Effects of P2Y(1) receptor antagonism on the reactivity of platelets from patients with stable coronary artery disease using aspirin and clopidogrel.

BACKGROUND AND PURPOSE: P2Y(1) is a purine receptor that triggers platelet aggregation. Its inhibition was studied in patients with stable coronary artery disease (CAD) receiving standard anti-platelet therapy. EXPERIMENTAL APPROACH: Blood samples from 10 patients on aspirin therapy (ASA, 80 mg·day(-1) ) were withdrawn before and 24 h after the administration of 450 mg clopidogrel (ASA/C) and were anti-coagulated with citrate or hirudin/PPACK in the presence or absence of the P2Y(1 ) inhibitor MRS2179 (M, 100 µM). Platelet responses to ADP (2.5 µM) and TRAP (2.5 µM), and collagen-induced thrombosis under flow conditions were analysed. KEY RESULTS: Compared with ASA, ASA + M strongly inhibited ADP-induced peak platelet aggregation (88%), late aggregation (84%), P-selectin expression (85%) and α(IIb) ß(3) activation (62%) (28%, 65%, 70% and 51% inhibition, respectively, for ASA/C vs. ASA). ASA + M also inhibited platelet/monocyte and platelet/neutrophil conjugate formation by 69% and 71% (57% and 59% for ASA/C vs. ASA). In TRAP-activated blood, ASA + M unexpectedly inhibited α(IIb) b(3) activation by 30%. In blood perfused in collagen-coated glass capillaries (shear rate of 1500 s(-1) ), ASA/C prevented thrombus growth beyond 5 min in relation to thrombus fragments embolization. ASA + M with or without clopidogrel completely prevented thrombus formation. Finally, ex vivo addition of MRS2179 and ASA to the blood of healthy donors markedly blocked thrombus formation on collagen in flow conditions, in contrast to ASA plus the P2Y(12) inhibitor 2-MeSAMP. CONCLUSIONS AND IMPLICATIONS: Through particularly efficient complementarities with ASA to inhibit platelet activation and thrombus formation, the inhibition of P2Y(1) in the blood of patients with CAD appears to play a more important role than previously anticipated.

Platelet glycoprotein IIb/IIIa inhibition in acute coronary syndromes. Gradient of benefit related to the revascularization strategy.

AIMS: To assess the efficacy of platelet glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes primarily medically managed. METHODS AND RESULTS: We performed a meta-analysis of the randomized clinical trials of platelet glycoprotein IIb/IIIa inhibitor therapy in the medical management of non-ST-elevation acute coronary syndromes. Among 29570 patients, IIb/IIIa integrin blockade was associated with a reduction in death or non-fatal myocardial infarction at 30 days, from 11.5% to 10.7% (odds ratio 0.91,P =0.02). Patients undergoing percutaneous coronary intervention during index hospitalization sustained a greater reduction in ischaemic events (odds ratio 0.82, P=0.01) than patients medically managed (odds ratio 0.95, P=0.27). Among patients undergoing intervention, the benefit was more pronounced if the procedure was performed during glycoprotein IIb/IIIa inhibitor infusion (odds ratio 0.74; P=0.02), than if revascularization was performed after drug discontinuation (odds ratio 0.87,P =0.17). CONCLUSION: This analysis, including the entire large-scale trial experience of intravenous glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes primarily medically managed, demonstrates an overall significant, albeit moderate, reduction in 30-day death or myocardial infarction associated with therapy. Although not based on a prospectively defined hypothesis, the findings suggest a gradient of benefit conferred by these agents depending on the revascularization strategy used.

An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI Risk Score for UA/NSTEMI in PRISM-PLUS.

AIMS: We evaluated the TIMI Risk Score for Unstable Angina and Non-ST Elevation Myocardial Infarction for predicting clinical outcomes and the efficacy of tirofiban in non-ST elevation acute coronary syndromes. METHODS AND RESULTS: Developed in TIMI 11B, the risk score is calculated as the sum of seven presenting characteristics (age > or =65 years, > or =3 cardiac risk factors, documented coronary disease, recent severe angina, ST deviation > or =0.5 mm, elevated cardiac markers, prior aspirin use). The risk score was validated in the PRISM-PLUS database (n=1915) and tested for interaction with the efficacy of tirofiban+heparin vs heparin alone. The risk score revealed an increasing gradient of risk for death, myocardial infarction or recurrent ischaemia at 14 days ranging from 7.7-30.5% (P<0.001). Dichotomized at the median, patients with a score > or =4 derived a greater relative risk reduction with tirofiban (P((Interaction))=0.025). Among patients with normal creatine kinase myocardial bands, the risk score showed a 3.5-fold gradient of risk (P<0.001) and identified a population that derived significant benefit from tirofiban (RR 0.73, P=0.027). CONCLUSION: The TIMI Risk Score is a simple clinical tool for risk assessment that may aid in the early identification of patients who should be considered for treatment with potent antiplatelet therapy.

Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes.

BACKGROUND: Diabetes mellitus is a major risk factor for adverse outcomes after acute coronary syndromes (ACS). Because this disease may be associated with increased platelet aggregation, we investigated whether diabetic patients with ACS derive particular benefit from platelet glycoprotein (GP) IIb/IIIa receptor inhibition. METHODS AND RESULTS: We performed a meta-analysis of the diabetic populations enrolled in the 6 large-scale platelet GP IIb/IIIa inhibitor ACS trials: PRISM, PRISM-PLUS, PARAGON A, PARAGON B, PURSUIT, and GUSTO IV. Among 6458 diabetic patients, platelet GP IIb/IIIa inhibition was associated with a significant mortality reduction at 30 days, from 6.2% to 4.6% (OR 0.74; 95% CI 0.59 to 0.92; P=0.007). Conversely, 23 072 nondiabetic patients had no survival benefit (3.0% versus 3.0%). The interaction between platelet GP IIb/IIIa inhibition and diabetic status was statistically significant (P=0.036). Among 1279 diabetic patients undergoing percutaneous coronary intervention (PCI) during index hospitalization, the use of these agents was associated with a mortality reduction at 30 days from 4.0% to 1.2% (OR 0.30; 95% CI 0.14 to 0.69; P=0.002). CONCLUSIONS: This meta-analysis, including the entire large-scale trial experience of intravenous platelet GP IIb/IIIa inhibitors for the medical management of non-ST-segment-elevation ACS, shows that these agents may significantly reduce mortality at 30 days in diabetic patients. Although not based on a randomized assessment, the survival benefit appears to be of greater magnitude in patients undergoing PCI. Therefore, the use of platelet GP IIb/IIIa inhibitors should be strongly considered in diabetic patients with ACS.

Increased mortality after coronary artery bypass graft surgery is associated with increased levels of postoperative creatine kinase-myocardial band isoenzyme release: results from the GUARDIAN trial.

OBJECTIVES: We sought to determine if elevated cardiac serum biomarkers after coronary artery bypass graft surgery (CABG) are associated with increased medium-term mortality and to identify patients that may benefit from better postoperative myocardial protection. BACKGROUND: The relationship between the magnitude of cardiac serum protein elevation and subsequent mortality after CABG is not well defined, partly because of the lack of large, prospectively studied patient cohorts in whom postoperative elevations of cardiac serum markers have been correlated to medium- and long-term mortality. METHODS: The GUARD during Ischemia Against Necrosis (GUARDIAN) study enrolled 2,918 patients assigned to the entry category of CABG and considered as high risk for myocardial necrosis. Creatine kinase-myocardial band (CK-MB) isoenzyme measurements were obtained at baseline and at 8, 12, 16 and 24 h after CABG. RESULTS: The unadjusted six-month mortality rates were 3.4%, 5.8%, 7.8% and 20.2% for patients with a postoperative peak CK-MB ratio (peak CK-MB value/upper limits of normal [ULN] for laboratory test) of < 5, > or = 5 to <10, > or =10 to < 20 and > or =20 ULN, respectively (p < 0.0001). The relationship remained statistically significant after adjustment for ejection fraction, congestive heart failure, cerebrovascular disease, peripheral vascular disease, cardiac arrhythmias and the method of cardioplegia delivery. Receiver operating characteristic curve analysis revealed an area under the curve of 0.648 (p < 0.001); the optimal cut-point to predict six-month mortality ranged from 5 to 10 ULN. CONCLUSIONS: Progressive elevation of the CK-MB ratio in clinically high-risk patients is associated with significant elevations of medium-term mortality after CABG. Strategies to afford myocardial protection both during CABG and in the postoperative phase may serve to improve the clinical outcome.

A risk score system for predicting adverse outcomes and magnitude of benefit with glycoprotein IIb/IIIa inhibitor therapy in patients with unstable angina pectoris.

Clinical outcomes of patients with unstable angina are variable. We sought to identify predictors of adverse clinical outcomes in patients with unstable angina and to investigate whether these factors would predict the magnitude of benefit achieved with platelet glycoprotein IIb/IIIa inhibition. We analyzed 20 variables in the 1,915 patients enrolled in the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. Five independent predictors were identified: age >65 years, prior coronary artery bypass grafting, antecedent aspirin use, antecedent beta-blocker use, and ST depressions on the presenting electrocardiogram. A risk score system was created using these predictors in which patients were assigned 1 point for the presence of each risk factor. There was a progressive increase in the rate of the composite end point of death, myocardial infarction, or refractory ischemia at 7 days with an increasing number of risk factors. For patients treated with heparin alone, the composite end point event rate was 6.5% in the group with 0 or 1 predictor, 14.6% in the group with 2 predictors, 22.7% in the group with 3 predictors, and 37.1% in the group with 4 or 5 predictors (p <0.00001). When dividing patients into low- (0 or 1 point), medium- (2 or 3 points), and high-risk (4 or 5 points) groups, the addition of tirofiban to heparin therapy was associated with no significant benefit in the low-risk group, a 5.2% absolute reduction in the medium-risk group (p = 0.05), and a 16% absolute reduction in the high-risk group (p = 0.0055). Thus, we have developed a risk score system using 5 variables that can be used to identify patients at high risk for death and cardiac ischemic events and who experience the greatest benefit from the addition of a glycoprotein IIb/IIIa inhibitor to their treatment regimen.

Randomized comparison of a novel anticoagulant, vasoflux, and heparin as adjunctive therapy to streptokinase for acute myocardial infarction: results of the VITAL study (Vasoflux International Trial for Acute Myocardial Infarction Lysis).

BACKGROUND: Vasoflux is a low-molecular-weight heparin derivative that inhibits factor IXa activation of factor X and catalyzes fibrin-bound thrombin inactivation by heparin cofactor II. We studied whether vasoflux improves the results of thrombolysis with streptokinase for acute myocardial infarction. METHODS AND RESULTS: We randomized 277 patients with acute myocardial infarction to standard intravenous unfractionated heparin (UFH) or intravenous vasoflux 1, 4, 8, or 16 mg/kg as a bolus followed by 1, 4, 8, or 16 mg/kg per hour infusion, on top of streptokinase and aspirin, until angiography at 90 minutes. Patency and corrected Thrombolysis in Myocardial Infarction (TIMI) frame count were studied at 60 and 90 minutes. Rates of TIMI grade 3 flow with vasoflux at any dose (35% to 42%) were not different from UFH (41%) at either time point, nor was the corrected TIMI frame count. However, there was an excess of bleeding in the patients randomized to vasoflux 8 or 16 mg/kg: 78% and 71%, compared with 53% for UFH (P =.004 and.043, respectively). Major bleeding was observed in 13% and 28% at these vasoflux doses compared with 8% with UFH (P =.558 and.01, respectively). CONCLUSION: At doses that increase the risk of bleeding, the addition of vasoflux to streptokinase and aspirin did not lead to improved patency rates compared with UFH. Targeting factor IXa and heparin cofactor II may not be a useful adjunct to thrombolysis.

A functional myeloperoxidase polymorphic variant is associated with coronary artery disease in French-Canadians.

BACKGROUND: One of the enzymes involved in the production of free radicals in atherosclerotic plaques is myeloperoxidase (MPO). There is a functional G/A polymorphism 463 bp upstream of the transcription start site of the enzyme with the G allele associated with a higher level of MPO expression than the A allele. Considering the potential role of MPO in the process of atherosclerosis, studying the relationship between this polymorphism and the incidence of coronary artery disease (CAD) seems reasonable. METHOD: We performed a case-control study. The case group consisted of 229 patients who had angiographically proved atherosclerotic plaques in their coronary arteries. The control group consisted of 217 individuals who did not have a history of coronary artery disease, stroke, or peripheral vascular disease. RESULTS: We found that allele A of the MPO gene was less frequent in cases with CAD. In a recessive model patients with the AA genotype had a decreased risk of CAD (odds ratio 0.138, 95% confidence interval 0.040-0.474). In a dominant model a significant protective role for AA or AG versus GG was also detected (odds ratio 0.639, 95% confidence interval 0.436-0.937). CONCLUSION: Our findings suggest that the -463 G/A polymorphism of the MPO gene influences the risk of CAD. This effect may be mediated by the effect of this polymorphism on the transcription level of the MPO gene.

Oral glycoprotein IIb/IIIa antagonism in patients with coronary artery disease.

Dose-finding studies and trials of interaction of oral glycoprotein IIb/IIIa antagonists with other antiplatelet agents have been limited. We hypothesized that these detailed assessments could be first performed in patients with stable coronary artery disease (CAD) and then extrapolated to the target population. To this end, we performed 2 sequential studies. The first study examined the dose-related effects on indexes of platelet and vascular function induced by the oral inhibitor RPR 109891, when given alone and in combination with aspirin, in patients (n = 100) with stable CAD. The second study (the Antagonism of the FIbrinogen Receptor after Myocardial Events trial) assessed the pharmacodynamics and safety of derived regimens in patients (n = 320) with unstable coronary syndromes. In patients with stable CAD, platelet aggregation was dose dependently inhibited by RPR 109891, and the dose-response relation was shifted to the right by the concomitant administration of aspirin (p = 0.0001). The degree of platelet inhibition induced by 3 doses of RPR 109891 (plus aspirin) was lower in patients with unstable than stable CAD. No drug-related major bleeding occurred in either study. RPR 109891 treatment was associated with acute and delayed thrombocytopenia. In conclusion, chronic treatment with an oral glycoprotein IIb/IIIa antagonist (1) induces antiplatelet effects that are potentiated by concomitant administration of aspirin, (2) may require dose adjustment in syndromes of platelet activation, (3) is associated with a low rate of clinically significant bleeding when doses inducing incomplete inhibition of platelet aggregation are used, and (4) requires frequent monitoring of platelet count unless reliable predictors of delayed thrombocytopenia become available.

Aspirin, warfarin, or the combination for secondary prevention of coronary events in patients with acute coronary syndromes and prior coronary artery bypass surgery.

BACKGROUND: Patients with a non-ST-elevation acute coronary syndrome and prior CABG are at high risk of a recurrent ischemic event despite aspirin therapy. This trial investigated the potential benefit of secondary prevention with warfarin. METHODS AND RESULTS: In a double-blind randomized trial, 135 patients with unstable angina or non-ST-segment elevation myocardial infarction, with prior CABG, and who were poor candidates for a revascularization procedure received therapy with aspirin and placebo+warfarin, warfarin and placebo+aspirin, or aspirin and warfarin for 12 months. Warfarin was titrated to an international normalized ratio of 2.0 to 2.5. The primary end point (death or myocardial infarction or unstable angina requiring hospitalization 1 year after randomization) occurred in 14.6% of the patients in the warfarin-alone group, in 11.5% of patients in the aspirin-alone group, and in 11.3% of patients randomized to the combination therapy (P=0.76). Subgroup analyses by risk features provided no indications that warfarin alone or in combination with aspirin could be of benefit over aspirin alone. Bleeding was more frequent in the 2 groups of patients administered warfarin. CONCLUSIONS: Moderate-intensity oral anticoagulation alone or combined with low-dose aspirin does not appear to be superior to low-dose aspirin in the prevention of recurrent ischemic events in patients with non-ST-elevation acute coronary syndromes and previous CABG.

Late (> 48 hr) myocardial infarction after PTCA: clinical and angiographic characteristics of infarction related or not to the angioplasty site.

Since late myocardial infarctions after percutaneous coronary interventions have not been well characterized, we intended to evaluate the characteristics of myocardial infarctions occurring > 48 hr after balloon angioplasty of native coronary arteries or saphenous vein grafts. The Montreal Heart Institute database (1985-1996) was interrogated for all patients readmitted with a diagnosis of MI more than 48 hr after successful percutaneous transluminal coronary angioplasty (PTCA). We compared the clinical, procedural, and angiographic variables between MIs related or not to the index PTCA site. One hundred and ninety-three patients presented with late myocardial infarction (MI) following balloon angioplasty. The median time elapsed between PTCA and MI was 55 days compared to 968 days when MI was unrelated to the PTCA site. MIs related to the PTCA site were more likely non-Q-wave (76% vs. 35%, P = 0.0001) with less marked CK-MB rise. Angiography showed less complex lesions (63% vs. 90%, P = 0.001) and better thrombolysis in myocardial infarction (TIMI) grade flow (TIMI II to III, 66% vs. 56%, P = 0.01) when the culprit lesion was at the PTCA site. Independent predictors of MI at the PTCA site were vein graft dilation, female sex, and residual stenosis post-PTCA. Myocardial infarctions occurring late after PTCA have a distinct time course and present specific characteristics according to their relationship or not to the previously dilated site.

Age-related differences in in-hospital mortality and the use of thrombolytic therapy for acute myocardial infarction.

BACKGROUND: Recent guidelines have acknowledged that thrombolysis decreases mortality from acute myocardial infarction (AMI) independently of age. The purpose of this study was to determine the age-related rates of thrombolytic administration and in-hospital mortality and the variables related to the use of thrombolytic therapy for patients with AMI. METHODS: A prospective cohort analysis involved a registry of 44 acute care Quebec hospitals that enrolled 3741 patients with AMI between January 1995 and May 1996. The main outcomes of interest were crude and adjusted age-related in-hospital mortality rates and rates of use of thrombolytic therapy. RESULTS: In-hospital mortality rates increased dramatically with age from 2.1% in patients with AMI who were less than 55 years of age to 26.3% in those who were 85 years of age or older. Overall, 35.8% of the patients received thrombolysis. There was a pronounced inverse gradient in the use of thrombolysis with age, ranging from 46.2% in the youngest age group (< 55 years) to 9.5% in the oldest group (> or = 85 years). After adjustment for potential confounders, the older patients remained significantly less likely to receive thrombolytic therapy. Compared with patients who were less than 55 years of age, the odds ratio of receiving thrombolytic therapy was 0.68 (95% confidence interval [CI] 0.52-0.89) for patients aged 65-74 years, 0.48 (95% CI 0.35-0.65) for patients aged 75-84 years and 0.13 (95% CI 0.06-0.26) for patients aged 85 years or more. Other variables related to thrombolytic therapy were diabetes (odds ratio [OR] 0.77, 95% CI 0.59-1.00), cerebrovascular disease (OR 0.46, 95% CI 0.30-0.72), angina (OR 0.73, 95% CI 0.56-0.95), typical chest pain (OR 2.56, 95% CI 1.88-3.47); ST elevation (OR 8.93, 95% CI 7.24-11.00), Q wave MI (OR 5.26, 95% CI 4.20-6.60) and increased length of time between onset of symptoms and arrival at hospital. INTERPRETATION: Age is an important independent predictor of in-hospital mortality and lower thrombolytic use following AMI. Other studies are required to further evaluate the appropriateness of thrombolytic therapy for elderly patients.

Point-of-care measured platelet inhibition correlates with a reduced risk of an adverse cardiac event after percutaneous coronary intervention: results of the GOLD (AU-Assessing Ultegra) multicenter study.

BACKGROUND: The optimal level of platelet inhibition with a glycoprotein (GP) IIb/IIIa antagonist necessary to minimize thrombotic complications in patients undergoing a percutaneous coronary intervention (PCI) is currently unknown. METHODS AND RESULTS: Five hundred patients undergoing a PCI with the planned use of a GP IIb/IIIa inhibitor had platelet inhibition measured at 10 minutes, 1 hour, 8 hours, and 24 hours after the initiation of therapy with the Ultegra Rapid Platelet Function Assay (Accumetrics). Major adverse cardiac events (MACES: composite of death, myocardial infarction, and urgent target vessel revascularization) were prospectively monitored, and the incidence correlated with the measured level of platelet function inhibition at all time points. One quarter of all patients did not achieve >/=95% inhibition 10 minutes after the bolus and experienced a significantly higher incidence of MACEs (14.4% versus 6.4%, P=0.006). Patients whose platelet function was <70% inhibited at 8 hours after the start of therapy had a MACE rate of 25% versus 8.1% for those >/=70% inhibited (P=0.009). By multivariate analysis, platelet function inhibition >/=95% at 10 minutes after the start of therapy was associated with a significant decrease in the incidence of a MACE (odds ratio 0.46, 95% CI 0.22 to 0.96, P=0.04). CONCLUSIONS: Substantial variability in the level of platelet function inhibition is achieved with GP IIb/IIIa antagonist therapy among patients undergoing PCI. The level of platelet function inhibition as measured by a point-of-care assay is an independent predictor for the risk of MACEs after PCI.

Upstream use of tirofiban in patients admitted for an acute coronary syndrome in hospitals with or without facilities for invasive management. PRISM-PLUS Investigators.

Management and prognosis of acute coronary syndromes may be influenced by the availability of catheterization facilities at admitting hospitals. Treatment effects of tirofiban were examined in a Canadian cohort of 834 patients enrolled in the Canadian Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial according to admission into hospitals without (n = 322) or with catheterization facilities (n = 512). Hospital transfers for cardiac catheterization were facilitated using preexisting networks accelerated for the purposes of the protocol. In hospitals without facilities, the relative risks for occurrence of death, infarction, or refractory ischemia among patients receiving tirofiban plus heparin compared with heparin alone were 0.52 at 7 days (p = 0.02), 0.59 at 30 days (p = 0.03), and 0.70 at 180 days (p = 0.09); and for death or infarction, 0.32 (p = 0.02), 0.46 (p = 0.04,) and 0.51 (p = 0.03), respectively. Benefit was seen regardless of transfer status, with no statistically significant interaction between treatment, hospital type, and catheterization for any end point at any time point. The incidence of Thrombolysis In Infarction defined major bleeding with respect to therapy was not significantly different between hospital types. Thus, upstream treatment with tirofiban plus heparin confers clinical benefits in unstable angina and/or non-ST-segment elevation infarction patients regardless of whether initial presentation is to a hospital without catheterization facilities or to a hospital with such facilities.

A randomized placebo-controlled trial to assess the efficacy of antiinflammatory therapy with methylprednisolone in unstable angina (MUNA trial).

AIMS: The purpose of this study was to assess the efficacy of antiinflammatory therapy with methylprednisolone during the acute phase of unstable angina. METHODS: This is a randomized 'prospective' double-blind, placebo-controlled trial. Patients with the diagnosis of unstable angina were randomized to a 48-h course of methylprednisolone (n=81) or placebo (n=85). Patient care and therapy were otherwise decided by their attending cardiologist. The primary end-point was a composite of in-hospital recurrence of angina, silent ischaemia on Holter recording, emergency coronary revascularization, readmission with unstable angina, and myocardial infarction or death during the 30-day follow-up. RESULTS: The two groups were well balanced and had similar clinical characteristics at baseline. Forty-eight hours after randomization, mean C-reactive protein levels decreased by 2.6 mg. l(-1)in the methylprednisolone group, but increased by 1.6 mg. l(-1)in the placebo group (P=0.03). The primary end-point occurred in 44% of the methylprednisolone patients and in 33% of the placebo patients (P=0.12). Coronary revascularization rates were equal between the two groups (38% and 40%). When adjustment was made for the difference in revascularization times, a trend towards better event-free survival was seen in the control group (67% vs 57%;P=0.09). CONCLUSION: A 48 h course of antiinflammatory therapy with methylprednisolone given at the doses of this study did not improve the short-term outcome of patients with unstable angina.

Glycoprotein IIb/IIIa receptor blockade improves outcomes in diabetic patients presenting with unstable angina/non-ST-elevation myocardial infarction: results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study.

BACKGROUND: Diabetic patients who present with unstable angina or non-ST-elevation myocardial infarction suffer a substantially greater incidence of subsequent infarction or death compared with nondiabetic patients. The present study was undertaken to examine whether diabetic patients in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study appeared to benefit from platelet glycoprotein IIb/IIIa receptor-mediated inhibition of platelet aggregation by tirofiban. METHODS AND RESULTS: Of the 1570 PRISM-PLUS patients treated with either tirofiban plus heparin (n=773) or heparin alone (n=797), approximately 23% in each treatment group were diabetic. A comparison of treatment outcomes in the diabetic subgroup revealed that the combination therapy compared with heparin alone was associated with reductions in the incidence of the composite primary end point of death, myocardial infarction (MI), or refractory ischemia at 2, 7, 30, and 180 days (7.7% versus 8.3%, 14. 8% versus 21.8%, 20.1% versus 29.0%, and 32.0% versus 39.9%, respectively; P=NS) and in the incidence of MI or death (0.0% versus 3.1%, P:=0.03; 1.2% versus 9.3%, P:=0.005; 4.7% versus 15.5%, P:=0. 002; and 11.2% versus 19.2%, P:=0.03). Tests for quantitative interaction between tirofiban therapy and diabetic status were significant. CONCLUSIONS: The addition of tirofiban to heparin and aspirin appears effective in the prevention of major ischemic events, particularly MI or death, in diabetic patients presenting with unstable angina and non-ST-elevation MI.

Redefining medical treatment in the management of unstable angina.

In 1994, the Agency for Health Care Policy and Research sponsored the development of guidelines for diagnosing and managing patients with unstable angina. Since their publication, several important developments have occurred. The prognostic value of biochemical assays for cardiac-specific troponins T and I have been shown in many studies. The possible role for C-reactive protein in determining prognosis deserves further investigation. Substantial clinical benefits have been obtained with intravenous inhibitors of the platelet glycoprotein (GP) IIb-IIIa receptor (abciximab, eptifibatide, tirofiban) and with one of the low-molecular-weight heparins (enoxaparin). The therapeutic potential of other low-molecular-weight heparins, direct thrombin inhibitors, and oral GP IIb-IIIa inhibitors remains to be clarified. On the basis of this evidence, consideration should be given to measuring serum levels of a cardiac troponin (either T or I) and using intravenous GP IIb-IIIa inhibitors and low-molecular-weight heparin in the standard management of patients with unstable angina.

Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes.

OBJECTIVES: The study was done to determine the role of partial agonist activity in the lack of effectiveness of the oral GPIIb/IIIa antagonist orbofiban. BACKGROUND: Orbofiban, an oral GPIIb/IIIa antagonist, was found to increase the mortality of patients with acute coronary syndromes (ACS) in the OPUS-TIMI-16 trial, despite the fact that it is a very potent anti-platelet agent and that IV agents have proven very effective. METHODS: Patients (n = 520) with ACS were randomized to orbofiban 30 mg, 40 mg or 50 mg twice daily or 50 mg once daily or placebo. Platelet activity was assessed in 175 patients by examining GPIIb/IIIa receptor conformation, expression of CD63 antigen, and platelet aggregation. RESULTS: Plasma concentrations of orbofiban at the highest dose (74 +/- 6 ng/ml peak, 61 +/- 5 ng/ml trough) exceeded the IC50 for platelet aggregation to adenosine diphosphate (ADP) (29 +/- 6 ng/ml) and thrombin-activating peptide (61 +/- 18 ng/ml). Orbofiban induced a conformational change in GPIIb/IIIa detected as the displacement of the monoclonal antibody mAb2; such conformational changes have been linked to partial agonist activity. Consistent with this, platelet expression of CD63 ex vivo was significantly increased at five time points during the study. In vitro, orbofiban increased platelet aggregation to a submaximal concentration of epinephrine (67 +/- 19% vs. 27 +/- 9%, n = 5) and increased thromboxane formation when the platelet GPIIb/IIIa were clustered using monoclonal antibodies to the receptor. CONCLUSIONS: Orbofiban is both an antagonist and a partial agonist of platelet GPIIb/IIIa. At low concentrations of the drug, this partial agonist activity may enhance platelet aggregation. Along with suboptimal plasma drug levels, these findings may help explain the lack of efficacy seen with orbofiban in patients with ACS.