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Biomedical subjects

P Theroux

Publications and source records attributed to P Theroux.

At least 19 recordsLinked to original sources
PubMed2002

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.

Acute Disease↗
PubMed2001

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.

Administration, Oral↗
PubMed2001

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.

Abciximab↗
PubMed2001

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.

Aged↗
PubMed2000

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.

Acute Disease↗
PubMed2000

Effects of tirofiban plus heparin versus heparin alone on troponin I levels in patients with acute coronary syndromes.

Elevated serum troponins following an acute coronary syndrome (ACS) predict a poor clinical outcome. Glycoprotein (GP) IIb/IIIa inhibitors reduce adverse clinical outcomes in patients with ACS, although their effect on serum troponin I (TnI) in this setting has not been described. We therefore studied the effects of the GP IIb/IIIa inhibitor tirofiban on serum TnI levels in a group of patients in the Platelet Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms trial. Serial blood samples were obtained in 53 patients receiving the combination therapy of tirofiban/heparin and in 52 receiving heparin alone, and were analyzed for baseline, peak, and mean concentrations of TnI. Baseline TnI levels were not different between the combination therapy and heparin-only groups (1.6 +/- 3.0 vs 3.1 +/- 6.7 ng/ml, p = 0.15). The peak TnI level was significantly lower in the combination therapy group than in the heparin group (5.2 +/- 8.3 vs 15.5 +/- 29.1 ng/ml, p = 0.017), and mean levels over the initial 24-hour period were also significantly lower in the combination therapy group (3.2 +/- 5.0 vs 8.5 +/- 14.8 ng/ml, p = 0.016). In univariate analysis, combination therapy was associated with lower TnI levels, whereas in a multivariate model, the lower peak and mean TnI levels as a consequence of tirofiban/heparin compared with heparin monotherapy remained significant (peak, p = 0.029; mean, p = 0.035). Among patients with negative TnI at baseline, treatment with the combination of tirofiban/heparin compared with heparin monotherapy still resulted in significantly lower peak (2.5 +/- 5.4 vs 14.6 +/- 32.8 ng/ml, p = 0.024) and mean (1.2 +/- 2.6 vs 6.9 +/- 15.8 ng/ml, p = 0.029) TnI levels. In patients with ACS, therapy with the combination of tirofiban and heparin (compared with heparin treatment alone) resulted in lower serum TnI levels, suggesting reduced myocardial injury.

Angina, Unstable↗
PubMed2000

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.

Abciximab↗
PubMed2000

Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial.

BACKGROUND: Platelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events. METHODS: Lotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [alphaIIb/beta3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease. RESULTS: The efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia.

Administration, Oral↗
PubMed2000

Effect of micronized fenofibrate on plasma lipoprotein levels and hemostatic parameters of hypertriglyceridemic patients with low levels of high-density lipoprotein cholesterol in the fed and fasted state.

A randomized, double-blind, placebo-controlled study was undertaken in 20 hypertriglyceridemic men [plasma triglyceride (TG), >2.3 mM] with low levels (<0.9 mM) of high-density lipoprotein cholesterol (HDL-C) to investigate the ability of micronized fenofibrate (Tricor or Lipidil; 200 mg/day) to affect atherogenic and thrombogenic plasma risk factors in the fed and fasted state. Each patient underwent (a) 4 weeks of dietary stabilization, (b) 8 weeks of treatment with fenofibrate or placebo, (c) a 5-week washout period, and (d) 8-weeks of treatment with the alternative medication. An oral fat-loading test (1 g fat/kg body weight) was carried out after both treatment periods. Before treatment, patients had a mean (+/- SD) total plasma TG of 3.31+/-0.93 mM; total C, 5.75+/-0.89 mM; HDL-C, 0.71+/-0.09 mM; and low-density lipoprotein (LDL)-C, 3.40+/-0.68 mM. Compared with placebo, fenofibrate reduced fasting TG levels by 36%, and triglyceride-rich lipoprotein (TRL, d<1.006 g/ml) -TG, and TRL-C levels by approximately 40%. In the postprandial state, fenofibrate reduced total TG, TRL-TG, TRL-C, TRL-apoC-III, and TRL-apoE levels by -35% (all values of p<0.01). Fasted and fed HDL-C and apoA-I levels were increased -10%, and total cholesterol/HDL cholesterol ratios were decreased -15% by fenofibrate. No significant differences were observed in mean LDL-C and LDL-apoB levels. A 6% increase in the LDL-C/LDL-apoB ratio during fenofibrate treatment indicated a shift to larger, more buoyant LDL particles. A small, but statistically significant (p<0.01) increase was observed in fasted and fed Lp(a) levels during fenofibrate treatment. Hemostatic parameters were not significantly affected by fenofibrate, except for a 12-15% decrease (p<0.05) in fibrinogen levels in the fasted and fed state, and a significant increase (43%; p<0.05) in fasting levels of plasminogen activator-inhibitor-1. These data demonstrate that micronized fenofibrate is highly effective, in both the fed and fasted state, in reducing TRL lipids and apolipoproteins, and in reducing plasma fibrinogen levels of men with an atherogenic lipoprotein profile.

Adult↗
PubMed1999

Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events.

OBJECTIVES: We sought to assess the influence of baseline lipid levels on coronary event rates and the effectiveness of pravastatin therapy in the Cholesterol And Recurrent Events (CARE) study. BACKGROUND: The CARE study cohort provided a relatively unique opportunity to examine the relation between lipid levels and clinical events in a post-myocardial infarction (MI) population with relatively low cholesterol and low density lipoprotein (LDL) cholesterol values. METHODS: There were 4,159 patients with a previous infarct and a total cholesterol level <240 mg/dl, LDL cholesterol level 115 to 174 mg/dl and triglyceride level <350 mg/dl randomly allocated to placebo (n=2,078) or pravastatin 40 mg/day (n=2,081). Time to either coronary death or nonfatal MI (primary end point) or to the secondary end point, which included undergoing a coronary revascularization procedure, was determined as a function of baseline lipids (total, LDL, high density lipoprotein [HDL] cholesterol and triglyceride levels). RESULTS: Quartile analysis indicated important effects for LDL cholesterol, in which a higher LDL was associated with greater cardiac event rates (in the placebo group, every 25-mg/dl increment in LDL was associated with a 28% increased risk [5% to 56%, p=0.015]) in the primary event. The differential event rates with respect to baseline LDL cholesterol for placebo and pravastatin groups reduced the difference in clinical outcomes at lower LDL cholesterol levels. In both the placebo and pravastatin groups, an inverse relation between baseline HDL cholesterol and cardiac events was observed (10 mg/dl lower baseline HDL cholesterol level was associated with a 10% [0% to 19%, p=0.046] increase in coronary death or nonfatal MI). CONCLUSIONS: Within the LDL cholesterol levels in CARE (115 to 174 mg/dl), baseline values influenced both the risk of events in the placebo group as well as the clinical effectiveness of pravastatin therapy.

Adult↗
PubMed1997

Circadian variation in the onset of unstable angina and non-Q-wave acute myocardial infarction (the TIMI III Registry and TIMI IIIB).

Circadian variation has been demonstrated in several types of acute cardiovascular disease, including acute myocardial infarction (AMI), sudden cardiac death, silent ambulatory ischemia, and thrombotic stroke. In contrast, no diurnal variation was observed in 1 study of non-Q-wave AMI, and limited data are available for unstable angina. To assess whether circadian variation is present in unstable angina and non-Q-wave AMI, we examined the time of onset of ischemic pain in 7,731 patients who were prospectively identified in the Thrombolysis in Myocardial Ischemia (TIMI) III Registry, 3,318 of whom were enrolled in the prospective study, and in 1,473 patients enrolled in the TIMI IIIB trial. A circadian variation in the onset of pain was observed, with an increase in the number of patients experiencing the onset of pain in the morning hours between 6 A.M. and 12 noon (p <0.001). This circadian variation was observed both in patients with unstable angina and in those with evolving non-Q-wave AMI. A similar circadian pattern was observed in all subgroups tested. These findings were confirmed in the TIMI IIIB trial and complement previous studies suggesting that circadian variation exists in the onset of the full spectrum of myocardial ischemic syndromes.

Aged↗
PubMed1997

Glycoprotein IIb/IIIa inhibitors in unstable angina.

The inhibitors of platelet membrane integrin receptor glycoprotein IIb/IIIa occupy the receptor, preventing fibrinogen binding and platelet aggregation. The inhibition is direct and may be advantageous over the partial inhibition induced by agents interfering at individual pathways to platelet aggregation. The inhibitors, and more specifically abciximab, the monoclonal antibody against the receptor, are effective to prevent the acute complications associated with percutaneous intervention procedures. Based on the positive results of these trials, which have enrolled a large proportion of patients with unstable angina, and on a few pilot studies in unstable angina, large trials have been completed and are ongoing in patients with an acute coronary syndrome. It is hoped that these drugs will prevent the acute complications associated with thrombus formation, and also, past the acute phase, prevent the recurrence of the disease and rapid progression of atherosclerosis.

Angina, Unstable↗
PubMed1996

Comparison of outcome of patients with unstable angina and non-Q-wave acute myocardial infarction with and without prior coronary artery bypass grafting (Thrombolysis in Myocardial Ischemia III Registry).

The aim of this study was to characterize patients with and without prior coronary artery bypass grafting (CABG) among a prospectively identified cohort of patients presenting with unstable angina or non-Q-wave myocardial infarction. Patients in the Thrombolysis in Myocardial Infarction phase III Registry Prospective Study presented within 96 hours of an episode of unstable angina or non-Q-wave acute myocardial infarction. Of 2,048 patients, 336 (16.4%) had prior CABG. Compared with those without prior CABG, patients were the same age, but were more likely to be men, white, diabetic, have a history of angina or myocardial infarction, to have received anti-ischemic medications in the prior week, and to receive intravenous heparin or nitroglycerin, or both, during hospitalization. They were equally likely to undergo coronary angioplasty or CABG. Death or nonfatal myocardial infarction occurred by day 10 in 4.5% of patients with prior CABG and 2.8% of patients without prior CABG (p = 0.11); and by day 42 in 7.7% and 5.1%, respectively (p = 0.03). The composite of death, myocardial infarction, or recurrent ischemia at 1 year was more common among patients with prior CABG (39.3% vs 30.2%, p = 0.002). By multiple logistic regression, prior CABG was not independently associated with the occurrence of death or myocardial infarction, or the composite of death, myocardial infarction, or recurrent ischemia either at 6 weeks or at 1 year. The likelihood of recurrent ischemic events is greater among patients with than without prior CABG, but is not likely explained by differences in baseline or treatment characteristics which reflect the degree of underlying cardiac disease.

Aged↗
PubMed1996

Enhancing Thrombolysis with Adjunctive Therapy.

The striking clinical benefits that can be derived from thrombolytic therapy in acute myocardial infarction emphasize the need for further improvement of our reperfusion strategies. New approaches in that direction include the development of more efficient thrombolytic drugs as well as an adjunctive therapy to control the ongoing thrombogenic stimulation. Aspirin is already useful in this regard as well as heparin with recombinant tissue-type plasminogen activator. The field of antithrombotic therapy is rapidly expanding with the development of patent drugs targeted at inhibiting specific steps of platelet activation and of the coagulation cascade. This new therapy provides opportunities to better understand the pathophysiological processes involved in acute ischemic syndromes and to modulate them. This article reviews the adjunctive antithrombotic therapy currently available or under clinical investigation with the potential of enhancing the benefits of thrombolysis.

Journal Article↗