Catheter Ablation versus Thoracoscopic Surgical Ablation in Long Standing Persistent Atrial Fibrillation (CASA-AF): study protocol for a randomised controlled trial

Adults with symptomatic LSPAF considered for treatment (DC cardioversion or catheter ablation) at the participating trial centres will be considered for inclusion in the study. The complete list of inclusion and exclusion criteria is presented in Table 1.

Patients considered eligible to take part in the study will be provided with a participant information sheet and given opportunities to discuss details of potential participation with the study team. They will be encouraged to discuss the information with their family, friends and general practitioners before making a decision to participate in the trial. When they confirm their interest in taking part, a hospital appointment will be arranged for them to sign an informed consent form and to complete baseline assessments. Participants’ progress through the study is shown schematically in Fig. 1.

As part of the baseline visit, we will collect blood samples for routine haematology, biochemistry and coagulation assessments as well as samples for cardiac biomarker evaluation. With patients’ permission, surplus samples will be stored for future research by biobanks at the participating centres (Cardiovascular Biomedical Research Unit Biobank at the Royal Brompton and Harefield NHS Trust and the Liverpool Bio-Innovation Hub Biobank associated with Liverpool Heart and Chest Hospital NHS Trust).

Routine haematology and biochemistry assessments include full blood count, electrolytes, renal function tests, coagulation profile, liver function tests, thyroid function tests, C-reactive protein, tests for diabetes (haemoglobin A1C) and lipid profile (high-density lipoprotein, low-density lipoprotein). Transthoracic echocardiogram (TTE) and cMRI assessment will ensure that patients do not have poor left ventricular (LV) function, valvular disease or other pathologies that meet the exclusion criteria. Additional clinical and study data collected at baseline, as well as at other study time points, are shown in Fig. 2 (SPIRIT figure). A detailed study codebook contains a complete list of all the variables, including type of data and reference values where appropriate.

cMRI will be performed during the baseline visit and again at 6 months after the ablation. It will be used to capture LA area and length [56, 57] and to calculate maximum and minimum LA volumes as well as the cross-sectional diameter of PVs. The images will be acquired using planes in the LV long- and short-axis stacks. A specific protocol of sequences for late gadolinium enhancement (LGE) of the LA will be used to evaluate location and quantification of LA scars [58]. The LV function will also be measured by volume quantification in systole and diastole using endocardial tracing [59‐61].

TTEs will be performed at baseline, 3 months after the ablation and at the last study visit (12 months after the ablation). In addition to the standard clinical protocol set out by British Society of Echocardiography, we will acquire images to allow for offline assessment of LA function (measurement of myocardial velocities, LA strain and strain rate) by using tissue Doppler and 2D speckle-tracking methods [62‐64].

The EHRA symptoms score and AFEQT and EQ-5D-5L questionnaires will be used at each study visit to assess any changes in patients’ symptoms and quality of life from baseline to the end of the follow-up period [39, 65, 66]. We have also designed a health economics questionnaire to collect patient-reported data on the use of primary, secondary and community health and social care services following ablation to estimate costs.

An independent data monitoring committee (DMC) consisting of four members (two cardiologists, a surgeon and a statistician) has been established, with functions and responsibilities detailed in a DMC charter. The DMC meets at least twice annually and communicates their advice to the trial steering committee (TSC).

The TSC has executive power and consists of seven members, five of whom are independent (two cardiologists, one surgeon and two lay members). This committee will meet twice annually for the duration of active patient recruitment and follow-up, and additional ad hoc meetings may also be scheduled if necessary. This group’s functions and remit are defined in the TSC charter. Two external independent groups of experts specialising in electrophysiology, cardiology and thoracic surgery will be formed to evaluate primary and safety endpoints of the trial.

All statistical analyses will be based on intention to treat, and the data analysed will be derived from all randomised participants. We will also perform sensitivity analyses to explore the impact of missing data, non-compliance and withdrawals. R statistical software version 3.0.2 (or later; R Foundation for Statistical Computing, Vienna, Austria) will be used to analyse data.

The primary outcome of the trial is the proportion of patients with LSPAF undergoing ablation who are free from atrial arrhythmias (defined as a single episode of ≥ 30 s) within 1 year after a single ablation procedure. ‘Arrhythmia-free’ patients will be identified through ILR data assessments performed monthly by a single blinded cardiac physiologist. Chi-square tests will be used for comparisons between the trial arms. A logistic regression model will be developed to estimate the probability of being free from AF at 1 year by either procedure. The primary measure to be reported is the OR of being ‘AF-free’ for the surgical group after the other factors in the model have been controlled for. The recurrence of AF and duration of AF freedom will be analysed using Kaplan-Meier survival curves.

Binary secondary outcomes (reduction in arrhythmia burden, freedom from arrhythmia following multiple procedures) will be analysed in the same manner as the primary outcome using a combination of chi-square tests and logistic regression. Freedom from arrhythmia following multiple procedures will be analysed using Kaplan-Meier survival curves.

Continuous data will be analysed using either Student’s t test or the Mann-Whitney U test and presented as mean ± SD, mean (95% CI) or median (IQR), depending upon distribution of obtained data. P < 0.05 will be considered significant.

Cost-effectiveness will be assessed using both trial-based and model-based health economic analyses. Both will follow international methodological guidelines [67‐70] and the ‘reference case’ recommended by the National Institute for Health and Care Excellence (NICE) for use in its technology appraisals [71‐74], including the use of an NHS and personal social services perspective for costing and discounting of costs and QALYs at an annual rate of 3.5%.

In the trial-based analysis we will use EQ-5D-5L and health and social care resource use data to estimate the costs and QALYs accrued over the 12-month follow-up period by trial participants. In our main analysis we will include costs for all health and social care recorded in the eCRF and reported by patients in the health economics questionnaire at 3, 6, 9 and 12 months. The unit costs of services will be based on national average estimates from published sources [75‐78]. We will also conduct a sensitivity analysis including only costs judged by the research team to be potentially related to AF or to AF treatment. QALYs will be estimated from survival data and quality of life (EQ-5D-5L) scores at 0, 3, 6, 9 and 12 months using an AUC approach. EQ-5D-5L scores will be calculated using the 2016 value set for England [79]. Mean between-group differences in QALYs and costs will be estimated using a bivariate regression approach, taking account of correlations between costs and effects and adjusting for any baseline differences in EQ-5D-5L scores or other key patient characteristics (such as age, CHA₂DS₂VASc score [congestive heart failure {or left ventricular systolic dysfunction}, hypertension {blood pressure consistently > 140/90 mmHg or treated hypertension on medication}, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack or thromboembolism, vascular disease {e.g., peripheral artery disease, myocardial infarction, aortic plaque}, age 65–74 years, sex category {i.e., female sex}] or HAS-BLED score [hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalised ratio, elderly, drugs/alcohol concomitantly]). Multiple imputations will be used to account for missing data if appropriate [39, 65, 69, 80]. If the results indicate a trade-off between costs and health effects, an incremental cost-effectiveness ratio will be calculated—the ‘cost per QALY’. The extent of uncertainty over the results will be estimated using bootstrap regression and presented in the form of a cost-effectiveness acceptability curve [81].

A model-based economic analysis will also be conducted to estimate long-term benefits, harms and costs of surgical and catheter ablation compared with AAD therapy in patients with LSPAF. This will extrapolate costs and health outcomes observed in the trial, including freedom from arrhythmia, utility (EQ-5D-5L scores) and incidence of major side effects, over a long time horizon (up to lifetime). The model will also allow us to estimate costs and outcomes for the trial participants under medical management, which will provide further information about the comparative cost-effectiveness of treatment options for this patient group for healthcare commissioners and research funders. The model will be based on the MAPGuide AF model [82]. This is a discrete event simulation which estimates lifetime costs and QALYs for a heterogeneous population of individuals with AF treated according to a defined pathway of care, including anti-thrombotic and AAD therapy. The base case version of the model reflects the recommended care pathway in the NICE clinical guideline for AF. This care pathway can be changed to estimate costs and QALYs associated with different treatments (e.g., catheter ablation, thoracoscopic surgical ablation or AAD).