PubMed Health⌕ Search

Biomedical subjects

R C Becker

Publications and source records attributed to R C Becker.

At least 19 recordsLinked to original sources
PubMed2005

First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS Trial.

BACKGROUND: Unfractionated heparin is widely used in patients with non-ST-elevation acute coronary syndromes but has important limitations. Anticoagulants with predictable kinetics and anticoagulant effects, better efficacy, and greater safety are needed. OBJECTIVE: To investigate the efficacy and safety of a direct, selective factor Xa inhibitor, DX-9065a (Daiichi Pharmaceuticals LTD, Inc.) compared with heparin, in patients with non-ST-elevation acute coronary syndromes. PATIENTS AND METHODS: Patients (n = 402) from the USA, Canada, and Japan were randomized to blinded, weight-adjusted heparin, low-dose DX-9065a, or high-dose DX-9065a. RESULTS: The primary efficacy endpoint of death, myocardial infarction, urgent revascularization, or ischemia on continuous ST-segment monitoring occurred in 33.6%, 34.3%, and 31.3% of patients assigned to heparin, low-dose DX-9065a, and high-dose DX-9065a (P = 0.91 for heparin vs. combined DX-9065a). The composite of death, myocardial infarction, or urgent revascularization occurred in 19.5%, 19.3%, and 11.9% (P = 0.125 for heparin vs. high-dose DX-9065a) of patients; major or minor bleeding occurred in 7.7%, 4.2%, and 7.0% of patients; and major bleeding in 3.3%, 0.8%, and 0.9% of patients. Higher concentrations of DX-9065a were associated with a lower likelihood of ischemic events (P = 0.03) and a non-significant tendency toward a higher likelihood of major bleeding (P = 0.32). CONCLUSIONS: In this small phase II trial, there was a non-significant tendency toward a reduction in ischemic events and bleeding with DX-9065a compared with heparin in patients with acute coronary syndromes. The absence of an effect on ST-monitor ischemia warrants further investigation. These data provide the rationale for adequately powered studies of DX-9065a in acute coronary syndromes or percutaneous intervention.

Acute Disease↗
PubMed2004

Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI Pilot.

BACKGROUND: Direct factor (F)Xa inhibition is an attractive method to limit thrombotic complications during percutaneous coronary intervention (PCI). OBJECTIVES: To investigate drug levels achieved, effect on coagulation markers, and preliminary efficacy and safety of several doses of DX-9065a, an intravenous, small molecule, direct, reversible FXa inhibitor during PCI. PATIENTS AND METHODS: Patients undergoing elective, native-vessel PCI (n = 175) were randomized 4 : 1 to open-label DX-9065a or heparin in one of four sequential stages. DX-9065a regimens in stages I-III were designed to achieve concentrations of > 100 ng mL-1, > 75 ng mL-1, and > 150 ng mL-1. Stage IV used the stage III regimen but included patients recently given heparin. RESULTS: At 15 min median (minimum) DX-9065a plasma levels were 192 (176), 122 (117), 334 (221), and 429 (231) ng mL-1 in stages I-IV, respectively. Median whole-blood international normalized ratios (INRs) were 2.6 (interquartile range 2.5, 2.7), 1.9 (1.8, 2.0), 3.2 (3.0, 4.1), and 3.8 (3.4, 4.6), and anti-FXa levels were 0.36 (0.32, 0.38), 0.33 (0.26, 0.39), 0.45 (0.41, 0.51), and 0.62 (0.52, 0.65) U mL-1, respectively. Stage II enrollment was stopped (n = 7) after one serious thrombotic event. Ischemic and bleeding events were rare and, in this small population, showed no clear relation to DX-9065a dose. CONCLUSIONS: Elective PCI is feasible using a direct FXa inhibitor for anticoagulation. Predictable plasma drug levels can be rapidly obtained with double-bolus and infusion DX-9065a dosing. Monitoring of DX-9065a may be possible using whole-blood INR. Direct FXa inhibition is a novel and potentially promising approach to anticoagulation during PCI that deserves further study.

Aged↗
PubMed2001

Age and the utilization of cardiac catheterization following uncomplicated first acute myocardial infarction treated with thrombolytic therapy (The Second National Registry of Myocardial Infarction [NRMI-2]).

Considerable data indicates that patients <50 years of age have lower morbidity and mortality after acute myocardial infarction (AMI) than older patients. It has been demonstrated that use of routine cardiac catheterization and revascularization in younger patients with AMI and successful thrombolysis does not confer benefit compared with a more conservative approach. Despite this, it has been our impression that cardiac catheterization is frequently employed in younger patients with AMI. Patients with uncomplicated initial AMI treated with thrombolytic therapy in the Second National Registry of Myocardial Infarction (NRMI-2) between June 1994 and April 1998 were identified. Patients were categorized into 4 age strata for purposes of analysis. A total of 61,232 cases met our inclusion criteria. Cardiac catheterization was performed during hospitalization in 78% of patients after an uncomplicated initial AMI. Age was inversely associated with receipt of cardiac catheterization: 85% of those < or =49 years old underwent catheterization compared with 63% of those > or =70 years old. Regression analysis revealed that use of catheterization was 2.9 times greater (95% confidence intervals 2.7 to 3.2) in patients < or =49 years old compared with those > or =70 years old. Geographic location and payor status also strongly influenced utilization of this procedure. In conclusion, routine coronary angiography after uncomplicated AMI is extensively utilized in all age groups, particularly in those <50 years of age. The efficacy and cost effectiveness of this strategy in these patients has not yet been determined in clinical trials.

Age Factors↗
PubMed2001

Early clinical outcomes and routine management of patients with non-ST-segment elevation myocardial infarction: a nationwide perspective.

BACKGROUND: Myocardial infarction (MI) in the absence of electrocardiographic ST-segment elevation or new bundle branch block is the cause of hospitalization for a large and steadily increasing proportion of patients with acute ischemic chest pain. Despite its prevalence, the common demographic features, current hospital-based management, and short-term clinical outcome among patients with non-ST-segment elevation MI remain poorly defined. METHODS: A total of 183 113 patients with non-ST-segment elevation MI were identified in the National Registry of Myocardial Infarction database. Using a validated model, 43 928 patients (24.0%) were retrospectively placed in major, 34 917 (19.1%) in intermediate, and 104 268 (56.9%) in minor severity clinical event categories that included hospital death, recurrent myocardial ischemia, and nonfatal recurrent MI. RESULTS: The administration of widely available and universally recommended pharmacologic therapies, including aspirin and beta-adrenergic blocking agents, was suboptimal, particularly among patients with major severity clinical events. In contrast, coronary angiography and mechanical revascularization procedures were commonplace (>60% of all patients) and most frequently performed in patients within the minor (compared with the major) severity clinical event category (58.2% and 42.7%, respectively). CONCLUSIONS: Patients with non-ST-segment elevation MI are a heterogeneous population, with readily identifiable demographic characteristics and clinical features associated with important early outcomes, including death. Nationwide efforts directed toward maximizing pharmacologic therapy utilization and the performance of invasive procedures according to established guidelines must continue.

Aged↗
PubMed2001

Short-term comparative outcomes associated with the use of GP IIb/IIIa antagonists in patients undergoing coronary intervention.

BACKGROUND: Platelet glycoprotein (GP) IIb/IIIa antagonists reduce the occurrence of death, myocardial infarction (MI) and urgent revascularization among patients undergoing percutaneous coronary intervention (PCI). Despite a similar mechanism of platelet inhibition, the three currently approved agents vary widely in cost. PURPOSE: The purpose of this prospectively designed, retrospective analysis was to determine clinical outcomes for patients receiving abciximab, tirofiban or eptifibatide as adjunctive therapy during PCI at a single center. We hypothesized that there would be no difference in outcomes during hospitalization following PCI in patients receiving tirofiban or eptifibatide compared with those patients who received abciximab. Outcomes examined included in-hospital mortality, hemorrhagic procedural complications, need for recatheterization, peak creatine kinase following intervention and length of hospital stay (LOS). RESULTS: Two hundred and sixty seven consecutive patients in whom GP IIb/IIIa antagonist therapy was initiated in the catheterization laboratory for PCI were analyzed. Abciximab-treated patients were more likely to be undergoing primary (p<0.001) and rescue (p=0.022) PCI and to have received fibrinolytic therapy (p=0.013) when compared to patients receiving tirofiban or eptifibatide. There were no significant differences between abciximab- and non abciximab-treated patients in either the primary PCI or non primary PCI groups in any of the studied endpoints. In patients undergoing primary PCI, abciximab-treated patients when compared with non abciximab-treated patients exhibited a trend toward an increase in hospital LOS (7.8+/-7.0 d vs 6.2+/-3.9, p=0.19) and in the frequency of hemorrhagic complications (22.1% vs 5.3%, p=0.11). In patients not receiving fibrinolytic therapy, abciximab-treated patients experienced a trend toward increased hemorrhagic complications following PCI when compared to non abciximab-treated patients (10.2% vs 6.0%, p=0.28). Complications distant from the vascular access site comprised 62.5% of hemorrhagic complications in the abciximab-treated group, but only 20% of the complications in the non-abciximab treated population (p<0.001). These data suggest no differences in acute outcomes between groups of patients receiving abciximab or other approved GP IIb/IIIa antagonists highlighting a potential significant cost saving. These data will require interpretation following the publication of comparative trials.

Abciximab↗
PubMed2001

Anticoagulation and the heart.

Cardiovascular disease is associated with a heightened risk of thrombosis that can manifest as acute myocardial infarction, cardiac death, and stroke. Similarly, valvular heart disease (which alters blood-flow dynamics) and the insertion of prosthetic materials (which stimulates localized thrombosis on foreign surfaces) are associated with platelet aggregation and thrombin-mediated bioamplification of the coagulation cascade. Physiologic principles and pathobiologic mechanisms determine the preferred means either to prevent or attenuate both thrombosis and subsequent cardiovascular events. Anticoagulant therapy in hospital- and outpatient-based settings has appropriately assumed a central role in the prevention and treatment of thrombotic disorders of the cardiovascular system. Carefully-designed clinical trials will establish safe and effective antithrombotic therapies for wide-scale implementation.

Algorithms↗
PubMed2001

Comparative efficacy of fibrinogen and platelet supplementation on the in vitro reversibility of competitive glycoprotein IIb/IIIa (alphaIIb/beta3) receptor-directed platelet inhibition.

BACKGROUND: Platelet surface glycoprotein (GP) IIb/IIIa (alphaIIb/beta(3)) receptor inhibition, by preventing fibrinogen binding and platelet aggregation, concomitantly attenuates arterial thrombotic capacity and impairs protective hemostasis, 2 divergent platelet-dependent processes. Because the currently available Food and Drug Administration-approved small molecule GP IIb/IIIa receptor antagonists are considered "competitive" inhibitors and because there is limited information on the reversibility of platelet inhibition by fibrinogen or platelet supplementation, the following series of in vitro experiments were performed. METHODS AND RESULTS: Washed platelets from 24 healthy volunteers were suspended in Tyrodes buffer and incubated with achievable (in vivo) steady-state concentrations of either tirofiban or eptifibatide before activation with TRAP (thrombin receptor agonist peptide) (15 micromol/L). Platelet aggregation was inhibited by 40% to 50%, but reversal was achieved by fibrinogen supplementation in a concentration-dependent manner. In a separate series of in vitro experiments, platelet inhibition exceeding 90% was established with tirofiban (average concentration 9.28 microg/L) and eptifibatide (average concentration 95.4 microg/L). Recovery of platelet aggregation to at least 50% was achieved after the addition of fibrinogen (0.76-0.80 g/L), platelets (2.4 x 10(11)/L), or their combination. There was an inverse relationship between plasma baseline fibrinogen and the amount of supplemental fibrinogen required to restore platelet aggregability (r = -0.60, P <.01). CONCLUSIONS: The reversibility of GP IIb/IIIa-directed platelet inhibition is influenced by cell surface receptor availability and the intrinsic pharmacodynamic mechanism of action. Fibrinogen supplementation with fresh frozen plasma or cryoprecipitate either alone or in combination with platelet transfusion, represents an important and readily available treatment consideration for restoring hemostatic potential and managing major hemorrhagic complications associated with the administration of small molecule competitive GP IIb/IIIa receptor antagonists.

Adult↗
PubMed2001

Markers of platelet activation and thrombin generation.

The laboratory assessment of platelet biology and coagulation has traditionally focused on abnormalities, congenital or acquired, that provide insights for understanding hemostatic defects, unexplained bleeding, and pharmacologic titration of compounds designed to attenuate thrombotic potential. Because atherosclerotic vascular disease is associated with thrombotic events and there exists a clear link between atherosclerosis, inflammation, and thrombosis, the development of markers that have pathobiologic, prognostic, and treatment- related relevance has taken on a role of considerable importance.

Arteriosclerosis↗
PubMed2000

Novel inhibitors of factor X for use in cardiovascular diseases.

The complementary roles of platelets and thrombin in the pathophysiology of acute coronary syndromes suggests that for treatment to be effective, both mediators must be targeted. Although great strides have been made in the development of antiplatelet therapies, attempts to inhibit thrombin have been less successful. Unfractionated heparin is limited by a number of pharmacologic shortcomings as well as an inability to meaningfully suppress thrombin generation. The low molecular weight heparins have yielded encouraging results in large-scale clinical trials, but it remains unclear whether their benefit stems from a superior pharmacologic profile to unfractionated heparin or is determined by an enhanced ability to suppress thrombin generation (by virtue of a direct anti-Xa effect). Regardless, investigators have become increasingly interested in factor Xa as a potential target for antithrombotic therapy. A number of naturally occurring Xa antagonists have been identified. Work with recombinant forms of these proteins confirms that factor Xa inhibition can suppress thrombin generation in a variety of animal thrombosis models. Accordingly, a number of synthetic direct and indirect Xa antagonists are under development for the prevention and treatment of thrombotic disorders. The following review summarizes the evolution of factor Xa antagonists.

Animals↗
PubMed2000

Early and pre-discharge aspirin administration among patients with acute myocardial infarction: current clinical practice and trends in the United States.

OBJECTIVES: The purpose of our study was to determine the frequency of aspirin administration among patients with acute myocardial infarction (MI) as dictated by physicians practicing in the United States. BACKGROUND: Aspirin (ASA), a widely available, inexpensive and generally well-tolerated platelet inhibitor, is recommended for patients with acute coronary syndromes, including acute MI. However, there is concern that aspirin is underutilized in daily clinical practice. METHODS: Early (<24 hours) and predischarge ASA administration were determined among 220,171 patients with suspected acute MI enrolled in the Second National Registry of Myocardial Infarction (NRMI 2) between June, 1994 and April 30, 1996. RESULTS: Overall, 165,122 (74.9%) of patients received ASA within 24 hours of hospital admission, whereas 55,049 patients did not. Early ASA recipients were younger, more often male, arrived at the hospital earlier, and were more likely to be classified as Killip Class II or less compared to those who did not receive ASA. Patients who received aspirin were also more likely to have chest pain, electrocardiographic ST segment elevation, and tended to arrive at the hospital earlier than those who did not receive ASA. However, over 20% of patients with ST segment elevation did not receive early ASA therapy. From the total cohort of early ASA recipients, only 69% received ASA at the time of hospital discharge. Trends in early and pre-discharge aspirin administration over a 2 year time period in all patients (72.6 to 75.1% and 71.5 to 74.6%, respectively; p < 0. 001) and in specific patient subsets were encouraging with a gradual but steady increase; however, utilization remained comparatively low in women and the elderly. By multivariable analysis, in-hospital recurrent MI (OR 0.90, 95% CI;.78-1.0, p = 0.04), stroke (OR 0.65, 95% CI,.52-.80, p < 0.001) and death (OR 0.24, 95% CI,.22-.26, p < 0. 001) occurred less frequently when ASA was administered within 24 hours of hospitalization. CONCLUSION: Aspirin is currently underutilized in routine clinical practice as both primary and adjunctive forms of therapy in MI, especially among patients known to be at risk for recurrent cardiothrombotic events. The targeted and timely use of aspirin reduces early cardiovascular events and should remain a priority in national health care efforts.

Aged↗
PubMed2000

Enoxaparin, a low molecular weight heparin, inhibits platelet-dependent prothrombinase assembly and activity by factor-Xa neutralization.

BACKGROUND: The available evidence suggests strongly that intravascular thrombosis is mediated predominantly by tissue-factor and its activation of factor X, which in the presence of factor Va, calcium, and phospholipid (prothrombinase complex) effectively converts prothrombin to thrombin. In vitro experiments have shown that low molecular weight heparins (LMWHs) have greater anti-Xa activity than unfractionated heparin; however, it remains unclear as to whether their antithrombotic effects in vivo are determined by a similar mechanism. We determined the ability of plasma obtained from patients with either unstable angina or non-ST segment elevation myocardial infarction (MI) receiving the LMWH enoxaparin (anti Xa:IIa ratio 3:1) to inhibit tissue factor-mediated thrombin generation and to inactivate platelet prothrombinase. METHODS: Platelet rich plasma was prepared by suspending washed donor platelets in the plasma of 7 patients participating in the TIMI 11A study. Samples were obtained before, 1 hour after a 30-mg IV bolus of enoxaparin and 6 hours after the third subcutaneous injection (1. 0-1.25 mg/kg given subcutaneously every 12 hrs). Tissue factor (0.1 ng/ml) and 10 mM CaCl(2) were added to initiate extrinsic coagulation. At timed intervals prothrombin activation fragment 1.2 (F1.2) levels (thrombin generation) were measured using an ELISA technique. Inactivation of reformed platelet prothrombinase by samples obtained at the same time points was also determined. RESULTS: Patient plasma obtained 1 hr after treatment initiation and 6 hours after the third subcutaneous injection inhibited tissue factor mediated prothrombinase assembly by 31% and 11%, respectively and platelet prothrombinase activity by 27% and 22%, respectively. CONCLUSION: We conclude that enoxaparin in plasma concentrations achieved routinely in clinical practice is able to: (1) inhibit tissue factor mediated extrinsic coagulation by preventing platelet surface prothrombinase assembly, and (2) inactivate platelet prothrombinase activity and resulting thrombin generation. These observations suggest that a LMWH's anti-Xa activity (and anti-Xa:IIa profile) is important in determining its overall antithrombotic potential. Clinical trials comparing agents with differing anti-Xa:IIa properties will be required, however, to provide proof of concept.

Angina, Unstable↗
PubMed2000

Inhibition of platelet-dependent prothrombinase activity and thrombin generation by glycoprotein IIb/IIIa receptor-directed antagonists: potential contributing mechanism of benefit in acute coronary syndromes.

The glycoprotein (GP) IIb/IIIa receptor antagonists used widely in the medical treatment of acute coronary syndromes and during percutaneous coronary interventions, prevent fibrinogen cross-linking and platelet aggregation, critical initiating steps in arterial thrombosis. Their anticoagulant properties, particularly when administered conjunctively with heparin preparations, are less well-characterized. In a series of in vitro studies, increasing concentrations of abciximab, tirofiban, and eptifibatide either alone or in combination with unfractionated heparin (UFH) or fractionated heparin (enoxaparin) were added to washed platelets suspended in Tyrode's buffer. Following platelet activation and prothrombinase assembly, thrombin generation was determined by enzyme-linked immunosorbent assay (ELISA). There was a concentration-dependent reduction in platelet-dependent thrombin generation with each of the GPIIb/IIIa receptor antagonists. The combination of tirofiban and UFH yielded percent, absolute and relative reductions (compared with tirofiban alone) of 48.0%, 16.9%, and 35.2%, respectively. The corresponding values for eptifibatide and abciximab were 38.0%, 13.5%, 35.5%, and 55.1%, 3.8%, 8.4%, respectively. Thrombin generation was decreased by an additional 2 to 3% (absolute reduction) with high concentrations of enoxaparin in combination with either eptifibatide or abciximab. Platelet GPIIb/IIIa receptor antagonists, beyond their ability to prevent fibrinogen-mediated aggregation, inhibit platelet-dependent prothrombinase activity and thrombin generation in a concentration-dependent manner. Heparin facilitates the existing anticoagulant properties, supporting combination therapy in clinical practice. The potential added benefit of fractionated heparin over UFH will require further investigation.

Abciximab↗
PubMed2000

Hirudin-based anticoagulant strategies for patients with suspected heparin-induced thrombocytopenia undergoing percutaneous coronary interventions and bypass grafting.

Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse drug reaction that is associated with thrombotic events of the venous and arterial circulatory systems stemming from an intense and well-characterized prothrombotic triad of platelet activation, coagulation cascade stimulation and vascular endothelial cell injury. Although heparin (or other sulfated mucopolysaccharide compound) cessation represents a vital first step in management, patients remain susceptible to life-threatening thrombosis for up to several weeks, providing a strong rationale for a 'proactive approach' to care that includes prompt initiation of an alternative anticoagulant strategy throughout the high-risk period. The importance of alternative options for anticoagulation is most evident in clinical situations wherein treatment is a recognized standard of care and prerequisite for an optimal outcome. The following review highlights the use of recombinant hirudin (lepirudin) among patients with suspected HIT requiring precutaneous coronary interventions (PCI) and coronary arterial bypass grafting.

Angioplasty, Balloon, Coronary↗