Midodrine for the Prevention of Vasovagal Syncope : A Randomized Clinical Trial.

BACKGROUND: Recurrent vasovagal syncope is common, responds poorly to treatment, and causes physical trauma and poor quality of life. Midodrine prevents hypotension and syncope during tilt tests in patients with vasovagal syncope. OBJECTIVE: To determine whether midodrine can prevent vasovagal syncope in usual clinical conditions. DESIGN: Randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT01456481). SETTING: 25 university hospitals in Canada, the United States, Mexico, and the United Kingdom. PATIENTS: Patients with recurrent vasovagal syncope and no serious comorbid conditions. INTERVENTION: Patients were randomly assigned 1:1 to placebo or midodrine and followed for 12 months. MEASUREMENTS: The primary outcome measure was the proportion of patients with at least 1 syncope episode during follow-up. RESULTS: The study included 133 patients who had had a median of 6 syncope episodes in the prior year (median age, 32 years; 73% female). Compared with patients receiving placebo, fewer patients receiving midodrine had at least 1 syncope episode (28 of 66 [42%] vs. 41 of 67 [61%]). The relative risk was 0.69 (95% CI, 0.49 to 0.97; P = 0.035). The absolute risk reduction was 19 percentage points (CI, 2 to 36 percentage points), and the number needed to treat to prevent 1 patient from having syncope was 5.3 (CI, 2.8 to 47.6). The time to first syncope was longer with midodrine (hazard ratio, 0.59 [CI, 0.37 to 0.96]; P = 0.035; log-rank P = 0.031). Adverse effects were similar in both groups. LIMITATION: Small study size, young and healthy patients, relatively short observation period, and high proportion of patients from 1 center. CONCLUSION: Midodrine can reduce the recurrence of syncope in healthy, younger patients with a high syncope burden. PRIMARY FUNDING SOURCE: The Canadian Institutes of Health Research.

Reduced quality of life and greater psychological distress in vasovagal syncope patients compared to healthy individuals.

BACKGROUND: Vasovagal syncope (VVS) patients have a reduced health-related quality of life (HRQoL). There are limited data comparing HRQoL and psychological profile in VVS patients and healthy individuals. We tested the hypothesis that VVS patients have greater impairment in both HRQoL and psychological profile compared to healthy nonfainting individuals, and that both outcome measures are negatively correlated for VVS patients. METHODS: The RAND 36-Item Health Survey (RAND36), global health visual analogue scale (VAS), Hospital Anxiety and Depression Scale, Anxiety Sensitivity Index, and Positive and Negative Affect Schedule - Expanded Form were completed by healthy individuals and at baseline by VVS patients enrolled in the Second Prevention of Syncope Trial, a randomized, placebo-controlled trial of fludrocortisone for VVS. RESULTS: Data were available on 76 VVS patients (34 ± 14 years; 68% F) and 85 healthy participants (35 ± 11 years; 80% F). Compared to healthy participants, VVS patients reported poorer HRQoL on all scales of the RAND36 and the VAS. VVS patients had significantly greater anxiety, depression, and anxiety sensitivity (each P < 0.001). VVS patients had more negative affect (P < 0.001) and less positive affect (P = 0.003) compared to healthy participants. Anxiety, depression, and anxiety sensitivity were negatively correlated with HRQoL for VVS patients, but not for healthy participants. CONCLUSION: In this first direct comparison, VVS patients have a significantly reduced HRQoL and more anxiety and depression compared to healthy nonfainting individuals. For VVS patients, there is a relationship between psychological distress and HRQoL, suggesting a potential benefit from more comprehensive assessment and treatment.

A culture of compassion: How timeless principles of kindness and empathy become powerful tools for confronting today's most pressing healthcare challenges.

The role of compassion in healthcare is receiving increased attention as emerging research demonstrates how compassionate patient care can improve health outcomes and reduce workplace stress and burnout. To date, proposals to encourage empathy, kindness, and compassion in healthcare have focused primarily on training individual care providers. This article argues that increasing the awareness and skills of individuals is necessary but insufficient. Compassionate care becomes an organizational norm only when health leaders create and nurture a "culture of compassion" that actively supports, develops, and recognizes the role of compassion in day-to-day management and practice. The article profiles four organizations that have adopted compassionate healthcare as an explicit organizational priority and implemented practical measures for building and sustaining a culture of compassion. Common principles and practices are identified. These organizations demonstrate how compassion can lead directly to improved outcomes of primary importance to healthcare organizations, including quality and safety, patient experience, employee and physician engagement, and financial performance. They show how compassion can be a powerful yet often underappreciated tool for helping organizations successfully manage current challenges.

Norepinephrine transport inhibition for treatment of vasovagal syncope.

INTRODUCTION: Norepinephrine transporter inhibitors, such as sibutramine, have been shown to prevent vasovagal syncope induced by tilt testing in healthy volunteers. As a test of concept we assessed whether sibutramine prevents fainting in highly symptomatic VVS patients. METHODS AND RESULTS: This was an open label, dose-ranging protocol of sibutramine 10, 15, and 20 mg daily for ≥4 weeks per dose, with progression dictated by response and tolerance. Responders were predefined as having >50% reduction in spell frequency, compared to baseline spell frequency. The cohort included seven subjects (6 women; 32 ± 7 years) who had a median of 593 faints over a median of 180 months. The patients had had 7 ± 4 previous treatment attempts without a satisfactory response. The mean duration of exposure to 10 mg, 15 mg, and 20 mg doses were 45 ± 33 days, 98 ± 89 days, and 137 ± 83 days. Six patients tolerated the maximum dose, and 1 patient dropped out due to adverse effects at 15 mg/day. The median frequency of spells at baseline, 10, 15, and 20 mg/day was 12, 4.4, 2.8, and 1 events/28 days (P = 0.0048). Five patients were responders and 2 were nonresponders. Among responders, the median frequency of spells at baseline, 10, 15, and 20 mg/day was 14, 4.8, 0.8, and 0.4 events per 28 days (P = 0.0089). No patients developed hypertension. CONCLUSION: In this open label series, sibutramine prevented vasovagal syncope in most highly symptomatic patients.

Randomized Pragmatic Trial of Pacemaker Versus Implantable Cardiac Monitor in Syncope and Bifascicular Block.

OBJECTIVES: In this study, the authors tested whether a strategy of empiric permanent pacing reduces major composite events more effectively than acting on the results of an implantable cardiac monitor (ICM). BACKGROUND: Syncope may be caused by intermittent complete heart block in patients with bifascicular heart block, but competing diagnoses coexist. Whether empiric permanent pacing or acting on investigative results provides best care is unknown. METHODS: This was a multinational, randomized, pragmatic clinical trial of patients ≥50 years of age with bifascicular block, preserved left ventricular function, and ≥1 syncope in the preceding year. The primary composite outcome measure comprised cardiovascular death, syncope, bradycardia resulting in pacemaker insertion, and device complications. RESULTS: There were 57 and 58 subjects randomized to receive a pacemaker or ICM. A total of 41 patients had left bundle branch block and 74 had right bundle branch block and a left fascicular block. Patients were followed for a median 33 months. There were fewer composite primary outcomes in patients randomized to pacemaker compared with ICM, respectively (20 [35%] vs 44 [76%]; chi square P < 0.0001), with lower actuarial probabilities of a primary outcome (0.45 and 1.00; P < 0.001). Syncope was as likely in the groups randomized to receive a pacemaker or ICM (29% vs 26%, chi-square P = 0.95). CONCLUSIONS: Empiric permanent pacing compared with ICM reduced major adverse events but not syncope in older patients with bifascicular block and recent syncope. There remains a substantial likelihood of syncope recurrence in patients who receive a permanent pacemaker likely caused by vasodepressor syncope. (Syncope: Pacing or Recording in the Later Years [SPRITELY]; NCT01423994).

Syncope and structural heart disease: historical criteria for vasovagal syncope and ventricular tachycardia.

INTRODUCTION: to develop evidence-based criteria that distinguish syncope due to ventricular tachycardia (VT) from vasovagal syncope (VVS) in patients with structural heart disease (SHD). METHODS AND RESULTS: one hundred and thirty-four patients with syncope and SHD completed a 118-item questionnaire and underwent noninvasive and invasive diagnostic assessments in a prospective cohort study. The contributions of symptoms to diagnoses were estimated with logistic regression and a point score was developed and then tested using receiver-operator characteristic analysis. The effectiveness of the decision rule was evaluated with long-term outcome. There were 21 patients with tilt-positive VVS, 78 with clinically declared or inducible VT, and 35 with no identified cause of syncope. Six features were significant predictors. Factors that predicted VT included male sex and age at onset >35 years; factors predicting VVS included prolonged sitting or standing; developing presyncope preceded by stress; recurrent headaches; and experiencing fatigue, which lasts longer than 1 minute after syncope. The point score correctly classified 92% of patients, diagnosing VT with 99% sensitivity and 68% specificity. The negative predictive value is ≥ 96%. Fully 67% of patients with undiagnosed syncope were classified as having VT based upon their symptoms. The decision rule predicted 9-year arrhythmia-free survival (VVS 84%, VT 39%, hazard ratio 4.32) and 9-year overall survival (VVS 66%, VT 37%, hazard ratio 2.87). CONCLUSIONS: the causes of syncope in patients with SHD, and their clinical outcomes, can be estimated accurately based on the clinical history. The history safely screens out the possibility of VT as a cause of syncope.

Recent history of vasovagal syncope in a young, referral-based population is a stronger predictor of recurrent syncope than lifetime syncope burden.

INTRODUCTION: accurate selection of patients for vasovagal syncope studies requires strong risk stratification and knowledge of the natural history of syncope. We aimed to test the hypothesis that recent history of vasovagal syncope compared to distant history better predicts subsequent recurrence of syncope. METHODS AND RESULTS: in all, 208 subjects with a positive tilt test and ≥ 3 lifetime syncope spells were followed for 1 year. Syncope episodes in the preceding year and total historical spells were compared for their ability to predict a syncope recurrence using the criteria of optimal statistical significance, best linear separation of risk populations, and impact on power calculations. The number of vasovagal syncope spells in the preceding year better predicted syncope recurrence when compared to total number of historical spells (likelihood ratio statistic 28.4, P < 0.0001; versus 20.4, P = 0.001), and showed a substantial effect as the number of syncope events increased. For example, syncope recurred in 22% of those with <2 spells in the previous year compared to 69% in those with >6 spells. A history of no syncope compared to any syncope in the preceding year was associated with a 1-year probability of 7% versus 46% for syncope recurrence. A study designed to detect a 50% decrease in syncope recurrence at P = 0.05 with 80% power would require 159 patients with at least 3 lifetime spells, and only 108 patients with at least 3 spells in the previous year. CONCLUSIONS: the number of syncope events in the year preceding clinical evaluation is the best predictor of syncope recurrence.

Effect of metoprolol on quality of life in the Prevention of Syncope Trial.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: The 3-dimensional CPF is simple, easy to use, stable over time, measures 3 independent variables, and documents that metoprolol does not reduce presyncope.

The development and preliminary validation of a scale measuring the impact of syncope on quality of life.

AIMS: To develop a brief syncope-specific measure of health-related quality of life. METHODS AND RESULTS: One hundred and fourteen patients with syncope completed a 48-item questionnaire derived from a generic measure of quality of life (the EQ-5D), the Syncope Functional Status Questionnaire, a depression scale (the CES-D) and historical symptoms. From these, clinical impact methodology was used to derive 12-item Impact of Syncope on Quality of Life (ISQL). The ISQL correlated with the number of syncopal spells in the previous year (r = 0.35), self-perceived health status (r = -0.55), the three scores from the SFSQ: [impairment (r = 0.77), fear and worry (r = 0.72), syncope dysfunction (r = 0.82), and depression (r = 0.62)], illustrating its convergent validity with these concepts. Known group differences were evident between patients who exhibited reduced quality of life on the EQ-5D and those who did not. There was no significant correlation between ISQL score and age or gender. ISQL score correlated better with the frequency of spells in the previous year than years prior to the previous year. CONCLUSION: The ISQL is a brief valid measure of the impact of syncope on quality of life. It measures impairment, fear, depression, and physical limitations, and correlates with recent syncope frequency.

Quality of life improves in vasovagal syncope patients after clinical trial enrollment regardless of fainting in follow-up.

BACKGROUND: Frequent syncope is linked to poorer health-related quality of life (HRQoL). Recurrent syncope has been observed to reduce in all groups after seeing a syncope expert and enrolling in a clinical trial. It is unknown if HRQoL improves with this reduction in syncope recurrence. OBJECTIVES: We examined the change in HRQoL over time in vasovagal syncope (VVS) patients seen by a syncope expert and enrolled in a trial. We also explored whether change differed with treatment or the frequency of fainting during follow up. METHODS: The Short Form Health Survey (SF36) was completed at baseline (BL), 6 m, and 12 m post-enrollment by VVS patients in the 1st and 2nd Prevention of Syncope Trials, which were multi-centered, randomized, placebo-controlled trials of metoprolol (POST) and fludrocortisone (POST2). Differences in HRQoL at BL, 6 m, and 12 m were analyzed and compared by faints in follow-up and randomization group. RESULTS: Complete study data were available for 143 VVS patients (40 ±â€¯17 years, 62% F). Over 12 months, patients reported improvement in all SF36 dimensions except for bodily pain. Post hoc analyses indicated that differences first occurred between BL and 6 m for all but general health. Fainting in follow-up or drug randomization group did not diminish the improvements. The baseline syncope burden was not different whether patients' HRQoL improved or not. CONCLUSION: HRQoL of VVS patients improves over time after enrolling in a clinical trial, even with recurrent faints or randomization to placebo. Improvements may result from alternative factors, such as interaction with experts or patient adjustment.

Genetic Association Study in Multigenerational Kindreds With Vasovagal Syncope: Evidence for Involvement of Sex-Specific Serotonin Signaling.

BACKGROUND: Several studies suggest that vasovagal syncope has a genetic origin, but this is unclear. We assessed whether plausible gene variants associate with vasovagal syncope. METHODS: We studied 160 subjects in 9 kindreds comprising 82 fainters and 78 controls. The diagnosis was ascertained with the Calgary Syncope Score. Common genetic variants were genotyped for 12 genes for vascular signaling, potassium channels, the HTR1A(serotonin 5-HT1A receptor), SLC6A4(serotonin reuptake transporter), and COMT(catecholamine O-methyltransferase). Sex-specific associations between genotypes and phenotypes were tested. RESULTS: In 9 out of 12 variants, there was no significant association between genotype and phenotype. However, the HTR1A(-1019) G alleles associated with syncope in males, but not in females ( P=0.005). CC and GG males had 9% versus 77% likelihoods of syncope. The SLC6A4 promoter L alleles associated with decreased syncope in males but increased in females ( P=0.059). The LL and SS males had 25% and 47% syncope likelihoods, whereas females had 75% and 50% syncope likelihoods. The COMT c.472 A alleles associated with decreased syncope in males but increased in females ( P=0.017). The GG and AA males had 50% and 15% syncope likelihoods, whereas females had 52% and 73% syncope likelihoods. CONCLUSIONS: There is a sex-dependent effect of alleles of serotonin signaling and vasovagal syncope, supporting the serotonin hypothesis of the physiology of vasovagal syncope.

Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope.

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: Metoprolol was not effective in preventing vasovagal syncope in the study population.

Worsening of symptoms before presentation with vasovagal syncope.

INTRODUCTION: Much of the natural history of vasovagal syncope is unknown. We determined whether patients presenting for care have had a recently worsened syncope frequency. METHODS AND RESULTS: 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). CONCLUSIONS: Many syncope patients present for care after a recent worsening of their frequency of syncope.

Prospective Assessment of the Risk of Vasovagal Syncope During Driving.

OBJECTIVES: 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. BACKGROUND: Recurrent vasovagal syncope poses a risk because of fainting while driving, but prospective, benchmarked estimates of this risk have not been reported. METHODS: 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. RESULTS: 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%. CONCLUSIONS: 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).

Statin Induced Regression of Cardiomyopathy Trial: A Randomized, Placebo-controlled Double-blind Trial.

BACKGROUND: Hypertrophic cardiomyopathy (HCM), characterized by a thickened, fibrotic myocardium, remains the most common cause of sudden cardiac death in young adults. Based on animal and clinical data, we hypothesized that atorvastatin would induce left ventricular (LV) mass regression. METHODS: Statin Induced Regression of Cardiomyopathy Trial (SIRCAT) was a randomized, placebo-controlled study. The primary endpoint was change in LV mass measured by cardiac magnetic resonance imaging 12 months after treatment with once-daily atorvastatin 80 mg or placebo. A key secondary endpoint was diastolic dysfunction measured echocardiographically by transmitral flow velocities. SIRCAT is registered with www.clinicaltrials.gov (NCT00317967). RESULTS: Of 222 screened patients, 22 were randomized evenly to atorvastatin and placebo. The mean age was 47 ± 10 years, and 15 (68%) were male. All subjects completed the protocol. At baseline, LV masses were 197 ± 76 g and 205 ± 82 g in the placebo and atorvastatin groups, respectively. After 12 months treatment, the LV masses in the placebo and atorvastatin groups were 196 ± 80 versus 206 ± 92 g (P = 0.80), respectively. Echocardiographic indices were not different in the two groups at baseline. After 12 months, diastolic dysfunction as assessed using transmitral flow velocities E/E', A/A', and peak systolic mitral velocity showed no benefit from atorvastatin. CONCLUSIONS: In patients with HCM, atorvastatin did not cause LV mass regression or improvements in LV diastolic function.

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

BACKGROUND: There is limited evidence whether being on fludrocortisone prevents vasovagal syncope. OBJECTIVES: The 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. METHODS: The 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. RESULTS: The 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). CONCLUSIONS: The 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).

Dissection of long-range heart rate variability: controlled induction of prognostic measures by activity in the laboratory.

OBJECTIVES: We sought to determine whether the long-range measures of heart rate variability (HRV)--the standard deviation of sequential 5-min heart period mean values (SDANN) and the heart period spectral amplitude in the ultra-low frequency band <0.0033 Hz (ULF)--had their origins partly in physical activity. BACKGROUND: The SDANN and ULF are prognostic HRV factors whose physiologic origins are obscure. Their discontinuous presence throughout the day suggested that they arise from changes in heart period due to activity. METHODS: Heart period sequences were recorded from 14 patients with left ventricular dysfunction and 14 control subjects during an unrestricted 24-h day, 4-h supine rest, and 4-h epoch with scripted activities. RESULTS: The SDANN was higher during activity than during rest (74 +/- 23 ms vs. 43 +/- 17 ms, p < 0.0001), as were ULF magnitudes (p < 0.0001). The increase in SDANN was due to specific activities that contributed heavily (p < 0.0001 by analysis of variance); for example, a 10-min walk and 90-min rest each contributed 22% of total SDANN. Patients with heart disease had a lower SDANN and ULF and a higher mean heart rate than control subjects during all recordings. The proportional ranges in heart period were the same in the two groups during controlled, scripted activities but were wider in control subjects than in patients during ambulatory recordings, suggesting decreased activity by patients. CONCLUSIONS: Activity increases SDANN by increasing the range of heart periods. Patients with diminished ventricular function have a reduced SDANN on ambulatory electrocardiograms, possibly and partly because of a higher mean heart rate and reduced variations in physical activity.

Historical criteria that distinguish syncope from seizures.

OBJECTIVES: We prospectively sought evidence-based criteria that distinguished between seizures and syncope. BACKGROUND: Loss of consciousness is usually due to either seizures or syncope. There are no evidence-based historical diagnostic criteria that distinguish them. METHODS: A total of 671 patients with loss of consciousness completed a 118-item historical questionnaire. Data sets were complete for all subjects. The data set was randomly divided into two equal groups. The contributions of symptoms to diagnoses in one group were estimated with logistic regression and point scores were developed. The accuracy of the decision rule was then assessed using split-half analysis. Analyses were performed with and without inclusion of measures of symptom burden, which were the number of losses of consciousness and the duration of the history. The scores were tested using receiver-operator characteristic analysis. RESULTS: The causes of loss of consciousness were known satisfactorily in 539 patients and included seizures (n = 102; complex partial epilepsy [50 patients] and primary generalized epilepsy [52 patients]) and syncope (n = 437; tilt-positive vasovagal syncope [267 patients], ventricular tachycardia [90 patients] and other diagnoses such as complete heart block and supraventricular tachycardias [80 patients]). The point score based on symptoms alone correctly classified 94% of patients, diagnosing seizures with 94% sensitivity and 94% specificity. Including symptom burden did not significantly improve accuracy, indicating that the symptoms surrounding the loss of consciousness accurately discriminate between seizures and syncope. CONCLUSIONS: A simple point score of historical features distinguishes syncope from seizures with very high sensitivity and specificity.

Diagnostic criteria for vasovagal syncope based on a quantitative history.

AIMS: Our goal was to develop historical criteria for the diagnosis of vasovagal syncope. METHODS AND RESULTS: We administered a 118-item historical questionnaire to 418 patients with syncope and no apparent structural heart disease. The prevalence of each item was compared between patients with positive tilt tests and those with syncope of other, known causes. The contributions of symptoms to diagnoses were estimated with logistic regression, point scores were developed, and the scores were tested using receiver operator characteristic analysis. The accuracy of the decision rule was assessed with bootstrapping. Data sets were complete for all subjects. The causes of syncope were known in 323 patients and included tilt-positive vasovagal syncope (235 patients) and other diagnoses such as complete heart block and supraventricular tachycardias (88 patients). The point score correctly classified 90% of patients, diagnosing vasovagal syncope with 89% sensitivity and 91% specificity. The decision rule suggested that 68% of an additional 95 patients with syncope of unknown cause and a negative tilt test have vasovagal syncope. CONCLUSION: A simple point score of historical features distinguishes vasovagal syncope from syncope of other causes with very high sensitivity and specificity.