An interventional study of Biventricular pacemaker in Diastolic Heart Failure, sponsored by Cardiff and Vale University Health Board. Completed at 2 sites in United Kingdom. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-06-02.
Sponsored by Cardiff and Vale University Health Board · Not applicable, Interventional, and Treatment
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.
This is an exploratory single-centre, open label, non-randomised, prospective cohort study comparing rate responsive pacing (RRP) with CRT in patients with confirmed HFpEF and chronotropic incompetence.
Setting:
The study will be conducted in Cardiff and Vale University Health Board, with patients drawn from Cardiology clinics and inpatient wards. Follow-up assessments will be conducted at Cardiff School of Sport, a research facility at a university campus close to the main hospital.
Number of subjects planned:
10 patients. This will be sufficient to establish estimates of variability in the diastolic reserve index (see below), allow estimation of treatment difference and gauge acceptability.
Target population:
Subjects with HFpEF and chronotropic incompetence
Endpoints:
Systolic and diastolic longitudinal reserve index are calculated by the following formulae:
Systolic reserve = Δs' x [1-(1/s'rest)] Diastolic reserve = Δe' x [1-(1/e'rest)]
These are known to be impaired in patients with HFpEF and are a marker of adaptation to exercise in terms of filling pressures and left ventricular relaxation. Tan et al report a significant difference between the results seen with 56 patients with HFpEF and 27 control subjects on exercise echocardiography with semi-supine bicycle.16 Patient characteristics were similar to those of our proposed study group (Ejection fraction (EF) >50%, New York Heart Association (NYHA) classification grade II, HFpEF according to Vasan and Levy criteria).28
The investigators will therefore investigate diastolic and systolic reserve index as possible endpoints of a future study into the efficacy of CRT versus RRP in HFpEF patients.
Planned interventions:
Visit 1 - Baseline Assessments: Patients will undergo initial assessment of baseline characteristics by echocardiography, cardiopulmonary exercise testing, 6-minute walk test (6MWT) and Minnesota Living with Heart Failure Questionnaire (MLHFQ). (Visit length: approx. 4 hours)
Visit 2 - Device Implantation (≤ 7 days after baseline assessments completed):
Eligible subjects will undergo implantation of a biventricular pacemaker under normal laboratory conditions. The device will be programme to administer rate-responsive pacing (DDDR). They will return to pacing clinic a week later for a programming check; during this visit, they will also undergo a chest x-ray according to local protocol to ensure correct lead placement (Visit length: 1 day + 2 hours)
Visit 3 - Assessments and Device Reprogramming After 12 weeks, the baseline parameters will be reassessed and patients will then have their device non-invasively reprogrammed to CRT. (Visit length: approx. 4 hours)
Visit 4 - Assessments After a further 12 weeks, the baseline assessments will be repeated. The pacemaker will be non-invasively reprogrammed to DDDR mode and the patient will go home. (Visit length: approx. 4 hours)
Optional extension (pending analysis of results) Visit 5 - Reprogramming If incremental benefit has been demonstrated with CRT above the benefit of RRP, the echocardiograms will be examined to establish the mechanism of improvement. Subjects will be invited to participate in a study extension using multisite technology. The device will be non-invasively reprogrammed to optimise the CRT settings targeted specifically for the mechanism identified. (Visit length: approx. 3 hour)
Visit 6 - Assessments 12 weeks after the final reprogramming, patients will attend for a final set of assessments as per baseline. Participant involvement will then cease. (Visit length: approx. 4 hours)
Total contact time with research team: Approximately 27 hours (22 hours without extension)
Exclusion Criteria:
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.
Also known as: Rate responsive pacing
Diastolic reserve index
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.
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
Systolic reserve index
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.
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
Global longitudinal strain
Peak systolic strain of 6 myocardial segments measured on echocardiography by speckle tracking, measured both at rest and on exercise
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
Left ventricular torsion
The twisting movement of the heart can be quantified with echocardiography using speckle tracking at rest and on exercise.
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
Exercise duration
Cardiopulmonary exercise testing will be used with standard local protocols to evaluate 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
Oxygen carrying capacity
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.
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
Distance walked in a six-minute walk test
Subjects walk down a pre-measured course, usually a hallway or corridor, and their distance achieved after six minutes is recorded.
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
New York Heart Association Function Class
Standard measure of heart failure severity that correlates with outcomes. Assessed using measures of impairment in activities of daily living, such as dressing, walking.
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
Minnesota Living with Heart Failure Quality of Life Score
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.
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
Prognostic biomarkers
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.
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
Drop-out rate
A measure of the number of participants who fail to complete the study processes, to inform further studies using a similar design
Time frame: At 24 weeks (or if study extension used, then following completion of this 6-week extension)
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Plan to share: No — 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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Cardiff and Vale University Health Board