Purpose: To describe mode of death and identify factors associated with cardiac and non-cardiac death in the MADIT-RIT trial. Methods: The trial randomized 1500 patients with a prophylactic indication for ICD or CRT-D to one of three ICD programming arms: (A) conventional programming (VT zone ≥ 170 bpm); (B) high-rate cut-off (VT zone ≥ 200 bpm); and (C) prolonged 60 second delay before therapy. Multivariate Cox model with best subset regression was used to identify predictors of cardiac- and non-cardiac death. Results: During a mean follow-up of 1.4±0.6 years, 71 (5%) of 1500 patients died, including 40 cardiac (56.3%), 23 non-cardiac (32.4%) and 8 unknown (11.3%). Of the 40 cardiac deaths, 14 died of arrhythmic causes, 21 of causes related to heart failure and 5 of unspecified cardiac causes. Of the 23 non-cardiac deaths, 5 were vascular, 8 were cancerous, 10 were for non-cardiac diseases. Randomization to conventional ICD programming (A) was identified as an independent predictor of cardiac and non-cardiac death compared to arm B, but not when compared to arm C. Predictors of cardiac death included lower diastolic blood pressure, lower ejection fraction, ischemic cardiomyopathy, appropriate shock and inappropriate ATP only (Table). Predictors of non-cardiac death included hypertension, NYHA class III, ICD:CRT-D, increased age and inappropriate shock (Table). Table 1. Cardiac and non-cardiac mortality Adjusted for time-dependent appropriate ATP only, which was not associated with cardiac or non-cardiac death (p=0.99, p=0.63, respectively). Conclusion: Cardiac and non-cardiac mortality was associated with different clinical characteristics and different types of ICD therapy.

Introduction: The randomized Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) was designed to determine if prophylactic cardiac resynchronization therapy with defibrillator (CRT-D) would reduce the primary end point (all cause mortality or heart failure events [iv diuretic Rx or hospitalization Rx for HF], whichever occurred first, when compared to patients receiving only an implanted cardiac defibrillator (ICD-only). The study population involved patients with ischemic (NYHA I & II) and non-ischemic (NYHA II) cardiomyopathy with ejection fraction ≤0.30 and QRS ≥ 130ms.

Background: We conducted a study of chronic therapy with flecainide versus placebo in a small group of LQT‐3 patients with the ΔKPQ deletion to evaluate the safety and efficacy of flecainide in this genetic disorder. In vitro studies have shown that flecainide provides correction of the impaired inactivation associated with the ΔKPQ deletion.Methods:A randomized, double‐blind, placebo‐controlled clinical trial was conducted with flecainide and placebo in six male LQT‐3 subjects with the ΔKPQ deletion.Results:The lowest possible dose of flecainide associated with at least a 40 ms reduction in the QTc interval was determined in an initial open‐label, dose‐ranging investigation using one‐fourth or half of the recommended maximal antiarrhythmic flecainide dose. QTc reduction was achieved with a flecainide dose of 1.5 mg/kg per day in 4 subjects and with 3.0 mg/kg per day in 2 subjects. Subjects were randomized to four 6‐month alternating periods of flecainide and placebo therapy based on the open‐label dose findings. Average QTc values during placebo and flecainide therapies were 534 ms and 503 ms, respectively, with an adjusted reduction in QTc of −27.1 ms (95% confidence interval: −36.8 ms to −17.4 ms; P < 0.001) at a mean flecainide blood level of 0.11 ±0.05 μg/ml. Minimal prolongation in QRS occurred (mean: +2.5 ms), and there were no major adverse cardiac effects.Conclusions:Chronic low‐dose flecainide significantly shortens the QTc interval in LQT‐3 subjects with the ΔKPQ mutation. No major adverse drug effects were observed with flecainide during this trial, but the sample size is not large enough to evaluate the safety of flecainide therapy in patients with this mutation.

BACKGROUND:Patients with nonischemic dilated cardiomyopathy are at substantial risk for sudden death from cardiac causes. However, the value of prophylactic implantation of an implantable cardioverter-defibrillator (ICD) to prevent sudden death in such patients is unknown.METHODS:We enrolled 458 patients with nonischemic dilated cardiomyopathy, a left ventricular ejection fraction of less than 36 percent, and premature ventricular complexes or nonsustained ventricular tachycardia. A total of 229 patients were randomly assigned to receive standard medical therapy, and 229 to receive standard medical therapy plus a single-chamber ICD.RESULTS:Patients were followed for a mean (+/-SD) of 29.0+/-14.4 months. The mean left ventricular ejection fraction was 21 percent. The vast majority of patients were treated with angiotensin-converting-enzyme (ACE) inhibitors (86 percent) and beta-blockers (85 percent). There were 68 deaths: 28 in the ICD group, as compared with 40 in the standard-therapy group (hazard ratio, 0.65; 95 percent confidence interval, 0.40 to 1.06; P=0.08). The mortality rate at two years was 14.1 percent in the standard-therapy group (annual mortality rate, 7 percent) and 7.9 percent in the ICD group. There were 17 sudden deaths from arrhythmia: 3 in the ICD group, as compared with 14 in the standard-therapy group (hazard ratio, 0.20; 95 percent confidence interval, 0.06 to 0.71; P=0.006).CONCLUSIONS:In patients with severe, nonischemic dilated cardiomyopathy who were treated with ACE inhibitors and beta-blockers, the implantation of a cardioverter-defibrillator significantly reduced the risk of sudden death from arrhythmia and was associated with a nonsignificant reduction in the risk of death from any cause.

Increased repolarization variability has been observed in various cardiac conditions. However, data on its relation to heart rate variability and on its value in predicting adverse outcomes in high risk patients are limited. Forty-seven patients with decreased left ventricular function and ICDs had high resolution 10-minute ECG recordings and were followed for 781 +/- 258 days (mean +/- SD) on average. The interval from the R peak to the T wave peak with maximum amplitude (RTmax) and from the R peak to the T wave offset (RToff) were determined automatically on a beat-to-beat basis. Temporal beat-to-beat RTmax and RToff variability were analyzed using traditional summary statistics, a complexity measure (approximate entropy [ApEn]), and the short-term scaling exponent (alpha(1)). Eight (17%) patients died and 16 (34%) patients experienced death/appropriate ICD shock during follow-up. RTmax-ApEn was significantly higher in patients who died compared with patients who survived (1.24 +/- 0.13 vs 1.01 +/- 0.21, respectively, P = 0.008). When RTmax-ApEn was tested together with the alpha(1) of the RR intervals, occurrence of ventricular arrhythmias before ICD implantation, and beta-blockers usage in the Cox regression analysis, it still independently predicted mortality; hazard ratio = 3.36 (1.28-8.83, 95% CI, P = 0.014) for every 0.10-increase in RTmax-ApEn. None of the repolarization variability parameters independently predicted death/appropriate ICD shocks. Increased temporal complexity of repolarization (RTmax-ApEn) independently predicts mortality in ICD patients.

For some time now, cardiologists have labored to identify coronary patients at high risk for arrhythmic death by noninvasive methods and develop effective protective pharmacologic therapies. This strategy has increasingly floundered on both fronts. Risk stratification using ventricular function in patients with and without congestive heart failure has had the greatest prognostic value in predicting overall survival but has had lesser impact with respect to sudden cardiac death survival (1,2). Signal-averaged electrocardiography and ambulatory electrocardiograph monitoring analyses have had a limited role to date as predictors of arrhythmic events largely due only to a modest specificity and predictive accuracy (3). Exercise testing has also had low sensitivity. Newer approaches such as heart rate variability, while promising, are yet to be

The treatment of ventricular arrhythmias in the elderly population is a challenging problem. Elderly patients are more predisposed to arrhythmias, are less responsive to antiarrhythmic agents and are more susceptible to the adverse effects of antiarrhythmic agents. Results from recent trial have altered the general approach to management of ventricular arrhythmias. The results of the Cardiac Arrhythmia Suppression Trials (CAST I and II) exemplified the disappointing results from numerous other studies, revealing the overall lack of efficacy of class I agents in reducing mortality in patients with coronary artery disease and asymptomatic premature ventricular complexes (PVCs). The results of CAST I and II also demonstrated the higher likelihood of older patients developing ventricular arrhythmias and toxicity to antiarrhythmic agents. Combined results of these studies have discouraged empirical antiarrhythmic therapy, especially in older patients with asymptomatic PVCs. In contrast, secondary prevention trials with beta-blockers in post-myocardial infarction patients have shown definitive survival benefit and reduction in ventricular arrhythmias, especially in the older patient population. Smaller trials with amiodarone have also shown survival benefit in post-myocardial infarction patients with or without PVCs. Management of ventricular tachycardia and fibrillation has become less empirical and more systematic with use of electrophysiologically guided and/or Holter monitor-guided therapy. Sotalol and amiodarone are especially effective agents. The efficacy of implantable cardioverter/defibrillators are also being compared with medical therapy systematically in multicentre trials. In general, empirical antiarrhythmic therapy is discouraged especially in the treatment of asymptomatic PVCs and should be reserved for systematic use in life-threatening arrhythmias.