This progress report on the prospective randomized study of the effect of coronary bypass surgery on prognosis presents the results of a minimum follow-up of 4 years. Seven hundred sixty-eight patients were recruited; all were men younger than age 65 years who had mild-to-moderate angina pectoris, at least two-vessel disease, and good left ventricular function. Of these, 373 were randomized to medical treatment and 395 to surgical treatment. Although 83 "medical" patients subsequently underwent surgery and 27 "surgical" patients did not undergo surgery, these patients were not excluded from the analysis, and the group randomized to coronary bypass surgery was compared with the group randomized to medical treatment. The surgical treatment group showed significantly better survival than the medical treatment group in the total patient population (p less than 0.001), particularly among patients with three-vessel disease (p less than 0.001). Although the 24% higher survival among surgical patients with left main coronary artery disease failed to reach statistical significance, the trend is probably meaningful. No significant difference in survival between medical and surgical treatment groups was noted in patients with two-vessel disease.

The current status of the Veterans Administration Cooperative Study of the effect of surgery on survival in patients with stable angina is presented. The outcome in 686 adult males randomly allocated to medical or surgical treatment groups in 1972-1974 was studied in subgroups of patients classified by invasive (arteriographic) and noninvasive risk factors. In 91 patients with left main lesions reducing the luminal diameter 50% or more, surgery significantly improved survival in the two-thirds characterized as middle or high risk by four simple noninvasive predictors of prognosis (New York Heart Association functional classification III or IV, history of myocardial infarction, history of hypertension, and ST-segment depression on the resting baseline ECG as assessed on a centralized reading). Patients with three-vessel disease and no significant disease of the left main coronary artery also had better survival rates when treated surgically. However, this was statistically significant at 6 years only in the 10 hospitals in which the aggregate operative mortality was 3.3%. Patients without left main lesions were also categorized by four noninvasive predictors of risk. Categorizing such patients into roughly equal groups of high, middle, and low risk identified a high-risk group, in which surgery was associated with statistically improved survival, and low- and middle-risk groups in which it was not. The use of both invasive and noninvasive factors to assess risk in patients with chronic stable angina pectoris provided greater predictive power than either angiography or noninvasive factors alone.

Coronary artery bypass surgery has been recommended for patients with a wide variety of signs, symptoms, and medical histories. Investigators have used historically controlled studies, registries and randomized clinical trials to compare the efficacy of medical and surgical management of coronary artery disease in well-defined patient groups. Historically controlled studies offer a weak basis for inference because of rapid changes in medical practice and in the prognosis for patients with coronary artery disease. Randomized trials are the ideal method for comparing therapies, but only a few trials, in highly selected patients, have been completed. Thus, registry studies provide an important part of the currently available evidence. In this paper, the strengths of randomized and registry studies are compared and the need for "meta-analyses" that integrate the evidence from both types of study is discussed. The institutional variation in surgical mortality and its implication for treatment strategy are also discussed.

In this report, we summarize the strengths and problems of an observational data base approach to evaluating therapy and studying patient outcomes in long-term chronic disease. Because this approach includes a greater spectrum of patients than randomized clinical trials, it offers a definite advantage with regard to the elucidation of prognostic factors and the application of results to specific patients. The major difficulty with the observational data base approach is that the important prognostic factors must be known for treatment comparisons to be valid. Both the observational data base and randomized trial approaches are susceptible to criticism because the multiple comparisons and multiple experiments usually involved make the results of any one study not definitive. Either approach is useful in generating or confirming a hypothesis about particular subgroups. Regardless of the method used, proof that a particular therapy increases survival in any group or subgroup of patients with coronary artery disease usually requires confirmation by multiple studies. Finally, observational data base approach, because it capitalizes on data generated and paid for in the patient care process, offers the most feasible approach for evaluating whether changes in prognosis are occurring over time and whether such changes are independent of the mix of the patient population.

The long-term prognostic implications of the electrocardiographic location of a myocardial infarction and the subsequent retention or disappearance of diagnostic Q waves were examined in patients enrolled in the Aspirin Myocardial Infarction Study (AMIS). The 4524 participants, ages 30-69 years, had sustained a myocardial infarction 8 weeks to 60 months before randomization to aspirin and placebo groups. Subjects were followed for at least 3 years (average 38.2 months). Using the Minnesota Code, myocardial infarctions were classified according to three electrocardiographic locations: lateral, inferior and anterior, with further subdivision into major, moderate and minor criteria based on Q-wave duration and Q/R rations. Total mortality was not significantly different among patients with single infarct sites: lateral 11.8%, inferior 8.0% and anterior 9.4%. Patients with multiple electrocardiographic infarct locations had a significantly higher mortality (14.6%, p less than 0.0002). Participants with Minnesota Code major criteria of infarction also had a significantly higher mortality (10.6%) than those with moderate (7.2%) or minor (7.4%) criteria (p less than 0.01). Loss of a previously documented diagnostic Q wave occurred in 14.2% of participants. Mortality among patients who lost Q waves (6.5%) was not significantly different from that among those with persistent Q waves in a single infarct location (8.7%). No long-term prognostic significance can be attributed to the site of infarction or loss of Q wave on the resting ECG. However, major Q-wave criteria and extent of infarction based on multiple coded sites are associated with a higher 3-year mortality.

The safety and efficacy of acebutolol in suppressing ventricular ectopy was evaluated in 60 males (average 59 years) using 24-hour Holter recordings and a double-blind, randomized, crossover protocol. Acebutolol, 200 mg and 400 mg thrice daily, was compared with placebo. Only patients who had a mean of at least 30 ventricular premature complexes (VPCs) per hour on three 24-hour control Holter recordings were included. Analysis of Holter recordings revealed greater than 70% reduction in VPCs/hour from control levels during acebutolol therapy in over 50% of the 60 patients; dose-related reduction in the mean number of single and paired VPCs and ventricular tachycardia episodes (p less than 0.05) by acebutolol; and significant, asymptomatic reduction in resting heart rate and blood pressure. All side effects were transient. Acebutolol was discontinued because of side effects in one patient only.

In this double-blind randomized study, 19 patients with acute transmural myocardial infarction were treated with methylprednisolone administered 4.4 +/- 0.7 hours (+/- SEM) after the onset of chest pain, and were compared with 21 patients who received placebo 4.5 +/- 0.4 hours after the start of clinical symptoms. The two groups were comparable in reference to sex, prevalence of risk factors, clinical status on admission, location of myocardial infarction and magnitude of ischemic injury as assessed by standard ECGs and precordial ST-segment and QRS maps. The treated patients, however, were older than the patients who received placebo. Methylprednisolone in an i.v. dose of 2.0 g was administered on admission and a similar dose was infused 3 hours later. Placebo administration followed an identical schedule. Mortality, cardiac rupture, incidence of ventricular arrhythmias, blocks, extension of myocardial infarction, pericarditis, postinfarction chest pain, persistent ST-segment elevation at discharge, and change in Killip class during hospitalization were the same in both groups. Peak enzyme values, and changes in ECG variables pertaining to resolution of ST-segment elevation or development of QRS evolutionary alterations were similar in both groups. Follow-up for 6 months did not reveal any differences in the clinical course of the two groups. Methylprednisolone infused in a total dose of 4.0 g within 12 hours after the onset of chest pain in patients with acute transmural myocardial infarction does not result in any demonstrable beneficial or harmful effects.

In a double-blind, crossover study in 20 patients with stable angina pectoris, the effects of long-acting propranolol, 160 mg administered once daily for 4 weeks, were compared with those of standard propranolol, 40 mg given four times daily for 4 weeks. The patients suffered no adverse effects when they were switched between treatment schedules. The average number of episodes of angina during the 4 weeks on long-acting propranolol was 7.3 and on standard propranolol. 6.3. Average nitroglycerin consumption was 5.8 and 4.9 tablets during therapy with these two drug programs. The resting values for heart rate, systolic blood pressure and rate-pressure product were similar when determined 25.4 hours after a dose of long-acting propranolol and 10.7 hours after standard propranolol. When the patients exercised at these times, patients on long-acting propranolol and standard propranolol had similar walking times to the onset of angina and to the development of moderate angina. The values for heart rate, systolic blood pressure and rate-pressure product were similar at rest and during exercise during these two treatment programs. We conclude that long-acting propranolol administered in a dose of 160 mg daily is as effective as 50 mg of standard propranolol four times daily.

The effects of encainide on ventricular arrhythmia and left ventricular function were studied in 21 patients with chronic, high-grade ventricular arrhythmia using a prospective, 3-month, placebo-controlled, single-blind trial design. Encainide caused a 96% decrease in the average hourly frequency of ventricular premature complexes (VPCs) and comparable reductions in salvos of nonsustained ventricular tachycardia (VT) and episodes of sustained VT. Intracardiac electrophysiologic testing showed prolonged intraatrial and intraventricular conduction times and increased atrial, atrioventricular nodal, and ventricular refractory periods with both i.v. and oral encainide without His-Purkinje block, despite marked prolongation of HV and QRS intervals. Induced repetitive ventricular beating after ventricular extrastimuli in 15 patients showed persistent repetitive ventricular beating with chronic oral encainide in seven patients, four of whom had sustained VT within 2 months of treatment on encainide. Encainide did not reduce exercise capacity or left ventricular ejection fraction at rest or during supine exercise. Minor adverse effects of encainide in 11 of 21 patients included dose-related visual disturbances, dizziness and sinus pauses (less than 3 seconds). Major adverse effects included the new appearance of sustained VT in three of 20 patients (15%). Oral encainide effectively reduces the frequency and grade of VPCs, prolongs intracardiac conduction times, and does not impair left ventricular performance. However, it is associated with frequent minor side effects and uncommon but potentially severe major side effects (sustained VT), both of which apparently have a direct relationship to the size of the dose.

The present study was designed to test the hypothesis that i.v. nitroglycerin is as effective as sodium nitroprusside for managing acute hypertension early after coronary artery bypass surgery. Seventeen patients received both nitroglycerin and nitroprusside in a randomized crossover protocol. Infusion rates were increased stepwise to lower mean arterial pressures comparably with each drug. In 14 of 17 patients, similar infusion rates of the two vasodilators resulted in equal lowering of both blood pressure and systemic vascular resistance. In the remaining three patients, very high infusion rates of nitroglycerin were required and achieved only 20-50% of nitroprusside's response in two of three. Hemodynamic responses to the two vasodilators were similar, except that nitroglycerin increased cardiac output more than nitroprusside did. In contrast, pulmonary gas exchange responses differed in that nitroglycerin improved intrapulmonary shunting, while nitroprusside worsened it. Similarly, nitroglycerin resulted in a significantly smaller increase in the alveolar arterial oxygen gradient than did nitroprusside. These results suggest that in the majority of patients, i.v. nitroglycerin was as effective as nitroprusside in controlling acute hypertension after coronary artery bypass surgery. In addition, nitroglycerin appeared to have more favorable effects on pulmonary gas exchange. Because nitroglycerin has more beneficial effects on intercoronary collateral blood flow in the setting of regional ischemia, it may be preferable to nitroprusside in patients with ischemic heart disease.

The effect of regular, moderate exercise on the lipoprotein subfractions of male survivors of myocardial infarction was studied. Nineteen men were randomly allocated to an incremental exercise program and 23 to a control group. Both groups were studied for 6 months. No change occurred in any lipoprotein class in the control group. In the trained group, total triglyceride and low-density lipoprotein (LDL) cholesterol concentrations decreased significantly (0.01 greater than p greater than 0.001 and 0.05 greater than p greater than 0.01, respectively) and high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1 rose (both p less than 0.001). The concentration of the HDL2 subfraction increased with training (0.01 greater than p greater than 0.001) and HDL2 did not change. No relationship was found between changes in lipoproteins and treadmill exercise test performance. Thus, in survivors of myocardial infarction, exercise may alter plasma lipoprotein values beneficially.

We compared the effects of a cardioselective beta-adrenergic blocking drug, metoprolol, with a nonselective beta-adrenergic blocker, propranolol, on the response of 10 normal men to dynamic treadmill exercise. The volunteers underwent a standard graded exercise test to exhaustion while receiving placebo; propranolol, 40 mg every 6 hours; propranolol, 80 mg every 6 hours; metoprolol, 50 mg every 6 hours; or metoprolol, 100 mg every 6 hours. The drugs were given in a double-blind fashion for 48 hours before exercise. Five days were allowed between successive drug administrations and the order of drug administration was randomized. Heart rate, arterial pressure, oxygen consumption, minute ventilation and CO2 production were monitored. Plasma drug concentrations were measured at the time of exercise. Judged by plasma levels, propranolol was about three times more potent than metoprolol in attenuating heart rate. Both drugs produced a wide variation in plasma levels after a given oral dose, and both drugs attenuated the systolic blood pressure response to exercise. Neither drug affected diastolic blood pressure or maximum oxygen consumption, maximum minute ventilation or the anaerobic threshold. We conclude that there is no evidence that the cardioselective drug metoprolol is superior to propranolol in terms of the ability to perform or respond to short-term maximal exercise. In addition, the fact that maximal oxygen consumption and the anaerobic threshold were unaffected implies that fatigue during exercise while on beta-adrenergic blocking drugs is not due to an effect of these drugs in limiting blood flow to the exercising extremities.

Flecainide acetate, a new antiarrhythmic agent, was given orally to 11 hospitalized patients with chronic high-frequency ventricular ectopic depolarizations. Drug effectiveness was evaluated with a dose-ranging single-blind protocol, which included placebo control and washout periods. Twice-daily dosing (average daily dose 436 mg) completely suppressed all ventricular ectopic activity in five of 11 patients; average suppression in the 11 patients was 96.3%. Complex ventricular arrhythmias, which were present in all 11 patients during the placebo control period, were completely suppressed in eight patients and markedly suppressed in the other three patients during flecainide therapy. Ejection fraction and velocity of circumferential fiber shortening measured by M-mode echocardiography did not change significantly during flecainide dosing. Ventricular arrhythmias returned in all patients during the placebo washout period. During subsequent outpatient therapy with flecainide, significant suppression was present after 1 and 2 weeks of treatment (94.4% and 93.3%, respectively). Drug elimination was slow (average plasma half-life 20 hours). Ninety-five percent suppression of ventricular ectopic depolarization during dosing and 5% reappearance of arrhythmias during washout occurred with flecainide concentrations of 200-800 ng/ml. Side effects occurred in five of 11 patients, but did not require discontinuation of the drug. These results indicate that flecainide is a very effective antiarrhythmic agent that merits further clinical investigation.

Patients with their first myocardial infarction not initially complicated by severe atrioventricular block or power failure were given a skin test and then randomized to receive either hyaluronidase or placebo in double-blind fashion. Hyaluronidase, 500 IU/kg i.v., was given every 6 hours for 42 hours. Of the 48 eligible patients, 26 received hyaluronidase and 22 received placebo. The mean CK serum entry was 3140 +/- 2111 mIU/ml (mean +/- SD) in hyaluronidase patients and 3574 +/- 1476 mIU/ml in placebo patients (p less than 0.21). The mean infarct size was 54.6 +/- 35.8 CK gram-equivalents in the hyaluronidase patients and 64.0 +/- 31.1 CK gram-equivalents in the placebo patients (p less than 0.20). Among the 21 patients treated within 6 hours of the onset of infarction, the difference in infarct size was greater (p less than 0.15). There was no significant difference in the incidence of power failure, ventricular arrhythmias, recurrence of ischemic pain, infarct extension or mortality. No benefit of hyaluronidase was demonstrated in this study, which was designed to detect a 50% reduction of infarct size. However, to detect a 20% reduction in infarct size would require a much larger study population.