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PubMed2002

Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers.

BACKGROUND: The novel anticoagulant fondaparinux proved to be effective and safe in the postoperative prevention of venous thrombosis. Current phase III trials with this synthetic selective factor Xa inhibitor focus on its use in the treatment of patients with venous and arterial thrombosis. As with any anticoagulant therapy, there is a risk of bleeding complications; hence, a strategy to reverse the effects of fondaparinux is desirable. The aim of this study was to investigate whether recombinant factor VIIa (rFVIIa) could neutralize the anticoagulant effects of subcutaneously administered fondaparinux. METHODS AND RESULTS: In a randomized, placebo-controlled design, 16 healthy male subjects received either a single subcutaneous dose of fondaparinux (10 mg) and a single intravenous bolus of rFVIIa (90 microg/kg; n=8), fondaparinux and placebo (n=4), or placebo and rFVIIa (n=4). Fondaparinux (or placebo) was administered 2 hours before rFVIIa (or placebo). Injection of rFVIIa after fondaparinux normalized the prolonged activated partial thromboplastin and prothrombin times and reversed the decrease in prothrombin activation fragments 1+2 (F(1+2)), as observed with fondaparinux alone. Thrombin-generation time and endogenous thrombin potential, which were inhibited by fondaparinux, normalized up to 6 hours after rFVIIa injection. CONCLUSIONS: rFVIIa is capable of normalizing coagulation times and thrombin generation during fondaparinux treatment. The duration of this effect ranged from 2 to 6 hours after rFVIIa injection. These results suggest that rFVIIa may be useful to reverse the anticoagulant effect of fondaparinux in case of serious bleeding complications or need for acute surgery during treatment with fondaparinux.

Adolescent↗
PubMed2002

Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers.

OBJECTIVE: Patients undergoing major orthopaedic surgery who are being treated with fondaparinux sodium for prevention of venous thromboembolism may be receiving treatment for coronary artery disease or chronic inflammatory disease of the joints or arthritis. Two separate studies assessed any possible interaction between fondaparinux sodium at steady state and aspirin (acetylsalicylic acid) or piroxicam in healthy volunteers. DESIGN: In the first study a single dose of aspirin 975mg was assessed initially, followed by single doses of aspirin or placebo on the fourth day of an 8-day regimen of subcutaneous fondaparinux sodium (10mg once daily). The second study was a three-way crossover, double-blind, randomised study which investigated fondaparinux sodium 10mg + placebo, fondaparinux sodium 10mg + piroxicam 20mg, or placebo + piroxicam 20mg. METHODS: Both studies obtained plasma concentration-time profiles of fondaparinux sodium administered alone and with aspirin or piroxicam. Noncompartmental parameters - peak concentration, trough concentration, time to reach peak concentration, and area under the concentration-time curve - were obtained. Both studies measured the pharmacodynamic parameters bleeding time and activated partial thromboplastin time (aPTT). Safety was monitored. RESULTS AND CONCLUSIONS: Neither aspirin nor piroxicam influenced the pharmacokinetics of fondaparinux sodium at steady state. Two hours after administration, prolongation of bleeding time with aspirin alone or with aspirin plus fondaparinux sodium was significantly greater than with fondaparinux sodium alone (p = 0.003 and p = 0.004, respectively). No significant differences were observed between aspirin alone or aspirin + fondaparinux sodium in effect on bleeding time. A small decrease in collagen-induced platelet aggregation was observed after administration of piroxicam alone or piroxicam + fondaparinux sodium. A small effect on aPTT was observed; it was similar for fondaparinux sodium whether administered alone or in combination with either aspirin or piroxicam. No serious adverse events were reported.

Adult↗
PubMed2002

Fondaparinux sodium.

Fondaparinux (Org-31540 / SR-90107A) is a new drug chemically synthesized for treatment and prophylaxis of thromboembolic disease. Fondaparinux is a selective inhibitor of activated factor X. Its structure is the copy of the heparin pentasaccharide sequence, the shortest chain required for antithrombin inhibition of activated factor X without antithrombin action. Fondaparinux has no effect on coagulation tests and does not bind to platelet factor 4 or promote heparin-induced thrombocytopenia. Fondaparinux inhibits thrombin generation and the growth of thrombi in in vitro and in vivo models. Phase I trials have shown a 100% bioavailability after subcutaneous (s.c.) administration, a rapid onset of action and an approximate half-life of 13.5 h. Fondaparinux is cleared as an active substance by the kidneys. In elderly patients, renal clearance is reduced and the half-life is longer. The phase II Pentathlon trial demonstrated significant dose-dependent reductions in the frequency of venous thromboembolism in total hip-replacement patients and the optimal dose was determined to be 2.5 mg s.c./24 h. Four phase III trials have evaluated fondaparinux starting 6 hours after surgery compared with enoxaparin for prevention of venous thromboembolism following orthopedic surgery in 7,344 patients. The risk of thrombosis was reduced by 50% with fondaparinux and no differences were observed in death or severe bleeding. In a phase II trial, similar efficacy and incidence of major bleeding were seen with fondaparinux s.c. compared with dalteparin s.c. in the treatment of deep venous thrombosis. In patients with acute myocardial infarction, the efficacy of fondaparinux during fibrinolytic therapy was assessed in 326 patients who had acute coronary syndromes of less than a 6 hour duration, showing a slight but statistically not significant advantage for fondaparinux over unfractionated heparin in the coronary angiographies. There is currently no antidote for fondaparinux.

Animals↗
PubMed2002

Fondaparinux: a new antithrombotic agent.

BACKGROUND: Venous thrombosis is usually triggered by a low-flow state, as in prolonged periods of bed rest after hip or knee surgery. Antithrombotic agents are the drugs of choice in such circumstances. The new factor Xa inhibitor fondaparinux has been approved by the US Food and Drug Administration for the prevention of venous thromboembolism in patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery. OBJECTIVE: The aim of this article was to review the clinical pharmacology of fondaparinux and summarize the data from available clinical trials of this agent. METHODS: The terms fondaparinux, SR90107A/ORG31540, and factor Xa were used to search MEDLINE and Current Contents/Clinical Medicine for English-language studies in humans published between 1996 and May 2002. Unpublished data were provided by the manufacturer of fondaparinux, and additional information was obtained from abstracts presented at the 2001 congress of the International Society on Thrombosis and Haemostasis in Paris. RESULTS: Fondaparinux is a synthetic pentasaccharide that selectively binds to antithrombin III, inducing a conformational change that increases anti-factor Xa activity. Phase III studies to date have reported that fondaparinux had greater efficacy compared with enoxaparin in terms of prevention of venous thromboembolism after hip or knee replacement surgery. Preliminary studies have suggested that this agent may have efficacy in the treatment of deep vein thrombosis, as well as in the management of acute coronary syndromes. However, 1 study reported a significant increase in the risk of major bleeding with fondaparinux compared with enoxaparin (2.1% vs 0.2%, respectively; P = 0.006), and another reported a significant increase in the risk of minor bleeding (4.1% vs 2.1%; P = 0.02). CONCLUSIONS: Fondaparinux has shown efficacy in the prevention of venous thromboembolism in patients undergoing hip or knee replacement surgery. Large-scale clinical trials of its potential efficacy in deep vein thrombosis and acute coronary syndromes are ongoing. Use of fondaparinux may be associated with an increased bleeding risk, and patients should be assessed individually to ensure that the possible benefits outweigh the risks. Routine use of fondaparinux as a replacement for low-molecular-weight heparin is not recommended at this time.

Arthroplasty, Replacement, Hip↗
PubMed2003

Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux).

Fondaparinux (Arixtra) is the first of a new class of selective indirect antithrombin-dependent factor Xa inhibitors, which inhibits thrombin generation. Fondaparinux is a completely synthetic pentasaccharide. It is a single molecular entity with a well-defined pharmacological target. Fondaparinux has nearly complete bioavailability after subcutaneous injection. The pharmacokinetics of fondaparinux appears predictable and consistent. The peak plasma level is obtained about 2 h after the subcutaneous injection, indicating that a rapid onset of antithrombotic activity is obtained on initiation of treatment. The elimination half-life is about 17 h and it is dose-independent, which allows a convenient once-daily dosing regimen. Fondaparinux is eliminated exclusively by the kidneys. Thus, the estimation of the renal function especially in elderly patients is important for the treatment with fondaparinux, whereas it is contraindicated in patients with severe renal insufficiency. Phase II clinical studies have identified a subcutaneous dose of 2.5 mg once daily for prophylaxis of venous thromboembolism in patients undergoing major orthopaedic surgery. Four phase-III clinical trials using bilateral phlebography for the diagnosis of DVT, demonstrated a combined 50% relative risk reduction of asymptomatic venous thromboembolic events in orthopaedic surgery patients in comparison to the low-molecular-weight heparin (LMWH) enoxaparin. Hemorrhagic complications for fondaparinux were either comparable or higher than those for LMWH but the authors did not judge that the increased bleeding was clinically relevant. A dose ranging study led to the selection of the dose of 7.5 mg at a single daily subcutaneous injection as optimal for the treatment of VTE. In two phase III clinical trials, the dose of 7.5 mg/day is expected to be as efficacious and safe as heparin for the treatment of DVT or PE, respectively. Phase II studies show that the efficacy-to-safety ratio of fondaparinux in the treatment of unstable angina or as an adjunct to thrombolysis in acute myocardial infarction is promising. These results demonstrated that a single anti-Xa agent devoid of antithrombin activity is a potent antithrombotic drug. Fondaparinux has obtained FDA and European health authorities approval. Its use on a large scale will allow the evaluation of its efficacy and tolerance in the daily clinical practice. Chemical modifications of the original synthetic pentasaccharide increase the affinity to AT resulting in a more potent inhibition of FXa and longer half-life. Idraparinux is the first of these new oligosaccharides that we named "meta-pentasaccharides." After subcutaneous injection the half-life of idraparinux is about 80 h allowing a single injection per week. A dose-finding study has established the optimal dose given once a week to be compared with warfarin for the treatment of DVT.

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

Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins.

BACKGROUND: Fondaparinux sodium is a novel antithrombotic agent, the first of a new class of selective factor Xa inhibitors. It has favourable pharmacokinetics including 100% bioavailability, low variability and a mean terminal half-life of 17 hours for young and 21 hours for elderly healthy volunteers, enabling once-daily administration. Studies on the prevention of venous thromboembolism (VTE) after orthopaedic surgery demonstrated significantly improved efficacy over the low-molecular-weight heparin enoxaparin, with a >50% reduced risk of VTE and a similar safety profile. OBJECTIVE: To investigate the in vitro binding of fondaparinux sodium to purified antithrombin III (ATIII) and other plasma proteins. METHODS: Fondaparinux sodium was incubated with human plasma, antithrombin-depleted plasma or purified human plasma proteins, including antithrombin, alpha1-acid glycoprotein, serum albumin and immunoglobulin. Non-protein-bound fondaparinux sodium was determined using a validated chromogenic assay method, enabling the calculation of the free fraction of fondaparinux sodium and its binding parameters. RESULTS: At steady state, fondaparinux sodium at therapeutic concentrations [i.e. those attainable in the prevention (0.14 to 0.50 mg/L) and treatment (up to approximately 2 mg/L) of VTE] was extensively bound (>97%) to plasma proteins and specifically bound (>94%) to purified ATIII. The specific binding parameters B(max) (binding capacity) and K(D )(dissociation constant) were similar for human plasma (B(max) = 2072 nmol/L, K(D) = 28 nmol/L) and purified ATIII (B(max) = 1627 nmol/L and K(D) = 32 nmol/L). There was no specific binding of fondaparinux sodium to other purified plasma proteins. CONCLUSION: At clinically relevant concentrations, fondaparinux sodium is highly and specifically bound to ATIII in human plasma, suggesting that potential interaction with drugs via albumin or alpha1-acid glycoprotein displacement is unlikely.

Antithrombin III↗
PubMed2002

Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs.

OBJECTIVE: To investigate the in vitro metabolism of the antithrombotic agent fondaparinux sodium in mammalian liver fractions and to evaluate its potential inhibitory effect on human cytochrome P450 (CYP)-mediated metabolism of other drugs. METHODS: Metabolism was evaluated by incubating radioisotope-labelled fondaparinux sodium with postmitochondrial liver fractions of rat, rabbit, monkey or human origin (three subjects). Human liver microsomal preparations and an NADPH-generating system were incubated with phenacetin, coumarin, tolbutamide, S-mephenytoin, bufuralol, chlorzoxazone or nifedipine. These are selectively metabolised by CYP isoforms: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4, respectively. Experiments were designed to determine apparent K(i) (inhibitory constant) values for fondaparinux sodium against each CYP isoform, by varying concentrations of fondaparinux sodium and the selective substrate. Each experiment included control reaction mixtures containing an isoform-selective inhibitor. After incubation, the mixtures were analysed by LC-MS/MS or with fluorometric detection. RESULTS: All liver fractions were enzymatically active, as demonstrated by degradation of [(14)C]testosterone. No metabolism of fondaparinux sodium was detectable in postmitochondrial liver fractions. Apparent K(i) values for fondaparinux sodium against the CYP isoforms could not be determined because the oxidative metabolism of the isoform-selective CYP substrates was not significantly inhibited in pooled microsomal reaction mixtures. In the presence of selective CYP inhibitors, metabolism of each substrate was significantly reduced, confirming that inhibition could be observed in these assays. CONCLUSION: The demonstrated lack of mammalian hepatic metabolism of fondaparinux sodium is consistent with animal and human studies. The absence of inhibition of the human CYP isoforms commonly involved in the metabolism of drugs suggests that clinical treatment with fondaparinux sodium is unlikely to interfere with the pharmacokinetics and metabolism of a wide range of other drugs which are associated with CYP inhibition.

Adult↗
PubMed2002

Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers.

OBJECTIVE: Fondaparinux sodium is the first of a new class of antithrombotic agents: the selective factor Xa inhibitors. Coadministration with digoxin may occur in clinical practice and both drugs are excreted almost completely by the renal route. In this study we assessed the possible pharmacokinetic and pharmacodynamic interaction of fondaparinux sodium with digoxin at steady state in healthy male volunteers. DESIGN: In a phase I randomised, crossover study, volunteers (n = 24) were treated in two periods. The first period was once-daily administration of fondaparinux sodium 10mg subcutaneously alone for 7 days; the second period was 7 days of digoxin 0.25mg orally alone followed by 7 days of coadministration with fondaparinux sodium 10mg. Each period was separated by a washout of 12 days. METHODS: Urinary volumes, plasma concentration-time profiles and noncompartmental pharmacokinetic parameters of fondaparinux sodium and digoxin were obtained at steady state, following administration alone or together for each period. A bioequivalence approach was taken to assess interaction. Pharmacodynamic parameters were supine blood pressure and heart rate and the ECG parameters PR interval, QRS interval, QT interval and QT(c). The safety of the treatments was monitored. RESULTS AND CONCLUSIONS: The pharmacokinetic profiles of both digoxin and fondaparinux sodium were unaffected by coadministration. Bioequivalence was concluded, based on the 90% confidence intervals of the ratio of adjusted geometric means calculated for the 2-by-2 comparison of peak concentration, area under the concentration-time curve and cumulative urinary excretion, which lay within the 0.80 to 1.25 reference interval. There were no clinically significant fluctuations in vital signs and ECG parameters. The coadministration of digoxin with fondaparinux sodium was well tolerated and no significant changes were observed in vital signs.

Adolescent↗
PubMed2003

Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study.

BACKGROUND: The benefit of thromboprophylaxis for 1 month has never been evaluated in patients undergoing hip fracture surgery, a setting in the highest risk category for postoperative venous thromboembolism (VTE). METHODS: In a double-blind multicenter trial, 656 patients undergoing hip fracture surgery were randomly assigned to receive prophylaxis with a once-daily subcutaneous injection of either 2.5 mg of fondaparinux sodium or placebo for 19 to 23 days. Before randomization, all patients had received fondaparinux for 6 to 8 days. The primary efficacy outcome was VTE occurring during the double-blind period (deep vein thrombosis detected by mandatory bilateral venography or documented symptomatic deep vein thrombosis or pulmonary embolism). The main safety outcome was major bleeding. RESULTS: The primary efficacy outcome was assessed in 428 patients. Fondaparinux reduced the incidence of VTE compared with placebo from 35.0% (77/220) to 1.4% (3/208), with a relative reduction in risk of 95.9% (95% confidence interval, 87.2%-99.7%; P<.001). Similarly, the incidence of symptomatic VTE was significantly lower with fondaparinux (1/326; 0.3%) than with placebo (9/330; 2.7%). The relative reduction in risk was 88.8% (P =.02). Although there was a trend toward more major bleeding in the fondaparinux group than in the placebo group (P =.06), there were no differences between the 2 groups in the incidence of clinically relevant bleeding (leading to death, reoperation, or critical organ bleeding). CONCLUSIONS: Extended prophylaxis with fondaparinux for 3 weeks after hip fracture surgery reduced the risk of VTE by 96% and was well tolerated.

Adult↗
PubMed2002

Fondaparinux sodium.

black triangle Fondaparinux sodium, a selective factor Xa inhibitor, is the first in a new class of antithrombotics. It binds selectively with high affinity to antithrombin III and specifically catalyses the inactivation of factor Xa. The elimination half-life of fondaparinux sodium permits once daily treatment. black triangle A randomised, double-blind, parallel-group, dose-ranging, multicentre phase IIb study in 933 eligible patients established that a subcutaneous dose of between 1.5 and 3mg of fondaparinux sodium has the optimum efficacy and safety profile for prophylaxis of venous thromboembolism in patients undergoing major orthopaedic surgery. black triangle Fondaparinux sodium, given to more than 3600 patients undergoing major orthopaedic surgery who participated in prospective, randomised, double-blind, multicentre phase III clinical trials, significantly reduced the incidence of venous thromboembolism, with an overall risk reduction of 55.2% compared with enoxaparin. black triangle Fondaparinux sodium was well tolerated by patients undergoing major orthopaedic surgery, and at the recommended clinical dose of 2.5mg has a similar tolerability profile, including bleeding events, to standard enoxaparin regimens. Fondaparinux sodium has not been reported to cause antibody-induced thrombocytopenia.

Animals↗
PubMed2002

Absence of placental transfer of pentasaccharide (Fondaparinux, Arixtra) in the dually perfused human cotyledon in vitro.

The synthetic pentasaccharide, fondaparinux, is the first of a new antithrombotic class: selective factor Xa inhibitors. Comparative clinical trials of fondaparinux versus heparins in prevention and treatment of venous thromboembolism are ongoing. Little is known about fondaparinux during pregnancy, as women of child-bearing potential were excluded from clinical trials. No particular safety issue, for either mother or fetus, has been reported for heparins. The objective of this study was to compare in vitro the steady state placental transfer of fondaparinux and enoxaparin at the plasma concentrations reached during acute treatment of venous thromboembolism (1.75 microg/mL and 1 anti-Xa IU/mL respectively), using antipyrine (20 mg/L) as reference. No biological activity was detectable in the fetal venous effluent during perfusion of enoxaparin-antipyrine, fondaparinux-antipyrine or control media. Furthermore, fetal venous samples did not differ significantly from fetal arterial samples. This apparent absence of placental transfer supports further evaluation of fondaparinux in pregnant women.

Adult↗
PubMed2002

Fondaparinux (Arixtra): a new anticoagulant.

Fondaparinux is a promising new antithrombotic agent. This pentasaccharide selectively and specifically inhibits coagulation factor Xa, and requires antithrombin as co-factor It is entirely synthetic, in contrast to conventional heparin and low molecular heparins which are derived from animal tissues. Fondaparinux exhibits a high bioavailability and is convenient to use as it only needs to be given once daily by subcutaneous injection. Peak plasma levels are achieved within two hours of dosing and the plasma half-life of fondaparinux is approximately 17 hours. There is no specific antidote for fondaparinux: it is not neutralised by protamine sulphate. Fondaparinux shows no cross-reactivity with antibodies associated with heparin-induced thrombocytopenia. Several randomised, double-blind studies have demonstrated superiority with respect to a low molecular weight heparin (enoxaparin) in preventing venous thromboembolism in the setting of orthopaedic surgery. The results of clinical trials of fondaparinux in the treatment of deep vein thrombosis and acute coronary syndrome are also presented.

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↗
PubMed2003

Effects of fondaparinux compared with dalteparin, enoxaparin and unfractionated heparin on human osteoblasts.

The objective of the this study was to examine the effects of fondaparinux, a synthetic anticoagulant substance similar to heparin, on osteoblasts compared with previously used heparins. Its effects have been shown in clinical trials to be highly effective in thromboembolism prophylaxis. Unfractionated heparin (UFH), dalteparin, enoxaparin and fondaparinux were added to osteoblast cultures in the therapeutic range and two decimal powers above and below it in each case. The results showed that the mitochondrial activity and protein synthesis of osteoblasts treated with fondaparinux were significantly higher than in the other groups. Similar effects could be demonstrated for the matrix collagen type II content and calcification. In contrast enoxaparin, dalteparin and UFH lead to a significant decrease of matrix collagen type II content and calcification in concentrations equal or higher than the therapeutic one. No inhibitory in-vitro effects of fondaparinux on human osteoblasts could be demonstrated within the concentration range investigated (0.01-100 microg/ml). We conclude that fondaparinux can be used to avoid the heparin-related negative influence on osteoblast-dependent fracture healing and endoprosthetic implant integration.

Aged↗
PubMed2002

In vitro comparison of the effect of heparin, enoxaparin and fondaparinux on tests of coagulation.

Low-molecular weight heparin (LMWH) is increasingly used in place of unfractionated heparin (UFH) in patients with unstable angina, and phase II clinical trials using fondaparinux for this indication are underway. Because unstable angina patients often require urgent percutaneous coronary interventions (PCI) or aortocoronary bypass surgery, a point-of-care test is needed to monitor the anticoagulant effect of these agents. The activated clotting time (ACT) and activated partial thromboplastin time (aPTT) are the tests most often used to monitor heparin. The purpose of this in vitro study was to determine whether the ACT or the aPTT can be used to monitor the anticoagulant effect of low-molecular weight heparin and fondaparinux. The ACT and aPTT were measured after heparin, enoxaparin or fondaparinux was added to the blood of healthy volunteers, in doses with equivalent inhibitory activity against activated factor X (factor Xa). To mimic the clinical scenario where an unstable angina patient, who has already received enoxaparin, is urgently taken for PCI or bypass surgery, the ACT was determined after heparin was added to blood containing clinically relevant doses of enoxaparin. We determined that enoxaparin produced significantly less prolongation of both the ACT and the aPTT than heparin, whereas fondaparinux had no effect on either of these tests. Addition of enoxaparin to heparin-containing plasma did not prolong the ACT beyond that produced by heparin alone. The ACT and aPTT therefore cannot be used to monitor low-molecular weight heparin or fondaparinux, highlighting the need for a point-of-care anti-factor Xa assay.

Anticoagulants↗
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

Absence of an interaction between the synthetic pentasaccharide fondaparinux and oral warfarin.

AIMS: To investigate the pharmacokinetic and pharmacodynamic interaction of the antithrombotic pentasaccharide fondaparinux (Org31540/SR90107A), given subcutaneously, and oral warfarin in healthy subjects. METHODS: This study was performed according to a randomised, three-way cross-over, placebo-controlled, double-blind design in 12 healthy male subjects. The treatment consisted of five subcutaneous (s.c.) injections of fondaparinux (4 mg) or placebo at 24 h intervals. Oral dosing of warfarin or placebo was added to the fourth (15 mg) and fifth (10 mg) s.c. injection. Blood samples for pentasaccharide assay, PT and APTT were drawn before the first s.c. dose of the pentasaccharide and over a 6 day period thereafter. RESULTS: Fondaparinux administered to healthy male volunteers alone or in combination with oral warfarin was well tolerated and no serious adverse events were observed. No differences were found in the AUC (43 vs 44 mg l(-1) h), Cmax (645 vs 678 ng ml(-1)) or elimination half-life (13.8 vs 14.1 h) of fondaparinux between the pentasaccharide-only and the combination treatment. The effect of warfarin on PT (mean maximal increase: 8.2 s.) was not influenced by the presence of the pentasaccharide (mean maximal increase in PT: 9.1 s.). After all treatments a small rise in APTT was seen. No further differences could be detected in the pharmacodynamic parameters following the three treatments. CONCLUSIONS: The coadministration of warfarin did not influence the pharmacokinetics of fondaparinux in healthy subjects. PT can still be used to monitor the effect of oral anticoagulants during the switch from antithrombotic treatment with pentasaccharide to full oral anticoagulant therapy.

Administration, Oral↗