Survival data after 8 years of follow-up for all patients and after 7 years for certain subgroups are reported from CASS, a randomized trial of surgical or medical treatment assignment in patients with coronary artery disease who have less than severe angina or are asymptomatic after myocardial infarction. After 8 years, survival curves are not significantly different between medical and surgical groups; 87% of patients assigned to surgical and 84% of those assigned to medical treatment are alive. A significant advantage favoring surgical assignment was observed in patients with three-vessel disease and reduced ejection fractions (less than 0.5. but greater than 0.35); after 7 years of follow-up, 88% of the patients in the surgical group and 65% of those in the medical group are alive (p = .009). Survival curves for patients with normal resting ejection fractions are identical after 7 years. We conclude that the CASS trial reveals a significant advantage favoring surgical therapy in patients with three-vessel disease and impaired ventricular function who are randomly assigned to treatment.

Selective inhibitors of thromboxane synthase have two theoretical advantages over inhibitors of the cyclooxygenase enzyme as potential antithrombotic compounds. First, they do not prevent formation of prostacyclin, a platelet-inhibitory, vasodilator compound, coincident with inhibiting thromboxane biosynthesis. Second, the prostaglandin endoperoxide substrate that accumulates in the platelet in the presence of thromboxane synthase inhibition may be donated to endothelial prostacyclin synthase at the site of platelet-vascular interactions (endoperoxide "steal"). Selective inhibition of thromboxane biosynthesis coincident with enhanced prostacyclin formation in vivo has been observed after administration of these compounds to man. Despite these attractive features and the efficacy of these compounds in diverse short-term animal preparations of thrombosis, investigations of their efficacy in human disease have proven disappointing. This may reflect on the importance of thromboxane A2 in the diseases that have been investigated. Alternatively, the lack of drug efficacy may have resulted from either incomplete suppression of thromboxane biosynthesis and/or substitution for the biological effects of thromboxane A2 by prostaglandin endoperoxides during long-term dosing studies. Given that selective inhibition of thromboxane formation can be approached with aspirin, the particular value of these compounds is dependent on enhancing prostacyclin formation. Aspirin inhibits thromboxane-dependent platelet activation, but many platelet agonists are likely to act in concert in vivo and prostacyclin inhibits platelet aggregation induced by both thromboxane-dependent and thromboxane-independent mechanisms. To test the hypothesis that thromboxane synthase inhibitors are efficacious in human disease, compounds of longer duration of action are required. Combination with antagonists of the prostaglandin/thromboxane A2 receptor may be necessary to reveal their full beneficial action.

Intracoronary streptokinase (STK) was given to 52 patients and 2 million U of intravenous urokinase was given to 15 patients with acute myocardial infarction less than 3 hr from onset of symptoms. Wall motion in the infarct region improved in 20 patients receiving STK alone (-2.5 +/- 1 to 2.1 +/- 1.1 SD/chord) and in 22 patients receiving STK and undergoing coronary bypass surgery within 24 hr (-2.5 +/- 1 to -1.5 +/- 1.0 SD/chord). Wall motion was unchanged in 10 patients not successfully reperfused with STK (-2.9 +/- 0.7 to -3.1 +/- 0.7 SD/chord). Regional wall motion improved at least 1.0 SD/chord in 71% of 14 patients treated within 2 hr of onset of symptoms, but in only 29% of 34 treated after 2 hr. Mean coronary artery stenosis after thrombolysis was 77 +/- 9%. Rethrombosis was associated with a stenotic cross-sectional area of less than 0.4 mm2. Ventricular function did not improve, with a residual stenosis of 0.4 mm or less in diameter. The Western Washington randomized trial reported a 1 year mortality of 2.5% in 80 successfully reperfused patients, but a mortality of 23% in 13 in whom reperfusion was partial and of 14.6% in 41 in whom reperfusion failed. The improved survival with successful reperfusion and improved ventricular performance with early and more complete reperfusion has stimulated interest in the need for angioplasty and coronary artery bypass grafting after thrombolytic therapy.

Trends in practice patterns at Duke University Medical Center were assessed in patient groups comparable to those enrolled in the three major randomized trials of coronary artery bypass grafting (CABG). In addition, changes in practice patterns that appeared unrelated to the randomized trials were examined. Most patients with 75% or greater left main stenosis have been treated surgically after publication of the Veterans Administration Cooperative Study, but little change was noted in the proportion of patients with 50% left main stenosis who have been treated surgically. A trend towards selection of surgical therapy for patients with three-vessel disease and normal left ventricular function was evident before the publication of the European Coronary Surgery Study, although one-third of patients in this category continue to be treated nonsurgically after publication of the results of the trial. For the past decade, most patients who would have been eligible for the Coronary Artery Surgery Study have been treated nonsurgically. We have also documented trends in practice patterns that are independent of the results of randomized trials. The advent of percutaneous transluminal angioplasty has provided another therapeutic alternative that has been used increasingly. In addition, growing numbers of patients with advanced age, unstable angina, or markedly depressed left ventricular ejection fraction are being evaluated with cardiac catheterization despite the lack of supporting randomized trials. Randomized trials have placed our understanding of the effects of CABG on a sound foundation, but it is evident that clinicians continue to consider many other factors when therapeutic decisions are made.

Stable angina is the most common form of presentation of ischemic heart disease, being more common in women (65%) than men (37%), while the reverse is true for the prevalence, being present in about 3.5% of men over 55 as opposed to 1.5% of women. The overall 10 year survival for individuals with stable angina at a mean age of 60 years is 58% for men and 68% for women. Prognosis is related to several factors: age, sex, the number of coronary vessels involved, collateral flow, ventricular function, and the extent of myocardium at risk. It is estimated that stable angina of recent onset is associated with single-vessel disease in about 40% of cases. Angina is a clinical diagnosis but, if doubt exists, one should exclude coronary atherosclerosis or spasm by cardiac catheterization and not rely on noninvasive techniques. Therapy for unstable angina or acute infarction receives considerable attention and is reasonably well defined, but such is not the case for stable angina. Conventionally, it consists of secondary prevention and prescription of nitrates, calcium blockers, or beta-blockers. There are several problems: No studies have been performed to assess efficacy in reducing the development of unstable angina. The group of drugs most appropriate for first-line therapy has not been identified. It has not been determined if nitrate tolerance is a major problem. The effect of beta-blockers on prognosis in patients with unstable angina has not been defined. A noninvasive means of identifying high and low risk patients with unstable angina has not been developed.

Beta-Adrenergic blockers have not been widely used in patients with peripheral vascular disease because these drugs have been reported to worsen the symptoms of intermittent claudication. To test this assumption we studied the effects of a beta 1-selective and a nonselective beta-adrenergic blocker on postexercise calf blood flow and symptoms of claudication in 19 patients with mild-to-moderate peripheral vascular disease. Subjects received placebo for 3 weeks, and then were randomized to 120 mg/day propranolol or 150 mg/day metoprolol with the use of a crossover design. Blood flow in the calf was measured by strain-gauge plethysmography at rest and immediately after exercise on a bicycle ergometer at a low and a high workload. The symptoms of claudication were monitored during bicycle exercise and by patient diaries maintained between visits. Maximal exercise heart rate was reduced an equivalent amount by metoprolol (19 beats/min) and propranolol (16 beats/min). Mean arterial pressure was reduced by propranolol at rest and by both drugs with exercise. Calf blood flow was not affected by either drug compared with placebo at rest or at either workload. In addition, the symptoms of claudication were not worsened by either drug. We conclude that despite evidence of beta 1-adrenergic blockade and a lowering of arterial pressure, neither beta-adrenergic blocker adversely affected the peripheral circulation.

After 30 min rest in the lying position, 12 healthy male volunteers (average age 22 years) received, in a randomized double-blind cross-over protocol, either saline or naloxone (10 mg iv followed by a continuous infusion of 10 mg/hr). Thereafter they rested for a further 30 min in the recumbent position and for 15 min sitting on a bicycle ergometer; they then exercised to exhaustion. At rest plasma levels of adrenocorticotropin (ACTH), cortisol, and aldosterone increased during infusion of naloxone, while body temperature decreased. During exercise the difference in plasma ACTH between naloxone and saline periods was abolished, while the differences in plasma cortisol and aldosterone lost statistical significance. Intra-arterial pressure, heart rate, ventilation, O2 uptake, and CO2 output were continuously monitored throughout the experiment and were not affected by naloxone. This was also the case for several hormonal and biochemical measurements, including those of plasma renin, angiotensin II, norepinephrine, 13,14-dihydro-15-keto-prostaglandin F2 alpha, glucose and lactate, and serum insulin and growth hormone. Exercise performance was not changed by naloxone. In conclusion (1) during exhaustive graded exercise of short duration opioidergic inhibition of the pituitary-adrenocortical axis is probably not sustained, (2) apart from the latter mechanism, the present study does not support the hypothesis that endogenous opioids are involved in various hemodynamic, respiratory, and hormonal responses to this type of exercise.

In a prospective, randomized, parallel study, two regimens of platelet-suppressant therapy (PST)--dipyridamole-aspirin and pentoxifylline-aspirin--were compared with standard oral anticoagulation with warfarin in the prevention of prosthetic heart valve thromboembolism. In the entire group of 254 patients followed for 395.6 patient-years, the thromboembolic rate was significantly less in the warfarin group (warfarin vs dipyridamole-aspirin, p less than .005; warfarin vs pentoxifylline-aspirin, p less than .05). Subgroup analysis disclosed that, in patients with isolated mitral valve replacement, warfarin was superior to both of the PSTs with respect to the prevention of thromboembolism (warfarin vs dipyridamole-aspirin, p = .005; warfarin vs pentoxifylline-aspirin, p less than .05). Furthermore, a significant number of our patients could not tolerate the antiplatelet agents. However, in the rare situation in which repeated significant bleeding occurs despite careful adjustment of the dosage of warfarin, PST may be an acceptable alternate method of thromboembolism prophylaxis.

We determined that the spontaneous changes in cardiac output (CO) over 12 hr in 21 patients with chronic severe aortic regurgitation averaged +/- 8.9% (p = .03). We then measured changes in CO over time after administering incremental doses of oral hydralazine (50, 100, 150, and 200 mg) every 12 hr and analyzed these changes by several methods. Changes over time of only + 14% were highly significant (p less than .001) when analyzed by t test, but were not significant by repeated-measures analysis of variance (ANOVA). When changes in CO were compared with internal control values (spontaneous changes over 12 hr), only changes of 20% or more were significant (p less than .05). Transient "peak effects" markedly overestimated the maximum effects after all doses. We then compared the incremental doses of hydralazine, given either every 8 or every 12 hr, with respect to (1) the hemodynamic changes induced, and (2) the relative incidence of acute side effects. Maximal increases in CO were similar when hydralazine was given every 8 hr (16 patients) and every 12 hr (21 patients), and ranged from + 14% after 50 mg to + 61% after 200 mg. After the 150 and 200 mg doses, marked sustained increases in CO were present at 8 hr and mild increases in CO were still present at 12 hr. Hydralazine every 8 hr was associated with side effects in 25% to 86% of patients, but when the drug was given every 12 hr it was associated with side effects in only 5% to 19% of patients (p less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclosporine has gained acceptance as the immunosuppressive agent of choice in cardiac transplantation, but the validity of this assumption has yet to be established. Since January 1983, 25 patients have been randomly assigned to receive either conventional immunosuppression (azathioprine/antithymocyte globulin/prednisone) and pretransplant transfusion (PAAP, n = 11) or cyclosporine immunosuppression (cyclosporine and prednisone [CyA], n = 14). There was no difference in the age distribution (41 +/- 9 vs 38 +/- 11 years), indications for transplantation, preoperative serum creatinine level (1.2 +/- 0.2 vs 1.4 +/- 0.3 mg/dl), or postoperative follow-up time (13.5 +/- 5.4 vs 13.5 +/- 5.2 months). Mortality was not different (PAAP = 2, CyA = 3) and there was no difference in rejection episodes per patient (PAAP = 1.8, CyA = 1.9). Patients in the PAAP group had more serious infections (PAAP = 8, CyA = 3; P less than .02), but those in the CyA group developed a greater incidence of systemic hypertension (PAAP = 1, CyA = 10; p less than .02), pericardial effusion (PAAP = 0, CyA = 6; p = .05), and impaired renal function (creatinine 1.5 mg/dl, PAAP = 2, CyA = 11; p less than .02). Thus it appears that in this small series, cyclosporine is not associated with a significant increase in early survival. It does appear that patients on PAAP immunosuppression develop a greater number of serious infections, but the incidence of rejection episodes appears to be the same. Renal dysfunction and hypertension in patients receiving cyclosporine continue to be long-term concerns and may add to the morbidity and mortality of patients treated with this immunosuppressive regimen.

It has been suspected that the increased sympathetic activity seen in patients with chronic congestive heart failure from dilated cardiomyopathy may be harmful. We therefore tested the long-term effect of metoprolol on eight patients in a double-blind, randomized protocol and 12 patients in an unblinded, crossover protocol who were treated for 12 months (range 10 to 24), and compared them with 16 similar subjects who were treated with placebo for 10 months (range 6 to 12) in a double-blind, randomized protocol. Patients were followed by serial clinical assessment, treadmill testing, radionuclide ventriculography, and echocardiography. Metoprolol-treated patients had an improvement in mean exercise capacity by 3 mets (p less than .0001) while experiencing a significant improvement in functional classification (p less than .001) during both the double-blind and open-label crossover studies and had an improved ejection fraction during the double-blind study (p less than .02). These improvements were not seen in matched control subjects receiving placebo. Seven of 20 patients receiving long-term metoprolol therapy had resolution of nearly all symptoms of heart failure, doubled their exercise capacity, and had progressive improvement in resting radionuclide left ventricular ejection fraction (12.6 +/- 3% to 26.9 +/- 6%) and echocardiographic left ventricular end-diastolic dimension (7.7 +/- 0.5 to 6.5 +/- 0.5 cm). Only one of 21 patients treated was intolerant of metoprolol. We conclude that metoprolol can be given safely to a select group of patients with dilated cardiomyopathy in doses that substantially reduce both resting and exercise heart rates. Long-term beta-blockade improved functional class and exercise capacity in 14 of 20 patients while producing an exceptional clinical response in seven that was accompanied by improved resting parameters of left ventricular function.

Digital vasospastic phenomena have been reported to result from use of nonselective and cardioselective beta-adrenoreceptor-blocking drugs. The effects of 80 mg/day propranolol and 100 mg/day metoprolol on finger hemodynamics and clinical responses were compared with those of placebo in 16 patients with Raynaud's phenomenon. A double-blind, 2 week crossover study design was used with a 2 week washout placebo period between drugs. Total fingertip blood flow (FBF) as determined by venous occlusion plethysmography, fingertip capillary flow (FCF) as determined by radioisotope disappearance rate, and finger systolic blood pressure (FSP) were measured in a 28.3 degrees and a 20 degrees C room at the end of each period. Subjects kept diaries to record vasospastic attacks. There were no significant changes in FBF, FCF, or FSP in the warm or cool environment during drug treatment as compared with during the placebo period. A decrease in pulse rate occurred with both drugs and there was a decrease in blood pressure with metoprolol. There were no significant changes in the number of vasospastic attacks or in the patients' overall evaluation of their conditions while they were receiving the drugs. It is concluded that the presence of Raynaud's phenomenon is not a contraindication to the use of beta-adrenoreceptor-blocking drugs in the normotensive population.

The relationships among clinical variables, coronary anatomy, and left ventricular function during the early hours of acute myocardial infarction (AMI) were evaluated from data acquired in the Western Washington Intracoronary Streptokinase Trial. All patients had symptoms and electrocardiographic changes typical of AMI. All data were obtained before treatment with streptokinase. Mean time to catheterization was 4.1 hr after onset of symptoms. Coronary angiograms (n = 245) were analyzed for location of infarct-related occlusion and collateral flow to the infarct bed. Left ventricular ejection fraction and regional left ventricular function were quantitated in 227. Sixty-two percent of occlusions were in the most proximal segment of the involved coronary artery. Collateral circulation was seen in 42% overall, in 31% with left anterior descending artery (LAD) occlusion, and in 52% with right coronary artery (RCA) occlusion (p less than .005). Left ventricular ejection fraction was lowest and regional function was most abnormal in the group with proximal LAD occlusion. Hyperkinesis was present in 32%; in those with hyperkinesis, hyperkinetic segment length was longest in those with RCA or circumflex occlusion. Multivariate analysis identified proximal LAD occlusion as the factor most closely associated with left ventricular ejection fraction and with measures of left ventricular regional hypofunction. We conclude that (1) AMI is usually caused by occlusion or subtotal occlusion in the most proximal portion of the involved coronary artery, (2) collateral circulation is more frequent with RCA than with LAD occlusion, and (3) location of the infarct-related occlusion is the most important determinant of global and regional left ventricular function in the early hours of AMI.

We performed a prospective, randomized crossover study to evaluate the comparative efficacy of transvenous cardioversion and rapid ventricular pacing for termination of induced ventricular tachycardia in patients with spontaneous ventricular tachycardia and organic heart disease. Sixty-two episodes of ventricular tachycardia were induced in 15 patients, mean age 60 +/- 10 years, during electrophysiologic studies. All patients underwent a preselected electrical therapy protocol in a randomized crossover sequence. Transvenous cardioversion was performed by an incremental protocol of three sequential shocks (0.5, 1.1, and 2.7 J). Six asynchronous sequential bursts of rapid ventricular pacing (10 and 15 paced stimuli at 90%, 75%, and 65% of ventricular tachycardia cycle length) were used. Mean cycle length of ventricular tachycardia for the study population was 391 +/- 85 msec. The morphology of the tachycardia was left bundle branch block in 27, right bundle branch block in 32, and indeterminate in three. Characteristics of ventricular tachycardia terminated by the two techniques were comparable. Rate of success for termination of tachycardia with the two methods was also comparable (transvenous cardioversion 83%, rapid ventricular pacing 80%; p greater than .1) and these responses were concordant in 78%. The modes of termination of ventricular tachycardia were similar. The incidence of acceleration of ventricular tachycardia per episode with these preselected protocols was also comparable (transvenous cardioversion 11%, rapid ventricular pacing 6%; p greater than .2). Transient supraventricular tachyarrhythmias were more frequent after transvenous cardioversion (23%) than after rapid ventricular pacing (3%). Significant patient discomfort occurred only after transvenous cardioversion (incidence of 57%).(ABSTRACT TRUNCATED AT 250 WORDS)

One hundred forty-seven consecutive coronary bypass patients were enrolled in a randomized, double-blind, risk-stratified, placebo-controlled prospective trial evaluating the effect on graft patency of 325 mg tid aspirin (ASA) plus 75 mg tid dipyridamole (DP) or ASA alone. One hundred twenty-seven patients (399 total grafts) underwent surgery, initiation of drug therapy 67 +/- 27 (SD) hr postoperatively, five clinic visits, and repeat angiography at 1 year. A logistic regression statistical model was used to determine the effects of 28 different measured variables on graft patency and to adjust for these effects in determining the relationship between antiplatelet therapy and graft occlusion. No patient-specific variable contributed significantly to the prediction of occlusion in either the placebo or the treated group. Six graft-specific variables (arterial diameter, severity of stenosis, graft flow, reactive hyperemia, presence or absence of collaterals, and graft type) did contribute and were included in the model. Twenty-one percent of placebo-treated grafts became occluded. Compared with placebo, the relative risk of graft occlusion with ASA was 0.47 (p = .04); with ASA + DP, it was 0.50 (p = .04). This benefit was principally due to reduction of occlusion in the most common and presumably most important groups of grafts, those in which flow exceeded 40 ml/min, or supplying arteries having luminal diameters greater than 1.5 mm. Grafts lacking reactive hyperemia had a 32% occlusion frequency in placebo-treated patients; relative risk of their occlusion averaged 0.26 (p less than .01) with platelet-inhibiting therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of orally administered diltiazem combined with maximally tolerated doses of beta-blockers and nitrates were assessed in 12 patients, who during stress testing exhibited persistent effort angina and continued objective evidence for inducible myocardial ischemia. Patients performed multistage semisupine exercise on a bicycle ergometer during equilibrium-gated radionuclide angiography after consecutive 2 week treatment periods of placebo or diltiazem 90 mg qid (mean dose 340 mg/day) combined with maximally tolerated propranolol (mean dose 178 mg/day) and isosorbide dinitrate (mean dose 137 mg/day). All medications (including diltiazem or placebo) were administered four times daily for the duration of the study. Diltiazem or placebo was administered according to a double-blind design, with randomized cross-over at the end of each 2 week treatment period. The average number of angina attacks decreased during the double-blind cross-over phase of the trial (7 +/- 7 episodes/week at baseline vs 4 +/- 3 on placebo vs 2 +/- 2 on diltiazem; p = .08). Angina pectoris was abolished during peak exercise in eight of 12 patients on diltiazem (p less than .05 vs placebo). Diltiazem increased total exercise duration from 276 +/- 92 to 310 +/- 78 sec (p less than .005 vs baseline). Diltiazem likewise increased the time to onset of angina from 231 +/- 84 sec at baseline to 305 +/- 77 sec (p less than .005), as well as the time to the onset of 1 mm ischemic ST segment depression (p = .01). Diltiazem decreased heart rate at rest, during submaximal workload, and at peak exercise (p less than .05), and decreased systolic blood pressure at peak exercise only (p less than .05). A significant decline in rate-pressure product at submaximal and peak exercise was noted (p less than .05). At any given workload there was significantly less ST segment depression during submaximal (p = .05) and peak exercise (p less than .025).(ABSTRACT TRUNCATED AT 250 WORDS)