Serious tachydysrhythmias occur in 10% to 30% of patients early after coronary artery bypass grafting (CABG). We studied the effects of digoxin and propranolol in preventing these dysrhythmias over the first week after CABG (average number of grafts, 2.7/patient). Consecutive patients (n = 179) undergoing CABG were randomized to a drug (group 1) or a control (group 2) group. Excluded were patients given digoxin before CABG and those with ejection fractions of less than 40%, those with dysrhythmias within 18 hr after CABG, those being pacer dependent, and those with low-output syndrome after CABG. Risk factors were comparable in both groups. Electrocardiographic examination showed perioperative myocardial infarction in five patients (2.8%). Digoxin (1 mg iv given over 24 hr, then 0.25 mg/day) and propranolol (10 mg given every 6 hr) were started 6 hr after CABG. Supraventricular dysrhythmias requiring treatment occurred in 3.4% of 89 group 1 patients and in 30% of 90 group 2 patients (p less than .001); ventricular dysrhythmias occurred in 1.1% of group 1 and 8.9% of group 2 patients (p less than .01). In this study, a regimen of post-CABG digoxin and propranolol significantly reduced the incidence of supraventricular and ventricular dysrhythmias without causing adverse reactions.

To develop a way to prevent the occlusion of the aortocoronary saphenous vein bypass grafts, we conducted a prospective, randomized, double-blind trial in 176 patients, some of whom received aspirin alone (975 mg/day) and some of whom took a combination of aspirin and dipyridamole (225 mg/day), and compared them with a parallel control group. Therapy was started 3 to 5 days after surgery. Follow-up angiography was performed in 142 patients (80%) at 1 year. Graft patency in the aspirin group (78%) was not significantly different from that in the aspirin-dipyridamole group (83%) or the control group (80%). Even in the patients at high risk for graft occlusion, i.e., those who had small recipient coronary arteries and poor graft flows, patency rates were not improved by the antiplatelet agents. When administered 3 to 5 days after surgery, aspirin alone or in combination with dipyridamole does not improve graft patency.

Of 12 healthy men with a mean age 50 +/- 4 years who had been at bed rest for 10 days, six were randomly assigned to perform individually prescribed physical exercise daily for 60 days after bed rest (exercise group) and six simply resumed their customary activities (control group). Exercise group subjects were significantly more active than control subjects during this interval (p less than .05). Two classic training effects observed in the 60 days after bed rest were significantly larger among exercise than among control group subjects; compared with values immediately after bed rest, heart rate at a constant submaximal workload declined by 36 +/- 11 beats/min in the exercise group vs 16 +/- 8 beats/min in the control group and peak oxygen consumption increased by 4.8 +/- 4.2 vs 2.2 +/- 5.0 ml/kg/min (both p less than .05). Despite these differences in the cardiovascular response to exercise, peak oxygen consumption in both groups returned to before-bed rest levels by 30 days after bed rest, and this was accompanied by significant (p less than .05) and similar increases in resting left ventricular end-diastolic and stroke volumes in both groups. Simple resumption of usual physical activities after bed rest was as effective as formal exercise conditioning in restoring functional capacity to before-bed rest levels.

Experiments in animals have shown that coronary artery reperfusion limits the extent of myocardial damage and brings about late return of regional contraction and overall left ventricular function over a period of several weeks. Such studies provide a basis for optimism that similar effects can be demonstrated after thrombolytic treatment in man, and such functional contractile recovery should provide an important end point in clinical investigations. However, before the initiation of a large-scale clinical trial, adequate methods for determining salvage of myocardium must be identified, and since changes in such measures may be small, the use of mortality as an end point should also be considered. In addition, the possibility of having two treatment groups to compare intracoronary and intravenous modes of therapy should be examined. Based on the growing number of uncontrolled clinical reports concerned with the success of intracoronary thrombolysis in restoring vessel patency and preliminary data on morbidity, mortality and potential improvement in left ventricular function with this procedure, planning for a randomized clinical trial sponsored by the National Institutes of Health is warranted.

A prospective randomized study comparing coronary bypass surgery (group 1, 51 patients) to drug therapy (group 2, 49 patients) was initiated in 1981. Supine graded exercise testing (SGXT) was performed initially, at 6 months, and annually with a bicycle ergometer. The presence or absence of ischemic ST segment changes (positive or negative SGXT) and chest pain were recorded. Initially, 63% of all patients had positive SGXT. For group 2, the frequency of positive SGXT results did not change significantly at 6 months (58%) or at 5 years (52%). At 6 months the number of patients without chest pain increased in group 1 compared with group 2 (28/41 vs 13/41, respectively; p less than .002), but there was no difference in the frequency of positive SGXT results (20/41 vs 24/41, respectively; p = NS). This occurred because a majority of the group 1 patients with positive SGXT no longer had associated chest pain (group 1, 11/20, group 2, 3/24; p less than .007). This response was associated with incomplete revascularization in eight of these 11 group 1 patients and may result from "silent ischemia." At 5 years, no significant difference existed in the incidence of positive SGXT (group 1, 10/32 vs group 2, 12/23; p = NS), but group 1 patients continued to have a reduction (although not statistically significant) in the number of patients without chest pain (group 1, 19/32 vs group 2, 7/23). The incidences of death and myocardial infarction were not significantly different between groups. Fewer episodes of unstable angia occurred in group 1 (10/51 vs 19/49; p less than .05). The prognosis of group 1 patients with positive SGXT and no chest pain and incomplete revascularization was not different from that of the entire group.

The effects of oral diltiazem (360 mg/day) on exercise tolerance, left ventricular performance, and plasma lactate and catecholamine levels were studied in 13 patients with atherosclerotic coronary artery disease in a placebo-controlled, randomized, double-blind protocol. Exercise duration to the onset of ischemic ST segment depression, time to angina pectoris, and time to peak exercise improved by 120, 174, and 144 sec, respectively (p less than .0001). Left ventricular ejection fraction, as determined by radionuclide angiography, increased in patients at rest from 52 +/- 11% (mean +/- SD) during placebo therapy to 58 +/- 11% during diltiazem therapy (p less than .001); at peak exercise ejection fraction increased from 44 +/- 11% during placebo treatment to 52 +/- 15% during diltiazem therapy (p less than .01). The mean plasma norepinephrine level in patients at rest increased from 498 +/- 221 pg/ml during placebo treatment to 667 +/- 272 pg/ml during diltiazem therapy (p less than .05). Resting standing blood pressure and supine and standing diastolic blood pressures decreased significantly with diltiazem. In all 10 patients followed over a long term, oral diltiazem caused persistent improvement in exercise performance at 12 to 20 weeks, without evidence of placebo effects. Thus, diltiazem is highly effective in divided doses of 360 mg/day for the therapy of chronic angina pectoris due to coronary artery disease.

Four hundred seventy-seven patients suspected of having had acute myocardial infarction within less than 12 hours were randomized to receive i.v. atenolol followed by oral treatment for 10 days or to a control group. In patients with ECG changes indicative of infarction at entry, i.v. atenolol significantly reduced enzyme release by one-third and enhanced R-wave preservation. In patients without such ECG changes, treatment significantly prevented the development of infarction in a proportion of patients. There was also a significant reduction in R-on-T ectopics, repetitive ventricular arrhythmias and supraventricular arrhythmias. Treated patients had significantly greater pain relief and required fewer opiate analgesics. Significantly fewer atenolol-treated patients died by 10 days (the treatment period), had nonfatal cardiac arrests, developed heart failure, or suffered reinfarction.

The effects of propranolol on lipids and lipoproteins were investigated in survivors of a recent myocardial infarction who were enrolled in the double-blind Beta-Blocker Heart Attack Trial. Nonfasting serum samples were obtained in more than 2800 patients assigned randomly to either propranolol or placebo. The propranolol-treated group had high-density lipoprotein cholesterol levels 3-4 mg/dl less and triglyceride concentrations 30-40 mg/dl higher than the placebo group. These effects occurred in men and women in all age categories.

The results from the Beta-Blocker Heart Attack Trial for patients ages 60-69 years indicate a significant beneficial effect of propranolol and an overall reduction in mortality of 33%. This beneficial effect appears to begin early and continues through 3 years of follow-up. Examination of patient complaints and medical reasons for withdrawing study medication indicates that side effects resulting from propranolol use were infrequent in both the younger and older age groups, and there were no major differences between the two groups. Given these results, and considering the large number of hospital-diagnosed myocardial infarctions that occur each year in persons older than 60 years of age, it appears that the use of propranolol, where not contraindicated, could delay mortality in a substantial number of older postinfarction patients.

We carried out a double-blind, randomized study, based at The Academic Department of Cardiology in Newcastle upon Tyne, to compare the effect of sotalol 320 mg once daily with that of placebo in patients from 20 hospitals who survived an acute myocardial infarction. Treatment was started 5-14 days after infarction in 1456 patients; 60% were randomized to sotalol and 40% to placebo. This represented 45% of those evaluated for entry. All patients were followed for 12 months and the analysis was done on an "intention-to-treat" principle. Sixty-four patients (7.3%) in the sotalol group died, compared with 52 (8.9%) in the placebo group. Although the mortality rate was 18% lower in the sotalol group, the difference was not statistically significant. There was a significant reduction in confirmed reinfarction, but not in all suspected reinfarctions.

A randomized, double-blind, placebo-controlled trial of propranolol was carried out in 560 high-risk survivors of myocardial infarction enrolled at 12 Norwegian hospitals. The main purpose of the study was to determine the effect of propranolol, 160 mg/day, on the incidence of sudden cardiac death over 12 months. The patients were randomized 4-6 days after the acute event. A statistically significant reduction in sudden cardiac deaths of 52% was noted (11 deaths in the propranolol group and 23 in the placebo group). Four placebo patients and one propranolol patient were successfully resuscitated from ventricular fibrillation. In addition, less severe ventricular arrhythmias were significantly more common among the placebo-treated patients. Twenty-five patients in the treatment group and 37 in the control group died (p = 0.11). Severe adverse effects of the drug were uncommon in this high-risk population. The findings support the results of the Beta-Blocker Heart Attack Trial and other long-term beta-blocker trials in survivors of myocardial infarction.

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.

Results based on small subgroups are prone to much random variation and firm conclusions based on subgroup analyses should be avoided. Caution is advisable, especially with regard to post hoc and multiple analyses. Subgroup findings for which a reasonable biologic explanation can be given and those supported by independent results from other subgroups within the trial are more likely to be real. The strongest support for a subgroup finding in one trial is a replication from another trial. Post hoc analyses from the Beta-Blocker Heart Attack Trial suggest, and are supported by the Norwegian Timolol Study, that myocardial infarction patients older than age 60 years and those with arrhythmic and other complications not severe enough to preclude treatment benefit the most in absolute terms from beta blockers.