Efficacy of compression stockings for treating recurrent vasovagal syncope: a triple-blind, multi-center, randomized controlled trial (COMFORTS-II)

Assessment of the effectiveness of elastic compression stockings in preventing recurrent vasovagal syncope

triple-blind, multi-center, randomized controlled trial

Using central online randomization, 268 participants will be allocated to two arms (1:1 ratio), wearing intervention ECS or sham ECS . All participants will receive standard VVS treatment in the form of education, and lifestyle modification recommendations (drinking 2-3 liters/day of fluids and consuming 10 grams/day—roughly half a tablespoon—of table salt). Adherence to ECS treatment will be evaluated through diary sheets, and compared between study arms. Follow-up continues for one year, and is conducted via a 24/7 phone line available to patients and trimonthly visits. The main study center is Tehran Heart Center.

Inclusion criteria: patients with 18 ≤ age ≤ 65 years and diagnosed vasovagal syncope who had ≥2 episodes of VVS during the last year. VVS is confirmed by Clinical diagnosis And Calgary syncope system score (CSSS) ≥-2; Exclusion criteria: Presence of other causes for syncope or loss of consciousness; Prior use of medications for vasovagal syncope; Prior use or other indication for compression stockings; Chronic severe illnesses; Pregnancy or intention to become pregnant during the study; Unwillingness to participate or lack of consent

Intervention: elastic compression stockings: 20-30mmHg pressure, manufactured by Right Arian Farmed, for 12 months Sham: elastic compression stockings: <10mmHg pressure, manufactured by Right Arian Farmed, for 12 months

proportion of participants with any syncopal recurrence, time to first syncopal episode

Eligible participants will be randomized 1:1 to two parallel treatment and control groups. The random sequence will be generated by computer software (R software, blockrand package) using permuted block randomization, in block sizes of 2, 4, 6, 8. To balance participant enrollment in each study recruitment site, randomization is stratified based on the trial sites. A separate randomization sequence will be generated for each study center (each stratum). Since seven centers will be participating in this study, seven sequences will be generated. Allocation of the random code will be centralized and conducted online through the study website (www.comfortstrial.com). Enrolling physicians will upload baseline data, informed consent confirmation, and the measured size of compression stockings, and after completion and confirmation of recruitment forms, the website will allocate a random code for the patient. A pair of compression stockings with the correct size and from the appropriate group (treatment or control) will then be posted to the patient from Tehran Heart Center. Allocation concealment is ensured since the recruiting physician and patients are blinded to the treatment group, randomization is web-based and centralized, and a random code would not be allocated until recruitment is confirmed.

The compression stockings in treatment and control groups are identical in appearance and touch, and are made from the same material. The stocking will be provided to patients in identical unlabelled boxing. The only difference between compression stockings would be the pressure to the lower extremity. This is not expected to affect blinding, since eligible patients would not be using compression stocking before the trial and would not be familiar with the amount of pressure they experience. To assess blinding of patients during the study, participants will be asked to guess their randomly allocated treatment group at the last follow-up. The proportion of correct responses will be compared to the expected rate of random correct guesses (50%). Blinding will be achieved with centralized web-based randomization, and similarity in appearance of treatments. In addition to patients, the primary investigator, recruiting physicians, nurse researcher that gather baseline data, and outcome assessors will all be blinded to the randomly allocated group. Moreover, statisticians who will analyze the data for the final report in the manuscript will be blinded until finalization of results.