Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04011800 |
| Other study ID # |
PRAGUE-25 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2021 |
| Est. completion date |
December 30, 2025 |
Study information
| Verified date |
November 2023 |
| Source |
Charles University, Czech Republic |
| Contact |
Pavel Osmancik |
| Phone |
00420721544447 |
| Email |
pavel.osmancik[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a prevalence of
2% in general population. Incidence and prevalence of AF has been slightly increasing due to
increasing age, improved ability to treat cardiac diseases, and higher incidence of obesity
and other risk factors associated with AF. AF is associated with higher morbidity and
mortality mainly caused by heart failure and stroke. Catheter ablation (with pulmonary vein
isolation as a cornerstone) presents the most effective treatment method of AF. Recent
observational studies have shown that intensive risk factor and lifestyle modifications, such
as weight loss, reduced alcohol intake, and increased physical activity, are also associated
with improved rhythm outocome. Head-to-head comparison of this very different methods has not
been done yet. The aim of the project is to compare the effect of catheter ablation with
lifestyle modification (risk factor modification) in a prospective, randomized, multicenter
study on the maintenance of sinus rhythm (monitored using implantable ECG reveal), and on the
progression of the fibrosis of the left ventricle.
Description:
GOALS OF THE PROJECT The aim of our study is to compare the effect of the invasive strategy
(catheter ablation) of atrial fibrillation with non-invasive strategy (non-amiodarone
antiarrhythmic drugs with risk factor modification) in a prospective, multicenter,
randomized, non-inferiority study. The main hypothesis is that strict risk factor
modification (weight loss, physical exercise improvement, and alcohol reduction) with AADs in
patients with AF will be associated with similar rhythm outcomes as catheter ablation. Beside
the AF-recurrence as the primary endpoint, the secondary endpoints will be the AF burden
(assessed using repeated Holter recordings), change in cardiorespiratory exercise (assessed
using cardiopulmonary exercise test), MRI endpoints (diffuse myocardial fibrosis, epicardial
adipose tissue), QoL (assessed using specific questionaiires), and metabolic endpoints
(lipids, pro-inflammatory cytokines),
JUSTIFICATION OF THE PROJECT The main reason for the project is the large and ever-increasing
number of AF patients, especially in light of the significant incidence of obesity in AF
patients. Keeping in mind the high number of AF patients (≈ 2% of the population), its
increasing incidence and prevalence, even if CAs were associated with a 100% success rate, it
would be impossible to treat all AF patients using CA. A significant portion of patients with
AF are obese. For instance, the median BMI was 29.2 in the EAST-AFNET Trial and 30 in the
CABANA Trial. Furthermore, and this is the second reason for the project, a significant
portion of AF patients are afraid of invasive procedures and would prefer a noninvasive
approach if the efficacy of this approach is known. The third reason is to compare the effect
of these two different methods on the structural and metabolic abnormalities associated with
AF and obesity
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 ≥ 30, and
(iii) signed informed content
Study population - exclusion criteria:
- permanent AF
- severe valve disease (significant aortic stenosis, mitral regurgitation ≥ 3)
- left ventricular ejection fraction < 40%
- severe pulmonary hypertension (PAP > 40 mm Hg)
- history of tachycardia-induced cardiomyopathy
- planned revascularization
- pregnancy
- left atrial size ≥ 60 mm
- BMI less than 30, 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 After informed content is given, all patients will undergo
baseline anthropometric measurements and baseline examinations. It will include (1) baseline
evaluation of physical fitness - functional diagnostic, (2) echocardiography, (3) quality of
life analysis, (4) blood biochemistry and cytokine analysis, and (5) a baseline one-week ECG
Holter recording, (6) cardiac MRI. All these examinations will be done within four weeks
after randomization.
Functional diagnostic (anthropometric measurement and cardiopulmonary exercise test) After
enrollment, standard anthropometric measurements will be gathered, i.e., height, weight,
percentage of body fat, and waist-to-hip ratio measurements. Functional diagnostics will be
performed in all patients. Based on the results of functional diagnostics, an individualized
and optimized physical training program will be prepared in patients randomized to the RFM
arm.
An initial maximum symptom limited cardiopulmonary exercise test (CEPT) will be carried out
within one month of enrollment.
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.
RANDOMIZATION Patients will be randomized to the catheter ablation group (CA) or risk factor
modification group plus AADs (RFM) in a 1:1 ratio; randomization will be done using
randomization software that will account for age, initial BMI, and AF type, with the goal of
having comparable groups relative to those characteristics. The randomization process will be
done outside all participating centers.
TREEATMENTS A. Catheter ablation (CA) arm CA will be done within two months of randomization.
In patients with paroxysmal AF, a PVI will be performed. In patients with non-paroxysmal AF
forms, additional lesion sets, except for a PVI, will be allowed according to the practice of
each participating center. The CA will be done using a 3D mapping system, intracardiac
echocardiography, contact-force sensing ablation catheters, and ablation index to achieve the
maximum available safety and to allow for the delivery of maximally effective ablation
lesions. During the study course, several centers have started to prefer pulsed-field
ablation. Per amendment, pentaspline pulsed-field ablation catheter with corresponding
pulsed-field energy generator can be used for catheter abaltion. Similarly as with
radiofrequency ablation, the goal will be to effectivelly isolate pulmonary vein. Based on
the discretion of the operator, additional lesions could be done.
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. Three months after ablation, AADs will
be discontinued.
B. Risk factor modification and antiarrhythmic drugs arm (RFM arm)
The aim will be (1) a 10% weight loss over 6-12 months,(2) an increase in physical fitness,
and (3) a reduction in alcohol consumption. Nutritional intervention: the initial patient
consultations with nutritional specialists will be done during the first month after
enrollment. A low-calorie, high protein, and low glycemic index dietary menu will be
suggested and optimized by a nutritional specialist for each patient. Patients will have
regular consultations with dietary specialists at least once a month during in-person visits
in the early follow-up or by phone visits later during the follow-up; however, non-planned
dietary consultations will be available every working day by calling a dietary specialist or
using mobile application. Moreover, patients will be encouraged to record the calory intake
in the OBEFIS application (either on the web www.obefis.cz, or using the mobile application)
on a daily basis, and the recordings will be discussed during the visits with dietary
specialists.
All patients will have an initial consultation with a physiotherapist (after the CPET) to set
the type and intensity of the physical intervention. The recommended physical intervention
will consist of three types of activities: (1) regular gym-based training (in small groups or
individual training with trainer),(2i) individual aerobic training (fast walking or similar
aerobic activity), and (3) home-based training: 20 min physical exercise sets. 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 under
surveillance. 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. At the end of the third
month, the majority of patients should be accustomed to regular physical activity; the ratio
of types of physical activities will be changed to a greater emphasis on individual physical
activity. However, based on the patient´s experiences with physical activity in the past, and
their options regarding participation in the organized training, activities will be
individualized, and some patients may start the physical activity program individually
without previous participation in group-based or surveillance-based training.
The intensity and frequency will be set individually based on initial CPET. The ESC
guidelines for obese individuals recommend that a minimum of 150 min/week of
moderate-intensity endurance exercise training should be combined with three weekly sessions
of resistance exercise with the heart rate during the activity being 55-74% of the maximum HR
(31). As such, the physical intervention will be based on regular (mainly moderate, ~ 55-74%
of the maximum HR) intensity aerobic exercise that will be gradually increased from 60
min/week up to 200 min/week (in some individuals up to 300 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; for moderate-intensity training, the heart rate during the activity should
be 55-74% of the max. HR. They will also be warned about exceeding their maximum possible
heart rate (i.e., not exceeding 85% of the maximum heart rate). 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 during each exercise using remote heart rate
monitoring (fitness bands) and the OBEFIS smartphone application. It also allows monitoring
of the heart rate during activity and an online discussion with therapists during the
follow-up period.
For patients in the RFM arm, contrary to patients in the CA arm, non-amiodarone AADs will be
allowed during the whole study period. The reoccurrence as AF/AT as an endpoint will be
considered starting at the 6-month visit, including a 7-day Holter, which is scheduled to be
done at the 6-month visit.
In both arms, 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 practices of participating centers. However,
because the indication for the aforementioned procedures or AAD initiation will be a
reoccurrence of AF or AT, it will be assessed as the primary endpoint (i.e., AF
reoccurrence).
OUTPATIENT FOLLOW-UP The follow-up protocol and ECG monitoring will be similar for both arms.
Starting on the day of the catheter ablation (D0 in the ablation arm), or at the start of the
metabolic activity (D0 in the RFM arm, approx. 3-4 weeks after randomization), follow-up
visits will be scheduled at 3, 6, 9, and 12 months during the first year, and then every six
months. At the 3-month follow-up visit, patients in AF (from both groups) will undergo
electrical cardioversion.
A routine 12-lead ECG will be recorded at each follow-up visit, along with a physical
examination of the patient and a medical history update. Long-term ECG recording will be done
using a 7-day Holter recording at baseline, and then at the 6, 9, and 12 months visits during
the first year, and then every six months in the second and third years. Baseline 7-day ECG
Holter recordings will be done in all patients after enrollment and within the first three
weeks for patients on antiarrhythmics before study entry; this will serve as background for
comparisons of AF burden.
The first three months in the CA arm and the first six months in the RFM arm will serve the
blanking period. Starting at 3M (CA) or 6 M control (RFM) control, any reoccurrence of AF/AT
will be considered an endpoint.
At the 12-month follow-up visit, echocardiography, MRI examination, anthropometric
measurements, and CPET will be done. Blood will be drawn for cytokine analysis, and patients
will also be asked to complete follow-up QoL questionnaires.
ENDPOINT MONITORING The AF reoccurrence will be detected either using planned 7-day Holter
recordings (at the 6, 9, and 12 m visits), during all planned outpatient visits using a
standard 12-lead ECG, and any time during the follow-up at an emergency non-planned visit
also using a standard 12-lead ECG (starting at the three-month visit in the CA arm and the
six-month visit in the RFM arm). The occurrence of AF > 30 sec during planned 7-day Holter
recordings, either planned or emergency, a non-planned visit will be assessed as a primary
endpoint. Importantly, during all outpatient in-person visits, AF reoccurrence has to be
documented using an ECG (i.e., a patient´s description of "palpitations" without ECG evidence
will not be assessed as AF reoccurrence).
STUDY OUTCOMES
Primary endpoints:
1) AF reoccurrence (any AF or atrial tachycardia lasting more than 30 sec) SECONDARY OUTCOMES
1. AF burden: calculated using all Holter recordings as a percentage of time spent in AF or
AT
2. AF reoccurrence and AF burden at the 12-month visit
3. Hospitalization for AF reoccurrence and/or emergency room visit due to AF
4. A composite of stroke, cardiovascular death, or hospitalization for heart failure
5. Changes in QoL questionnaires between baseline and 12 months
6. Change in cardiorespiratory fitness as assessed using CPET between baseline and 12
months (ml/kg/min)
7. Metabolic endpoint: changes in weight, fasting glucose, lipid levels, glycated
hemoglobin, and cytokines associated with inflammation and atrial function
(interleukin-6, natriuretic peptides)
8. Imaging endpoints: change in the amoubnt of EAT and % in ventricular fibrosis between
baseline and the 12-month examination (MRI), and a change in left atrial parameters
(echocardiography)
Power calculation and statistical analysis The expected efficacy of the Catheter ablation In
a meta-analysis of RCT comparing CA with AADs, the single procedure success rate of CA OFF
AADs was 57% (96%CI 50-64%) In the CABANA trial, AF freedom was present in 63.6% of the
ablation patients by 12 months. The expected one-year AF freedom in the CA arm is ≈ 60%.
The expected efficacy of AADs and RFM In a meta-analysis of 24 randomized control trials
comparing AADs with placebo, the overall success rate of AADs, defined as the disappearance
of arrhythmia during follow-up, was present in 52% (95%CI 47%-57%) of patients on AADs. The
highest efficacy was achieved using amiodarone (58%), followed by flecainide and propafenone
(48%). In the CABANA trial, by 12 months, the one-year AF freedom on AADs was present in
47.1% of patients. Finally, in the recently published STOP-AF trial, one-year AF freedom
(assessed using repeated 24-Hour Holter recordings) was present in 45.0% (95%CI 34.6-54.7) of
patients, but only 2% were on amiodarone, and the rest were on flecainide, sotalol and
propafenone. Therefore, a one-year AF freedom of 45% could be expected for non-amiodarone
AADs. In the LEGACY study, the achieved AF freedom significantly depended on weight loss.
Relative to weight loss, patients were categorized as >10%, 3%-9%, and < 3% weight loss.
During follow-up, 45.5% patients in the >10%, 22.2% in the 3-9%, and 13.4% in the < 3% group
remained AF-free without AADs or ablation. In the ARREST AF, at the final follow-up (mean
duration 41 months), 32.9% of patients in the RFM arm vs. 9.7% controls remained AF-free
after a single CA procedure. No study has compared the additive effect of weight loss on top
of AADs; however, an additional effect of 20% could be expected in these patients. Therefore,
we expected a ≈ 65% one-year AF freedom in the noninvasive treated patients.
According to the aforementioned data, we expect one-year AF freedom in 65% of patients in the
RFM arm and 60% in the CA arm. The primary analysis will be done using the intention-to-treat
principle; however, based on the non-inferiority nature of the study, a per-protocol analysis
will be done. The sample size calculation assumed: 80% power, 5% one-sided alpha, a
non-inferiority margin of 12% (or 1.65, if expressed as an odds ratio). Using this
assumption, 202 patients (101 in each arm) will need to be enrolled to prove non-inferiority
of the noninvasive arm relative to the invasive arm. With an expected drop-out rate of 5%,
therefore, 212 patients will be enrolled.
Study organization, randomization process and data management
The institution responsible for the organization and implementation of the study is the 3rd
Faculty of Medicine, Charles University in Prague, Czech Republic. Data obtained during each
patient visit will be collected using a safe electronic CRF form. A tailor-made website was
developed for the study. Each participating medical center will have access to a dedicated
part of the website. The database and randomization software has been prepared by an outside
party (i.e., the Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech
Republic), and no investigator will have access to the database or the randomization
software.
Safety and endpoint monitoring The local investigator at each site will continuously review
safety data during the trial. A Data Safety Monitoring Board (DSMB) will be constituted
before the commencement of the trial. Reporting of adverse events will be reported to the
DSMB immediately by the principal investigator. Serious adverse events (SAE) will be defined
as life-threatening events or events resulting in death or hospitalization. All SAEs linked
with the study will be reported to the DSMB, to the FNKV Ethics Committee (a multicenter
ethics committee, EC), and to the local ECs within 24 hours of study staff becoming aware of
the event. Clinical endpoints will be analyzed by a dedicated clinical endpoint committee.
The recording and analyses of all Holter recordings in all participating centers will be done
centrally using an MDT (medical data transfer) company.
DISCUSSION In the last five years, lifestyle modification with risk factor management 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 ablations. Furthermore, a substantial number
of patients would prefer a non-invasive treatment if both strategies were comparable. So
while risk factor 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 a
modern noninvasive strategy has yet to be done. If the effect of both strategies were
comparable, the noninvasive strategy could be offered to patients with a preference for a
noninvasive treatment. Only a randomized study can really answer the question of how
effective lifestyle modification is supported by safe non-amiodarone AADs compared to a
modern invasive strategy. Additionally, a randomized study has the potential to show the
additional effect of both strategies (effect on CMR measures or pro-inflammatory cytokines
concentrations) and to determine which patients would most likely benefit from a non-invasive
treatment, thus increasing the number of successfully treated AF patients, without the use of
invasive methods.
