Temporal relationship between haemodynamic changes and activation of closed-loop stimulation during a tilt-induced vasovagal syncope.

AIMS: A dual-chamber pacemaker with closed-loop stimulation (CLS) mode is effective in reducing syncopal recurrences in patients with asystolic vasovagal syncope (VVS). In this study, we explored the haemodynamic and temporal relationship of CLS during a tilt-induced vasovagal reflex. METHODS AND RESULTS: Twenty patients underwent a tilt test under video recording 3.9 years after CLS pacemaker implantation. Three patients were excluded from the analysis because of no VVS induced by the tilt test (n = 1) and protocol violation (n = 2). In 14 of the remaining 17 patients, CLS pacing emerged during the pre-syncopal phase of circulatory instability when the mean intrinsic heart rate (HR) was 88 ± 12 b.p.m. and systolic blood pressure (SBP) was 108 ± 19 mmHg. The CLS pacing rate thereafter rapidly increased to 105 ± 14 b.p.m. within a median of 0.1 min [inter-quartile range (IQR), 0.1-0.7 min] when the SBP was 99 ± 21 mmHg. At the time of maximum vasovagal effect (syncope or pre-syncope), SBP was 63 ± 17 mmHg and the CLS rate was 95 ± 13 b.p.m. The onset of CLS pacing was 1.7 min (IQR, 1.5-3.4) before syncope or lowest SBP. The total duration of CLS pacing was 5.0 min (IQR, 3.3-8.3). Closed-loop stimulation pacing was not observed in three patients who had a similar SBP decrease from 142 ± 22 mmHg at baseline to 69 ± 4 mmHg at the time of maximum vasovagal effect, but there was no significant increase in HR (59 ± 1 b.p.m.). CONCLUSION: The reproducibility of a vasovagal reflex was high. High-rate CLS pacing was observed early during the pre-syncopal phase in most patients and persisted, although attenuated, at the time of maximum vasovagal effect. REGISTRATION: ClinicalTrials.gov identifier: NCT06038708.

Short-duration head-up tilt test potentiated with sublingual nitroglycerin in suspected vasovagal syncope: the fast Italian protocol.

BACKGROUND: The traditional nitroglycerin (NTG) head-up tilt test (HUTT) is time-consuming and the test duration is a barrier to widespread utilization in clinical practice. It was hypothesized that a short-duration protocol is not inferior to the traditional protocol regarding the positivity rate and has a similar distribution of hemodynamic response. METHODS AND RESULTS: Patients undergoing HUTT were randomized 1:1 to a 10 min passive phase plus a 10 min 0.3 mg NTG if the passive phase was negative (Fast) or to a 20 min passive phase plus a 15 min 0.3 mg NTG if the passive phase was negative (Traditional). A sample size of 277 patients for each group achieved 80% power to detect an expected difference of 0% with a non-inferiority margin of -10% using a one-sided t-test and assuming a significant level alpha of 0.025. A total of 554 consecutive patients (mean age 46.6 ± 19.3 years, 47.6% males) undergoing HUTT for suspected vasovagal syncope were randomly assigned to the Fast (n = 277) or Traditional (n = 277) protocol. A positive response was defined as the induction of syncope in presence of hypotension/bradycardia, and was observed in 167 (60.3%) patients with Fast and in 162 (58.5%) patients with the Traditional protocol. There was a trend of lesser vasodepressor response (14.8% Fast vs. 20.6% Traditional) which was significant during the passive phase (P = 0.01). CONCLUSION: The diagnostic value of the Fast HUTT protocol is similar to that of the Traditional protocol and therefore the Fast protocol can be used instead of the Traditional protocol.

Prevalence of asystole during tilt test-induced vasovagal syncope may depend on test methodology.

This review addresses tilt-testing methodology by searching the literature which reports timing of asystole and loss of consciousness (LOC). Despite the Italian protocol being the most widely adopted, its stipulations are not always followed to the letter of the European Society of Cardiology guidelines. The discrepancies permit reassessment of the incidence of asystole when tilt-down is early, impending syncope, compared with late, established LOC. Asystole is uncommon with early tilt down and diminishes with increasing age. However, if LOC is established as test-end, asystole is more common, and it is age-independent. Thus, the implications are that asystole is commonly under-diagnosed by early tilt-down. The prevalence of asystolic responses observed using the Italian protocol with a rigorous tilt down time is numerically close to that observed during spontaneous attacks by electrocardiogram loop recorder. Recently, tilt-testing has been questioned as to its validity but, in selection of pacemaker therapy in older highly symptomatic vasovagal syncope patients, the occurrence of asystole has been shown to be an effective guide for treatment. The use of head-up tilt test as an indication for cardiac pacing therapy requires pursuing the test until complete LOC. This review offers explanations for the findings and their applicability to practice. A novel interpretation is offered to explain why pacing induced earlier may combat vasodepression by raising the heart rate when sufficient blood remains in the heart.

Theophylline in patients with syncope without prodrome, normal heart, and normal electrocardiogram: a propensity-score matched study verified by implantable cardiac monitor.

AIMS: Syncope without prodromes in subjects with normal heart and normal electrocardiogram (ECG) is classified as non-classical neurally mediated syncope and is characterized by low adenosine plasma levels (APLs) and frequent asystolic syncope. We assessed the efficacy of theophylline, a non-selective adenosine receptor antagonist, in preventing syncopal events. METHODS AND RESULTS: Participants received an implantable cardiac monitor, underwent APL measurement, and received oral theophylline at maximum tolerated dose (starting dose 300 mg b.i.d.). They were compared with a historical cohort of untreated patients with implantable cardiac monitor who had the same inclusion criteria and were balanced with the propensity score (PS) method as regard age, sex, lifetime syncopal episodes, APL, and antihypertensive drugs. Primary endpoint was time to first syncopal recurrence at 24 months. There were 76 patients in the theophylline group and 58 in the control group. Syncope recurred in 25 (33%) patients in the theophylline group and in 27 (47%) patients in the control group, with an estimated 2-year recurrence rate of 33% and 60%, respectively, and a hazard ratio of 0.53 [95% confidence interval (CI), 0.30-0.95; P = 0.034]. Most of the benefit of theophylline is derived from reduction of syncope due to asystolic atrioventricular (AV) block (hazard ratio of 0.13; 95% CI, 0.03-0.58; P = 0.008). Thirty (39%) patients discontinued theophylline after a median of 6.4 (interquartile range 1.7-13.8) months due to side effects. CONCLUSION: Theophylline was effective in preventing recurrences in patients with syncope without prodromes, normal heart, and normal ECG. The benefit was greater in patients with syncope due to asystolic AV block. CLINICALTRIALS.GOV IDENTIFIER: NCT03803215.

Cardiac Pacing in Cardioinhibitory Reflex Syncope: Clinical Use of Closed-loop Stimulation.

Cardiac pacing has been studied extensively in patients with reflex syncope over the past two decades. The heterogeneity of the forms and clinical manifestations of reflex syncope explain the controversial results of older randomised clinical trials. New evidence from recent trials has changed medical practice, now leading to clear indications for pacing in patients with asystolic syncope documented during carotid sinus massage, implantable cardiac monitoring or tilt testing. Given that recent trials in reflex syncope have been performed using the closed-loop stimulation algorithm, the authors will briefly discuss this pacing mode, review hypotheses about the mechanisms underlying its activation during syncope and provide practical instructions for programming and troubleshooting.

Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole.

AIM: The benefit of cardiac pacing in patients with severe recurrent reflex syncope and asystole induced by tilt testing has not been established. The usefulness of tilt-table test to select candidates for cardiac pacing is controversial. METHODS AND RESULTS: We randomly assigned patients aged 40 years or older who had at least two episodes of unpredictable severe reflex syncope during the last year and a tilt-induced syncope with an asystolic pause longer than 3 s, to receive either an active (pacing ON; 63 patients) or an inactive (pacing OFF; 64 patients) dual-chamber pacemaker with closed loop stimulation (CLS). The primary endpoint was the time to first recurrence of syncope. Patients and independent outcome assessors were blinded to the assigned treatment. After a median follow-up of 11.2 months, syncope occurred in significantly fewer patients in the pacing group than in the control group [10 (16%) vs. 34 (53%); hazard ratio, 0.23; P = 0.00005]. The estimated syncope recurrence rate at 1 year was 19% (pacing) and 53% (control) and at 2 years, 22% (pacing) and 68% (control). A combined endpoint of syncope or presyncope occurred in significantly fewer patients in the pacing group [23 (37%) vs. 40 (63%); hazard ratio, 0.44; P = 0.002]. Minor device-related adverse events were reported in five patients (4%). CONCLUSION: In patients aged 40 years or older, affected by severe recurrent reflex syncope and tilt-induced asystole, dual-chamber pacemaker with CLS is highly effective in reducing the recurrences of syncope. Our findings support the inclusion of tilt testing as a useful method to select candidates for cardiac pacing. STUDY REGISTRATION: ClinicalTrials.gov identifier NCT02324920, Eudamed number CIV-05-013546.

Neuro-arrhythmology: a challenging field of action and research: a review from the Task Force of Neuro-arrhythmology of Italian Association of Arrhythmias and Cardiac Pacing.

: There is a growing interest in the study of the mechanisms of heart and brain interactions with the aim to improve the management of high-impact cardiac rhythm disorders, first of all atrial fibrillation. However, there are several topics to which the scientific interests of cardiologists and neurologists converge constituting the basis for enhancing the development of neuro-arrhythmology. This multidisciplinary field should cover a wide spectrum of diseases, even beyond the classical framework corresponding to stroke and atrial fibrillation and include the complex issues of seizures as well as loss of consciousness and syncope. The implications of a more focused interaction between neurologists and cardiologists in the field of neuro-arrhythmology should include in perspective the institution of research networks specifically devoted to investigate 'from bench to bedside' the complex pathophysiological links of the abovementioned diseases, with involvement of scientists in the field of biochemistry, genetics, molecular medicine, physiology, pathology and bioengineering. An investment in the field could have important implications in the perspectives of a more personalized approach to patients and diseases, in the context of 'precision'medicine. Large datasets and electronic medical records, with the approach typical of 'big data' could enhance the possibility of new findings with potentially important clinical implications. Finally, the interaction between neurologists and cardiologists involved in arrythmia management should have some organizational implications, with new models of healthcare delivery based on multidisciplinary assistance, similarly to that applied in the case of syncope units.

[Do we need syncope units? : Experience from Bolzano, South Tyrol (Italy)]. / Benötigen wir Syncope Units? : Erfahrungsbericht aus Bozen, Südtirol (Italien).

Syncope is a common cause for presentation to the emergency department. Because of the numerous differential diagnoses which can be life-threatening, it can be a challenging work-up for the physician. This often results in admission rates that are too high and hospital stays that are too long with consequent high costs. Several studies have shown the inferiority of best-clinical practice to an evidence-based approach in syncope work-up, which results in underdiagnosis and often incorrect diagnosis of syncope. The consequences are undirected therapies and subsequently high recurrence rates of syncope, which lead to limited quality of life and readmissions. For this reason, the European Society of Cardiology (ESC) Guidelines for the diagnosis and management of syncope recommend the organization of Syncope Units. Through a standardized and evidence-based approach, the diagnostic and therapeutic work-up can be done in a safe and effective manner, allowing an organized follow-up and further management of patients with syncope. This article summarizes the reasons for the need of syncope units and explains the practical implementation of the guidelines using the example of the Syncope Unit in Bolzano, South Tyrol (Italy).

The benefit of pacemaker therapy in patients with neurally mediated syncope and documented asystole: a meta-analysis of implantable loop recorder studies.

Aim: Although the efficacy of cardiac pacing in patients with neurally mediated syncope (NMS) and documented asystole is established, a more robust point estimate of the benefit, which is not possible with any individual study, is lacking. Methods and results: We undertook a meta-analysis of individual participant data from four studies that reported follow-up data on syncope recurrence with cardiac pacing in patients with NMS who had had an electrocardiographic (ECG) documentation of an asystolic event by means of implantable loop recorder (ILR). Of a total of 1046 patients, who had ILR implanted, 383 (36.6%) patients had an ECG documentation of a diagnostic event during mean follow-up of 13 ± 10 months. Of these, 201 (52%) patients, corresponding to 19.2% of the total ILRs, had an asystolic event of 12.8 ± 11.0 s duration documented and met the criteria for pacemaker therapy. Follow-up was available in 121 (60%) of those patients with asystolic events. Syncope recurred after pacing in 18 (14.9%) patients with an actuarial rate of 13% [95% confidence interval (CI) ±6] at 1 year, 21% (95%CI ±10) at 2 years, and 24% (95%CI ±11) at 3 years. On multivariable Cox regression analysis, positive tilt test response was the only significant predictor of syncope recurrence with a hazard ratio (95% CI) of 4.3 (1.4-13). On the contrary, type of asystolic event (sinus arrest or atrioventricular block), prodrome, cardiac abnormalities, number and duration of history of syncope, age, and gender were not predictors of recurrence of syncope. Conclusion: A long asystolic pause, suitable for pacemaker therapy, was found in one of five patients with ILR. After pacemaker implantation, most of these patients remained free of syncope recurrence for up to 3 years. The benefit of pacemaker was greater in patients with negative tilt test.

Vasovagal syncope with asystole: the role of cardiac pacing.

Whereas cardiac pacing has a very limited role overall in patients with vasovagal syncope (VVS), there are three reasons which support pacing efficacy in tilt-induced asystolic VVS. These are: (1) contrary to mixed and vasodepressor forms, an asystolic tilt response is specific, i.e., diagnostic, of VVS and is unlikely to occur in control patients without history of syncope and in patients with cardiac syncope; (2) contrary to mixed and vasodepressor forms, an asystolic tilt response predicts a similar asystolic event during prolonged ECG monitoring with a positive predictive value of 86%; (3) the available evidence from trials supports the efficacy of dual-chamber pacing with a low recurrence rate of syncope after pacing ranging from 6% up to 23% during 3 years of follow-up. The latter results should be confirmed by an ongoing double-blind randomized controlled trial before cardiac pacing becomes an established indication. It is commonly believed that the most frequent cause of recurrence of syncope in patients treated with a pacemaker is an associated hypotensive reflex. In these cases additional measures should be used to counteract hypotension. Recognizing prodromal symptoms, avoiding triggers, and performing counterpressure maneuvers are the well-known first steps. There are two additional useful measures when these fail: stopping/reducing hypotensive drugs and (in selected cases) adding fludrocortisone.

Benefit of dual-chamber pacing with Closed Loop Stimulation in tilt-induced cardio-inhibitory reflex syncope (BIOSync trial): study protocol for a randomized controlled trial.

BACKGROUND: The efficacy of dual-chamber cardiac pacing in neuro-mediated reflex syncope with a cardio-inhibitory response to the Tilt-Table test (TT) has not been definitively assessed so far. The lack of reproducibility of results from previous studies may be partially explained by discrepancies in subject selection and some weaknesses in design and methods. The European Society of Cardiology (ESC) has set a class IIb indication to pacemaker implantation in this population recommending further research. METHODS/DESIGN: The BIOSync study is a multicenter, patient- and outcome-assessor-blind, randomized, parallel-arm, placebo-controlled trial with the objective of assessing the clinical benefit of cardiac pacing in patients with frequently recurrent reflex syncope, suspected (but not proven) to be triggered by asystolic pauses as showing a VASIS 2B response to the TT (>3-s pause regardless of blood pressure drop). The primary and secondary endpoints are time to first post-implantation recurrence of syncope or the combination of pre-syncope or syncope, respectively. One hundred and twenty-eight consenting patients will be 1:1 randomized to dual-chamber cardiac pacing 'on' or 'off' after pacemaker implantation, and followed up until the first adjudicated primary endpoint event for a maximum of 2 years. The so-called Closed Loop Stimulation function on top of dual-chamber pacing is the pacing mode selected in the study active arm. Participating patients are asked to self-report syncopal symptoms at least every 3 months with self-administered questionnaires addressed to an independent Adjudication Committee. Patients and members of the Adjudicating Committee are blinded to randomization. The study is designed to detect a 40% relative reduction in the 2-year incidence of syncopal recurrences with 80% statistical power. DISCUSSION: The BIOSync study is designed to definitively assess the benefit of pacing against placebo in reflex syncope patients with a cardio-inhibitory response to the TT. The study will also provide important information on the efficiency of the TT in appropriately selecting reflex syncope patients for cardiac pacing. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02324920 (27 October 2016, date last accessed).

Mechanism of syncope without prodromes with normal heart and normal electrocardiogram.

BACKGROUND: "Unexplained syncope, no prodromes, and normal heart" has been described as a distinct clinical and biological entity. OBJECTIVE: The purpose of this study was to assess the mechanism of syncope. METHODS: In this prospective multicenter study, 58 patients presenting with unexplained syncope, no prodromes, and a normal heart received an implantable loop recorder (ILR) and were followed up until a diagnosis was established. Their outcomes were compared with those of 389 patients affected by reflex syncope with prodromes who received an ILR. RESULTS: During a mean observation period of 16 ± 13 months, a diagnostic event was documented by the ILR in 29 patients (50%); an asystolic pause of 11 ± 5 seconds (range 3.5-22 seconds) was present at the time of the diagnostic event in 19 patients (66%). Compared with patients affected by reflex syncope with prodromes, patients with unexplained syncope, no prodromes, and a normal heart more frequently had an asystolic syncope (66% vs 47%; P = .001), and this was more frequently due to idiopathic paroxysmal atrioventricular block (47% vs 21%; P = .04). Ten patients with asystolic pauses underwent cardiac pacing, and 8 patients underwent oral theophylline treatment. During the subsequent 17 ± 12 months of follow-up, syncope recurred in 1 patient on theophylline and presyncope occurred in 1 patient with pacemaker. CONCLUSION: A long asystolic pause, frequently due to idiopathic paroxysmal atrioventricular block, played a role in the mechanism of syncope in two-thirds of patients who had electrocardiographic documentation of a diagnostic event. When a specific therapy was administered in patients with asystolic syncope, the short outcome was favorable.

Stop vasodepressor drugs in reflex syncope: a randomised controlled trial.

OBJECTIVES: Most elderly patients affected by reflex vasodepressor syncope take one or more hypotensive drugs. The role of these drugs in causing syncope has not yet been established. We hypothesised that recurrence of syncope and presyncope can be reduced by discontinuing/reducing vasoactive therapy without increasing the risk of cardiovascular and neurological events. METHODS: This randomised, parallel, prospective, trial was conducted from January 2014 to March 2016 in four general hospitals. Of 328 initially screened participants, 58 patients (mean (SD) age 74±11 years) affected by vasodepressor reflex syncope, which was reproduced by tilt testing (n=54) or carotid sinus massage (n=4), were randomised to stop/reduce vasoactive therapy or to continue it. Primary end point was recurrence of syncope, presyncope or adverse events (defined as stroke, cerebral transient ischaemic attacks, worsening heart failure, myocardial infarction). RESULTS: Of 58 patients who were randomised, 55 completed the trial. After 1 month, systolic blood pressure was significantly higher in the 'stop/reduce' group than in the 'continue' group, in both supine (141±13 mm Hg vs 128±14 mm Hg; p=0.004) and standing (133±13 mm Hg vs 122±15 mm Hg; p=0.02) positions. During a mean follow-up of 13±7 months, the primary combined end point occurred in seven 'stop/reduce' patients (23%): three had syncope, three had presyncope and one had heart failure. Conversely, it occurred in 13 'continue' patients (54%): 10 had syncope, 2 had presyncope and 1 had cerebral transient ischaemic attack. The log-rank p value was 0.02 and the HR was 0.37 (95% CI 0.15 to 0.91). CONCLUSIONS: Recurrence of syncope and presyncope can be reduced by discontinuing/reducing vasoactive therapy in most elderly patients affected by reflex vasodepressor syncope. TRIAL REGISTRATION NUMBER: NCT01509534; EudraCT2013-004364-63; Results.

Standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncope: 3-year insights from the Syncope Unit Project 2 (SUP 2) study.

AIMS: The aim of this study was to determine the long-term effects and determinants of success of cardiac pacing in patients affected by reflex syncope enrolled in the Syncope Unit Project 2 (SUP 2) study. Initial results have validated the effectiveness of a standardized guideline-based algorithm which can be used in clinical practice in order to select suitable candidates for cardiac pacing. METHODS AND RESULTS: In this prospective, multicentre, observational study, patients aged >40 years, affected by severe unpredictable recurrent reflex syncope, underwent carotid sinus massage (CSM), followed by tilt testing (TT) if CSM was negative, followed by implantation of an implantable loop recorder (ILR) if TT was negative. Those who had an asystolic response to one of these tests received a dual-chamber pacemaker. Of 281 patients who met the inclusion criteria, 137 (49%) received a pacemaker and were followed up for a mean of 26 ± 11 months: syncope recurred in 25 (18%) of them. At 3 years, the actuarial syncope recurrence rate was 20% [95% confidence interval (CI) 12-30] and was significantly lower than in 142 patients who did not receive a pacemaker and were observed by means of an ILR [43% (95% CI 29-57), P = 0.01]. The 3-year recurrence rate was not different among 78 CSM+, 38 TT+, and 21 ILR+ patients, whereas it was lower in 20 patients with negative TT [5% (95% CI 0-15)] than in 61 patients with positive TT [24% (95% CI 10-38)]. CONCLUSION: The benefit of cardiac pacing is maintained at 3 years, irrespective of the index diagnostic test, and is maximum in patients with negative TT. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01509534.

Assessment of a standardized algorithm for cardiac pacing in older patients affected by severe unpredictable reflex syncopes.

AIMS: Opinions differ regarding the effectiveness of cardiac pacing in patients affected by reflex syncope. We assessed a standardized guideline-based algorithm in different forms of reflex syncope. METHODS AND RESULTS: In this prospective, multi-centre, observational study, patients aged >40 years, affected by severe unpredictable recurrent reflex syncopes, underwent carotid sinus massage (CSM), followed by tilt testing (TT) if CSM was negative, followed by implantation of an implantable loop recorder (ILR) if TT was negative. Those who had an asystolic response to one of these tests received a dual-chamber pacemaker. POPULATION: 253 patients, mean age 70 ± 12 years, median 4 (3-6) syncopes, 89% without or with short prodromes. Of these patients, 120 (47%) received a pacemaker and 106 were followed up for a mean of 13 ± 7 months: syncope recurred in 10 (9%). The recurrence rate was similar in 61 CSM+ (11%), 30 TT+ (7%), and 15 ILR+ (7%) patients. The actuarial total syncope recurrence rate was 9% (95% confidence interval (CI), 6-12) at 1 year and 15% (95% CI, 10-20) at 2 years and was significantly lower than that observed in the group of 124 patients with non-diagnostic tests who had received an ILR: i.e. 22% (95% CI, 18-26) at 1 year and 37% (95% CI, 30-43) at 2 years (P = 0.004). CONCLUSION: About half of older patients with severe recurrent syncopes without prodromes have an asystolic reflex for which cardiac pacing goes along with a low recurrence rate. The study supports the clinical utility of the algorithm for the selection of candidates to cardiac pacing in everyday clinical practice. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01509534.

Physical counter-pressure manoeuvres in preventing syncopal recurrence in patients older than 40 years with recurrent neurally mediated syncope: a controlled study from the Third International Study on Syncope of Uncertain Etiology (ISSUE-3)†.

AIMS: Physical counter-pressure manoeuvres (PCM) are effective in young patients with vasovagal syncope and recognizable prodromal symptoms. The aim of this study was to investigate their effectiveness in patients ≥40 years with severe neurally mediated syncope (NMS) enroled in the Third International Study on Syncope of Uncertain Etiology (ISSUE-3). METHODS AND RESULTS: In the ISSUE-3 study, 63 out of 162 patients had a diagnosis of hypotensive NMS (Types 2, 3, and 4A) documented by implantable loop recorder; of these, 40 were instructed to perform isometric leg and arm PCM therapy. Their mean age was 62 ± 13 years; 47% of patients had a history of some episodes without prodrome. A group of 45 untreated patients acted as controls. The primary endpoint was the time to first syncope recurrence. During follow-up, syncope recurred in 15 PCM patients (37%) and in 24 control patients (53%) (P = 0.14). At 21 months, the modelled syncope recurrence rates were 42% [95% confidence interval (CI): 27-61] and 64% (95% CI: 48-80), respectively (P = 0.27). CONCLUSION: In conclusion, many ISSUE-3 patients affected by hypotensive NMS have syncopal recurrence despite PCM. Older age and the absence of sufficiently long recognizable prodromal symptoms in the ISSUE-3 population might have hampered the effectiveness of PC therapy.

Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3).

BACKGROUND: In the Third International Study on Syncope of Uncertain Etiology (ISSUE-3), cardiac pacing was effective in reducing recurrence of syncope in patients with presumed neurally mediated syncope (NMS) and documented asystole but syncope still recurred in 25% of them at 2 years. We have investigated the role of tilt testing (TT) in predicting recurrences. METHODS AND RESULTS: In 136 patients enrolled in the ISSUE-3, TT was positive in 76 and negative in 60. An asystolic response predicted a similar asystolic form during implantable loop recorder monitoring, with a positive predictive value of 86%. The corresponding values were 48% in patients with non-asystolic TT and 58% in patients with negative TT (P=0.001 versus asystolic TT). Fifty-two patients (26 TT+ and 26 TT-) with asystolic neurally mediated syncope received a pacemaker. Syncope recurred in 8 TT+ and in 1 TT- patients. At 21 months, the estimated product-limit syncope recurrence rates were 55% and 5%, respectively (P=0.004). The TT+ recurrence rate was similar to that seen in 45 untreated patients (control group), which was 64% (P=0.75). The recurrence rate was similar between 14 patients with asystolic and 12 with non-asystolic responses during TT (P=0.53). CONCLUSIONS: Cardiac pacing was effective in neurally mediated syncope patients with documented asystolic episodes in whom TT was negative; conversely, there was insufficient evidence of efficacy from this data set in patients with a positive TT even when spontaneous asystole was documented. Present observations are unexpected and need to be confirmed by other studies. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01463358.

Pacemaker therapy in patients with neurally mediated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial.

BACKGROUND: The efficacy of cardiac pacing for prevention of syncopal recurrences in patients with neurally mediated syncope is controversial. We wanted to determine whether pacing therapy reduces syncopal recurrences in patients with severe asystolic neurally mediated syncope. METHODS AND RESULTS: Double-blind, randomized placebo-controlled study conducted in 29 centers in the Third International Study on Syncope of Uncertain Etiology (ISSUE-3) trial. Patients were ≥40 years, had experienced ≥3 syncopal episodes in the previous 2 years. Initially, 511 patients, received an implantable loop recorder; 89 of these had documentation of syncope with ≥3 s asystole or ≥6 s asystole without syncope within 12 ± 10 months and met criteria for pacemaker implantation; 77 of 89 patients were randomly assigned to dual-chamber pacing with rate drop response or to sensing only. The data were analyzed on intention-to-treat principle. There was syncope recurrence during follow-up in 27 patients, 19 of whom had been assigned to pacemaker OFF and 8 to pacemaker ON. The 2-year estimated syncope recurrence rate was 57% (95% CI, 40-74) with pacemaker OFF and 25% (95% CI, 13-45) with pacemaker ON (log rank: P=0.039 at the threshold of statistical significance of 0.04). The risk of recurrence was reduced by 57% (95% CI, 4-81). Five patients had procedural complications: lead dislodgment in 4 requiring correction and subclavian vein thrombosis in 1 patient. CONCLUSIONS: Dual-chamber permanent pacing is effective in reducing recurrence of syncope in patients ≥40 years with severe asystolic neurally mediated syncope. The observed 32% absolute and 57% relative reduction in syncope recurrence support this invasive treatment for the relatively benign neurally mediated syncope. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359203.