There is evidence that aspirin is partially effective in the prophylaxis of various vasoocclusive disorders. This article reviews pharmacologic opportunities for improvement over and above the therapeutic effect of aspirin. It is concluded that several rational possibilities merit consideration, in particular, the use of combinations of drugs that affect the thrombotic process at different points. Such strategies will ultimately require validation by clinical trial.

Nonsteroidal anti-inflammatory drugs and sulfinpyrazone compete dose-dependently with arachidonate for binding to platelet cyclooxygenase. Such a process closely follows systemic plasma drug concentrations and is reversible as a function of drug elimination. Peak inhibition and extent of its reversibility at 24 hr varies consistently with individual pharmacokinetic profile. Inhibition of platelet cyclooxygenase activity by these agents is associated with variable effects on prostaglandin (PG) synthesis in the gastric mucosa and the kidney. Aspirin acetylates platelet cyclooxygenase and permanently inhibits thromboxane (TX) A2 production in a dose-dependent fashion when single doses of 0.1 to 2.0 mg/kg are given. Acetylation of the enzyme by low-dose aspirin is cumulative on repeated dosing. The fractional dose of aspirin necessary to achieve a given level of acetylation by virtue of cumulative effects approximately equals the fractional daily platelet turnover. Serum TXB2 measurements obtained during long-term dosing with 0.11, 0.22, and 0.44 mg/kg aspirin in four healthy subjects could be fitted by a theoretical model assuming identical acetylation of platelet (irreversible) and megakaryocyte (reversible) cyclooxygenase. For a given dose within this range, both the rate at which cumulative acetylation occurs and its maximal extent largely depend upon the rate of platelet turnover. Continuous administration of low-dose aspirin (20 to 40 mg/day) has no statistically significant effect on urinary excretion of either 6-keto-PGF1 alpha or 2,3-dinor-6-keto-PGF1 alpha, i.e., indexes of renal and extrarenal PGI2 biosynthesis in vivo. Whether a selective sparing of extraplatelet cyclooxygenase activity by low-dose aspirin will result in increased antithrombotic efficacy, fewer toxic reactions, or both remains to be established in prospective clinical trials.

Myocardial thallium-201 (201Tl) scintigraphy or radionuclide angiography performed in conjunction with exercise stress testing can provide clinically useful information regarding the functional significance of underlying coronary artery stenoses in patients with known or suspected coronary artery disease. Knowledge of type, location, and extent of myocardial 201Tl perfusion abnormalities or the severity of exercise-induced global and regional dysfunction has prognostic value. Risk stratification can be undertaken with either radionuclide technique by consideration of the magnitude of the ischemic response and may assist in the selection of patients for coronary artery bypass graft surgery (CABG). In patients with coronary artery disease, delayed 201Tl redistribution observed on exercise or dipyridamole 201Tl scintigraphy, particularly when present in multiple vascular regions and associated with increased lung 201Tl uptake, has been shown to be predictive of an adverse outcome, whereas patients with chest pain and a normal exercise 201Tl scintigram have a good prognosis with medical treatment. Similarly, a marked fall in the radionuclide ejection fraction from rest to exercise has been found to correlate with high-risk anatomic disease. In one published nonrandomized study, patients with coronary artery disease who demonstrated an abnormal ejection fraction response to exercise preoperatively had a better survival with CABG than with medical therapy. Another important application of radionuclide imaging in patients being considered for CABG (particularly those with a depressed resting left ventricular ejection fraction) is the determination of myocardial viability and potential for improved blood flow and enhanced regional function after revascularization. There are certain limitations of exercise 201Tl scintigraphy and radionuclide angiography that can be reduced by improved methods of quantitation of perfusion and function and further development of tomographic imaging approaches.

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)

On the basis of our recent experimental studies in dogs and pigs and a prospective clinical study in 407 patients, we describe four consecutive phases of aortocoronary artery bypass vein-graft disease. We focus on the role of platelets in its pathogenesis and of platelet inhibitor drugs in its prevention: (1) an early postoperative phase of platelet thrombotic occlusion, which is significantly prevented by platelet inhibitor therapy when started in the perioperative period; (2) an intermediate phase of platelet-related intimal hyperplasia, within the first postoperative year, which is not prevented with platelet inhibitor therapy; (3) a late phase of occlusion, towards 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 the thrombotic type of occlusion; (4) a phase of atherosclerotic disease, after the first postoperative year, in which the role of platelets and of platelet inhibitor therapy is under investigation. Vein graft disease and occlusion rates vary widely according to time after operation and risk factors of occlusion. Currently, it appears that occlusion rates are decreasing, perhaps related to better surgical and technical experience.

Repeat coronary artery bypass grafting (CABG) accounts for approximately 5% of all myocardial revascularization procedures in the United States annually; it is estimated that nearly 7000 reoperations will be performed in 1984. Angiographic indications for repeat CABG include primary bypass graft obstruction, progressive coronary arteriosclerosis, and combined graft failure and new coronary artery disease. Saphenous vein obstruction secondary to arteriosclerosis occurs in more than half the bypass grafts at 10 years after CABG. Successful aortocoronary reoperation is dependent on careful attention to special surgical technical considerations such as chest reentry, cardiopulmonary bypass management and myocardial preservation, primary graft handling and identification of the target coronary vessel, choice of available bypass conduits, completeness of revascularization, and hemostasis and blood conservation. Operative mortality for repeat CABG is approximately twice that for an initial aortocoronary bypass procedure. Overall operative morbidity is not significantly different for primary and subsequent myocardial revascularization. Five-year survival after repeat aortocoronary surgery is approximately 90% and compares favorably with survival rates after initial CABG. However, symptomatic relief of angina pectoris is not as effective after a repeat myocardial revascularization as it was after the first CABG; only half the patients are angina-free 5 years after reoperation. As with primary revascularization, long-term graft patency rates after coronary reoperation are superior for the internal artery as compared with the saphenous vein.

This is a review of relative indications and contraindications for the selection of patients for coronary arteriography. Patients with angina pectoris at rest ("unstable" angina pectoris) and after low levels of effort despite a good medical regimen, those with chest pain that cannot be distinguished from angina pectoris at low or moderate levels of effort with or without abnormal 201Tl perfusion scans or radionuclide ventriculograms during stress, and those with suspected significant left main coronary arterial stenosis based on exercise testing should undergo coronary arteriography. In addition, coronary arteriography is usually an important part of the clinical evaluation of the patient with unexplained and clinically important congestive heart failure, recent myocardial infarction treated with thrombolytic therapy, a mechanical complication of myocardial infarction requiring cardiac surgery, including a large ventricular septal defect, hemodynamically important mitral insufficiency, or a large ventricular aneurysm leading to heart failure, hemodynamically important valvular, subvalvular, or supravalvular heart disease in whom corrective surgery is contemplated, suspected anomalous origin or communication of a major coronary artery, and sudden death syndrome unrelated to acute myocardial infarction.

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)

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.

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.

HCM is a disorder associated with significant morbidity and mortality and a propensity to cause sudden, often unexpected death. The similarity to the symptom complex of aortic stenosis and the presence of a pressure gradient justified the initial assumption that obstruction was of prime importance in HCM and that relief of obstruction was the focal point of rational therapy. However, it is our belief that the dogma of obstruction has impeded progress in and obscured the understanding of HCM and interpretation of its manifestations. The purpose of this article is to call attention to significant discrepancies in the obstructive concept that have been reinforced as new techniques emerged that have allowed further study of the disease. Since neither the presence of a gradient nor SAM can be justifiably equated with the presence of an obstruction, it is proposed that the appellation "obstruction" be reserved for those cases in which the rate of outflow or the rate or degree of ventricular emptying are demonstrably impeded, as in aortic stenosis. Therapy with beta-adrenergic-receptor and calcium channel-blocking agents have shown promise for alleviating symptoms and possibly prolonging life without systematically or predictably affecting the pressure gradient, probably because of their beneficial effects on ventricular relaxation and diastolic filling. Antiarrhythmic therapy has been effective in reducing mortality. Ideally, prevention or regression of the pathologic hypertrophy should be the major focus of future therapeutic interventions in hypertrophic cardiomyopathy.

The current dispute over the effects of "low" vs "high" doses of aspirin should take into consideration the pharmacokinetics of this drug. In fact, different pharmaceutical formulations of aspirin may deliver little or no aspirin to the systemic blood. This was the case, for instance, in healthy volunteers taking 320 mg of compressed aspirin or 800 mg of enteric-coated aspirin. In all instances thromboxane B2 generation in serum was fully inhibited. Platelet cyclooxygenase might therefore be effectively acetylated by exposure to aspirin in the portal circulation, whereas vascular cyclooxygenase could be spared. Thus aspirin formulations ensuring complete first-pass deacetylation should be sought rather than "low" or "high" doses of unspecified aspirin formulations. Regardless of the type and dose of aspirin administered, salicylate is formed and accumulates in the circulation. It may antagonize the effects of aspirin on cyclooxygenase, at least in acute conditions. As an example, after administration of 1 g of salicylate to healthy volunteers, when plasma levels of the drug were about 75 micrograms/ml, the effect of 40 mg iv aspirin (given 40 min later) on platelet cyclooxygenase and aggregation was significantly diminished. In contrast, in patients undergoing saphenectomy, the same dose of salicylate (1 g) gave plasma drug levels of about 25 micrograms/ml; salicylate was unable to prevent the inhibitory effect on platelets of 40 mg iv aspirin (given 1 hr later) but did act on vascular prostacyclin. Thus the combination of salicylate with aspirin at an appropriate dose and blood level ratio may result in almost complete dissociation of the drug's effect on platelets and vessels in man.(ABSTRACT TRUNCATED AT 250 WORDS)

During the past 15 years coronary artery bypass surgery (CABG) has evolved into a procedure with low operative mortality and morbidity resulting in excellent improvement in lifestyle and improved longevity in some instances. Operative risk factors have been identified. Their significance has changed during this time. Currently, clinical congestive heart failure and emergency operation are the most commonly observed adverse results. Since the patients being operated upon, especially those emergent, are sicker, the improvements in mortality and morbidity with CABG are not due to patient selection, but rather to improvement in preoperative, intraoperative, and postoperative management. The major areas of management that have been responsible for the current status of CABG are myocardial protection, conduit selection and preservation, blood conservation, anesthetic management, pulmonary arterial catheter monitoring, pharmacologic unloading, intraaortic balloon assistance, cardiac assist devices, and arrhythmia control.

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.