JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 68, NO.

1, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.03.595

EDITORIAL COMMENT

Finally, a Drug Proves to Be Effective

Against Vasovagal Syncope!
But Not in All Patients*

Michele Brignole, MD

M
The list
any drugs have been tested for the treat-
ment of vasovagal syncope; for the most
part, the results have been disappointing.
includes beta-blockers, disopyramide,
The results of the POST 2 trial (Prevention of Syn-
cope Trial 2), a randomized, double-blind, placebo-
controlled study of fludrocortisone in the prevention
of vasovagal syncope, are presented in this issue of
scopolamine, theophylline, ephedrine, etilefrine, the Journal (5). This is an important study because,
midodrine, clonidine, and serotonin reuptake inhibi-
SEE PAGE 1
tors. Although results have been satisfactory in
uncontrolled trials or short-term controlled trials, for the first time, a drug has been demonstrated to
the few long-term placebo-controlled prospective reduce recurrences of vasovagal syncope in young
trials conducted have been unable to show a benefit patients (median age 30 years) affected by moder-
of the active drug over placebo. ately frequent vasovagal syncopes. The primary
For example, because failure to achieve proper endpoint showed only a marginal nonsignificant
vasoconstriction of the peripheral vessels commonly reduction in syncope in the fludrocortisone group
occurs in reflex syncope, alpha-agonist vasoconstric- compared with the placebo group (hazard ratio: 0.69;
tors (etilefrine and midodrine) have been used. 95% confidence interval: 0.46 to 1.03; p ¼ 0.069).
Etilefrine has been studied in a large randomized, However, the difference became more significant in
placebo-controlled, double-blind clinical trial (1). an exploratory subgroup analysis restricted to out-
During follow-up, patients treated twice daily with comes after 2-week dose stabilization and to those
etilefrine 25 mg or placebo showed no difference in patients who achieved 0.2-mg dose stabilization at
the frequency of syncope or the time to recurrence. 2 weeks. The evidence of benefit was reinforced by a
Midodrine has proved effective in 4 small studies (2), strong underlying pathophysiological rationale.
but none of these satisfied the criteria of a pivotal Indeed, vasovagal syncope is often preceded by
clinical trial. Beta-blockers have been advocated in orthostatic stress, pooling of venous blood in the
vasovagal syncope on the presumption that they lower limbs, ineffective venoconstrictive responses,
lessen ventricular mechanoreceptor activation owing and decreased venous return and pre-load, which in
to their antisympathetic and negative inotropic effect turn reduces cardiac output, causing hypotension and
in reflex syncope. However, beta-blockers failed to be reduced cerebral perfusion (6–8). By increasing renal
effective in 2 randomized double-blind controlled sodium reabsorption and expanding plasma volume,
trials (3,4), and the underlying rationale has been fludrocortisone counteracts this mechanism and
questioned. blocks the physiological cascade leading to the vaso-
vagal reflex. The mechanism of action is similar to
that of saline infusion, which has also proved to be
effective in short-term tilt-test studies (9,10).
*Editorials published in the Journal of the American College of Cardiology
WILL THE POST 2 TRIAL CHANGE
reflect the views of the authors and do not necessarily represent the
views of JACC or the American College of Cardiology. CURRENT CLINICAL PRACTICE?

From the Arrhythmologic Center & Syncope Unit, Department of Cardi-

ology, Ospedali del Tigullio, Lavagna, Italy. Dr. Brignole has reported that In the POST 2 trial, the clinical benefit of flu-
he has no relationships relevant to the contents of this paper to disclose. drocortisone therapy was modest and the risk of
JACC VOL. 68, NO. 1, 2016 Brignole 11
JULY 5, 2016:10–2 Good, But Not for All Patients

potential adverse effects elevated. Moreover, at Because the biological effect of fludrocortisone is to
12 months, 44.0% of patients in the fludrocortisone increase renal sodium reabsorption and expand
arm continued to experience syncopal spells, a rate plasma volume, thereby increasing arterial blood
only slightly lower than the 60.5% rate observed in the pressure, such therapy seems particularly appealing
patients in the placebo arm. This corresponds to a for patients in whom hypotension is a predisposing
difference of 12 patients between the 2 groups (42 of factor for vasovagal syncope. The average baseline
105 vs. 54 of 105) and to a number needed to treat of supine blood pressure was rather low, around
about 6. In the meantime, a similar number of patients 113 mm Hg (interquartile range: 104 to 120 mm Hg),
discontinued fludrocortisone therapy because of side and was lower than that of similar patients affected
effects, thus equalizing the benefit/risk ratio. Drug by vasovagal syncope enrolled in the POST 1 trial
titration was particularly challenging. As per protocol, (129 mm Hg) (4) and the VASIS (Vasovagal Syncope
treatment started with 0.1 mg of the study drug daily, International Study) (130 mm Hg) (1). Compared
with the intent to increase to 0.2 mg daily within 5 to with the patients of these latter studies, POST 2 pa-
14 days. However, patients who were intolerant of tients had more syncopal episodes and, on average,
the study medication had their dose reduced to were 10 years younger. Moreover, in a subgroup
0.05 mg daily. analysis, the authors found that the patients who
Fludrocortisone is expected to have other impor- benefitted most were those who had low baseline
tant adverse effects which, owing to the study systolic blood pressure <110 mm Hg (hazard ratio:
design, could not be fully assessed. As per protocol, 0.48). These findings suggest that the patients in the
patients with significant comorbidities, a permanent POST 2 trial were partly different from those of the
pacemaker, glaucoma, diabetes mellitus, hepatic general population of patients with vasovagal syn-
disease, or blood pressure $130/85 mm Hg were cope. Indeed, they seem to have clinical features
excluded. Although no upper age limit was defined in overlapping with hypotensive syndrome of the
the protocol, the actual median age of enrolled young adult.
patients was 30 years, suggesting that the in- Despite several limitations and precautions, which
vestigators themselves were not confident about are clearly acknowledged by the authors themselves,
prescribing long-term fludrocortisone for older the POST 2 trial provided convincing data supporting
patients. The authors were well aware of the side the benefit of fludrocortisone for the prevention of
effects of the drug and wisely recommended that it syncopal recurrences, especially in young patients
should not be used in patients with hypertension or with low–normal values of arterial blood pressure and
heart failure. without comorbidities. The study cannot be consid-
ered conclusive; indications, benefit, and risk need to
WOULD THE BENEFIT BE GREATER IF
be assessed in larger studies with longer follow-up.
FLUDROCORTISONE WERE PRESCRIBED
However, thanks to the POST 2 trial results, flu-
FOR A SELECTED POPULATION?
drocortisone fills an important gap in the medicine
cabinet, which contains few therapies for vasovagal
Probably, yes. This is a typical study in which some
syncope that have passed the test of evidence limited
patients benefit from the therapy, whereas others
to controlled clinical trials.
do not or must discontinue it because of side
effects. Fludrocortisone is not for all patients with
vasovagal syncope. Learning to identify responders REPRINT REQUESTS AND CORRESPONDENCE: Dr.
will be crucial to acceptance of this therapy by Michele Brignole, Arrhythmologic Center & Syncope
the scientific community and will be the subject of Unit, Department of Cardiology, Ospedali del Tigullio,
future research. However, some indications are Via don Bobbio, 16033 Lavagna, Italy. E-mail:
already suggested by the results of the POST 2 trial. [email protected].

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