SYNCOPE
Pacing for neurally mediated syncope: is placebo powerless?
1 Department of Cardiology, Ospedali del Tigullio, Via don Bobbio, 16033 Lavagna, Italy; 2 Department of Cardiology, Royal Brompton and Harefield Hospitals, London, UK
Manuscript submitted 24 August 2006. Accepted after revision 16 November 2006.
* Corresponding author. Tel: +39 0185 329569; fax: +39 0185 306506. E-mail address: mbrignole{at}asl4.liguria.it
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Background After two recent controlled trials failed to prove superiority of cardiac pacing over placebo in patients affected by neurally mediated syncope, a widely accepted opinion is that cardiac pacing therapy is not very effective and that a strong placebo effect exists.
Aim To measure the effect of placebo pacing therapy.
Method and results We compared the recurrence rate of syncope during placebo vs. no treatment in controlled trials of drug or pacing therapy. Syncope recurred in 38% of 252 patients randomized to placebo pooled from five trials vs. 34% of 881 patients randomized to no treatment pooled from eight trials. The corresponding recurrence rate with active cardiac pacing was 15% in 203 patients from six trials.
Conclusions Placebo is not an effective therapy for neurally mediated syncope. Different selection criteria in patients who are candidates for cardiac pacing—for example, presence, absence, or severity of the cardioinhibitory reflex may separate positive from negative trials.
Key Words: Syncope, Neurally mediated syncope, Pacemaker therapy, Electrocardiographic monitoring, Implantable loop recorder
Convictions are more dangerous enemies of truth than lies Friedrich Nietzsche
The efficacy of pacemaker therapy for prevention of syncopal recurrences in patients affected by neurally mediated syncope was questioned after two recent controlled trials failed to prove superiority of cardiac pacing over placebo of unselected patients with positive tilt testing.1
,2 In these studies, patients in the control arm had received a pacemaker implant that was switched off, thus acting as a placebo. Three previous open studies, that had given positive results,3–5 differed from the above because the patients in the control arm did not receive a placebo pacemaker. Based on this fact, a widely accepted opinion is that pacemaker therapy is not very effective for neurally mediated syncope and that a strong placebo effect exists. In the era of evidence-based medicine, the blind vs. unblind design theory is so attractive that it has overshadowed other alternative explanations.
We disagree with this interpretation of results. We believe that use of placebo as treatment cannot be so powerful as to cancel the positive effects of pacemakers shown in the previous studies. For the following reasons:
- Placebo does not seem to be an effective therapy for neurally mediated syncope. Indeed, the recurrence rate observed in the placebo arm of the two randomized placebo-controlled dual-chamber pacemaker trials1,2 was 38 and 40%, and the recurrence rate observed in the placebo arm in three randomized placebo-controlled drug trials was 24, 36, and 46%.6–8 Overall, these percentages are similar to those of the natural history of 881 patients with untreated neurally mediated syncope of similar severity:3–5,9–12 38% vs. 34% (Table 1).
- Moreover, placebo efficacy has been assessed in a systematic review of clinical trials in which patients were randomly assigned to either placebo or no treatment.13 The authors found little evidence that placebos had powerful clinical effect. In particular, when binary subjective outcomes were evaluated, such is the presence or absence of syncope recurrence, the placebo effect accounted for a non significant 5% reduction in events in pooled data of 1928 patients from 23 studies. That is the likely difference in results to be expected in neurally mediated syncope trials with and without a placebo control arm.
,2 was not that the placebo was effective but rather the active pacemaker was less effective than expected. Indeed, the recurrence rates in the active pacemaker arm were actually 32 and 50%, i.e. much higher than that of the other trials (Table 2).
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If placebo effect is powerless what is the true reason for the failure to show a benefit of pacing therapy in some trials but not in others?
Different selection criteria are probably the most important reasons. Recent data from implantable loop recorder studies11,12 showed that the mechanism of spontaneous syncope was heterogeneous with bradycardia or asystole accounting for only approximately one-half of the syncope events. While pacing may be potentially effective when asystole is documented at the time of syncope, there is no rationale for the use of pacing in patients without documented bradyarrhythmias. Indeed, in the ISSUE 2 study,11 the 1-year syncopal recurrence rate was of 5% in those patients receiving a pacemaker after documentation of an asystolic spontaneous syncope (compared with 41% recurrence rate in the non-asystolic group).
In the most positive studies, i.e. VASIS4 and SYDIT5 trials, the patients had a positive cardioinhibitory response during tilt testing, whereas this was not the case in VPS 1 and 21,3 and only about a half in SYNPACE.2 We know from the ISSUE 2 study14 that an asystolic response during tilt testing has a 80% positive predictive value that spontaneous syncope detected by implantable loop recorder is also asystolic. In other words, the patients with asystolic tilt response are likely to benefit more from pacing therapy because their spontaneous syncope is also asystolic. Selection based on a positive cardioinhibitory response during tilt testing limits greatly the number of potential candidates for pacemaker therapy since a cardioinhibitory response occurs in about 10% of patients undergoing passive or nitroglycerin tilt testing (20% of positive). For example, in VASIS4 only 42 patients—all with a cardioinhibitory response to tilt testing—were enrolled in 18 centres in a 6-year period; conversely, in VPS-2, 100 patients—most without a cardioinhibitory response to tilt testing–were enrolled in 15 centres in 3.5 years. Thus, the VASIS patients were probably more highly selected than VPS 2 patients. The new strategy assessed in the ISSUE 2 study11 based on a relatively straightforward initial clinical evaluation, early application of an implantable loop recorder and therapy delayed until documentation of the apparent basis of syncope, allows great enlargement of the number of candidates for pacing while maintaining the strict inclusion criteria concerning cardioinhibitory reflex.
Apart from the cardioinhibitory reflex, there were other important differences in the selection of patients that can explain the different results of the trials, namely different patients’ characteristics [for example, the mean age in VASIS4 was 64 years, whereas it was 50 years in VPS-21], the non-uniform definition of neurally mediated syncope and the different diagnostic work-up. Finally, some methodological weaknesses could also have had a role, such as, for example, the small population of all the studies and the lack of true blindness in all the trials.
Principles of evidence-based medicine rank most highly double-blind randomized clinical trials. Randomized clinical trials bring a final quantification even if they offer little scientific novelty in themselves. Before an idea can be confirmed or quantified it must have a convincing scientific background. We think that the above considerations re-evaluate the likely efficacy of pacemaker therapy for the prevention of asystolic neurally mediated syncope and therefore justify the execution of a formal randomized clinical trial. In this issue of the journal, the rationale and the study design of ISSUE 3, a multi-centre, prospective, randomized controlled double-blind study are presented.15 If the results of that study confirm the study hypothesis, pacemaker therapy will become established for cardioinhibitory neurally mediated syncope.
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[15] ISSUE 3: International Study on Syncope of Uncertain Etiology 3. Pacemaker therapy for patients with asystolic neurally-mediated syncope. ClinicalTrials.gov 2006 Identifier: NCT 00359203.
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