Steven N. Singh

Effects of amiodarone on the circadiam pattern of sudden cardiac death (department of veterans affairs Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy)

Some antiarrhythmic drugs have been shown to influence the circadian pattern of sudden cardiac death (SCD). The effect of chronic amiodarone therapy on this pattern is unknown. This study determines the circadian pattern of deaths in the Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy (CHF-STAT) and compares the distribution of SCD between the amiodarone and the placebo arms of the trial. CHF-STAT was a multicenter trial that determined whether amiodarone reduces mortality in patients with heart failure and asymptomatic ventricular arrhythmias. The time of death was retrospectively analyzed in patients who died from pump failure and SCD. In patients who died suddenly, the circadian pattern of deaths was compared between patients receiving amiodarone and those receiving placebo. In CHF-STAT, 274 patients died during follow-up. The time of death was available in 65 of the 74 patients who died from pump failure, and in 96 of the 139 patients who died suddenly. There was a circadian variation of all SCDs compared with other deaths with a distinct peak during the morning (p = 0.04). A similar morning peak of sudden cardiac death was found in both the amiodarone (n = 42) and the placebo (n = 54) groups, and the overall circadian pattern did not differ between them (p = 0.16). In contrast, death from pump failure occurred equally distributed over time. Thus, SCD occurs predominantly during the morning, whereas death from heart failure does not exhibit a morning peak. Amiodarone does not influence the circadian pattern of SCD.

Sotalol for refractory sustained ventricular tachycardia and nonfatal cardiac arrest

The efficacy and safety of sotalol were assessed by electrophysiologic testing and ambulatory recordings in 16 patients with recurrent sustained ventricular tachycardia (VT) or nonfatal cardiac arrest who were refractory to an average of 4.8 conventional antiarrhythmic agents. Twenty-four-hour ambulatory recordings were performed before and after sotalol therapy. Fourteen patients underwent baseline electrophysiologic study and sustained VT was inducible in 12. Oral sotalol (320 to 960 mg/day) completely suppressed inducible sustained VT in 7 patients (58%), with modification in 3 (25%). Ventricular premature complexes were suppressed from baseline (mean +/- standard deviation) 431 +/- 616 to 60 +/- 110/hr (p less than 0.03). After a mean follow-up of 19 +/- 7 months, 12 of 14 patients receiving sotalol treatment had successful suppression of ventricular premature complexes (60 +/- 85/hr) and remained clinically free of sustained VT, except 2 who needed additional antiarrhythmic drugs to suppress the recurrent sustained VT. One patient died suddenly after 25 months of sotalol treatment. No severe side effects were noted during sotalol therapy. This study demonstrates that sotalol is a well-tolerated, effective antiarrhythmic agent in patients at high-risk for sudden death. It appears to be beneficial in patients who did not benefit from multiple drug treatment.

Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects ☆

OBJECTIVESnWe investigated the acute and long-term hemodynamic and neurohumoral effects of the vasopeptidase inhibitor omapatrilat in human heart failure.nnnBACKGROUNDnAngiotensin-converting enzyme (ACE) inhibition constitutes a major advance in the treatment of chronic heart failure (CHF). Simultaneous inhibition of both neutral endopeptidase and ACE with omapatrilat may represent a new treatment strategy in CHF.nnnMETHODSnThree hundred and sixty-nine patients with symptomatic heart failure were randomized to double-blind treatment with omapatrilat (first 190 patients: 2.5 mg, 5 mg or 10 mg; last 179 patients: 2.5 mg, 20 mg or 40 mg once daily) for 12 weeks.nnnRESULTSnAcutely, the 10 mg, 20 mg and 40 mg doses of omapatrilat produced greater reductions in pulmonary capillary wedge pressure (PCWP), systolic blood pressure (SBP) and systemic vascular resistance compared with 2.5 mg. Higher doses were associated with greater increases in vasodilator and natriuretic peptides, in addition to ACE inhibition. After 12 weeks, omapatrilat 20 mg and 40 mg showed greater falls from baseline in PCWP (40 mg: 0 h to 12 h average change -7.3 +/- 0.8 mm Hg) and SBP (40 mg: -11.7 +/- 1.7 mm Hg) than 2.5 mg (both p < 0.01 vs. 2.5 mg). The incidence of adverse experiences and patient withdrawal were similar in all groups.nnnCONCLUSIONSnIn CHF, the acute hemodynamic benefit seen with higher doses of omapatrilat was associated with increases in plasma vasodilator and natriuretic peptide levels in addition to ACE inhibition. After 12 weeks, the hemodynamic benefit was maintained. Omapatrilat may be a promising new agent in CHF.

Effect of moricizine hydrochloride in reducing chronic high-frequency ventricular arrhythmia: Results of a prospective, controlled trial

The antiarrhythmic efficacy of moracizin HCl (Ethmozine), a new oral phenothiazine derivative, was evaluated in 20 patients with chronic high-frequency ventricular arrhythmia confirmed by multiple ambulatory electrocardiographic recordings. Comparison with 72 +/- 24 hours (+/- standard deviation) of ambulatory recordings on moracizin treatment (average dose 295 +/- 58 mg 3 times daily or 9.8 +/- 1.0 mg/kg/day) was made. Maximal treadmill exercise provocation of arrhythmia and echocardiographic studies to detect effects on left ventricular function were also compared. The group had an average of 378 +/- 97 ventricular premature beats (VPBs) per hour while receiving placebo, with a mean VPB grade of 3.4 +/- 1.1 (modified Lown). When the patients received moracizin HCl, VPB frequency was reduced 53% (p less than 0.01), to a mean VPB grade of 2.2 +/- 1.4 (p less than 0.05). Seventy percent of the patients (14 of 20) showed a reduction in VPB frequency that exceeded the maximal expected variation; in 3 the frequency did not change and in 3 it increased with moracizin HCl. Resting electrocardiographic changes consisted of modest prolongations of PR interval (0.03 second) and QRS duration (0.02 second); however, QT prolongation was not observed. Heart rate and blood pressure at rest and peak exercise, exercise-related arrhythmia, exercise durations and echocardiographic measures of left ventricular function were unchanged by moracizin HCl compared with placebo. Side effects of moracizin++ HCl at these dosages were minimal (diarrhea in 1 patient, dizziness in 1 and diaphoresis in 1), although 2 patients tested at higher dosages had sustained ventricular tachycardia that may have been related to moracizin HCl.(ABSTRACT TRUNCATED AT 250 WORDS)

Acebutolol and left ventricular function: Assessment by radionuclide angiography

We assessed the effects of acebutolol, a cardioselective beta blocker, on global and regional left ventricular function in 26 patients with chronic angina pectoris. All patients underwent rest and maximal supine bicycle exercise radionuclide angiography while on placebo and oral acebutolol (400 mg three times a day). Resting ejection fraction on placebo was 51 ± 3% and on acebutolol was 54 ± 3% (p < 0.05). No resting ejection fraction decreased ≥7%. Only one patient (resting ejection fraction 28% on placebo and 21% on acebutolol) developed signs of fluid retention. Exercise nuclear studies on placebo revealed responses consistent with coronary artery disease (abnormal ejection fraction response to exercise and regional wall motion abnormalities) in 24 of 26 patients. Peak exercise ejection fraction was of the same order on placebo and acebutolol (51 ± 3% and 54 ± 3%, p = NS). In four patients the ejection fraction response to exercise became normal and in five patients all regional wall motion abnormalities became normal on acebutolol. Cardioselective beta blockade with acebutolol in effective antianginal doses is safe and may improve resting and exercise ventricular function.

Relation between ventricular function and antiarrhythmic responses to sotalol

Abstract Sotalol, a unique β-receptor antagonist with additional class III antiarrhythmic action, has remarkable efficacy for suppression of ventricular and supraventricular arrhythmias. 1–6 Unlike other β blockers, sotalol significantly prolongs the myocardial action potential duration. This additional action of sotalol probably accounts for its greater antiarrhythmic efficacy and perhaps its minimal negative or positive inotropic action. Comparison of the effects of sotalol on ventricular premature complex (VPC) suppression in patients with normal and abnormal left ventricular function has not been well studied. We examined the efficacy of sotalol in the treatment of ventricular arrhythmia with respect to left ventricular function.

Hemodynamic effects of the class III antiarrhythmic drug, d-sotalol, in patients with congestive heart failure

In contrast to Vaughan Williams class I drugs, class III drugs, such as d-sotalol, may not be negative inotropic. These drugs block potassium ion channels and prolong repolarization, theoretically leading to improved contractility. We investigated the hemodynamic actions of acute intravenous administration of 1.5 mg/kg of d-sotalol in 28 patients with congestive heart failure randomized to receive placebo (n = 10) or active drug (n = 18) in a double-blind study. A Swan-Ganz catheter was placed in all patients > or = 16 hours before drug administration. All hemodynamic variables were assessed at baseline and 30 minutes and 1, 2, 4, 8, and 12 hours after administration of the drug. Electrocardiograms were obtained before and 1, 2, 4, and 12 hours after drug administration. The QT interval increased from 370 +/- 9 to 426 +/- 14 ms at 1 hour, whereas the QTc increased from 433 +/- 5 to 470 +/- 12 ms (both p < 0.001). The increase was still statistically significant at 12 hours. There was no change in the placebo group. Although heart rate decreased in the d-sotalol group (84 +/- 2 to 76 +/- 2 at 1 hour, p < 0.001), there were no changes in blood pressure or right atrial pressure. Cardiac index decreased slightly (2.0 +/- 0.2 to 1.9 +/- 0.1 mm Hg), consistent with the lower heart rate. Pulmonary capillary wedge pressure decreased from 18.9 +/- 2.4 to 17.9 +/- 1.9 mm Hg at 1 hour despite reduced cardiac index. We conclude that in contrast to class I, II, and IV antiarrhythmic drugs, d-sotalol exerts no clinically important acute hemodynamic actions at doses that produce electrophysiologic effects.

Long-Term Effect of Mexiletine on Left Ventricular Function and Relation to Suppression of Ventricular Arrhythmia

The effects of oral mexiletine on left ventricular (LV) ejection fraction (EF) and ventricular arrhythmias--and a possible relation between these effects--were evaluated during 3 months of therapy in 29 patients with chronic ventricular premature complexes (VPCs) and a moderately reduced to normal LVEF by 24-hour Holter monitoring and by radionuclide ventriculography at rest and during maximum tolerable exercise testing. After an average titration period of 13 days, a mean daily mexiletine dose of 739 mg was maintained throughout the treatment. At the end of titration and after 3 months of treatment, patients with a baseline LVEF less than or equal to 40% (group 2) responded with a median reduction of the hourly VPC rate by 90 and 81%, respectively, compared with 79 and 72% in those with a baseline LVEF greater than 40% (group 1). Couplets and runs of ventricular tachycardia were almost completely suppressed in nearly all patients. A single patient had a proarrhythmic increase in VPCs during treatment. Compared with baseline, there were no significant changes in resting or exercise LVEF after 1 or 3 months of treatment in either of the 2 groups of patients. No correlation was found between treatment-induced changes in arrhythmia frequency and in resting EF. No symptoms of congestive heart failure developed. The study confirms that long-term use of mexiletine is efficacious and relatively free of cardiac depressant effects even in patients with diminished LV function.

Costs and clinical consequences of suboptimal atrial fibrillation management

Atrial fibrillation (AF) places a considerable burden on the US health care system, society, and individual patients due to its associated morbidity, mortality, and reduced health-related quality of life. AF increases the risk of stroke, which often results in lengthy hospital stays, increased disability, and long-term care, all of which impact medical costs. An expected increase in the prevalence of AF and incidence of AF-related stroke underscores the need for optimal management of this disorder. Although AF treatment strategies have been proven effective in clinical trials, data show that patients still receive suboptimal treatment. Adherence to AF treatment guidelines will help to optimize treatment and reduce costs due to AF-associated events; new treatments for AF show promise for future reductions in disease and cost burden due to improved tolerability profiles. Additional research is necessary to compare treatment costs and outcomes of new versus existing agents; an immediate effort to optimize treatment based on existing evidence and guidelines is critical to reducing the burden of AF.

Role of aminophylline in refractory heart failure: a comparison to the vasodilator sodium nitroprusside, the old and the new

Aminophylline [(theophylline ethylene diamine (TED)] reportedly improves cardiac hemodynamics by lowering vascular resistances and increasing contractility. TED as used clinically has not been compared to the vasodilator sodium nitroprusside (NP). To assess the relative hemodynamic effects of these two commonly used agents, the following comparison was made.