The Beta-Blocker Heart Attack Trial was a multicenter, randomized, double-blind, placebo-controlled trial of propranolol therapy in 3837 men and women with acute myocardial infarction. The patients began their treatment 5-21 days after hospital admission (mean 13.8 days). During an average follow-up of 25 months, there were statistically significant reductions in total mortality (26%), cardiovascular mortality (26%), arteriosclerotic heart disease (27%), sudden death (28%) and coronary incidence (definite nonfatal reinfarction plus coronary heart disease mortality) (23%). There was no group difference in incidence of congestive heart failure. Of the many potential side effects that were monitored, broncho-spasm, cold hands and feet, and fatigue occurred more frequently in the propranolol group. Propranolol not only reduced coronary mortality and morbidity, but also was administered with a great degree of safety. Based on these results, its use is recommended for at least 3 years in patients with no contraindications to beta blockade who have had a recent myocardial infarction.

The Beta-Blocker Heart Attack Trial (BHAT) was a multicenter, randomized, double-blind, placebo-controlled trial that tested the effectiveness of propranolol in reducing the mortality rate in patients after myocardial infarction (MI). Twenty-four hour ambulatory ECG monitoring was done on 3279 of the 3837 enrolled patients at baseline (5-21 days after hospital admission) and repeated after 6 weeks of therapy in a random sample of 25% of the study population. Ventricular arrhythmias were divided into seven different categories and the prevalence of each category is presented. Ventricular arrhythmia at baseline appears to increase with patient age, past history of myocardial infarction, and use of diuretics. Other selected variables--sex, CPK ratio and history of smoking, diabetes and hypertension--appear to be less clearly associated with ventricular arrhythmia. Paired data analysis performed on 826 patients who had ambulatory electrocardiograms both at baseline and after 6 weeks of treatment showed an increased prevalence of ventricular arrhythmia at 6 weeks. This increase was blunted by propranolol therapy.

In this study, 1884 patients who were selected from 3647 consecutive patients who survived at least 6 days after an acute myocardial infarction were randomized to double-blind treatment with either placebo or timolol and followed for 12-33 months. One hundred fifty-two patients in the placebo group and 98 in the timolol group died. The life-table cumulative probability of total death was 21.9% in the placebo group and 13.3% in the timolol group, corresponding to a relative reduction of 39.4% (p = 0.0003). One hundred thirty-one nonfatal reinfarctions were confirmed in the placebo group and 90 were confirmed in the timolol group, including events among withdrawn patients. The life-table probability rate of reinfarction was 16.4% in the placebo and 11.8% in the timolol group (p = 0.001). We conclude that chronic treatment with timolol in survivors of acute myocardial infarction who can tolerate beta-adrenergic blockade is effective in reducing both total mortality and reinfarction over 33 months.

In the Göteborg Metoprolol Trial, 1395 patients with suspected acute myocardial infarction were, on admission, randomly allocated to double-blind treatment, 697 to placebo and 698 to metoprolol (15 mg i.v. + 200 mg/day) for 90 days. During this period, there were 62 deaths in the placebo group (8.9%) and 40 in the metoprolol group (5.7%), a mortality reduction of 36% (p less than 0.03). This effect persisted regardless of age, previous infarction or previous chronic beta blockade. All deaths were classified as cardiovascular. After 3 months, all patients were recommended open treatment with metoprolol, and the difference in mortality between the two groups was maintained after 1 year. Early institution of metoprolol (within 12 hours) influenced infarct development during the first 3 days (infarct diagnosis and indirect measures of infarct size). Metoprolol also reduced the incidence on fatal and nonfatal infarction during the next 4-90 days by 35%. Furthermore, fewer episodes of ventricular fibrillation were recorded in the metoprolol than in the placebo group (six vs 17 patients). The tolerance was judged to be very good. The same percentage of patients (19%) was withdrawn from the blind treatment in the two groups. Fewer patients in the metoprolol group used lidocaine, furosemide and analgesics. We conclude that metoprolol therapy instituted on admission in patients with suspected acute myocardial infarction reduced 3-month mortality and exerted beneficial clinical effects.

The Timolol Myocardial Infarction Study was a completely randomized program of 1884 survivors of myocardial infarction comparing timolol maleate, 10 mg twice daily, with placebo for the secondary prevention of sudden death and reinfarction. In that study, timolol maleate reduced total mortality (152 placebo vs 98 timolol) and the incidence of first nonfatal reinfarctions (131 placebo vs 90 timolol). This report evaluates the effect of timolol in selected categories--age, sex, infarction site, heart size, transmural infarction, diabetes, smoking, multiple reinfarctions and pulse. These data document two important facts. First, the effects of timolol in the total sample were also seen in different subpopulations, and there were no major subgroups for which this positive effect would not be expected. Second, the consistency of the effects observed with respect to pulse, transmural infarction, age and infarct site are in contrast to some previous studies with practolol, propranolol, and alprenolol. Thus, beta blockers may not be identical with respect to reducing the mortality and morbidity associated with acute myocardial infarction.

The extent of abnormality in early thallium-201 and gated cardiac blood pool scintigrams has been reported to be useful for predicting mortality in patients with acute myocardial infarction (AMI). To compare the two techniques, 91 patients admitted consecutively with evident or strongly suspected AMI underwent both imaging studies within 15 hours of the onset of symptoms. Patients with pulmonary edema or shock were excluded. AMI developed in 84% of patients, and 6-month mortality for the entire group was 16%. A thallium defect score of 7.0 or greater (corresponding to at least a moderate reduction of activity involving 40% of the left ventricular circumference) identified a subgroup of 14 patients with 64% 6-month mortality rate. Similarly, a left ventricular ejection fraction of 35% or less identified a high-risk subgroup of 10 patients with a 6-month mortality of 60%. Mortality in the remaining patients was 8% for thallium score less than 7 and 11% for ejection fraction greater than 35%. The mortality rate was highest among patients who had concordant high-risk scintigrams (five of six, 83%), lowest in those with concordant low-risk studies (five of 64, 8%) and intermediate in those with discordant results (four of 11, 36%). Of a number of clinical variables, only the appearance of Q waves, peak creatine kinase greater than 1000 IU/I, and history of infarction were significantly associated with mortality. High-risk thallium or blood pool scintigraphic results were significantly more predictive and a thallium score of 7 or greater was more sensitive for detecting nonsurvivors than ejection fraction 35% or less at a similar level of specificity. Stepwise multiple logistic analysis showed that the thallium score was the best predictor of mortality, but that appearance of Q waves and ejection fraction were additive. Using these three variables, 11 patients were calculated to have a 50% or greater chance of dying and eight (73%) actually died, compared with six of 70 (9%) with a calculated chance of death of less than 50%. These results in a prospectively identified and consecutive group of patients support the value of early thallium and blood pool scintigraphy for separating high- and low-risk subgroups of hemodynamically stable infarct patients.

Ten randomized clinical trials of beta-blocking drugs in secondary prevention of coronary heart disease are reviewed. The six trials of long-term treatment involving three drugs have completed recruitment; the results should be reported during the next few years. In addition to the possibility of confirming the positive results from other trials, the findings may provide further information on the timing of treatment initiation and the mechanism of benefit. Three of the four trials concerned with the efficacy of beta blockers in the early acute phase of myocardial infarction are still recruiting. Two of these (the Prehospital Myocardial Infarction Study and the International Study of Infarct Survival) are large trials aiming to determine the effect on mortality from all causes. The third (Multicenter Investigation of the Limitation of Infarct Size) has infarct size as the primary end point, as does the one trial with completed follow-up (Belfast), whose preliminary findings indicate no effect on threatened infarction.

Recent reports have shown that beta-adrenergic blockade may exacerbate variant angina. On theoretical grounds, alpha-adrenergic blockade may be beneficial in these patients. To test this hypothesis, we assessed the efficacy of prazosin, an alpha-adrenergic blocking agent, in six men, mean age 49 years, with variant angina. Prazosin, 14.0 +/- 2.4 mg/day (mean +/- SD) in three equal doses, was compared with placebo in a double-blind, randomized, double-crossover trial lasting 4 1/2 months: 2 weeks of open-label prazosin followed by four 1-month periods of blinded alternating therapy. No other vasoactive medications were administered during the study. Prazosin reduced sitting systolic arterial pressure from 145 +/- 18 to 127 +/- 16 mm Hg (p = 0.02), but exerted no effect on diastolic arterial pressure or heart rate. Prazosin did not change the weekly number of episodes of chest pain (2.5 +/- 2.3 with placebo vs 3.1 +/- 3.0 with prazosin, NS), nitroglycerin tablets used (3.9 +/- 3.7 with placebo vs 4.6 +/- 4.2 with prazosin, NS), or transient ST-segment deviations (by calibrated two-channel Holter monitoring for 24 hours/week throughout the study) (6.5 +/- 10.1 with placebo vs 11.8 +/- 17.4 with prazosin, NS). During prazosin therapy, three patients had orthostatic dizziness and one patient had headache. Thus, in a long-term, randomized, double-blind trial, prazosin exerted no obvious beneficial effect in patients with variant angina.

The antiarrhythmic efficacy and safety of oral flecainide acetate and quinidine sulfate were compared in a double-blind, 16-center parallel trial involving 280 patients with chronic premature ventricular complexes (PVCs). Eighty-five percent of the flecainide patients had at least 80% suppression of PVCs, vs 57% of the quinidine patients (p less than 0.0001). Sixty-eight percent of the flecainide patients met the above criterion and also had complete suppression of couplets and beats of ventricular tachycardia, vs 33% of the quinidine patients (p less than 0.0001). PR and QRS intervals were prolonged by flecainide without clinical consequence, but they were not substantially affected by quinidine (p less than 0.0001). Quinidine prolonged JT (QT minus QRS) intervals significantly more than flecainide (p less than 0.05). Nineteen of 141 flecainide patients and 21 of 139 quinidine patients discontinued therapy because of side effects (p greater than 0.50). Flecainide side effects included dizziness, blurred vision, headache and nausea. Quinidine side effects included diarrhea, nausea, headache and dizziness. Flecainide was more effective than quinidine in suppressing chronic ventricular arrhythmias (especially complex forms), and thus is an important new antiarrhythmic agent.

The respective contributions of beta-adrenoceptor subtypes to the hemodynamic, humoral and metabolic consequences of adrenergic stimulation during graded exercise in man were investigated using nonselective beta-adrenoceptor blockade with propranolol and beta 1-adrenoceptor blockade with atenolol. Doses of these agents that produced comparable suppression of beta 1 response as measured by antagonism of cardioacceleration during exercise were selected. Six healthy, nonsmoking males received these drugs in a placebo-controlled, Latin-square, randomized manner using a double-blind protocol. Both drugs produced comparable reductions of systolic blood pressure and elevation of diastolic blood pressure compared with placebo as exercise load increased. Propranolol produced higher peak epinephrine levels than atenolol or placebo (808 +/- 162, 640 +/- 190 and 584 +/- 153 pg/ml, respectively, p = 0.03), but norepinephrine levels did not show significant differences. Plasma renin activity was similarly suppressed both at rest and during all grades of exercise by both drugs. Lactate levels during moderate exercise were significantly lower after propranolol than after either atenolol or placebo (p = 0.03), but were similar at heavy work loads. Plasma glucose values rose on placebo (from 96.5 +/- 2.1 to 97.7 +/- 2.7 mg/dl) and on atenolol (from 99.7 +/- 2.2 to 102.1 +/- 4.8 mg/dl), but fell on propranolol (from 96.4 +/- 1.9 mg/dl to 87.2 +/- 2.5 mg/dl, p less than 0.01). These results indicate that blockade of vascular smooth muscle beta 2 receptors does not substantially alter hemodynamics during intense short-term exercise. Stimulation of renin release and lipolysis are produced through beta 1-adrenoceptor mechanisms, whereas beta 2 adrenoceptors are important in the provision of carbohydrate as an energy substrate for exercising muscle.

We studied 30 patients with moderate-to-severe congestive heart failure in a double-blind, randomized, placebo-controlled trial to determine the acute and long-term effects of isosorbide dinitrate on clinical status and on resting and exercise hemodynamics. Seventeen patients received placebo and 13 isosorbide dinitrate. First-dose isosorbide dinitrate (40 mg orally) decreased resting and exercise pulmonary capillary wedge pressure, pulmonic and systemic arterial pressures and pulmonic and systemic vascular resistances without augmenting exercise capacity. Compared with placebo, chronic therapy with isosorbide dinitrate (40 mg orally every 6 hours for 12 weeks) significantly improved clinical status and exercise capacity. Resting and exercise systemic blood pressure and systemic vascular resistance returned to baseline values during chronic isosorbide dinitrate therapy, but pulmonary capillary wedge pressure, pulmonary artery pressure and pulmonary vascular resistance remained improved. In patients with congestive heart failure, 12 weeks of oral isosorbide dinitrate therapy improves resting and exercise hemodynamics, exercise capacity, and clinical status; tolerance develops to the systemic arterial vascular effects without attenuation of the venous and pulmonary vascular effects.

In eight mechanically ventilated patients in cardiogenic shock, we assessed the hemodynamic effects of an infusion of dopamine and dobutamine and evaluated its role in preventing the deleterious effects of administering each amine alone. Each patient received three infusions in a randomly assigned order: dopamine, 15 micrograms/kg/min; dobutamine, 15 micrograms/kg/min; and a combination of dopamine, 7.5 micrograms/kg/min, and dobutamine, 7.5 micrograms/kg/min. Stroke volume index increased similarly with the three infusions, but dopamine alone increased oxygen consumption (p less than 0.05 vs dobutamine alone and dopamine-dobutamine combined). The dopamine-dobutamine combination increased mean arterial pressure (p less than 0.05 vs dobutamine), maintained pulmonary capillary wedge pressure within normal limits (p less than vs dopamine), and prevented the worsening of hypoxemia induced by dopamine (p less than 0.05). The dopamine-dobutamine combination appears to be useful in the management of mechanically ventilated patients in cardiogenic shock.

One hundred patients with angina pectoris who fulfilled specific entry criteria were randomly assigned to either medical therapy or bypass surgery. These groups were subjected to annual exercise testing during a 5-year follow-up period. The degree of revascularization was assessed by graft and native vessel angiography at 3 weeks, 1 year and 5 years after the operation. The exercise tolerance of the medical group remained largely unchanged during the follow-up. Eighty-five to 95% of the patients were using beta-blocking compounds at the successive testing situations. The surgical group exhibited a sustained improvement in exercise tolerance: Total work increased by 39-66% (p less than 0.02-0.001) and maximal ergometric load by 23-35% (p less than 0.01-0.001), and maximal ST depression decreased by 39-61% (p less than 0.05-0.001). The use of beta-blocking compounds in the surgical group steadily increased, from 44% at 6 months after operation to 63% of patients at 5 years. Division of the surgical group into subsets of complete and incomplete revascularization revealed that the improvement was confined to complete revascularization. Thus, the improved exercise tolerance after bypass surgery was a result of successful reestablishment of effective coronary perfusion; despite graft attrition (15% in 5 years) and new lesions in the native arteries, this improvement persisted for 5 years with appropriate medical therapy.

Of 2144 patients age 65 years or older entered into the registry of the Coronary Artery Surgery Study (CASS) who had coronary arteriography, 1086 underwent isolated coronary artery bypass grafting. Complications of angiography included death in four patients and nonfatal myocardial infarction in 17. Eight patients suffered neurologic complications, which were transient in five. The perioperative mortality was 5.2% (57 of 1086), which is significantly greater than the perioperative mortality of 1.9% (151 of 7827) in patients younger than 65 years entered in CASS (p less than 0.001). There was a trend toward an increased mortality rate with age; it was 4.6% (37 of 803) in patients age 65-69 years, 6.6% (16 of 241) in those 70-74 years and 9.5% (four of 42) in those 75 years or older. The duration of hospital stay after operation was significantly longer for the patients 65 years or older than for the patients younger than 65 (13.3 vs 11.4 days; p less than 0.001). Stepwise linear discriminant analysis identified five variables predictive of perioperative mortality: presence of 70% or more stenosis of the left main coronary artery and a left-dominant circulation, left ventricular end-diastolic pressure, a history of current cigarette smoking, pulmonary rales on auscultation, and presence of one or more associated medical diseases. A second linear discriminant analysis, incorporating 7658 CASS patients who underwent isolated coronary artery bypass surgery irrespective of age, examined whether age 65 years or older was an independent predictor of perioperative mortality. The variables selected, in order of significance, were congestive cardiac failure score, left main coronary artery stenosis and a left-dominant circulation, age 65 years or older, left ventricular wall motion score, sex and history of unstable angina pectoris. In patients 65 years or older, the mortality from coronary arteriography is low, whereas mortality from coronary artery bypass surgery is greater than that in CASS patients younger than 65 years.

This study was designed to clarify discrepancies in the literature concerning platelet survival time and beta-thromboglobulin (beta TG) levels in patients with coronary artery disease (CAD) and the effect of platelet-suppressant drugs on these tests. Platelet survival time and plasma beta TG levels were determined in 48 patients with angiographically documented CAD. The effect of sulfinpyrazone or aspirin/dipyridamole on these measurements was investigated in a double-blind, crossover trial that included a placebo phase. In patients with CAD, the mean plasma beta TG concentration was significantly elevated, but the mean platelet survival time was not significantly different from that in controls. Treatment with sulfinpyrazone or aspirin/dipyridamole did not produce changes in platelet survival time or plasma beta TG concentration that were significantly different from the values during the placebo phase. This study demonstrates that compared with the spontaneous variation in platelet survival time or beta TG concentration, there was no measureable effect of sulfinpyrazone or aspirin/dipyridamole on the results of the tests.

To compare acute effects of nitroglycerin (0.8 mg sublingually), nifedipine (5 ng/kg/min i.v.) and metoprolol (0.15 mg/kg i.v.) on normal, ischemic and scarred myocardial segments in man, we performed simultaneous hemodynamic and radionuclide measurements of left ventricular functions. Sixteen patients with isolated left anterior descending (LAD) disease were studied at rest and during exercise. Nine patients had angina and exercise-induced ischemia (LAD stenosis) and seven patients had previous transmural myocardial infarction and no ischemic changes during thallium imaging (LAD occlusion). The effects of the drugs on regional ejection fraction of the involved anteroseptal region and the normal posterolateral area were compared. Global ejection fraction at rest did not change after nitroglycerin, increased after nifedipine and decreased after metoprolol. In patients with ischemia, the exercise ejection fraction improved after all drugs due to increased regional ejection fraction in ischemic segments: i.e., a regional antiischemic effect evidenced by improved regional function could be demonstrated with all three agents. Regional ejection fraction increased from 35.8 +/- 19.5% to 66.2 +/- 15.2% (+/- SD) after nitroglycerin (p less than 0.001), to 61.7 +/- 8.7% after nifedipine (p less than 0.001), and to 48.4 +/- 7.0% after metoprolol (p less than 0.01). In regions of myocardial scar, regional ejection fraction was not changed after any drug. In normal areas, regional ejection fraction remained unchanged after nitroglycerin and nifedipine, but decreased after metoprolol. Despite similar antiischemic effects of all three drugs, underlying hemodynamic mechanisms were quite different and may provide a rationale for combined forms of treatment. These results may help to select optimal drug combinations to improve myocardial performance in patients with chronic ischemic heart disease.

A prospective, randomized study of i.v. nitroglycerin (TNG) in the management of repetitive spontaneous angina pectoris was undertaken in 40 consecutive patients. The clinical effectiveness of i.v. TNG (group A) was compared with that of oral isosorbide dinitrate (ISDN) and topical 2% nitroglycerin ointment (NO) in combination (group B) during a 72-hour treatment period. The doses of both nitrate regimens were adjusted so that the mean arterial pressure in the two groups was reduced by 15 +/- 3% of control values to the same level (77 mm Hg). The i.v. TNG dose of 10-200 micrograms/min yielded arterial plasma TNG levels of 1.2-65.3 ng/ml and estimated plasma (arterial) clearance of 106 +/- 55 ml/min/kg of body weight (mean +/- SD). In group B, the doses were 20-60 mg (oral ISDN) and 1/2-2 inches (NO) every 6 hours. Intravenous TNG reduced the number of spontaneous ischemic episodes from 3.3 +/- 0.8 per 24 hours during the control period to 1.0 +/- 0.3 per 24 hours during the treatment period (p less than 0.01), while the ISDN/NO combination reduced the number of episodes from 3.1 +/- 0.4 to 1.4 +/- 0.3 (p less than 0.01). Overall, the magnitude of the therapeutic effect of i.v. TNG was statistically indistinguishable from that of ISDN/NO, although i.v. TNG did have somewhat greater clinical benefit on day 2 of the 3-day treatment period. Furthermore, the data suggested more consistent control of ischemic episodes with i.v. TNG during the first 24 hours of the trial. Although both regimens markedly reduced the frequency of spontaneous ischemic episodes, only 36% of patients in group A and 17% in group B experienced no ischemic episodes during the study period (NS). Forty-three percent of patients in group A and 61% in group B (NS) required early coronary artery bypass surgery to control recurrent ischemic episodes refractory to medical therapy. We conclude that i.v. TNG and ISDN/NO, when administered in doses adjusted to produce similar effects on systemic arterial pressure, have nearly equivalent clinical effects in the management of patients with frequent episodes of spontaneous angina pectoris. Intravenous TNG offers the advantage of more consistent control of ischemic episodes during the first 24 hours of treatment. Nevertheless, the recurrence rate of spontaneous ischemic episodes during medical therapy is high with both regimens, and early coronary artery bypass surgery may be required for long-term management.

We investigated the relevance of the selective alpha 1-adrenergic receptor blockade produced by prazosin to its blood pressure-lowering efficacy in man. The hemodynamic and neuroendocrine responses to the acute and chronic oral administration of prazosin and phenoxybenzamine were compared in a randomized, double-blind, placebo-controlled, crossover study of 11 patients with essential hypertension. These responses were also evaluated during lower body negative pressure and dynamic bicycle exercise, which produce potent but diversified activation of the sympathetic nervous system. In the acute studies, arterial blood pressure decreased to similar levels with prazosin or phenoxybenzamine; however, hemodynamic and neuroendocrine responses differed both before and during sympathetic nervous system activation. Prazosin lowered arterial blood pressure by reducing total peripheral resistance (p less than 0.05). In contrast, phenoxybenzamine produced a modest reduction in cardiac output (8%, p less than 0.05) with little change in total peripheral resistance, forearm vascular resistance or forearm blood flow. Additionally, plasma norepinephrine concentration and heart rate rose to significantly higher levels with prazosin (p less than 0.02) than with phenoxybenzamine, a difference that was most evident with lower body negative pressure or dynamic exercise. Baroreceptor control of arterial pressure homeostasis was preserved with both agents, except during marked degrees of cardiovascular stress. With chronic therapy, the circulatory responses adapted to the alpha-adrenergic antagonists, and both drugs produced similar hemodynamic and neuroendocrine profiles. The differences with acute administration may be the result of a more rapid onset of action and a more marked degree of alpha-adrenergic blockage with prazosin than with phenoxybenzamine therapy, rather than to any difference in their alpha 1- and alpha 2-adrenergic receptor blocking properties. Moreover, the findings of the present study suggest that the prejunctional alpha 2-receptor, autoinhibitory to sympathetic neuronal norepinephrine release, is of no functional significance in patients with essential hypertension.

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.