Catheter Ablation vs. Risk Factor Modification.

INTRODUCTION Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, having a prevalence of about ~ 2% in the general population. Among healthy men and women age 40 years, the risk of lifelong AF occurrence is approximately 25%. The current estimated prevalence of AF is approximately 50 million patients worldwide, and its incidence has been increasing due to improved diagnostics, better treatment of chronic diseases and increasing age. Therefore, its prevalence is expected to increase by nearly 3-fold during the next 3 decades. AF is associated with a three-fold increase in the risk of stroke and a two-fold increase in mortality risk. The essential treatment methods for "rhythm control," i.e., restoration and maintenance of sinus rhythm, take the form of antiarrhythmic drugs (AADs) and catheter ablation. Catheter ablation with pulmonary vein isolation (PVI) has been found to be superior to AADs in several randomized control trials in patients with paroxysmal as well as non-paroxysmal AF. The one-year efficacy of catheter ablation ranges from 40-90% (depending on the type of AF ablated, patient cohort, ablation procedure, and follow-up methods) and is higher than AADs treatment by 20-45%. According to one of the meta-analyses of randomized trials comparing catheter ablation with AADs, one-year AF-free survival (i.e., complete AF freedom) was present in 77% of ablated patients but only 29% of patients on AADs.

According to several studies, obesity has been found to be independently associated with a higher risk of occurrence, and as well as maintenance and progression of AF. In our population, obesity is, after hypertension, the second most common AF risk factor, and with regard to its severity, it is considered to be a higher risk than hypertension. As a risk factor of AF, obesity is independent even from obstructive sleep apnea, i.e., a disease that is often present in obese patients, and is known also be associated with very high of AF. According to a meta-analysis of 51 studies, which included more than 60,000 patients, an increase of BMI by 5 points is associated with a 19%-29% increase in the incidence of AF. On the pathophysiological level, factors present in obese patients that contribute to AF are dilation and remodeling of the left atrium, hyperdynamic circulation, the effect of adipocytokines, elevation of pro-inflammatory cytokines, and a common association with other risk factors (hypertension). Besides obesity, other modifiable risk factors include hypertension, sleep apnea, and alcohol consumption.

Several recent interventional studies have shown that all the aforementioned factors are not only known epidemiological variables associated with a higher risk of AF, but their intensive treatment and elimination is associated with a significant decrease in AF reoccurrences. In the prospective non-randomized ARREST-AF study, 149 patients with a body mass index (BMI) ≥ 27 after catheter ablation of AF were offered an opportunity to participate in a physician-driven intensive risk factor management program, consisting of dietary changes and regular physical exercise. Sixty-one patients entered the risk factor management program, and 88 patients served as a control group. Risk factor management, which focused predominantly on weight loss, was associated not only with blood pressure reductions and cholesterol decreases, but also a 23.9% reduction in AF reoccurrences. Simultaneously, left atrial remodeling and size was found to be positively affected, as well as a decrease in left ventricular hypertrophy. In the prospective, non-randomized observational LEGACY study, risk factor management, which also focused on weight loss, was offered to a cohort of 355 AF patients with a BMI ≥ 27 who had been referred to a tertiary center for AF treatment (this is in contrast to ARREST-AF study, patients in this LEGACY study had no history of AF ablation). According to the extent of weight loss, patients were divided into three groups (weight loss ≥ 10%, between 3 and 9%, and ≤ 3%). SR maintenance significantly differed between groups: the highest AF-freedom, 45%, was achieved in patients with most significant weight loss, 22% in those with intermediate weight loss, and only 13% in the those with the lowest weight loss. The intervention focused on the increase of physical performance produced similar results as the intervention focused on weight loss. In a study by Malmo et al., 51 patients with paroxysmal AF were randomized to a twelve-week of physical training (without dietary intervention) vs. controls, and AF paroxysms were tracked using implantable loop recorders. While the number of AF paroxysms remained unchanged in controls, in patients undergoing regular physical activity, AF paroxysms were reduced from 8.1% to 4.8%. Moreover, the recently published ALCOHOL-AF study has shown that alcohol abstinence (in alcohol non-addicted patients) is also associated with a reduction of AF paroxysms in patients with paroxysmal AF. It seems that AF treatment could lie, at least in some patients, outside the electrophysiological cath-labs. However, so far, the majority of aforementioned studies were either observational, or have had a non-randomized control arm (the only randomized one was focused only on physical training, and not complex risk factor intervention).

Diffuse myocardial fibrosis is often present in patients in AF patients. As it was shown, the degrees of diffuse myocardial fibrosis is higher even in paroxysmal AF patients compared to healthy subjects Myocardial fibrosis could be assessed using cardiac magnetic resonance (CMR) by either postcontrast-enhanced T1 mapping, or, if present in higher degree, by late gadolinium enhancement. In the CAMERA-MRI study, the degree of left ventricular fibrosis before the ablation of AF predicted the improvement of ejection fraction of the left ventricle post-ablation, and also the effect of catheter ablation Recently, diffuse myocardial fibrosis assessed by post-contrast T1 mapping predicted the effect of catheter ablation of AF in paroxysmal patients. In patients with persistent AF, the improvement in the left ventricular ejection fraction and reverse ventricular remodeling following successful catheter ablation was accompanied by a regression of diffuse myocardial fibrosis. Early changes on CMR, such as higher left ventricular mass, or cardiac remodeling index, were described also in patients with abdominal obesity without hypertension, AF or overt heart failure. It is to be investigated whether sinus rhythm maintenance, achieved by the two very different aforementioned methods (catheter ablation, or risk factor modification), would avoid (and in which degree) adverse further cardiac remodeling and diffuse cardiac fibrosis. It will be the other topic of investigation of our study.

GOALS OF THE PROJECT The aim of our study is to compare the effect of catheter ablation of atrial fibrillation with risk factor modification strategy in a randomized study. The main hypothesis is that strict risk factor modification (weight loss, physical exercise improvement, and alcohol absence) in patients with AF will be associated with similar rhythm outcomes as catheter ablation. Beside the AF-recurrence and AF-burden as the primary endpoint, the co-primary endpoint will be the change in diffuse myocardial fibrosis and left ventricular mass, as assessed by cardiac MRI.

JUSTIFICATION OF THE PROJECT As mentioned above, the estimated prevalence of AF is approx. 2% in general population, i.e. about 200,000 patients only in the Czech Republic. Moreover, the incidence of AF has been increasing. Despite wide use of catheter ablation of AF, such huge number of patients could not be handled by the current capacity of electrophysiological cath - labs in any country. The searching for other, alternative approaches in treatment of AF is warranted. This approach has been already validated in previous, aforementioned trials+ however, these trials enrolled either patients either after or before catheter ablation, and so far, no head-to-head randomized study comparing this two treatment strategies has been done. If the risk factor modification management has been proven to have similar efficacy as catheter ablation, many motivated patients could be treated using this simple, non-invasive approach.

METHODS The study is planned as prospective, multicenter, randomized, non-inferiority trial comparing two different approaches in the treatment of AF. Symptomatic AF patients indicated for rhythm control strategy (i.e. restoriation and maintenance of SR) will be enrolled and randomized to catheter ablation or risk factor modification.

Study population - inclusion criteria (all of three have to be met for enrollment) (i) symptomatic AF (paroxysmal, persistent, or long-standing persistent), and (ii) BMI ≥ 25, and (iii) signed informed content

Study population - exclusion criteria:

- permanent AF

- severe valve disease

- left ventricular ejection fraction < 40%

- severe pulmonary hypertension (PAP > 60 mm Hg)

- history of tachycardia-induced cardiomyopathy

- planned revascularization

- pregnancy

- left atrial size ≥ 60 mm

- BMI ≤ 20 or BMI ≥ 40

- indication for surgical treatment of obesity

- age ≥ 75 let

- a significant physical limitation that could affect physical activity (musculoskeletal disorders, COPD)

- life expectancy less than 2 years Patients with significant structural heart disease (left ventricular dysfunction, significant valve disease, moderate or severe pulmonary hypertension, significant left atrial dilation) will be excluded. Also, patients who could not actively participate (musculoskeletal disorders, heart failure, patients older than 75 years) in regular physical activity will be excluded. Diabetes will be an exclusion criterion because of significant interference associated with antidiabetic medication relative to some of the endpoints.

BASELINE DIAGNOSTIC EXAMINATION

Anthropometric measurement and the assessment of physical fitness - functional fiagnostics After informed content has been given, and before the randomization, all patients will undergo baseline anthropometric measurements (the height, weight, percentage of body fat, and waist-to-hip ratio measurement) and baseline evaluation of physical fitness (functional diagnostic). Additionally, blood will be drawn for biochemistry and cytokine analysis and baseline cardiac magnetic resonance (CMR) will be done. All patients will be asked to complete specific questionnaires for quality of life (QoL) assessment, and all patients will be implanted with an implantable ECG loop recorder (ILR). Functional diagnostics will be performed in all patients to assess the cardiorespiratory fitness, ventilatory parameters at rest and exercise. In the risk factor modification group, functional diagnostics will also be used to reveal any contraindication for physical training. Based on the results of functional diagnostics, an individualized and optimized physical training program will be prepared.

An initial exercise spiroergometry test Vita Maxima with 12-lead ECG monitoring, blood pressure monitoring, and ventilation monitoring using exhaled air analysis will be carried out within one month of enrollment. The protocol will consist of a 3-min warm-up period (0.5 W/kg), followed by a ramp test with exercise intensity increased by 0.2 W/kg/min in women and 0.3 W/kg/min in men up to the maximal subjective tolerance. Criteria of test termination will be physical intolerance, inability to maintain ergometer rotation speed (in a range of 60-100/min), significant ECG changes, occurrence of significant cardiac arrhythmias, and an unacceptable increase in blood pressure. Based on the results of spiroergometry, the heart rate for mild and moderate aerobic exercise will be determined, as well as the maximum heart rate that could be even achieved (i.e., 85% of maximum heart rate).

Cardiac magnetic resonance (CMR) CMR will be done using 1.5 Tesla scanners located at each of the three participating centers. Before CMR evaluation, the ventricular rate will be optimized with a target ventricular rate < 100/min. The evaluation of systolic function of both ventricles will be done using steady-state free precesion (SSFP) cine CMR sequences in long- and short axis, during breath-holds of 10-15 s with measurement of end-systolic and end-diastolic volumes, a calculation of the ejection fraction of both ventricles, and with a measurement of left ventricular myocardial mass. Parametric T1 mapping will be performed using shortened modified look-locker inversion recovery (ShMOLLI) breath-hold sequence in short axis to visualize and assess the diffuse myocardial fibrosis. This will be done natively and then after an i.v. injection of gadolinium contrast agent, which allows the calculation of the extracellular volume. Furthermore, standard late gadolinium enhancement imaging of regional myocardial fibrosis using inversion recovery T1-weightened sequences will be done.

RANDOMIZATION Patients will be randomized to the catheter ablation group (CA) or risk factor modification group (RFM) in a 1:1 ratio; randomization will be done using randomization software. The software will be designed to account for BMI, and AF type, with the goal of having comparable groups regarding those characteristics. The randomization will be done in blocks of 10 patients.

TREEATMENTS A. Catheter ablation arm Catheter ablation will be done within one month (maximum two months) of randomization. In patients with paroxysmal AF, PVI will also be performed. In patients with non-paroxysmal AF forms, additional lesion sets, except for PVI, will be allowed according to the guidelines of each participating center. The first three months following catheter ablation will be considered as a "blanking period," i.e., AF reoccurrences won´t be assessed as an endpoint. If AF reoccurs during this period, treatment using AADs or cardioversion will be allowed. During this period, AF episodes recorded on ILRs will not be calculated. Three months after ablation, AADs will be discontinued and ECG monitoring, using ILR, will be started, In case of a reoccurrence of symptomatic AF or atrial tachycardia (AT), re-do ablations, cardioversion, or AADs treatment during the follow-up period will be allowed, in accordance with the current guidelines and practice of participating centers. However, because the indication for any of them will be a reoccurrence of AF or AT, it will be assessed as the primary endpoint (i.e., AF reoccurrence).

B. Risk factor modification arm The risk factor management intervention will be started after fulfillment of all the baseline diagnostic and functional examinations (spiroergometry, anthropometrical measurement, CMR) within one month after the enrollment of the patient.

The aim will be a 10% weight loss over 6 - 12 months, an increase in physical fitness, and alcohol (optimally absolute, if possible) abstinence. To achieve weight loss goal, standard recommendations according to the standards of the national and international professional societies will be used, in particular, societies on obesitology and cardiology. The approach will be highly individualized. In general, low-caloric dietary menu will be used based on current recommendations in combination with low or moderate physical activity, based on the individualization principle. Aerobic exercise will initially be prescribed for 20 minutes per week gradually increasing to 200 min/week until the end of the study. The physical activity part of the intervention will be performed using different activities: gym-based exercise in small groups with a physician, individual exercise with remote activity monitoring, outpatient follow-up consultation with regular education, and assessment of achieved results. Based on the results of functional diagnostics, changes in individual heart rate for mild and moderate intensity training will be assessed.

Nutritional intervention: intensive consultations with nutritional specialists will be done during the first three months after enrollment. The flow-chart of the on-line and personal consultation within the first three months is shown in the Table 1. A low-caloric dietary menu will be suggested and optimized by a nutritional specialist for each patient on individual basis respecting the comorbidities of the particular patient and planned increase in physical activity. Regular consultation with dietary specialists (on personal basis, or by phone) are planned for all patients also after three months, with less frequent intensity.

The physical intervention will consist of three types of activities. i)regular gym-based training in small groups of approx. 5 patients, or individual training with trainer. Initially, training will be performed three times a week as circuit training to increase physical condition, muscle balance stabilization, and education of proper functional respiration (respiratory training).

ii)Individual aerobic training: fast walking or Nordic walking: The intensity and frequency will be set individually based on initial spiroergometry, 1-2 training weekly in the beginning of the study with further increase.

iii)Home-based training: 20 min physical exercise sets including functional respiratory training to increase respiratory capacity, and balance exercise to balance muscle disproportions.

The physical intervention will be based on regular mild and moderate intensity aerobic exercise that will be gradually increased from 60 min/week up to 200 min/week and then continued until the end of the study. Patients will be taught how to use their optimal heart rate for aerobic exercise, and also warned about exceeding their maximum possible heart rate (i.e., not exceeding 85% of the maximum heart rate).

All the aforementioned physical interventions will be continued through the end of the study period. The type and ratio of the aforementioned physical exercises will be changed over the study period. In the first three months, there will be more emphasis on regular gym-based training in small groups, and less emphasis on individual exercise. The goal will be to teach patients how to properly perform all the exercises as well as assisting patients in getting used to regular exercise. By the end of the third month, when the majority of patients should be used to perform regular physical activity, the ratio of types of physical activities will change a greater emphasis on individual physical activity and less emphasis on gym-based programs, done in groups.

Since it is known that the adherence of patients to regular activity is affected by activity monitoring, all patients will have an opportunity to be monitored using remote activity monitoring (fitness bands) with a freely available smartphone application. Patient will be encouraged to use the fitness bands for the whole study period to monitor the habitual activity (steps/hour units) to document the increase of the activity in the risk factor modification arm since the randomization. Moreover, all physical activities could be stored at the web-page www.casprozdravi (energy income, weight, physical activities). This web-based tool allows the on-line discussion with therapeutic and will be free for all participants.

Similarly, as in the catheter ablation group, the first three months will be assessed as a "blanking period" regarding the rhythm measurement It means, no rhythm assessment will be done and AF reoccurrences will not count as an endpoint. The use of AADs will be allowed during this period. In patients in sustained AF at the end of three months, electrical cardioversion will be recommended. Also, as in the catheter ablation group, AADs will be withdrawn at the end of the "blanking period," and the ECG monitoring using ILR will be started. Any AF reoccurrence after the "blanking period" will be assessed as endpoints (AF recurrence). Electrical cardioversion, AAD re-initiation, or catheter ablation will be allowed during the follow-up period, based on clinical judgment, patient symptoms, and current recommendations according to the guidelines. However, because these treatment modalities are indicated only in patients with AF, all of them could be done only in endpoint (i.e. AF recurrence) appearance. Moreover, the recommendation, especially for catheter ablation, will be that they are postponed so that the effect of the risk factor modification strategy can be fully pronounced.

OUTPATIENT FOLLOW-UP

After the end of the blanking period, follow-up visits will be scheduled at 3, 6, 9, and 12 months during the first year, and then every 6 months afterward. The follow-up protocol and ECG monitoring are the same in both arms. Routine 12-lead ECGs will be recorded at follow-up visit along with a physical examination of the patient, and a medical history update.

At the 12-month follow-up, CMR, blood drawing, antropometric measurement, and physical diagnostics will be done. During this visit, patients will also be asked to complete follow-up QoL questionnaires. The anthropometric measurement will be done finally at the last visit of each patient, at the end of the 3rd year of the study.

ENDPOINT MONITORING Any symptomatic or asymptomatic episode of AF or regular AT lasting > 30 sec will be considered as an arrhythmia reoccurrence. AF-free survival will be defined as a complete absence of any AF or AT during the follow-up period. The AF burden will be calculated as the percentage of time spent in AF or AT. All ECG endpoint will be analyzed using ILR recordings. All recordings from patients ILRs will be sent by home monitoring equipment, and analyzed by the core lab using commercially available software supplied by the monitoring equipment manufacturer. The core lab will consist from two experienced biomedical engineers and cardiologists.

ENDPOINTS

Primary endpoints:

1. AF recurrence (i.e. the first recurrence of any AF or AT lasting more than 30 sec)

2. AF burden: calculated using ILR as a percentage of time spent in AF or AT

3. Change in left ventricular mass and myocardial fibrosis (LV mass, diffuse myocardial fibrosis, late gadolinium enhancement) between the baseline and one-year CMR examinations

Secondary endpoints

1. Hospitalization for AF reoccurrence and/or emergency room visit due to AF

2. A composite of stroke, cardiovascular death, or hospitalization for heart failure

3. Changes in QoL questionnaires between baseline and 1 year

4. Metabolic endpoint: changes in weight, fasting glucose, lipid levels, glycated hemoglobin, and cytokines associated with inflammation and LV fibrosis (hsCRP, TGF-beta, GDF-15)

Power calculation and statistical analysis According to the present data, about 60-70% efficacy could be expected in the catheter ablation arm, and 50-60% in the lifestyle modification arm. Assuming the power of 80%, with alfa value of 5%, and non-inferiority margin 10%, 60 patients have to be randomized to each arm. For data description, standard descriptive statistical methods will be used: absolute and relative frequencies for categorical data and the median with 5-95% percentiles for continuous data. For categorical variables, statistical analysis was done using the chi-square or the Fisher exact test; for continuous variables, the Student t-test or Mann-Whitney U test will be used. Kaplan-Meier curves will be calculated for visualizing the occurrence of endpoints during follow-up. The influence of patient characteristics on the occurrence of endpoints will be calculated using logistic regression and the Cox proportional risk model, as appropriate. Statistical analyses will be done using SPSS v. 22.0 software (IBM Corporation, 2013).

Randomization process and data management Randomization software will be developed by the team of statisticians and computer specialists of the Institute of Biostatistics and Analyses (IBA). The randomization software will respect the risk characteristics of patients, the randomization software will be designed to account for age, BMI, AF type, and LA size, with the goal of having comparable groups regarding those characteristics. The randomization will be done in blocks of ten patients. IBA presents the institution with the largest experience in biomedical statistics and data management in the Czech Republic, and has been participating in several similar studies. The randomization process will be done outside all participating centers using web-based randomization software, and therefore it will be independent of study subjects and site personnel. The website will be used not only for collection of baseline data and randomization, but also for collection of all outpatient follow-up data during the whole follow-up. IBA will be also responsible for data management during the whole study period. Each participating center will have an access to a dedicated part of the web page. The local investigator at each site will be responsible for data completeness and validity. The first interim analysis will be done after enrollment of the first 50 of patients, the next on annual basis. The final analysis will be done when the last enrolled patient will achieve 6 months follow-up. All regulations regarding medical confidentiality and data protection will be fulfilled.

Safety monitoring The local investigators will be responsible for reporting of all adverse and serious adverse events to the local and multicenter ethical committee. Serious adverse event (SAE) will be defined as life-threatening events resulting in death or hospitalization. A Data Safety Monitoring Board will be constituted before the onset of the trial. All the interim analyses will be reported to the DSMB by the principal investigator on the annual basis. DSMB may suggest termination of the study at any time based on appearance of SAEs, or if one treatment approach is shown to be significantly superior than other during the interim analysis, using statistical criteria for acceptable deviations from the null hypothesis.

DISCUSSION In the last 5 years, lifestyle modification has been shown to be a very promising treatment modality for AF. AF is the most common sustained cardiac arrhythmia with an estimated worldwide prevalence of about 33.5 million people. According to recent epidemiological studies, its prevalence may triple by 2050. Even if catheter ablations were associated with a 100% success rate, it would be impossible to treat the current or projected numbers using catheter ablation. So will lifestyle modification studies may seem to offer a panacea, those studies suffer from significant limitations and possible biases. For example, the most important and most extensive studies were both non-randomized, and all patients had either a history of catheter ablation (ARREST-AF), or were without a history of catheter ablation, but catheter ablation was allowed without limitations, based on the judgment of the attending physician during the follow-up period (LEGACY). A randomized study that directly compares catheter ablation with lifestyle modification strategy has not yet been done. Only a randomized study can really answer the question, how effective is lifestyle modification compared to catheter ablation. Additionally, a randomized study has to potential to indicate which patients would be most likely to benefit from a non-invasive treatment, thus increasing the number of successfully treated AF patients, without the use of invasive methods. Due to increasing incidence and prevalence of AF, the searching for other, alternative approaches in treatment of AF is warranted. If the risk factor modification management has been proven to have similar efficacy as catheter ablation, many motivated patients could be treated using this simple, non-invasive approach.