The pharmacokinetics of milrinone were studied in sequential ascending doses in New York Heart Association Class III and IV patients receiving oral and intravenous medication. The parameters determined after parenteral administration were estimated by fitting the plasma concentration data to an open two-compartment body model. After oral medication, regression-independent parameters were determined. After either oral or parenteral administration of milrinone, plasma levels were dose dependent and the drug had an apparent first-order terminal elimination half-life of approximately 2 hr. The apparent volume of distribution was approximately 400 to 500 ml/kg, and total body clearance was approximately 130 ml/kg/hr. These values obtained in patients receiving milrinone were compared with those obtained for milrinone in volunteers, as well as those noted with the other inotropic bipyridine, amrinone. Milrinone's elimination from the blood stream patients was slower that that in normal healthy subjects and faster than amrinone's elimination in patients with congestive heart failure. Milrinone's pharmacokinetic parameters in these patients were unchanged after approximately 30 days of continuous oral medication.

Coagulation and fibrinolysis were studied in patients with acute myocardial infarction during intravenous infusion of recombinant human tissue-type plasminogen activator (rt-PA) (0.75 mg/kg over 90 min, n = 101), streptokinase (1,500,000 IU over 60 min, n = 61), or placebo (n = 40). In the rt-PA group, the plasma level of rt-PA antigen was 1.2 +/- 0.6 micrograms/ml (mean +/- SD) and the euglobulin fibrinolytic activity (EFA) was 910 +/- 735 IU t-PA/ml. In the streptokinase group, the EFA was equivalent to 430 +/- 435 IU t-PA/ml. At the end of the infusion, the plasma fibrinogen level measured with a coagulation rate assay was decreased to 57 +/- 33% of the preinfusion value in the rt-PA group, to 7 +/- 10% in the streptokinase group, and remained unchanged in the placebo group. Fibrinogen-fibrin degradation products increased to 0.75 +/- 0.54 mg/ml in the streptokinase group but to only 0.10 +/- 0.13 mg/ml in the rt-PA group. The plasma levels of alpha 2-antiplasmin, plasminogen, and factor V decreased to between 30% and 45% in the rt-PA group but significantly more in the streptokinase group (to between 15% and 25%). Thus rt-PA induced much less systemic fibrinolytic activation than streptokinase. In the patients who received rt-PA, a weak correlation (r = .21, n = 89, .1 greater than p greater than .05) was found between the extent of fibrinogen breakdown at 90 min and the plasma rt-PA concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

The value of the addition of beta-blockers to coronary vasodilator therapy in the treatment of patients with unstable angina at rest is controversial. We conducted a double-blind, randomized, placebo-controlled 4 week trial of propranolol in 81 patients with unstable angina, 39 of whom were assigned to placebo and 42 of whom received propranolol in a dose of at least 160 mg daily. All patients were also treated with coronary vasodilators, including 80 mg nifedipine daily and long-acting nitrates. The incidences of cardiac death, myocardial infarction, and requirement for bypass surgery or coronary angioplasty did not differ between the two groups (propranolol = 16; placebo = 18). The propranolol group had a lower cumulative probability of experiencing recurrent resting angina than the placebo group (p = .013), and over the first 4 days of the trial the mean number of clinical episodes of angina (propranolol 0.9 +/- 0.2, placebo 1.8 +/- 0.3, p = .036), duration of angina (propranolol 15.1 +/- 4.3 min, placebo 38.1 +/- 8.4, p = .014), and nitroglycerin requirement (propranolol 1.1 +/- 0.3 tablets, placebo 3.5 +/- 0.8, p = .003) were also fewer. Continuous electrocardiographic recording for ischemic ST segment changes revealed fewer daily ischemic episodes in the propranolol group (2.0 +/- 0.5) than in the placebo group (3.8 +/- 0.7, p = .03), and a shorter duration of ischemia (propranolol 43 +/- 10 min, placebo 104 +/- 28 min, p = .039). Thus propranolol, in patients with unstable angina, in the presence of nitrates and nifedipine is not detrimental and reduces the frequency and duration of symptomatic and silent ischemic episodes.

To study the prevention of occlusion of aortocoronary-artery bypass grafts, we conducted a prospective, randomized, double-blind trial comparing long-term administration of dipyridamole (begun 2 days before operation) plus aspirin (begun 7 hr after operation) with placebo in 407 patients. Results at 1 month and at 1 year showed a reduction in the rate of graft occlusion in patients receiving dipyridamole and aspirin. On the basis of our clinical trial and our experimental studies in dogs and pigs, we describe four consecutive phases of aortocoronary artery bypass vein-graft disease: an early postoperative phase of platelet thrombotic occlusion, which is significantly prevented by platelet inhibitor therapy when started in the perioperative period; in addition, occlusion rates are presently decreasing, perhaps related to better surgical and technical experience; an intermediate phase of platelet-related intimal hyperplasia, within the first postoperative year, which is not prevented with platelet inhibitor therapy; a late phase of occlusion, toward the end of the first postoperative year, in which intimal hyperplasia or complicating platelet thrombi superimposed on the intimal hyperplasia may contribute to occlusion; platelet inhibitor therapy is of significant benefit in the prevention of this thrombotic type of occlusion; a phase of atherosclerotic disease, after the first postoperative year, in which the role of platelets and of platelet inhibitor therapy is under investigation.

Aspirin has been convincingly shown to reduce stroke and death in men with transient ischemic attacks (it may possibly be beneficial to women also), myocardial infarction and death in patients with unstable angina, thromboembolic complications associated with artificial heart valves in patients receiving oral anticoagulants (although gastrointestinal bleeding is prohibitive with this combination), and thrombotic occlusion of silicone rubber arteriovenous cannulae in uremic patients undergoing hemodialysis. In addition, aspirin may possibly decrease occlusion of saphenous vein aortocoronary grafts and venous thrombosis in men after hip replacement, although these reports require confirmation. Aspirin is ineffective in the secondary prevention of stroke and has unproven benefit in the secondary prevention of myocardial infarction. Dipyridamole in combination with oral anticoagulation decreases the thromboembolic complications associated with mechanical heart valves. The combination of aspirin and dipyridamole prevents both early and late occlusion of saphenous vein aortocoronary bypass grafts and protects renal function in patients with membranoproliferative glomerulonephritis. The relative importance of combining aspirin and dipyridamole compared with either agent used singly remains to be established. Sulfinpyrazone reduces the thrombotic occlusion of arteriovenous cannulae and early occlusion of saphenous vein aortocoronary grafts. The reported benefit in the secondary prevention of myocardial infarction is controversial.

The effects of four levels of activity on heart rate, blood pressure, cardiac index, total peripheral resistance index (TPRI), norepinephrine (NE) spillover rate, insulin sensitivity, and levels of lipids and some hormones were studied in 12 normal subjects. The randomized periods were (1) 4 weeks of below-sedentary activity, (2) 4 weeks of sedentary activity, (3) 4 weeks of 40 min of bicycling three times per week, and (4) 4 weeks of similar bicycling seven times per week. Exercise three times per week reduced resting blood pressure by 10/7 mm Hg (p less than .01) and it was reduced by 12/7 mm Hg after exercise seven times per week (both p less than .01). This was associated with reduction in TPRI, an increase in cardiac index, and cardiac slowing. At the highest level of activity, NE spillover rate, an index of sympathetic activity, fell to 35% of the sedentary value (p less than .001) in eight of 10 subjects. In two other subjects NE spillover rate rose, although blood pressure and TPRI were reduced. Metabolic changes included lowering of total cholesterol, but high-density lipoprotein level was unchanged. Insulin sensitivity rose by 27% after exercise three times per week, but declined to sedentary levels with seven times per week exercise. Maximum oxygen uptake increased linearly with activity. Exercise performed three times per week lowers blood pressure and should reduce cardiovascular risk. The same exercise seven times per week enhances physical performance with little further reduction in cardiovascular risk factors. Exercise is potentially a major nonpharmacologic method of lowering blood pressure.

This report from the European Prospective Randomised Study presents 8 year results on survival and 5 year results on myocardial infarction and employment status. The 768 recruited patients were all men under age 65 with mild or moderate angina, 50% or greater stenosis in at least two major coronary arteries, and a left ventricular ejection fraction of 50% or greater. One "surgical" patient was lost to follow-up immediately after randomization and is therefore excluded from the statistical analysis. Thus 394 patients allocated to surgery were compared with 373 patients allocated to medical treatment, regardless of what subsequently happened to the patients. The policy of early surgery improved survival significantly compared with the conventional medical treatment policy in the total population (89% to 80%, respectively; p = .0013) and in the subgroup with three-vessel disease (92% and 77%, respectively; p = .00015). Reclassification of vessel disease by greater than 75% instead of 50% or greater stenosis as the criterion was undertaken to facilitate comparison of these results with those of other studies, which apply 70% or greater stenosis as the criterion of significant disease. Of the 767 patients, a cohort of 711 were identified as having greater than 75% obstruction in one, two, or three vessels. A significant improvement in survival with surgery was found in the total cohort (89% and 80%, respectively; p = .0022), the subgroup with three-vessel disease (91% and 73%, respectively; p = .0044), and that with two-vessel disease in which one of the diseased vessels was the proximal segment of the left anterior descending artery (LAD) (90% and 79%, respectively; p = .013). There was no significant difference in survival between the two treatments in patients with one-vessel disease and those with two-vessel disease without proximal LAD stenosis. Four noninvasive prognostic variables were independently predictive of the effect of surgery: resting electrocardiogram (in 767 patients), ST segment response to exercise (in 656), history and physical signs of peripheral arterial disease (in 722), and age (in 767). A reduction in cardiac deaths was entirely responsible for the improved survival with surgery. The incidence of myocardial infarction in the medical group (11%) was not significantly different from that in the surgical group (15%). Repeat angiography in 71 patients showed 6% graft closure between 1 and 5 years of follow-up. Surgery did not influence the gradually increasing annual rate of retirement from work.

The long-term effect of coronary artery bypass grafting on mortality and the incidence of nonfatal myocardial infarction was evaluated in 686 patients in the randomized Veterans Administration study of medical vs surgical treatment for stable angina. Average follow-up was 11.2 years. The 11 year cumulative mortality rates for all patients and for the 595 patients without left main diseases were not significantly different in the two treatment groups. The 7 year mortality rates were 30% in medically assigned and 23% in surgically assigned patients (p = .043) and the 11 year rates were 43% and 42% (p = .45), respectively. The rates in patients without left main disease were 28% for medical and 23% for surgical treatment policy at 7 years (p = .267) and rose to 42% in both groups at 11 years (p = .813). A statistically significant reduction in mortality with surgical policy was found both at 7 and 11 years in high-risk patients without left main disease who had multiple clinical or angiographic risk factors or both. In the subgroup with angiographic high risk, the 7 year mortality rates were 48% in medically assigned and 24% in surgically assigned patients (p = .002); the 11 year rates were 62% and 50%, respectively (p = .026). Corresponding rates in the clinically defined high-risk group were 48% vs 28% (p = .003) at 7 years and 64% vs 51% (p = .015) at 11 years for medical vs surgical policy, respectively. For the subgroup of patients with combined angiographic and clinical high risk, the 7 year mortality rates were 64% for medical and 24% for surgical policy (p = .002); the 11 year rates were 76% and 46%, respectively (p = .005).(ABSTRACT TRUNCATED AT 250 WORDS)

The 5 year effect of medical vs surgical treatment on symptoms and exercise performance was evaluated in patients with stable angina who entered the Veterans Administration Cooperative Study from 1972 to 1974. Severity of angina was evaluated by a physician-administered angina questionnaire and physical working capacity was assessed by exercise testing. Angina was substantially relieved in surgical patients at 1 year, with 78% having mild or no angina compared with only 28% at entry. The corresponding rates in medical patients showed little change: 38% at 1 year and 32% at entry. At 5 years the percentage of surgical patients with mild or absent angina decreased from the 1 year rate of 78% to 64%, whereas the medical group exhibited a small increase from 38% to 49%. Similar results were obtained by evaluating changes in angina compared to entry. At 1 year 49% of surgical patients were markedly improved compared with only 12% of medical patients. At 5 years the percentage of surgical patients who remained markedly improved decreased to 41%, whereas the medical group with marked improvement increased slightly from 12% at 1 year to 17% at 5 years. Medication requirements were markedly reduced in surgical patients with only a slight increase in medical patients. Exclusion of nonadherers from the analysis did not change the results. Exercise testing revealed comparable changes in physical performance. At 1 year surgical patients had fewer tests stopped by angina compared with medical patients (28% vs 64%), a higher estimated oxygen consumption (26 vs 21 ml/kg/min) and treadmill exercise duration (7.3 vs 4.9 min). Other measures of exercise performance were comparably improved.(ABSTRACT TRUNCATED AT 250 WORDS)

Both the Veterans Administration Cooperative Study and the European Coronary Surgery Study have provided only brief accounts of graft patency rates in their surgically treated patients. In the Veterans Administration Cooperative Study, at an average of 1 year after operation, 69% of the grafts were patent among 208 patients; 88% of patients had at least one patent graft, and 58% had all grafts patent. In the European Coronary Surgery Study, angiographic examination of the grafts was performed within 9 months of operation in 84 patients, and showed a patency rate of 90%; in 223 patients, the examination was performed at between 9 and 18 months, and showed a 77% patency rate. In the Coronary Artery Surgery Study (CASS), graft patency rates were evaluated within 60 days of operation in 129 patients, a median of 18 months after operation in 121 patients, and a median of 5 years after operation in 197 patients. Cumulative vein graft patency (per distal anastomosis) was 90% early, 82% at 18 months, and 82% at 5 years. At least one graft anastomosis was patent early in 97% of patients, at 18 months in 96% of patients, and at 5 years in 97% of patients; all graft anastomoses were patent early in 81% of patients, at 18 months in 70% of patients, and at 5 years in 67% of patients. The incidence of vein graft stenosis of 50% or more was 10% at 18 months and 8% at 5 years after operation. The excellent results reported in CASS were associated with marked improvement in quality of life and excellent survival 5 years after operation in surgically treated patients, as previously reported.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise electrocardiographic stress testing was performed in 81% of the 780 patients randomized in the Coronary Artery Surgery Study at entry. The cumulative survival at the end of 7 year follow-up was 90% for those assigned to surgical treatment and 88% for those assigned to medical therapy (p = NS). These survival rates did not differ significantly from either those of the entire randomized cohort or those of the 149 patients who did not have a qualifying exercise test at baseline. No differences in important baseline characteristics existed between those who were exercised and not exercised at entry. Stratification of patients according to the degree of ST segment depression (less than 1 mm, greater than or equal to 1 mm, greater than 2 mm) and final exercise stage achieved during a Bruce protocol treadmill test (final stage less than or equal to 1, stage 2 and greater than or equal to stage 3) failed to show any significant differences in 7 year survival rates between medically and surgically assigned patients. Additionally no differences in survival were noted within either the medical or surgical groups regardless of the degree of ST segment depression or the final stage achieved. The presence of exercise-induced angina, however, identified patients who had a survival advantage if assigned to surgical therapy, with a 7 year survival rate of 94% compared with 87% for medically assigned patients (p = .007).(ABSTRACT TRUNCATED AT 250 WORDS)

The three major randomized studies of medical vs surgical therapy in patients with coronary artery disease have had a major impact in the management of patients with this disease. For the most part, these multicenter trials have provided concordant information regarding the influence of surgery on survival in asymptomatic or mildly symptomatic patients. It has been demonstrated that coronary artery bypass surgery improves survival in patients with stenosis of the left main coronary artery. Bypass surgery probably should be performed in most patients with this lesion, although studies have identified low-risk subgroups in whom surgery may not improve survival. There are also concordant data that survival is not enhanced by surgery in mildly symptomatic patients with either one- or two-vessel disease. The important discrepancies regarding the role of surgery in three-vessel disease have been resolved to a major extent. Long-term follow-up studies in the Veterans Administration Cooperative Study and the Coronary Artery Surgery Study (CASS) demonstrate improved survival with surgical management in patients with three-vessel disease and left ventricular dysfunction. The remaining controversy regards management of patients with three-vessel disease and normal left ventricular function; this may be resolved by studies indicating that inducible left ventricular ischemia in patients with three-vessel disease and preserved left ventricular function at rest identifies patients at higher risk during medical management. Different proportions of such patients entered into the multicenter studies may explain the discordant results in three-vessel disease and normal left ventricular function reported by the European trial and CASS.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized, double-blind clinical trial in 1266 men with unstable angina showed that 324 mg of aspirin daily for 12 weeks reduced the incidence of myocardial infarction by 51% (p = .001), and the data suggested a similar reduction in mortality. The only other therapy for unstable angina that has been studied in randomized trials of adequate size to evaluate mortality and rate of infarction is aortocoronary bypass surgery. Results with heparin therapy have been encouraging, but the studies in which this drug has been tested have been flawed. Nitrates, beta-blockers, calcium blockers, fibrinolytic therapy, and coronary angioplasty have not been adequately evaluated. Randomized trials of aortocoronary bypass surgery have not demonstrated decreased mortality or rates of myocardial infarction in patients with unstable angina. Although surgical techniques have improved since these trials were conducted, medical management has also improved. Mortality and infarct rate in patients with unstable angina are now lower than in the early 1970s. New well-controlled clinical trials are needed.

Myocardial ischemia is an important determinant of survival in patients with coronary artery disease (CAD) and it may be silent. Coronary bypass surgery (CBS) is more effective than medical treatment in the relief of myocardial ischemia, anginal pain, and of events that are related to myocardial ischemia such as episodes of angina and left ventricular dysfunction caused by ischemia. Patients with chronic, stable angina assigned to CBS have an improved survival if they have left main CAD, three-vessel CAD with normal or impaired left ventricular function, proximal left anterior descending CAD that is part of two-vessel CAD, or two- or 3-vessel CAD with a positive exercise test for ischemia. In other respects, patients assigned to medical therapy fare as well as or better than those assigned to surgical therapy. Many issues that cause concern with regard to the randomized trials were considered in detail. The greatest problems are biostatistical tenets, small numbers of patients randomized in many of the subgroups, physician bias before and after randomization, crossovers, and inappropriate conclusions and unjustified extrapolations of the results. Timely, detailed, and comprehensive publication of the methods and results of these clinical trials is necessary. Meticulous, detailed, and critical reading of all of the published data is urged.