Repeat angiography was performed at 63 +/- 9 months in 26 medically treated patients and at 66 +/- 10 months in 32 surgically treated patients with chronic angina. The native coronary arteries were divided into three major trunk vessels and 15 angiographic segments. Progression of disease was defined as the appearance of new (greater than 50%) obstruction or significant worsening of existing lesions in a segment or vessel. The incidence of progression was similar in medical and surgical patients, comparing individual segments (69 of 312 [22%] and 91 of [23%], respectively) or vessels (49 of 78 [63%] and 60 of 96 [63%], respectively). In both medical and surgical patients, segments initially free of disease showed a 14% incidence of developing new lesions, compared with the 37% progression in segments initially diseased (p less than 0.001). In the surgical patients, progression occurred in 48 of 219 (22%) nongrafted and 43 of 177 (24%) grafted segments (NS). When analyzed by major trunk vessel, progression occurred in 40 of 57 grafted arteries (70%) and 20 of 39 nongrafted arteries (51%) (NS). The incidence of new total occlusions was similar in medical and surgical patients (6% and 8%, respectively); new total occlusions occurred predominantly in diseases segments (15% and 22%, respectively). In patients with stable angina pectoris who have medical or surgical treatment assigned by randomization, progression of coronary disease at 5 years is not influenced by which mode of therapy was received. Vessels initially free of disease are at relatively low risk for development of disease within 5 years. In surgical patients, grafted and nongrafted vessels show similar rates of progression.

We determined the pharmacokinetics, efficacy and therapeutic plasma concentration of encainide, a new antiarrhythmic drug that affects His-Purkinje conduction but not ventricular refractoriness. Nine patients with frequent and complex premature ventricular complexes were studied in a 3-day double-blind protocol. Each day, each patient received 75 mg of i.v. or oral encainide or placebo. Frequent blood samples for encainide plasma concentration determination and continuous ambulatory ECGs were obtained. There was a marked intersubject variation in bioavailability (mean 42 +/- 24%, range 7.4-82%), clearance (13.2 +/- 5.6 ml/min/kg, range 3.75-22.1 ml/min/kg) and half-life (3.4 +/- 1.7 hours i.v., 2.5 +/- 0.8 hours oral). Eight of nine patients had more than 90% suppression of premature ventricular complexes for 3-36 hours. Minimal antiarrhythmic plasma concentration was higher (39 +/- 54 ng/ml, range 3.5-170 ng/ml) after i.v. dosing than after oral dosing (14 +/- 16 ng/ml, range 1.5-48 ng/ml), suggesting an active metabolite after oral dosing in many patients. Minimal side effects were seen despite high peak plasma concentrations (range 794-1556 ng/ml i.v., 36-495 ng/ml oral). The minimal ratio of toxic to therapeutic plasma concentration ranged from 4.3-326 (median 23) after oral dosing. Antiarrhythmic action was associated with an 11-44% widening of the QRS complex that was not associated with other adverse effects. We conclude that encainide effectively suppresses ventricular arrhythmias. Despite a variable bioavailability, high clearance and short half-life, its wide ratio of toxic to therapeutic concentration and probable active metabolite permit a long duration of action, which should allow a reasonable dose schedule in most patients during chronic oral dosing.

A multivariate risk function was developed on data from all 508 medical patients in the Veterans Administration (VA) randomized study of coronary bypass surgery. The variables, in order of importance, were ST-segment depression on resting ECG, history of myocardial infarction, history of hypertension and New York Heart Association functional classification III or IV. These noninvasive variables have been reported to be risk factors in natural-history studies of coronary heart disease (CHD). Applying the risk function to medical and surgical patients of the 1972-1974 cohort yielded a 5-year probability of dying for each patient. Investigation of treatment effects in approximate terciles obtained by collapsing the probability distribution into low-, middle- and high-risk groups showed that surgery was beneficial for patients in the high-risk tercile even after removal of patients with left main coronary artery disease (17% surgical vs 34% medical mortality at 5 years; p less than 0.01). This finding was accentuated when patients in the 10 hospitals with the lowest operative mortality (3.3%) were compared. Mortality results in the low-risk tercile favored medical treatment (medical vs surgical mortality 7% vs 17%; p less than 0.05). The risk function predicted mortality well not only for te VA medical group, but also for an independent symptomatic CHD population from the University of Alabama arteriography registry. This report further delineates the advantages and limitations of coronary bypass surgery in CHD patients with chronic stable angina.

The hemodynamic and myocardial metabolic responses to the cold pressor test were studied in 15 patients with coronary artery disease and stable exertional angina. Every patient had abnormal coronary vasoconstriction during a control cold pressor test, even though 14 were receiving propranolol and 12 were receiving long acting nitrates. Mean coronary vascular resistance for the group increased 18 +/- 6% (SD) (from 0.80 +/- 0.12 to 0.94 +/- 0.20 mm Hg/ml/min, p less than 0.05); coronary sinus blood was unchanged, and the arterial-coronary sinus oxygen difference widened significantly (from 11.5 +/- 1.2 to 12.3 +/- 1.2 ml/100 ml, p less than 0.05). Four patients developed angina, accompanied in each instance by a negative arterial-coronary sinus lactate difference. After the administration of nifedipine (10 mg buccally) in 10 patients, the coronary vascular responses to a repeat cold pressor test were normal in each patient. Mean coronary sinus blood flow increased 27 +/- 12% (from 122 +/- 32 to 153 +/- 35 ml/min, p less than 0.05), coronary vascular resistance decreased 10 +/- 6% (from 0.85 +/- 0.16 to 0.76 +/- 0.16 mm Hg/ml/min, p less than 0.05), and the arterial-coronary sinus oxygen difference was unchanged. No patient experienced angina. The hemodynamic and coronary vascular responses to a repeat cold pressor test in five patients given placebo were unaltered from control responses. The protective effects of nifedipine were unaccompanied by any change in mean arterial pressure, left ventricular filling pressure or myocardial oxygen consumption either at rest or in response to the cold pressor test. Nifedipine appears to exert a selective antivasoconstrictor effect on the coronary vasculature.

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.

Twelve patients completed a double-blind, crossover antiarrhythmic drug trial in which 300 mg of quinidine, 500 mg of procainamide, 100 mg of phenytoin, or placebo was given four times daily on subsequent weeks. Analysis of 24-hour Holter tapes with a computerized analysis system (Argus/H) permitted accurate counting of premature ventricular complexes (PVCs) subclassified according to coupling interval. No antiarrhythmic agent demonstrated a significant overall reduction in the number of PVCs, but both quinidine and procainamide showed a statistically significant (p less than 0.05) reduction of PVCs with coupling intervals less than 400 msec. This effect was noted both in isolated PVCs (quinidine only) and in PVCs that were part of a couplet or run (both drugs). These findings demonstrate that clinically important effects of procainamide and quinidine can occur in the absence of an overall reduction in the number of PVCs.

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.

The Anturane Reinfarction Trial evaluated the effect of sulfinpyrazone (Anturane) (200 mg four times a day) vs placebo on cardiac mortality rates among patients recently recovered from an acute myocardial infarction. This study involved 1558 eligible patients who were observed for an average period of 16 months (maximum 2 years). The trial differed from studies on other platelet-active drugs in that it was designed as a clinical efficacy study rather than an "intent-to-treat" trial, and all patients were entered within a very narrow window, i.e., 25-35 days after infarction, which allowed for the drug to be evaluated against the natural history of mortality after an acute myocardial infarction. At the end of the trial, there were 105 analyzable cardiac deaths among eligible patients. 62 in the placebo group and 43 in the sulfinpyrazone group; this represented a reduction in mortality rate by sulfinpyrazone of 32% and was of borderline statistical significance (p = 0.044-0.058 using three methods of analysis). This reduction was attributable primarily to a significant reduction in sudden death (37 in the placebo group vs 22 in the sulfinpyrazone group, sudden death mortality reduction of 43%, p = 0.023-0.041). Interpretation of the data by time period and cause revealed that the effect of sulfinpyrazone was restricted to the prevention of sudden death during the high-risk period for this event, i.e., the first 6 months after trial entry (24 in the placebo group vs six in the sulfinpyrazone group, sudden death mortality reduction of 74%, p = 0.001-0.003).

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.

Postoperative fever and pericardial-pleural reaction, designated postpericardiotomy syndrome (PPS), is a common complication of cardiac surgery involving entry into the pericardium. To determine whether the etiology of PPS is viral or immunologic, we undertook a prospective, triple-blind study of consecutive long-term survivors of intrapericardial surgery in the pediatric age group. We evaluated clinical evidence of syndrome and concurrent appearance of antiheart antibody (AHA) by indirect immunofluorescence and antiviral antibody (AVA) by complement fixation in sera preoperatively and serially postoperatively. Incidence of PPS was 27% overall in 400 subjects, but only 3.5% in infants younger than 2 years of age. AHA in high titer appeared in all patients with PPS. A fourfold or greater rise in titer to AVA was found in 70% of these but in only 5% of those with negative AHA and no PPS. AVA rise, tested in 280 consecutive patients, was to no single one of the eight viruses studied (adenovirus, cytomegalovirus, and coxsackievirus B 1-6). Instead, the rise and fall, consistent with antiviral response to a recent infection, was exhibited usually to one but occasionally to two or more viruses, and the viral prevalence changed from year to year, as did that in the community. The study suggests that concurrent fresh or reactivated viral illness plays a role in triggering the immunologic response that characterizes the PPS.

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 efficacy and safety of a combination of Persantine and aspirin, of aspirin alone and of a placebo as a regimen for preventing reinfarction were compared in 2026 patients who had recovered from a documented acute myocardial infarction (MI) that had occurred 8 weeks to 5 years previously. Baseline variables were comparable, and almost all surviving patients were treated for 3 years. There was a trend toward improved survival rates both for the combination and single drug compared with placebo. Coronary incidence was significantly lower in the combination group compared with placebo at each 4-month interval during the first 24 months of treatment, whereas significant reductions in the aspirin group occurred only at 8 and 24 months. Gastric and renal side effects were more common in the treated groups. To confirm the above results and the findings that the group of patients enrolled within 6 months of last MI had the largest reduction in mortality in the combination group, another study has been designed to compare the combination with a placebo in a large group of patients.

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.

The basic design features of eight clinical trials of platelet-active drugs in the secondary prevention of myocardial infarction are reviewed. Study populations are compared with regard to size, time of enrollment after the qualifying infarction and the length of follow-up. Differences in the drug regimens in terms of dose are given and there are comments on the selection of response variables, the withdrawal of patients from analysis and repeated significance testing.