A RANDOMIZED CLINICAL TRIAL OF MIDODRINE FOR THE PREVENTION OF VASOVAGAL SYNCOPE BY THE POST4 INVESTIGATORS

Vasovagal syncope (VVS) affects almost 40% of Canadians by age 60 y. Recurrent VVS reduces quality of life and causes physical trauma and social isolation. No therapies have been proven to be effective. We sought to determine whether the alpha-1 adrenergic prodrug midodrine, compared to placebo, reduces the likelihood of syncope in patients with moderate-to-severe VVS. The Fourth Prevention of Syncope Trial (POST 4) was a longitudinal, prospective, parallel design, placebo-controlled, randomized clinical trial conducted in 17 centres in Canada, the United States, Mexico, and the UK (NCT01456481). The Canadian Institutes of Health Research funded it. Patients with ≥2 faints in the previous year and a diagnosis of VVS determined by the Calgary Syncope Symptom Score were randomized to escalating doses of midodrine or matching placebo starting at 5 mg tid and followed for a fixed period of 12 months. POST 4 had an 85% power to detect, at p < 0.05, a relative risk (RR) of 0.50 of patients with a syncope recurrence analysed on an intent-to-treat (ITT) basis. The mean prior published RR was 0.38. There were 134 patients with median age 33y (69% female), who started fainting at median age 17y. They had a lifetime median 20 faints with a median 4 faints in the year before randomization, and were followed for medians of 7.1 and 11.0 months in the midodrine and placebo groups, respectively (p=ns). Rates of premature study exit were high: 26/67 midodrine pts and 15/67 placebo pts exited from followup before a primary outcome. In ITT analysis there were 29/67 and 38/67 primary outcomes in the midodrine and placebo arms (p=0.12). In on-treatment analysis there were 11/22 and 19/32 primary outcomes in the midodrine and placebo arms (p=0.58). The 1-year actuarial syncope rates in the ITT analysis were 43.3% and 56.7% in the midodrine and placebo arms; RR 0.76 (p=0.2). The 1-year actuarial syncope rates in the on-treatment analysis were 50.0% and 59.4% in the midodrine and placebo arms; RR 0.85 (p=0.26). In the ITT analysis there were totals of 72 and 117 faints in the midodrine and control arms, respectively. In the midodrine and placebo arms, there were 26 and 20 patients with side effects, notably paresthesias in 13 and 4 patients, respectively (p=0.018). The Fourth Prevention of Syncope Trial failed to demonstrate a statistically significant benefit of midodrine in the prevention of vasovagal syncope.