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Response to treatment during medium-term follow-up in a series of patients with neurocardiogenic syncope
Archives of Medical Research 35 (2004) 416–420
ORIGINAL ARTICLE
Response to Treatment during Medium-Term Follow-Up in a Series of Patients with Neurocardiogenic Syncope Enrique Asensio Lafuente, Lilia Castillo Martı´nez, Jorge Oseguera Moguel, Rene´ Narva´ez David, Joel Dorantes Garcı´a, Arturo Orea Tejeda, Pablo Herna´ndez Reyes and Vero´nica Rebollar Gonza´lez Departamento de Cardiologı´a, Clı´nica de Marcapasos, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n (INCMNSZ), Mexico City, Me´xico Received for publication December 15, 2003; accepted June 4, 2004 (03/210).
Background. Syncope is a common symptom that has different recurrence ratios. We hypothesized that an individualized treatment regimen including pharmacologic and nonpharmacologic measures considering kind of neurocardiogenic syncope (NCS) and basal characteristics of each patient could allow optimized therapy to avoid recurrences. Methods. We conducted a prospective study to evaluate performance of diverse accepted treatments for NCS. Each patient received specific treatment including general measures such as an increase in salt and water intake, tilt training, specific pharmacologic treatment according to head-up tilt table test (HUTT) result, and patient basal blood pressure and heart rate measurements. Results. We followed a group of 127 patients during a main period of 20.8 ⫾ 9 months (range, 6–38 months). Mean age was 47.8 ⫾ 19.2 years and 66.9% were females. We had six (4.7%) patients with recurrence of symptoms 4 ⫾ 0.9 months after diagnostic HUTT. Medications used were atenolol in 20 patients, pindolol in 17, dysopiramide in 50, and fluoxetine in 25. Two patients received fludrocortisone. Tilt training was not indicated initially for patients with recurrences but was indicated later; to date, these patients have not experienced further episodes. Conclusions. Increase in water and salt intake, as well as tilt training, showed great value in prevention of syncope recurrences in this specific set of patients. Pharmacologic treatment has an important role, but there is no single medication associated with significant improvement in symptom control. 쑖 2004 IMSS. Published by Elsevier Inc. Key Words: Syncope, Recurrence, Tilt training, Treatment of syncope, Medium-term follow-up.
Introduction Syncope is a common symptom and has different etiologies. Among the most frequent is neurocardiogenic or neurally mediated syncope. This variant usually has excellent prognosis with regard to survival, but recurrences are rather common and render distress in the patient and sometimes disability due to fear regarding the possibility of trauma or
Address reprint requests to: Dr. Enrique Asensio Lafuente, Departamento de Cardiologı´a, Clı´nica de Arritmias y Marcapasos, INCMNSZ, Vasco de Quiroga #15, Col. Seccio´n XVI, Tlalpan, 14000 Me´xico, 14000 D.F., Me´xico. Telefax: (⫹52) (55) 5655-3306; E-mail: [email protected]
0188-4409/04 $–see front matter. Copyright d o i : 10 .1 0 1 6/ j.ar c med .2 0 04 .0 6 .0 0 9
certain other major events, including death (1–3). Recurrences are not infrequent because they can occur in up to 34% of patients during a 3-year follow-up (4), although they can be different among different populations, as occurs in pediatric patients (5,6). Treatment for such a common disease has been to date directed in a rather intuitive or empirical manner and usually involves symptomatic rather than curative therapy. Several papers show significant benefits with diverse pharmacologic agents; nonetheless, when followed for 1-year intervals these agents apparently lose their beneficial effect. Seemingly, medical treatment lacks long-term benefits because recurrences among differently treated patients remain relatively
쑖 2004 IMSS. Published by Elsevier Inc.
Treatment Response in Neurocardiogenic Syncope
high (7). Moreover, pharmacologic agents have no apparent benefit over placebo. This finding emphasizes the important role of nonpharmacologic treatments such as increased water and salt intake and tilt-training programs in the therapeutic approach to syncope patients. In the present study, we evaluated the impact of several pharmacologic agents combined with general measures for avoidance of recurrent syncope events.
Patients and Methods Patients. We performed a prospective study to evaluate the outcome of a group of patients diagnosed with neurally mediated syncope who received treatment with several pharmacologic agents. Initially (for patients whose test was performed from April 2000 to February 2001) we did not recommend tilt training as a routine measure, although we consider increasing water and salt intake as routine.
417
Patients were selected for tilt testing (HUTT) according to their history and physical examination, as we described elsewhere (8); tilt-test protocol is the same as described in that previous work (8). We considered tilt test as cardioinhibitory when blood pressure diminished as a result of a heart rate drop of at least 20% of the initial value or when nodal or other slow ectopic rhythms appeared. Vasodepression was diagnosed as a result of a drop of at least 20% in basal blood pressure measurement and when this correlated with symptoms. Mixed type was diagnosed when both phenomena (cardioinhibition and vasodepression) occurred simultaneously. Procedures. Taking into account the previous history in which all patients mentioned at least one syncope episode, and the tilt-test results, we started medication considering the test’s basal heart rate and also blood pressure, as seen in Figure 1A–D. After positive HUTT result, we recommended to all patients that they increase water and salt
Figure 1. (A) Initial approach. (B) Algorithmic approach proposal to neurally mediated syncope of the cardioinhibitory subtype. (C) Algorithmic approach to neurally mediated syncope of the vasodepressor subtype diagnosed through HUTT. (D) Algorithmic approach to neurally mediated syncope of the mixed subtype diagnosed through HUTT.
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Asensio Lafuente et al. / Archives of Medical Research 35 (2004) 416–420
intake (except under the conditions mentioned later) as a therapeutic measure. Within the first 2 months after HUTT, patients had a first follow-up visit in which we recorded symptoms, treatment compliance, and presence of recurrences defined as new syncope events. Dizziness accompanied by neurovegetative symptoms such as diaphoresis, nausea, or others without syncope were not considered as recurrences but as assured adjustments in the patient’s treatment. We also checked for hypotension or other treatment-associated side effects. If no new events were recorded, the patients were (and are to date) followed in 4-month intervals. If symptoms occurred, we adjusted the therapy and checked patients again within 2 months. We added pharmacologic agents in a stepwise pattern when necessary. Follow-up is carried out on a clinical-review basis; to date, no control HUTT has been performed. Patients can freely seek a check-up visit if symptoms are not controlled or if the patient shows any significant change. From February 2001, we started to routinely recommend tilt training. Patients who had recurrences despite optimal pharmacologic doses were encouraged to begin tilt training, and we insisted upon increase in water and salt intake. We did not suggest increases in salt intake among hypertensive patients. We suggested tilt training for 15–20 min twice daily at an approximately 70⬚-tilt angle against a vertical wall for patients who tolerated HUTT passive phase without symptoms. For patients who experienced reproduced syncope during HUTT passive phase, we arbitrarily recommended lying against a wall for a period of 2 min before the patients began to feel severe symptoms during HUTT. After 3–4 weeks, patients should attempt an increase in tilting time, again measuring time until severe symptoms arose and then adjusting tilting time in a similar manner to that described previously. Statistical analysis. Results are presented as mean value ⫾ standard deviation (SD) for continuous variables and median for abnormal distribution variables. Categorical variables are presented as proportions. We obtained efficacy of the different treatments comparing proportion (number) of recurrences with chi-square test. Differences in clinical characteristics between patients with recurrent syncope and nonrecurrence were assessed by Student t test. Significance level was set at p ⬍0.05.
age of 47.8 ⫾ 19.2 years. For the entire group, patients had a median of four syncope events before tilt testing (average of 4.2 ⫾ 5.4) and a median of 70 months since the first episode (mean 65.5 ⫾ 131.1) in reaction to performance of tilt testing. Patients followed ⬎30 months are 23 (18%), and we have followed-up five (3.9%) patients for at least 6 months. We found no demographic differences among different subtypes of syncope, although there was a trend toward younger men in the cardioinhibitory group, as we stated in a previous work (8), but this did not reach statistical significance. In Figure 2 we show the number of patients taking one, two, or three different medications to control their symptoms. Main combinations were dysopiramide plus fluoxetine in eight patients, atenolol plus fluoxetine in three patients, and pindolol with dysopiramide in two patients. We had two patients on three medications that included dysopiramide, fluoxetine, and atenolol. Average daily drug dosage is mentioned in Table 1. The decision to increase medication dosage or to combine several agents was reached during follow-up to minimize symptoms. Patients who experienced syncope recurrence were those who needed combinations, as well as some patients without syncope but with dizziness perceived as an incapacitating symptom. All patients received the recommendation to increase their water and salt intake unless they were hypertensive. We have a group of 24 patients treated only with general measures and tilt training; none has shown recurrence of symptoms. In such cases, we only recommended increase in water intake. We indicated tilt training to 5 (17.8%) of 28 patients prior to February 2001 and to 84 (84.8%) of 99 patients since that date. Table 2 shows the main differences between recurrent and nonrecurrent groups, in which we found that tilt training is associated with fewer recurrences. Another feature associated with recurrence is the number of previous episodes. Seventy two (56.7%) patients were on medication to treat other problems such as hypertension, diabetes, systemic lupus erythematosus, rheumatoid arthritis and other illnesses, or those who were on antidepressant therapy. If patient medication was considered appropriate within the syncope context (beta-blocking agents, fluoxetine, or fludrocortisone) (11 patients, 8.6%), we only adjusted dosage Table 1. Average drug dosage Average ⫾ SD
Daily dosage/no. of patients
Dysopiramide
110 ⫾ 30.3
Atenolol
41.9 ⫾ 11.9
Pindolol
3.12 ⫾ 1.3
Fluoxetine
19.2 ⫾ 2.8
100 mg/45 200 mg/5 50 mg/21 25 mg/10 2.5 mg/3 5 mg/1 20 mg: 23 10 mg: 2
Results During a 3-year period we have performed HUTT in 148 patients. We did not include 17 patients because they had ⬍6 months of follow-up, nor did we include for analysis purposes the four patients with negative HUTT, although they had no recurrent episodes during follow-up period. We have followed 127 patients for a mean of 20.8 ⫾ 14.3 months (range, 6–38 months). There were 89 women with average
Treatment Response in Neurocardiogenic Syncope Table 2. Main clinical characteristics
Gender Age Evolution time Previous events Vasodepressor Cardioinhibitory Mixed Beta blockers Dysopiramide Fluoxetine Water and salt Tilt training before recurrence
Recurrent (n ⫽ 6)
Non-recurrent (n ⫽ 121)
Women 4 (66.7%) 50.7 ⫾ 20.2 67.3 ⫾ 122.9 8.8 ⫾ 9.9 5 (83.3%) 0 1 (16.7%) 2 (33.4%) 4 (44.7) 3 (50%) 6 (100%) 0
Women 81 (66.9%) 47.6 ⫾ 19.2 65.4 ⫾ 131.9 3.9 ⫾ 5 53 (43.8%) 6 (4.9%) 46 (38%) 35 (28.9) 46 (38%) 22 (18.2%) 107 (88.4%) 66 (55.4%)
p ns ns ns 0.03 0.08 ns 0.4 ns ns 0.05 ns 0.008
ns, nonsignificant.
and according to the patient’s symptoms added another medication along with the general measures mentioned previously. No hypertensive patients were on diuretics. We had six patients who presented with syncope recurrences and 60 (47.2%) patients who experienced nondisabling dizziness. While we did not consider dizziness as a recurrence, we carried out therapy adjustments to minimize symptoms among these patients. In patients with negative tests, none has had any symptom recurrence. After tilt training was initiated among patients with recurrent syncope and at 1 year of follow-up, there have been no new syncope episodes. Patient compliance with therapy has been acceptable. One hundred two (80.3%) patients have taken their medication regularly at 1 year of HUTT performance. Patients usually accept with no problems increase in salt and water intake, because at each visit we insist on this as well as on tilt training. Patients scarcely mention water retention (5%, mainly young women who present leg edema associated with high environmental temperatures or their menstrual period) and no weight gain. At 3 years of follow-up, all patients continue to drink larger amounts of water (1–2 metric liters per day). Compliance with tilt training is as follows: at 1 year of follow-up, 65% of patients train regularly; compliance at 2 years is 40%, while at 3 years, compliance is 15%. Remaining patients mention that they train, but not on a regular basis.
Discussion We have a series of patients with recurrence ratio comparable to those described by others (9,10). We found no important relation of recurrences with a specific kind of neurocardiogenic syncope, although these occurred mainly in vasodepressor group, which is the largest. As others have found,
419
an important issue related to presence of recurrence is number of previous episodes without being related to evolution time. This pattern of timely evolution can support the hypothesis of a certain benignity regarding the natural history of neurally mediated syncope. Even if we did not include negative HUTT patients for statistical analysis, their number and lack of recurrence do not influence the present results. The diverse treatments we used have been previously evaluated and have shown apparent benefit based on the different pathophysiologic mechanisms of syncope (7,11– 15). However, we found that there is a tendency showing that dysopiramide and fluoxetine are more frequently associated with syncope recurrences; nevertheless, we are unable to draw conclusions from such a reduced group. Beta blockers are generally useful. This could be in agreement with the recent European guidelines (7) that go further, highlighting the marginal benefit of pharmacologic interventions. Our results suggest that the combination of pharmacologic treatment in combination with the so-called general measures or nonpharmacologic treatments can achieve an acceptable success rate in prevention of syncope recurrence. There are recent works regarding the usefulness of tilt training to prevent syncope recurrences. A study by Ector et al. (16) showed important improvements in clinical conditions of such patients who received only tilt training with no pharmacologic intervention; the investigators proceed to recommend routine use of tilt training among their patients (10,17,18). Nevertheless, there is little experience with this kind of therapy, and our results add to the scarce body of evidence actually available on this kind of therapeutic intervention. In our group, patients with recurrence who began to train on a regular basis experienced no additional syncope episodes. This kind of intervention has the advantage of being simple, easy to carry out, and does not require special training. The possibility of adverse effects is very low, and if these do occur they should be of the same magnitude and kind of the possible complications of the neurocardiogenic syncope itself. Tilt training can reduce number of medications used to control recurrent syncope; our group has a majority of patients taking only one pharmacologic agent. This fact could support the hypothesis regarding the usefulness of tilt training. On the other hand, other authors have found that beneficial effects of tilt training are lost if training is discontinued, and several of their patients complained because they found the tilting position to be uncomfortable (19,20). Our patients are compliant with treatment mainly during the first months of treatment; afterward, there is a clear tendency to diminish frequency and duration of training, perhaps due to lack of recurrence and the possibility of withdrawal of medication if patients continue to train on an irregular basis. Nonetheless, there is a benefit apparently even under these conditions. The present study has some limitations; perhaps the most important is that we did not randomize the population. These
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100 80 60 40 20 0 One Medication
Two Medications
Three No Medications Medications
Figure 2. Number of medications used by patients (%).
patients were receiving several treatments according to their different chronic problems because our population is heterogeneous with regard to this aspect. On the other hand, this is one of the largest series of patients treated with tilt training as part of an integral approach. Our goal was not to evaluate the different pharmacologic approaches but to attempt integrated therapeutic intervention and explore its possible advantages for preventing recurrent episodes. Although pharmacologic measures remain an important therapeutic tool to date and the fact that the majority of our patients received a drug or drugs, apparently there is a role for nonpharmacologic interventions that must be considered and reevaluated in larger series. It is important to mention that neurocardiogenic syncope has a somewhat elusive pathophysiology; this leads to a rather empirical approach regarding pharmacologic therapy, as shown in the recent guidelines. To control patients with symptomatic syncope, a multiple-angle approach should be undertaken that includes medication but also diet and tilt training as important adjunctive measures, perhaps even more relevant than pharmacologic intervention itself. In conclusion, our present results suggest that the approach to treatment of neurocardiogenic syncope, considered a benign entity, must be carried out with an intention to treat diverse elements. This kind of integral approach should include tilt training as an important measure to control symptoms, and patients should be monitored and encouraged to perform such training as an important component of their treatment to minimize recurrences.
References 1. Kapoor W. An overview of the evaluation and management of syncope. In: Grubb B, Olshansky B, editors. Syncope, mechanisms and management. 1st ed. Armonk, NY, USA: Futura Publishing Company; 1998. pp. 1–13. 2. Kapoor W, Fortunato M, Hanusa B, Schulberg H. Psychiatric illnesses in patients with syncope. Am J Med 1995;99:505–512. 3. Shaffer C, Jackson L, Jarecki S. Characteristics, perceived stressors and coping strategies of patients who experience neurally mediated syncope. Heart Lung 2001;30(4):244–249.
4. Kapoor W, Peterson J, Wieand H, Karpf M. Diagnostic and prognostic implications of recurrences in patients with syncope. Am J Med 1987; 83:700–788. 5. Biffi M, Boriani G, Bronzetti G, Frabetti L, Picchio F, Branzi A. Neurocardiogenic syncope in selected pediatric patients—natural history during long term follow-up and effect of prophylactic pharmacological therapy. Cardiovasc Drugs Ther 2001 Mar;15(2):161–167. 6. Dı´az J, Tercedor L, Moreno E, Garcı´a R, Alvarez M, Sa´nchez J, Azpitarte J. El sı´ncope vasovagal en pacientes pedia´tricos: un ana´lisis de la evolucio´n a medio plazo. Rev Esp Cardiol 2002;55(5):487–492. 7. Brignole M, Alboni P, Benditt D, Bergfeldt L, Blanc J, Bloch-thomsen P, van Dijk G, Fitzpatrick A, Honhloser S, Janousek J, Kapoor W, Kenny R, Kulakowski P, Moya A, Raviele A, Sutton R, Theodorakis G, Wieling W. Guidelines on management (diagnosis and treatment) of syncope. Eur Heart J 2001;22:1256–1306. 8. Asensio E, Oseguera J, Lorı´a A, Go´mez M, Narva´ez R, Dorantes J, Herna´ndez P, Orea A, Rebollar V, Ocaranza R. Clinical findings as predictors of positivity of head-up tilt table test in neurocardiogenic syncope. Arch Med Res 2003;34:287–291. 9. Nakagawa H, Kobayashi Y, Kikushima S, Shinohara M, Obara C, Zinbo Y, Chiyoda K, Miyata A, Tanno K, Baba T, Katagiri T. Long term effects of pharmacological therapy for vasovagal syncope on the basis of reproducibility during head-up tilt testing. Jpn Circ J 1998;62(10):727–732 (MedLine abstract). 10. Reybrouck T, Heidbuchel H, Van de Werf F, Ector H. Long term follow-up results of tilt training therapy in patients with recurrent neurocardiogenic syncope. Pacing Clin Electrophysiol 2002;25(10): 1441–1446. 11. Mahanonda N, Bhuripayo K, Kangkagate C, Wansanit K, Kulchot B, Nademanee K, Chaithiraphan S. Randomized placebo-controlled trial of oral Atenolol in patients with unexplained syncope and positive upright tilt table test result. Am Heart J 1995;130(6):1250–1253. 12. Flevari P, Livanis E, Theodorakis G, Zarvalis E, Mesiskli T, Kremastinos D. Vasovagal syncope: a prospective randomized crossover evaluation of the effect of propranolol, nadolol and placebo on syncope recurrence and patient’s well-being. J Am Coll Cardiol Aug 7 2002; 40(3):499–504. 13. Ventura R, Maas R, Zeidler D, Schoder V, Nienaber C, Schuchert A, Meinertz T. A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients with a positive or negative response to head-up tilt test. Pacing Clin Electrophysiol 2002;25(5):816–821. 14. Moullis C, Leitch J, Yee R, Klein G. A placebo controlled trial of dysopiramide for neurally mediated syncope induced by head-up tilt. J Am Coll Cardiol 1993;22:1843–1848. 15. Grubb B, Wolfe D, Samoil D, Temesy-Armos P, Hahn H, Elliott L. Usefulness of fluoxetine hydrochloride for prevention of resistant upright tilt-induced syncope. Pacing Clin Electrophysiol 1993;16:458– 464. 16. Ector H, Reybrouck T, Heidbu¨chel H, Ramaekers D, Van der Werf D. Tilt training: a new treatment for neurocardiogenic syncope (NASPE abstract). Pacing Clin Electrophysiol 1998;21(4 pt 1):806. 17. Ector H, Reybrouck T, Heidbuchel H, Gewillig M, Van de Werf F. Tilt training: a new treatment for recurrent neurocardiogenic syncope and severe orthostatic intolerance. Pacing Clin Electrophysiol 1998;21 (1 pt 2):193–196. 18. Abe H, Kondo S, Kohshi K, Nakashima Y. Usefulness of orthostatic self-training for prevention of neurocardiogenic syncope. Pacing Clin Electrophysiol 2002;25(10):1454–1458. 19. Ector H, Reybrouck T, Heidbuchel H, Van de Werf F. Long term follow-up of tilt training in patients with recurrent neurocardiogenic syncope. Pacing Clin Electrophysiol 2001;24(4 pt 2):574 (abstract 141). 20. Foglia Manzillo G, Giada F, Gaggioli G, Bartoletti A, Lolli G, Del Rosso A, Santarone M, Brignole M. Efficacy of tilt training in the treatment of recurrent neurocardiogenic syncope: a randomized study. Pacing Clin Electrophysiol 2001;24(4 pt 2):574 (abstract 142).
ORIGINAL ARTICLE
Response to Treatment during Medium-Term Follow-Up in a Series of Patients with Neurocardiogenic Syncope Enrique Asensio Lafuente, Lilia Castillo Martı´nez, Jorge Oseguera Moguel, Rene´ Narva´ez David, Joel Dorantes Garcı´a, Arturo Orea Tejeda, Pablo Herna´ndez Reyes and Vero´nica Rebollar Gonza´lez Departamento de Cardiologı´a, Clı´nica de Marcapasos, Instituto Nacional de Ciencias Me´dicas y Nutricio´n Salvador Zubira´n (INCMNSZ), Mexico City, Me´xico Received for publication December 15, 2003; accepted June 4, 2004 (03/210).
Background. Syncope is a common symptom that has different recurrence ratios. We hypothesized that an individualized treatment regimen including pharmacologic and nonpharmacologic measures considering kind of neurocardiogenic syncope (NCS) and basal characteristics of each patient could allow optimized therapy to avoid recurrences. Methods. We conducted a prospective study to evaluate performance of diverse accepted treatments for NCS. Each patient received specific treatment including general measures such as an increase in salt and water intake, tilt training, specific pharmacologic treatment according to head-up tilt table test (HUTT) result, and patient basal blood pressure and heart rate measurements. Results. We followed a group of 127 patients during a main period of 20.8 ⫾ 9 months (range, 6–38 months). Mean age was 47.8 ⫾ 19.2 years and 66.9% were females. We had six (4.7%) patients with recurrence of symptoms 4 ⫾ 0.9 months after diagnostic HUTT. Medications used were atenolol in 20 patients, pindolol in 17, dysopiramide in 50, and fluoxetine in 25. Two patients received fludrocortisone. Tilt training was not indicated initially for patients with recurrences but was indicated later; to date, these patients have not experienced further episodes. Conclusions. Increase in water and salt intake, as well as tilt training, showed great value in prevention of syncope recurrences in this specific set of patients. Pharmacologic treatment has an important role, but there is no single medication associated with significant improvement in symptom control. 쑖 2004 IMSS. Published by Elsevier Inc. Key Words: Syncope, Recurrence, Tilt training, Treatment of syncope, Medium-term follow-up.
Introduction Syncope is a common symptom and has different etiologies. Among the most frequent is neurocardiogenic or neurally mediated syncope. This variant usually has excellent prognosis with regard to survival, but recurrences are rather common and render distress in the patient and sometimes disability due to fear regarding the possibility of trauma or
Address reprint requests to: Dr. Enrique Asensio Lafuente, Departamento de Cardiologı´a, Clı´nica de Arritmias y Marcapasos, INCMNSZ, Vasco de Quiroga #15, Col. Seccio´n XVI, Tlalpan, 14000 Me´xico, 14000 D.F., Me´xico. Telefax: (⫹52) (55) 5655-3306; E-mail: [email protected]
0188-4409/04 $–see front matter. Copyright d o i : 10 .1 0 1 6/ j.ar c med .2 0 04 .0 6 .0 0 9
certain other major events, including death (1–3). Recurrences are not infrequent because they can occur in up to 34% of patients during a 3-year follow-up (4), although they can be different among different populations, as occurs in pediatric patients (5,6). Treatment for such a common disease has been to date directed in a rather intuitive or empirical manner and usually involves symptomatic rather than curative therapy. Several papers show significant benefits with diverse pharmacologic agents; nonetheless, when followed for 1-year intervals these agents apparently lose their beneficial effect. Seemingly, medical treatment lacks long-term benefits because recurrences among differently treated patients remain relatively
쑖 2004 IMSS. Published by Elsevier Inc.
Treatment Response in Neurocardiogenic Syncope
high (7). Moreover, pharmacologic agents have no apparent benefit over placebo. This finding emphasizes the important role of nonpharmacologic treatments such as increased water and salt intake and tilt-training programs in the therapeutic approach to syncope patients. In the present study, we evaluated the impact of several pharmacologic agents combined with general measures for avoidance of recurrent syncope events.
Patients and Methods Patients. We performed a prospective study to evaluate the outcome of a group of patients diagnosed with neurally mediated syncope who received treatment with several pharmacologic agents. Initially (for patients whose test was performed from April 2000 to February 2001) we did not recommend tilt training as a routine measure, although we consider increasing water and salt intake as routine.
417
Patients were selected for tilt testing (HUTT) according to their history and physical examination, as we described elsewhere (8); tilt-test protocol is the same as described in that previous work (8). We considered tilt test as cardioinhibitory when blood pressure diminished as a result of a heart rate drop of at least 20% of the initial value or when nodal or other slow ectopic rhythms appeared. Vasodepression was diagnosed as a result of a drop of at least 20% in basal blood pressure measurement and when this correlated with symptoms. Mixed type was diagnosed when both phenomena (cardioinhibition and vasodepression) occurred simultaneously. Procedures. Taking into account the previous history in which all patients mentioned at least one syncope episode, and the tilt-test results, we started medication considering the test’s basal heart rate and also blood pressure, as seen in Figure 1A–D. After positive HUTT result, we recommended to all patients that they increase water and salt
Figure 1. (A) Initial approach. (B) Algorithmic approach proposal to neurally mediated syncope of the cardioinhibitory subtype. (C) Algorithmic approach to neurally mediated syncope of the vasodepressor subtype diagnosed through HUTT. (D) Algorithmic approach to neurally mediated syncope of the mixed subtype diagnosed through HUTT.
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Asensio Lafuente et al. / Archives of Medical Research 35 (2004) 416–420
intake (except under the conditions mentioned later) as a therapeutic measure. Within the first 2 months after HUTT, patients had a first follow-up visit in which we recorded symptoms, treatment compliance, and presence of recurrences defined as new syncope events. Dizziness accompanied by neurovegetative symptoms such as diaphoresis, nausea, or others without syncope were not considered as recurrences but as assured adjustments in the patient’s treatment. We also checked for hypotension or other treatment-associated side effects. If no new events were recorded, the patients were (and are to date) followed in 4-month intervals. If symptoms occurred, we adjusted the therapy and checked patients again within 2 months. We added pharmacologic agents in a stepwise pattern when necessary. Follow-up is carried out on a clinical-review basis; to date, no control HUTT has been performed. Patients can freely seek a check-up visit if symptoms are not controlled or if the patient shows any significant change. From February 2001, we started to routinely recommend tilt training. Patients who had recurrences despite optimal pharmacologic doses were encouraged to begin tilt training, and we insisted upon increase in water and salt intake. We did not suggest increases in salt intake among hypertensive patients. We suggested tilt training for 15–20 min twice daily at an approximately 70⬚-tilt angle against a vertical wall for patients who tolerated HUTT passive phase without symptoms. For patients who experienced reproduced syncope during HUTT passive phase, we arbitrarily recommended lying against a wall for a period of 2 min before the patients began to feel severe symptoms during HUTT. After 3–4 weeks, patients should attempt an increase in tilting time, again measuring time until severe symptoms arose and then adjusting tilting time in a similar manner to that described previously. Statistical analysis. Results are presented as mean value ⫾ standard deviation (SD) for continuous variables and median for abnormal distribution variables. Categorical variables are presented as proportions. We obtained efficacy of the different treatments comparing proportion (number) of recurrences with chi-square test. Differences in clinical characteristics between patients with recurrent syncope and nonrecurrence were assessed by Student t test. Significance level was set at p ⬍0.05.
age of 47.8 ⫾ 19.2 years. For the entire group, patients had a median of four syncope events before tilt testing (average of 4.2 ⫾ 5.4) and a median of 70 months since the first episode (mean 65.5 ⫾ 131.1) in reaction to performance of tilt testing. Patients followed ⬎30 months are 23 (18%), and we have followed-up five (3.9%) patients for at least 6 months. We found no demographic differences among different subtypes of syncope, although there was a trend toward younger men in the cardioinhibitory group, as we stated in a previous work (8), but this did not reach statistical significance. In Figure 2 we show the number of patients taking one, two, or three different medications to control their symptoms. Main combinations were dysopiramide plus fluoxetine in eight patients, atenolol plus fluoxetine in three patients, and pindolol with dysopiramide in two patients. We had two patients on three medications that included dysopiramide, fluoxetine, and atenolol. Average daily drug dosage is mentioned in Table 1. The decision to increase medication dosage or to combine several agents was reached during follow-up to minimize symptoms. Patients who experienced syncope recurrence were those who needed combinations, as well as some patients without syncope but with dizziness perceived as an incapacitating symptom. All patients received the recommendation to increase their water and salt intake unless they were hypertensive. We have a group of 24 patients treated only with general measures and tilt training; none has shown recurrence of symptoms. In such cases, we only recommended increase in water intake. We indicated tilt training to 5 (17.8%) of 28 patients prior to February 2001 and to 84 (84.8%) of 99 patients since that date. Table 2 shows the main differences between recurrent and nonrecurrent groups, in which we found that tilt training is associated with fewer recurrences. Another feature associated with recurrence is the number of previous episodes. Seventy two (56.7%) patients were on medication to treat other problems such as hypertension, diabetes, systemic lupus erythematosus, rheumatoid arthritis and other illnesses, or those who were on antidepressant therapy. If patient medication was considered appropriate within the syncope context (beta-blocking agents, fluoxetine, or fludrocortisone) (11 patients, 8.6%), we only adjusted dosage Table 1. Average drug dosage Average ⫾ SD
Daily dosage/no. of patients
Dysopiramide
110 ⫾ 30.3
Atenolol
41.9 ⫾ 11.9
Pindolol
3.12 ⫾ 1.3
Fluoxetine
19.2 ⫾ 2.8
100 mg/45 200 mg/5 50 mg/21 25 mg/10 2.5 mg/3 5 mg/1 20 mg: 23 10 mg: 2
Results During a 3-year period we have performed HUTT in 148 patients. We did not include 17 patients because they had ⬍6 months of follow-up, nor did we include for analysis purposes the four patients with negative HUTT, although they had no recurrent episodes during follow-up period. We have followed 127 patients for a mean of 20.8 ⫾ 14.3 months (range, 6–38 months). There were 89 women with average
Treatment Response in Neurocardiogenic Syncope Table 2. Main clinical characteristics
Gender Age Evolution time Previous events Vasodepressor Cardioinhibitory Mixed Beta blockers Dysopiramide Fluoxetine Water and salt Tilt training before recurrence
Recurrent (n ⫽ 6)
Non-recurrent (n ⫽ 121)
Women 4 (66.7%) 50.7 ⫾ 20.2 67.3 ⫾ 122.9 8.8 ⫾ 9.9 5 (83.3%) 0 1 (16.7%) 2 (33.4%) 4 (44.7) 3 (50%) 6 (100%) 0
Women 81 (66.9%) 47.6 ⫾ 19.2 65.4 ⫾ 131.9 3.9 ⫾ 5 53 (43.8%) 6 (4.9%) 46 (38%) 35 (28.9) 46 (38%) 22 (18.2%) 107 (88.4%) 66 (55.4%)
p ns ns ns 0.03 0.08 ns 0.4 ns ns 0.05 ns 0.008
ns, nonsignificant.
and according to the patient’s symptoms added another medication along with the general measures mentioned previously. No hypertensive patients were on diuretics. We had six patients who presented with syncope recurrences and 60 (47.2%) patients who experienced nondisabling dizziness. While we did not consider dizziness as a recurrence, we carried out therapy adjustments to minimize symptoms among these patients. In patients with negative tests, none has had any symptom recurrence. After tilt training was initiated among patients with recurrent syncope and at 1 year of follow-up, there have been no new syncope episodes. Patient compliance with therapy has been acceptable. One hundred two (80.3%) patients have taken their medication regularly at 1 year of HUTT performance. Patients usually accept with no problems increase in salt and water intake, because at each visit we insist on this as well as on tilt training. Patients scarcely mention water retention (5%, mainly young women who present leg edema associated with high environmental temperatures or their menstrual period) and no weight gain. At 3 years of follow-up, all patients continue to drink larger amounts of water (1–2 metric liters per day). Compliance with tilt training is as follows: at 1 year of follow-up, 65% of patients train regularly; compliance at 2 years is 40%, while at 3 years, compliance is 15%. Remaining patients mention that they train, but not on a regular basis.
Discussion We have a series of patients with recurrence ratio comparable to those described by others (9,10). We found no important relation of recurrences with a specific kind of neurocardiogenic syncope, although these occurred mainly in vasodepressor group, which is the largest. As others have found,
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an important issue related to presence of recurrence is number of previous episodes without being related to evolution time. This pattern of timely evolution can support the hypothesis of a certain benignity regarding the natural history of neurally mediated syncope. Even if we did not include negative HUTT patients for statistical analysis, their number and lack of recurrence do not influence the present results. The diverse treatments we used have been previously evaluated and have shown apparent benefit based on the different pathophysiologic mechanisms of syncope (7,11– 15). However, we found that there is a tendency showing that dysopiramide and fluoxetine are more frequently associated with syncope recurrences; nevertheless, we are unable to draw conclusions from such a reduced group. Beta blockers are generally useful. This could be in agreement with the recent European guidelines (7) that go further, highlighting the marginal benefit of pharmacologic interventions. Our results suggest that the combination of pharmacologic treatment in combination with the so-called general measures or nonpharmacologic treatments can achieve an acceptable success rate in prevention of syncope recurrence. There are recent works regarding the usefulness of tilt training to prevent syncope recurrences. A study by Ector et al. (16) showed important improvements in clinical conditions of such patients who received only tilt training with no pharmacologic intervention; the investigators proceed to recommend routine use of tilt training among their patients (10,17,18). Nevertheless, there is little experience with this kind of therapy, and our results add to the scarce body of evidence actually available on this kind of therapeutic intervention. In our group, patients with recurrence who began to train on a regular basis experienced no additional syncope episodes. This kind of intervention has the advantage of being simple, easy to carry out, and does not require special training. The possibility of adverse effects is very low, and if these do occur they should be of the same magnitude and kind of the possible complications of the neurocardiogenic syncope itself. Tilt training can reduce number of medications used to control recurrent syncope; our group has a majority of patients taking only one pharmacologic agent. This fact could support the hypothesis regarding the usefulness of tilt training. On the other hand, other authors have found that beneficial effects of tilt training are lost if training is discontinued, and several of their patients complained because they found the tilting position to be uncomfortable (19,20). Our patients are compliant with treatment mainly during the first months of treatment; afterward, there is a clear tendency to diminish frequency and duration of training, perhaps due to lack of recurrence and the possibility of withdrawal of medication if patients continue to train on an irregular basis. Nonetheless, there is a benefit apparently even under these conditions. The present study has some limitations; perhaps the most important is that we did not randomize the population. These
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100 80 60 40 20 0 One Medication
Two Medications
Three No Medications Medications
Figure 2. Number of medications used by patients (%).
patients were receiving several treatments according to their different chronic problems because our population is heterogeneous with regard to this aspect. On the other hand, this is one of the largest series of patients treated with tilt training as part of an integral approach. Our goal was not to evaluate the different pharmacologic approaches but to attempt integrated therapeutic intervention and explore its possible advantages for preventing recurrent episodes. Although pharmacologic measures remain an important therapeutic tool to date and the fact that the majority of our patients received a drug or drugs, apparently there is a role for nonpharmacologic interventions that must be considered and reevaluated in larger series. It is important to mention that neurocardiogenic syncope has a somewhat elusive pathophysiology; this leads to a rather empirical approach regarding pharmacologic therapy, as shown in the recent guidelines. To control patients with symptomatic syncope, a multiple-angle approach should be undertaken that includes medication but also diet and tilt training as important adjunctive measures, perhaps even more relevant than pharmacologic intervention itself. In conclusion, our present results suggest that the approach to treatment of neurocardiogenic syncope, considered a benign entity, must be carried out with an intention to treat diverse elements. This kind of integral approach should include tilt training as an important measure to control symptoms, and patients should be monitored and encouraged to perform such training as an important component of their treatment to minimize recurrences.
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