Syncope, metoprolol, and tilt-table testing

Neurocardiogenic syncope (vasovagal syncope) is the most common cause of loss of consciousness, ranging in various studies from 18% to 58% of all syncopal events.^1-4 Tilt-table testing has been the mainstay among diagnostic modalities, along with a detailed history, and treatment with β-adrenergic blockers is commonplace. In their randomized, placebo-controlled study, Dr Baggs and colleagues examine the effectiveness of metoprolol in preventing future syncopal events in the midst of a multitude of conflicting prior studies. They found that there was no significant difference in the likelihood of recurrent syncope between the metoprolol-treated and placebo groups, even when stratified for age, in contrast with prior studies. Finally, it was found that the need for isoproterenol to provoke a positive test did not correlate with drug efficacy.

Vasovagal syncope is actually only one of many disorders of the autonomic nervous system that manifests as a syncopal or near-syncopal event. Many entities result in abnormal orthostatic regulation (these are classified as “dysautonomic syncope”), and one of the more common disorders is delayed orthostatic hypotension (or as more recently termed, pure autonomic failure).⁵ This disorder is quite prevalent, particularly among the elderly, and is perhaps one of the most underdiagnosed causes of syncope in this age group. It is often lumped together with vasovagal syncope and treated with β-adrenergic blockers, leading to ineffective treatment. This condition often coexists with hypertension and is exacerbated by vasodilators. There is often concomitant sinus bradycardia, which can lead to pacemaker implantation followed by recurrence of syncope. Orthostatic intolerance can also accompany Parkinson’s disease, multiple systems atrophy, and secondary causes such as diabetic autonomic neuropathy.⁶

Accordingly, several responses to head-up tilt testing have been characterized. These include the classic reflex neurocardiogenic response, the dysautonomic response, and the postural orthostatic tachycardia syndrome (POTS). It is the first of these responses that is referred to as vasovagal. With the other responses, β-adrenergic blockers are usually ineffective and can actually exacerbate symptoms by blunting a compensatory tachycardia. For example, patients with POTS generally experience palpitations due to sinus tachycardia and mild lightheadedness, but when this tachycardia is attenuated patients can develop near-syncope or syncope.

The current study challenges previous studies, many of which were nonrandomized, observational, or open label. It also brings attention to the fact that there are clinical entities other than reflex vasovagal syncope, and the distinctions among these entities are often blurred. As the authors point out, there is no “gold standard” tilt protocol, and this study allowed any currently used protocol, which can vary widely. With the exception of the substudy, this study did not control for the use of isoproterenol. Although only patients with positive tests were included, a positive test was not defined. In addition, widely varied false-positive rates are reported in the literature. A variety of responses and trends can be seen during tilt-table testing, and it may not be sufficient to simply refer to a test as either positive or negative. In the isoproterenol substudy, a fixed dose of 30 ng/kg/min was used, rather than a dose titrated to heart-rate response, so the exogenous catecholamine effect was likely at different levels among subjects. Finally, it is important to note that this was a study using metoprolol, a lipophilic, β₁-selective antagonist, and in at least 1 study non-selective β blockers were found to be more effective, presumably by their β₂-mediated vasoconstriction.⁷

It is clear that syncope related to the autonomic nervous system can be due to a variety of different conditions, and both testing modalities and therapeutic strategies vary widely. Each patient should be considered individually, and interpretation of tilt-table testing as well as selection of therapy needs to be individually tailored.