Prevention Of Syncope Trial Research Articles

A comparison of health-related quality of life in autonomic disorders: postural tachycardia syndrome versus vasovagal syncope.

Postural tachycardia syndrome (POTS) and vasovagal syncope (VVS) are two disorders of orthostatic intolerance which are often misdiagnosed as the other. In each case, patients experience a reduced health-related quality of life (HRQoL) compared to healthy populations. This study was conducted to test the hypothesis that HRQoL is worse in POTS. POTS patients were recruited from the Dysautonomia International Annual Patient and Caregiver Conference. VVS patient data came from those enrolled in the Second Prevention of Syncope Trial. Participants aged ≥ 18years (177 POTS and 72 VVS) completed the RAND 36-Item Health Survey, a generic and coherent health-related quality of life survey. POTS patients reported reduced HRQoL compared to VVS patients in physical functioning (42.5 ± 1.7 vs. 76.5 ± 2.9, p < 0.001), role limitations due to physical health (11.4 ± 1.9 vs. 33.0 ± 5.0, p < 0.001), energy and fatigue (27.2 ± 1.3 vs. 50.7 ± 2.6, p < 0.001), social functioning (45.2 ± 1.8 vs. 71.2 ± 2.9, p < 0.001), pain (48.8 ± 1.9 vs. 67.7 ± 2.9, p < 0.001), and general health (31.2 ± 1.5 vs. 60.5 ± 2.6, p < 0.001) domains. Scores did not differ significantly in the role limitations due to emotional health (p = 0.052) and emotional well-being (p = 0.271) domains. Physical and general health composite scores were lower in the POTS population, while mental health composite scores were not different. Differences in HRQoL exist between these patient populations. POTS patients report lower scores in physical and general health domains than VVS patients, but emotional health domains do not differ significantly. Targeting physical functioning in these patients may help improve quality of life.

PHARMACOLOGICAL NOREPINEPHRINE TRANSPORTER INHIBITION FOR THE PREVENTION OF VASOVAGAL SYNCOPE: A SYSTEMATIC REVIEW AND META-ANALYSIS

Vasovagal syncope is a common clinical problem that significantly reduces quality of life yet lacks effective medical therapies. Pharmacological norepinephrine transporter (NET) inhibition increases sympathetic tone, leading to suggestions that it might be able to prevent hypotension and syncope. The objective of this systematic review and meta-analysis was to evaluate the ability of selective NET inhibitors – reboxetine, sibutramine, and atomoxetine – to prevent syncope in healthy subjects and patients with recurrent VVS. We conducted a systematic search and meta-analysis of studies in MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and CINAHL without language restriction from database inception to March 2019. We included all randomized controlled trials that compared the effect of selective NET inhibitors versus placebo in healthy and VVS populations. Studies were required to report a dichotomous outcome of syncope or a predefined syncope surrogate. Four studies (101 subjects) met criteria for inclusion. The mean study size was 25 (range 11-56) participants. Three studies tested the ability of NET inhibition to prevent induced syncope induced by tilt-table testing in healthy subjects (I2 = 0%). NET inhibition drastically reduced the likelihood of positive test outcomes (Relative Risk (RR) = 0.14; 95% CI: 0.04-0.48; p = 0.002). One study (the Prevention of Syncope Trial 6) examined the efficacy of NET inhibition in patients with recurrent vasovagal syncope and found a similar effect of atomoxetine in preventing syncope induced by tilt-table testing (RR = 0.49; 95% CI: 0.28-0.86; p = 0.01). NET inhibition is very effective at the prevention of syncope induced by tilt-table testing in both healthy participants and patients with recurrent vasovagal syncope. Pharmacological NET inhibition holds promise as a potential treatment for recurrent syncope given the 51% relative risk reduction in vasovagal syncope patients. A formal randomized controlled clinical trial is necessary to properly assess the clinical relevance of NET inhibition as an effective treatment for vasovagal syncope.

GENDER DIFFERENCES IN PRESENTATION AND OUTCOME OF VASOVAGAL SYNCOPE: A POST HOC ANALYSIS OF THE PREVENTION OF SYNCOPE TRIALS (POST) I AND II

Vasovagal syncope is the loss of consciousness due to decreased heart rate(HR) and blood pressure(BP) from increased parasympathetic tone and concomitant inhibition of sympathetic outflow. It occurs in >40% of Canadians, however differences in presentation and outcomes between male and female patients are not understood. The Prevention of Syncope Trial (POST) I and II were multicenter randomized controlled trials testing the effectiveness of metoprolol and fludrocortisone, respectively on patients with syncope. We investigated sex-dependent differences in presentation and outcome of vasovagal syncope. We hypothesized that women would suffer a greater burden of syncope and that the triggers for syncopal spells would differ. There were 418 patients with >2 lifetime syncope events, with no significant comorbidities, pacemaker, glaucoma, diabetes, hepatic disease, hypertension or contraindication to the study medications. Data regarding clinical presentation, outcomes and time to first syncopal event after randomization were compared between men and women. χ2 analysis was used for categorical variables and Student t-test for continuous variables; the Wilcoxon rank-sum-test was used to compare median values. Survival analysis was performed using the Kaplan Meier method and the log-rank test for significance. A Cox proportional hazards model was used to perform multivariate analysis for time to syncope. There were 280 women (67%) and 138 men (33%). Baseline systolic BP was lower in women (117 vs 124mmHg, p < 0.001) while baseline HR was higher in women (71 vs 69 bpm, p=0.01). Men were older at the time of randomization (42 vs 35, p < 0.0001). Women were younger at the time of the first syncope event (20.5 vs 26.1 years p=0.0009); women had more median lifetime episodes than men (14.5 vs 8.0; p < 0.0001). Syncope due to venipuncture was a more common trigger in men (5% vs 0%, p=0.02), while response to heat was more common in women (65.7% vs 50%, p=0.01). Clinical presentation in women consisted more commonly of feeling warm, having a seizure and having palpitations, as opposed to men (49.1% vs 40.5% p=0.05, 10.5% vs 2.7% p=0.01, 15.4% vs 9.1% p < 0.05, respectively). Post-syncope fatigue was more common in women (53.0% vs 40.6%, p =0.04). After randomization, men were less likely to experience recurrent syncope, after adjustment for pre-randomization syncope burden in the last 12 months and randomization assignment (active treatment vs placebo) (HR 0.64 95% CI 0.45,0.91 p=0.0117) (See Figure). Clinical presentation and triggers of vasovagal syncope differ between men and women, as do recurrent events.

VASOVAGAL SYNCOPE PATIENTS HAVE A REDUCED QUALITY OF LIFE AND GREATER PSYCHOLOGICAL DISTRESS COMPARED TO HEALTHY SUBJECTS

Patients with vasovagal syncope (VVS) are highly symptomatic and have a reduced health-related quality of life (HRQoL). There is limited data comparing the HRQoL and psychological profile between VVS patients and healthy individuals. The purpose of this study was to examine the differences in HRQoL and psychological distress between VVS patients and healthy subjects. We tested the hypothesis that VVS patients will have greater impairment in both HRQoL and psychological profile compared to healthy individuals. The RAND 36-Item Health Survey (RAND36), Hospital Anxiety and Depression Scale (HADS), and Anxiety Sensitivity Index (ASI) were completed at baseline by VVS patients and healthy subjects enrolled in the Second Prevention of Syncope Trial (POST II), a randomized, placebo-controlled trial of fludrocortisone for VVS. Data are reported as mean±SD with Student’s t-tests. Data are available on 76 VVS patients (34±14 years; 68% F) and 85 healthy subjects (35±11 years; 80% F). For the RAND36 (Table), VVS patients reported poorer physical functioning (p < 0.001), emotional well-being (p < 0.001), social functioning (p < 0.001), and general health (p < 0.001) compared to healthy subjects. They also had less energy (p < 0.001), more pain (p < 0.001), and greater role limitations due to both physical health (p < 0.001) and emotional problems (p < 0.001). For the HADS, VVS patients had greater anxiety (p < 0.001) and were more depressed (p < 0.001). VVS patients also reported greater anxiety sensitivity in the ASI (p < 0.001). VVS patients have a reduced HRQoL and poorer psychological profile compared to healthy subjects. VVS patients may benefit from targeted interventions addressing these concerns.

Clusters, Gaps, and Randomness: Vasovagal Syncope Recurrence Patterns.

This study elucidated the temporal recurrence patterns of syncope in patients with frequent vasovagal syncope (VVS). Understanding the temporal distribution of fainting spells in syncope patients may illuminate biological processes and inform decision making. Patients from the POST 2 (Prevention of Syncope Trial 2) were included; all had VVS and fainted≥4 times in the study year, providing≥3 interevent intervals (IEIs). Only fainting spells separated by≥1 day were included. IEI distributions were analyzed using Poisson modeling and cumulative sum distributions. Twenty-four patients (5 males, 19 females; mean 33 years of age) had a total of 286 syncopal events and 262 IEIs, with a median 6 IEI. They resembled excluded subjects in age and sex but fainted more often in their lives (median:57 vs. 13 fainting spells, respectively; p< 0.0001) and in the previous year (median: 23 vs. 3 fainting spells, respectively; p< 0.0001). Subjects had a median IEI duration of 8 (interquartile range: 4 to 19) days. The IEI distributions were fit well by Poisson models with a median r2 of 0.94 (95% confidence interval: 0.91 to 0.97). The patients' Poisson rate constant frequencies were 7 to 263 fainting spells/year with a median rate of 19 fainting spells/year. The modal syncope frequency was 10 to 15 fainting spells per year. Seven patients had biexponential distributions, and many patients fainted in clusters. Patients with frequent VVS have fainting spells that occur randomly in time. Clusters of syncope occur, and in this population, there is a central tendency to 10 to 15 fainting spells per year. This provides a quantitative measure of frequency and predictability that may afford individualized treatment goals.

Fludrocortisone for the Prevention of Vasovagal Syncope: A Randomized, Placebo-Controlled Trial

BackgroundThere is limited evidence whether being on fludrocortisone prevents vasovagal syncope. ObjectivesThe authors sought to determine whether treatment with fludrocortisone reduces the proportion of patients with recurrent vasovagal syncope by at least 40%, representing a pre-specified minimal clinically important relative risk reduction. MethodsThe multicenter POST 2 (Prevention of Syncope Trial 2) was a randomized, placebo-controlled, double-blind trial that assessed the effects of fludrocortisone in vasovagal syncope over a 1-year treatment period. All patients had >2 syncopal spells and a Calgary Syncope Symptom Score >−3. Patients received either fludrocortisone or matching placebo at highest tolerated doses from 0.05 mg to 0.2 mg daily. The main outcome measure was the first recurrence of syncope. ResultsThe authors randomized 210 patients (71% female, median age 30 years) with a median 15 syncopal spells over a median of 9 years equally to fludrocortisone or placebo. Of these, 96 patients had ≥1 syncope recurrences, and only 14 patients were lost to follow-up before syncope recurrence. There was a marginally nonsignificant reduction in syncope in the fludrocortisone group (hazard ratio [HR]: 0.69: 95% confidence interval [CI]: 0.46 to 1.03; p = 0.069). In a multivariable model, fludrocortisone significantly reduced the likelihood of syncope (HR: 0.63; 95% CI: 0.42 to 0.94; p = 0.024). When the analysis was restricted to outcomes after 2 weeks of dose stabilization, there was a significant benefit due to fludrocortisone (HR: 0.51; 95% CI: 0.28 to 0.89; p = 0.019). ConclusionsThe study did not meet its primary objective of demonstrating that fludrocortisone reduced the likelihood of vasovagal syncope by the specified risk reduction of 40%. The study demonstrated a significant effect after dose stabilization, and there were significant findings in post hoc multivariable and on-treatment analyses. (A randomised clinical trial of fludrocortisone for the prevention of vasovagal syncope; ISRCTN51802652; Prevention of Syncope Trial 2 [POST 2]; NCT00118482)

Prospective Assessment of the Risk ofVasovagal Syncope During Driving.

This study sought to estimate the likelihood of a motor vehicle accident causing serious risk or harm in patients with frequent vasovagal syncope, and compare this with international accident data. Recurrent vasovagal syncope poses a risk because of fainting while driving, but prospective, benchmarked estimates of this risk have not been reported. Data were from the POST (Prevention of Syncope Trial)-1 and -2, which were multicenter randomized studies of patients with≥3 lifetime vasovagal syncope spells. POST-1 patients (reported in 2005) received metoprolol or placebo for≤1 year between 1998 and 2004; POST 2 patients received fludrocortisone or placebo for≤1 year between 2006 and 2011. Accident data were recovered from Internet reports from the United States, United Kingdom, and Canada. A total of 418 patients (age 38 ± 17 years) had a median of 10 lifetime faints and a median of 3 faints in the previous year. Total follow-up time was 323 years, or 0.77 years per person. A total of 174 subjects fainted, having a total of 615 faints. Two patients fainted while driving, without fatality or injury, with a likelihood of 0.62% per person-year. The risk of serious harm or death was<0.0035% per person-year, and 0.0018% per faint. In the general U.S., U.K., and Canadian driving populations, the risk of serious harm or death was 0.067% per driver-year, and the risk of death was 0.009%. The estimated risk of serious harm or death was<0.0035% per person-year in highly symptomatic patients, less than the risk of serious harm or death in the general population. (A Randomized Clinical Trial of Fludrocortisone for Vasovagal Syncope: The Second Prevention of Syncope Trial [POST II]; NCT00118482).

Gynecological and menstrual disorders in women with vasovagal syncope

Vasovagal syncope (VVS) is a chronic debilitating condition seen mostly in young women of reproductive age. There are anecdotal reports of increased syncope and presyncope around menstruation. This case-control study assessed the effects of the menstrual cycle on lightheadedness episodes and compared the gynecological and pregnancy history of VVS patients to healthy subjects. A custom-designed gynecological and menstrual cycle questionnaire was previously developed for patients with orthostatic intolerance. This questionnaire was administered to female patients with VVS (n = 128) as a part of the multicenter Second Prevention of Syncope Trial, and to gender-matched healthy subjects (n = 92). VVS patients and healthy subjects reported significant variability in self-reported lightheadedness throughout the menstrual cycle. Both cohorts experienced greatest lightheadedness during menses (53 ± 2 vs. 56 ± 4), which decreased during the follicular phase (44 ± 2 vs. 41 ± 4). VVS patients reported less severity in premenstrual symptoms (Fisher's method P = 2.7E-06) compared to healthy controls. There is no difference in the incidence of gynecological abnormalities (Fisher's exact P = 0.193) and pregnancy complications (P = 1.0) between the two cohorts. VVS patients have similar pregnancy rates compared to healthy subjects (P = 0.674). The severity of lightheadedness varies during the menstrual cycle and is similar in both VVS patients and healthy controls. VVS patients have no greater risk of gynecological abnormalities and pregnancy complications than healthy subjects.

Age-Dependent Effect of β-Blockers in Preventing Vasovagal Syncope

β-blockers have little effectiveness in preventing vasovagal syncope in unselected populations, but they might be effective in older patients. We determined whether β-blockers prevent vasovagal syncope in an age-related fashion. Two populations were studied. A proportional hazards analysis was performed on an observational cohort study of 153 patients with vasovagal syncope, 52 of whom received β-blockers. A multivariable proportional hazards model stratified by center was performed on 208 participants in the randomized Prevention of Syncope Trial (POST), examining the interaction between age group and treatment with metoprolol. Age-specific hazard ratios were estimated for both studies and combined using the inverse variance meta-analytic method. In the cohort study, the hazard ratio for syncope if treated with β-blockers was 1.54 (95% CI, 0.78-3.05) for patients aged <42 years and 0.48 (95% CI, 0.12-1.92) for patients aged ≥ 42 years. In POST, the proportional hazards model showed interactions between age and treatment effect (P=0.026). The hazard ratio for patients aged ≥ 42 years who received metoprolol was 0.53 (95% CI, 0.25-1.10); in patients aged <42 years, the hazard ratio was 1.62 (95% CI, 0.85-3.10). A pooled analysis of both studies yielded an estimate of the hazard ratio of 1.58 (CI, 1.00-2.31) for patients aged <42 years, and the hazard ratio was 0.52 (CI, 0.27-1.01) for patients aged ≥ 42 years. The 2 age groups differed significantly in response to β-blockers (P=0.007). β-blocker treatment may suppress vasovagal syncope in middle-aged patients aged >42 years.

Treatment of Vasovagal Syncope: An Update

Vasovagal syncope (VVS) remains the most common cause of syncope and transient loss of consciousness in all age groups. The treatment of VVS focuses on measures that interrupt or prevent its pathophysiologic mechanism, as well as on avoidance of triggers. Although the evidence supporting an increase in salt and water intake is weak, it is a cost-effective and safe strategy that should always be used as first-line therapy. Patients should be educated on how to respond to further episodes of syncope, especially if they experience prodromal warning signs. In these cases, counterpressure maneuvers in younger patients are clearly effective. Orthostatic training exercises may improve symptoms in patients with recurrent VVS; however, this strategy is only effective in younger, highly motivated patients. Multiple medications have been tested in small trials, and there is sparse evidence on efficacy. β-Adrenergic antagonists and selective serotonin reuptake inhibitors have shown contradictory results on efficacy in a variety of studies; thus, their use should be restricted. Midodrine is the only drug proven to prevent VVS recurrence; however, no consistent prescription guidelines exist. The ongoing Second Prevention of Syncope Trial (POST II) is investigating the benefits of fludrocortisone in this population. In the meantime, measures such as increased salt and water intake and counterpressure maneuvers should be used in all cases if no contraindications are present. Pharmacologic treatment should be restricted to midodrine and fludrocortisone, with the other treatments as options in highly refractory cases. Implantation of a permanent pacemaker should be a measure of last resort in highly refractory cases, particularly in the cardioinhibitory type of VVS.

Effect of Metoprolol on Quality of Life in the Prevention of Syncope Trial

Vasovagal syncope is common, often recurrent, and reduces quality of life. No therapies have proven useful to improve quality of life in adequately designed randomized clinical trials. Beta-blockers have mixed evidence for effectiveness in preventing syncope. The Prevention of Syncope Trial was a randomized, placebo-controlled, double-blind, multinational, clinical trial that tested the hypothesis that metoprolol improves quality of life in adult patients with vasovagal syncope in a 1-year observation period. Randomization was stratified in strata of patients <42 and > or =42 years old. The quality of life questionnaires Short Form-36 (SF-36) and Euroqol EQ-5D were completed at baseline and after 6 and 12 months of treatment by 204, 132, and 121 patients, respectively. There were 208 patients, mean age 42 +/- 18, of whom 134 (64%) were females. All had positive tilt tests. There was no improvement in quality of life during the trial in the entire group or in either treatment arm. Patients in the metoprolol treatment arm did not have improved quality of life compared to the patients in the placebo arm using either the SF-36 or EQ5D after either 6 or 12 months. Finally, there was no improvement in quality of life associated with metoprolol use in patients either <42 or > or =42 years of age. Metoprolol does not improve quality of life in patients with recurrent vasovagal syncope and a positive tilt test.

Design and Use of a Quantitative Scale for Measuring Presyncope

Vasovagal syncope is common and distressing. One important symptom is presyncope, but there are no clinimetric measures of this. We developed the Calgary Presyncope Form (CPF) and used it to test whether metoprolol reduces presyncope in a randomized trial. The CPF captures the frequency, duration, and severity of presyncope. We administered it to participants in the Prevention of Syncope Trial (POST), a randomized clinical trial that tested the hypothesis that metoprolol reduces syncope and presyncope in adult patients with vasovagal syncope. The CPF was completed by 44 patients on metoprolol and 39 patients on placebo, of a total of 208 subjects. Completion of the CPF for each of the threedimensions was 84-87% in the 83 respondents. Results were centrally distributed in duration and severity dimensions, but not in frequency. Patients had a median of 1.2 presyncopal spells per day, with a median moderate severity, lasting a median 10 minutes. The 3 scales were statistically independent of each other. These results were independent of subject age, and results in all 3 dimensions were stable over the observation period. There was no significant difference between patients on metoprolol and placebo in any dimension. The 3-dimensional CPF is simple, easy to use, stable over time, measures 3 independent variables, and documents that metoprolol does not reduce presyncope.

Worsening of Symptoms Before Presentation with Vasovagal Syncope

Much of the natural history of vasovagal syncope is unknown. We determined whether patients presenting for care have had a recently worsened syncope frequency. We compared 208 subjects in the referral-based Prevention of Syncope Trial (POST) and 122 subjects who fainted > or =1 in a community survey study. Their mean ages and gender proportions were similar. The POST population had a higher median lifetime syncope frequency (1.16 vs 0.12 spells/year, P < 0.0001) and more subjects began fainting at age > or =35 years (26% vs 6%, P < 0.0001). In POST, the median frequency of syncopal spells in the preceding year was higher than in all previous years (3 vs 0.57, P < 0.0001). POST subjects presented sooner after their first spell (median 11.0 vs 16.8 years, P = 0.0002), and after their last spell (median 0.3 vs 7.4 years, P < 0.0001). POST subjects > or =35 years old had a shorter history than similar community-survey subjects (2.8 vs 14.9 y, P < 0.0001) and presented earlier after their first syncopal spell than POST subjects with a younger onset of syncope (median 2.8 vs 14.7 y, P < 0.0001), despite having fewer faints (median 6 vs 10, P = 0.0002). Many syncope patients present for care after a recent worsening of their frequency of syncope.

Prevention of Syncope Trial (POST): A Randomized, Placebo-Controlled Study of Metoprolol in the Prevention of Vasovagal Syncope

Prevention of Syncope Trial (POST): A Randomized, Placebo-Controlled Study of Metoprolol in the Prevention of Vasovagal Syncope

The Second Prevention of Syncope Trial (POST II)—a randomized clinical trial of fludrocortisone for the prevention of neurally mediated syncope: Rationale and study design

Neurally mediated syncope is a common and frequently distressing problem. It is associated with a poor quality of life, which improves when the frequency of syncope is reduced. Few therapies for neurally mediated syncope have been proven effective. Fludrocortisone is commonly used to prevent recurrences of syncope but with little evidence to support its use. A placebo-controlled clinical trial of fludrocortisone for the prevention of neurally mediated syncope is needed. POST II is a multicenter, international, randomized, placebo-controlled study of fludrocortisone in the prevention of neurally mediated syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive fludrocortisone 0.05 to 0.2 mg or matching placebo and followed for 1 year. Secondary end points include syncope frequency, presyncope, and quality of life. Primary analysis will be performed with an intention-to-treat approach, with a secondary on-treatment analysis. Assuming a 40% risk of syncope in the control arm, a relative reduction of 40% by fludrocortisone, and a dropout rate of 20%, the enrollment of 310 patients will give an 80% power of reaching a positive conclusion about fludrocortisone therapy, with P = .05. POST II is registered with both (ISRCTN 51802652) and (NCT00118482). This study will be the first adequately powered trial to determine whether fludrocortisone is effective in preventing neurally mediated syncope. If it is effective, then fludrocortisone may become the first-line medical therapy for this condition.

AB28-2: Effect of metoprolol on presyncope burden in the prevention of syncope trial

AB28-2: Effect of metoprolol on presyncope burden in the prevention of syncope trial

Prevention of Syncope Trial (POST)

Previous studies that assessed the effects of beta-blockers in preventing vasovagal syncope provided mixed results. Our goal was to determine whether treatment with metoprolol reduces the risk of syncope in patients with vasovagal syncope. The multicenter Prevention of Syncope Trial (POST) was a randomized, placebo-controlled, double-blind, trial designed to assess the effects of metoprolol in vasovagal syncope over a 1-year treatment period. Two prespecified analyses included the relationships of age and initial tilt-test results to any benefit from metoprolol. All patients had >2 syncopal spells and a positive tilt test. Randomization was stratified according to ages <42 and > or =42 years. Patients received either metoprolol or matching placebo at highest-tolerated doses from 25 to 200 mg daily. The main outcome measure was the first recurrence of syncope. A total of 208 patients (mean age 42+/-18 years) with a median of 9 syncopal spells over a median of 11 years were randomized, 108 to receive metoprolol and 100 to the placebo group. There were 75 patients with > or =1 recurrence of syncope. The likelihood of recurrent syncope was not significantly different between groups. Neither the age of the patient nor the need for isoproterenol to produce a positive tilt test predicted subsequent significant benefit from metoprolol. Metoprolol was not effective in preventing vasovagal syncope in the study population.