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The natural history of carotid sinus syncope and the effect of cardiac pacing

Michele Brignole, Carlo Menozzi
DOI: http://dx.doi.org/10.1093/europace/euq516 462-464 First published online: 29 March 2011

This editorial refers to ‘The role of pacemaker in hypersensitive carotid sinus syndrome’ by R. Lopes et al., on page 572.

Despite the fact that permanent cardiac pacing for patients affected by cardioinhibitory carotid sinus syncope (CSS) is ranked as a class I or class IIa indication by the most recent European and American guidelines,13 the evidence supporting these recommendations is weak (level of evidence B or C), due to the lack of large randomized trials. The reason is that pacemaker implantation for CSS is a common clinical practice accepted by most cardiologists since the pioneering phase of cardiac pacing in the early 1970s4,5 when the methodology of evidence-based medicine was not as rigorous as today. Many studies were observational without a control group and only two small trials were randomized with no treatment control arm.6,7 On the other hand, the natural history of patients with recurrent severe symptoms is not well known because these patients are usually treated, thus lacking an estimation of the expected benefit of pacing therapy. Finally, recent reports8,9 raise some concerns regarding the specificity of the current criteria for carotid sinus hypersensitivity (defined as ≥3 s asystole and/or fall in systolic blood pressure of ≥50 mmHg) as they are arbitrary and frequently observed in the general older population. A recent randomized trial failed to show any benefit of cardiac pacing in patients with carotid sinus hypersensitivity and unexplained recurrent falls.10

Therefore, a question arises as to what the real usefulness of pacing therapy is and which patients need this therapy. Lopes et al.11 performed a retrospective analysis of 138 patients who were followed-up for ∼5 years, thus adding an important contribution to the effect of cardiac pacing in CSS patients. Taking into account this study, in this article we tried to summarize the current knowledge about pacing therapy of this old syndrome.

We performed a MedLine search among peer-review journals in the English language for articles dealing with the natural and unnatural history of CSS; we excluded case reports. We found 12 studies6,7,1120 which reported sufficient follow-up data for analysis. In total, we were able to analyse the natural history of 305 patients and the effect of cardiac pacing in another 601 patients affected by severe recurrent syncope. The results are shown in Figure 1. The studies were largely heterogeneous in regard to the selection of patients, duration, and position (supine or standing) of the carotid sinus massage, criteria for identification of mixed forms, and different mode of pacing (single- vs. dual-chamber). Despite these limitations, the figure suggests that syncopal recurrence rates during follow-up with pacing ranged between 0 and 20%, whereas the recurrence of syncope was always higher in untreated patients, with the rates between 20 and 60%.

Figure 1

Syncope recurrence rate reported in 12 studies of untreated and treated CSS patients plotted against the duration of the follow-up. In total, the studies accounted for 305 untreated and 601 treated patients.

The specificity of carotid sinus massage increases if reproduction of spontaneous syncope during carotid massage is a requisite for positivity of the test. The so-called ‘Method of Symptoms' requires a longer duration of the massage, in general for 10 s. The recent ESC guidelines on syncope2 recommend that CSS be diagnosed if spontaneous symptoms are reproduced together with the documentation of an abnormal reflex. Figure 2 shows the results of metanalysis of three controlled studies6,7,15 in which carotid sinus massage was performed according to the ‘Method of Symptoms'. The studies were sufficiently homogeneous (Mantel–Haenszel heterogeneity test: P = 0.39). The mean length of the pause induced by the carotid sinus massage ranged from 5.2 to 7.3 s. During a mean observation period of up to 3.3 years, syncope recurred in 9% of patients treated with a pacemaker and in 38% of control untreated patients. The cumulative odds ratio was 0.15 (95% CI 0.06–0.36). Finally, in a registry of 169 consecutive patients treated with permanent pacemaker in our departments from 1988 to 1994,19 the actuarial estimate of syncopal recurrence was 7% at 1 year, 16% at 3 years, and 20% at 5 years.

Figure 2

Relative risk reduction of syncope recurrence after pacemaker therapy in three controlled studies in which CCS was diagnosed by means of the ‘Method of Symptoms'. PM, pacemaker; n/N, patients with syncope recurrence/total patients.

Cardiac pacing seems less effective in preventing pre-syncope than syncope. Indeed, pre-syncope and minor symptoms have been reported in 25,6 27,7 and 43%20 patients after pacemaker implant. Moreover, two randomized trials6,7 failed to show the superiority of cardiac pacing compared with no pacing in reducing the rate of pre-syncope. It seems that pacing transforms syncope to pre-syncope probably because it is effective in counteracting the asystolic reflex that causes syncope but it is less effective against the vasodepressor component of the reflex which is frequently associated even with the so-called dominant cardioinhibitory forms. Lopes et al.11 reported a lower 6% rate of pre-syncope after pacing therapy. The authors attribute this contrasting finding to the lower number of mixed CSS patients and the higher utilization of dual-chamber pacemaker in their population.

Two variables are well known to hamper the efficacy of pacing therapy in CSS patients. These are mixed forms of syncope and VVI pacing.

Owing to the lack of a standardized methodology of execution of the carotid sinus massage, the prevalence of mixed forms shows a great variability among different studies, being higher in those studies in which the massage was prolonged ≥10 s, it was performed in standing position and the magnitude of the vasodepressor component was fully evidenced after suppression of the cardioinhibitory component by i.v. atropine.2,6,21 Conversely, the prevalence of mixed forms was probably underestimated in those studies in which a less rigorous methodology was applied. Nevertheless, the presence of an associated vasodepressor reflex, either documented by the massage itself or by a positive response during tilt table testing, increased the risk of syncope recurrence after pacemaker implant. In an earlier study in which carotid sinus massage was performed both in supine and in standing positions according to the ‘Method of Symptoms',21 we showed that syncope or pre-syncope recurred in 12% of patients affected by the dominant cardioinhibitory form and in 58% of those affected by the mixed form (P = 0.04). Lopes et al.11 showed that mixed CSS was the only independent predictor of symptom recurrence in total population (HR = 2.8; P = 0.017). However, in a randomized trial,6 cardiac pacing was proved to be effective compared with no treatment also in the subgroup of patients with a mixed form, thus supporting its use in mixed CSS. In the study of Gaggioli et al.,19 patients with CSS and a positive response during the head-up tilt test had a 2.7-fold increased risk of syncopal recurrence: syncope occurred in 15 (21%) of 70 patients who had a positive response to the head-up tilt test, and in 9 (9%) of 99 patients who had a negative response (P = 0.02). Lopes et al.11 did not confirm the above result, although they found an association between mixed form of CSS and positive response to tilt table testing.

The optimal pacing mode is dual-chamber pacing. In an acute intra-patient study,22 VVI pacing mode caused a significant deterioration compared with DVI pacing characterized by a greater fall in systolic blood pressure (59 vs. 37 mmHg, P = 0.001) and a higher rate of symptom persistence (91 vs. 27%, P = 0.008). In a 2-month randomized cross-over study of DVI vs. VVI mode in 23 patients affected by mixed CSS,23 syncope occurred in 0 vs. 13% (P = 0.25), pre-syncope in 48 vs. 74% (P = 0.04); DVI was the mode preferred by 64% of patients, whereas the remaining 36% did not express any preference (P = 0.001). In the Westminster study,24 of the 202 patients, syncope recurred in 9% of DDD paced patients, while in VVI paced patients the rate of recurrence was twice as high (18%).

Conclusion and perspectives

Despite the lack of large randomized controlled trials, the review of the literature supports the benefit of cardiac pacing in patients affected by CSS and justifies a class I recommendation even with a level of evidence B. Compared with the natural history of CSS, we can expect that patients who receive a pacemaker will have ∼75% reduction in the recurrence of syncopal episodes. However, syncopal recurrences are still expected to occur in up to 20% of paced patients within 5 years. Mixed forms and VVI mode hamper the efficacy of pacing therapy. In addition, cardiac pacing is not effective in preventing pre-syncope.

We do not think that a large randomized trial would change this knowledge too much. Rather, since CSS does not affect survival, the reduction in burden of syncope, i.e. number of syncopal episodes per patient per year, and the reduction of related morbidities, i.e. trauma secondary to syncope, should probably describe better the benefit of cardiac pacing therapy. These outcome measures have not yet been used in CSS studies. Future studies should probably focus on these outcomes in order to elucidate better the benefit of pacing therapy.

Conflict of interest: none declared.

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of Europace or of the European Society of Cardiology.

References