By Michael Crawford, MD, Editor

SYNOPSIS: A multicenter, randomized, double-blind, controlled trial of fludrocortisone at a range of doses in patients with recurrent vasovagal syncope showed an overall trend toward reduced syncope, which was statistically significant in those who achieved the 0.2 mg daily dose.

SOURCES: Sheldon R, Raj SR, Rose MS, et al. Fludrocortisone for the prevention of vasovagal syncope: A randomized, placebo-controlled trial. J Am Coll Cardiol 2016;68:1-9.

Brignole M. Finally, a drug proves to be effective against vasovagal syncope!: But not in all patients. J Am Coll Cardiol 2016;68:10-12.

Fludrocortisone is on the list of potential drugs to prevent vasovagal syncope events, but there are no clinical trials demonstrating its effectiveness. Thus, investigators conducted a multicenter, double-blind, placebo-controlled, dose-ranging, clinical trial of fludrocortisone for the prevention of recurrent vasovagal syncope. Patients were included if they were > 14 years of age, experienced more than two syncopal spells, and presented with a Calgary Syncope Score of > -3. Patients with other causes of syncope, pacemakers, previous experience with fludrocortisone, or with other major comorbidities that would preclude fludrocortisone were excluded. Researchers educated all 210 patients enrolled about precipitators of syncope and counter pressure maneuvers. Those randomized to fludrocortisone started with 0.1 mg/day, which increased, if possible, to 0.2 mg daily, or decreased to 0.05 mg, if necessary. Investigators discouraged nonstudy medications and pacemakers. Women made up 70% of the population, and the subjects’ mean age was 30 years. The median number of syncopal spells was 15 over a median of nine years. During the median follow-up of 364 days, 96 patients experienced at least one syncope episode. In an intention-to-treat analysis, 42 of 105 patients randomized to fludrocortisone and 54 of 105 randomized to placebo experienced at least one syncopal spell (hazard ratio [HR] = 0.69; 95% confidence interval [CI], 0.46-1.03; P = 0.069). There were no serious adverse events, but 58 patients withdrew from the study for a variety of reasons. Successful dose titration to 0.2 mg daily in 61% increased adverse effects, but reduced the recurrence rate (HR, 0.51; CI, 0.28-0.89; P = 0.02). The authors concluded that although fludrocortisone did not achieve a statistically significant reduction in vasovagal syncope in the overall intention-to-treat analysis, in those who achieved dose stabilization at 0.2 mg daily, syncopal events were significantly lower.


Small, uncontrolled and short follow-up controlled trials have produced variable results for several pharmaceutical agents, pacing, counter pressure maneuvers, and increased salt and water consumption for preventing vasovagal syncope. This is the first long-term randomized, controlled, double-blind study that has been performed for any therapy for vasovagal syncope. Fludrocortisone features a strong pathophysiologic basis. Saline infusions in tilt table testing studies have led to reduced syncope with further tilt testing. Fludrocortisone increases renal salt and water retention and results in increased plasma volume. It has been a mainstay of therapy for orthostatic hypotension and autonomic dysfunction. It is probably more consistently effective than telling patients to increase salt and water intake, although this has not been tested. Vasovagal syncope is thought to be due to inappropriate vasodilation, which results in reduced venous return. Thus, the therapeutic rationale for fludrocortisone is strong.

This study failed to demonstrate the prespecified goal of a > 40% reduction in syncopal spells, which drove the power calculation for the trial. However, it did result in a 31% reduction in the intention-to-treat analysis, which was not quite statistically significant. In those who were successfully titrated to the 0.2 mg daily dose (61% of those treated with fludrocortisone), recurrent syncope fell 49%, which was statistically significant (P = 0.02). The highest recommended dose for orthostatic hypotension is 0.3 mg daily. The dose range in this study was 0.05-0.2 mg daily, so some patients may have been underdosed. On the other hand, 28% of the patients withdrew from the study, many of whom experienced adverse effects. Also, even in those who achieved a 0.2 mg daily dose, 44% still had at least one syncopal spell over the year of follow-up. Thus, fludrocortisone is not going to be the treatment for everyone. The investigators’ subgroup analysis showed that those who benefited most were those with a baseline systolic blood pressure of < 110 mmHg. Such patients undoubtedly have little blood pressure reserve. Also, the median age in this study was 30 years, suggesting the investigators were loath to use fludrocortisone in older patients. Of course, older patients are more likely to present with the comorbidities that were exclusion criteria in this study, such as high baseline blood pressure.

The study, the accompanying editorial, and my own experience suggest that fludrocortisone is worth trying in the subgroup of vasovagal syncope patients who are young and otherwise healthy, who demonstrate low systolic blood pressures at rest, and who experience frequent vasovagal episodes. In this study, the median number of syncopal spells in the year prior to study enrollment was three to four. One strength of this study was that clinical criteria (Calgary Syncope Score) were used to diagnose vasovagal syncope. Head up tilt testing was not used, which makes the results more widely applicable.