A randomized trial of surgical vs nonsurgical management was carried out in men 60 years of age or younger who had recovered from a recurrent myocardial infarction. Of 205 patients considered, 100 had few or no symptoms and had coronary vessels favorable for bypass grafting; these patients fulfilled the trial conditions and were randomized (50 surgical and 50 nonsurgical). In 41 patients (elective nonsurgical group), randomization was not considered justifiable because of relatively unfavorable coronary anatomy or severe left ventricular dysfunction. Nineteen patients had elective surgery because of disabling angina despite full medical treatment or because of significant left main coronary stenosis. In 45 patients, coronary angiography was not undertaken because of medical contraindications or reluctance of the patient to enter the study. Actuarial survival curves (mean follow-up 4.5 years) show an annual mortality rate of 3-4% per year for all investigated patients, and no advantage for the randomized surgical over the randomized nonsurgical group. The results suggest that in the absence of disabling angina or left main coronary artery stenosis, coronary artery surgery need not be advised for survivors of recurrent infarctions who have severe coronary artery disease. Moreover, the prognosis for the group of patients not treated surgically appears to be better than has been previously described.

In 19 patients with unstable angina pectoris at rest, plasma levels of the platelet-derived proteins beta-thromboglobulin and platelet factor 4 were significantly elevated in blood samples obtained during or within 4 hours after episodes of angina, but were usually normal during quiescent intervals. Plasma levels of the arachidonic acid metabolite thromboxane B2 were less clearly related to angina, and there was no association of angina with levels of the coagulation product fibrinopeptide A. This demonstration of an association of platelet activation and secretion with unstable angina pectoris by radioimmunoassay of circulating platelet constituents offers a new approach to assessment of therapy in ischemic heart disease and suggests that agents that alter platelet function should be evaluated in patients with unstable angina.

The study was designed to investigate the possible role of endogenous opioids in the fall in blood pressure (BP) seen during initial sleep. Seven normal men, ages 20-30 years, were studied for three consecutive nights. Each night, electroencephalogram, chin electromyogram, electrooculogram, heart rate (all continuously), and blood pressure (every 15 minutes) were recorded. Night 1 was used for orientation. On nights 2 and 3, subjects received, in randomized order, an infusion of naloxone 0.2 mg/kg over 1 minute or volume-matched saline. Blood pressure data from the first 4 hours of non-rapid eye movement sleep were combined. On the placebo night, systolic BP fell from 114.6 +/- 6 mm Hg to 103.7 +/- 8 mm Hg (+/- SD) (p < 0.05, Wilcoxon rank-sum test). On the naloxone night, systolic BP did not change. Neither diastolic BP nor heart rate were influenced by naloxone. these data suggest that endogenous opioids could be involved in the fall in systolic BP seen during initial sleep.

The Aspirin Myocardial Infarction Study (AMIS) was a multicenter, randomized, double-blind, placebo-controlled trial of 1.0 g of aspirin daily in men and women who had had a documented myocardial infarction. In the trial 4524 persons, ages 30-69 years, were recruited; 2267 were randomized to aspirin and 2257 to placebo. The major end point, total mortality, was 10.8% in the aspirin group and 9.7% in the placebo group. There was a nonsignificant trend indicating a lower incidence of nonfatal myocardial infarction in the aspirin group (6.3%) compared with the placebo group (8.1%). Symptoms suggestive of gastrointestinal irritation appeared in 23.7% of the aspirin group and in 14.9% of the placebo group. Based on these findings, routine use of aspirin after myocardial infarction is not recommended.

Three randomized controlled trials of aspirin and secondary mortality have been conducted in patients who had had a myocardial infarction. One trial was based on 1239 men followed for 1-2 years; the second was based on 1468 men and 257 women followed for 1 year after infarction. Although the results are not statistically significant in either trial, they are consistent with a reduction in mortality during the year after infarction of about 24% and 17%. Detailed analyses, in which allowance is made for small imbalances between the groups on aspirin and on placebo, indicate that the estimate of benefit of 17% in one of the trials is almost certainly an underestimation. The third trial, in which we analyzed only very early mortality based on 2530 patients, did not show evidence of benefit from aspirin given during the acute phase of infarction.

In the Canadian Cooperative Study of aspirin and sulfinpyrazone in patients with threatened stroke, there was no demonstrable benefit of sulfinpyrazone but there was a significant overall risk reduction in stroke or death of 31% with aspirin (p less than 0.05). This benefit of aspirin was restricted to males, in whom the risk reduction in stroke or death was 48% (p less than 0.005). As with a large-scale clinical trials, questions have been raised about the methodology of the study, including the type of patient included, the choice of outcome measures, the factorial design and the analysis of subgroups. In this report, the design and principal results of the study are summarized and the above methodologic concerns are discussed.

The findings from a double-blind multicenter clinical trial of aspirin for treatment of cerebral ischemia are reviewed. Of 303 patients who had carotid transient ischemic attacks (TIAs), 125 were selected for carotid reconstructive surgery and were then randomly assigned treatment with aspirin or placebo. The remaining 178 patients were also randomly assigned to an aspirin or placebo regimen. Analysis of the first 6 months of follow-up showed a differential in favor of aspirin when death, nonfatal cerebral or retinal infarction and the occurrence of TIAs were grouped and considered together as end points. Restriction of end points to death or nonfatal cerebral or retinal infarction yielded no statistically significant differential between the aspirin and placebo groups. After these results were published, a study group from Canada reported that aspirin was effective in preventing threatened stroke, but that this effect was limited to males. Review of our nonsurgical group with respect to sex shows findings consistent with those of the Canadian study for the end points of stroke or death. Inclusion of the occurrence of TIAs in the group of end points, however, revealed that aspirin is effective in females as well as males.

Two randomized, double-blind clinical trials in cerebrovascular disease are described. The Controlled trial of Aspirin in Cerebral Ischemia compared aspirin (650 mg twice daily) with placebo in medically and surgically treated groups of patients who had experienced transient ischemic attacks. The Randomized Trial of Aspirin and Sulfinpyrazone in Threatened Stroke compared aspirin (325 mg four times daily), sulfinpyrazone (200 mg four times daily) and aspirin plus sulfinpyrazone with placebo in patients with transient cerebral ischemia.

The Coronary Drug Project Aspirin Study (CDPA), started in late 1972 and terminated in early 1974, involved men selected from three groups originally receiving dextrothyroxine or estrogen therapy in the Coronary Drug Project. All patients had a history of myocardial infarction, most of them several years earlier. Length of follow-up ranged from 10-28 months (average 22 months). A total of 1529 patients were recruited and were randomly assigned on a double-blind basis to aspirin therapy -- one 324-mg tablet three times daily or a corresponding placebo treatment. Data indicate a high level of adherence to the study protocol. No major differences were recorded in use of nonstudy medications in the two treatment groups. Overall mortality was 5.8% in the aspirin group and 8.3% in the placebo group (an observed difference of 30%). This difference, suggestive of a beneficial effect for aspirin in the treatment of post-myocardial infarction men, was not large enough to be conclusive.

In a multicenter clinical trial on the prevention of recurrent myocardial infarction, 946 patients who had survived a myocardial infarction for 30-42 days were randomly allocated to acetylsalicylic acid (ASA, 1.5 g/day) (317 patients), placebo (309 patients) or phenprocoumon treatment (320 patients) and were followed to determine the incidence of total mortality, coronary death and nonfatal recurrent myocardial infarction. The ASA and placebo groups were treated in double-blind fashion. The observation period for each patient was 2 years. Total mortality was lower in the ASA group (27 patients) than in the placebo (32 patients) and phenprocoumon groups (39 patients). There were 13 coronary deaths (fatal myocardial infarction and sudden death) in the ASA group, 22 in the placebo group and 26 in the phenprocoumon group. This represents a reduction rate of 42.3% in the ASA group compared with placebo (p less than 0.1) and of 46.3% in the ASA group with phenprocoumon (p approximately 0.07). Considering male patients alone, the difference regarding coronary death is significant between ASA vs placebo (p less than 0.05, reduction rate 56.4%) and ASA vs phenprocoumon (p less than 0.05, reduction rate 55.6%). Coronary events (coronary death and nonfatal recurrent myocardial infarctions) were lower in the ASA group (24 events) than in the placebo (37 events) (p less than 0.07) or phenprocoumon group (32 events).

In a double-blind randomized study, 30 mg/kg of methylprednisolone sodium succinate (MPN) or 15 mg/kg of mannitol placebo (PL) were infused in 28 patients after acute myocardial infarction. Measurements were obtained immediately before and after for 24 hours after the initial infusion. The partial pressure of oxygen at 50% saturation of hemoglobin (P50) did not change significantly in vitro or in vivo after MPN, whereas 2,3 diphosphoglycerate (2,3 DPG) increased from 13.2 to 14.2 mumol/g Hb (p < 0.05) in the group receiving PL. The arteriovenous oxygen difference (Ca-VO2) remained constant after MPN or PL. The cardiac index (CI) increased after MPN (p < 0.02) associated with an increase in the oxygen consumption index (CI X A-V O2) from 146 to 170 ml/min/m2 (p < 0.05). These data show that MPN increases CI after acute myocardial infarction, but has no specific effects on P50, 2,3 DPG or Ca-VO2.

The Persantine-Aspirin Reinfarction Study (PARIS) was a randomized, controlled, double-blind study of dipyridamole (Persantine) and aspirin in secondary prevention of coronary heart disease. Two thousand twenty-six men and women with myocardial infarction (MI) documented by electrocardiographic findings, clinical history and cardiac enzymes were followed for a minimum of 3 years and monitored for mortality (total and cause-specific), recurrent MI and other cardiovascular events. The study had a unique structure that provides a model for large-scale industry-sponsored clinical trials. Although financed by a private pharmaceutical firm, the study was completely independent of the funding sponsor. Sixteen American and four British clinics participated in the study, along with a Coordinating Center, and ECG Reading Center, a Central Laboratory, and a Drug Distribution Center. In addition, the study included an independent Data Quality Control Center that monitored the performance of the Coordinating Center. The rationale, organization, design and baseline results are presented in this report.

Plasma lipids and lipoprotein cholesterol concentrations were determined before and at 3 months and 1 year after partial ileal surgery in 28 male survivors of first myocardial infarction (eight normolipidemic subjects and eight type II-A, two type II-B, eight type IV and two type V hyperlipoproteinemic subjects). All subjects had marked reductions in plasma total cholesterol (average 45% and 33% in the type V subjects and 37% and 31% in the other 26 subjects at 3 months and 1 year after surgeryyy). Except for the two type V subjects, all had even more marked reductions in low-density lipoprotein (LDL)-cholesterol than in the total plasma cholesterol, averaging 51% at 3 months and 49% at 1 year after surger. There were no significant changes in high-density lipoprotein (HDL)-cholesterol levels. The hypertriglyceridemic subjects had marked reductions in plasma triglycerides and very low density lipoprotein-cholesterol, whereas the normotriglyceridemic subjects (normals and II-A) had slight increases in these two measurements after surgery. Partial ileal bypass tends to normalize elevated plasma lipid and lipoprotein levels and results in a maximal lowering in LDL-cholesterol concentrations without altering the HDL-cholesterol level.

In the Persantine-Aspirin Reinfarction Study (PARIS) trial, 2026 persons who had recovered from myocardial infarction (MI) were randomized into three groups: Persantine plus aspirin (PR/A) (n = 810); aspirin alone (ASA) (n = 810); placebo (PLBO) (n = 406). The average length of follow-up study was 41 months. Results for the three specified primary end points were: total mortality 16% lower in PR/A and 18% lower in ASA compared with PLBO; coronary mortality 24% and 21% lower; incidence of nonfatal MI plus fatal coronary disease 25% and 24% lower. These differences were not satistically significant by the study criterion (Z greater than or equal to 2.6). By life-table analysis, the rates of coronary mortality and coronary incidence were about 50% lower in the PR/A group than in the PLBO group from 8-24 months, and for coronary incidence all Z values were greater than or equal to 2.6; ASA rates were about 30% lower than PLBO rates, and for coronary incidence, Z values were greater than or equal to 2.6 at two points. For these end points, from 8-20 months, PR/A rates were about 30% lower than ASA rates, but all Z values were less than 2.0 PR/A and ASA patients entering within 6 months of last MI showed the largest percentage reductions in mortality; only the difference between PR/A and PLBO groups for 3-year coronary mortality yielded a Z value of 2.6.

In a randomized trial of pulsatile vs nonpulsatile cardiopulmonary bypass for coronary artery surgery, we studied hemodynamic and hormonal responses. Anesthesia did not produce a response but, from the time of the incision, cortisol and antidiuretic hormone levels and plasma renin activity all increased. Cortisol levels continued to rise after surgery, whereas the other began to fall. Systemic vascular resistance fell dramatically during cardiopulmonary bypass but rapidly rose after bypass with a reciprocal change in cardiac index. We did not see the changes ascribed to nonpulsatile bypass by others. There ws no difference between our pulsatile and nonpulsatile cases. High-flow cardiopulmonary bypass, vasodilating inhalation anesthesia and continuation of Inderal therapy may account for our results.

Sixteen healthy men were evaluated for left ventricular performance changes and beta-blockade after therapeutic oral doses of disopyramide and propranolol administered alone and concurrently. The volunteers were randomly assigned to receive one of two drug treatment regimens that differed in the sequence and duration of administration of the drugs. Left ventricular function was assessed by echocardiographically determined ejection fraction (EF) and systolic time intervals. Beta-blockade was assessed by changes in exercise heart rate. Both disopyramide and propranolol exhibited negative inotropic activity, as evidenced by significant, although clinically inconsequential, decreases in EF and increases in the ratio of preejection period to left ventricular ejection time. The negative inotropic effects of a single 200-mg dose of disopyramide and an 80-mg dose of propranolol were comparable, while chronic disopyramide therapy (200 mg every 6 hours for 1 week) had a greater negative inotropic effect than chronic propranolol therapy (80 mg every 8 hours for 1 week). Only propranolol had beta-adrenoceptor blocking activity. When the drugs were administered concurrently, the negative inotropic effects of oral propranolol and disopyramide were neither additive nor synergistic.