b-Blockers for Prevention of Vasovagal Syncope:
Who Benefits from Treatment?
R.S. SHELDON
Catecholamines and Vasovagal Syncope
Vasovagal syncope is a common problem that reduces quality of life [1–3]
and may be difficult to treat. Although β-adrenergic blockers are frequently prescribed to prevent syncope, there is limited evidence for their effective- ness. However, there is considerable evidence supporting a role for cate- cholamine involvement in the haemodynamic response to head-up tilt, and perhaps in the vasovagal reflex itself (for review, see [4]). Both norepineph- rine and epinephrine increase steadily during prolonged head-up tilt, with terminal levels of epinephrine significantly higher in patients in whom the vasovagal reflex is induced than in those resistant to prolonged tilt testing [4–6]. Older patients may release more epinephrine than younger subjects [5]. The amount of the increase in norepinephrine varies considerably from study to study. Taken together, these findings suggest that sympathetic stim- ulation, perhaps of β-adrenergic receptors, is important in the genesis of vasovagal syncope. Consistent with this is the ability of an isoproterenol infusion to provoke vasovagal syncope far more quickly in patients undergo- ing tilt tests than in those examined by simple passive prolonged head-up tilt testing [7, 8]. Whether isoproterenol simply accelerates the onset of the vaso- vagal reflex or identifies a subset of patients is unclear. For example, both isoproterenol and nitrates provoke syncope on tilt tests, but do so in only partly overlapping populations [9]. There is ample evidence that acute β- blockade during isoproterenol tilt tests can prevent the vasovagal reflex (for a summary, see [10]). However, they are less effective in preventing syncope during passive head-up tilt tests [6], suggesting that while stimulation of the
Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Alberta, Canada
β-adrenergic receptor may be important in isoproterenol tilt tests, it is sig- nificantly less important in the vasovagal reflex provoked by passive head-up tilt. Finally, Dendi and Goldstein reported a meta analysis of 19 papers and 1060 patients who received β-blockade during tilt testing. They reported that that β1-selective adrenoreceptor blockade resulted in 68% negative tilt tests, while non-selective blockade resulted in 94% negative tilt tests. The authors concluded that non-selective β-blockers are likely to be more effective than β1-selective blockers in preventing vasovagal syncope [10]. Unfortunately, the types of tilt tests were not reported, so it is not clear whether this was a study of the physiology of isoproterenol or a study of the physiology of vaso- vagal syncope. Whether the findings have therapeutic implications for patients with recurrent vasovagal syncope is also not known.
Observational Studies
Three observational studies yielded conflicting information about whether β-blockade prevents syncope. In a nonrandomised trial, Cox et al. [11]
administered a variety ofβ-blockers to 118 syncope patients who had fainted a median three times and who had a positive tilt test. Control patients were those who either refused β-adrenergic blocker treatment or discontinued it.
After 28 ± 11 months, the proportion of patients with a recurrence of syn- cope was 10-23% in the persistently treated patients and 42-58% in the par- tially or completely untreated patients. The estimated absolute effect size was about 34% with a relative reduction of 68%. We studied a cohort of 153 syn- cope patients who had positive tilt tests and a historical median of seven syncopal spells [12]. Syncope recurred in 17 of the 52 patients who received β-blockers and in 28 of the 101 patients who were untreated; the actuarial probability of remaining free of syncope was the same in both groups.
Alegria et al. recently reported similar results in a large observational report [13]. They followed 163 patients treated with β-blockers and 75 control sub- jects treated with conservative, non-pharmacologic measures for 20 ± 13 months. Most (82%) patients who received a β-blocker took either atenolol or metoprolol. Patients who received β-adrenergic blockers were somewhat younger than those managed conservatively. There was a trend to a worse outcome in patients on β-blockers; 20% of control subjects and 35% of patients who received β-adrenergic blockers had at least one recurrence of syncope (P = 0.056). At the very least, this study provides little evidence of a beneficial effect ofβ-blockers.
Randomised Clinical Trials
There have been five randomised clinical trials testing the efficacy or effec- tiveness of β-adrenergic blockers for the prevention of syncope [14–18].
Although the results are not completely consistent, they do suggest strongly that β-blockade does not prevent vasovagal syncope. Mahanonda et al. stud- ied 42 patients with an unspecified mix of historical presyncope and syn- cope, and a positive tilt test [14]. The patients then were randomised to atenolol or placebo. After 1 month, 71% of patients receiving atenolol, but only 29% of patients receiving placebo reported feeling better and had expe- rienced fewer combined presyncopal and syncopal spells. The absolute effect size was 42% and the relative risk reduction was 61%. The frequency of pre- syncopal and syncopal events was 1 ± 2 vs 6 ± 9 spells per week in the atenolol vs the placebo populations, with a relative reduction of 83%.
Madrid et al. randomised 50 patients with vasovagal syncope to treat- ment with atenolol (50 mg daily) or placebo [15]. The subjects were selected on the basis of a clinical diagnosis provided by the investigators and all underwent passive prolonged head-up tilt testing. This modestly sympto- matic study population had a median of only three lifetime syncopal spells, and were included regardless of whether the tilt test was positive or negative.
Patients were followed for up to 1 year, during which there was a non-signif- icant increase in the number of patients who had a recurrence of syncope in the group taking atenolol compared to those taking placebo. There was no significant difference in outcome in patients who had a negative or positive baseline tilt test. The authors concluded that patients with a clinical diagno- sis of syncope, regardless of tilt-test outcome, did not benefit from attempted treatment with atenolol. Although this was a small study, there was not even a trend to benefit from atenolol.
Flevari et al. carried out a prospective, randomised crossover study of nadolol, propranolol, and placebo in 30 patients with recurrent vasovagal syncope and a positive tilt test [16]. Each treatment arm in this Latin Square design lasted 3 months, and the authors reported the number of presyncopal and syncopal spells for each observation period. Nadolol was selected because it is a hydrophilic non-selective β-blocker, while propranolol is a hydrophobic non-selective β-blocker. There was a remarkable 80–90% reduc- tion in all measures of presyncope and syncope in all three treatment arms (placebo, propranolol, and nadolol), with no significant difference among the three arms. Therefore, this small study, with short observation periods, did not detect any clinical benefit from β-blockers above that seen with placebo.
Ventura et al. [17] randomised 56 patients with recurrent syncope to treatment with β-blockers or to no treatment. In a 1-year follow-up period, syncope recurred in 71% of untreated patients but in only 29% of patients who received β-blockers. In a subsequent Cox regression analysis, only β- blocker treatment predicted the absence of syncope recurrence. The strength of the conclusions of this study is compromised by its lack of placebo control and blinding.
We carried out the Prevention of Syncope Trial, whose design was previ- ously described [18]. This randomised, placebo-controlled, double-blind trial was designed to assess the effects of metoprolol in vasovagal syncope over a 1-year treatment period. The primary hypothesis was that in patients at moderate-to-high risk for frequent recurrence of vasovagal syncope, a deci- sion to treat with metoprolol would increase the time to the first recurrence of syncope compared to treatment with placebo. The major secondary hypotheses were that metoprolol would reduce the frequency of recurrent syncopal spells as well as the frequency, duration, and severity of presynco- pal spells; and that it would improve quality of life. In addition, we hypothe- sised that older age or the need to use isoproterenol to induce syncope pre- dicts a beneficial clinical response to metoprolol.
Each pat ient had > 2 sy ncopal spells and a posit ive t ilt test.
Randomisation was stratified according to ages < 42 and ≥ 42 years. Patients received either metoprolol or matching placebo at best-tolerated doses from 25 to 200 mg daily. The main outcome measure was the first recurrence of syncope. In total, there were 208 patients, mean age 42 ± 18 years who had had a median of nine syncopal spells. This was, therefore, a group of fairly symptomatic patients. Nearly 40% had at least one recurrence of syncope during the 1-year observation period, as predicted in the initial power calcu- lations, which were based on earlier epidemiologic studies from our institu- tion [18, 19]. The likelihood of recurrent syncope was not significantly dif- ferent between groups by either intent-to-treat or on-treatment analyses.
Therefore, metoprolol was no more effective than placebo in preventing vasovagal syncope in the study population as a whole. Taken together with the results of the previous four smaller studies, metoprolol, and probably β- adrenergic receptor blockade in general, appear to be ineffective in prevent- ing vasovagal syncope in the broad patient population.
Baseline Clinical and Tilt-Test Variables
Part of the explanation for the discrepant conclusions about β-adrenergic blocker effect may relate to patient selection. There may be specific baseline variables that predict a beneficial response to β-blockers, such as age, sinus
tachycardia preceding syncope during tilt, and the requirement for isopro- terenol to induce syncope. We examined the effect of age on outcome of patients taking β-adrenergic blockers in a large population whose character- istics were previously reported [12, 19]. A multivariate analysis showed that age was an independent risk factor for the recurrence of syncope in patients taking β-blockers but not in untreated patients. The relative hazard of recur- rent syncope for patients taking β-blockers was 3.0 at age 20, 1.0 at age 42, and 0.3 at age 70. Natale et al. reported an observational study of 112 patients who were treated with metoprolol [21]. Patients responding to metoprolol were older (55 ± 12 years vs 42 ± 15 years, P < 0.05). Age > 42 years was associated with a lower likelihood of syncope on metoprolol (P < 0.02). This was an unblinded observational study, and numerous confounding factors, such as patient selection and the placebo effect, could have biased the find- ings.
Accordingly the placebo-controlled Prevention of Syncope Trial con- tained a prespecified secondary analysis of the effects of age on patient response to metoprolol [18]. Patient randomisation was stratified at age 42, which was the age of neutral response predicted from our previous unpub- lished work. In a stratified analysis, we found a highly significant reduction in the likelihood of syncope in subjects ≥ 42 years old, with no detectable benefit in younger patients. Based on these studies, it seems clear that treat- ment with β-blockers confers no benefit on younger patients, but might be beneficial in older patients. Both studies were retrospective secondary analy- ses but we still lack an adequately powered study targeting older patients.
Two studies also suggested that patients who do not faint during passive drug-free tilt tests, but do so during an isoproterenol infusion are more like- ly to benefit from β-blockers. Natale et al. [21] used multivariate analysis to show that isoproterenol-dependent syncope gave an odds ratio of 3.6 as a predictor of response to β-blockers. Leor et al. [22] reported isoproterenol- dependent syncope predicted clinical outcome with positive and negative predictive values of 94% and 37%, respectively. As both these were observa- tional, open-label, retrospective studies, we tested this hypothesis prospec- tively in the Prevention of Syncope Trial (POST) [18]. A majority of the sub- jects underwent a standardised tilt test consisting of a preliminary passive head-up tilt for 30 min followed, if necessary, by an infusion of isopro- terenol. The effect of metoprolol on eventual clinical outcome was analysed in patients who fainted during passive head-up tilt and in those who required isoproterenol to induce a vasovagal response. The need for isopro- terenol to produce a positive tilt test did not predict subsequent benefit from metoprolol. These substudy results from POST conflict with those of two previous reports [21, 22]. However, as POST was a prospective, randomised, placebo-controlled study, it seems likely that the need for isoproterenol at
baseline tilt testing does not predict eventual clinical response to metoprolol.
Finally, two groups reported observational studies showing that sinus tachycardia during head-up tilt predicts an eventual response to β-blockers.
Leor et al. [22] reported that during a follow-up period of 18 ± 6 months syncope recurred in only 9% of patients who had sinus tachycardia during the baseline tilt test compared to 54% who did not have sinus tachycardia (P
< 0.01). Development of tachycardia was a better predictor of drug efficacy than an isoproterenol-induced positive tilt test. Klingenheben et al. [22] per- formed baseline head-up tilt, then treated patients with metoprolol and tilt- ed them again. Syncope occurred during the second tilt test in only 17% of patients who had sinus tachycardia during the baseline tilt test compared to 80% who did not have sinus tachycardia (P < 0.05). These interesting pre- liminary results await confirmation in prospective randomised studies.
Patient Selection for β-Blocker Therapy
Clearly,β1-selective blockers are not effective in patients under 40 years of age, and thus cannot be recommended for this group. Given the weakness of the evidence, they should not be used generally as first-line therapy. There is some evidence from non-randomised studies and from a POST subgroup analysis that β1-selective blockers may be effective in patients older than 40 years. They might also be effective, although the data are weak, in patients who develop sinus tachycardia preceding syncope during tilt testing. It would therefore be prudent to recommend β-adrenergic blockers as therapy for the prevention of vasovagal syncope only in older patients who have already proven resistant to at least one medical attempt, or have another pos- sible indication for β-blocker treatment. For example, one might reasonably suggest that β-blockers be used for patients with both recurrent vasovagal syncope and hypertension.
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