindication to implantation of permanent pacemaker, namely unresolved infective process or sepsis, vascular access difficulties, advanced neoplastic process, expected lifespan less than 1 year or patient choice
  • Ejection fraction <50%
  • Known valvular disease graded severe or moderate-to-severe
  • Cardiac arrhythmia (paroxysmal or persistent) within 1 year of recruitment
  • Exertional chest pain suggestive of angina or personal history of coronary artery disease without subsequent revascularisation, or coronary angiogram within the past 5 years demonstrating >50% stenosis in ≥ 1 epicardial coronary artery
  • Significant chronic lung disease (FEV1 <80%)
  • Inability to complete follow-up process for any reason not defined above

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): NCT03338374


Contacts
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Contact: Freya M Lodge, MB BS +447734755529 freyalodge@doctors.org.uk
Contact: Zaheer R Yousef, MD +442920742972 zaheer.yousef@wales.nhs.uk

Locations
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United Kingdom
Cardiff and Vale University Health Board Recruiting
Cardiff, Mid Glamorgan, United Kingdom, CF14 4XW
Contact: Freya M Lodge, MD    +447734755529    freyalodge@doctors.org.uk   
Contact: Zaheer R Yousef, MB BS    +442920742972    zaheer.yousef@wales.nhs.uk   
Principal Investigator: Zaheer R Yousef, MD         
Sub-Investigator: Freya M Lodge, MB BS         
Cardiff Metropolitan University Active, not recruiting
Cardiff, Mid Glamorgan, United Kingdom, CF23 6XD
Sponsors and Collaborators
Cardiff and Vale University Health Board
Abbott
Cardiff Metropolitan University
Investigators
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Study Director: Zaheer Yousef, MD Cardiff and Vale University Health Board
  Study Documents (Full-Text)

Documents provided by Freya Lodge, Cardiff and Vale University Health Board:
Informed Consent Form  [PDF] May 15, 2017

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Responsible Party: Freya Lodge, Clinical Research Fellow, Cardiff and Vale University Health Board
ClinicalTrials.gov Identifier: NCT03338374    
Other Study ID Numbers: 17/WA/0004 190938
First Posted: November 9, 2017    Key Record Dates
Last Update Posted: January 18, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Access to individual participant data (IPD) will be at the discretion of the study team. No plan is currently in place to share IPD. This is a small, exploratory study where full transparency will be demonstrated in publication of results; fully-anonymised individual participant data may be referenced in publication of results.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Freya Lodge, Cardiff and Vale University Health Board:
Cardiac chronotropy
Cardiac resynchronisation therapy
Rate responsive pacemaker
Heart failure with preserved ejection fraction
Additional relevant MeSH terms:
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Heart Failure
Heart Failure, Diastolic
Heart Diseases
Cardiovascular Diseases