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Kenneth A Bauer

Publications and source records attributed to Kenneth A Bauer.

34 records · Page 2Linked to original sources
PubMed2003

New pentasaccharides for the prophylaxis of venous thromboembolism: clinical studies.

Fondaparinux, a selective inhibitor of factor Xa, is the first of a new class of antithrombotic compounds, the synthetic pentasaccharides. Its benefit-to-risk ratio in preventing venous thromboembolism after major orthopedic surgery was investigated in four randomized, double-blind international phase III trials in patients undergoing surgery for hip fracture, elective hip replacement, and major knee surgery. Compared to enoxaparin, fondaparinux administered at a subcutaneous dose of 2.5 mg qd, starting postoperatively, reduced the overall incidence of venous thromboembolism up to day 11 by 55.2% (p < 0.001). The incidence of clinically relevant bleeding was low and did not differ between the two groups. Overall, fondaparinux achieved optimal efficacy and safety when treatment was initiated > or =6 h after the surgical procedure. In a further randomized double-blind trial, 4 weeks of prophylaxis with fondaparinux after hip fracture surgery reduced the risk of venous thromboembolism by 96% as compared to 1 week of prophylaxis, and was well tolerated. Fondaparinux has been recently approved for use in thromboprophylaxis after major orthopedic surgery. The clinical development of fondaparinux in other thromboprophylactic indications is ongoing.

Anticoagulants↗
PubMed2002

Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies.

BACKGROUND: Orthopedic surgery remains a condition at high risk of venous thromboembolism (VTE). Fondaparinux, the first of a new class of synthetic selective factor Xa inhibitors, may further reduce this risk compared with currently available thromboprophylactic treatments. METHODS: A meta-analysis of 4 multicenter, randomized, double-blind trials in patients undergoing elective hip replacement, elective major knee surgery, and surgery for hip fracture (N = 7344) was performed to determine whether a subcutaneous 2.5-mg, once-daily regimen of fondaparinux sodium starting 6 hours after surgery was more effective and as safe as approved enoxaparin regimens in preventing VTE. The primary efficacy outcome was VTE up to day 11, defined as deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism. The primary safety outcome was major bleeding. RESULTS: Fondaparinux significantly reduced the incidence of VTE by day 11 (182 [6.8%] of 2682 patients) compared with enoxaparin (371 [13.7%] of 2703 patients), with a common odds reduction of 55.2% (95% confidence interval, 45.8% to 63.1%; P<.001); this beneficial effect was consistent across all types of surgery and all subgroups. Although major bleeding occurred more frequently in the fondaparinux-treated group (P =.008), the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups. CONCLUSION: In patients undergoing orthopedic surgery, 2.5 mg of fondaparinux sodium once daily, starting 6 hours postoperatively, showed a major benefit over enoxaparin, achieving an overall risk reduction of VTE greater than 50% without increasing the risk of clinically relevant bleeding.

Aged↗
PubMed2002

Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial.

BACKGROUND: Elective hip-replacement surgery carries significant risk of venous thromboembolism, despite use of thromboprophylaxis. We aimed to see whether the pentasaccharide fondaparinux, the first drug of a new class of synthetic antithrombotic agents, could reduce this risk to a greater extent than other available treatments. METHODS: In a double-blind study, we randomly assigned 2275 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to receive postoperative subcutaneous injections of either 2.5 mg fondaparinux once daily or 30 mg enoxaparin twice daily. The primary efficacy outcome was venous thromboembolism to day 11. The main safety outcomes were bleeding and death. Patients were followed up for 6 weeks. FINDINGS: We assessed venous thromboembolism to day 11 in 1584 (70%) of 2275 patients. By day 11, venous thromboembolisms were recorded in 48 (6%) of 787 patients on fondaparinux and in 66 (8%) of 797 patients on enoxaparin. The relative reduction in risk was 26.3% (95% CI -10.8 to 52.8, p=0.099). The two groups did not differ in the number of patients who died or in the number who had clinically relevant bleeding. INTERPRETATION: In patients undergoing elective hip-replacement surgery, 2.5 mg fondaparinux once daily was not significantly more effective than 30 mg enoxaparin twice daily in reducing risk of venous thromboembolism. However, the lower risk recorded with fondaparinux than enoxaparin was clinically important, with no increase in clinically relevant bleeding.

Adult↗
PubMed2002

Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison.

BACKGROUND: Despite use of thromboprophylaxis, elective hip-replacement surgery carries a high risk of venous thromboembolic complications. We aimed to assess the ability of the pentasaccharide fondaparinux, the first of a new class of synthetic antithrombotic agents, to further reduce this risk. METHODS: In a double-blind study, we randomly assigned 2309 consecutive patients aged 18 years or older who were undergoing elective hip-replacement surgery to once daily, subcutaneous injections of either 2.5 mg fondaparinux, starting postoperatively, or 40 mg enoxaparin, starting preoperatively. The primary efficacy outcome was venous thromboembolism up to day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The main safety outcomes were bleeding and death. The duration of follow-up was 6 weeks. Analysis was per protocol. FINDINGS: We assessed the primary efficacy outcome in 1827 (79%) of 2309 patients. By day 11, venous thromboembolisms were recorded in 37 (4%) of 908 patients assigned to fondaparinux and in 85 (9%) of 919 assigned to enoxaparin (difference -5.2% [95% CI -8.1 to -2.7], p<0.0001). The relative reduction in risk was 55.9% (95% CI 33.1-72.8). The two groups did not differ in frequency of death or clinically relevant bleeding. INTERPRETATION: Drugs that act through specific inhibition of factor Xa, such as fondaparinux, could be more effective than low molecular weight heparins in prevention of venous thromboembolism in patients undergoing hip-replacement surgery.

Adult↗
PubMed2002

Selective inhibition of coagulation factors: advances in antithrombotic therapy.

Heparin and coumarin derivatives have long been used for the prophylaxis and treatment of venous thromboembolism (VTE). Although they have demonstrated efficacy and safety, they act at multiple targets within the coagulation cascade and their efficacy is influenced by many patient variables. Because of the need to improve the benefit-to-risk ratio of antithrombotic drugs, newer agents that target single coagulation factors have been developed. These include selective factor Xa inhibitors, direct thrombin inhibitors (DTIs), and inhibitors of factor IXa and the factor VII-tissue factor complex. Three DTIs-hirudin, bivalirudin, and argatroban-have been approved for clinical use. Fondaparinux, a novel pentasaccharide and the first selective factor Xa inhibitor to be approved by the U.S. Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products, is indicated for the prevention of VTE after major orthopedic surgery. Fondaparinux has predictable pharmacokinetics, is almost 100% bioavailable, and has a half-life that allows once-daily dosing in all indications. In addition, the routine monitoring of standard indicators of hemostasis is not required. The availability of these agents and the continued development of investigational selective coagulation inhibitors have the potential to improve efficacy and decrease adverse events in patients at risk for VTE.

Anticoagulants↗
PubMed2002

Factor Xa inhibition in the prevention of venous thromboembolism and treatment of patients with venous thromboembolism.

Venous thromboembolism (VTE) is a life-threatening complication following orthopedic surgery. Selective factor Xa inhibition is a new antithrombotic approach designed to avoid difficulties associated with heparins and other current anticoagulants. Several antifactor Xa compounds are in early investigation, but fondaparinux (Arixtra; NV Organon, Oss, The Netherlands; Sanofi-Synthelabo, Paris, France) is the first and most advanced compound in the development of a new class of synthetic antithrombotic agents--the selective factor Xa inhibitors. Fondaparinux has a highly favorable pharmacokinetic profile; four large phase 3 trials comparing subcutaneous fondaparinux 2.5 mg once daily with the low molecular weight heparin (LMWH) enoxaparin in doses approved by regulatory bodies showed that fondaparinux reduced the overall risk of VTE in major orthopedic surgery by > 50% without increasing clinically relevant bleeding. Fondaparinux also appears to be a very promising candidate for the treatment of patients with existing VTE.

Animals↗
PubMed2002

Fondaparinux, a synthetic pentasaccharide: the first in a new class of antithrombotic agents - the selective factor Xa inhibitors.

Despite currently available antithrombotic therapies, venous thromboembolism (VTE) remains a major cause of morbidity and mortality. Fondaparinux sodium (pentasaccharide), the first in a new class of antithrombotic agents developed for the prevention and treatment of VTE, inhibits thrombin generation by selectively inhibiting factor Xa. Fondaparinux exhibits complete bioavailability by the subcutaneous route and is rapidly absorbed, reaching its maximum concentration approximately 2 h post dosing. It has a terminal half-life of 13 to 21 h, permitting once-daily dosing. Fondaparinux's reproducible linear pharmacokinetic profile exhibits minimal intrasubject and intersubject variability, suggesting that individual dose adjustments will not be required for the vast majority of the population and that there will be no need for routine hemostatic monitoring. At therapeutic concentrations (<2 mg/L), fondaparinux exhibits >94% binding to its target protein, antithrombin. Within this same concentration range there is no specific binding by fondaparinux to plasma proteins commonly involved in drug binding, indicating a low potential for drug-drug interactions by protein displacement. Unlike antithrombotic agents prepared from animal extracts (heparins), fondaparinux is chemically synthesized; this leads to batch-to-batch consistency and the absence of potential risk of contamination problems. In recently completed phase III clinical trials in VTE prevention in major orthopedic surgery, fondaparinux showed significant superiority over the low-molecular-weight heparin enoxaparin, providing an overall >50% (P < 0.001) reduction in VTE risk without increasing clinically important bleeding. Additional clinical data support its potential benefits in other venous and arterial thrombotic disorders. In view of these collective findings, fondaparinux is expected to play a major role in the prevention and treatment of venous and arterial thrombotic disease.

Animals↗
PubMed2002

Hypercoagulability: too many tests, too much conflicting data.

It is now possible to identify hereditary and acquired risk factors in a substantial percentage of patients presenting with a venous thrombotic event. The clinician is faced with an ever-growing number of laboratory tests that can be ordered in such patients, and there is considerable uncertainty as to how this information should be utilized in patient management. Some have argued that widespread testing of thrombosis patients for prothrombotic abnormalities such as the factor V Leiden and prothrombin G20210A mutations has been prematurely adopted into clinical practice as there are few data that their identification leads to improved clinical outcomes. Dr. Rosendaal provides an overview of the epidemiology of venous thrombosis with an emphasis on hereditary and acquired risk factors. The presentation will include information obtained from properly designed case-control studies as well as family studies. While some have suggested treatment strategies for managing patients with hereditary thrombophilia with prior thrombotic events or for managing patients undergoing procedures associated with increased thrombotic risk, clinical decision making is complicated by the need to assess the risk of recurrence and the likely benefit of prolonged anticoagulation versus the associated bleeding risk. Drs. Bauer, Heit, and Rosendaal discuss their approaches to patient management. Case presentations are used to illustrate the impact of laboratory test results on decisions.

Anticoagulants↗
PubMed2002

Clinical utility of factor V leiden (R506Q) testing for the diagnosis and management of thromboembolic disorders.

OBJECTIVE: To review the current state of the art regarding the role of the clinical laboratory in diagnostic testing for the factor V Leiden (FVL) thrombophilic mutation (and other protein C resistance disorders), and to generate, through literature reviews and opinions of recognized thought-leaders, expert consensus recommendations on methodology and diagnostic, prognostic, and management issues pertaining to clinical FVL testing. DATA SOURCES, EXTRACTION, AND SYNTHESIS: An initial thorough review of the medical literature and of current best clinical practices by a panel of 4 experts followed by a consensus conference review, editing, and ultimate approval by the majority of a panel of 28 additional coagulation laboratory experts. CONCLUSIONS: Consensus recommendations were generated for topics of direct clinical relevance, including (1) defining those patients (and family members) who should (and should not) be tested for FVL; (2) defining the preferred FVL laboratory testing methods; and (3) defining the therapeutic, prophylactic, and management ramifications of FVL testing in affected individuals and their family members. As FVL is currently the most common recognized familial thrombophilia, it is hoped that these recommendations will assist laboratorians and clinicians caring for patients (and families) with this common mutation.

Abortion, Habitual↗
PubMed2002

Recombinant nematode anticoagulant protein c2, a novel inhibitor of tissue factor-factor VIIa activity, abrogates endotoxin-induced coagulation in chimpanzees.

Systemic activation of coagulation leading to disseminated intra-vascular coagulation (DIC) is an important feature in patients with severe sepsis. Tissue factor has been shown to play a primary role in this pathological response, as revealed by the use of specific inhibitors and antagonists of the tissue factor/factor VIIa pathway. This class of agents has been demonstrated to attenuate the coagulation response in human volunteers with induced low-grade endotoxemia and to reduce mortality in primate models of Gram-negative sepsis. The efficacy of these agents in attenuating the activation of coagulation and formation of microvascular thrombosis in sepsis may depend on the mechanism of inhibition. Here we demonstrate the efficacy of recombinant nematode anticoagulant protein c2 (rNAPc2) that specifically inhibits the tissue factor/factor VIIa complex by a novel mechanism, in a model of endotoxin-induced coagulation activation in chimpanzees. Administration of a low dose of Gram-negative endotoxin induced marked increases of thrombin generation as measured by plasma levels of prothrombin activation fragment F(1+2) and thrombin-antithrombin complexes, which were completely blocked by rNAPc2. In chimpanzees receiving rNAPc2 alone, there was a significant reduction in the activation of factor X but not factor IX, compared to animals receiving placebo. In contrast to the effect of rNAPc2 on thrombin generation, there was no effect of this inhibitor on the well known enhanced systemic fibrinolytic response induced by endotoxin. In conclusion, the recombinant peptide rNAPc2 is an effective inhibitor of tissue factor-driven thrombin generation during low grade endotoxemia. These results suggest that rNAPc2 may be a promising therapeutic option to inhibit coagulation activation in patients with sepsis.

Animals↗
PubMed2002

Two naturally occurring mutations on FVII gene (S363I-W364C) altering intrinsic catalytic activity.

Factor VII (FVII) requires the cleavage of an internal peptide bond and the association with tissue factor (TF) to attain its fully active FVIIa conformation. This event alone leaves FVIIa in a zymogen-like state of relatively low specific activity. The TF-induced allosteric enhancement of FVIIa's activity contributes to the procoagulant activity of the complex. We have characterized two naturally occurring mutations (S363I - W364C) on FVII gene. Both homozygous patients for each mutation have a normal FVII: Ag level associated to an undetectable FVII coagulant activity. The patient carrying the allele 364C had a more severe hemorrhagic diathesis than the S363I mutant. To understand the mechanism of these deficiency, in vitro expression analysis with further biochemical characterization of recombinant proteins of both mutants FVII-363I, FVII-364C and wild type (WTFVII) FVII constructs were done. The results recapitulated the patients' plasma data with normal Ag level and no detectable coagulant activity. The D-F-Pip-R-pNA and CH(3)SO(2)-D-CHA-A-But-R chromogenic substrates were used to evaluate the amidolytic activity of WT and mutant FVII in presence and absence of recombinant tissue factor (rTF). Binding of FVII to rTF by a solid phase binding assay was done using recombinant human rTF. The results of amidolytic assays showed that rTF enhances 28 fold the value of the specificity of constant (kcat/K(m)) in WT but no activity was detectable in either mutant constructs under any condition. The equilibrium dissociation constant of rTF-FVIIa interaction showed Kd equal to 4.4 +/- 0.2nM, 4.9 +/- 0.5nM and 6 +/- 0.9 of WT, 363I and 364C FVII forms, respectively. The K(d) values of the non activated forms were equal to 24.7 +/- 3.3, 24.4 +/- 3.1 and 20.6 +/- 4nM, respectively. These data demonstrate that, compared to the WT form, FVII-363I and FVII-364C have no significant affinity change for TF and that the detrimental effect of these two mutations is attributable to the loss of an efficient catalytic machinery in the FVII molecule causing a severe deficiency of coagulant activities.

Adult↗
PubMed2002

Fondaparinux: basic properties and efficacy and safety in venous thromboembolism prophylaxis.

The synthetic pentasaccharide fondaparinux is the first in a novel class of antithrombotic agents. By selectively inactivating factor Xa in an antithrombin-dependent mechanism of action, fondaparinux exerts its anticoagulant effect through inhibition of thrombin generation, without any direct effect on thrombin activity. Unlike unfractionated heparin and low-molecular-weight heparins, fondaparinux is a single molecular entity produced by total chemical synthesis. Its favorable pharmacokinetic profile and pharmacodynamics allow for safe and effective once-daily dosing in the majority of populations. Initial clinical development of fondaparinux has focused on the prevention of venous thromboembolism following major orthopedic surgery--that is, hip and knee replacement and hip fracture. Results of the largest phase III clinical trial program to date in these major hip and knee surgeries demonstrate comparable safety, in terms of clinically relevant bleeding, and an overall 55% reduction in risk of venous thromboembolism with fondaparinux relative to the low-molecular-weight heparin enoxaparin.

Anticoagulants↗
PubMed2002

A meta-analysis of fondaparinux versus enoxaparin in the prevention of venous thromboembolism after major orthopaedic surgery.

A worldwide phase III program, consisting of four randomized, double-blind trials in patients undergoing surgery for hip fracture, in elective hip replacement surgery patients and in elective major knee surgery patients, was conducted to compare the benefit-to-risk ratio of a subcutaneous 2.5-mg once-daily regimen of fondaparinux, a synthetic selective factor Xa inhibitor, starting postoperatively with enoxaparin in preventing venous thromboembolism. The overall incidence of venous thromboembolism up to day 11 was reduced from 13.7% in the enoxaparin group to 6.8% in the fondaparinux group with a common odds reduction of 55.2% in favor of fondaparinux (95% confidence interval: 45.8-63.1%, p = 10(-17)). This superior efficacy of fondaparinux was also demonstrated for proximal deep vein thrombosis with a reduction of 57.4%. The overall incidence of clinically relevant bleeding was low and did not differ between the two groups. The benefit of fondaparinux was consistent across all types of surgery and all subgroups.

Adolescent↗
PubMed2002

A new antithrombotic strategy, the selective inhibition of coagulation factors, and its importance to the orthopedic specialist.

Traditional anticoagulant drugs including vitamin K antagonists and heparins have several limitations. Despite their use, the burden of venous thromboembolism remains high, particularly in patients undergoing major orthopedic surgery. A new strategy for the design of new antithrombotic drugs is based on selective inhibition of a specific coagulation factor. Fondaparinux is a synthetic selective inhibitor of factor Xa, which is critically positioned at the start of the common pathway of the coagulation system. Its pharmacokinetic profile allows for once-daily administration without the need for laboratory monitoring or dose adjustment. Fondaparinux has demonstrated its efficacy compared to a widely used low-molecular-weight heparin in a number of thromboprophylaxis trials after major orthopedic surgery and is approved for use in this setting.

Anticoagulants↗
PubMedDate not supplied

Fondaparinux.

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Biological Availability↗