Study population

We included all consecutive patients from the hospitalization ward or outpatient department who presented with one of the following criteria: a single syncope, if severe (i.e. not preceded by prodrome, which resulted in an injury) and recent (i.e. occurring within the previous six months); or at least two syncopes in the past 12 months. The syncope had to remain unexplained at the end of the clinical examination, and after performing a 12-lead electrocardiogram (ECG), echocardiography and head-up tilt-test, meaning that a further diagnostic workup was mandatory. The exclusion criteria were as follows: significant heart disease (i.e. left ventricular ejection fraction < 40%); a history of myocardial infarction or unstable coronary artery disease; a history of arrhythmia; potentially arrhythmogenic drug use; a family history of sudden death; presence of bifascicular intraventricular conduction disturbance on the ECG; hypertrophic cardiomyopathy with or without obstruction; and aortic stenosis. Patients provided written informed consent to participate in the study. Institutional review board approval was obtained at all study sites.

Study design

This national prospective randomized open-label multicenter study included a representative sample of French academic and non-academic hospitals.

Included patients were randomized either to receive an ILR (Reveal ^® or Reveal ^® Plus, Medtronic Inc., Minneapolis, MN, USA) immediately (ILR group) or to be investigated according to the conventional evaluation strategy commonly used by the attending physician, with exclusion of the use of an ILR (CONV group). By protocol, the final diagnosis, whether ECG-documented or not, was left to the investigator.

Patients were randomly allocated into the CONV and ILR groups using a computer-generated randomization list. The patients were followed for a period of 14 months, with outpatient consultations scheduled at two, six, 10 and 14 months in the ILR group and at six and 14 months in the CONV group. As these visits were performed only for the purpose of the study, they were not entered into the cost analysis. In both arms, non-scheduled consultations were performed if necessary and were entered into the cost analysis.

Cost analysis

To evaluate the economic burden on healthcare providers, we assessed the duration of the hospitalizations and the number of different consultations and medical tests performed. The costs were assessed based on the number of hospitalization days and the number of consultations or tests, to put the analysis in the context of society. Of note, the cost of the ILR was not included in the cost analysis as it was not reimbursed at that time in France.

Consultations were defined as physician visits according to the French care system, done by the general practitioner (GP) or a specialist (cardiologist, neurologist or other specialist). We identified four categories of tests, as follows: standard cardiological tests (12-lead ECG, transthoracic echocardiography, 24-hour Holter monitoring, head-up tilt test); advanced cardiological tests (transoesophageal echocardiography, electrophysiological study, carotid ultrasound, ambulatory blood pressure monitoring, treadmill test, coronary angiography); neurological tests (electroencephalogram, brain computed tomography scan); and any other tests (blood sampling, chest X-ray, any other non-detailed tests).

For the tests listed above, the cost unit was the total number of examinations performed. This arbitrary listing provides a plausible order of magnitude.

Quality-of-life analysis

An analysis of QoL using the 36-Item Short Form Health Survey (SF-36) questionnaire was performed at baseline, six months and the end of the study. The SF-36 questionnaire is a self-administered questionnaire that measures health in eight multi-item dimensions, covering functional status, well-being and overall evaluation of health .

Statistical analysis

Analysis was by intention-to-treat. Variables are expressed as mean ± standard deviations. Comparisons were made, where appropriate, by Fisher’s exact test or the Mann–Whitney U test.

Diagnosis efficacy was compared between the two methods. An analysis based on the comparison, by volume, of the various tests for each of the different diagnostic methods was performed.

Regarding the number of patients to include, a preliminary study (not published) showed that the cost-effectiveness ratio (CER) using the conventional strategy for a patient referred for syncope to our department was €9336/percentages of diagnosis, and that the relative CER was €12,195/percentages of diagnosis. We considered that the variance of the costs and effectiveness would be identical with both methods, with a magnitude effect of 1. Assuming a bilateral situation, with a power of 80% and a type I error risk of 5%, a sample of 35 patients was necessary in each group to detect an effect size of 30%. In view of losses to follow-up and dropouts, the sample size was increased by 10%, resulting in a requirement for 77 patients to be included in the study.