We decided to compare flecainide and a beta-blocker as they are the two most used drugs in our setting for the treatment of INVA. Among beta-blockers, we chose carvedilol due to its dosing schedule being similar to that of flecainide and because studies suggest that carvedilol may be superior to other beta-blockers in preventing ventricular arrhythmias.13

The study “CARvedilol versus FLECainide Treatment in Idiopathic Ventricular Extrasystoles and Tachycardias (CARFLECT IV)” is an open-label, prospective, randomized 1:1, and single-center study conducted in a tertiary care hospital. Blinding is limited to third parties. Patients were screened from among all individuals followed at the only cardiology service of a healthcare area covering approximately 450000 people.

All patients treated by the cardiologists participating in the study who meet all the inclusion criteria and none of the exclusion criteria will be consecutively included for participation.

Patients will be randomized to receive either flecainide followed by carvedilol or carvedilol followed by flecainide. Patients will be followed for a total of three years and 26 weeks: 12 weeks with one drug, one week–two months of washout, and 12 weeks with the subsequent drug, plus an additional week to report adverse events occurring immediately after drug withdrawal. Follow-up will also include a telephone assessment at one year and another at three years (graphical abstract).

Between the washout period and the initiation of the second drug, an additional period of up to two months may be established to allow proper scheduling of subsequent visits. During this period, the patient may resume the drug already tested if deemed necessary by their clinician, but they must remain off treatment during the week prior to starting the second drug in the study.

Before initiating treatment, a baseline electrocardiogram, Holter ECG, standardized echocardiogram (ETT), and SF-36 quality of life questionnaire will be performed. During the drug titration phase, weekly in-person clinical evaluations will be conducted, including dose adjustments if indicated, along with Holters, ETTs, and ECGs. Once titration is completed, evaluations will be conducted every four weeks via telephone. After completing the 12-week follow-up for each drug, the same tests performed before starting the drug (ECG, baseline Holter ECG, standardized ETT, and SF-36 quality of life questionnaire) will be repeated. These results will be compared with those obtained before starting the drug. One week later, the patient will be contacted by phone to assess the occurrence of adverse events in the days following drug discontinuation.

Titration will be performed with the following doses:

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  Oral flecainide: 50 mg every 12 hours, 100 mg every 12 hours, 150 mg every 12 hours (the highest dose will only be administered if GFR >60 ml/min and body weight >75 kg).

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  Oral carvedilol: 6.25 mg every 12 hours, 12.5 mg every 12 hours, 25 mg every 12 hours.

The maximum required dose will be considered achieved when the burden of PVCs has been reduced by at least 85%.

If mild dose-dependent toxicity occurs during titration, the dose will be reduced to the last tolerated level. In the event of a severe dose-dependent or any non-dose-dependent adverse effect, treatment will be discontinued immediately. The following will be considered indicative of dose-dependent toxicity:

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  In a 12-lead ECG: PR >250 ms and/or resting sinus bradycardia <50 bpm.

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  In Holter monitoring: asymptomatic sinus pauses >3 seconds or atrioventricular block of Mobitz II, high-grade, or third-degree.

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  For patients on flecainide, a QRS widening >25% will also be considered indicative of overdosing.

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  Symptoms such as asthenia or general discomfort will be considered signs of overdosing. Digestive discomfort is also recognized as a potential adverse effect of flecainide.

Serious adverse events will be defined as those requiring hospital admission or resulting in the patient's death.

For patients receiving flecainide, low doses of atrioventricular node blockers (beta-blockers or calcium channel blockers) may be administered at the clinician's discretion to prevent class 1C-related flutter.

All patients who agree to participate in the clinical trial will also be invited to take part in an observational study on the effects of the H558R polymorphism on the response to flecainide. Patients may decline genetic sampling without being excluded from the clinical trial. The presence of this polymorphism will be assessed using a blood sample obtained by venipuncture. The information from both studies may be combined if patients consent. For more information about the genetic study, refer to the supplementary material.

In addition to the variables included in the endpoints, anthropometric data such as height and weight, comorbidities, and concomitant treatments will be collected. Data on date of birth, date of diagnosis, and start date of each treatment will also be recorded. Heart rate, glomerular filtration rate, and toxic substance use will be documented, as well as electrocardiographic variables such as QRS complex duration.

As we anticipate a 90% reduction in the number of PVCs in the flecainide group and a 75% reduction in the carvedilol group, with a standard deviation of 25%, an alpha error of 0.05, and a statistical power of 0.8, a sample size of 58 patients would be required. As a crossover design will be used, 29 patients will be sufficient. Assuming a 10% dropout rate due to loss to follow-up or adverse effects, a total of 32 patients will be needed. Patients will be recruited until the target sample size is achieved.

For the analysis of continuous quantitative dependent endpoints, linear regression, Student's t-test, and/or the Wilcoxon signed-rank test will be used, as appropriate. Normality will be assessed using the Shapiro–Wilk test (significant if p<0.1).

For the analysis of discrete quantitative dependent endpoints, Student's t-test, ANOVA, and logistic regression will be used, as appropriate.

For the analysis of qualitative dependent endpoints, logistic regression and chi-square testing will be used, as appropriate.

The clinical trial has been registered with the European Medicines Agency under the code 2023-510362-26-00 and approved by the relevant authorities. Similarly, the H558R sub-study was approved by the ethics committee of our institution. All procedures will be conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent will be obtained from all participants prior to enrollment.

Recruitment has commenced, and the first three patients have already been enrolled in the study.

This study has several limitations, primarily due to the small target sample size (n=32), which may result in insufficient statistical power to detect moderate differences between groups or to assess low-incidence endpoints such as adverse events.

The use of a minimum of 1000 PVCs as an inclusion criterion is somewhat arbitrary. Furthermore, it does not take into account the percentage of PVCs, even though this is one of the study endpoints.

Additionally, the crossover design also presents challenges, mainly due to potential lifestyle changes during the study that could influence the effect size observed during the first treatment phase. For example, differences between pre- and post-treatment Holter results could reflect a combination of lifestyle changes and drug effects. Another potential limitation of a crossover approach could be spontaneous remissions. However, these should not pose a significant limitation, as they are typically reported after longer follow-ups, with a low spontaneous resolution rate (<15%) at six months.2

The requirement for women of childbearing age to initiate oral contraception to participate in the study could potentially influence arrhythmic burden. However, thanks to the crossover design and the fact that these patients will receive oral contraception during both treatment periods, the risk of bias is reduced.

An additional limitation of the crossover design is that, if the first treatment normalizes LVEF and GLS), it may be difficult to assess the effects of the second treatment on this parameter. This is because, if the second treatment were effective, no changes might be observed given that function was already normalized before its initiation; conversely, if it were ineffective, no changes might be seen either, as 12 weeks may not be sufficient for dysfunction to recur. This limitation could compromise the statistical power to detect differences in LVEF and GLS.

All these problems are partially addressed by the 1:1 randomization of patients to each treatment arm. Furthermore, the study is only blinded to third parties, which means that blinding will not be implemented for the patient or the treating physician. However, echocardiographic studies and Holter-ECGs performed at the beginning and end of each treatment period will be assessed in a blinded manner. In addition, the database will be coded so that the statistician remains unaware of treatment allocation. This approach minimizes the risk of bias in the primary outcome and in the secondary endpoints related to arrhythmic burden and imaging, although the possibility of bias in the assessment of quality of life cannot be excluded.

Finally, this is a low-intervention clinical trial designed to compare the real-world use of both treatment strategies. For this reason, we allowed the co-administration of low-dose beta-blockers with flecainide to prevent class 1C-related atrial flutter when considered appropriate by the treating physician. If, upon completion of recruitment and follow-up, a substantial number of patients in the flecainide arm are found to have received concomitant low-dose beta-blockers, this could lead to the conclusion that flecainide is superior to optimally dosed beta-blockers, when in fact what may have been demonstrated is that flecainide in combination with low-dose beta-blockers is superior. Nevertheless, this would also represent a clinically relevant finding. Therefore, we do not believe this limitation undermines the value of the study. In the end publication, we will report on the number of patients who received beta-blockers in combination with flecainide, and a subgroup analysis of these patients may also be performed.