The prophylactic antianginal efficacy of nitroglycerin (NTG) oral spray was assessed in 20 patients with angiographically documented coronary disease and stable angina pectoris. The evaluation was by a randomized crossover trial involving treadmill exercise testing. On study day 1, a control treadmill exercise test was performed, followed 30 minutes later by a second exercise test 2 minutes after administration of either placebo (group A, 10 patients) or NTG spray 0.8 mg (group B, 10 patients). One week later, on study day 2, the patients again underwent control treadmill exercise testing followed by a second exercise test after either NTG spray (group A) or placebo (group B). NTG spray delayed the onset of anginal pain during exercise by a mean of 100 +/- 64 seconds (p less than 0.001) in 13 patients and prevented pain entirely in seven. Placebo did not significantly delay the appearance of angina and prevented chest pain in only one patient. NTG spray increased treadmill exercise duration by 31% before the onset of angina (p less than 0.001); placebo did not significantly alter the duration of exercise. NTG spray abolished in six patients and delayed in 14 patients the onset of exercise-induced ST-segment depression of 1 mm (p less than 0.001). Patients achieved a higher heart rate at peak exercise with NTG spray, and yet the maximal exercise-induced ST-segment depression of 2.1 +/- 1.0 mm during the control study declined to 1.3 +/- 0.9 mm on NTG spray (p less than 0.001). Placebo had no effect on exercise ST-segment depression. These data indicate that the oral NTG spray is an effective prophylactic for exercise-induced angina.

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).

Blood banks represent a recruitment source with relatively high volumes of initial contacts and entries, a low ratio of entries to initial contacts and a relatively low effort level requirement for the recruitment team. For the CPPT, blood banks were used to some extent by all centers; they provided 26% of initial contacts and 15% of first protocol visits and entries. Probably the most critical determinant of a successful collaboration was the early negotiation with the blood bank director. Several features seemed to characterize successful LRC/blood bank collaborations: Blood banks that were willing to release names and addresses to the LRC, provided staff support, did not request monetary reimbursement, and agreed, sometimes enthusiastically, to participate in joint media campaigns tended to produce the most referrals. Blood banks are well adapted to identify healthy, asymptomatic men with an abnormal laboratory finding identifiable by a blood test.

The effect of naloxone on the hypotensive and bradycardiac action of clonidine was studied in 27 hospitalized patients with uncomplicated mild-to-moderate essential hypertension. In a double-blind, crossover study, clonidine, 0.3 mg/day orally for 3 days, significantly reduced systolic and diastolic blood pressure and heart rate, whereas placebo was ineffective. Naloxone, 0.4 mg given intravenously on the third day of clonidine treatment, caused a rapid increase in blood pressure and heart rate in 14 patients (reacting group), but was ineffective in the remaining 13 patients (nonreacting group). Naloxone given during the placebo period was ineffective in all patients. Both the clonidine-induced hypotension and the rebound increase in blood pressure after cessation of clonidine were significantly greater in the reacting than in the nonreacting group. These observations suggest that release of an endogenous opioid contributes to the antihypertensive action of clonidine; this mechanism may be also involved in the discontinuation syndrome after cessation of clonidine.

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.

Long-term treatment with timolol in patients ages 65--75 years who survived myocardial infarction was related to a significant reduction, compared with placebo, in overall mortality (p less than 0.05), total cardiac death (p less than 0.01), sudden death (p less than 0.05) and reinfarction (p less than 0.01). The analyses were based on 732 patients (384 taking placebo and 348 timolol) from a cohort of 1884 patients in the Norwegian multicenter timolol study. The dosage of timolol was 10 mg twice daily and the patients were followed for 12--33 months (mean 17 months). There were 83 deaths in the placebo group and 52 deaths in the timolol group, a reduction of 35.5%. There were 69 initial reinfarctions in the placebo group and 38 in the timolol group, a reduction of 39.2%. There was no difference in the reduction of mortality and reinfarction between patients 65--75 years of age and patients less than 65 years of age. The incidence of side effects, the number of withdrawals and the reasons for withdrawal were similar in older and younger patients. We conclude that age should not be a decision-making factor concerning timolol therapy in postinfarct patients.

Direct and indirect costs of medical and of surgical treatment are presented for patients entered into the Birmingham portion of the Coronary Artery Surgery Study. For comparison, similar results are shown for the Birmingham portion of the national Cooperative Unstable Angina Study. In the Unstable Angina Study, mean inpatient costs at the end of 1 year in the study were $6867 for medical therapy, $10,574 for surgical therapy and $23,045 for those who failed medical therapy and required late surgery. A stepwise multiple regression analysis shows that the single best predictor of cost was the number of myocardial infarctions that the patient had while in the study. A discriminant-function analysis identified 85% of the medical patients who required late surgery. A significantly lower proportion of surgical than medical patients returned to work. Total inpatient costs for patients in the Coronary Artery Surgery Study (i.e, patients with stable angina) were $3432, $11,100 and $13,554 for medical, surgical and late surgical patients, respectively, for the first year in the study. There was no significant difference in the percentage of medical and surgical patients who were working at the end of 1 year. According to their own perceptions, the surgical group was in the best and the late surgical group in the worst health.

Data from the National Heart, Lung, and Blood Institute's Coronary Artery Surgery Study (CASS) are used to describe the types of persons who undergo coronary angiography for possible coronary artery bypass surgery, the reasons patients receive coronary bypass surgery, and operative mortality results, as well as changing trends in the therapy assigned. The review is designed to provide background material for those assessing coronary artery bypass technology.

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.

Ten men with stable angina not completely relieved by full doses of propranolol (mean 218 mg/day) were administered an oral dose of 10 mg of nifedipine or placebo on alternate mornings in a double-blind fashion. Patients had been trained in a protocol that precipitated angina after 3-6 minutes of bicycle exercise. On test days, with propranolol continued, bicycle exercise to angina or fatigue was performed before nifedipine or placebo administration, and hourly thereafter for 8 hours. Mean exercise duration was greater 1 hour after nifedipine than after placebo by 123 seconds (372 +/- 21 vs 249 +/- 16 seconds, p less than 0.001). By the fifth hour, the increase in exercise time was reduced to 93 seconds (p less than 0.001), and a significant, though further diminished, difference of 57 seconds was still present at 8 hours (p less than 0.01). Nifedipine lowered resting systolic blood pressure by 20 mm Hg (p less than 0.001) without appreciably changing heart rate. We conclude that nifedipine is a very effective and reasonably long-acting antianginal supplement to propranolol.

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.

Diltiazem is a calcium slow-channel blocking drug that may be effective in the treatment of chronic stable angina pectoris. To evaluate the therapeutic efficacy 3 hours after a single oral dose of 120 mg, 12 men with chronic stable angina pectoris performed a maximal exercise test on a bicycle ergometer after ingesting either placebo or diltiazem administered in a double-blind fashion. During submaximal exercise at a fixed work load, diltiazem decreased the average heart rate response from 119 +/- 17 to 107 +/- 14 beats/min (p less than 0.01), systolic blood pressure from 182 +/- 15 to 175 +/- 15 mm Hg (p less than 0.05) and the rate-pressure product from 21.8 +/- 4.2 to 18.8 +/- 3.2 x 10(-3) units (p less than 0.01). The average submaximal work load at which significant ST-segment depression (0.1 mV) first appeared was increased from 355 +/- 142 to 525 +/- 143 seconds (p less than 0.01) after diltiazem. At peak exercise after diltiazem, the average depth of ST-segment depression in any one lead and the extent of myocardial ischemia observed in all 12 ECG leads were decreased (p less than 0.01), even though the average work load was increased by 29% (p less than 0.01). Peak heart rate, systolic blood pressure and rate-pressure product were similar with placebo and diltiazem. The plasma diltiazem concentration was 13.9 +/- 29 ng/ml 3 hours after ingestion and was significantly (p less than 0.05) related to the increased time to the onset of important ST-segment depression (r = 0.65) and to the decrease in the extent of myocardial ischemia observed in all 12 ECG leads (r = -0.61) compared with placebo. Thus, diltiazem is effective in treating chronic stable angina pectoris. It decreases myocardial oxygen requirements during upright exercise and appears to increase myocardial oxygen delivery.

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.

There are institutional variations in the operative mortality of coronary artery bypass graft surgery (CABG). Patient selection, based on clinical and angiographic criteria, is a significant factor. Even after adjustment for patient selection, institutional differences remain. Operative experience and volume of cases are also related to institutional variations. Recent attention to the technique of myocardial preservation has highlighted its significance in reducing the incidence of perioperative myocardial infarction and operative mortality. Institutional heterogeneity also exists in the nonoperative management of ischemic heart disease. However, undetected factors probably significantly affect the outcome. These institutional variations emphasize a major advantage of randomized clinical trials--that they should equalize these unknown factors.

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.