Clinical outcome of patients with neurocardiogenic syncope (NCS) after therapy interruption

Abstracts

OBJETIVO: Avaliar a evolução clínica de pacientes com SNC após a suspensão do tratamento farmacológico e investigar as possíveis variáveis clínicas preditivas de recidiva. MÉTODOS: Trinta e sete pacientes (média de idade de 31 ± 16 anos) com SNC recidivante refratária, dos quais 19 eram mulheres, foram estudados prospectivamente. Todos os pacientes estavam assintomáticos e apresentaram teste de inclinação ortostática (TI) negativo após a introdução da terapia farmacológica. Um novo TI foi realizado um mês após a suspensão do tratamento. A probabilidade livre de sintomas foi analisada de acordo com sexo, idade, número de síncopes prévias ao tratamento, tempo de história clínica, tempo de tratamento, resultado do TI após interrupção do tratamento e período sem medicação. RESULTADOS: Vinte e dois pacientes (59%) apresentaram recidiva durante um acompanhamento médio de 21 ± 19,7 meses. As variáveis relacionadas com maior recidiva foram número de síncopes anteriores (p = 0,0248), TI positivo após a suspensão da terapia (p = 0,0002) e sexo feminino (p = 0,0131). CONCLUSÕES: A maior parte dos pacientes altamente sintomáticos com SNC apresenta recidiva após a supressão do tratamento. A realização do TI após a suspensão do tratamento pode identificar os pacientes com maior risco de recidiva, sobretudo durante o primeiro ano de acompanhamento.

Síncope neurocardiogênica; teste de inclinação; tratamento

ORIGINAL ARTICLE

Clinical outcome of patients with neurocardiogenic syncope (NCS) after therapy interruption

Silvana Bastos; Mauricio Scanavacca; Francisco Darrieux; Ana Cristina Ludovice; Eduardo Sosa; Denise Tessariol Hachul

Instituto do Coração do Hospital das Clínicas - FMUSP - São Paulo, SP - Brazil

^{Mailing Address}

ABSTRACT

OBJECTIVE: To evaluate the outcome of patients with NCS after interruption of pharmacological therapy and to investigate the possible clinical variables predicting recurrence.

METHODS: Thirty-seven patients (age 31±16 years) with refractory recurrent NCS being 19 females where prospectively studied. All patients became asymptomatic and had a negative tilt table test (TT) after pharmacological therapy. The treatment was interrupted and one month later, a new TT with no medication was carried out. The probability free of symptoms recurrence was analyzed according to sex, age, number of syncope episodes previously to the treatment, clinical history time, treatment time, drug free from treatment time and TT result.

RESULTS: Twenty-two patients (59%) presented recurrence during a mean follow-up of 21±19.7 months. The variables related to greater recurrence were number of previous syncope (p=0.0248), positive TT after interruption of the therapy (p=0.0002) and female gender (p= 0.0131).

CONCLUSIONS: Most of the very symptomatic patients with NCS present recurrence after the suppression of a specific therapy. A TT carried out after treatment discontinuation can identify patients with higher risk of recurrence, specially in the first year of follow-up.

Key words: Vasovagal syncope, tilt -table test, treatment.

Syncope is a common clinical issue^1,2 and affects both men and women, with an incidence of 3% and 3.5%, respectively³. Data of the Framingham's study⁴ showed that the vasovagal or neurally mediated syncope (NMS) corresponds to 21.2% of all cases and is not related to increase in the cardiovascular risk, confirming its benignity.

The vasovagal syncope occurs by the sudden development of hypotension and bradicardia due to a deep failure of the cardiocirculatory mechanisms that maintain blood pressure and cerebral perfusion^5,6.

The tilt-table test (TT) is a good tool to identify those patients susceptible to vasovagal syncope^7-11.Most of the vasovagal episodes is sporadic and easily recognized by their prodromic symptoms and signs^12,13. However, some patients present not so typical symptoms, what increases the risk of physical injuries^14,15.

The introduction of pharmacological therapy for NMS must be considered in case the general dietetic and behavioral measures do not prevent recurrences and also to improve quality of life^13-16. The use of TT for the therapeutic follow-up of the neurocardiogenic syncope is controversial, but there are some data supporting a better clinical outcome when a negative TT is achieved after treatment^17-19. Once initiated, the treatment suppression is empirically carried out and there are no established criteria to evaluate when to do it and how to evaluate patients after the interruption^13,20,21.

The objectives of this study were to evaluate the clinical outcome of very symptomatic patients with NMS after interruption of the specific pharmacological treatment and the possible clinical variables predicting recurrence during the follow-up.

METHODS

Patients from the Syncope Unit of Heart Institute –São Paulo University were prospectively evaluated. The inclusion criteria for the study were: history of recurrent syncope (two or more episodes in the previous 12 months); positive response to the tilt-table test; indication of specific pharmacological therapy (presence of symptoms in spite of the general behavioral and dietetic measures); negative tilt in the course of treatment; asymptomatic after therapy.

The exclusion criteria were: history of physical trauma related to the syncope; short or absent prodrome symptoms and risky professional activity.

Thirty-seven patients with average age of 31 + 16 years (from 10 to 80 years - median 18) were selected: 19 females (51.35%) and 18 males (48.64%).

The mean history time of syncope was 52.8+90.7 months (median=24) and the average number of syncope was 3.5+1.5/year (median=3). The patients were receiving betablockers; fludrocortisone or association of these two drugs. The treatment average time was 27.1+16.4 months (median=44).

Study design

The selected patients were oriented to discontinue the pharmacological therapy and were then submitted to a tilt table test, 30 days after the discontinuation. The tilt protocol carried out after therapy suppression was identical to the diagnostic test (prolonged baseline)¹³. Regardless of the test result, the patients were maintained with no specific treatment, but with general recommendations (increase of hydro-saline ingestion, elastic stockings, avoiding onset factors and postural education). They were instructed to return to the Outpatient Syncope Unit for routine consultation every three months or immediately in case of syncope recurrence.

Statistical analysis

The variables were described through averages, standard deviations, minimum, maximum and median values, or through absolute and relative frequencies. The patient groups were compared by Student-t and Person and Fisher's Chi-square tests for categorized variables and Wilcoxon's test for independent samples and continuous variables. The probability free of symptom recurrence was estimated by Kaplan-Meier actuarial analysis and compared between the groups by log rank's test^22-24.

RESULTS

The probability free of recurrence observed after therapy supression is described in figure 1.

Most of the patients presented recurrence along the follow-up. After 6 months with no treatment, the event-free probability was estimated to be 77% and 64% after one year. At the end of follow-up however, the symptom-free probability was estimated to be 24%.

Thirteen (35%) patients showed a positive TT response and 24 (65%) patients remained with a negative response to tilt after therapy discontinuation.

When clinical outcome of the patients with positive and negative TT were separately analyzed, a statistically significant difference was observed between them (p<0.0102). Most of the patients (84%) with positive tilt test recurred within the first year (figure 2).

The average time for first recurrence in those patients with positive TT was 7.97±10.37 months and 24±13.21 months for those with negative TT. (p=0.00044).

Among the clinical variables analyzed, it was observed that patients with recurrence showed a higher frequency of previous syncope spells in relation to the asymptomatic ones (p= 0.0248) and females were predominant in relation to males (p=0.0131). (Table 1).

DISCUSSION

The vasovagal syncope is characterized by a functional and intermittent disorder of the autonomic nervous system, which most of the times commits young, cardiologically healthy individuals^1-4. In general, the majority of patients benefit from general dietetic and behavioral measures, however, pharmacological intervention is required in a specific subgroup in whom symptoms are not adequately controlled^25,26. Kapoor et al^25-27, observed that accidents were reported in 6% of the patients with NMS, with the smaller injury being laceration. Contusions occurred in 29% of the cases. Another study showed that the recurrent syncope is associated to fractures and soft tissue injuries in 12% of the cases²⁸.

The positive tilt test identifies individuals susceptible to the vasovagal syncope with a positivity rate between 40 and 60% and with a good diagnostic specificity^9,10,11,13. The difficulty to predict recurrences has been the ground for several studies in the last few years^29-33, aiming to identifying high- and low-risk patients.

In our study it was observed that 32% of the patients who discontinued therapy recurred within the first follow-up year, increasing to 59% when the average follow-up of 21+19.7 month was considered.

When evaluating patients diagnosed with neurocar-diogenic syncope by the positive tilt test who refused or suspended the proposed treatment, Natale et al³⁴ observed that 64.8% of them showed recurrence of the symptoms within 3±1.5 years of follow-up, 28% presenting syncope. The remaining patients were able to abort the event when feeling the first prodromic symptoms, thus preventing the syncope episode. Most of the patients presented early recurrence within the first 5 months. Probably, the maintenance of the general dietetic and behavioral measures has influenced the evolution behavior of these patients. In addition, the knowledge of the breaking-out situations and the acknowledgement of the prodromic symptoms led them to protect themselves.

Different clinical variables have been evaluated as possible predictors of recurrence. The frequency and number of syncope episodes previously to the diagnosis are described as independent risk factors^25,26,30,31.

Sheldon et al³² tried to identify those patients at high risk of recurrence after a positive test, among the NMS patients diagnosed by the tilt test. For such, they used the time to the first recurrence episode. The actuarial analysis of the event-free probability within the first and second years was 72% and 60%, respectively. The authors showed that the number of syncope and the duration of symptoms previously to the diagnosis were important predictors of the recurrence probability.

From those studies, the patients with NMS were classified into three subgroups. Those with history of more than six syncope episodes are considered as at higher recurrence risk; from three to six episodes, moderate risk, and less than three episodes, lower risk.

Patients selected in our study are considered as at moderate risk, with an average pre-test syncope incidence of three episodes/year. All were highly symptomatic, with commitment of the quality of life, reason why the specific treatment had been indicated. Among the clinical variables analyzed, the higher number of previous syncope was related to a higher probability of recurrence after therapy suppression, which corroborates the literature data. Females were also correlated to a higher probability of recurrence (p=0.0131), although other authors have not observed this^32,33.

The studies evaluating the role of tilt test in the clinical follow-up of syncope have conflicting results, hence its utility being still considered as controversial^32-34. Sheldon et al observed that the unexplained syncope patients and those with typical history of neurocardiogenic syncope with positive or negative tilt test, showed similar clinical behavior, i.e., the same probability of recurrence during follow-up³². Brignole et al³⁵ suggested that after a positive test, there is a trend to decrease the symptom recurrence rate over time, regardless of the administration of placebo or tilt guided treatment. An explanation for this fact is perhaps the patient's learning of how to prevent syncope from the first prodromic symptoms and avoiding the breaking-out factors. In a previous study, Hachul et al¹⁸ evidenced a significantly lower recurrence rate after therapy introduction, when a negative tilt was achieved in relation to those patients maintaining a positive test (p<0.001). Natale et al³⁴ evaluated the efficacy of different therapeutic strategies in neurocardiogenic syncope patients and observed that the recurrence was significantly lower in those patients at tilt test-guided therapy (p<0.01).

The tilt test result after treatment interruption was an independent predictor factor for recurrence risk in our study, especially within the first year. The time for first recurrence in patients with positive test was significantly lower than for those with negative test. Although literature has many controversial results in relation to tilt test usefulness in the therapeutic management of NMS, studies analyzing patients after therapy interruption are scarce. From our data, we observed that almost all patients with indication for specific therapy present recurrence after its interruption. To decide keeping them or not using medications, the tilt test should be considered as a criterion of risk evaluation.

CONCLUSIONS

The majority of the patients with NMS and indication of specific treatment present symptom recurrence over time after therapy supression. A TT carried out after treatment discontinuation can identify patients with higher risk of recurrence, specially in the first year of follow-up.

No potential conflict of interest relevant to this article was reported.

REFERENCES

Received on 07/24/05

Acepted on 07/25/05

• 1. Day SC, Cook EF, Funkenstein H, Goldman L. Evaluation and outcome of emergency room patients with transient loss of consciousness. Am J Med 1982;73:15-23.
• 2. Gendelman HE, Linzer M, Gabelman M. Syncope in general hospital patient population. NY State J Med 1983;83:1161-5.
• 3. Savage DD, Corwin L, Mc Gee DL. Epidemiologic features of isolated syncope: the Framingham Study. Stroke 1985;16:626-9.
• 4. Soteriades ES, Evans JC, Larson MG et al. Incidence and Prognosis of Syncope. N Engl J Med 2002;12:878-85.
• 5. Rea RF, Thomas MD. Neural Control Mechanism and Vasovagal Syncope. J Cardiovasc. Eletrophysiol 1993;4(5):587-95.
• 6. Kenny RA, Ingram A, Bayless J, Sutton R. Head up tilt: a useful test for investigation of unexplained syncope. Lancet 1986;1:1352-55.
• 7. Kapoor W, Smith M, Miller NL. Upright tilt testing in evaluating syncope: A comprehensive literature review. Am 1994;97:78-88.
• 8. Mansouratti J, Blanc JJ. Tilt test procedure: angle, duration, positivity criteria. In: Blanc JJ, Benditt D, Sutton, R, eds. Neurally mediated syncope. pathophysiology, investigations and treatment. 1st ed. Armonk: Futura Publishing Company 1996:79-83.
• 9. Sutton R, Bloomfield D. Indications, Methodology, and classification of results of tilt table testing. Am J Cardiol 1999;84:10-9.
• 10. Hachul D, Consolin F, Sosa E et al. Valor diagnóstico do teste de inclinação na avaliação da síncope de origem indeterminada. Resultados preliminares. Arq Bras Cardiol 1994;62:7-9.
• 11. Hachul D, Consolim F, Sosa E et al. Reprodutibilidade do teste de inclinação em pacientes com síncope neurocardiogênica. Arq Bras Cardiol 1994;62:297-9.
• 12. Ruiz GA, Peralta A, Gonzalez-Zuelgaray J, Duce E. Evolution of patients with clinical neurocardiogenic (vasovagal) syncope not subjected to specific treatment. Am Heart J 1999;130:345-50.
• 13. Guidelines on Management (Diagnosis and Treatment) of Syncope The Task Force on Syncope, European Society of Cardiology. Eur Heart J. 2004; 25:2054-72.
• 14. Linzer M, Gold DT, Pontinen M, Divine GW, Felder A, Brooks WB. Recurrent syncope as chronic disease. J Gen Intern Med 1994;9:181-6.
• 15. Linzer M, Pontinen M, Gold DT, Divine GW, Felder A, Brooks WB. Impairment of Physical and Psychosocial Function in Recurrent Syncope. J Clin Epidemiol 1991;44:1037-43.
• 16. Rose S, Kosman ML, Mc Donald S, Sheldon R. Health-related quality of life in patients with neuromediated syncope (abstr). Can J Cardiol 1996;12: 131E.
• 17. Natale A, Newby KH, Dhala A. Response to beta-blockers in patients with neurocardiogenic syncope: How to predict beneficial effects. J Cardiovasc Eletrophysiol 1996;7:1154-8.
• 18. Hachul D, Scanavacca M, Sosa E. Does a role exist for tilting-guided therapy in the management of neurocardiogenic syncope? Arq Bras Cardiol 2002;78(2):167-71.
• 19. Benditt D, Remole S, Bailin S, Dunnigan A, Asso A, Milstein S. Tilt table testing for Evaluation of neurally-mediated (cardioneurogenic) syncope: rationale and proposed protocols. PACE 1991;14:1528-37.
• 20. Benditt D, Lurie K, Adler WS. Pathophysiology of vasovagal syncope. In: Blanc JJ, Benditt D, Sutton R, eds. Neurally Mediated Syncope: Pathophysiology, Investigation and Treatment. Armonk: Futura Publishing Company, 1996:p.1-24.
• 21. Kapoor W. An overview of the evaluations and management of syncope. In: Grubb BP, Olshansky B, eds. Syncope: Mechanisms and Management. Armonk: Futura Publishing Company, 1998:p.1-13.
• 22. Rosner B. Fundamentals of Biostatistics. 2^nd Edition. ,Massachusetts: PWS Publishers, 1986:p.339-42.
• 23. Rosner B. Fundamentals of Biostatistics. 2nd Edition. Massachusetts: PWS Publishers, 1986:p.288-93.
• 24. Kalbafleisch Jd, Prentice Rl. The Statistical Analysis of FAILURE Time Data. New York: John Wiley and Sons, 1980.
• 25. Kapoor W, Peterson J, Wieand Hs, Karps M. Diagnostic and prognostic Implications of recurrences in patients with syncope. Am J Med 1997;83: 700-8.
• 26. Martin TP, Hanusa BH, Kapoor W. Risc Stratification of patients with syncope. Annals Emerg Med 1997;29:459-66.
• 27. Kapoor W, Peterson J, Wieand HS, Karpf M. Diagnostic and prognostic implications of recurrences in patients with syncope. Am J Med 1999;159: 375-80.
• 28. Kapoor W. Evaluation and outcome of patients with syncope. Medicine.1990;69:169-75.
• 29. Mathias CJ, Deguchi K, Schatz I. Observations on recurrent syncope and presyncope in 641 patients. Lancet 2001;357:348-53.
• 30. Grimm W, Degenhardt M, Hoffoman J. Syncope recurrence can better be predicted by history than by head-up tilt testing in untreated patients with suspected neurally-mediated syncope. Eur Heart J 1997;18:1465-9.
• 31. Natale A, Geiger MJ, Maglio C. Recurrence of neurocardiogenic syncope without pharmacologic interventions. Am J Cardiol 1996;77:1001-3.
• 32. Sheldon R, Rose S, Flanagan P. Risk factors for syncope recurrence after a positive tilt-table testing in patients with syncope. Circulation 1993;93:973-81.
• 33. Sheldon RS, Rose S, Koshman ML. Comparison of patients with syncope or unknown cause having negative or positive tilt table test. Am J Cardiol 1997; 80:581-5.
• 34. Natale A, Sra J, Dhaja A et al. Efficacy of different treatment strategies for neurocardiogenic syncope. PACE.1995;18:655-62
• 35. Brignole M, Menozzi C, Gianfranchi LA. Controlled trial of acute and long-term medical therapy in tilt-induced neurally mediated syncope. Am J Cardiol 1992;70:339-42.

Publication Dates

• Publication in this collection
  25 Apr 2006
• Date of issue
  Apr 2006

History

• Accepted
  25 July 2005
• Received
  24 July 2005