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Randomised clinical trials of drug therapy for vasovagal syncope

An article from the e-journal of the ESC Council for Cardiology Practice

Evidence for therapy of neurally-mediated syncope is in general weak. Many drugs have been used in the treatment of vasovagal syncope (beta-blockers, disopyramide, scopolamine, clonidine, theophilline, fludrocortisone, ephedrine, dihydroergotamine, etilephrine, midodrine, clonidine, serotonin reuptake inhibitors, enalapril). In general, while the results have been satisfactory in uncontrolled trials or short-term controlled trials, the majority of long-term placebo-controlled prospective trials have been unable to show a benefit of the active drug over placebo.

Syncope


Background

Vasovagal syncope refers to a reflex response that, when triggered, gives rise to vasodilatation and bradycardia, although the contribution of both to systemic hypotension and cerebral hypoperfusion may differ considerably. It is valuable to assess the relative contribution of cardioinhibition and vasodepression before embarking on treatment as there are different therapeutic strategies for the two aspects.  The triggering events might vary considerably over time in any individual patient. The ‘classical’ vasovagal syncope is mediated by emotional or orthostatic stress and can be diagnosed by history taking. ‘Non-classical’ presentations are frequent and these forms are diagnosed by minor clinical criteria, exclusion of other causes for syncope (absence of structural heart disease) and the positive response to tilt testing or carotid sinus massage. Examples of non-classical vasovagal syncope include episodes without clear triggering events or premonitory signs.

Beta-blockers

Beta-adrenergic blocking drugs have failed to be effective in 5 of 6 long-term follow-up controlled studies (1-6). Atenolol proved to be ineffective in preventing syncopal recurrences in a well designed double blind randomised controlled trials (4). As regard this latter, both tilt positive and tilt negative patients with a history of a median of 3 episodes of vasovagal syncope were randomised to receive 50 mg/day of atenolol or placebo. In the intention-to-treat analysis there was a trend towards a better outcome in patients treated with placebo (p=0.09), especially in the tilt-negative subgroup. Adverse events occurred more likely in the active arm patients (p=0.05). Thus the evidence fails to support beta-blocker efficacy.
In vasovagal syncope, beta-blockers, owing to their negative inotropic effect, have been supposed to lessen the degree of mechanoreceptor activation associated with abrupt falls in venous return and to block the effects of elevated circulating adrenaline, but this theory has not been supported by facts. A rationale for use of beta-blockers is lacking in the other forms of neurally-mediated syncope and they may be detrimental in the dysautonomic syndromes.  Beta-blockers may enhance bradycardia in the carotid sinus syndrome and in all other cardioinhibitory forms of neurally-mediated syncope.

Alpha-agonists

Since failure to achieve proper vasoconstriction of the peripheral vessels is common to all the forms of neurally-mediated syncope, several vasoconstrictive substances have been employed, but only etilefrine and midodrine have been evaluated by means of a randomised controlled trial. Etilefrine proved to be ineffective in preventing syncopal recurrences in a large multicenter double blind etilefrine arm of the Vasovagal Syncope International Study (VASIS) (7). The 126 patients had had a median of 4 syncopal episodes during the previous 2 years and had a positive response to tilt test. During the follow-up the patients were treated with etilefrine or placebo 25 mg twice a day; syncope recurred in 24% of patients and in 24 % of controls and the time to first syncopal recurrence was also similar (106 days etilefrine versus 112 days placebo).  Thus, the evidence fails to support etilefrine efficacy.
Midodrine - at a dose of 5-15 mg t.i.d. - seemed to be effective in reducing symptoms (syncope and presyncope) and improving quality of life (evaluated by standardised questionnaires) during the short term in 2 small open label controlled trials (8,9) performed in patients affected by very frequent ‘hypotensive’ symptoms (>1 syncope/month); the spontaneous symptoms were reproduced during tilt test which showed a dominant vasodepressor response. Even if defined as ‘neurocardiogenic’, the clinical features of the patients of these studies seems different from those of the typical vasovagal syncope and of the VASIS-like patients and probably overlap with some forms of orthostatic hypotension. Vasoconstrictor drugs are potentially more effective in orthostatic hypotension caused by autonomic dysfunction than in the neurally-mediated syncopes. Midodrine was thoroughly investigated for orthostatic hypotension and was shown to be an effective treatment in some randomised controlled trials (10,11). Thus, available data are insufficient to prove an efficacy of midodrine for typical vasovagal syncope. Orthostatic hypotension and vasovagal syncope are two different syndromes; midodrine is an effective treatment for orthostatic hypotension; the data to support the use of midodrine in vasovagal syncope are far less compelling.

Miscellanea

Paroxetine (serotonin reuptake inhibitors) has been shown to be effective in one placebo-controlled open-label trial (12) which included a small number of highly symptomatic patients in one institution, but failed to show a significant effect on baroreflex control of sympathetic nerve activity in a double-blind randomised 6-month follow study performed in healthy subjects (13). Until the study is confirmed by others, use of this drug cannot be recommended.
 Transdermal scopolamine was ineffective for the prevention of neurally-mediated syncope in a randomised placebo controlled evaluation performed in 60 patients (14): during follow-up syncope recurred in 79% of patients with scopolamine and in 75% of patients with placebo. 
 Clonidine was not superior to metoprolol in a study (15).
 Finally, no follow-up randomised controlled trials exist for disopyramide, enalapril, theophilline, fludrocortisone, ephedrine, and dihydroergotamine.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

Conclusion:

The evidence shows that beta-blocking drugs are inefficacious and might be even deleterious in selected cases. To date there are not sufficient data to support the use of any other pharmacological therapy for vasovagal syncope.

References


1. Brignole M, Menozzi C, Gianfranchi L, et al. A controlled trial of acute and long-term medical therapy in tilt-induced neurally mediated syncope. Am J Cardiol 1992; 70: 339-342.
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2. Sheldon R, Rose S, Flanagan P, et al. Effects of beta blockers on the time to first syncope recurrence in patients after a positive isoproterenol tilt table test. Am J Cardiol 1996; 78: 536-539
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4. Madrid A, Ortega I, Rebollo GJ et al.  Lack of efficacy of atenolol for the prevention of neurally-mediated syncope in highly symptomatic population: a prospective double-blind, randomized and placebo-controlled study. J Am Coll Cardiol 2001; 37: 554-557
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7. Raviele A, Brignole M, Sutton R, et al. Effect of etilefrine in preventing syncopal   recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope International Study. Circulation 1999; 99(11):1452-57.
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9. Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc electrophysiol 2001; 12: 935-938
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10. Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension:  A double-blind placebo-controlled study with midodrine.Am J Med 1993; 95: 38-48
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11. Low PA, Gilden JL, Freeman R, et al.  Efficacy of midrodrine vs placebo in neurogenic orthostatic hypotension. JAMA 1997;13:1046-1051.
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12. Di Gerolamo E, Di iorio C, Sabatini O, et al. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1999; 33: 1227-1230.
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13. Takata T, Wasmund S, Smith M, et al. Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction associated with carotid sinus massage and/or lower body negative pressure in healthy volunteers. PACE 2002; 106: 1500-1504
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14. Lee TM, Su SF, Chen MF, et al. Usefulness of transdermal scopolamine for vasovagal syncope. Am J Cardiol 1996; 78: 480-482
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15. Biffi M, Boriani G, Sabbatani P, et al. Malignant vasovagal syncope: a randomised trial of metoprolol and clonidine. Heart 1997;  77: 268-72. 
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Notes to editor


Dr M. Brignole
Lavagna, Italy
Chairman of the ESC Task Force on Management (diagnosis and treatment) of syncope

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.