Faculty Bibliography

An example from the Cardiac Arrhythmia Suppression Trial (CAST) illustrates what we term the 'healthy responder' phenomenon. The hypothesis is that patients who respond to a given treatment are healthier than patients who do not respond. In observational studies this results in an apparent but not real benefit for the treatment. The unique design of CAST, namely, titration before randomization, allows illustration of this phenomenon since we can view the study as both a non-randomized as well as a randomized trial of therapy. We conclude that, in demonstration of a drug effect, randomized trials are essential

Three clinical trial designs for use in testing the effect of long-term drug therapy on an outcome are considered: empiric (randomization to one of several specified and fixed therapies); randomization followed by dose-adjustment of the drug; and dose adjustment followed by randomization of responders. It is shown that the latter, though some information may be lost and bias may be introduced, can be more efficient because of the reduction of noise. These results are illustrated using information gathered by the Cardiac Arrhythmia Pilot Study (CAPS) and Cardiac Arrhythmia Suppression Trial (CAST), the former being a pilot study using the second design, and the latter a large clinical trial adopting the third design. For CAST, the efficiency (represented by ratio of sample sizes) is 0.78 relative to the empiric design, and 0.6 relative to the design incorporating randomization followed by dose adjustment

BACKGROUND AND METHODS. In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo. RESULTS. Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo). After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.01), and 8 of noncardiac causes (3 receiving drug vs. 5 receiving placebo). Almost all cardiac deaths not due to arrhythmia were attributed to acute myocardial infarction with shock (11 patients receiving drug and 3 receiving placebo) or to chronic congestive heart failure (4 receiving drug and 2 receiving placebo). There were no differences between the patients receiving active drug and those receiving placebo in the incidence of nonlethal disqualifying ventricular tachycardia, proarrhythmia, syncope, need for a permanent pacemaker, congestive heart failure, recurrent myocardial infarction, angina, or need for coronary-artery bypass grafting or angioplasty. CONCLUSIONS. There was an excess of deaths due to arrhythmia and deaths due to shock after acute recurrent myocardial infarction in patients treated with encainide or flecainide. Nonlethal events, however, were equally distributed between the active-drug and placebo groups. The mechanisms underlying the excess mortality during treatment with encainide or flecainide remain unknown

The diagnosis of cor triatriatum in an adult was made from routine two-dimensional transthoracic echocardiography. The findings of aliasing and turbulence in the roof of the left atrium suggested pulmonary venous stenosis. A transesophageal echocardiogram defined both the hemodynamic features of nonobstructing cor triatriatum and the presence of isolated pulmonary venous stenosis. The clinical use of transesophageal echocardiography with color flow Doppler in the elucidation of complex anatomic substrate is demonstrated

The occurrence of ventricular premature depolarizations in survivors of myocardial infarction is a risk factor for subsequent sudden death, but whether antiarrhythmic therapy reduces the risk is not known. The Cardiac Arrhythmia Suppression Trial (CAST) is evaluating the effect of antiarrhythmic therapy (encainide, flecainide, or moricizine) in patients with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more ventricular premature beats per hour) after myocardial infarction. As of March 30, 1989, 2309 patients had been recruited for the initial drug-titration phase of the study: 1727 (75 percent) had initial suppression of their arrhythmia (as assessed by Holter recording) through the use of one of the three study drugs and had been randomly assigned to receive active drug or placebo. During an average of 10 months of follow-up, the patients treated with active drug had a higher rate of death from arrhythmia than the patients assigned to placebo. Encainide and flecainide accounted for the excess of deaths from arrhythmia and nonfatal cardiac arrests (33 of 730 patients taking encainide or flecainide [4.5 percent]; 9 of 725 taking placebo [1.2 percent]; relative risk, 3.6; 95 percent confidence interval, 1.7 to 8.5). They also accounted for the higher total mortality (56 of 730 [7.7 percent] and 22 of 725 [3.0 percent], respectively; relative risk, 2.5; 95 percent confidence interval, 1.6 to 4.5). Because of these results, the part of the trial involving encainide and flecainide has been discontinued. We conclude that neither encainide nor flecainide should be used in the treatment of patients with asymptomatic or minimally symptomatic ventricular arrhythmia after myocardial infarction, even though these drugs may be effective initially in suppressing ventricular arrhythmia. Whether these results apply to other patients who might be candidates for antiarrhythmic therapy is unknown

The efficacy of combination drug therapy in the suppression of ambient ventricular arrhythmia was retrospectively evaluated in a study of 49 patients discharged from the hospital taking 2 membrane-active antiarrhythmic agents. Thirty-one patients (63%) had ischemic heart disease, 15 had miscellaneous cardiac disorders and 3 were free of ostensible heart disease. Therapy in all patients had previously been unsuccessful with an average of 3.7 single membrane-active drugs. Antiarrhythmic agents were discontinued for at least 48 hours to determine baseline arrhythmia levels by Holter monitoring and maximal exercise treadmill testing. Ventricular premature beats were evaluated according to the grading system of Lown and Wolf. Data on ventricular ectopic activity were obtained during Holter monitoring and exercise testing for both a control ('drug-free') period and for a period of combination therapy. During the control period, ventricular tachycardia was recorded during 23% of monitored hours, and the level was nearly twofold greater during stress testing. After institution of combined therapy, the percent of monitored hours of arrhythmia were reduced during Holter monitoring, with a greater reduction in couplets and ventricular tachycardia than in single ventricular premature beats. Ventricular tachycardia was more difficult to provoke by exercise testing in patients taking combination therapy than in control subjects. These data indicate that combination therapy can significantly reduce the density of ventricular ectopic activity in patients refractory to monotherapy. During an average follow-up of 26 months, 23 patients (47%) were able to receive decreased drug dosages, affording diminished adverse effects and improved tolerance to long-term use