Efficacy of the Biosync trial, or when facts prompt a reconsideration of theories

This commentary refers to the article ‘Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole’, by M. Brignole et al., https://doi.org/10.1093/eurheartj/ehaa936; ‘Effectiveness of Closed Loop Stimulation pacing in patients with cardio-inhibitory vasovagal reflex syncope is questionable’, by W. Wieling and D.L. Jardine, https://doi.org/10.1093/eurheartj/ehab157; and the discussion pieces ‘Efficacy of the Biosync Trial: the information published from this trial to date is not sufficient to change theory’, by W. Wieling, https://doi.org/10.1093/eurheartj/ehab379 and ‘About syncopal recurrences in Biosync trial’, by M. Brignole, https://doi.org/10.1093/eurheartj/ehab383.

The Biosync trial described the effectiveness of cardiac pacing in patients over 40 years of age with unpredictable severe recurrent reflex syncope and tilt-induced asystole.¹ Wieling and Jardine² stated several reasons why they questioned the effectiveness of pacing in this trial. While most of their arguments were rebuked convincingly,³ one was not addressed.

Wieling and Jardine stated that the definition of asystole during a tilt table test in the Biosync study differed from that of the VASIS 2B classification: asystole in the Biosync study was noted ‘regardless of when heart rate fell with blood pressure’. They added that this ‘is relevant because it meant that patients with asystoles occurring after syncope were included in the Biosync study’, in addition to those with early asystole. They did not refer to the source of this ‘late asystole’ concept though; the source study, investigating tilt-induced vasovagal syncope, defined late asystole more precisely as starting 3 s before the onset of loss of consciousness, or later.⁴ Late asystole occurred in one-third of subjects, in whom pacing may have had little benefit as it would probably start too late to prevent syncope.⁴ However, pacing with the Closed Loop System (CLS) used in Biosync begins well before asystole which may have offered some benefit.

While we stress the importance of the timing of asystole with regard to the onset of loss of consciousness, the presence of late asystole cannot be assessed in all centres, so excluding patients with late asystole from a pacing study is at present impractical. The inclusion of patients with late asystole in the Biosync study does not invalidate the results. It may have reduced the chance of finding a positive result of pacing, so the actual positive effect argues for a benefit of pacing in those patients over 40 years of age with ‘early asystole’.

We do not agree with Wieling and Jardine that plausibility needs to be backed up by theory; the factual benefit of pacing in the Biosync study suggests that it may be the theory that needs reconsideration, as outlined previously.⁵ The Biosync facts suggest the theory that pacing works well in those elderly with vasovagal syncope who have strong cardioinhibition and some vasodepression, because relatively intact venous return then allows pacing to increase cardiac output. Unfortunately, this combination is probably rare in the elderly.

In any case, the Biosync facts allow improved care for these highly symptomatic patients.

Conflict of interest: none declared.

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