From bench to bedside: GP IIb-IIIa inhibitors.

Our understanding of the pathophysiology of acute coronary syndromes (ACS) has now been substantiated by many studies showing that atherothrombosis plays a predominant role. This article reviews the molecular interactions in thrombosis that may serve as therapeutic targets for more effective management of these syndromes. In particular, the discovery of the fact that the glycoprotein (GP) IIb-IIIa receptor plays a central and common role in platelet-mediated thrombosis has focused the therapeutic efforts. Blockade of this receptor has emerged as a new and potent strategy for inhibition of platelet aggregation and thus of clot formation. A number of trials have now corroborated the need for such antithrombotic drugs in the management of patients with non-ST-segment elevation ACS.

Management of patients with non-ST-segment elevation acute coronary syndromes: insights from the PURSUIT trial.

The glycoprotein (GP) IIb-IIIa inhibitor eptifibatide (INTEGRILIN, COR Therapeutics, Inc., South San Francisco, California, and Key Pharmaceuticals, Inc., Kenilworth, New Jersey) is a novel and highly potent antithrombotic agent indicated for the management of patients with non-ST-segment elevation acute coronary syndromes (ACS) and those undergoing percutaneous coronary intervention. The approval of eptifibatide for non-ST-segment elevation ACS was based on the positive results of the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. With enrollment of almost 11,000 patients, not only is the PURSUIT trial the largest trial of a GP IIb-IIIa inhibitor to date, but it is also the largest clinical study ever conducted in patients with non-ST-segment elevation ACS. The key feature of the PURSUIT trial is that patient management closely resembled standard clinical practice, because decisions about the use and timing of invasive cardiac procedures were made by the individual physicians rather than being prespecified in the study protocol. Eptifibatide therapy was associated with a significant reduction in the incidence of the primary endpoint--a composite of death or myocardial infarction at 30 days (14.2 vs. 15.7% in the placebo group; p = 0.042). Of importance is the fact that the beneficial effect of eptifibatide was independent of the management strategy pursued during study drug infusion (invasive or conservative), and it was achieved with few major safety concerns. These findings demonstrate that the use of eptifibatide should be considered for all patients presenting with signs and symptoms of intermediate- to high-risk non-ST-segment elevation ACS.

Drug eruptions and isotypic antibody responses to streptokinase after infusions of anisoylated plasminogen-streptokinase complex (APSAC, anistreplase).

BACKGROUND: Anisoylated plasminogen-streptokinase complex (APSAC, anistreplase) is a thrombolytic agent (131 kd) used for treatment of myocardial infarction. Like its principal antigenic determinant, streptokinase, APSAC has been reported to cause a variety of allergic reactions. OBJECTIVE: This study was intended to determine any association between isotypic antibody responses to streptokinase and observed allergic reactions to APSAC. METHODS: We measured sequential IgM, IgG, IgA, and IgE antistreptokinase serum levels in 21 patients who received APSAC or tissue-type plasminogen activator in a prospective, double-blind study. RESULTS: Of 11 patients who received APSAC, four had maculopapular rashes and one had urticaria; those with maculopapular rashes had significantly higher rises in serum IgM, IgG, IgA, and IgE antistreptokinase levels. We could not, however, define a temporal relationship between rises in antistreptokinase levels of a particular isotype and the onset of maculopapular rashes. The patient who had urticaria had no antistreptokinase responses but had also received several other potentially causal drugs. None of 10 patients who received tissue-type plasminogen activator had allergic reactions or significant rises in serum antistreptokinase levels. CONCLUSION: The more vigorous panisotypic antistreptokinase responses observed in patients who received APSAC and had maculopapular rashes may reflect generalized immune system activation that included other immune responses (such as cell-mediated hypersensitivity) that were responsible for these reactions.

Anistreplase versus alteplase in acute myocardial infarction: comparative effects on left ventricular function, morbidity and 1-day coronary artery patency. The TEAM-3 Investigators.

OBJECTIVES: This double-blind, randomized, multicenter trial was designed to compare the effects of treatment with anistreplase (APSAC) and alteplase (rt-PA) on convalescent left ventricular function, morbidity and coronary artery patency at 1 day in patients with acute myocardial infarction. BACKGROUND: Anistreplase (APSAC) is a new, easily administered thrombolytic agent recently approved for treatment of acute myocardial infarction. Alteplase (rt-PA) is a rapidly acting, relatively fibrin-specific thrombolytic agent that is currently the most widely used agent in the United States. METHODS: Study entry requirements were age less than or equal to 75 years, symptom duration less than or equal to 4 h, ST segment elevation and no contraindications. The two study drugs, APSAC, 30 U/2 to 5 min, and rt-PA, 100 mg/3 h, were each given with aspirin (160 mg/day) and intravenous heparin. Prespecified end points were convalescent left ventricular function (rest/exercise), clinical morbidity and coronary artery patency at 1 day. A total of 325 patients were entered, stratified into groups with anterior (37%) or inferior or other (63%) acute myocardial infarction, randomized to receive APSAC or rt-PA and followed up for 1 month. RESULTS: At entry, patient characteristics in the two groups were balanced. Convalescent ejection fraction at the predischarge study averaged 51.3% in the APSAC group and 54.2% in the rt-PA group (p less than 0.05); at 1 month, ejection fraction averaged 50.2% versus 54.8%, respectively (p less than 0.01). In contrast, ejection fraction showed similar augmentation with exercise at 1 month after APSAC (+4.3% points) and rt-PA (+4.6% points), and exercise times were comparable. Coronary artery patency at 1 day was high and similar in both groups (APSAC 89%, rt-PA 86%). Mortality (APSAC 6.2%, rt-PA 7.9%) and the incidence of other serious clinical events, including stroke, ventricular tachycardia, ventricular fibrillation, heart failure within 1 month, recurrent ischemia and reinfarction were comparable in the two groups; and mechanical interventions were applied with equal frequency. A combined clinical morbidity index was determined and showed a comparable overall outcome for the two treatments. CONCLUSIONS: Convalescent rest ejection fraction was high after both therapies but higher after rt-PA; other clinical outcomes, including exercise function, morbidity index, and 1-day coronary artery patency, were favorable and comparable after APSAC and rt-PA.

Usefulness of single-photon emission computed tomography of thallium-201 uptake after dipyridamole infusion for detection of coronary artery disease.

The diagnostic performance of single-photon emission computed tomography (SPECT) and planar imaging of thallium-201 uptake for the detection of coronary artery disease (CAD) was compared in 79 patients who underwent both dipyridamole thallium-201 scintigraphy and coronary angiography. Clinical subgroups were assigned by severity of CAD, presence of a prior myocardial infarction and the number of narrowed coronary arteries. The overall detection of CAD was 89% for SPECT and 67% for planar (p less than 0.001). For the anterior vascular territory, sensitivities for SPECT and planar imaging were 69 and 44% (p less than 0.01), respectively; for the posterior vascular territory, sensitivities were 80 and 54% (p less than 0.01). Receiver-operating characteristic analysis, using a 5-point evaluation scale, was performed for the anterior and posterior vascular territories. Receiver-operating characteristic curves generated for SPECT and planar studies demonstrated improved diagnostic performance by SPECT in the anterior vascular territory, but showed similar performance in the posterior territory because of lower SPECT specificity despite higher sensitivity at clinically relevant decision thresholds. In each clinical subgroup of patients, the detection of CAD by SPECT was significantly superior to that by planar imaging, regardless of the severity of stenosis or the number of significantly narrowed coronary arteries, or whether a myocardial infarction was present. Thus, SPECT thallium-201 scintigraphy is an important and necessary clinical tool for detecting CAD after dipyridamole infusion.

Improved diagnostic performance of exercise thallium-201 single photon emission computed tomography over planar imaging in the diagnosis of coronary artery disease: a receiver operating characteristic analysis.

Qualitative interpretation of tomographic and planar scintigrams, a five point rating scale and receiver operating characteristic analysis were utilized to compare single photon emission computed tomography and conventional planar imaging of myocardial thallium-201 uptake in the accuracy of the diagnosis of coronary artery disease and individual vessel involvement. One hundred twelve patients undergoing cardiac catheterization and 23 normal volunteers performed symptom-limited treadmill exercise, followed by stress and redistribution imaging by both tomographic and planar techniques, with the order determined randomly. Paired receiver operating characteristic curves revealed that single photon emission computed tomography was more accurate than planar imaging over the entire range of decision thresholds for the overall detection and exclusion of coronary artery disease and involvement of the left anterior descending and left circumflex coronary arteries. Tomography offered relatively greater advantages in male patients and in patients with milder forms of coronary artery disease, who had no prior myocardial infarction, only single vessel involvement or no lesion greater than or equal to 50 to 69%. Tomography did not appear to provide improved diagnosis in women or in detection of disease in the right coronary artery. Although overall detection of coronary artery disease was not improved in patients with prior myocardial infarction, tomography provided improved identification of normal and abnormal vascular regions, particularly of the left anterior descending and circumflex artery regions. These results indicate that single photon emission computed tomography provides improved diagnostic performance compared with planar imaging in many clinical subgroups, and suggest that it represents the diagnostic imaging procedure of choice in exercise thallium-201 perfusion studies.

Risk factors in siblings of people with premature coronary heart disease.

Prior studies of the contribution of coronary disease risk factors to familial aggregation of premature coronary disease may have underestimated risk factors by relying on self-reported risk factor prevalence levels or, when risk factors have been measured, by using cut points in excess of the 90th percentile. To determine the actual prevalence of hyperlipidemia, hypertension and diabetes, and the awareness of these coronary risk factors in unaffected family members, 150 apparently coronary disease-free siblings of 86 people who had documented coronary disease before 60 years of age were studied. All subjects participated in a 1 day screening preceded by a self-administered risk factor questionnaire and a personal interview. Participation of both the index patients and siblings exceeded 86%. With the use of nationally established recommendations for blood pressure and lipids, which are based on coronary disease risk curves, screening revealed that 48% of brothers and 41% of sisters were hypertensive, 45% of brothers and 22% of sisters had a lipid abnormality, 38% of siblings were current cigarette smokers and 4.7% were diabetic. Two or more risk factors were present in 42% of brothers and 26% of sisters. More than 75% of siblings had one or more risk factors that would require intervention. When compared with a race-, gender- and age-matched reference population from the Lipid Research Clinics Prevalence Study, distributions for blood pressure and for total and low density lipoprotein cholesterol were higher for the siblings in every gender and age group.(ABSTRACT TRUNCATED AT 250 WORDS)

Low heart rate variability and sudden cardiac death.

Our results indicate the following. 1. HRV is markedly depressed in inducible SCD survivors, a group at high risk of a subsequent episode of SCD. 2. Studies on patients who developed SCD during Holter monitoring indicate that HRV is depressed prior to SCD. 3. HRV is markedly depressed in inducible "asymptomatic ventricular ectopy" patients, with the degree of reduction paralleling that observed in inducible SCD survivors. In contrast, HRV of noninducible "asymptomatic ventricular ectopy" patients did not differ statistically from normal. 4. The findings provide additional evidence that cardiac parasympathetic function is depressed in patients prone to development of SCD and that altered autonomic function contributes to the development of electrical instability in such individuals. This accords with findings that such risk factors for sudden death as coronary artery disease, myocardial infarction, congestive failure, and hypertension all have been associated with reduced parasympathetic activity or attenuation of parasympathetically mediated reflexes. It is tempting to believe that diminished cardiac parasympathetic activity, perhaps by failing to counter excess sympathetic activity, contributes to SCD. 5. It may be inferred that HRV measurements have potential for serving as an independent predictor of inducibility in response to programmed ventricular stimulation and that they could represent a noninvasive screen for patients referred for evaluation of risk of SCD because of asymptomatic ventricular ectopy or other causes. In a larger sense, the data suggest that HRV measurements may provide information pertinent to the identification of individuals at increased risk of SCD that is independent of that provided by other risk factors. Given the human and economic stakes, further study is clearly warranted.

Tissue factor in cultured cells: metabolic control.

Tissue factor content of WISH amnion cells in spinner culture increases 3- to 10-fold within 12 hours after subculture, then declines to a basal level within 30 to 50 hours. Maximal development of activity requires fresh serum and fresh medium. When added at the time of subculture, actinomycin D and cycloheximide completely inhibit development of coagulant activity; when added several hours after transfer, these inhibitors suppress the development but do not affect the disappearance of activity. Of the oxidative phosphorylation inhibitors tested, dinitrophenol had no effect whereas carbonyl cyanide m-chlorophenylhydrazone inhibited the activity increase but did not alter the decline. The kinetics of development and decay are similar over a pH range of 6.7 to 7.6 and with fetal calf serum concentration between 5 and 30 per cent. At pH 6.7 or in 30 per cent fetal calf serum, cell division did not occur. 3H-leucine and 35SO4= incorporation into the cell surface coat did not change appreciably during the burst of coagulant activity nor did the levels of naphthylamidase or alkaline phosphatase; 3H-thymidine incorporation reached a peak within 2 hours of the tissue factor maximum.

Tissue factor in cultured cells: pharmacologic effects.

Tissue factor activity in suspension cultures of WISH amnion cells is modulated by pharmacologic doses of agents which alter membrane structure and function. Lysosomal stabilizing steroids (hydrocortisone, dexamethasone, aldosterone, prednisolone, and estradiol) suppress the change in activity which follows subculture; lytic steroids (testosterone and progesterone) are ineffective. Chloroquine both increases the specific activity and extends the time before return to the basal level. Dimethyl sulfoxide and ouabain suppress the complete expression of activity but do not inhibit the subsequent decay. The effect of cytochalasin B is complex, the drug being either suppressive or slightly stimulatory depending on the time of addition. Cyclic nucleotides (AMP or GMP) or insulin do not regulate the expression of tissue factor in these cells. A dramatic increment and prolongation of activity occurs when colchicine or vinblastine is added to the cell suspension shortly after subculture; there is much less stimulation by griseofulvin. Lumicolchicine has no effect while deuterium oxide is inhibitory. From these experiments, we conclude that increased membrane fluidity or altered secretory processes resulting from microtubule disruption stabilize tissue factor in cultured cells. Since contradictory results were obtained with agents which stabilize lysosomes or inhibit transport, the role of these cellular functions in tissue factor production or decay is unclear.