Fifteen patients with congestive cardiomyopathy (six idiopathic and nine alcoholic) manifested by heart failure (New York Heart Association class III or IV) were randomly assigned to a protocol in which dobutamine (n = 8) or 5% dextrose in water (n = 7) was infused continuously for 72 hr. The dose of dobutamine was titrated to increase cardiac output to twice the baseline values. The patients were evaluated before infusion, shortly after infusion, and 1, 2, and 4 weeks thereafter. Functional class improved in six of eight dobutamine-treated patients but in only two of seven control patients during the 4 week observation period. Maximal exercise time and left ventricular ejection fraction increased significantly above baseline only in the dobutamine group. However, neither dobutamine nor placebo infusion produced significant changes shortly after infusion in heart rate, cardiac index, or total peripheral vascular resistance at rest or during exercise at similar workloads. The group receiving dobutamine did show a reduction in systemic systolic and pulmonary arterial mean and diastolic pressure at rest (123 +/- 5 to 108 +/- 6, 32 +/- 5, to 24 +/- 3, and 26 +/- 4 to 20 +/- 2 mm Hg, respectively). In addition, total body oxygen consumption during similar workloads was lower after dobutamine infusion than before.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous nitroglycerin (NG) infusion in patients with acute myocardial infarction (AMI) has been shown to improve left ventricular function and myocardial perfusion and to decrease ischemic injury and creatine kinase (CK) indexes of infarct size. To determine whether early NG infusions in patients with AMI decreases the extent of left ventricular asynergy, we used two-dimensional echocardiography to measure asynergic segments (akinesis and/or dyskinesis) at four serial short-axis levels from base to apex (mitral, M; chordal, C; midpapillary, MP; low papillary, LP) in 22 patients with a first anterior AMI. Patients were randomized between infusions of NG (n = 11) or 5% dextrose in water (controls, n = 11) within 5.6 hr after the onset of pain. NG infusion rates were titrated to lower mean arterial pressure to an average level of 7% below control (but not below 80 mm Hg) and were maintained at this level for the duration of the infusions (39 hr). After NG, left ventricular function improved as left ventricular filling pressure decreased (p less than .005), and sigma ST on precordial ST segment mapping decreased (p less than .001). These parameters did not change in control subjects. Computed CK infarct size was smaller in the NG group than in the control group (p less than .05). Before the infusions, the mean extent of left ventricular asynergy (% left ventricular circumference) were similar in both groups: M, 18% vs 21%; C, 22% vs 23%; MP, 26% vs 24%; LP, 32% vs 29%. In addition, the computed total left ventricular asynergy (% surface area) was also similar for these two groups before therapy (25% vs 25%). There was no change in left ventricular asynergy from pretreatment values by 1 hr and 10 days among control subjects: M, 18% vs 18% vs 17%; C, 22% vs 22%; MP, 26% vs 26% vs 22%; LP, 32% vs 33% vs 33%; total 25% vs 25% vs 24% (multiple measures analysis of variance). In contrast, there was a significant decrease (p less than .001) in left ventricular asynergy from pretreatment values by 1 hr and 10 days with NG: M, 21% vs 10% vs 8%; C, 23% vs 12% vs 10%; MP, 24% vs 13% vs 9%; LP, 29% vs 14% vs 10%; total, 25% vs 12% vs 9%.(ABSTRACT TRUNCATED AT 400 WORDS)

With the use of equilibrium radionuclide ventriculography the effects on left ventricular (LV) function of 160 mg oral propranolol daily and 360 mg verapamil daily alone and in combination were compared in 18 patients with chronic exertional angina. A randomized, double-blind, placebo-controlled, crossover protocol was used. The reduction in exercise rate-pressure product induced by the combination (118 +/- 28 mm Hg/min) was significantly greater (p less than .05) than that by propranolol (135 +/- 27 mm Hg/min) or verapamil alone (163 +/- 28 mm Hg/min). In patients at rest, neither single nor combined therapy altered global or regional left ventricular ejection fractions (EFs). Verapamil, but not propranolol, increased (p less than .05) cardiac volumes of resting subjects; used in combination, no further increase in LV volume occurred. With placebo, exercise global EF did not decrease from the level at rest and therefore no drug effect could be demonstrated for this parameter of LV function. By an evaluation of normalized regional EF measurements the combination was shown to reduce exercise-induced hypokinesis (placebo 52 +/- 20%, combination 61 +/- 23%; p less than .01). No significant improvement was noted with propranolol or verapamil alone; only the combination prevented a significant increase in end-systolic and end-diastolic volumes during exercise. Thus, propranolol and verapamil, used alone in moderate doses, exert no beneficial effect on exercise LV function as measured by EF and volume changes, and resting function deteriorates slightly with verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

To evaluate the relative thrombolytic efficacy and complications of intracoronary vs high-dose, short-term intravenous streptokinase infusion in patients with acute myocardial infarction, we performed baseline coronary arteriography and then randomly allocated 51 patients with acute myocardial infarction to receive either intracoronary (n = 25) or intravenous (n = 26) streptokinase. Patients getting the drug by the intracoronary route received 240,000 IU of streptokinase into the infarct-related artery over 1 hr, whereas those getting the drug by the intravenous route received either 500,000 IU of streptokinase over 15 min (n = 10) or 1 million IU of streptokinase over 45 min (n = 16). Angiographically observed thrombolysis occurred in 76% (19/25) of the patients receiving intracoronary streptokinase, in 10% (1/10) of the patients receiving 500,000 IU of streptokinase intravenously, and in 44% (7/16) of the patients receiving 1 million IU of streptokinase intravenously. Among patients in whom thrombolysis was observed, mean elapsed time from onset of streptokinase infusion until lysis was 31 +/- 18 min in patients receiving intracoronary streptokinase and 38 +/- 20 min in those receiving intravenous streptokinase (p = NS). Among patients in whom intravenous streptokinase "failed," intracoronary streptokinase in combination with intracoronary guidewire manipulation recanalized only 7% (1/15). Fibrinogen levels within 6 hr after streptokinase were significantly lower in the patients receiving intravenous streptokinase (39 +/- 17 mg/dl) than the levels in those receiving intracoronary streptokinase (88 +/- 70 mg/dl) (p less than .05) but were similar 24 hr after streptokinase in the two groups. Bleeding requiring transfusion occurred in one patient in each group. Thus, in this prospective randomized trial of intracoronary vs intravenous streptokinase, hemorrhagic complications were few, although both regimens produced a systemic lytic state. Although the thrombolytic efficacy of intracoronary streptokinase was superior to that of high-dose, short-term intravenous streptokinase, the higher-dose intravenous regimen (1 million IU over 45 min) achieved thrombolysis in a significant minority (44%) of patients and might be useful therapy for patients not having access to emergency catheterization.

To evaluate the comparative effects of medical and surgical therapy on quality of life of patients with stable ischemic heart disease, 780 patients who had been randomly assigned to medical or surgical therapy in the CASS were systematically followed for a mean of 5.5. years. Analysis was performed according to original treatment assignment. Patients in the surgical group had significantly less chest pain, fewer activity limitations, and required less therapy with nitrates and beta-blockers. Treadmill exercise tests performed 6, 18, and 60 months after entry documented significantly longer treadmill time, less exercise-induced angina, and less ST segment depression among surgical group patients. However, employment status and recreational status did not differ significantly between medical and surgical groups. Total number of hospitalizations after randomization was higher in the surgical group owing primarily to rehospitalization during the first year of follow-up for the coronary artery bypass graft surgery. Risk factors, including high blood pressure, cigarette smoking, high cholesterol levels, overweight, and poor exercise habits remained similar between medical and surgical groups. This randomized collaborative study shows that coronary artery bypass graft surgery improves the quality of life as manifested by relief of chest pain, improvement in both subjective and objective measurements of functional status, and a diminished requirement for drug therapy. However, no significant effect on employment or recreational status was observed.

CASS includes a multicenter patient registry and a randomized controlled clinical trial. It is designed to assess the effect of coronary artery bypass surgery on mortality and selected nonfatal end points. From August 1975 to May 1979, 780 patients with stable ischemic heart disease were randomly assigned to receive surgical (n = 390) or nonsurgical (n = 390) treatment and were followed through April 15, 1983. At 5 years, the average annual mortality rate in patients assigned to surgical treatment was 1.1%. The annual mortality rate in those receiving medical therapy was 1.6%. Annual mortality rates in patients with single-, double-, and triple-vessel disease who were in the surgical group were 0.7%, 1.0%, and 1.5%; the corresponding rates in patients in the medical group were 1.4%, 1.2%, and 2.1%. The differences were not statistically significant. Nearly 75% of the patients had entry ejection fractions of at least 0.50. The annual mortality rates in patients in the surgical group in this subgroup with single-, double-, and triple-vessel disease were 0.8%, 0.8%, and 1.2% and corresponding rates in the medical group were 1.1%, 0.6%, and 1.2%. The annual rate of bypass surgery in patients who were initially assigned to receive medical treatment was 4.7%. The excellent survival rates observed both in CASS patients assigned to receive medical and those assigned to receive surgical therapy and the similarity of survival rates in the two groups of patients in this randomized trial lead to the conclusion that patients similar to those enrolled in this trial can safely defer bypass surgery until symptoms worsen to the point that surgical palliation is required.

We determined the efficacy, pharmacokinetics, and plasma concentration-response relationships of propafenone, a promising new antiarrhythmic drug. Thirteen patients with frequent and complex ventricular premature beats were studied after receiving four increasing doses, during drug washout and during a randomized double-blind placebo-controlled trial, to evaluate the optimal dose in each patient. A nonlinear relationship was found between propafenone dose and steady-state mean concentration with a 10-fold increase in drug concentration as dose increased threefold from 300 to 900 mg/day. There was great intersubject variability in elimination half-life (mean 6 hr, range 2.4 to 11.8), steady-state mean concentration on 900 mg/day of propafenone (mean 1008 ng/ml, range 482 to 1812), and "therapeutic" plasma concentration (mean 588 ng/ml, range 64 to 1044). The interaction of these three parameters in individual patients determined the duration of the antiarrhythmic action of propafenone during washout (mean 11.5 hr, range 4 to 22). There was a greater than 90% reduction of ventricular premature beats in 10 subjects during dose ranging and in seven during double-blind crossover. Side effects requiring discontinuation of the drug occurred in three patients and included apparent worsening of arrhythmias in two. We conclude that propafenone effectively suppresses ventricular arrhythmias and that nonlinear drug accumulation and intersubject variability in elimination of half-life, steady-state mean plasma concentration, and therapeutic concentration indicate a need for individual therapy.

Ten men with stable angina not fully relieved by optimal doses of propranolol were given on each of four mornings a single dose of 10 mg nifedipine, 120 mg verapamil, isosorbide dinitrate (5 to 30 mg, previously titrated to lower systolic blood pressure by 15 to 20 mm Hg), or placebo, in double-blind fashion. Bicycle exercise to angina was performed hourly for 8 hr thereafter. All three vasodilators increased exercise time by at least 50% by the first hour (p less than .001), with a gradually diminishing effect persisting for 6 to 8 hr (p less than .01). Although for the group there were no differences in magnitude and duration of effect among the three drugs, in five of the individual patients there were important differences in response favoring one or another vasodilator. We conclude that nifedipine, verapamil, and isosorbide dinitrate are equally effective and reasonably long-acting antianginal supplements to propranolol, although some patients may benefit more from one than another of the three.

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.

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.

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.