PREFECTUS
Research type
Research Study
Full title
The PREFECTUS Study: Heart Failure with Preserved Ejection Fraction Treated by Cardiac Resynchronisation Therapy Versus Rate Responsive Pacing: a Feasibility Study\n\n
IRAS ID
190938
Contact name
Freya Lodge
Contact email
Duration of Study in the UK
1 years, 3 months, 1 days
Research summary
Research Summary
Heart Failure with Preserved Ejection Fraction Treated by Cardiac Resynchronisation Therapy VersUS Rate Responsive Pacing \nOutline\nHalf 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. However, evidence based treatment options are limited in this group; therapy mainly relies on water tablets and treatment of blood pressure. \nCardiac resynchronisation therapy (CRT), using specialised ‘biventricular’ pacemakers, 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 synchronisation.\nWe propose a feasibility study assessing CRT in patients with HFpEF. We will implant biventricular pacemakers in 20 HFpEF patients with insufficient heart rate and randomise them to one of two treatment periods: RRP then CRT, or CRT then RRP. At baseline patients will undergo exercise testing, heart scanning and symptom questionnaires. After 12 weeks, we will test them again and then switch groups (the CRT group will receive RRP and vice versa). 12 weeks later they will be retested. \nResearch Aim: To assess the feasibility of using a crossover study to assess CRT in HFpEF patients. \n\nPotential Benefits\nTo inform future trial designs and give provisional indications of efficacy.\n
Summary of results
"This study looked into the feasibility of a proposed trial design to test a type of pacemaker treatment called Cardiac Resynchronisation Therapy (CRT) against a standard dual-chamber 'rate response' pacemaker (DDDR) in patients with a condition called Heart Failure with Preserved Ejection Fraction (HFPEF). HFPEF occurs where the pumping action of the heart is within normal limits, but patients become breathless on exertion due to a number of mechanisms, including stiffening of the heart muscle and increased pressure inside the heart chambers.
CRT is designed to improve the coordination of heart contraction with each beat; DDDR is designed only to increase the heart rate during exercise or exertion. The study design was a single-blinded 2x2 crossover design that recruited 10 participants with HFPEF and confirmed chronotropic incompetence (an inability to increase the heart rate on exercise). Each participant received 3 months with each pacing mode in a randomised order, with half having CRT first and half DDDR first. The effect of the pacing modes was assessed using exercise testing, echocardiography (ultrasound scanning of the heart) and symptom questionnaires.10 subjects have now completed the study period. Some delays were experienced due to recruitment difficulties followed by COVID-19, which meant that we were unable to bring subjects in for testing. One participant did not receive the CRT pacing mode as the pacemaker lead (the flexible wire that sits inside the heart) could not be satisfactorily programmed and the subject declined repositioning of the lead. Their results were included in an intention-to-treat analysis.
Whilst it has been reported that chronotropic incompetence (CI) is common in HFPEF, in practice we found that true CI was not widely prevalent. Additionally, many subjects screened had atrial fibrillation (an irregular heart beat), which was an exclusion criterion for study participation due to its effects on pacemaker function. Furthermore, many subjects identified as potentially eligible had significant mobility issues that precluded exercise testing, many had significant comorbidities that not only would have confounded the results but also made some of the study activities technically difficult, and many approached also declined to receive pacemaker therapy as a potential treatment. Once recruited, it was notable that the implantation of the CRT pacemakers, usually used in subjects with severely dysfunctional and enlarged hearts, was technically more challenging in this population with smaller hearts.
In terms of selecting parameters for testing, image quality on echocardiography was often limited by body habitus and made worse by acquiring images during exercise, but we found that in the majority of subjects, useful data could be collected from echocardiography. Cardiopulmonary exercise testing was reasonably well tolerated in all but the frailest of patients (performed both during study activities and pre-recruitment screening). However, the use of bicycle exercise rather than treadmill exercise is known to reduce peak exercise output due to limitations on leg muscle strength rather than aerobic fitness. Nonetheless, the use of bicycle exercise permitted us to compare performance between baseline and each of the pacing modes, and patients found this acceptable.
We found no significant signal of benefit from CRT compared with DDDR in this patient group using any of the primary or secondary outcomes that we defined. There was a non-significant trend on some exercise parameters on echocardiography favouring CRT compared to DDDR. Whilst we cannot exclude that there is no benefit from these devices, it is also possible that any signal was too small to detect given the low patient numbers used in this pilot study (a Type 1 statistical error). We recommend that further work is undertaken with larger studies to confirm or refute these findings.
In summary, the use of exercise echocardiography, cardiopulmonary exercise testing, six-minute walk tests and questionnaires was acceptable to patients, produced reproducible and easily analysed results, and was practically achievable. Patient selection in this condition was challenging, particularly where atrial fibrillation is an exclusion factor and where the study population forms a varied group prone to comorbid conditions that may affect testing or results. Finally, the implantation of the devices was challenging and if signals of benefit were found in future, it is likely that HFPEF-specific techniques would need to be developed to aid placement of these devices."
REC name
Wales REC 3
REC reference
17/WA/0004
Date of REC Opinion
29 Mar 2017
REC opinion
Further Information Favourable Opinion