M. GULIZIA, G.M. FRANCESE
By definition, syncope is not a disease, but a symptom clinically charac- terised by transient loss of consciousness, which generally leads to falling, followed by spontaneous recovery [1]. It can be due to neuromediated mech- anisms as well as to cardiac or cerebrovascular causes. The Framingham study [2], which investigated 5209 patients with 26 years’ follow-up, indicat- ed that syncope occurring in patients without cardiovascular or neurological pathology is likely to be neuromediated in nature, with a proportion ranging from 0.8% in the age group between 35 and 44 years to 4% in the oldest patients (age > 75 years). No increase in the incidence of sudden death, acute myocardial infarction, or cerebral stroke was noticed with respect to the syncope-free group throughout the follow-up. Nevertheless, some authors [3] define particular forms of vasovagal syncope as ‘malignant’, not because they carry an increased likelihood of sudden death, but because they can result in severe trauma, especially when the syncope is not preceded by relevant prodromes, as frequently happens in the elderly. Therefore, therapy against neuromediated syncope should essentially be aimed at preventing trauma and improving quality of life, especially in patients involved in risky professional activities, such as public transport drivers and aircraft pilots.
All patients should be reassured as to the benign nature of the disorder and receive behavioural advice. They should be trained to avoid syncope- triggering conditions (such as over-warm or crowded environments, or pro- longed standing up) and to recognise possible prodromes and all signs and symptoms preceding the event, in order to react with appropriate manoeu- vres to abort the syncope and prevent any injury. A volume increase is neces- sary, which can be achieved by liquid (2–3 l water) [4] and salt injection (up
Cardiology Department, San Luigi - S. Currò Hospital, Catania, Italy
to 120 mmol/day NaCl) [5]. Regular light physical exercise is recommended.
Alcohol drinking and other addictions should be avoided or strongly reduced.
Several drugs with various mechanisms of action have been proposed for the prevention of syncopal events: e.g. clonidine, scopolamine, domperidone, ethylephrine, beta-blockers, dihydroergotamine, enalapril, disopyramide, theophylline, paroxetine, fludrocortisone, and midodrine. The wide spec- trum of drugs reflects both the variability of and the limited knowledge about the pathophysiological mechanisms of neuromediated syncope in dif- ferent patients. Generally, while results from uncontrolled or short-term con- trolled studies were satisfactory [6], with few exceptions, all but one studies with control versus placebo design were disappointing. Beta-blockers have been used for their negative inotropic effects, with the aim of reducing the mechanoreceptor activation associated with decreased venous return, as well as to counteract the rate increase induced by high levels of circulating adren- aline, which precedes the loss of consciousness [7]. Studies performed by Scott et al. [8] and Ventura et al. [9], with follow-up longer than 6 months, demonstrated a reduction in recurrences with respect to untreated patients, while Brignole et al. [10] and Madrid et al. [11], who studied the effects of atenolol–ergotamine–domperidone and atenolol alone, respectively, did not confirm the drug benefit. Data from Ventura et al. [9] indicate that lipophilic beta-blockers, like propranolol and methoprolol, which can cross the blood–brain barrier, show a greater effect (29% recurrences versus 79% in non-treated patients; P = 0.004). Nevertheless, a placebo mechanism cannot be excluded. At present, it is not clear whether beta-blockers are effective in reducing syncopal recurrences. An arm of the randomised controlled versus placebo study VASIS, designed to analyse the effects of ethylephrine, was closed after 10 months because the drug proved ineffective [12]. Similarly, controlled studies performed with domperidone [10], disopyramide [13], and dihydroergotamine [10] did not demonstrate significant drug effects.
The main limitations of these studies are short follow-up and the lack of placebo-treated control groups. Ward et al. [14] performed a prospective controlled study on the short-term effects of midodrine in severely sympto- matic aged patients affected by vasodepressive vasovagal syndrome with fre- quent syncopal episodes. Positive results were reported, but the study was not controlled versus placebo. Another study from Natale et al. [15] investi- gated the effectiveness of midodrine in 6 months follow-up, showing a reduction in the number of syncopal events, but this study also had a short follow-up and no placebo administration in the control group. Di Girolamo et al. [16] demonstrated positive effects of paroxetine, a serotonin reuptake inhibitor, in a large controlled versus placebo study with a follow-up of 25 months. A reduction of syncope prevalence from 53% to 17% was reported,
but the results were not confirmed in other investigations and the drug is not indicated at present. Enalapril, an ACE inhibitor, was used in a study by Zeng et al. [17] with positive results, which were likely due to the inhibition of the sympathetic nervous system (Table 1).
Available clinical information does not show clearly whether drug treat- ment is advisable in patients affected by vasovagal syncope and what drug could be selectively indicated. The usually benign course of the disorder, often showing long periods without symptoms, together with the possible therapeutic effects of tilt testing and increased self-confidence in the patient, which can be helped by reassurances from the physician, can produce a false impression of efficacy for any drug treatment under evaluation. In the past, an expected drug action had to be confirmed by the tilt test, since lack of syncope in previously tilt-test-positive patients was considered a marker of therapeutic effectiveness. This technique is no longer used, however, since some trials have reported equal reduction in the occurrence of syncope in treated and untreated patients [10, 12, 13, 18].
In conclusion, no drug has proved clearly effective in syncope prevention so far, and further randomised placebo-controlled studies are required to ascertain the real effectiveness of any pharmacological treatment.
Table 1.Effects of different drugs in the prevention of vasovagal syncope recurrences
Author Year Drug Dosage No. Follow-up Results
pts (months)
Madrid et al. [11] 2001 Atenolol 50 50 12 N.S.
Scott et al. [8] 1995 Atenolol 25–100 29 6 Effective
Brignole et al. [10] 1992 Atenolol 100 15 10 N.S.
Ventura et al. [9] 2002 Propranolol 80–100 56 12 Effective Ventura et al. [9] 2002 Metoprolol 50–100 56 12 Effective
Moya et al. [18] 1995 Ethylephrine 30 60 12 N.S.
Raviele et al. [12] 1999 Ethylephrine 75 126 12 N.S.
Morillo et al. [13] 1993 Diisopyramide 800 21 29 N.S.
Brignole et al. [10] 1992 Dihydroergotamine 18 4 10 N.S.
Brignole et al. [10] 1992 Domperidone 60 4 10 N.S.
Natale et al. [15] 1999 Midodrina 15–45 61 6 Effective
Zeng et al. [17] 1998 Enalapril 10 30 13 Effective
Di Girolamo 1999 Paroexetine 20 68 25 Effective
et al. [16]
Scott et al. [8] 1995 Fludrocortisone 100–200 29 6 Effective
References
1. Brignole M, Alboni P, Benedict L et (2001) Guidelines on management (diagnosis and treatment) of syncope. Eur Heart J 22:1256–1306
2. Savage DD, Corwin L, Mc Gee DL et al (1985) Epidemiologic features of isolated syncope: the Framingham study. Stroke 16:626–629
3. Fitzpatrick A, Theodorakis G, Travill C et al (1991) Incidence of malignant vasova- gal syndrome in patients with recurrent syncope. Eur Heart J 12:389–394
4. Younoszai AK, Franklin WH, Chan DP et al (1998) Oral fluid therapy. A promising treatment for vasodepressor syncope. Arch Pediatr Adolesc Med 152:165–168 5. El-Sayed H, Hainsworth R (1996) Salt supplement increases plasma volume and
orthostatic tolerance in patients with unexplained syncope. Heart 75:114–115 6. Raviele A, Themistoclakis S, Gasparini G (1996) Drug treatment of vasovagal syn-
cope. In: Blanc JJ, Beneditt D, Sutton R (eds) Neurally mediated syncope: pathophy- siology, investigations, and treatment, Futura, Armonk, NY, pp 113–121
7. Klingenheben T, Kalusche D, Li Y-G et al (1996) Changes in plasma epinephrine concentration and in heart rate during head-up tilt testing in patients with neuro- cardiogenic syncope: correlation with successful therapy with B-receptor antagoni- st. J Cardiovasc Electrophysiol 7:802–808
8. Scott WA, Giacomo P, Bromberg BI et al (1995) Randomized comparison of ateno- lol and fludrocortisone acetate in the treatment of pediatric neurally mediated syncope. Am J Cardiol 76:400–402
9. Ventura R, Maas R, Zeidler D et al (2002) A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients a positive or negative response to head-up tilt test. Pacing Clin Electrophysiol 25:816–821 10. Brignole M, Menozzi C, Gianfranchi L et al (1992) A controlled trial of acute and
long-term medical therapy in tilt-induced neurally mediated syncope. Am J Cardiol 70:339–342
11. Madrid AH, Ortega J, Rebollo RG et al (2001) Lack of efficacy of atenolol for the prevention of neurally mediated syncope in a highly symptomatic population: a prospective double blind, randomised and placebo controlled study. J Am Coll Cardiol 37:554–559
12. Raviele A, Brignole M, Sutton R et al (1999) Effect of etilefrine in preventing synco- pal recurrence in patients with vasovagal syncope: a double-blind, randomized, placebo-controlled trial. The Vasovagal Syncope International Study. Circulation 99:1452–1457
13. Morillo C, Leitch J, Yee R et al (1993) A placebo-controlled trial of intravenous and oral disopyramide for prevention of neurally mediated syncope induced by head- up tilt test. J Am Coll Cardiol 22:1843–1848
14. Ward CR, Gray JC, Gilroy JJ et al (1998) Mididrine: a role in the management of neurocardiogenic syncope. Heart 79:45–49
15. Natale A, Beheiry S, Tomassoni GF et al (1999) Randomized placebo control asses- sment of midodrine in the treatment of neurocardiogenic syncope. J Am Coll Cardiol 33:269 (abs)
16. Di Girolamo E, Di Forio C, Sabatini O et al (1999) Effects of paroxetine hydrochlo- ride, a selective serotonin reuptake inhibitor, on refractory vasovagal sincope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 33:1227–1230
17. Zeng C, Zhu Z, Liu G et al (1998) A randomized, double-blind, placebo-controlled trial of oral enalapril in patients with neurally-mediated sincope. Am Heart J 136:852–858
18. Moya A, Permanyer-Miralda G, Sagrista-Sauleda J et al (1995) Limitations of head- up tilt test for evaluating the efficacy of therapeutic interventions in patients with vasovagal syncope: results of a controlled study of etilefrine versus placebo. J Am Coll Cardiol 25:65–69
