Refractory Vasovagal Syncope Research Articles

Refractory Vasovagal Syncope Despite Tilt Training: Should Paroxetine be Included in the Treatment?

Refractory Vasovagal Syncope Despite Tilt Training: Should Paroxetine be Included in the Treatment?

Cardioneuroablation for severe neurocardiogenic syncope

Introduction and objectivesCardioneuroablation (CNA), a technique based on radiofrequency ablation of cardiac vagal ganglia, was developed to treat recurrent vasovagal syncope (VVS) with a predominant cardioinhibitory component, as an alternative to pacemaker implantation. The aim of our study was to evaluate the safety and success rate of CNA guided by extracardiac vagal stimulation in patients with highly symptomatic cardioinhibitory VVS. MethodsProspective study of patients who underwent anatomically guided CNA at two cardiology centers. All patients had a history of recurrent syncope with a predominant cardioinhibitory component and refractory to conventional measures. Acute success was determined by the absence or significant reduction of cardiac parasympathetic response to extracardiac vagal stimulation. The primary endpoint was the recurrence of syncope during follow-up. ResultsIn total, 19 patients (13 males; mean age 37.8±12.9 years) were included. Ablation was acutely successful in all patients. One patient had a convulsive episode after the procedure, which was deemed unrelated to the ablation, requiring admission to intensive care but without sequelae. No other complications occurred. At a mean follow-up of 21.0±13.2 months (range 3–42 months), 17 patients remained free of syncope. The remaining two patients had recurrence of syncope and, despite undergoing a new ablation procedure, required pacemaker implantation during follow-up. ConclusionCardioneuroablation, confirmed by extracardiac vagal stimulation, appears to be an effective and safe treatment option for highly symptomatic patients with refractory VVS with a predominant cardioinhibitory component, providing a new potential approach as an alternative to pacemaker implantation.

Cardioneuroablation for vasovagal syncope: Asystematic review and meta-analysis.

Cardioneuroablation (CNA) has emerged as promising therapy for patients with refractory vasovagal syncope (VVS). The purpose of this study was to provide a freedom from syncope estimate for CNA, including subgroup analysis by method and target of ablation. A systematic search was performed in MEDLINE and EMBASE according to the PRISMA guidelines until February 14, 2022. Observational studies and clinical trials reporting freedom from syncope were included. Meta-analysis was performed with a random-effects model. A total of 465 patients were included across 14 studies (mean age 39.8 ± 4.0 year; 53.5% female). Different techniques were used to guide CNA: 50 patients (10.8%) by mapping fractionated electrograms, 73 (15.7%) with the spectral method, 210 (45.2%) with high-frequency stimulation, 73 (15.7%) with a purely anatomically guided method, and 59 (12.6%) with a combination. The target was biatrial in 168 patients (36.1%), left atrium only in 259 (55.7%), and right atrium only in 38 (8.2%). The freedom from syncope was 91.9% (95% confidence interval [CI] 88.1%-94.6%; I2 = 6.9%; P = .376). CNA limited to right atrial ablation was associated with a significant lower freedom from syncope (81.5%; 95% CI 51.9%-94.7%; P <.0001) vs left atrial ablation only (94.0%; 95% CI 88.6%--6.9%) and biatrial ablation (92.7%; 95% CI 86.8%-96.1%). Subgroup analysis according to the technique used to identify ganglionated plexi did not show any significant difference in freedom from syncope (P = .206). This meta-analysis suggests a high freedom from syncope after CNA in VVS. Well-designed, double-blind, multicenter, sham-controlled randomized clinical trials are needed to provide evidence for future guidelines.

Syncope recurrence and long-term heart rate variability after cardioneuroablation for vasovagal syncope: a systematic review and meta-analysis

Abstract Background Cardioneuroablation (CNA) has emerged as a promising therapy in patients with refractory vasovagal syncope (VVS). Well-designed randomized clinical trials (RCT) are lacking. Purpose To provide an estimate of the procedural success rate of CNA, including subgroup analysis by method and target of ablation, as well as serial measurements of autonomic tone after CNA with heart rate variability (HRV). Methods A systematic search of studies was performed in MEDLINE and EMBASE according to the PRISMA guidelines, from inception to 14 February 2022. Observational studies and clinical trials reporting success rates were included. Quality assessment was performed using the CONSORT and STROBE recommendations. The primary outcome was freedom from syncope after CNA. Meta-analysis was performed with a random-effects model. The secondary outcome was serial HRV analysis (heart rate, SDNN, rMSSD and LF/HF ratio) analysed with one-way ANOVA with Bonferroni's correction for multiple testing. Results A total of 465 patients were included across 14 studies (mean age 40±4 years; 54% females). All included studies were of intermediate quality (median 17, IQR 16–18). Procedural approach to CNA was variable: 50 patients (10.8%) by mapping of fractionated electrograms, 73 patients (15.7%) with the spectral method, 210 (45.2%) with high frequency stimulation, 73 (15.7%) with a purely anatomically guided method, and 59 patients (12.6%) with a combination. The target was bi-atrial in 168 patients (36.1%), left atrium only in 259 patients (55.7%), and right atrium only in 38 patients (8.2%). The freedom from syncope was 91.9% (95% CI 88.1–94.6%; I2=6.9%, p=0.376; Figure 1). CNA limited to right atrial ablation was associated with a significantly lower success rate (p&amp;lt;0.0001; 81.5%, 95% CI 51.9–94.7%) versus left atrial ablation only (94.0%, 95% CI 88.6–96.9%) and bi-atrial ablation (92.7%, 95% CI 86.8–96.1%). Subgroup analysis according to the technique used to identify GPs did not show any significant difference in success rate (p=0.206). Ten studies (n=317, 68.2%) reported at least one HRV parameter. Results are presented in Figure 2 with the mean and standard deviations. There were significant increases in heart rate, and significant decrease in SDNN, rMSSD and LF/HF ratios for each follow-up timepoint available (p&amp;lt;0.0001 for all analyses). Recovery of these parameters was observed in 2 studies, but these were not associated with an increased risk in syncope recurrence. Conclusion This meta-analysis suggests a high procedural success rate of CNA in VVS of 92%. CNA induces long-term changes in HRV, however some studies reported recovery of these parameters without an association with syncope recurrence. Therefore, HRV changes may not be an appropriate surrogate endpoint for clinical response. Well-designed double-blind, multi-center sham controlled RCTs are needed to provide evidence for future treatment guidelines. Funding Acknowledgement Type of funding sources: Foundation.

Clinical Efficacy of Catheter Ablation in the Treatment of Vasovagal Syncope.

Catheter ablation of ganglionated plexi (GPs) performed as cardioneuroablation in the left atrium (LA) has been reported previously as a treatment for vasovagal syncope (VVS). However, the efficacy and safety of catheter ablation in the treatment of VVS remains unclear. The objective of this study is to explore the efficacy and safety of catheter ablation in the treatment of VVS and to compare the different ganglion-mapping methods for prognostic effects. A total of 108 patients with refractory VVS who underwent catheter ablation were retrospectively enrolled. Patients preferred to use high-frequency stimulation (HFS) (n = 66), and anatomic landmark (n = 42) targeting is used when HFS failed to induce a positive reaction. The efficacy of the treatment is evaluated by comparing the location and probability of the intraoperative vagal reflex, the remission rate of postoperative syncope symptoms, and the rate of negative head-up tilt (HUT) results. Adverse events are analyzed, and safety is evaluated. After follow-up for 8 (5, 15) months, both HFS mapping and anatomical ablation can effectively improve the syncope symptoms in VVS patients, and 83.7% of patients no longer experienced syncope (<0.001). Both approaches to catheter ablation in the treatment of VVS effectively inhibit the recurrence of VVS; they are safe and effective. Therefore, catheter ablation can be used as a treatment option for patients with symptomatic VVS.

Pacing for vasovagal syncope: Tips for use in practice.

Vasovagal syncope (VVS) continues to be the most frequent cause of syncope in all age groups. Recent randomized double-blinded trials (RCTs) provide further support for pacing in selected cases of patients with recurrent refractory VVS with significant cardio-inhibitory response either documented spontaneously or induced during head-up tilt testing (HUTT). Cardiac pacing is the only therapy of proven efficacy for the predominant cardio-inhibitory phenotype of vasovagal (reflex) syncope; however, several questions regarding the best candidates remain. The current review focuses on practical tips for use of cardiac pacing in practice.

Effect of psychotherapy on recurrence of events and quality of life in patients with vasovagal syncope

Emotional distress is related to recurrence of syncope compromising patient's quality of life (QoL). The aim of this study was to determine if weekly sessions of psychotherapy reduce recurrence of events and improve QoL by SF-36 among patients with refractory vasovagal syncope. A randomised controlled pilot trial including 10 patients with recurrent vasovagal syncope and positive tilt table test was conducted. Known cardiac disease and ongoing psychotherapeutic interventions were the main exclusion criteria. All patients received standard of care treatment. Additionally, after randomisation, half of the patients underwent weekly sessions of psychotherapy for 12 months. Analysis of recurrence of events and QoL showed no significant change in the control group but, in the intervention group, there was a significant reduction in the rate of near-syncope episodes per month (5.7 ± 1.4 × 1.7 ± 1.0; P < 0.01), syncope in 1 year (4.6 ± 0.9 × 1.0 ± 0.7; P < 0.01) and a significant improvement in the overall assessment of QoL (44.1 ± 10.0 vs. 70.3 ± 10.3, P < 0.01). In conclusion, patients with refractory vasovagal syncope undergoing regular psychotherapeutic intervention had less recurrence of events and improved their quality of life in 1 year.Trial Registration: ClinicalTrials.gov number, NCT04252729.

Cardiac deceleration capacity as an indicator for cardioneuroablation in patients with refractory vasovagal syncope.

Cardioneuroablation is an emerging therapy for refractory vasovagal syncope (VVS), but the standard enrollment criterion is undetermined. Mainstream studies empirically enroll patients with cardioinhibitory and mixed types of VVS on the basis of the head-up tilt (HUT). However, a variety of studies have shown that the results of HUT exhibit unpleasant reproducibility. We aimed to investigate the prognostic value of baseline deceleration capacity in patients with refractory VVS after cardioneuroablation. This study enrolled 123 patients (mean age 42.2±17.7 years; 54 males [43.9%]) with the diagnosis of VVS, of whom 16 patients had a negative result of HUT (13.0%), 8 (6.5%) had vasodepressive VVS, 32 (26.0%) cardioinhibitory VVS, and 67 (54.5%) mixed VVS. All patients underwent cardioneuroablation that was performed in the left atrium. After a mean follow-up of 4.0±1.1 years, 33 patients experienced syncope/presyncope events (26.8%). Patients with recurrent syncope/presyncope have a lower baseline deceleration capacity level than do those without (8.9±3.2 ms vs 11.3±3.7 ms; P < .001). Each 1-ms increase in deceleration capacity had a 34% (95% confidence interval [CI] 12%-50%) reduced risk of syncope/presyncope recurrence after cardioneuroablation. Nighttime deceleration capacity had the highest discrimination value (area under the curve 0.757; 95% confidence interval 0.657-0.858). At a high-risk threshold of 51% (nighttime deceleration capacity at a cutoff of 9.9 ms), the nighttime deceleration capacity enrollment strategy additionally benefited 18 per 100 patients after cardioneuroablation without syncope/presyncope recurrence as compared with the HUT strategy in decision curve analyses. Baseline nighttime deceleration capacity ≥ 10 ms may act as an indication for cardioneuroablation in patients with refractory VVS.

Clinician needs and perceptions about cardioneuroablation for recurrent vasovagal syncope: An international clinician survey.

Cardioneuroablation (CNA) targets the intrinsic cardiac autonomic nervous system ganglionated plexi located in the peri-atrial epicardial fat. There is increasing interest in CNA as a treatment of vasovagal syncope (VVS), despite no randomized clinical trial (RCT) data. The purpose of this study was to poll the opinion on CNA) for VVS. A REDCap (Research Electronic Data Capture) survey was administered to international physicians treating patients with VVS on their opinion about patient selection criteria, ablation approach, RCT design, and most appropriate end points for CNA procedures. The survey was completed by 118 physicians; 86% were cardiac electrophysiologists. The majority of respondents (79%) would consider referring a patient with refractory VVS for CNA, and 27% have performed CNA for VVS themselves. Most felt patient selection should require a head-up tilt test with a cardioinhibitory response (67%) and suggest a minimum age of 18 years with a median of 3 (interquartile range 2-5) episodes in the past year. There were differences in patient selection between physicians who have performed CNA themselves and those who have not. The majority felt that the ablation strategy should include both atria (70%) with an anatomical approach in combination with autonomic stimulation (85%). Performing a sham procedure in the control arm was supported by 56% of respondents, providing equipoise in RCT design. The preferred primary outcome was freedom from syncope within 1 year of follow-up. There is widespread support for well-designed RCTs to confirm the hypothesized clinical benefit of CNA, provide data to guide the risk-benefit equations during patient selection, and appropriately estimate the placebo effect.

Selective serotonin reuptake inhibitors for debilitating vasovagal syncope: looking for copper and finding gold

Abstract Funding Acknowledgements Type of funding sources: None. Background Despite its benign course, recurrent and unpredictable vasovagal syncope (VVS) may be disabling. Even though a non-pharmacological approach is generally regarded as first-line, a variety of drugs might also be of use. In this respect, the clinical value of selective serotonin reuptake inhibitors (SSRIs) is still a matter of debate. Purpose To perform a meta-analysis aimed at evaluating the extent to which SSRIs might reduce VVS recurrences in susceptible patients. Methods We systematically searched MEDLINE, Embase, Web of Science, Cochrane Library and Google Scholar for prospective studies, addressing the effect of SSRIs on the recurrence rate of VVS in predisposed patients, published up until December 31st, 2020. In order to be included in the quantitative analysis, studies were required to encompass a positive head-up tilt table (HUTT) test for VVS diagnosis and a minimum patient follow-up of 6 months. The primary endpoint was recurrent spontaneous VVS, whereas secondary endpoints included the efficacy outcome of HUTT test-induced VVS and the safety outcome of drug discontinuation for adverse effects. Randomized controlled trials (RCTs) and studies including the most represented SSRI drug were further investigated separately, with respect to the primary endpoint. Study-specific odds ratios (ORs) were pooled using traditional meta-analytic techniques, under a random-effects model. Results 3 RCTs (2 placebo-controlled and 1 both placebo- and active-controlled) and 1 non-randomized prospective study, encompassing 222 and 127 patients, respectively, were regarded as eligible for quantitative evaluation. Patient follow-up ranged between 6 and 24 months. 131 patients were allocated to the SSRI arm, which featured fluoxetine as the most represented element (97 cases). The absolute number of events for each outcome may be reported as follows: primary efficacy endpoint, 57; secondary efficacy endpoint, 68 (only 2 RCTs reporting); secondary safety endpoint, 4 (only 2 RCTs reporting). In the main analysis, SSRIs were not found to significantly reduce VVS recurrence rate (OR 0.48, 95% CI 0.13-1.81, P 0.28, i2 74%). This null result was, however, single-handedly driven by the only non-randomized study included (OR 4.5, 95% CI 0.85-23.8). Likewise, fluoxetine was not able to significantly reduce the primary efficacy endpoint (OR 0.7, 95% CI 0.12-4.12, P 0.7, i2 78%), while SSRIs only numerically cut HUTT test-induced VVS events (OR 0.66, 95% CI 0.24-1.84, P 0.43, i2 59%). Nevertheless, when only RCTs are considered, SSRIs exerted a meaningful reduction in VVS recurrence rate, with no heterogeneity (OR 0.25, 95% CI 0.12-0.5, P 0.0001, i2 0%). In addition, drug discontinuation for safety reasons was rare and comparable between the SSRI and the placebo arms (OR 1.51, 95% CI 0.21-10.74, P 0.59, i2 0%). Conclusion SSRIs do represent one more safe pharmacological option to reduce syncope recurrences in patients with otherwise refractory VVS. Abstract Figure.

Usefulness of post-procedural heart rate response to predict syncope recurrence or positive head up tilt table testing after cardioneuroablation.

Previous reports have suggested that cardioneuroablation (CNA) can be effective in reducing syncopal recurrences in patients with vasovagal syncope (VVS). This study assessed the efficacy of CNA in preventing a positive response to head-up tilt testing (HUT). This is a single-centre retrospective study reviewing prospectively collected data. Fifty-one consecutive patients with VVS were included in the study. After confirmation of >3 s asystole on HUT, all patients underwent CNA. Head-up tilt testing was repeated 1 month after CNA. The main outcome measures were recurrence of syncope episode and positive response on HUT. During a median follow-up period of 11 months (interquartile range 3-27 months), all but 3 (5.8%) of 51 patients were free of syncope. Repeated HUTs were negative in 44 (86.2%) patients. When patients with recurrent syncope were excluded, vasodepressor response was seen in three cases and cardioinhibitory response in one case, respectively. Cardioneuroablation caused significant and durable shortening of RR interval in all cases. This effect was significantly higher in patients without positive HUT responses. This pilot study shows that CNA can effectively prevent recurrent syncopal episodes in patients with refractory VVS. Head-up tilt testing seems as a valuable diagnostic tool not only to select suitable candidates and but also to evaluate success of CNA.

A novel strategy to treat vaso-vagal syncope: Cardiac neuromodulation by cryoballoon pulmonary vein isolation

BackgroundClinical management of vaso-vagal syncope (VVS) remains challenging since no therapy has proven to completely prevent VVS recurrence. ObjectiveThe purpose of this study was to analyze the mid-term outcome of cryoballoon (CB) cardioneuroablation achieved by pulmonary vein isolation (PVI) in patients with VVS. MethodsPatients who underwent CB cardioneuroablation in our centers between January 2014 to June 2018 were included. All patients had a history of VVS or pre-syncope despite therapeutic attempts with medical and/or pacing treatments. Patients were excluded in case of structural heart diseases, cerebrovascular diseases or suspected drug-related syncope. Both heart rate (HR) and atrio-ventricular (AV) interval were analyzed on the 12-lead electrocardiogram (ECG) the day before the procedure, the day after, and in the follow-up. ResultsIn total, 26 patients (76.9% males, 37.5 ± 9.0 years old) were included. All patients underwent a successful procedure with the 28 mm second-generation Arctic Front Advance CB. No major complication occurred. At a mean follow-up of 20.1 ± 11.6 months the freedom from VVS or reflex pre-syncope was 83,7%, with 22 patients free from any clinical recurrence. Basal HR significantly increased the day after the procedure (57.2 bpm vs 78.3 bpm, p < 0.001), while at the final follow-up it stabilized at a value halfway between the 2 previous ones (69.8 bpm, p = 0.0086). The AV interval didn’t modify significantly after the procedure. ConclusionEndocardial autonomic denervation achieved by CB PVI appears to be an effective and safe treatment option for patients with refractory VVS and reflex pre-syncope.

CLOSED-LOOPED STIMULATION PACING FOR THE PREVENTION OF RECURRENT VASOVAGAL SYNCOPE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Vasovagal syncope (VVS) is defined by transient loss of consciousness with spontaneous rapid recovery. Recently, a closed loop stimulation pacing system (CLS) has shown superior effectiveness to conventional pacing in refractory VVS. However, there have been no systematic review and meta-analysis.

Role of closed loop stimulation pacing (CLS) in vasovagal syncope.

Vasovagal syncope (VVS) or neurocardiogenic syncope is defined by transient loss of consciousness with spontaneous and rapid recovery. Recently, a closed loop stimulation (CLS) pacing system has emerged as a new strategy which appears superior to conventional pacing for patients with refractory syncope. However, its efficacy remains of considerable debate and large randomized controlled clinical trials are needed. Between 2002 and 2017, 12 total studies evaluated the use of CLS pacing in patients with refractory VVS, and are summarized in this article.

Ongoing clinical trials for Vasovagal Syncope: where are we in 2014?

Vasovagal Syncope (VVS) can lead to a markedly diminished quality of life for some patients. While there are many treatments for this condition including physical, mechanical, pharmacologic, and device-based control of heart rate, there are few that have been shown to be effective in randomized clinical trials. In our local experience, we have achieved significant improvement in symptom frequency and quality of life using algorithms based on the data available and on clinical acumen for the majority of patients with VVS. Despite this, there are still many patients who suffer from treatment refractory VVS. Fortunately, there are a number of ongoing clinical trials that are likely to add to our knowledge. Ongoing clinical trials are reviewed to examine new treatment methods for VVS that were listed on public trial registries as of April 15, 2014. Data from these trials should inform future strategies in the care of patients with VVS.

The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: a prospective, randomised, single-blind, crossover study

BackgroundThe closed-loop stimulation (CLS) pacemaker algorithm is a system that permanently monitors the contractile state of the myocardium and converts the intrinsic information into rate regulation. The role that the...

Selective Atrial Vagal Denervation Guided by Evoked Vagal Reflex to Treat Refractory Vasovagal Syncope

A 57-year-old woman with refractory vasovagal syncope and a sinus pause of 6.8 seconds during tilt-table test accepted the suggestion of atrial vagal denervation. Radiofrequency pulses were delivered on positive vagal reflex sites according to the standard of heart rate (HR) drop ≥20% after high frequency stimulation (HFS). The endpoint of inexistence of HR decrease at repeating HFS was achieved in 18 sites. No syncope attacked during 12 months and three tilt-table tests performed at 1, 6, and 12 months were negative. Extensive ablation on atrial endocardium for vagal denervation is suggested to be efficient in cardioinhibition type of VVS.

Closed-loop cardiac pacing vs. conventional dual-chamber pacing with specialized sensing and pacing algorithms for syncope prevention in patients with refractory vasovagal syncope: results of a long-term follow-up

Closed-loop stimulation (CLS) pacing has shown greater efficacy in preventing the recurrence of vasovagal syncope (VVS) in patients with a cardioinhibitory response to head-up tilt test (HUTT) compared with conventional pacing. Moreover, there is no conclusive evidence to support the superiority of CLS over the conventional algorithms for syncope prevention. This study retrospectively evaluated the effectiveness of CLS pacing compared with dual-chamber pacing with conventional specialized sensing and pacing algorithms for syncope prevention in the prevention of syncope recurrence in patients with refractory VVS and a cardioinhibitory response to HUTT during a long-term follow-up. Forty-one patients (44% male, 53 ± 16 years) with recurrent, refractory VVS (26% with trauma) and a cardioinhibitory response to HUTT who had undergone pacemaker implantation were included in the analysis. Twenty-five patients received a dual-chamber CLS pacemaker (CLS group) and 16 patients received a dual-chamber pacemaker with conventional algorithms for syncope prevention (conventional pacing group): 9 patients with Medtronic rate drop response algorithm and 7 patients with Guidant-Boston Scientific sudden brady response algorithm. During the follow-up (mean 4.4 ± 3.0 years, interquartile range 2.2-7.4 years) one patient (4%) in the CLS group and six (38%) in the conventional pacing group had syncope recurrences (P= 0.016). The Kaplan-Meier actuarial estimate of first recurrence of syncope after 8 years was 4% in the CLS group and 40% in the conventional pacing group (P= 0.010). The results of this retrospective analysis show that, in order to prevent a recurrence of VVS in patients with a cardioinhibitory response to HUTT, dual-chamber CLS pacing was more effective than dual-chamber pacing with conventional algorithms for syncope prevention in preventing bradycardia-related syncope.

Cobalamin deficiency presenting as refractory vaso vagal syncope

Vaso vagal syncope (VVS) is a common disorder seen in clinical practice. Although often benign, it can sometimes be refractory to treatment and be recurrent, interfering with activities of daily life with secondary trauma, leading to significant morbidity.

The Expectation Effect and Cardiac Pacing for Refractory Vasovagal Syncope

Background Clinical trials of pacing for vasovagal syncope have shown conflicting results. We performed a meta-analysis to determine whether permanent pacemaker therapy prevents refractory vasovagal syncope. Methods Randomized trials comparing pacemaker therapy with medical therapy, usual care, placebo, or different pacing algorithms in the prevention of recurrent vasovagal syncope were considered. The primary endpoint was first recurrence of syncope. Results Nine randomized trials (2 double blind, 7 open label or single blind) were included. There was significant heterogeneity when all 9 trials were pooled ( P =.0009 and I 2 = 69.6%), reflecting methodological diversity in blinding and the nature of the control therapy. When pooled by trial methodology, heterogeneity was no longer apparent. Permanent pacing reduced the risk of recurrent syncope in unblinded studies (odds ratio [OR] 0.09, 95% confidence interval [CI], 0.04 to 0.22) and in studies comparing pacemaker algorithms (OR 0.04, 95% CI, 0.0 to 0.23). No effect was seen in double-blinded trials (OR 0.83, 95% CI, 0.41 to 1.70). Awareness that a permanent pacemaker was implanted and functional was associated with a significant ‘expectation’ effect, which itself reduced the risk of recurrent syncope (OR 0.16, 95% CI, 0.06 to 0.40, P =.0001). Results were similar when restricted to patients with a marked cardioinhibitory response on baseline tilt table testing. Conclusion The results of small, preliminary trials have overestimated the treatment effect of pacemakers due to a lack of blinding of physicians and patients. Blinded trials suggest that the apparent response is due to a strong expectation response to pacing.