Efficacy of tilt training in the treatment of neurally mediated syncope. A randomized study

Transcription

1 Europace (2004) 6, 199e204 Efficacy of tilt training in the treatment of neurally mediated syncope. A randomized study Giovanni Foglia-Manzillo a, ), Franco Giada b, Germano Gaggioli c, Angelo Bartoletti d, Gino Lolli e, Maurizio Dinelli f, Attilio Del Rosso g, Mauro Santarone a, Antonio Raviele b, Michele Brignole h a Department of Cardiology of Ospedale Valduce, Como, Italy b Department of Cardiology of Ospedale Umberto I, Mestre, Italy c Department of Cardiology of Ospedale Civile Genova-Sampierdarena, Italy d Department of Cardiology of Ospedale S. Maria Annunziata, Firenze, Italy e Department of Cardiology of Ospedale S. Maria Nuova, Reggio Emilia, Italy f Department of Cardiology of Ospedale Civile, Cento, Italy g Department of Cardiology of Ospedale Civile, Fucecchio, Italy h Department of Cardiology of Ospedali Riuniti, Lavagna, Italy Submitted 18 September 2003, and accepted after revision 27 January 2004 KEYWORDS neurally mediated syncope; tilt testing; tilt training; treatment Abstract Recurrent neurally mediated syncope represents a common clinical event and a therapeutic challenge. Recently tilt training has been proposed for the treatment of recurrent neurally mediated syncope. To evaluate the efficacy of tilt training in preventing tilt-induced syncope and its feasibility, this controlled, randomized study was undertaken. Sixty-eight consenting patients (25 males and 43 females, mean age 40 G 19 years) with recurrent neurally mediated syncope and 2 consecutive positive nitroglycerin-potentiated head-up tilt tests were randomized to tilt training (35 patients) or no treatment (controls, 33 patients). The tilt training programme consisted of daily 30-min sessions of upright standing against a vertical wall 6 days a week for at least 3 weeks, until a reevaluation tilt test (3 patients of both groups dropped out). On this third head-up tilt test, 19 (59%) of 32 tilt trained patients and 18 (60%) of 30 controls still had a positive test. Treated patients performed a mean number of 15 G 7 sessions (median 16) and only 11 patients (34%) did all the programmed sessions. Only 1 patient (3%) discontinued treatment because of intolerance, while all other patients did not perform tilt training adequately, because of poor compliance. Thus, in our study tilt training was not effective in reducing tilt testing positivity rate in patients with neurally mediated syncope. Because of poor compliance, tilt training appears to be a feasible ) Corresponding author. U. O. Cardiologia, Ospedale Valduce, Via Dante, 11, Como, Italy. Tel.: D ; fax: D address: gfoglia@valduce.it (G. Foglia-Manzillo) /$30 ª 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi: /j.eupc

2 200 G. Foglia-Manzillo et al. treatment only for highly motivated patients, but not for the majority of patients with recurrent neurally mediated syncope. ª 2004 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. Recurrent neurally mediated syncope represents a common clinical event and a therapeutic challenge. Many pharmacological treatments have been proposed, but randomized, controlled studies gave conflicting results [1e6]. Pacemaker implantation has proved to be effective [7e9], but recently this issue has been questioned [10]. Recently tilt training has been proposed as a treatment for recurrent neurally mediated syncope [11,12]. It was postulated that repeated orthostatic stress could be of benefit to the regulation of cardiovascular control mechanisms. No randomized studies are available concerning the efficacy of tilt training in the treatment of neurally mediated syncope. We have performed a prospective, randomized, multicentre, acute study to test the efficacy of tilt training in preventing tilt-induced syncope and a feasibility follow-up study. Methods Study population Sixty-eight consenting patients (25 males and 43 females, mean age 40 G 19 years) with recurrent neurally mediated syncope and 2 consecutive positive nitroglycerin-potentiated head-up tilt tests were enrolled in the study. The diagnosis of neurally mediated syncope was based, in addition to a positive tilt test result, on the exclusion of all other possible causes of syncope, by means of a systematic work-up previously described [13]. No patient had structural heart disease. Baseline head-up tilt test Patients underwent head-up tilt test between 8 AM and 1 PM, after at least a 4-h fasting period. The Italian Protocol [14] was used. After baseline blood pressure and heart rate measurement, patients were tilted to 60( for 20 min. If syncope did not develop during the initial passive phase, 400 mg spray nitroglycerin was administered sublingually, and patients continued to be tilted for an additional 15 min. Continuous ECG monitoring of heart rate and rhythm was performed, while blood pressure was non-invasively measured beat-to-beat by means of a Finapress 2300 photoplethysmographic device Ohmeda, Englewood, USA. The end point of the test was the reproduction of syncope. A positive head-up tilt test was considered positive when syncope was reproduced in association with hypotension, bradycardia, or both. Positive responses were classified according to Vasovagal Syncope International Study [15]: type 1 (mixed), types 2A and 2B (cardioinhibitory), and type 3 (vasodepressor). An asystolic response was defined as the development of ventricular asystole of O3 s duration. Heart rate and blood pressure immediately before or at the time of syncope were used to define positive responses. Time to syncope was defined as the interval from the beginning of head-up tilt test to the loss of consciousness. Study design After diagnostic head-up tilt test, another tilt test was performed a few hours to 7 days later. If the head-up tilt test was reproducibly positive, patients entered the study. The pathophysiology of neurally mediated syncope and the end points of the programme were explained to each patient. Patients were then randomized to tilt training (35 patients) or no treatment (controls, 33 patients). The tilt training programme consisted of daily sessions for 6 days a week for at least 3 weeks, until a reevaluation tilt test. Patients assigned to treatment were instructed to perform tilt training at home by standing against a wall (with the ankles together 20 cm from the wall) once a day for a planned duration of up to 30 min, depending on their orthostatic tolerance. Patients were instructed to maintain the standing position until pre-syncopal symptoms appeared prompting early cessation, or otherwise to terminate their session at 30 min. Patients were asked to perform tilt training sessions in a comfortable and safe environment in order to avoid the risk of trauma, possibly under the supervision of a family member. Patients were given a form to record each tilt training session, its duration and symptoms. To test the effect of tilt training on tilt testing, at the end of the tilt training programme, the response to head-up tilt test was reevaluated in the same laboratory, using the same protocol as the baseline test, in both treated and control groups.

3 Efficacy of tilt training 201 After the third reevaluation head-up tilt test, independently of test response, patients were left free to continue or discontinue tilt training at home. Every patient was asked to report recurrence of spontaneous syncope, and they were contacted by telephone regularly every 6 months. Statistical analysis Parametric data are represented as mean and SD of the mean, non-parametric data are expressed as median and interquartile range. Patients were classified as positive or negative for the head-up tilt tests and their clinical course on the basis of whether or not syncope occurred. The response rate between the 2 groups was compared by chisquare test. Other continuous data were compared by Student s t-test. A p value % 0.05 was considered significant. Results Patient characteristics Clinical baseline characteristics of patients in the 2 groups are listed in Table 1. There was no significant difference between them with respect to all variables considered. Baseline and repeat head-up tilt test responses are listed in Table 2. There were no significant differences for all the intra-test variables considered between baseline and repeat test in both treated and control groups. Tilt training The 32 patients assigned to treatment performed at home a mean number of 15 G 7 tilt training sessions (median 16, interquartile range 12e18) of a mean programmed number of 20 G 5 tilt training sessions (median 18, interquartile range 18e21). Eleven patients (34%) performed all the programmed sessions. Three patients (9%) performed less than half, 3 patients (9%) less than 2/3 and 1 patient (3%) none of the programmed sessions. Only 1 patient (3%) did not perform tilt training because of intolerance (severe back pain at first session). Head-up tilt test reevaluation Three patients of each group refused to perform the reevaluation head-up tilt test and dropped out of the study. At the third or reevaluation head-up tilt test, performed at the end of the tilt training programme, in the treatment group 19 of 32 patients (59%) still had a positive test, while 13 patients (41%) had a negative test. Among the untreated patients (control group) 18 of 30 patients (60%) still had tilt-induced syncope, while 12 patients had a negative test (p ¼ ns). Time to syncope was 25 G 2 min in treated patients and 23 G 5 min in untreated patients (p ¼ ns). Thus, there was no significant difference in tilt test outcome and duration between treated and untreated patients. The responses on tilt test reevaluation are listed in Table 2. None of the patients, treated or untreated, had spontaneous syncope during this phase of the study. Follow-up Four patients were lost to follow-up. Thus 58 patients were followed-up for 1 year. Spontaneous syncope recurrence occurred in 16 patients (28%). Pre-syncope recurred in 26 patients (45%). Only 5 (17%) of the 29 tilt trained patients kept on performing tilt training, but very sporadically, during 1-year follow-up. There were no significant differences between tilt training compliant and non-compliant patients as regards gender, age, historical number of syncopal spells and historical symptom duration. Of the 5 compliant patients, 3 (60%) had a negative third reevaluation tilt testing, while 2 (40%) had a positive reevaluation. None of them had recurrences of syncope. Table 1 Baseline characteristics of the patients Tilt training (n ¼ 35) Controls (n ¼ 33) Gender (F/M) 25/10 18/15 Age 36 G G 20 Lifetime syncopal spells, median (interquartile range) 5 (3e10) 5 (2e10) Syncopal spells in the last year, median (interquartile range) 3 (1e3) 2 (1e3) Duration of symptoms, months, median (interquartile range) 66 (33e135) 63 (21e180)

4 202 G. Foglia-Manzillo et al. Table 2 Characteristics of positive head-up tilt (HUT) responses observed in the 2 baseline HUTs and in the third HUT performed after 3 weeks tilt training First HUT Second HUT Third HUT Tilt training arm (n ¼ 35=35) (n ¼ 35=35) (n ¼ 19=32) Passive phase (%) 2 (6%) 4 (11%) 0 After TNG s.l. (%) 33 (94%) 31 (89%) 19 (100%) Duration (min) 25 G 5 23G 4 25G 2 Type 1 (%) 20 (57%) 19 (54%) 12 (63%) Type 2A (%) 9 (26%) 11 (31%) 4 (21%) Type 2B (%) 5 (14%) 4 (12%) 2 (11%) Type 3 (%) 1 (3%) 1 (3%) 1 (5%) Asystole (%) 11 (31%) 8 (23%) 3 (16%) Control arm (n ¼ 33=33) (n ¼ 33=33) (n ¼ 18=30) Passive phase (%) 7 (21%) 7 (21%) 2 (11%) After TNG s.l. (%) 26 (79%) 26 (79%) 16 (89%) Duration (min) 22 G 5 23G 5 23G 5 Type 1 (%) 18 (55%) 25 (76%) 15 (82%) Type 2A (%) 9 (27%) 4 (12%) 1 (6%) Type 2B (%) 3 (9%) 3 (9%) 1 (6%) Type 3 (%) 3 (9%) 1 (3%) 1 (6%) Asystole (%) 12 (36%) 6 (18%) 1 (6%) TNG, nitroglycerin; s.l., sublingual. Among patients with syncopal recurrence in the tilt training group, none resumed tilt training after spontaneous syncope during follow-up. When interviewed, of 29 patients of tilt training group, 7 (24%) would have performed tilt training indefinitely, 19 (66%) would have performed tilt training only for limited short periods and 3 patients (10%) would have refused to perform tilt training as treatment of neurally mediated syncope. Discussion In this prospective, randomized study out-of hospital tilt training did not prove to be effective in reducing tilt testing positivity rate, which was 59% and 60% in active and control arms, respectively. Tilt training was not successful even in prolonging time to tilt-induced syncope. These data seem not to confirm the pathophysiological hypothesis that repeated orthostatic stress could positively influence the regulation of cardiovascular mechanisms involved in neurally mediated syncope [11]. In fact, if this postulate were true, we should expect a significant reduction of tilt testing positivity rate after a tilt training programme. Our results are in contrast with a previous study by Di Girolamo et al. [12], who demonstrated great efficacy of tilt training in reducing the positivity rate of repeat tilt testing. In fact, in that study only 4.2% of treated patients still had a positive repeat headup tilt test, in contrast to 73.9% of patients in the control group. Furthermore, the patients in the tilt training group reported a significant increase in test duration. In that study the population was represented by adolescents, with very frequent and refractory syncopal spells. Moreover, it was not a randomized study. In the study by Reybrouck et al. [11] tilt training was started in hospital and only after 2 consecutive negative tilt tests the patients were recommended to continue the treatment at home. During in-hospital tilt training all the patients became asymptomatic by a maximum of 8 sessions (median 3). Those patients did not differ from our patients in age and gender, but many of them were highly symptomatic, much more than our patients. The diagnostic tilt testing protocol was different in the 2 studies: passive tilt testing in the study of Reybrouck et al. [11] and nitroglycerin-potentiated tilt testing in our study. These different diagnostic protocols may have selected patients with different responses to tilt training. Besides, only patients with 2 consecutive positive head-up tilt tests entered our study; in the study of Reybrouck et al. [11] 18 patients had a negative second tilt test and would not have entered our study. Previous studies [2,4,8] have demonstrated that tilt testing is not useful in evaluating treatment efficacy, mainly due to its poor reproducibility. Thus, even tilt training should be better evaluated by the outcome during the follow-up.

5 Efficacy of tilt training 203 Another important finding raised by this study is the poor compliance of patients with a long-term out-of hospital tilt training programme. In fact, only 34% of patients performed all the programmed sessions, while several patients did not adequately perform tilt training. This poor compliance is particularly striking, since it was observed in a shortterm follow-up, until tilt testing reevaluation. After tilt testing reevaluation our patients were left free to continue or discontinue tilt training at home. Only 17% of patients spontaneously performed tilt training at home, even if very sporadically. Interestingly, none of the patients who had syncopal recurrence during follow-up spontaneously resumed tilt training after the recurrence. When asked about feasibility of tilt training as longterm treatment of neurally mediated syncope, 66% of patients found tilt training feasible, but only for limited periods, while only 17% would have continued tilt training indefinitely and 10% would not undertake it at all. In the study of Di Girolamo et al. [12] the compliance with tilt training was very high: only 2 of 24 (8%) patients discontinued the training after 18 and 20 months, respectively. In the study of Reybrouck [11] the compliance with tilt training was also high: after 15-month follow-up only 13 of 42 (31%) patients had discontinued the training. Our study did not include in-hospital sessions of tilt training: this could have affected patients confidence in tilt training, thus diminishing their compliance, which may have affected the efficacy of our out-of hospital tilt training programme. In our study there was a 28% incidence of syncopal recurrence at 1-year follow-up. This result is not different from what is expected of the natural history of neurally mediated syncope, after tilt testing evaluation [16]. Therefore, we were unable to reproduce the results of the 2 other previous studies that evaluated this treatment [11,12]. In the study of Reybrouck et al. [11] 36 of 42 patients remained completely asymptomatic after a mean follow-up of 15 months. In the study of Di Girolamo et al. [12] there was no syncope recurrence in the tilt training group in contrast to 56.5% rate of syncopal recurrence in the control group during a 15-month follow-up. Admittedly, in our study, of 5 patients who spontaneously continued tilt training at home, even if very sporadically, none had syncopal recurrence during 1-year follow-up, but the small number does not allow the drawing of definite conclusions on the effect of the treatment in these patients. In conclusion, in our study tilt training failed to reduce tilt-induced syncope. The quite poor compliance with such treatment may have affected its efficacy. Out-of hospital tilt training appears to be a feasible treatment only for highly motivated patients, but not for the majority of those with recurrent neurally mediated syncope. References [1] Brignole M, Menozzi C, Gianfranchi L, Lolli G, Bottoni N, Oddone D. A controlled trial of acute and long-term medical therapy in tilt-induced neurally mediated syncope. Am J Cardiol 1992;70:339e42. [2] Morillo CA, Leitch JW, Yee R, Klein GL. A placebo-controlled trial of intravenous and oral disopyramide for prevention of neurally mediated syncope induced by head-up tilt. J Am Coll Cardiol 1993;22:1843e8. [3] Mahanonda N, Bhuripanyo K, Kangkagate C, Wansanit K, Kulchot B, Nademanee K, et al. Randomized double-blind, placebo-controlled trial of oral atenolol in patients with unexplained syncope and positive upright tilt table test results. Am Heart J 1995;130:1250e3. 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