The Coronary Drug Project was a randomized, placebo-controlled trial of lipid-influencing drugs in men who had recovered from one or more documented myocardial infarctions. Determinations of high-density lipoprotein (HDL) cholesterol were made at baseline in a group of 354 men randomized to the placebo group. Five-year mortality was highest (33.0%) in men with baseline serum HDL cholesterol levels of less than 35 mg/dl; it was 15.9%, 17.7%, and 21.8% in men with levels of 35--39, 40--44, and greater than or equal to 45 mg/dl, respectively (for the linear inverse relationship between HDL cholesterol and 5-year mortality, p = 0.029). Adjustment for 40 baseline variables had a minimal effect on this relationship (p = 0.042).

Pirbuterol (PB), an oral beta-adrenergic-receptor agonist, has the pharmacologic effects of vasodilation and positive inotropy. The present studies were undertaken to determine the value of PB in the long-term therapy of chronic cardiac failure. A double-blind, randomized, 7-week trial comparing PB (20 mg three times daily) with placebo in 12 patients was followed by 12 weeks of open PB therapy. Dose-dependent nervousness and tremulousness limited the unit PB dose to less than 20 mg in six patients. In all patients, clinical status, exercise tolerance and maximal oxygen uptake, left ventricular echocardiographic dimension and cardiothoracic ratio were unchanged from control after 7 weeks of placebo or PB or after 12--19 weeks of PB. To assess the adequacy of 20 mg of PB, the dose-response relations of cardiocirculatory effects to 10, 15, 20 and 30 mg of PB were compared in seven of the above patients and nine other patients. Cardiac output was significantly elevated and wedge pressure reduced after all four doses, but these changes were sustained from 6 hours after 20- and 30-mg doses only. Thus, the role of PB in the management of chronic cardiac failure appears limited; judgment of its utility must await the results of additional controlled trials.

The effect of acebutolol (1 mg/kg i.v. during the first 2 days followed by a daily oral dose of 600 mg for 3 weeks) was studied in a randomized trial involving 26 patients seen within 24 hours after the onset of uncomplicated anterior transmural myocardial infarction (TMI). Myocardial ischemia and necrosis were evaluated by precordial maps recorded daily for 9 days. Left ventricular pump function and dyssynergy were quantitatively measured on 30 degrees right anterior oblique cineangiograms. Angiography was performed, using the postextrasystolic potentiation technique, within the first 24 hours after TMI and was repeated 1 month later. The basal and postextrasystolic beats from the initial angiography were computerized and compared with those from the final angiogram. MB-CK serum level was measured from blood samples drawn every 3 hours for the first 72 hours. Fourteen patients selected at random received acebutolol within the first 24 hours; 12 subjects were untreated and served as controls. During the 1-month study, no other drugs were administered. Treated patients showed a significant reduction in capillary wedge pressure, extent of hypokinesis and ST-segment elevation; no significant differences were observed in the control group. However, the predictability based on the angiographic data was the same in both groups, and beta blockade did not alter this predictability significantly. Furthermore, no significant difference was found during the final evaluation for treated compared with control patients for any single variable or set of variables. The incidence of infarct extension was not decreased, but only significantly delayed in treated patients. The high variability of the measurements, probably related to the high variability of the pathophysiologic factors, may account for the failure to demonstrate the efficacy of acebutolol.

In 18 patients with stable effort angina, verapamil, 80 mg four times daily, was compared with propranolol, 80 mg four times daily, in a double-blind, placebo-controlled trial to assess the effects on anginal threshold, exercise capacity and left ventricular function measured by gated equilibrium blood pool scanning. Both propranolol and verapamil improved exercise capacity (placebo 424 +/- 135 W-min; propranolol 513 +/- 168 W-min, p less than 0.01; verapamil 545 +/- 215 W-min, p less than 0.005) and prolonged the time to 1 mm of ST depression (placebo 4.5 +/- 1.3 minutes; propranolol 7.4 +/- 1.4 minutes, p less than 0.005; verapamil 6.6 +/- 1.9 minutes, p less than 0.005). At rest, the mean left ventricular ejection fraction did not change significantly during drug therapy (placebo 57 +/- 13%, propranolol 55 +/- 12%, verapamil 55 +/- 13%). While taking placebo, all 18 patients had a decrease in exercise ejection fraction. In contrast, 12 patients taking propranolol and 14 patients taking verapamil had a 5% or greater increase in ejection fraction during exercise. Verapamil is an effective primary therapy and a satisfactory alternative to propranolol in patients with stable effort angina.

The effects of verapamil were assessed in 26 patients with stable exertional angina pectoris in a double-blind, placebo-controlled, randomized crossover protocol using serial treadmill tests. Verapamil, 480 mg/day, reduced anginal frequency from 5.6 +/- 7.3 to 2.2 +/- 3.9 attacks per week (p less than 0.001) and nitroglycerin consumption from 3.4 +/- 4.9 to 1.2 +/- 2.5 tablets per week (p less than 0.05) compared with placebo. Treadmill time increased from 6.4 +/- 2.1 minutes during the placebo phase to 7.5 +/- 1.8 minutes during the verapamil phase (p less than 0.001). Verapamil's beneficial effect appeared to be related, in part, to a 10% reduction of the rate-pressure product at rest (p less than 0.05) and a 12% reduction during submaximal exercise (p less than 0.001). Verapamil also caused less marked ST-segment depressions at peak exercise (p less than 0.05) at a similar rate-pressure product, suggesting a favorable redistribution of coronary blood flow to the ischemic zone. Side effects from verapamil were minimal, consisting mainly of constipation (six patients). Verapamil appears to be a safe and effective drug for treating angina of effort.

Platelet survival and plasma concentrations of beta thromboglobulin and platelet factor 4 were measured in 44 patients before and 6 months after coronary artery bypass grafting. Postoperatively, patients were randomized to receive sulfinpyrazone, 800 mg/day, or placebo. Preoperatively, platelet survival was significantly shorter than normal, and plasma concentrations of both platelet-specific proteins were significantly elevated. Postoperatively, all three indexes of platelet function tended to become normal, but these changes were statistically significant only in patients treated with sulfinpyrazone. Postoperative exercise testing correlated significantly with plasma concentrations of beta thromboglobulin and platelet factor 4 measured preoperative and postoperative. These results are consistent with reports of the effects of sulfinpyrazine on platelet involvement in other conditions, and suggest that the drug reduces platelet activation and inhibits actual destruction. The results also show a relationship between abnormalities of platelet function and an index of postoperative myocardial ischemia.

The effects of an exercise program started early after myocardial infraction and the added effects of an outpatient teaching-counseling program were studied. At random, 84 patients were allocated to a control group (A), 88 patients to an exercise group (B1) and 86 patients to an exercise and teaching-counseling group (B2). The same exercise program was prescribed for patients in groups B1 and B2 and was started about 4.5 days after myocardial infarction and continued for 3 months. The outpatient teaching-counseling program consisted of eight group sessions pertaining to risk factor reduction and psychosocial adjustment to myocardial infraction. A low-level treadmill test and an exercise test were performed at 3 months and the exercise test was repeated at 6 months. The clinical, hemodynamic and electrocardiographic responses to these tests were not different among the three groups. However, by the end of 3 months, patients in group B1 and B2 reported walking greater distances than patients in group A. The incidence of morbidity and mortality was not different between the groups. No deleterious or beneficial physiologic effects of an exercise program either by itself or combined with a teaching-counseling program were demonstrated. Routine medical care and our interventions were equally effective in permitting the spontaneous hemodynamics improvements after myocardial infraction. More than 3 months after myocardial infarction, the group as a whole manifested spontaneous recovery in the form of a significant decrease in resting heart rate (p less than 0.001) and a significant increase in systolic and diastolic blood pressure at rest and with submaximal exercise (p less than 0.001). No further improvements were observed between 3 and 6 months.

Continuous 72-hour infusions of dobutamine reportedly effect sustained clinical improvement in patients with congestive heart failure. This study was designed to determine if shorter, more frequent infusions, delivered in an outpatient setting, elicit a similar response. Twenty-six patients with moderately severe congestive heart failure were randomized, 11 into a control group and 15 into a dobutamine treatment group. Baseline data were collected for 4 weeks in each group. Thereafter, the dobutamine treatment group received 4-hour infusions of dobutamine weekly for 24 weeks. Systolic time intervals, echocardiography, cardiac index and treadmill exercise tolerance were used to follow the progress of the control and dobutamine treatment groups. The ratio of preejection period to left ventricular ejection time and the cardiac index did not change significantly in either group. The velocity of circumferential fiber shortening and the percent change in the minor axis of the left ventricle during systole improved modestly (p less than 0.05) above baseline in the dobutamine group after 14 weeks of treatment and above the corresponding control values (p less than 0.05) after 22 weeks. Exercise tolerance (duration) improved 25--51% (all p less than 0.05) above baseline in the dobutamine group compared with 10--17% (all p greater than 0.05 vs baseline) in the control group. Heart rate at maximal exercise did not change significantly from baseline for either group and did not differ significantly between the two groups. Functional classification improved in 12 of 15 dobutamine treatment patients and in only two of 11 control patients (p less than 0.05). In our patients with congestive heart failure, weekly 4-hour dobutamine infusions did not elicit a major change in resting left ventricular function; however, exercise performance and clinical status improved considerably.

To determine the effects of verapamil on left ventricular (LV) systolic function and diastolic filling in patients with coronary artery disease (CAD), we performed gated radionuclide angiography at rest and during exercise in 16 symptomatic patients before and during oral verapamil therapy (480 mg/day). Twelve patients were also studied during oral propranolol (160--320 mg/day). LV ejection fraction at rest was normal in 13 patients, but abnormal diastolic filling at rest, defined as peak filling rate (PFR) less than 2.5 end-diastolic volumes (EDV)/sec or time to PFR greater than 180 msec, was present in 15. During verapamil, resting ejection fraction decreased (control 50 +/- 10% [+/- SD), verapamil 45 +/- 12%, p less than 0.005), but resting diastolic filling improved: PFR increased (control 1.9 +/- 0.6 EDV/sec, verapamil 2.3 +/- 0.9 ECV/sec, p less than 0.005) and time to PFR decreased (control 185 +/- 38 msec, verapamil 161 +/- 27 msec, p less than 0.05). Exercise ejection fraction did not change during verapamil (control 42 +/- 13%, verapamil 43 +/- 12%, NS), but exercise PFR increased (control 3.1 +/- 0.9 EDV/sec, verapamil 3.6 +/- 1.1 EDV/sec, p less than 0.05) and exercise time to PFR decreased (control 108 +/- 30 msec, verapamil 91 +/- 17 msec, p less than 0.05). In contrast, propranolol did not alter ejection fraction, PFR, or time to PFR at rest or during exercise. Thus, LV ejection fraction is decreased by verapamil at rest but is unchanged during exercise. While LV systolic function is not improved by verapamil, LV diastolic filling is enhanced by verapamil, both at rest and during exercise. These mechanisms may account in part for the symptomatic improvement in many patients during verapamil therapy.

Several prospective randomized studies of medical or surgical therapy have not shown that either form of management alone is uniformly superior with respect to mortality for unstable angina pectoris. Patients managed medically have a greater incidence of angina pectoris. Earlier studies indicated a higher rate of nonfatal myocardial infarction with urgent surgery. Present management includes hospitalization and early intensive medical therapy with nitrates and, usually, beta-blocking agents. Coronary arteriography is advised within a few days. If the patient has left main coronary artery disease or three-vessel disease, early coronary artery bypass graft surgery within days to a couple of weeks is advised. Otherwise, medical management is advised and elective surgery can be performed if the patient remains symptomatic.

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.

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 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.