Robert S. Sheldon

Canadian Implantable Defibrillator Study (CIDS) A Randomized Trial of the Implantable Cardioverter Defibrillator Against Amiodarone

BACKGROUND Patients surviving ventricular fibrillation (VF) or sustained ventricular tachycardia (VT) are at a high risk of death due to a recurrence of arrhythmia. The implantable cardioverter defibrillator (ICD) terminates VT or VF, but it is not known whether this device prolongs life in these patients compared with medical therapy with amiodarone. METHODS AND RESULTS A total of 659 patients with resuscitated VF or VT or with unmonitored syncope were randomly assigned to treatment with the ICD or with amiodarone. The primary outcome measure was all-cause mortality, and the secondary outcome was arrhythmic death. A total of 328 patients were randomized to receive an ICD. A thoracotomy was done in 33, no ICD was implanted in 18, and the rest had a nonthoracotomy ICD. All 331 patients randomized to amiodarone received it initially. At 5 years, 85.4% of patients assigned to amiodarone were still receiving it at a mean dose of 255 mg/day, 28.1% of ICD patients were also receiving amiodarone, and 21.4% of amiodarone patients had received an ICD. A nonsignificant reduction in the risk of death was observed with the ICD, from 10.2% per year to 8.3% per year (19.7% relative risk reduction; 95% confidence interval, -7.7% to 40%; P=0.142). A nonsignificant reduction in the risk of arrhythmic death was observed, from 4.5% per year to 3.0% per year (32.8% relative risk reduction; 95% confidence interval, -7.2% to 57.8%; P=0.094). CONCLUSIONS A 20% relative risk reduction occurred in all-cause mortality and a 33% reduction occurred in arrhythmic mortality with ICD therapy compared with amiodarone; this reduction did not reach statistical significance.

Cardiac-Resynchronization Therapy for Mild-to-Moderate Heart Failure

BACKGROUND Cardiac-resynchronization therapy (CRT) benefits patients with left ventricular systolic dysfunction and a wide QRS complex. Most of these patients are candidates for an implantable cardioverter-defibrillator (ICD). We evaluated whether adding CRT to an ICD and optimal medical therapy might reduce mortality and morbidity among such patients. METHODS We randomly assigned patients with New York Heart Association (NYHA) class II or III heart failure, a left ventricular ejection fraction of 30% or less, and an intrinsic QRS duration of 120 msec or more or a paced QRS duration of 200 msec or more to receive either an ICD alone or an ICD plus CRT. The primary outcome was death from any cause or hospitalization for heart failure. RESULTS We followed 1798 patients for a mean of 40 months. The primary outcome occurred in 297 of 894 patients (33.2%) in the ICD-CRT group and 364 of 904 patients (40.3%) in the ICD group (hazard ratio in the ICD-CRT group, 0.75; 95% confidence interval [CI], 0.64 to 0.87; P<0.001). In the ICD-CRT group, 186 patients died, as compared with 236 in the ICD group (hazard ratio, 0.75; 95% CI, 0.62 to 0.91; P = 0.003), and 174 patients were hospitalized for heart failure, as compared with 236 in the ICD group (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). However, at 30 days after device implantation, adverse events had occurred in 124 patients in the ICD-CRT group, as compared with 58 in the ICD group (P<0.001). CONCLUSIONS Among patients with NYHA class II or III heart failure, a wide QRS complex, and left ventricular systolic dysfunction, the addition of CRT to an ICD reduced rates of death and hospitalization for heart failure. This improvement was accompanied by more adverse events. (Funded by the Canadian Institutes of Health Research and Medtronic of Canada; ClinicalTrials.gov number, NCT00251251.).

The North American vasovagal pacemaker study (VPS) : A randomized trial of permanent cardiac pacing for the prevention of vasovagal syncope

OBJECTIVES This study was done to evaluate pacemaker therapy for severe recurrent vasovagal syncope. BACKGROUND Nonrandomized studies have suggested that permanent pacing might help control the symptoms of recurrent vasovagal syncope. The study goal was to evaluate the effect of permanent pacemaker implantation on syncope in patients with frequently recurrent vasovagal syncope. METHODS Patients with > or = 6 lifetime episodes of syncope and with a tilt-table test that induced syncope or presyncope, as well as a relative bradycardia, were randomized to receive a dual-chamber pacemaker or not. The pacemaker prevented bradycardia and provided high-rate pacing if a predetermined drop in heart rate occurred (rate-drop response). The primary outcome was the first recurrence of syncope. Patients also completed a detailed diary recording presyncopal episodes. RESULTS A total of 284 patients was originally planned and a pilot study of 60 patients was initiated. At the planned first formal interim analysis of efficacy of the pilot study, an unanticipated large treatment effect was observed which fulfilled the prespecified criteria for early termination of the study. At that time, there were 54 patients enrolled, randomized evenly to no pacemaker or to pacemaker. In the no-pacemaker and pacemaker groups the mean ages were 40 and 46 years; 74% and 70% patients, respectively, were female. The baseline tilt-table test showed a slowest heart <60/min or longest heart period >1000 ms in 60% of no-pacemaker patients and 72% of pacemaker patients. There was a marked reduction in the postrandomization risk of syncope in pacemaker patients (relative risk reduction 85.4%, 95% confidence interval 59.7% to 94.7%; 2p=0.000022). CONCLUSIONS Dual-chamber pacing with rate-drop response reduces the likelihood of syncope in patients with recurrent vasovagal syncope.

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.

Risk Factors for Syncope Recurrence After a Positive Tilt-Table⇓ Test in Patients With Syncope

BACKGROUND Recent work with head-up tilt-table testing has suggested that many patients with syncope may have recurrent neurally mediated episodes of bradycardia, hypotension, or both. The purpose of this study was to determine how to identify patients at high risk of a recurrence of neuromediated syncope after a positive isoproterenol/tilt-table test. METHODS AND RESULTS A cohort of 101 drug-free patients in a university hospital outpatient clinic with syncope and a positive isoproterenol/tilt-table test underwent baseline assessment of demographic variables, symptomatic burden, and hemodynamic and clinical responses to tilt testing. The primary outcome measure was the time to the first recurrent syncopal spell. The actuarial probabilities of remaining syncope free after 1 and 2 years were 72% and 60%, respectively. Multivariate proportional hazards analysis demonstrated that the most powerful predictor of a recurrence of syncope was the logarithm of the number of preceding syncopal spells (P<.001). Other predictive variables included the duration of syncopal symptoms, tilt test symptomatic outcome, and trough heart rate. The probability of a recurrence of syncope also varied with the logarithm of the frequency of preceding spells (P=.008). The median frequency of pretest spells was 0.3/month; after the tilt test, the median frequency dropped approximately 90% to 0.03 per month. CONCLUSIONS The risk of a recurrence of syncope after a positive tilt-table test can be predicted with simple pretest and intratest variables.

New-Onset Atrial Fibrillation

Background—Although sex differences in coronary artery disease have received considerable attention, few studies have dealt with sex differences in the most common sustained cardiac arrhythmia, atrial fibrillation (AF). Differences in presentation and clinical course may dictate different approaches to detection and management. We sought to examine sex-related differences in presentation, treatment, and outcome in patients presenting with new-onset AF. Methods and Results—The Canadian Registry of Atrial Fibrillation (CARAF) enrolled subjects at the time of first ECG-confirmed diagnosis of AF. Participants were followed at 3 months, at 1 year, and annually thereafter. Treatment was at the discretion of the patients’ physicians and was not directed by CARAF investigators. Baseline and follow-up data collection included a detailed medical history, clinical, ECG, and echocardiographic measures, medication history, and therapeutic interventions. Three hundred thirty-nine women and 560 men were followed for 4.1...

Identification of Patients Most Likely to Benefit From Implantable Cardioverter-Defibrillator Therapy The Canadian Implantable Defibrillator Study

BACKGROUND Patients with resuscitated ventricular tachyarrhythmias (ventricular tachycardia/ventricular fibrillation) benefit from implantable cardioverter-defibrillators (ICDs) compared with medical therapy. We hypothesized that the patients who benefit most from an ICD are those at greatest risk of death. METHODS AND RESULTS In the Canadian Implantable Defibrillator Study (CIDS), 659 patients with resuscitated ventricular tachyarrhythmias were randomly assigned to receive an ICD or amiodarone and were then followed for a mean of 3 years. There were 98 and 83 deaths in the amiodarone and ICD groups, respectively. We used multivariate Cox analysis to assess the impact of baseline parameters on the mortality in the amiodarone group. Reduced left ventricular ejection fraction, advanced age, and poor NYHA status identified high-risk patients (P=0.0001 to 0.0009). Quartiles of risk were constructed, and the mortality reduction associated with ICD treatment in each quartile was assessed. There was a significant interaction between risk quartile and the ICD treatment effect (P=0.011). In the highest risk quartile, there was a 50% relative risk reduction (95% CI 21% to 68%) of death in the ICD group, whereas in the 3 lower quartiles, there was no benefit. Patients who are most likely to benefit from an ICD can be identified with a simple risk score (>/=2 of the following factors: age >/=70 years, left ventricular ejection fraction </=35%, and NYHA class III or IV). Thirteen of 15 deaths that were prevented by the ICD occurred in patients with >/=2 risk factors. CONCLUSIONS In CIDS, patients at highest risk of death benefited most from ICD therapy. These can be identified easily on the basis of age, poor ventricular function, and poor functional status.

Developmental Changes in the Delayed Rectifier K+ Channels in Mouse Heart

Expression of cardiac transient outward current and inwardly rectifying K+ current is age dependent. However, little is known about age-related changes in cardiac delayed rectifier K+ current (IK, with rapidly and slowly activating components, IKr and IKs, respectively). Accordingly, the purpose of the present study was to assess developmental changes in IK channels in fetal, neonatal, and adult mouse ventricles. Three techniques were used: conventional microelectrode to measure the action potential, voltage clamp to record macroscopic currents of IK, and radioligand assay to examine [3H]dofetilide binding sites. The extent of prolongation of action potential duration at 95% repolarization (APD95) by a selective IKr blocker, dofetilide (1 mumol/L), dramatically decreased from fetal (137% +/- 18%) to day-1 (75% +/- 29%) and day-3 (20% +/- 15%) neonatal mouse ventricular tissues (P < .01). Dofetilide did not prolong APD95 in adult myocardium. IKr is the sole component of IK in day-18 fetal mouse ventricular myocytes. However, both IKr and IKs were observed in day-1 neonatal ventricular myocytes. With further development, IKs became the dominant component of IK in day-3 neonates. In adult mouse ventricular myocytes, neither IKr nor IKs was observed. Correspondingly, a high-affinity binding site for [3H]dofetilide was present in fetal mouse ventricles but was absent in adult ventricles. The complementary data from microelectrode, voltage-clamp, and [3H]dofetilide binding studies demonstrate that expression of the IK channel is developmentally regulated in the mouse heart.

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 &bgr;-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 ≥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 ≥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.

2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope

Robert S. Sheldon, Blair P. Grubb II, Brian Olshansky, Win-Kuang Shen, Hugh Calkins, Michele Brignole, Satish R. Raj, Andrew D. Krahn, Carlos A. Morillo, Julian M. Stewart, Richard Sutton, Paola Sandroni, Karen J. Friday, Denise Tessariol Hachul, Mitchell I. Cohen, Dennis H. Lau, Kenneth A. Mayuga, Jeffrey P. Moak, Roopinder K. Sandhu, Khalil Kanjwal