Study design

Effects of Detraining in Endurance Athletes with Atrial Fibrillation (NEXAF Detraining) is an international multicentre, two-armed, RCT with blinded endpoint evaluation (ClinicalTrials.gov Registry Identifier NCT04991337). The study protocol (V.4.7, 9 March 2023) is in accordance with the SPIRIT 2013 statement regarding standard protocol items for clinical trials (online supplemental table 1),22 and meets the requirements of the WHO Trial Registration Data Set (online supplemental table 2). Study participants are included at seven participating centres across three countries: Bærum Hospital, Bærum (Norway), St. Olavs Hospital, Trondheim (Norway), The Baker Heart and Diabetes Institute, Melbourne (Australia), The University Hospital of Leuven (Belgium), Antwerp University Hospital (Belgium), AZ Jan Palfijn Gent (Belgium) and Jessa Hospital Hasselt (Belgium). A total of 120 study participants will be randomised to an intervention arm with training adaption or a control arm upholding high intensity exercise for a period of 16 weeks (online supplemental graphical abstract, figure 2). All study participants receive an insertable cardiac monitor (ICM) during the first study visit for continuous monitoring of AF burden. Subsequently, participants will practice their regular exercise for 4 weeks to allow quantification of baseline AF burden. During the second study visit (week 5) participants will undertake baseline examinations, including echocardiography, cardiopulmonary exercise testing (CPET), questionnaire, blood samples, 24-hour ambulatory ECG and randomisation. All examinations will be repeated during a follow-up study visit after 16 weeks (figure 3).

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Figure 2

Study design. Overview of the design of the randomised controlled trial NEXAF Detraining. HRmax, maximum heart rate; NEXAF Detraining, Effects of Detraining in Endurance Athletes with Atrial Fibrillation.

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Figure 3

Study visit schedule and study procedures of the randomised controlled trial. AF, atrial fibrillation; CPET, cardiopulmonary exercise testing; NEXAF Detraining, Effects of Detraining in Endurance Athletes with Atrial Fibrillation.

Objectives and hypothesis

The primary objective of the study is to clarify whether a period of training adaption reduces AF burden in endurance athletes with paroxysmal AF. Secondary objectives are to study the adherence to training adaption, effects of training adaption on AF symptoms and health-related QoL, risk of cardiac arrhythmias related to upholding high-intensity training and to improve the understanding of underlying mechanisms for AF by studying structural and electrical cardiac remodelling. We hypothesise that a period of tailored training will reduce AF burden and improve QoL in endurance athletes with paroxysmal AF.

Endpoints

The primary endpoint is AF burden, as measured by continuous monitoring with ICMs and calculated as the cumulative duration of all AF episodes lasting ≥30 s divided by total duration of monitoring. All AF episodes will be adjudicated by a blinded endpoint committee consisting of two cardiologists, who will adjudicate AF episodes independently and reach consensus in the case of discrepancy. Table 1 shows an overview of study endpoints.

Study population and eligibility criteria

Eligibility criteria include female and male endurance athletes aged ≥18 years, diagnosed with paroxysmal AF. Participants in this study are athletes of elite and recreational levels, who are performing structured, repetitive exercise aiming to improve their physical fitness and are engaged in regular endurance sports such as running and rowing for at least 5 hours/week or cycling and cross-country skiing for at least 8 hours/week on average, or a combination of these sports or other comparable endurance sports characterised by medium or high intensity.20 As weekly hours of exercise are an arbitrary measure, cut-offs are pragmatic choices and indicative.

We include athletes reporting at least two episodes of AF, of which at least one that has occurred during the past 6 months. To minimise the impact of other factors that may have caused AF or may affect AF burden, athletes with arterial hypertension and other cardiovascular risk factors or conditions are excluded from participating in the study. People at high risk of adverse cardiovascular events, including athletes with cardiovascular risk factors, a strong family history of coronary artery disease or sudden death or symptoms during activity, are excluded after a preparticipating screening by questionnaire.20 23 24 Box 1 shows the eligibility criteria for the study. To be included, participants must fulfil all inclusion criteria and have no exclusion criteria.

Informed consent

Eligible participants receive written and oral information about the study and must sign an informed consent form approved by the ethical committee for medical research of the respective study centres.

Atrial fibrillation monitoring

We insert a wireless ICM (Confirm Rx, Abbott, Sylmar, California, USA) subcutaneously near the left parasternal area over the third or fourth intercostal space at 45° to the sternum in men and 10°–15° in women. At the end of the procedure, we confirm reliable signal quality and R-wave sensing using an external programmer. ICMs are programmed to detect and record arrhythmic events defined as AF episodes lasting ≥30 s, pauses ≥3 s, bradycardia with heart rate (HR) ≤30 beats per minute (bpm) and tachycardia lasting ≥12 beats with a HR ≥180 bpm. In participants with a measured maximum HR (HRmax) >170 bpm, we programme the ICM to detect tachycardia when HR exceeds the recorded HRmax by ≥10 bpm. The device connects via Bluetooth and a smartphone application, and the data are uploaded to a secure server every 24 hours. Summarised reports of data from the ICM are generated every fourth week during the entire study period, reporting total time in AF, number and duration of AF episodes, pauses, bradycardia and tachycardia episodes. The ICM will be removed after the study or kept for up to the battery life expectancy of 2 years, on the participants’ request.

Intervention

The study participants are randomised 1:1, stratified by recruiting centre and AF burden during the 4-week baseline observation (<4% or ≥4%), to training adaption (intervention) or a control group. The participants are assigned to each group using a predefined permuted block randomisation to avoid imbalanced data. The allocation sequence was prepared by a statistician not directly involved in the study and is unavailable to the study personal and is implemented at each participating centre during the second study visit by use of sealed envelopes.

The training adaption is individually tailored, based on HRmax and the self-reported average weekly hours of training during the past 6 months. The intervention group is instructed to avoid high-intensity exercise corresponding to a HR >75% of HRmax, and a total duration of exercise (hours/week) corresponding to <80% of the self-reported average weekly amount of exercise (hours/week) for a period of 16 weeks. The control group is instructed to perform at least 3 weekly sessions of high-intensity training, corresponding to a HR of ≥85% HRmax, and otherwise continue endurance exercise as usual, for a period of 16 weeks. For practical reasons, we have chosen to define exercise intensity as a percentage of the individual’s HRmax. We use the highest reliable HRmax value measured in sinus rhythm via ECG monitoring during the CPET or during exercise with a HR chest-strap and a connected sports watch. To avoid caveats related to the use of HRmax in participants using beta-blockers, we use the HRmax derived from CPET performed while the participant has taken their medication.

Based on a pragmatic approach, we have defined training adaption as reducing exercise intensity to ≤75% of HRmax, corresponding to the threshold for moderate intensity suggested in exercise guidelines for the general population.25 Furthermore, to avoid compensation of the reduced intensity by increased training volume, participants are instructed to reduce their weekly hours of endurance exercise by 20%. Based on previous studies of detraining in animal models and athletes, we considered a period of reduced training intensity of 16 weeks to be sufficient to affect AF burden and at the same time acceptable to the athletes.15–17

Exercise monitoring

Participants are instructed to wear a HR monitor strapped around the chest and a sports watch when exercising throughout the entire study period. The HR chest-strap and watch connect using Bluetooth technology. We make use of the study participants’ personal sports watches. Alternatively, study participants receive a HR chest-strap (Garmin HRM-PRO) and sports watch (Garmin Forerunner 745) for the study period. The sports watch connects with Bluetooth technology to a web-based platform (Fitrockr, Digital Rebels, Berlin, Germany or TrainingPeaks, Louisville, Colorado, USA). We register the total amount of exercise and time during exercise sessions at different HR zones, <61%, 61%–70%, 71%–75%, 76%–80%, 81%–84%, 85%–90% and >90% of HRmax, respectively. This exercise monitoring allows assessment of adherence to the study intervention.

Blood samples

Fasting blood samples for analyses of biomarkers for cardiovascular risk factors are collected at rest at baseline and follow-up. Serum and plasma are stored at −80°C for subsequent batch analyses of biomarkers relevant for AF. In addition, we collect blood samples before and at maximal effort during CPET to assess the acute response to exercise (High-sensitive Troponins, NT-proBNP).

Questionnaires

At baseline and follow-up, the participants are asked to fill out the Atrial Fibrillation Effect on QualiTy-of-life questionnaire (AFEQT), assessing severity and frequency of AF symptoms, daily activity, treatment concerns and satisfaction.26 We score the AF symptom severity from none (1) to disabling (4) using the Modified European Heart Rhythm Association Symptom Scale.27 At baseline, we also obtain patients characteristics, self-reported history of endurance exercise and frequency, duration and triggers of AF episodes. At follow-up, participants are requested to fill out a questionnaire concerning AF treatment during the study and their experience with the ICM and the study intervention.

Transthoracic echocardiography

Transthoracic echocardiography is performed in sinus rhythm with a study-specific protocol in line with current recommendations.28 29 For assessment of cardiac structure and function, we perform resting two-dimensional (2D) and three-dimensional (3D) transthoracic echocardiography using the Vivid E95 ultrasound system (GE Healthcare, Horten, Norway). Images are obtained using a 1.5-4MHz matrix-array transducer (GE 4Vc-D Matrix 4D cardiac probe, GE healthcare, Horten, Norway). 2D-greyscale, colour Doppler and tissue Doppler imaging data will be obtained, in addition to 3D of the left atrium. A physician blinded to the participant’s clinical and study information will analyse the acquired images offline (Echo Pac, V.204, GE Vingmed Ultrasound, Horten, Norway). We assess systolic and diastolic volumes of both atria and the left ventricle, and right ventricular size. Comprehensive two-dimensional speckle tracking analyses will be performed of all four chambers, combined with established Doppler parameters to obtain information about systolic and diastolic function.

Cardiopulmonary exercise testing (CPET)

We perform CPET using a study-specific protocol. A standard 12-lead ECG is recorded at rest and throughout the test.23 Peak oxygen consumption (VO2peak) is measured in sinus rhythm using one of three predefined continuous ramp bicycle protocols, based on the patient’s estimated physical capacity. All protocols start with 2 min rest on the bicycle, followed by a 3 min steady state warm-up at 40 or 50 W before gradually increasing resistance at a rate of 20–30 W/min until exhaustion, corresponding to 17–20 on the Borg 6–20 scale.30 In the recovery phase, the participant will stop cycling completely and rest for at least 6 min, until normalisation of blood pressure. VO2peak is defined as the maximal value obtained from a 30 s rolling average of the six consecutive highest VO2 values recorded from the 5 s averaged data.

24-hour ECG monitoring

We use ambulatory 24-hour ECG monitoring at baseline and follow-up to assess arrhythmias that are not properly registered by the ICM and that may be induced by the maximal effort during CPET.

Adverse events

Any unfavourable and unintended sign, symptom or illness that develops or worsens during the trial period will be reported as adverse events (AE). A serious adverse event (SAE) is defined as death, any life-threatening event or any inpatient hospitalisation. In the analyses, AE will be summarised per treatment group by event type, intensity, seriousness and relationship. The timing of SAE will be categorised as occurring during exercise, within the first hour postexercise, or 1–24-hour postexercise. The activity at the time of the event will be further characterised as occurring during training or competition, at rest or during sleep.31 All SAE will be reported to the Study Safety Monitoring Committee (SMC) that will independently evaluate the safety of the study. Formal interim analyses of AE summarised per treatment group will be reported to study SMC after 25% and 50% of the participants have completed the study.

Blinding

This is an open label study and participants are not blinded to group allocation. Researchers and staff are unblinded during all procedures. AF burden will be adjudicated by a blinded endpoint committee.

Data management

Data sources are stored at each participating centre according to local procedures. Data entry is performed by local study personal using a web-based electronic case report form (Ledidi Core, Oslo, Norway). After study completion, before database lock and unblinding, all data from 10% of the participants will be checked by a monitor not involved in the study for consistency with source data. Due to the non-commercial nature of the study, the type of intervention and relatively small study size, we considered a data monitoring committee and formal interim analyses not to be required. The final dataset will be accessed by a statistician blinded to group allocation, and researchers will be blinded when performing statistical analyses.

Statistical considerations

We consider a mean difference in the burden of AF of 0.5% between the detraining group and the control group to be clinically meaningful. A 0.5% difference with a SD in each group of 1% was used to calculate a minimum sample size of 64 participants per group using an independent samples t-test and β=0.2 (power 80%) at α=0.05. However, the primary analysis will be a linear mixed model for repeated measurements and a sample size estimation based on t-test provides thereby a conservative estimate. We also performed a power calculation based on a study of Malmo et al,3 for the outcome difference between the groups in change of AF from baseline to follow-up. In that study AF burden measured with ICMs was reduced by 41% (−3.3% (SD 7.2) from a baseline value of 8.1% (SD 11.2) after a 12-week exercise intervention, compared with+4.2% in the control group). Based on t-tests of means, to detect a difference in change in AF burden of 7.5% between the groups with β=0.2 (power 80%) and α=0.05, a minimum of 28 participants per group is required. Because the baseline AF burden is likely to be lower in the current study than in the study by Malmo, we suggested 60 participants per group. Since we cannot rule out a possible worse outcome in the intervention group, we plan to use a two-sided hypothesis test.

All randomised participants will be included in the main analysis of primary and secondary endpoints. Since adherence to detraining is a secondary outcome measure, major comparisons between randomised groups will be performed by the ‘intention-to-treat’ principle, meaning that patients will be analysed according to the planned intervention. However, some analyses may also be performed using ‘per-protocol’ or ‘as-treated’ data. We define adherence to the detraining intervention as ≥80% of total volume of endurance exercise during the study period performed at an intensity corresponding to a HR of ≤75% of HRmax, based on the exercise monitoring with chest-straps and sports watches.

We plan to publish a detailed statistical analysis plan separately before randomisation of the last study participant.