Metoprolol for the prevention of vasovagal syncope

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Vasovagal syncope is a distressing problem affecting approximately 40% of the population.¹ The symptom burden varies from a single syncope spell in a lifetime to daily fainting. Most patients with vasovagal syncope improve following diagnosis, but at least 30% to 40% continue to faint. Few therapies have been proven to prevent vasovagal syncope in large, randomized clinical trials. Of these, beta-blocker therapy is one of the oldest and most commonly prescribed treatments. The evidence for its effectiveness, however, is inconsistent. Results regarding efficacy were conflicting in 3 observational studies^2-4 and in 4 clinical trials.^5-8

The rationale for beta-blocker therapy is based on both physiologic and clinical observations. Sympathetic stimulation of beta-adrenergic receptors is believed to be important in the pathophysiology of vasovagal syncope.⁹ Terminal levels of norepinephrine and epinephrine are significantly higher in syncope patients compared with control subjects immediately following head-up tilt testing.¹⁰ In addition, the time to reach a positive tilt test response is reduced in patients who receive isoproterenol hydrochloride (Isuprel) compared with those exposed to passive head-up tilt.¹¹ Therefore, treatment directed at the beta receptor seems reasonable.

Studies have also assessed whether subsets of patients might be more likely to respond to beta blockers. For example, it seemed reasonable that beta-blocker treatment would be more likely to be effective in patients who required isoproterenol to faint on tilt tests compared with those who faint in response to a drug-free tilt.¹² Similarly, previous studies also suggested that those who are older may show a greater benefit from beta-blocker therapy than those who are younger.¹³ The observational nature of these studies combined with the possibility of a placebo effect prohibits conclusive evidence for this theory.

The Prevention of Syncope Trial (POST) was designed to evaluate whether: (1) treatment with metoprolol (Lopressor, Toprol) prevents vasovagal syncope, (2) the need for isoproterenol to faint identifies patients more likely to respond to metoprolol, and (3) older patients are more likely to respond to metoprolol.

Patients and methods

POST was a longitudinal, prospective, parallel-design, 2-arm, placebo-controlled, randomized clinical trial undertaken to examine the effectiveness of metoprolol, a selective beta₁ receptor blocker, in preventing vasovagal syncope.¹⁴ Patient enrollment for the trial started in 1999 and concluded in 2003. All patients were followed for a minimum of 12 months. To be eligible for the study, patients were required to have a positive tilt table test and either 3 lifetime syncope spells prior to the tilt test or at least 1 syncope spell within 6 months following a positive tilt test. Metoprolol was titrated from 50 mg twice daily up to a maximum of 100 mg twice daily. A minimum dose of 25 mg daily was given to patients who did not tolerate the initial dose. The primary outcome measure was the time to first recurrence of syncope.

Two substudies were performed. The first substudy examined the effect of age on the response to metoprolol treatment. Patients were stratified according to whether they were younger or older than 42 years of age and were randomly allocated to receive placebo or metoprolol for 1 year. The second substudy assessed whether the need for isoproterenol to elicit positive results on the baseline tilt test was useful in predicting a favorable response to metoprolol. The 151 patients who were included in the isoproterenol substudy underwent a passive head-up tilt at 80° for 30 minutes, which was followed immediately by a head-up tilt with 30 ng/kg/min of isoproterenol given intravenously for 10 minutes.

Results

P

P

A total of 208 patients were randomized in 14 centers located in Canada, Colombia, Germany, the United States, and Australia. Women made up 64% of the sample. The mean age was 42 ± 18 years. Patients had a median of 9 lifetime syncope spells and a median of 3 syncope spells in the year prior to randomization. Medication dosage between treatment and placebo groups at the time of the first syncope event was similar. The intention-to-treat analysis showed no significant difference ( = .87) in treatment failure, defined as syncope or treatment discontinuation, in those taking metoprolol (63 of 108) compared with those taking placebo (58 of 100). The number of subjects who experienced syncope was 38 of 107 with metoprolol and 35 of 97 with placebo ( = .99), as shown in Figure 1. There was no benefit from metoprolol, therefore, in preventing syncope in the population as a whole.

The substudy results were equally negative. In the on-treatment analysis, the need for isoproterenol to evoke a positive tilt test did not portend any later benefit from metoprolol, as shown in Figure 2. When groups were compared on the basis of age (those older or younger than 42 years), there was no difference between patients in the metoprolol and placebo groups regarding the median duration or frequency of spells. There was only a nonsignificant trend for improvement shown for older patients taking metoprolol. In these individuals, the number of syncope episodes was 16 of 50 for the metoprolol group compared with 15 of 42 for the placebo group. In younger patients, treatment failure was similar for the metoprolol and placebo groups.

Discussion

The POST showed that patients with vasovagal syncope received no benefit from metoprolol. For patients in both the treatment and control groups, there was no significant difference in the occurrence of syncope after 1 year. These findings are in agreement with some^2,3,6,7 but not all studies^4,5 that have investigated the effectiveness of beta-blocker therapy in reducing the frequency of syncope symptoms. For example, in a previous nonrandomized trial of 118 syncope patients, a beneficial effect of beta blockers was found following 28 months of therapy.⁴ In another smaller randomized trial of 42 patients, 71% of those taking atenolol versus 29% in the placebo group reported a treatment benefit.⁵ These earlier studies were either observational and open-label, or consisted of a small population studied for a brief time. On the whole, there is little evidence that beta blockers help patients with vasovagal syncope.

We also found little evidence that subsets of patients who might respond to treatment could be identified. For example, the need for isoproterenol to evoke a vasovagal response during tilt testing was not useful in predicting a favorable response to metoprolol. This is in contrast to results of other studies that suggested this as a predictor of response to beta-blocker treatment.^12,13 Our inability to confirm these results may be attributable to the differences in study design; the 2 earlier studies were single-centered, ob­servational, and open-labeled. Similarly, we could not show that metoprolol was more effective in patients aged 42 years and older. Thus, older age was not predictive of a beneficial effect from metoprolol.

This study has 2 major implications. First, metoprolol—and possibly other beta-adrenergic blockers—have no role as first-line therapy in the majority of patients with vasovagal syncope. Second, the failure to show an effect with metoprolol should prompt a reevaluation of current theories of syncope physiology that feature a role for beta-adrenergic stimulation. However, even though POST was a negative study, there were some potential limitations. Meto­prolol was possibly ineffective in preventing vasovagal syncope because it is either hydrophobic or selective for the beta₁ receptor. This raises the possibility that a less selective beta blocker might be effective. Similarly, only patients who had had a positive tilt test were included in the study. Tilt tests are well known to have imperfect sensitivity and specificity, and a broader population of patients with vasovagal syncope may have responded differently.¹⁵

Conclusion

The POST assessed whether beta-blocker treatment with metoprolol decreased the risk of syncope in patients with vasovagal syncope. Metoprolol was not shown to be effective in reducing the burden of syncope symptoms. Furthermore, neither age nor response to isoproterenol was useful in selecting which patients might benefit from metoprolol.