A Cost-Utility Analysis of the Syncope: Pacing or Recording in The Later Years (SPRITELY) Trial.

Background: The Syncope: Pacing or Recording in the Later Years (SPRITELY) trial reported that a strategy of empiric permanent pacing in patients with syncope and bifascicular block reduces major adverse events more effectively than acting on the results of an implantable cardiac monitor (ICM). Our objective was to determine the cost-effectiveness of using the ICM, compared with a pacemaker (PM), in the management of older adults (age > 50 years) with bifascicular block and syncope enrolled in the SPRITELY trial. Methods: SPRITELY was a pragmatic, open-label randomized controlled trial with a median follow-up of 33 months. The primary outcome of this analysis is the cost per additional quality-adjusted life-year (QALY). Resource utilization and utility data were collected prospectively, and outcomes at 2 years were compared between the 2 arms. A decision analytic model simulated a 3-year time horizon. Results: The mean cost incurred by participants randomized to the PM arm was $9918, compared to $15,416 (both in Canadian dollars) for participants randomized to the ICM arm. The ICM strategy resulted in 0.167 QALYs fewer than the PM strategy. Cost and QALY outcomes are sensitive to the proportion of participants randomized to the ICM arm who subsequently required PM insertion. In 40,000 iterations of probabilistic sensitivity analysis, the PM strategy resulted in cost-savings in 99.7% of iterations, compared with the ICM strategy. Conclusions: The PM strategy was dominant-that is, less costly and estimated to result in a greater number of QALYs. For patients with unexplained syncope, bifascicular block, and age > 50 years, a PM is more likely to be cost-effective than an ICM.

Contexte: L'essai SPRITELY ( S yncope: P acing or R ecording i n t h e L ater Y ears) a été mené auprès de patients ayant subi une syncope et un bloc bifasciculaire. Elle a montré qu'une méthode de stimulation électrique permanente et empirique du cœur permet de réduire les événements indésirables majeurs plus efficacement qu'une méthode reposant sur les résultats d'un moniteur cardiaque implantable. Notre objectif était de déterminer le rapport coût-efficacité de l'utilisation du moniteur cardiaque implantable par rapport à un stimulateur cardiaque dans la prise en charge de personnes âgées de plus de 50 ans présentant un bloc bifasciculaire et une syncope, inscrits à l'essai SPRITELY. Méthodologie: SPRITELY était un essai contrôlé ouvert et pragmatique à répartition aléatoire, dont le suivi médian était de 33 mois. Le paramètre d'évaluation principal de cette analyse était le coût supplémentaire par année de vie ajustée en fonction de la qualité (AVAQ). Les données sur l'utilisation des ressources et l'utilité ont été recueillies de manière prospective, et les résultats à deux ans ont été comparés entre les deux groupes. Un modèle décisionnel analytique a été utilisé pour simuler un horizon temporel de trois ans. Résultats: Le coût moyen pour les participants répartis aléatoirement dans le groupe utilisant un stimulateur cardiaque était de 9 918 $ CAN comparativement à 15 416 $ CAN pour ceux utilisant un moniteur cardiaque implantable. La stratégie du moniteur cardiaque implantable s'est traduite par une réduction de 0,167 du nombre d'AVAQ par rapport à la stratégie reposant sur le stimulateur cardiaque. Les résultats relatifs aux coûts et aux AVAQ sont sensibles à la proportion de participants répartis aléatoirement dans le groupe du moniteur cardiaque implantable qui ont par la suite dû recevoir un stimulateur cardiaque. Sur 40 000 itérations de l'analyse de sensibilité probabiliste, la stratégie du stimulateur cardiaque a occasionné des économies dans 99,7 % des itérations comparativement à la stratégie du moniteur cardiaque implantable. Conclusions: La stratégie du stimulateur cardiaque était dominante, autrement dit moins coûteuse et, selon les estimations, entraînerait un plus grand nombre d'AVAQ. Pour les patients de plus de 50 ans présentant une syncope idiopathique et un bloc bifasciculaire, un stimulateur cardiaque est plus susceptible d'être moins coûteux qu'un moniteur cardiaque implantable.

Postural orthostatic tachycardia syndrome is associated with significant employment and economic loss.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a debilitating form of chronic orthostatic intolerance that primarily affects women and causes substantial impairment in quality of life and function. Yet, there is minimal literature describing the employment and economic consequences of POTS. We explored these aspects of the POTS patient experience through a self-reported study designed using community-based participatory research principles. METHODS AND RESULTS: A comprehensive questionnaire, including employment and economic consequences, was developed in partnership with Dysautonomia International, a patient advocacy organization. The POTS community engaged in all stages of the research design and analysis. Participants were recruited through Dysautonomia International's website and social media channels. The analysis included 5,556 adult (age ≥18 years) participants with a physician-confirmed diagnosis of POTS. The majority of participants were female (95%). Forty-eight per cent of participants reported employment during the three months prior to the survey, and of these participants, 66.8% would work greater hours if not for illness limitations. Over two-thirds (70.5%) of participants have lost income due to POTS symptoms, with 36.0% of the total cohort losing more than $10,000 USD in the 12 months prior to the survey. Almost all (95%) participants reported POTS-related out-of-pocket medical expenses since diagnosis, with 51.1% of participants spending $10,000 USD or more. CONCLUSIONS: This is the largest study reporting the employment and economic challenges experienced by individuals with POTS. Exposure of these challenges emphasizes the need for earlier diagnosis and improved therapeutic strategies to reduce the negative individual and societal consequences of this disorder.

Ambulance Use, Health Outcomes, and Costs for Emergency Department Visits for Primary Diagnosis of Syncope in Canada.

BACKGROUND: Syncope is a common presentation to the emergency department (ED), yet little is known regarding patient mode of arrival. METHODS: We identified patients ≥20 years old who presented to the ED with a primary diagnosis of syncope in Alberta and Ontario, Canada, between 2010 and 2016. Outcomes included 30-day in-hospital mortality, ED revisits, and rehospitalizations according to mode of arrival and discharge status. The estimated cost for ambulance use was calculated based on the provincial rates (Alberta CAD$385 and Ontario $240). RESULTS: A total of 271,601 syncope presentations to the ED were identified and 60.7% arrived by ambulance. A total of 76.3% (n = 125,793) of ambulance users and 87.0% of self-presenters (n = 92,845) were discharged from the ED. Regardless of mode of arrival, discharged patients were younger with fewer comorbidities. Compared with ambulance users admitted, those discharged had lower in-hospital mortality (0.2% vs 3.5%, P < 0.001), ED revisits (4.4% vs 10.4%, P < 0.001), and rehospitalizations (3.6% vs 10.7%, P < 0.001). Discharged self-presenters also had significantly lower outcomes (P < 0.001, for each outcome) compared with admitted self-presenters. The estimated cost for ambulance use among patients discharged from the ED was $33,137,735. CONCLUSION: A majority of syncope patients arrived to the ED by ambulance, and over 3 quarters were directly discharged home. Although discharged patients had a favourable short-term prognosis, they incurred high transportation costs. Strategies aimed at preventing unnecessary ambulance use are needed.

CONTEXTE: La syncope est une manifestation courante chez les patients qui se présentent au service des urgences; pourtant, on en sait peu sur la façon dont ces patients arrivent à l'hôpital. MÉTHODOLOGIE: Nous avons examiné les dossiers de patients âgés de 20 ans ou plus qui se sont présentés au service des urgences d'hôpitaux de l'Alberta et de l'Ontario, au Canada, et qui ont reçu un diagnostic de syncope entre 2010 et 2016. Les issues évaluées comprenaient la mortalité hospitalière à 30 jours, les nouvelles visites au service des urgences et les réadmissions à l'hôpital en fonction du mode d'arrivée et du statut au moment de la sortie de l'hôpital. Le coût estimatif des services d'ambulance a été calculé à partir des tarifs provinciaux (385 $ en Alberta et 240 $ en Ontario). RÉSULTATS: En tout, 271 601 cas de syncope ont été recensés dans les services des urgences; dans 60,7 % des cas, le patient est arrivé en ambulance. Au total, 76,3 % (n = 125 793) des patients arrivés en ambulance et 87,0 % des patients qui se sont présentés d'eux-mêmes (n = 92 845) ont reçu leur congé du service des urgences. Quel que soit leur mode d'arrivée, les patients qui ont reçu leur congé étaient plus jeunes et présentaient moins d'affections concomitantes. Chez les patients arrivés en ambulance, ceux qui ont reçu leur congé ont affiché des résultats inférieurs à ceux qui ont été admis à l'hôpital quant à la mortalité hospitalière (0,2 % vs 3,5 %, p < 0,001), aux nouvelles visites au service des urgences (4,4 % vs 10,4 %, p < 0,001) et aux réadmissions à l'hôpital (3,6 % vs 10,7 %, p < 0,001). Dans le cas des patients qui se sont présentés d'eux-mêmes, l'incidence des issues évaluées était aussi plus faible chez ceux qui ont reçu leur congé (p < 0,001 pour chaque issue) que chez ceux qui ont été admis à l'hôpital. Le coût estimatif du recours aux services d'ambulance par les patients qui ont reçu leur congé du service des urgences se chiffrait à 33 137 735 $. CONCLUSION: La majorité des patients subissant une syncope sont arrivés au service des urgences en ambulance, et plus des trois quarts ont reçu directement leur congé à la maison. Bien que le pronostic à court terme des patients ayant reçu leur congé du service des urgences ait été favorable, ces patients ont dû payer des frais de transport élevés. Des stratégies visant à prévenir le recours inutile aux services d'ambulance s'imposent.

The Current and Future Hospitalization Cost Burden of Syncope in Canada.

BACKGROUND: Single-center studies have shown the high costs associated with the hospital evaluation of syncope. National cost estimates for syncope-related hospitalizations are sparse, and none exist in Canada. METHODS: The Canadian Institute for Health Information Discharge Abstract Database was used to identify acute care hospitalizations with a primary diagnosis of syncope between fiscal years (FY) 2004 and 2015 in all provinces and territories (except Quebec). We used multiple linear regression to calculate the trends in prevalence of hospital admissions and generalized linear regression to estimate the costs of a hospitalization. The syncope hospitalization rate and the cost per hospitalization in Quebec were assumed to be the average of the rest of the country. The future hospitalization cost burden of syncope was projected to 2030. RESULTS: There were 128,263 hospitalizations for a primary diagnosis of syncope over the 10-year study period, resulting in a total cost of $619.9 million (Canadian). An estimate of 41,044 syncope hospitalizations occurred in Quebec, costing $198.7 million. The total hospitalization cost of syncope in Canada was estimated at $818.5 million. The annual costs of syncope hospitalizations increased from $66.6 to $68.5 million between FY2004 and FY2015, respectively, and are projected to increase to $87.1 million in 2030. CONCLUSION: Hospitalization costs for syncope in Canada are high and rising. Research is needed to identify opportunities to deliver more efficient and cost-effective care.

CONTEXTE: Des études monocentriques ont mis en lumière les coûts élevés associés à l'évaluation hospitalière d'une syncope. Les estimations nationales du coût des hospitalisations liées aux syncopes sont rares, et il n'en existe aucune au Canada. MÉTHODOLOGIE: La base de données sur les congés des patients de l'Institut canadien d'information sur la santé a été utilisée pour recenser les hospitalisations de courte durée liées à un diagnostic primaire de syncope entre les années financières (AF) 2004 et 2015 dans toutes les provinces et territoires (sauf le Québec). Nous avons eu recours, d'une part, à la régression linéaire multiple pour calculer les tendances de la prévalence d'admissions à l'hôpital et, d'autre part, à la régression linéaire généralisée pour estimer les coûts d'une hospitalisation. Le taux d'hospitalisations liées à une syncope et le coût par hospitalisation au Québec ont été établis hypothétiquement à la moyenne du reste du pays. Le futur fardeau du coût des hospitalisations liées à une syncope a été projeté jusqu'en 2030. RÉSULTATS: Nous avons recensé 128 263 hospitalisations liées à un diagnostic primaire de syncope au cours de la période de 10 ans à l'étude, ce qui se traduit par un coût total de 619,9 M$ (canadiens). Selon une estimation, 41 044 hospitalisations liées à une syncope seraient survenues au Québec, au coût de 198,7 M$. Le coût total des hospitalisations liées à une syncope au Canada a été estimé à 818,5 M$. Les coûts annuels des hospitalisations liées à une syncope ont augmenté, passant de 66,6 à 68,5 M$ entre les AF 2004 et 2015, respectivement, et ils devraient encore augmenter pour atteindre 87,1 M$ en 2030. CONCLUSION: Les coûts des hospitalisations liées à une syncope au Canada sont élevés et en hausse. D'autres travaux de recherche devront être effectués pour cerner les possibilités de prestations de soins plus efficaces et rentables.

Canadian Cardiovascular Society Clinical Practice Update on the Assessment and Management of Syncope.

Syncope is a symptom that occurs in multiple settings and has a variety of underlying causes, ranging from benign to life threatening. Determining the underlying diagnosis and prognosis can be challenging and often results in an unstructured approach to evaluation, which is ineffective and costly. In this first ever document, the Canadian Cardiovascular Society (CCS) provides a clinical practice update on the assessment and management of syncope. It highlights similarities and differences between the 2017 American College of Cardiology/American Heart Association/Heart Rhythm Society and the 2018 European Society of Cardiology guidelines, draws on new data following a thorough review of medical literature, and takes the best available evidence and clinical experience to provide clinical practice tips. Where appropriate, a focus on a Canadian perspective is emphasized in order to illuminate larger international issues. This document represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific advice. The primary writing panel wrote the document, followed by peer review from the secondary writing panel. The CCS Guidelines Committee reviewed and approved the statement. The practice tips represent the consensus opinion of the primary writing panel authors, endorsed by the CCS. The CCS clinical practice update on the assessment and management of syncope focuses on epidemiology, the initial evaluation including risk stratification and disposition from the emergency department, initial diagnostic work-up, management of vasovagal syncope and orthostatic hypotension, and syncope and driving.

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.

Alternative Approaches to the Assessment of the Systemic Circulation and Left Ventricular Performance: A Proof-of-Concept Study.

BACKGROUND: The purpose of this article is to examine the systemic circulation and left ventricular (LV) performance by alternative, nonconventional approaches: systemic vascular conductance (G SV ) and the head-capacity relation (ie, the relation between LV pressure and cardiac output), respectively; in so doing, we aspired to present a novel and improved interpretation of integrated cardiovascular function. METHODS: In 16 open-chest, anaesthetized pigs, we measured LV pressure (P LV ), central aortic pressure (P Ao ), and central venous pressure (P CV ) and aortic flow (Q Ao ). We calculated heart rate (HR), stroke volume, cardiac index (CI = cardiac output/body weight), mean PLV ( P ¯ LV ) , and the average arteriovenous pressure difference ( Δ P = P ¯ Ao - P ¯ CV ); G SV  = CI/( P ¯ Ao - P ¯ CV ). We studied the effects of changing loading conditions with the administration of phenylephrine (Δ P ¯ Ao ≥ +25 mm Hg), isoproterenol (ΔHR ∼+25%), sodium nitroprusside (Δ P ¯ Ao ≥ -25 mm Hg), and proximal aortic constriction (to maximize developed P LV and minimize Q Ao ). RESULTS: Sodium nitroprusside and isoproterenol increased G SV compared with phenylephrine and constriction. A maximum head-capacity curve was derived from pooled data using nonlinear regression on the maximum P ¯ LV values in Q Ao bins 12.5 mL/min/kg wide. The head-capacity relation and the plots of conductance were combined using CI as a common axis, which illustrated that CI is the output of the heart and the input of the circulation. CONCLUSIONS: Thus, at a given CI, G SV determines the driving pressure and, thereby, P Ao . We also demonstrated how decreases in G SV compensate for arterial hypotension by restoring the arteriovenous pressure difference and arterial pressure.

CONTEXTE: Le présent article examine l'efficacité de la circulation générale et la fonction ventriculaire gauche à l'aide de paramètres de rechange non conventionnels, soit la conductance vasculaire systémique (G VS ) pour l'une et la relation pression-volume (c.-à-d. la relation entre la pression ventriculaire gauche et le débit cardiaque) pour l'autre, dans le but de présenter une interprétation nouvelle et améliorée de la fonction cardiovasculaire intégrée. MÉTHODOLOGIE: Chez 16 porcs anesthésiés, nous avons mesuré à thorax ouvert la pression ventriculaire gauche (P VG ), la pression aortique centrale (P AC ), la pression veineuse centrale (P VC ) et le flux aortique (Q A ). Nous avons établi la fréquence cardiaque (FC), le volume d'éjection systolique, l'index cardiaque (IC; rapport entre le débit cardiaque et le poids corporel), la P VG moyenne ( P ¯ VG ) et la différence de pression artérioveineuse moyenne ( Δ P = P ¯ A C − P ¯ V C ); G VS  = IC/( P ¯ AC − P ¯ VC ). Nous avons aussi étudié les effets d'une modification des conditions de charge cardiaque provoquée par l'administration de phényléphrine (Δ P ¯ AC ≥ + 25 mmHg), d'isoprotérénol (ΔFC d'environ + 25 %) ou de nitroprussiate de sodium (Δ P ¯ AC ≥ − 25 mmHg) et par la constriction de l'aorte proximale (pour maximiser la P VG développée et réduire le plus possible le Q A ). RÉSULTATS: Le nitroprussiate de sodium et l'isoprotérénol ont augmenté la G VS comparativement à la phényléphrine et à la constriction. Une courbe de la relation pression-volume maximale a été dérivée à partir des données groupées, au moyen d'une régression non linéaire sur les valeurs maximales de la P ¯ VG réparties dans des classes de Q A de 12,5 ml/min/kg d'amplitude. La courbe de la relation pression-volume et le tracé de la conductance ont été superposés en utilisant l'IC comme axe commun, ce qui a permis de constater que l'IC correspond au débit cardiaque et au volume entrant dans la circulation. CONCLUSIONS: Pour un IC donné, la G VS détermine la pression motrice et donc, la P AC . Nous avons aussi démontré comment une diminution de la G VS compense l'hypotension artérielle en rétablissant la différence de pression artérioveineuse et la pression artérielle.

Geographical Differences in Comorbidity Burden and Outcomes in Adults With Syncope Hospitalizations in Canada.

A recent study found that rates of hospitalization for syncope vary across provinces; however, it is unknown whether differences in comorbidity burden and outcomes also exist. The Canadian Institute for Health Information Discharge Abstract Database was used to identify primary syncope hospitalizations (ICD-10 code R55) from 2004 to 2013 for all provinces (except Quebec). Charlson comorbidity score was calculated from comorbidities at the time of hospitalization. Outcomes were defined as in-hospital mortality, 30-day readmission for any cause, and syncope. Logistic regression models were constructed for odds ratios (ORs) and 95% confidence intervals (CIs) to estimate interprovincial differences in outcomes. The interprovincial range (IPR) for mean age was 61.1 ± 17.5 to 73.7 ± 16.3 years, and at least half were male patients. There were significant differences in comorbidity burden across provinces (P < 0.01); however, the majority of patients had a Charlson comorbidity score = 0 (IPR, 53.9%- 71.9%). In multivariable analysis, compared with Ontario, in-hospital mortality was higher for British Columbia (OR, 1.59; 95% CI, 1.22-2.06), Nova Scotia (OR, 1.67; 95% CI, 1.05-2.65), and Newfoundland (OR, 2.27; 95% CI, 1.29-4.00); 30-day readmission for any cause was higher for British Columbia (OR, 1.15; 95% CI, 1.06-1.26), Alberta (OR, 1.19; 95% CI, 1.07-1.31), Manitoba (OR, 1.36; 95% CI, 1.18-1.56), and Prince Edward Island (OR, 1.38; 95% CI, 1.0-1.89), and all outcomes were higher in Saskatchewan. There is significant interprovincial heterogeneity in comorbidity burden and outcomes for hospitalizations for syncope. Future research evaluating whether standardized practices for management of syncope reduce variability and improve healthcare utilization and costs is needed.

A Population-Based Cohort Study Evaluating Outcomes and Costs for Syncope Presentations to the Emergency Department.

OBJECTIVES: This study sought to examine outcomes and costs of patients with syncope admitted and discharged from the emergency department (ED). BACKGROUND: ED visits for syncope are common, yet the impact on health care utilization is relatively unknown. METHODS: A total of 51,831 consecutive patients presented to the ED with a primary diagnosis of syncope (International Classification of Diseases-9 code 780.2 and International Classification of Diseases-10 code R55) in Alberta, Canada from 2006 to 2014. Outcomes included 30-day syncope ED and hospital readmissions; 30-day and 1-year mortality; and annual inpatient, outpatient, physician, and drug costs, cumulative. RESULTS: Of adults presenting to the ED, 6.6% were hospitalized and discharged with a primary diagnosis of syncope (Cohort 1), 8.7% were hospitalized and discharged with a primary diagnosis other than syncope (Cohort 2), and 84.7% were discharged home with a syncope diagnosis (Cohort 3). The 30-day ED revisits for syncope varied from 1.2% (Cohort 2) to 2.4% (Cohort 1) (p < 0.001), and readmission rates were <1% among cohorts. Short- and long-term mortality rates were highest for Cohort 2 and lowest for Cohort 3 (30-day mortality: Cohort 1 of 1.2%, Cohort 2 of 5.2%, Cohort 3 of 0.4%; p < 0.001) (1-year mortality: Cohort 1 of 9.2%, Cohort 2 of 17.7%, Cohort 3 of 3.0%; p < 0.001). Total cost of syncope presentations was $530.6 million (Cohort 1: $75.3 million; $29,519/patient, Cohort 2: $138.1 million; $42,042/patient, Cohort 3: $317.3 million; $9,963/patient; p<0.001). CONCLUSIONS: Most patients with syncope presenting to the ED were discharged and had a favorable prognosis but overall costs were high compared with patients hospitalized. Further research is needed for cost-saving strategies across all cohorts.

Rationale for the Assessment of Metoprolol in the Prevention of Vasovagal Syncope in Aging Subjects Trial (POST5).

BACKGROUND: Vasovagal syncope (VVS) is a common problem associated with a poor quality of life, which improves when syncope frequency is reduced. Effective pharmacological therapies for VVS are lacking. Metoprolol is a ß-adrenergic receptor antagonist that is ineffective in younger patients, but may benefit older (≥40 years) VVS patients. Given the limited therapeutic options, a placebo-controlled clinical trial of metoprolol for the prevention of VVS in older patients is needed. STRUCTURE OF STUDY: The POST5 is a multicenter, international, randomized, placebo-controlled study of metoprolol in the prevention of VVS in patients ≥40 years old. The primary endpoint is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive metoprolol 25 to 100 mg BID or matching placebo, and followed up for 1 year. Secondary end points include syncope frequency, presyncope, quality of life, and cost analysis. Primary analysis will be intention to treat, with a secondary on-treatment analysis. POWER CALCULATIONS: A sample size of 222, split equally between the groups achieves 85% power to detect a hazard rate of 0.3561 when the event rates are 50% and 30% in the placebo and metoprolol arms. Allowing for 10% dropout, we propose to enroll 248 patients. IMPLICATIONS: This study will be the first adequately powered trial to determine whether metoprolol is effective in preventing VVS in patients ≥40 years. If effective, metoprolol may become the first line pharmacological therapy for these patients.

Auto-entrainment risk assessment in heart failure.

BACKGROUND: Risk assessment studies use a suite of nominally independent noninvasive heart rate metrics, often brought together in a statistical model to compute a risk score. The ongoing need to noninvasively identify the higher risk patients requiring more invasive investigations/interventions drives the search for better noninvasive predictive metrics, with increased sensitivity. Many varieties of autoregulatory malfunction occur within the cardiovascular system; thus, it seems a daunting challenge to build predictive models that account for all potential modes of failure. Auto-entrainment (AE) methodology was developed to help address this challenge. METHODS AND RESULTS: AE methodology tests intrinsic capacity to maintain a stable and coherent oscillatory dynamic of autoregulatory control via respiratory entrainment of the blood pressure and heart period. Using cardiovascular death (n=18) at follow-up (1.5 years) as the end point, analysis of AE measurements from 148 patients with heart failure revealed 2 parameters significantly predictive of death. Using logistic regression, the magnitude of systolic pulsus alternans measured during AE had predictive sensitivity of 90% (confidence interval, 62%-100% and specificity of 62% (confidence interval, 49%-74%). The capacity to maintain a stable oscillatory dynamic was measured by the fraction of the total RR-interval spectral power contained within the AE-band. This capacity had predictive sensitivity of 73% (confidence interval, 47%-99%) and specificity of 55% (confidence interval, 43%-66%). CONCLUSIONS: AE methodology provides a noninvasive platform to assess the integrity of cardiovascular autoregulatory control systems for risk assessment in heart failure patients.

Rationale for the prevention of syncope trial IV: assessment of midodrine.

BACKGROUND: Vasovagal syncope is a common problem associated with a poor quality of life, which improves when the frequency of syncope is reduced. Effective pharmacological therapies for vasovagal syncope have been elusive. Midodrine is a pro-drug whose primary metabolite is an alpha-1 adrenoreceptor agonist. A few studies have suggested that it may be beneficial in syncope, but all have had significant methodological limitations. A placebo-controlled clinical trial of midodrine for the prevention of vasovagal syncope is needed. STRUCTURE OF STUDY: The prevention of syncope trial IV (POST 4) is a multicenter, international, randomized, placebo-controlled study of midodrine in the prevention of vasovagal syncope. The primary end point is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive midodrine 10-30 mg/day 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. POWER CALCULATIONS: A total sample size of 112, split equally between the two groups, achieves 85 % power to detect a 50 % relative risk reduction when the event rates are 55 and 27.5 % in the placebo and midodrine arms. Allowing for 20 % dropout, we propose to enroll 140 patients. REGISTRATION: POST 4 is registered with http://www.clinicaltrials.gov (NCT01456481). IMPLICATIONS: This study will be the first adequately powered trial to determine whether midodrine is effective in preventing vasovagal syncope. If it is effective, then midodrine may become the first-line pharmacological therapy for this condition.

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.

Noninvasive risk assessment early after a myocardial infarction the REFINE study.

OBJECTIVES: This study sought to determine whether combined assessment of autonomic tone plus cardiac electrical substrate identifies most patients at risk of serious events after myocardial infarction (MI) and to compare assessment at 2 to 4 weeks versus 10 to 14 weeks after MI. BACKGROUND: Methods to identify most patients at risk of serious events after MI are required. METHODS: Patients (n = 322) with an ejection fraction (EF) <0.50 in the initial week after MI were followed up for a median of 47 months. Serial assessment of autonomic tone, including heart rate turbulence (HRT), electrical substrate, including T-wave alternans (TWA), and EF was performed, interpreted blinded, and categorized using pre-specified cut-points where available. The primary outcome was cardiac death or resuscitated cardiac arrest. All-cause mortality and fatal or nonfatal cardiac arrest were secondary outcomes. RESULTS: Mean EF significantly increased over the initial 8 weeks after MI. Testing 2 to 4 weeks after MI did not reliably identify patients at risk, whereas testing at 10 to 14 weeks did. The 20% of patients with impaired HRT, abnormal exercise TWA, and an EF <0.50 beyond 8 weeks post-MI had a 5.2 (95% confidence interval [CI] 2.4 to 11.3, p < 0.001) higher adjusted risk of the primary outcome. This combination identified 52% of those at risk, with good positive (23%; 95% CI 17% to 26%) and negative (95%; 95% CI 93% to 97%) accuracy. Similar results were observed for the secondary outcomes. CONCLUSIONS: Impaired HRT, abnormal TWA, and an EF <0.50 beyond 8 weeks after MI reliably identify patients at risk of serious events. (Assessment of Noninvasive Methods to Identify Patients at Risk of Serious Arrhythmias After a Heart Attack; http://www.clinicaltrials.gov/ct/show/NCT00399503?order=1; NCT00399503).