Efficacy and safety of perhexiline maleate in refractory angina. A double-blind placebo-controlled clinical trial of a novel antianginal agent.

Despite large gains in the medical and surgical treatment of angina pectoris in the past two decades, many patients are refractory to conventional medical therapy and are unsuitable for a first or, more commonly, repeat coronary revascularization procedure. We evaluated the efficacy of perhexiline maleate, a drug with an antianginal mechanism of action in humans that is as yet unknown, by using a randomized double-blind placebo-controlled crossover design in 17 patients with refractory angina who continued to receive maximal antianginal therapy, typically including nitrates, a beta-blocker, and a calcium channel antagonist. In view of perhexiline's potential for hepatic and neurological toxicity, plasma drug levels were monitored and maintained in the 150-600 ng/ml range. Sixty-three percent of patients were judged perhexiline responders by objective exercise testing criteria, as compared with 18% of patients on placebo (p less than 0.05). By blinded review of subjective measures of anginal frequency and severity, 65% of patients noted an improvement while on perhexiline, whereas no patient identified the placebo phase with improvement. Side effects observed in 29% of patients were minor and related to transient elevations of blood levels of more than 600 ng/ml; no patient suffered hemodynamic or cardiac conduction abnormalities attributable to perhexiline. With attention to the pharmacokinetics of perhexiline's elimination in individual patients, this novel antianginal agent seems to be safe and effective and deserves further evaluation in patients already receiving maximal antianginal therapy who are not candidates for revascularization procedures.

Therapy of refractory symptomatic atrial fibrillation and atrial flutter: a staged care approach with new antiarrhythmic drugs.

One hundred nine patients with recurrent episodes of symptomatic atrial fibrillation or flutter, or both, who had failed one to five previous antiarrhythmic drug trials were treated with propafenone and, subsequently, sotalol if atrial fibrillation recurred. The clinical profile of the study group was as follows: age 63 +/- 13 years, left atrial anteroposterior dimension 4.4 +/- 0.9 cm and left ventricular ejection fraction 57 +/- 14%. Paroxysmal atrial fibrillation occurred in 56 patients (51%) and chronic atrial fibrillation occurred in 53 patients (49%). After loading and dose titration phases were completed, the maintenance doses of drugs were 450 to 900 mg/day for propafenone and 160 to 960 mg/day for sotalol. Life table estimates of the duration of freedom from atrial fibrillation were constructed for each drug trial. The percent of patients free of recurrent symptomatic arrhythmia at 6 months was 39% for propafenone and 50% for sotalol. The cumulative proportion of patients successfully treated with propafenone or sotalol, or both, by 6 months was 55% and remained relatively constant beyond that point. The incidence of intolerable side effects necessitating discontinuation of therapy ranged from 7% to 8%. Thus, despite previous unsuccessful drug trials, a substantial proportion of patients with recurrent symptomatic atrial fibrillation refractory to conventional therapy can be treated successfully and safely with newer antiarrhythmic drugs. Treatment failures tend to occur early in the course of follow-up, permitting easy identification of candidates for alternative therapeutic approaches.

Long-term oral propafenone therapy for suppression of refractory symptomatic atrial fibrillation and atrial flutter.

Sixty patients who had recurrent episodes of symptomatic atrial fibrillation or flutter, or both, and who had failed one to five prior drug trials were treated with open label oral propafenone hydrochloride. On a mean maximal tolerated dose of 795 +/- 180 mg/day, actuarial estimates of the percent of individuals free of recurrences of symptomatic atrial fibrillation/flutter during propafenone treatment were: 1 month, 54%; 3 months, 44% and 6 months, 40%. No individual baseline characteristic achieved statistical significance as a correlate of poor response to propafenone. Drug-related adverse reactions were reported in 22% of patients but were severe enough to require termination of propafenone in only 5%. Thus, oral propafenone is a useful and well tolerated drug for long-term suppression of symptomatic recurrences of atrial fibrillation/flutter despite a history of unresponsiveness to prior antiarrhythmic drug treatment.

Diagnostic implications for myocardial ischemia of the circadian variation of the onset of chest pain.

To determine whether the occurrence of chest pain is randomly distributed during the day and to study whether the time of onset is useful in discriminating among causes of chest pain, patients older than 30 years who presented to 7 emergency departments with a chief complaint of chest pain unexplained by trauma or chest x-ray abnormalities were studied. A total of 7,759 patients presented during the study period; of these, 3,990 presented within 6 hours of the onset of pain and were included in the primary analysis. Chest pain caused by acute myocardial infarction, unstable angina pectoris and stable angina pectoris was more likely to begin during the period from 6 AM to noon than would be expected if the onset were uniformly distributed during the day (relative risks 1.15, 1.29 and 1.32, respectively), but chest pain that was caused by nonischemic cardiac causes and by noncardiac causes was also more likely to begin during the same time period (relative risks 1.28 and 1.17). Although chest pain from coronary arterial causes had a distinct circadian variation, the time of onset of pain was not a helpful criterion for determining the cause of chest pain.