Bruce S. Stambler

Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing

BACKGROUND: Standard clinical practice permits the use of either single-chamber ventricular pacemakers or dual-chamber pacemakers for most patients who require cardiac pacing. Ventricular pacemakers are less expensive, but dual-chamber pacemakers are believed to be more physiologic. However, it is not known whether either type of pacemaker results in superior clinical outcomes. METHODS: The Pacemaker Selection in the Elderly study was a 30-month, single-blind, randomized, controlled comparison of ventricular pacing and dual-chamber pacing in 407 patients 65 years of age or older in 29 centers. Patients received a dual-chamber pacemaker that had been randomly programmed to either ventricular pacing or dual-chamber pacing. The primary end point was health-related quality of life as measured by the 36-item Medical Outcomes Study Short-Form General Health Survey. RESULT: The average age of the patients was 76 years (range, 65 to 96), and 60 percent were men. Quality of life improved significantly after pacemaker implantation (P<0.001), but there were no differences between the two pacing modes in either the quality of life or prespecified clinical outcomes (including cardiovascular events or death). However, 53 patients assigned to ventricular pacing (26 percent) were crossed over to dual-chamber pacing because of symptoms related to the pacemaker syndrome. Patients with sinus-node dysfunction, but not those with atrioventricular block, had moderately better quality of life and cardiovascular functional status with dual-chamber pacing than with ventricular pacing. Trends of borderline statistical significance in clinical end points favoring dual-chamber pacing were observed in patients with sinus-node dysfunction, but not in those with atrioventricular block. CONCLUSION: The implantation of a permanent pacemaker improves health-related quality of life. However, the quality-of-life benefits associated with dual-chamber pacing as compared with ventricular pacing are observed principally in the subgroup of patients with sinus-node dysfunction.

Efficacy and Safety of Repeated Intravenous Doses of Ibutilide for Rapid Conversion of Atrial Flutter or Fibrillation

Background Currently available antiarrhythmic drugs have limited efficacy for acute termination of atrial fibrillation and flutter, especially if the arrhythmia is not of recent onset. The purpose of this multicenter study was to determine the efficacy and safety of repeated doses of intravenous ibutilide, a class III antiarrhythmic drug, in terminating atrial fibrillation or flutter. Methods and Results Two hundred sixty-six patients with sustained atrial fibrillation (n=133) or flutter (n=133), with an arrhythmia duration of 3 hours to 45 days, were randomized to receive up to two 10-minute infusions, separated by 10 minutes, of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo. The conversion rate was 47% after ibutilide and 2% after placebo ( P <.0001). The two ibutilide dosing regimens did not differ in conversion efficacy (44% versus 49%). Efficacy was higher in atrial flutter than fibrillation (63% versus 31%, P <.0001). In atrial fibrillation but not flutter, conversion rates were higher in patients with a shorter arrhythmia duration or a normal left atrial size. Arrhythmia termination occurred a mean of 27 minutes after start of the infusion. Of 180 ibutilide-treated patients, 15 (8.3%) developed polymorphic ventricular tachycardia during or soon after the infusion. The arrhythmia required cardioversion in 3 patients (1.7%) and was nonsustained in 12 patients (6.7%). Conclusions Intravenous ibutilide given in repeated doses is effective in rapidly terminating atrial fibrillation and flutter and under monitored conditions is an alternative to current cardioversion options.

Efficacy of intravenous ibutilide for rapid termination of atrial fibrillation and atrial flutter: A dose-response study☆

OBJECTIVES Currently available antiarrhythmic drugs have limited efficacy for short-term, rapid termination of atrial fibrillation and atrial flutter. BACKGROUND Ibutilide fumarate is an investigational class III antiarrhythmic agent that prolongs repolarization by increasing the slow inward sodium current and by blocking the delayed rectifier current. It can be administered intravenously and has a rapid onset of electrophysiologic effects. METHODS The efficacy and safety of ibutilide were studied in 200 patients with atrial flutter > 3 h in duration or atrial fibrillation 3 h to 90 days in duration. Patients were randomized to receive a single intravenous dose of placebo or an infusion of ibutilide fumarate at 0.005, 0.010, 0.015 or 0.025 mg/kg body weight over 10 min. Conversion was defined as termination of the atrial arrhythmia during or within 60 min after infusion. Forty-one patients received placebo and 159 received ibutilide (0.005 mg/kg [n = 41], 0.010 mg/kg [n = 40], 0.015 mg/kg [n = 38] or 0.025 mg/kg [n = 40]). RESULTS The arrhythmia terminated in 34% of drug-treated patients. The rates of successful arrhythmia termination were 3% for placebo and 12%, 33%, 45% and 46%, respectively, for 0.005-, 0.010-, 0.015- and 0.025-mg/kg ibutilide. The placebo and 0.005-mg/kg ibutilide groups had lower success rates than all other dose groups (p < 0.05). The mean time to termination of the arrhythmia was 19 min (range 3 to 70) from the start of infusion. Successful arrhythmia termination was not affected by enlarged left atrial diameter, decreased ejection fraction, presence of valvular heart disease or the use of concomitant medications (beta-adrenergic blocking agents, calcium channel blocking agents or digoxin). Arrhythmia termination was not predicted by the magnitude of corrected QT interval prolongation but was associated with a shorter duration of atrial arrhythmia. The most frequent adverse events in ibutilide-treated patients were sustained and nonsustained polymorphic ventricular tachycardia (3.6%). All patients with sustained polymorphic ventricular tachycardia were successfully treated with direct current cardioversion and had no recurrence. The occurrence of proarrhythmia did not correlate with ibutilide plasma concentration. CONCLUSIONS These data demonstrate that ibutilide is able to rapidly terminate atrial fibrillation and atrial flutter.

Impact of QRS duration on clinical event reduction with cardiac resynchronization therapy: meta-analysis of randomized controlled trials.

BACKGROUND Cardiac resynchronization therapy (CRT) is effective in reducing clinical events in patients with heart failure and prolonged QRS interval. Studies using surrogate measures and subgroup analysis of large trials suggest that only patients with severely prolonged QRS benefit from CRT. Our objective was to determine whether the effect of CRT on adverse clinical events (eg, death, hospitalizations) is different in patients with moderately (ie, 120 to 149 milliseconds) [corrected] vs severely (ie, ≥150 milliseconds) prolonged QRS duration. METHODS Searches of MEDLINE, SCOPUS, and Cochrane databases were conducted for randomized controlled CRT trials. Trials reporting clinical events according to different QRS ranges were identified. Five randomized trials fulfilling the inclusion criteria (total patients, n = 5813) were included in the meta-analysis. RESULTS In patients with severely prolonged QRS, there was a reduction in composite clinical events with CRT (risk ratio, 0.60; 95% confidence interval [CI], 0.53-0.67) (P < .001). In contrast, there was no benefit of CRT in patients with moderately prolonged QRS (RR, 0.95; 95% CI, 0.82-1.10) (P = .49), resulting in a significantly different impact of CRT in the 2 QRS groups (P < .001). There was a significant relationship between baseline QRS duration and risk ratio (P < .001) with benefit of CRT appearing at a QRS of approximately 150 milliseconds and above. The differential response of the 2 QRS groups was evident for all New York Heart Association classes. CONCLUSIONS Cardiac resynchronization therapy was effective in reducing adverse clinical events in patients with heart failure and a baseline QRS interval of 150 milliseconds or greater, but CRT did not reduce events in patients with a QRS of less than 150 milliseconds. These findings have implications for the selection of patients for CRT.

Right Ventricular Outflow Versus Apical Pacing in Pacemaker Patients with Congestive Heart Failure and Atrial Fibrillation

Introduction: Prior studies suggest that right ventricular apical (RVA) pacing has deleterious effects. Whether the right ventricular outflow tract (RVOT) is a more optimal site for permanent pacing in patients with congestive heart failure (CHF) has not been established.

Antiarrhythmic Actions of Intravenous Ibutilide Compared With Procainamide During Human Atrial Flutter and Fibrillation Electrophysiological Determinants of Enhanced Conversion Efficacy

BACKGROUND The selective class III antiarrhythmic agent ibutilide prolongs action potential duration and terminates atrial flutter (AFL) and fibrillation (AF), but the mechanism of its antiarrhythmic efficacy in humans has not been fully characterized. This study compared the antiarrhythmic effects of ibutilide with the class IA agent procainamide in humans during AFL and AF. Antiarrhythmic drug actions and electrophysiological characteristics of AFL and AF that enhanced pharmacological termination were investigated. METHODS AND RESULTS Right atrial monophasic action potentials were recorded during 148 episodes of AFL (n=89) or AF (n=59) in 136 patients treated with intravenous ibutilide (n=73) or placebo (n=22) as participants in randomized, double-blinded comparative studies or intravenous procainamide (n=53) in a concurrent open-label study. The conversion rates in AFL with ibutilide, procainamide, and placebo were 64% (29 of 45 patients), 0% (0 of 33), and 0% (0 of 11), respectively, whereas in AF the rates were 32% (9 of 28), 5% (1 of 20), and 0% (0 of 11), respectively. In AFL, ibutilide increased atrial monophasic action potential duration (MAPD) more (30% versus 18%, P<.001) and prolonged atrial cycle length (CL) less (16% versus 26%, P<.001) than procainamide. Ibutilide shortened and procainamide prolonged action potential diastolic interval during AFL (-12% versus 51%, P<.001). Ibutilide increased MAPD/CL ratio, whereas procainamide tended to decrease this ratio (13% versus -6%, P<.01). In AF, ibutilide and procainamide induced similar increases in atrial CL (48% versus 45%), but ibutilide induced a greater increase in MAPD (52% versus 37%, P<.05). Independent electrophysiological predictors of pharmacological arrhythmia termination were increase in MAPD/CL ratio (P=.005) in AFL and longer baseline mean MAPD (P=.011) in AF. Termination of AFL with ibutilide was characterized by significant increases in beat-to-beat atrial CL, MAPD, and diastolic interval variability. Ibutilide was significantly more effective in converting AF when the mean atrial CL was > or = 160 ms (64% versus 0%, P<.001) or MAPD was > or = 125 ms (57% versus 0%, P=.002) at baseline. CONCLUSIONS Enhanced conversion efficacy of ibutilide compared with procainamide in AFL is correlated with a relatively greater prolongation of atrial MAPD than atrial CL, and termination of AFL by ibutilide is characterized by oscillations in atrial CL and MAPD. Conversion of AF by ibutilide is enhanced by a longer baseline mean atrial CL or MAPD.

Cardiovascular Safety Profile of Combretastatin A4 Phosphate in a Single-Dose Phase I Study in Patients with Advanced Cancer

Purpose: The purpose of our study was to review and determine the cardiovascular safety profile of combretastatin A4 phosphate (CA4P) in a Phase I study in 25 patients with advanced solid tumors. Experimental Design: CA4P was administered in a dose-escalating fashion starting at 18 mg/m2 i.v. every 21 days, and the maximal dosage was 90 mg/m2. Continuous evaluation included bedside blood pressure and pulse monitoring, 12-lead electrocardiogram (ECG) at fixed time points for measured QT interval determination, determination of the corrected QT interval (QTc) using Bazett’s formula QTc = QT/(R-R interval)1/2, and chart review. Pharmacodynamic correlations of CA4P dose, CA4P/CA4 area under the curve, and Cmax versus heart rate (HR), blood pressure, QT, and QTc intervals, over the first 4 h postdosing were analyzed. Results: After CA4P administration, there were significant increases in QTc interval at the 3-h and 4-h time points [27.2 ms (P < 0.0001) and 30.8 ms (P < 0.0001), respectively] and HR at the 3- and 4-h time points [13.2 beats per minute (bpm; P < 0.01) and 15.1 bpm (P < 0.001), respectively]. Three of 25 patients had prolonged QTc intervals at baseline, whereas 15 (60%) of 25 and 18 (75%) of 24 patients had prolonged QTc intervals at 3 and 4 h. The slope of HR and QTc increasing as a function of time during the first 4 h was correlated to dose (in milligrams) of CA4P (P = 0.01 and r = 0.49 for HR, P = 0.005 and r = 0.55 for QTc) and to CA4 area under the curve (P = 0.04 and r = 0.41 for HR, P = 0.02 and r = 0.44 for QTc); blood pressure and uncorrected QTc interval dose-response correlations were not significant. Two patients had ECG changes consistent with an acute coronary syndrome within 24 h of CA4P infusion. Conclusions: CA4P prolongs the QTc interval. There was a temporal relationship with the CA4P infusion and with ECG changes consistent with an acute coronary syndrome in two patients. It is advisable that future trials with CA4P have eligibility guidelines limiting patients with known coronary artery disease or those with multiple coronary artery disease risk factors until more experience is gained regarding potential cardiovascular toxicity with this agent.

Swelling-Activated Chloride Current Is Persistently Activated in Ventricular Myocytes From Dogs With Tachycardia-Induced Congestive Heart Failure

The hypothesis that cellular hypertrophy in congestive heart failure (CHF) modulates mechanosensitive (ie, swelling- or stretch-activated) anion channels was tested. Digital video microscopy and amphotericin-perforated-patch voltage clamp were used to measure cell volume and ion currents in ventricular myocytes isolated from normal dogs and dogs with rapid ventricular pacing-induced CHF. In normal myocytes, osmotic swelling in 0.9T to 0.6T solution (T, relative osmolarity; isosmotic solution, 296 mOsmol/L) was required to elicit ICl,swell, an outwardly rectifying swelling-activated Cl- current that reversed near -33 mV and was inhibited by 1 mmol/L 9-anthracene carboxylic acid (9AC), an anion channel blocker. Block of ICl,swell by 9AC simultaneously increased the volume of normal cells in hyposmotic solutions by up to 7%, but 9AC had no effect on volume in isosmotic or hyperosmotic solutions. In contrast, ICl,swell was persistently activated under isosmotic conditions in CHF myocytes, and 9AC increased cell volume by 9%. Osmotic shrinkage in 1.1T to 1.5T solution inhibited both ICl,swell and 9AC-induced cell swelling in CHF cells, whereas osmotic swelling only slightly increased ICl,swell. The current density for fully activated 9AC-sensitive ICl,swell was 40% greater in CHF than normal myocytes. In both groups, 9AC-sensitive current and 9AC-induced cell swelling were proportional with changes in osmolarity and 9AC concentration, and the effects of 9AC on current and volume were blocked by replacing bath Cl- with methanesulfonate. CHF thus altered the set point and magnitude of ICl,swell and resulted in its persistent activation. We previously observed analogous regulation of mechanosensitive cation channels in the same CHF model. Mechanosensitive anion and cation channels may contribute to the electrophysiological and contractile derangements in CHF and may be novel targets for therapy.

Mapping of Atrial Activation During Sustained Atrial Fibrillation in Dogs with Rapid Ventricular Pacing Induced Heart Failure: Evidence for a Role of Driver Regions

Introduction: Dogs with rapid ventricular pacing (RVP)‐induced congestive heart failure (CHF) have inducible atrial tachycardia, flutter, and fibrillation (AF). We tested the hypothesis that rapid atrial activation in multiple regions and at different rates is responsible for sustained AF in this CHF model.

Selective aldosterone blockade suppresses atrial tachyarrhythmias in heart failure

Introduction: Renin‐angiotensin‐aldosterone system activation may be involved in the pathogenesis of atrial arrhythmias in congestive heart failure (CHF). The effects of aldosterone blockade on atrial tachyarrhythmias have not been evaluated. This studys aim was to determine whether selective aldosterone blockade suppresses atrial tachyarrhythmia inducibility and modifies atrial electrical and/or structural remodeling in a canine model of rapid ventricular pacing (RVP)‐induced CHF.