Study design

This protocol follows guidance from the Consolidated Standards of Reporting Trials (CONSORT) [29]. A CONSORT checklist is provided as an Additional File. Fig 1 shows the SPIRIT schedule. CREED AF is a single-centre, pragmatic randomised controlled trial comparing the impact of a cardiac prehabilitation and rehabilitation programme including supervised exercise training and risk factor education/modification, (i.e. alcohol intake, smoking, hypertension, diabetes, exercise, sleep apnoea), with usual care in people undergoing first time catheter AF-ablation (Fig 2). The randomisation allocation ratio will be 1:1.

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Fig 1. Trial schedule of events (SPIRIT schedule).

https://doi.org/10.1371/journal.pone.0310951.g001

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Fig 2. Flowchart of the CREED AF study, demonstrating the patient pathway.

AF, atrial fibrillation; QoL, quality of life; RU, resource use; MACE, major adverse cardiovascular events.

https://doi.org/10.1371/journal.pone.0310951.g002

Ethics approval and consent to participate

The trial design and research protocol have been approved by the West Midlands-Solihull Ethics Committee, UK (23/WM/0125). The trial will be conducted in accordance with Good Clinical Practice, UK Law, and the Declaration of Helsinki 2002. Written, informed consent to participate will be obtained from all participants.

Study population, participant identification, recruitment, and informed consent

People who have been listed for first-time AF ablation and meet the eligibility criteria (Fig 3), will be identified from specialist arrhythmia clinics at University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK and approached either face-to-face during a clinic appointment, or remotely via telephone and/or by post. Potential participants will be provided a participant information sheet (PIS) and invitation letter. Those expressing interest in participating will be invited to attend a baseline assessment, with eligibility reconfirmed and informed consent obtained in writing.

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Fig 3. Eligibility criteria.

https://doi.org/10.1371/journal.pone.0310951.g003

AF ablation pathway

Participants are only eligible for the CREED AF trial if they have been listed for AF ablation. AF ablation is not part of the CREED AF intervention. Normal local clinical practice and procedures will be followed. Briefly, people will be identified for catheter AF-ablation by a cardiologist specialising in arrhythmia management. Depending on the AF sub-type, any cardiac imaging findings (i.e., ventricular and/or atrial cardiomyopathy) and burden of co-morbidities, people will be informed that success of first AF ablation procedure is 40–80% (70–80% for paroxysmal AF, 40–60% for persistent AF) at 12 months. Therapeutic oral anticoagulation will be initiated (if not already in place) and taken reliably for at least 21-days prior to the procedure. Structured risk factor management is not routinely implemented in clinical assessments. A review of medications, along with bloods tests, and 12-lead ECG will take place during pre-procedure assessment (see Fig 1). People may undergo electrical direct current cardioversion (DCCV), as a temporising procedure, especially if in persistent AF and highly symptomatic. People undergoing first time AF-ablation have pulmonary vein isolation (PVI) only as the initial strategy for both paroxysmal and persistent AF. This will be done using either cryoablation or radio-frequency ablation technology; pulse-field ablation is currently not available at our centre but could be included if it becomes available. Routine outpatient clinical review takes place at 6-months post-ablation. If there is a persistent episode of AF in the first 3 months post-ablation (during the ‘blanking period’) people will be listed for DCCV to restore sinus rhythm. If there are further episodes of AF after the blanking period, the AF treatment strategy will be re-considered, and may include listing for a redo-AF ablation, performed using 3D mapping/ablation. Further follow-up will depend on the treatment strategy agreed between the clinician and the patient. All participants will undergo first-time AF ablation with isolation of the pulmonary veins only as described above. Data will be collected on details of their AF ablation procedure, including energy type and duration of lesions. Any procedural complications will be recorded.

Randomisation and blinding

After completion of baseline assessments, randomisation will occur using the integrated randomisation generator from Castor Electronic Data Capture [30]. The randomisation sequence is based on variable pre-specified block randomisation. Participants will be stratified by sex (male/female), AF sub-type (paroxysmal/persistent), left ventricular ejection fraction (<50%/≥50%), and amiodarone use (yes/no). Participants and CREED AF practitioners will be notified of the treatment allocation. Outcomes assessors will be blind to group allocation. We will request that participants do not reveal their treatment allocation and will record if they do so.

Control group: Standard care

Participants will be invited for a single 30-minute one-to-one education session with a CREED AF practitioner (specialist nurse or doctor) prior to their AF ablation. This will be focused only on exploring the impact of AF related risk factors guided by freely available information leaflets from reliable charity organisations (Arrhythmia Alliance, https://heartrhythmalliance.org/aa/uk/resources/arrhythmia-alliance-patient-resources).

Intervention group: CREED AF intervention

The CREED AF intervention will involve a comprehensive programme of structured exercise training and risk factor modification delivered both before AF-ablation (prehabilitation) and after AF-ablation (rehabilitation). To ensure generalisability to the UK NHS, the underpinning framework of the CREED AF exercise intervention is based on UK cardiopulmonary rehabilitation guidelines and service delivery models [31]. To maximise accessibility, exercise will be delivered as a ‘rolling’ programme. Participants can immediately join existing cardio-pulmonary rehabilitation exercise programmes rather than waiting for the recruitment of sufficient numbers to form a discrete group. The CREED AF intervention has 4 components:

Outcomes

In line with the International Consortium for Health Outcomes Measurement (ICHOM) standard of outcome measures for AF [32], the primary outcome is aerobic capacity as determined by relative peak oxygen consumption (VO_2peak) measured by CPET at 10±2 weeks post-ablation (Fig 2). This time interval was chosen to ensure the 3-month blanking period was excluded in the reassessment. The CPET will be performed according to national professional body standards in a UKAS accredited respiratory lab [33]. The local standard operating procedure for CPET will be followed.

Secondary outcomes, measured at 10 weeks and 12 months post-ablation, include HRQoL as determined by the AF Effect on Quality-of-Life Questionnaire (AFEQT) [34] and 36-Item Short Form Survey (SF-36) [35]. Recurrence of AF post-ablation, as well as assessment for AF burden and requirement for redo AF ablation, will be evaluated with 7-day cardiac Holter monitors, and on review of participant medical records at 12 months post-ablation. All AF recurrence (defined as AF lasting ≥30-seconds) [3], AF/AT burden, and time of occurrence will be recorded. At 12 months post-ablation, medical records will be used to review health service activity for major adverse cardiovascular events (MACE): hospital admission related to AF, heart failure hospitalisation, new heart failure diagnosis, non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, and all-cause mortality.

As part of the embedded economic evaluation, quality adjusted life years (QALYs) will be calculating using participants’ responses to the EQ-5D-5L instrument [36, 37], which comprises a visual analogue scale (EQ VAS) and a health status descriptive system. The latter asks respondents to indicate their health state by ticking boxes next to the statement that represents the level of health (no problems, slight problems, moderate problems, severe problems, and extreme problems) across five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each participant’s responses to the EQ-5D-5L will be translated into a single, preference-based HRQoL index score (utility value) using recommended UK value sets at the time of the analysis. QALYs will be calculated as the area under the curve connecting utility values reported at different time points in time [38].

Resource use and relevant costs will include the cost of implementing and delivering the intervention, further use of NHS care, patients’ out-of-pocket expenses and time-related costs captured using resource use questionnaires on the day of ablation (pre-ablation period), at 10-week post-ablation, and 12-month post-ablation. Local medical records, primary care records and data from other hospitals will also allow for accurate recording of health service activity. Adverse events will be recorded as per good clinical practice (GCP) guidelines.

Study design feedback

Prior to submission to the research ethics committee, the study protocol and other patient facing documents have been reviewed by expert members in the field of cardiology and ablation. The study was also presented to the Patient and Public Research Advisory Group (PPRAG) at UHCW to receive expert lay feedback on the study design and methodology. Following engagement with the PPRAG at UHCW, they were supportive of this project. They recommended that people who do not have access to video conferencing software (smartphones or webcams) be excluded due to the reliance on the live exercise sessions at home in the CREED AF intervention. The group were also happy to see the familiarisation period incorporated into the programme.

Sample size

The sample size calculation was based on the analysis of the change in the primary outcome (relative VO_2peak) at 10-week post-ablation from baseline. Previous studies investigated VO_2peak at 6 months post-ablation, which we assume to be similar at 10-week post-ablation. Based on Kato et al, we can assume that the VO_2peak standard deviation is around 3ml/kg/min at baseline and 4ml/kg/min at 10-week post-ablation [23]. As the correlation between the time points is unknown, we assume a value of r = 0.5. Consequently, the standard deviation of the difference from 10-week post-ablation to baseline is around 3.6ml/kg/min. Based on Fiala et al and Mujovic et al, we can assume that the change in VO_2peak will be around 2ml/kg/min due to AF ablation in both AF-types, and a further 4ml/kg/min due to cardiac rehabilitation (which comprises pre- and post-AF ablation rehabilitation) [23, 39, 40]. Therefore, the difference between the intervention arm and standard care is expected to be 4ml/kg/min at 10-week post-ablation compared with baseline. To detect a conservative difference of 2.5ml/kg/min (an increase in 2.5ml/kg/min VO_2peak in the intervention arm from standard care at 10-week post-ablation compared with baseline) at 5% significance level, and 90% power, we require 88 participants. To allow a drop-out rate of 20%, we will recruit 106 people, with 53 randomly allocated to each group.

Data analysis

Demographics and baseline characteristics categorical data will be summarised as frequency and percentage, continuous data will be summarised using the following descriptive statistics: frequency (total number of missing and non-missing available for summary), mean and standard deviation (SD), median, 25th and 75th percentiles, minimum and maximum by treatment arm and as overall.

The primary outcome measure will be the difference in means between the two treatment arms by fitting a linear regression model where the relative VO_2peak at 10-weeks post-ablation is the response, and the predictors are the relative VO_2peak at baseline and treatment arm. We will adjust for other baseline measures, e.g., AF type, sex, left ventricular ejection fraction and amiodarone use. All participants with both relative VO_2peak at baseline and 10-week post-ablation are the target population with those assigned to standard care through randomisation will be the control group and those to CREED AF intervention will be the active intervention group. The intercurrent event that we expect is treatment discontinuation due to any reason and this will be addressed as treatment policy strategy. We may also explore for any potential confounders in relative VO_2peak within the study, and the complier averaged causal effect (CACE) analysis as a sensitivity analysis.

For secondary outcomes: all the scoring of HRQoL (AFEQT and SF-36) will be computed as per the instrument algorithm. The scores will then be summarised descriptively overall and by treatment arms at baseline and the short- (10-week) and long-term (12-month) follow-up time points. The change of HRQoL from baseline to 10-week, from baseline to 12-month post-ablation, and the difference between treatment arms will be estimated with their associated 95% confidence intervals (CIs). We will explore the HRQoL longitudinal effect by visualising the change against time. Proportion of significant AF events by treatment arms will be estimated with associated 95% confidence interval (CI) using Kaplan-Meier analysis. Similarly, the proportion of individual and composite MACE and its associated 95% CI by treatment arms will be estimated. The recurrence of AF burden from the Holter and each of the MACE occurrence will also be estimated by treatment arms as a time-to-event estimand. We will also perform a subgroup analysis by types of AF (persistent and paroxysmal AF) for all endpoints. Analysis will be performed with the appropriate statistical software and package available at time of analysis. The statistical analysis plan will be finalised prior to primary outcome analysis.

Health economic analysis

The economic analysis will be conducted on an ‘intention to treat’ basis. Missing data will be accounted for by using appropriate techniques, such as multiple imputation, depending on the extent and type of missing items. As cost distribution is skewed by existence of people with very high costs, calculated mean per-person costs will be provided with confidence intervals obtained through non-parametric bootstrap methods [41]. We will perform an incremental analysis to calculate difference in costs and in outcomes associated with the compared options. The findings will be presented as incremental cost-effectiveness ratios reflecting the extra cost for additional units of outcome. A sensitivity analyses will be done to assess impacts of different assumptions on results [42]. Due to inherent uncertainty secondary to sampling variation, the joint distribution of differences in cost and outcomes (QALYs) will be derived by performing non-parametric bootstrap simulations [43]. The simulated costs and outcome pairs will be depicted on a cost-effectiveness plane and plotted as cost-effectiveness acceptability curves (CEAC). CEAC will show the probability of CREED AF being cost-effective across a range of values of willingness to pay for an additional QALY [44].

Adverse event management

In our study an adverse event (AE) is defined as any untoward medical occurrence involving a participant, which does not necessarily have a causal relationship with the intervention or trial. Adverse events will be collected only once the participant has provided consent and enrolled into the study. Expected AEs, related to the exercise outcome assessments or the exercise intervention, include ‘normal’ levels (for each individual) of: breathlessness, light-headedness/dizziness, muscle and joint stiffness/soreness, and tiredness/fatigue. There are a few AEs which are expected following AF ablation and occur after roughly 2–4% of all AF ablation cases, including: vascular injury, pericardial effusion/tamponade, stroke/transient ischaemic attack, myocardial infarction, phrenic nerve injury, atrioventricular (heart) block, and pulmonary vein stenosis. Because of the post-AF ablation conditions, there is a small risk (1:400) of requiring further cardiac surgery or a blood transfusion. Each AE will be assessed by the Chief Investigator, or a delegated clinician, to assess the causality to the CREED AF intervention. In the unlikely event that it is decided that one of the above post-AF ablation conditions is related to the CREED AF intervention, this will be reported as such in line with local Trust policy and national safety reporting guidelines. Expected AEs will be recorded on the participants’ case report form (CRF) (AE form). Any unexpected AEs related to the exercise outcome assessments or the exercise intervention for all participants will be recorded on the CRF (AE form), logged, and reported at trial management group (TMG) meetings. Should multiples of the same unexpected AE occur during the trial period, then this will trigger the TMG to review the study procedures and consider any changes that need implementing. For the purposes of the study, serious adverse events (SAEs) will be an untoward medical occurrence that fulfils one or more of the following: results in death, is life-threatening, requires hospitalisation or prolongation of an existing hospitalisation, results in persistent or significant disability or incapacity, requires medical intervention to prevent one of the preceding, or is otherwise considered medically significant by the investigator. Though all admissions to hospital are an SAE, the following are expected within the study and do not require additional reporting but must be recorded in the CRF: disease progression (worsening symptoms/AF attrition unrelated to the exercise intervention), treatment (elective or pre-planned for a pre-existing condition) not associated with any deterioration in condition, and general care not associated with any deterioration in condition. SAEs will be collected from self-report and from medical records checks. Reportable SAEs in both groups will be any event occurring within 24 hours of each assessment appointment (baseline and 10 weeks (±2 weeks) post-AF ablation), and in the intervention group any event that occurs at any time between baseline outcomes assessment and the 10 weeks (±2 weeks) post-AF ablation. All SAEs will be recorded and reviewed by the Chief Investigator to determine if it is directly attributable to the intervention and investigated in line with the hospital Trusts’ standard operating procedure (SOP). Those SAEs that are deemed to be unexpected, probably, or definitely related to the trial interventions or outcomes assessments, will be notified to the Research Ethics Committee within 15 days, and reported to the TMG at the next meeting.

Trial status

The CREED AF study started recruitment as of December 2023 and is expected to finish recruitment by February 2025.

Monitoring, audit & inspection

The study may be monitored by the Research & Development Department at UHCW as representatives of the Sponsor, to ensure that the study is being conducted as per protocol, adhering to Research Governance and GCP.

Committees

The trial steering committee (TSC) will consist of exercise, respiratory and arrhythmia specialists, and a member from the Patients and Public Engagement Committee (who have informed this study protocol). This group will meet regularly to review the progress of the study in terms of recruitment, endpoints, and adverse events. The publication of results will be overseen by the TSC. There is no data monitoring committee (DMC).