Where We Were
In the late 1980s and early 1990s, we had already achieved a high standard of implant techniques and devices were well constructed with rare failure.2,3 Langenfeld et al. found a 3.5 % recurrence of syncope in AVB (Second and Third Degree) in 5 years; a question of reflex syncope did not arise.2
However, by 1991, Pavlovic et al., in a detailed analysis of 46 VVI- paced patients with recurrent syncope, found only two with exit block and an additional patient with sensing failure, which was unlikely to have been the cause of syncope.3 Thus, 4.3 % had pacing failure as the cause of syncope, while at the same time 8.6 % had orthostatic hypotension and 36.9 % were tilt positive. These tilt findings were invoked as explaining the syncope sustained by these patients but no explanation was found in another 30.4 %. They concluded that reflex syncope may be the most common cause of recurrent syncope in paced patients, with pacing hardware failure being quite rare.
This theme was reiterated by Sgarbossa et al. in a large series of 507 sick sinus syndrome patients from the Cleveland Clinic.4 In 62 ± 38 months of follow-up, they found syncope recurrence in 3 % at 1 year, 8 % at 5 years and 13 % predicted at 10 years. Their analysis of the causes of syncope indicated lead or pacemaker failure in 6.5 %, vasovagal in 18 %, orthostatic hypotension in 25.5 %, unexplained in 29.5 %, atrial tachyarrhythmias in 11.5 % and ventricular tachyarrhythmias in 5 %. They concluded that autonomic disturbances were the main contributors to syncope recurrence and pacing hardware failure was uncommon. Such conclusion was reached at a time when syncope in sick sinus syndrome was considered to be sinus arrest without effective escape mechanism rather than reflex in origin. However, Sgarbossa et al. noted that syncope prior to implant was the only reliable predictor of syncope post-implant.
Helguera et al. focused on endocardial lead malfunction with a broad definition including exit block in 1,474 patients from the Cleveland Clinic.5 In 33 ± 32 months follow-up, only 54 patients had lead malfunction and 37 % had either syncope in 7 or pre-syncope in 13 patients. These symptomatic lead malfunctions were more common in ventricular leads and in those who had severe symptoms pre-implant. No deaths were attributed to lead malfunction. The authors recommended closest attention to those patients with severe presenting symptoms and pacemaker dependency.
A PubMed search shows that little has been published on these issues between the mid-1990s and the recent past.
Where We Are Now
New information on patients with sick sinus syndrome emerged from the DANPACE study, in which 1,415 patients were followed for 5.4 years.6 Syncope occurred in 17.5 % of patients after pacing; of those with AAIR pacing, 19 % had syncope whereas the figure was 15.8 % in DDDR-paced patients. Predictors for syncope were: for age 0–39 years, hazard ratio (HR) 2.9; >80 years, HR 1.4; and syncope pre-implant, HR 1.8. Patients with syncope after pacing suffered a higher mortality (HR 1.6). The authors of this highly regarded trial concluded that syncope after pacing in sick sinus syndrome is common, carries an increased mortality and is multifactorial. It would appear that reflex syncope may have been an important factor because syncope in the general population and in their paced group share a bimodal distribution curve with respect to age. Given the longer follow-up in these patients, they have confirmed the earlier findings in much smaller populations. The increased mortality raises some anxiety, but may be explained by comorbidities rather than by a direct effect of syncope itself.
It is well known that vasovagal syncope recurs and risk of recurrence increases with more historical attacks, approaching 50 % after six lifetime events.7 It is therefore likely that a patient who has experienced many attacks in the past will have recurrences after pacing, even if the clear indication for pacing was not reflex syncope. Further, if the indication for pacing is reflex syncope, recurrence is highly likely. Much more has been learned recently in the latter group of patients. It is also necessary to restate, in this context, that reflex syncope has two components, bradycardia/asystole and vasodepression. The former of these may be well treated by a pacemaker but vasodepression is uninfluenced by pacing. Thus, the blood pressure may fall profoundly with a maintained heart rate by a pacemaker.
The ISSUE-3 study was to the first to demonstrate that pacing is significantly effective in older vasovagal syncope patients.8 However, the results were tempered by the recurrence of syncope within 2 years of 25 % in those paced versus 57 % in those unpaced (P< 0.04). Reassurance was garnered from the nearly 18 % syncope recurrence in sinus node disease reported from Denmark.6 Once the ISSUE-3 randomised controlled trial data were combined with the ISSUE-3 registry including patients (or physicians on their behalf) who refused pacing or the concept of randomisation at the point of randomisation, the importance of the tilt result was seen to be in terms of the outcome.9 Tilt-negative patients (with implantable loop recorder (ILR) showing asystole in a spontaneous attack and otherwise clinically identical to those who were tilt positive with the same ILR findings) did well with pacing – 5 % recurrence of syncope in 21 months. Tilt-positive patients did no better than if they had no pacemaker, with 55 % recurrence rate of syncope.9
This finding at first appeared counter-intuitive, but analysis of the reported results of tilt testing over 28 years since the test was introduced for diagnosis of syncope pointed to an explanation.10,11
The hypothesis suggests that tilt testing merely reveals a hypotensive or vasodepressive tendency and no longer should be termed diagnostic because this tendency is hidden by severe cardioinhibition. So a tilt-positive patient with severe cardioinhibition will not readily reveal accompanying vasodepression. Once paced, the pacemaker is expected to prevent cardioinhibition but cannot combat vasodepression, rendering recurrence of syncope likely. The argument was strengthened by the literature on carotid sinus syndrome (CSS), a similar reflex syncope, where those CSS patients with a positive tilt test had 2.7 times the recurrence rate of those who were tilt negative.12 These data have been further supported by a later report from the same group, with more patients showing very similar findings.13 The Italian SUP-2 study, including 10 Italian centres, recently reported a decision algorithm for older patients presenting clinically likely reflex syncope.14 The decision-tree demanded carotid sinus massage (CSM) according to the ‘method of symptoms’ as a first test. Those who had positive CSM were paced, those negative proceeded to a tilt test and, if positive with asystole, were also paced. Those who were tilt negative proceeded to ILR and, if positive with asystole in a spontaneous attack, were then paced. This algorithm permitted assessment of those who were tilt negative and ILR positive and it has been shown separately from the ISSUE-3 study that these patients do well with pacing with a very low syncope recurrence rate in 13 months of follow-up.
Thus, in reflex syncope, both vasovagal and CSS, recurrence of syncope can be predicted after pacing by the tilt test result. The hypothesis also addressed the frequent question in this age group of hypertension and its treatment.11 Hypertension in these patients is often aggressively treated, producing side effects of episodes of orthostatic hypotension. It is considered likely that some of these patients, as a result, start to experience vasovagal syncope or it recurs (patients having sustained a few attacks in youth). Great care in administering hypotensive medication must now be the norm for these patients and randomised controlled trials are indicated. This group of patients should be considered at risk for syncope recurrence similarly to those who are tilt positive as in the ISSUE-38,9 and SUP-214 studies.
Syncope in paced patients has become much more clear now. It is either rarely due to pacing hardware malfunction or much more commonly due to reflex syncope occurring spontaneously or favoured by hypotensive treatment of hypertension.