David W. Richardson

Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial.

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.

Biobehavioral variables and mortality or cardiac arrest in the Cardiac Arrhythmia Pilot Study (CAPS)

The frequency of ventricular premature complexes and the degree of impairment of left ventricular ejection fraction are major predictors of cardiac mortality and sudden death in the year after acute myocardial infarction. Recent studies have implicated psychosocial factors, including depression, the interaction of social isolation and life stress, and type A-B behavior pattern, as predictors of cardiac events, controlling for known parameters of disease severity. However, results tend not to be consistent and are sometimes contradictory. The present investigation was designed to test the predictive association between biobehavioral factors and clinical cardiac events. This evaluation occurred in the context of a prospective clinical trial, the Cardiac Arrhythmia Pilot Study (CAPS). Five-hundred two patients were recruited with greater than or equal to 10 ventricular premature complexes/hour or greater than or equal to 5 episodes of nonsustained ventricular tachycardia, recorded 6 to 60 days after a myocardial infarction. Baseline behavioral studies, conducted in approximately 66% of patients, included psychosocial questionnaires of anxiety, depression, social desirability and support, and type A-B behavior pattern. In addition, blood pressure and pulse rate reactivity to a portable videogame was assessed. The primary outcome was scored on the basis of mortality or cardiac arrest. Results indicated that the type B behavior pattern, higher levels of depression and lower pulse rate reactivity to challenge were significant risk factors for death or cardiac arrest, after adjusting statistically for a set of known clinical predictors of disease severity. The implication of these results for future research relating behavioral factors to cardiac endpoints is discussed.

Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (The Cardiac Arrhythmia Pilot Study)

The Cardiac Arrhythmia Pilot Study (CAPS) was a randomized, double-blind trial of antiarrhythmic drugs (encainide, flecainide, moricizine, imipramine and placebo) in 502 patients with at least 10 ventricular premature complexes/hour, 6 to 60 days after acute myocardial infarction. CAPS tested the feasibility of performing a larger study to determine if suppression of ventricular ectopic activity after acute myocardial infarction could improve survival. Patients in CAPS were followed for 1 year. All death or cardiac arrest events were evaluated by at least 2 investigators using a classification scheme that characterized the underlying mechanism as cardiac arrhythmic, cardiac nonarrhythmic or noncardiac. Forty-five patients (9%) died or had cardiac arrest during the 1-year follow-up, 29 (64%) within 1 hour from the onset of symptoms and 16 greater than 1 hour from the onset of symptoms. Twenty-three deaths (51%) were classified as arrhythmic, 19 (42%) as nonarrhythmic and 3 (7%) as noncardiac. Acute myocardial ischemia or infarction was associated with the death/cardiac arrest event in 16 patients (36%), 8 in the arrhythmic death group. Discrepancies in classification among reviewers were particularly common in patients with long-standing symptoms of congestive heart failure, in whom it was frequently difficult to identify the precise moment of the onset of symptoms in the death/cardiac arrest event. Using only the temporal relation of symptoms to categorize deaths or cardiac arrests, the mechanism of 12 (27%) of the 45 patients was in disagreement with the classification based on the Events Committee review. Classification of death as sudden or nonsudden is not equivalent to the classification of death as arrhythmic or nonarrhythmic.

Intracoronary thrombus in syndromes of unstable myocardial ischemia

The association of coronary thrombosis and transmural myocardial infarction is well documented. We have recently observed apparent intracoronary thrombi in patients with unstable myocardial ischemia without transmural infarction. To assess the frequency and angiographic characteristics of intracoronary defects consistent with thrombi, we reviewed the angiograms of all patients undergoing catheterization within 1 month of the onset of unstable angina or the intermediate coronary syndrome. Of 129 such patients, eight (6.2%) had nonoccluding, hazy, or nonopacified intracoronary filling defects consistent with thrombus in angiographically well-opacified vessels. All defects were just distal to a significant (80% to 99%) coronary stenosis. In each instance the thrombus-involved vessel supplied a myocardial segment referable to the electrocardiographically defined area of ischemia. Support for the theory that the intracoronary defects were thrombi includes three patients with enlargement of the filling defects, who underwent repeat angiography within 7 days, and two patients with embolization of defect fragments. Furthermore these defects were angiographically similar to poststenotic intraluminal defects seen transiently in some patients after partial intracoronary streptokinase recanalization. In conclusion, we have observed, angiographically, intracoronary filling defects consistent with thrombus in some patients with unstable myocardial ischemia.

Norepinephrine Depletion in Idiopathic Orthostatic Hypotension

Five patients with idiopathic orthostatic hypotension and defective vasoconstrictor responses to the Valsalva maneuver and to application of ice to the forehead were found to have absent vasoconstriction in the forearm in response to intra-arterial administration of tyramine and enhanced vasoconstrictor responses in response to intra-arterial administration of norepinephrine. These findings strongly suggested norepinephrine depletion from the nerve endings and inability of the sympathetic nerve endings to take up norepinephrine. The depletion of norepinephrine from sympathetic nerve endings was confirmed in four patients by demonstrating histochemically the absence of catecholamine-specific fluorescence in sympathetic vasomotor nerves from deltoid muscle. It is suggested that depletion of norepinephrine from nerve endings was responsible for autonomic dysfunction and orthostatic hypotension in these patients.

Mechanisms of Renal Release of Renin by Electrical Stimulation of the Brainstem in the Cat

Electrical stimulation of the dorsolateral pons for 5-minute periods in anesthetized cats produced a rise in blood pressure of 40%, a reduction in renal blood flow of 28%, and an increase in the rate of renin release (the product of renal plasma flow and the venoarterial difference of plasma renin activity) of more than 100% in intact kidneys. Comparison of an intact kidney with the contralateral denervated one showed that denervation abolished the decrease in renal blood flow and the increase in renin release induced by pontine stimulation. Infusion of phenoxybenzamine into an otherwise intact kidney prevented the decrease in renal blood flow on that side, but brain-induced renin release was at least equal to that from the contralateral kidney in which the vasomotor response remained unchanged. Treatment of the animal with intravenously administered propranolol (1.3–3.0 mg/kg) abolished any rise in renin release, although propranolol accentuated the reduction in renal blood flow during stimulation of the brainstem. We concluded that the increased renal release of renin induced by electrical stimulation of a pressor area of the brainstem was dependent on intact renal nerves and on mechanisms blocked by propranolol but was not dependent on changes in renal blood flow or on renal alpha receptors.

Modification by Beta-Adrenergic Blockade of the Circulatory Responses to Acute Hypoxia in Man*

In 17 healthy men, beta-adrenergic blockade reduced significantly the tachycardia and the elevation of cardiac output associated with inhalation of 7.5% oxygen for 7 to 10 minutes. Hypoxia did not increase plasma concentrations of epinephrine or norepinephrine in six subjects. Furthermore, blockade of alpha and beta receptors in the forearm did not modify the vasodilation in the forearm induced by hypoxia, providing pharmacologic evidence that hypoxia of the degree and duration used was not associated with an increase in the concentrations of circulating catecholamines in man. Part of the increase in cardiac output and heart rate during acute hypoxia in man is produced by stimulation of beta-adrenergic receptors, probably by cardiac sympathetic nerves. The mechanism of the vasodilation in the forearm during hypoxia remains uncertain.

Effect of Propranolol on Elevated Arterial Blood Pressure

Nineteen patients with moderately severe arterial hypertension received propranolol (120 mg daily), or chlorthalidone (100 mg daily), both medications together, and placebos in a double-blind crossover trial. Each treatment was given for 5 weeks; blood pressure was measured at weekly intervals. Propranolol alone reduced arterial pressure by 9/8 mm Hg, a statistically insignificant change. Use of chlorthalidone alone was accompanied by an average reduction in arterial blood pressure of 23/9 mm Hg. Both drugs together lowered blood pressure by 33/15 mm Hg. Heart rate was lower in regimens including propranolol; body weight and serum potassium and chloride concentration were lower and blood urea nitrogen and serum creatinine were higher in regimens containing chlorthalidone. Propranolol, in the dose given, is a less effective hypotensive drug than is chlorthalidone.

Circulatory Effects of Guanethidine Clinical, Renal, and Cardiac Responses to Treatment with a Novel Antihypertensive Drug

Guanethidine, a new synthetic hypotensive drug that probably interferes with release of norepinephrine from sympathetic nerve endings and that does not inhibit parasympathetic activity, has proved an effective agent in reducing blood pressure in 25 hypertensive patients studied for periods up to 6 months. Untoward effects have been limited to orthostatic hypotension and mild diarrhea. The drug apparently lowers blood pressure by reduction in cardiac output rather than by relaxation of the arterioles. Reduction in renal blood flow and glomerular filtration rate accompanied administration of the drug, but in no case did progressive azotemia or oliguria occur. This agent is an extremely potent hypotensive drug with a remarkably prolonged duration of action and with none of the parasympatholytic side effects produced by ganglionic-blocking agents.

Anticoagulants in acute myocardial infarction. The failure of anticoagulants to alter mortality in a randomized series.

Abstract 1. 1. The effect of anticoagulation therapy on mortality and morbidity in 147 consecutive male patients with acute myocardial infarction was evaluated. 2. 2. The patients were divided into three groups: those adequately anticoagulated, those inadequately anticoagulated, and those not anticoagulated. The patients were randomly assigned, and the groups were shown to be comparable, except for an increased incidence of a history of previous heart failure in the untreated group. 3. 3. There was no significant reduction in mortality in the anticoagulated groups when compared to the control group. 4. 4. The incidence of thromboemboli was too low to be of significance in assessing the effects of anticoagulants as antithrombotic agents. 5. 5. We conclude from this study that routine anticoagulation therapy is not indicated in acute myocardial infarction, and that factors other than those affected by anticoagulants determine the prognosis in this disease.