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Abstract
Fondaparinux sodium is the first in a new class of antithrombotic medications called pentasaccharides. As a highly selective inhibitor of factor Xa, it leads to the inhibition of thrombin generation without a direct effect on thrombin itself. Fondaparinux was designated approvable by the FDA in August for the prevention of venous thromboembolic events following orthopedic surgery. Recently published results from two large phase III trials and preliminary data from two more phase III studies have indicated that fondaparinux is more effective than enoxaparin for prevention of venous thromboembolism in patients undergoing orthopedic surgery. A small trial has also shown that it may have a role as an adjunct to thrombolytics in patients with acute myocardial infarction. Fondaparinux offers once-daily subcutaneous dosing and has demonstrated a favorable safety profile in studies to date, including no cases of thrombocytopenia. If approved by the FDA, fondaparinux will provide another safe and effective option for the prevention of thromboembolic disorders. If its superiority over enoxaparin is maintained in the final results from all phase III trials in orthopedic surgery patients, it may become the preferred therapy in this setting.
This article discusses a new agent to treat deep vein thrombosis and pulmonary embolism.
A review with 93 references. Heparins are high molecular weight, hydrophilic polyanions, which are unstable under acidic conditions; and therefore they exhibit poor oral bioavailability. Consequently they must be administered via the parenteral route which is expensive, inconvenient, and limits use by outpatients. The development of an oral form of heparin is warranted. This review examined the literature, mostly published between January 2000 and January 2005, pertaining to the gastrointestinal absorption of heparin by lipidization or coadministration with penetration enhancers. A lipidization strategy that was examined involved conjugation of low molecular weight heparin with deoxycholic acid. The majority of studies examined the ability of different formulations, typically utilizing penetration enhancers, to improve heparin bioavailability. The penetration enhancers used included fatty acids, Labrasol, Gelucire 44/14, polycationic lipophilic-core dendrons, saponins, mono-N-carboxymethyl chitosan, Carbopol 934P, a combination of thiolated polycarbophil and glutathione, polymeric nanoparticles, polymeric microparticles, sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC), and sodium N-[10-(2-hydroxybenzoyl)amino]decanoate (SNAD). The variety of models used and doses of heparin/penetration enhancers applied, however, made it difficult to compare the results between studies. Nevertheless, all of the reviewed drug delivery systems showed therapeutic value and confirmation of the promising results obtained from animal studies, by progression to clinical trials, is necessary. Overall, progress has been made in the quest for an oral heparin formulation.
Despite thromboprophylaxis, major knee surgery carries a high risk of venous thromboembolism. Fondaparinux, the first of a new class of synthetic antithrombotic agents, may reduce this risk.
In a double-blind study, we randomly assigned 1049 consecutive patients undergoing elective major knee surgery to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily or 30 mg of enoxaparin twice daily, with both treatments initiated postoperatively. The primary efficacy outcome was venous thromboembolism up to postoperative day 11, defined as deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or documented symptomatic pulmonary embolism. The primary safety outcome was major bleeding.
The primary efficacy outcome was assessed in 724 patients. The fondaparinux group had a significantly lower incidence of venous thromboembolism by day 11 (12.5 percent [45 of 361 patients]) than the enoxaparin group (27.8 percent [101 of 363 patients]; reduction in risk, 55.2 percent; 95 percent confidence interval, 36.2 to 70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the fondaparinux group (P=0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ.
In patients undergoing elective major knee surgery, postoperative treatment with 2.5 mg of fondaparinux once daily was significantly more effective in preventing deep-vein thrombosis than 30 mg of enoxaparin twice daily.
Surgery for hip fracture carries a high risk of venous thromboembolism, despite the use of current thromboprophylactic treatments. Fondaparinux, a synthetic pentasaccharide, is a new antithrombotic agent that may reduce this risk.
In a double-blind study, were randomly assigned 1711 consecutive patients undergoing surgery for fracture of the upper third of the femur to receive subcutaneous doses of either 2.5 mg of fondaparinux once daily, initiated postoperatively, or 40 mg of enoxaparin once daily, initiated preoperatively, for at least five days. The primary efficacy outcome was venous thromboembolism up to postoperative day 11. Venous thromboembolism was 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 major bleeding and mortality from all causes. The duration of follow-up was six weeks.
The incidence of venous thromboembolism by day 11 was 8.3 percent (52 of 626 patients) in the fondaparinux group and 19.1 percent (119 of 624 patients) in the enoxaparin group (P<0.001). The reduction in risk with fondaparinux was 56.4 percent (95 percent confidence interval, 39.0 to 70.3 percent). There were no significant differences between the two groups in the incidence of death or clinically relevant bleeding.
In patients undergoing surgery for hip fracture, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism and equally safe.
Introduction Pentasaccharide Org31540/SR90107A (P) is the first of a new class of synthetic and highly selective factor Xa inhibitors. Its PK profile is highly favorable in man: complete unavailability by s.c. route, a rapid onset of action and no evidence of metabolism. The terminal half-life of 15h-20h and the linear PK profile allow once dai y dosing and no monitoring. To study the tolerability of co-administration of P and aspiiin (ASA) at steady state, PK and PD interactions between P and ASA were investigated in healthy volunteers. Methods In this double-blind, cross-over randomised placebo controlled study, 6 healthy male volunteers received 10 mg s.c. P on a daily basis for 8 days with a single do (e placebo or 975 mg oral ASA on day 4. The effects of ASA on PK parameters of P, bleedii ig time and activated partial thromboplastin time (APTT) were measured at day 4. Results Steady state (day 4) PK parameters of P were not altered by the c 5administration of ASA (see table). P+placebo P+aspirin C (mg/1) 1.47(0.13) 1.46(0.10) l.J"(h) 2.14(0.50) 1.95(0.44) AUC 0-24h (mg.h/1) 19.60(1.41) 19.82(1.49) <:_ (mg/l) 0.39 (0.06) 0.39 (0.06) ASA caused bleeding time to increase, but no further increase was seen when c administered with P. A small increase in APTT was induced by P alone, and no further ri ie was seen with ASA. Co-administration of ASA and P did not lead to significant AE. Conclusion The PK profile of P was not modified by oral ASA. Furthermore, the 1 e were no additional effects between ASA and P in terms of bleeding parameters. The: e results indicate that P could be concomitantly administered with aspirin without a change in dosing or the need for monitoring P. In arterial thrombotic disease, co-therapy with P and ASA could offer enhanced antithrombotic protection by blocking two key mechanisn is -thrombin generation and platelet activation.
This article discusses the prevention of venous thromboembolism (VTE) and is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggestions imply that individual patient values may lead to different choices (for a full discussion of the grading, see the “Grades of Recommendation” chapter by Guyatt et al). Among the key recommendations in this chapter are the following: we recommend that every hospital develop a formal strategy that addresses the prevention of VTE (Grade 1A). We recommend against the use of aspirin alone as thromboprophylaxis for any patient group (Grade 1A), and we recommend that mechanical methods of thromboprophylaxis be used primarily for patients at high bleeding risk (Grade 1A) or possibly as an adjunct to anticoagulant thromboprophylaxis (Grade 2A).
For patients undergoing major general surgery, we recommend thromboprophylaxis with a low-molecular-weight heparin (LMWH), low-dose unfractionated heparin (LDUH), or fondaparinux (each Grade 1A). We recommend routine thromboprophylaxis for all patients undergoing major gynecologic surgery or major, open urologic procedures (Grade 1A for both groups), with LMWH, LDUH, fondaparinux, or intermittent pneumatic compression (IPC).
For patients undergoing elective hip or knee arthroplasty, we recommend one of the following three anticoagulant agents: LMWH, fondaparinux, or a vitamin K antagonist (VKA); international normalized ratio (INR) target, 2.5; range, 2.0 to 3.0 (each Grade 1A). For patients undergoing hip fracture surgery (HFS), we recommend the routine use of fondaparinux (Grade 1A), LMWH (Grade 1B), a VKA (target INR, 2.5; range, 2.0 to 3.0) [Grade 1B], or LDUH (Grade 1B). We recommend that patients undergoing hip or knee arthroplasty or HFS receive thromboprophylaxis for a minimum of 10 days (Grade 1A); for hip arthroplasty and HFS, we recommend continuing thromboprophylaxis > 10 days and up to 35 days (Grade 1A). We recommend that all major trauma and all spinal cord injury (SCI) patients receive thromboprophylaxis (Grade 1A). In patients admitted to hospital with an acute medical illness, we recommend thromboprophylaxis with LMWH, LDUH, or fondaparinux (each Grade 1A). We recommend that, on admission to the ICU, all patients be assessed for their risk of VTE, and that most receive thromboprophylaxis (Grade 1A).
This study compares the pharmacokinetic and the antithrombotic properties of two pentasaccharides with high affinity to antithrombin III with those of a conventional low molecular weight heparin, CY216, in the rabbit. On a weight basis, SR 90107A/ORG 31540 (natural pentasaccharide [NPS]) and SR 80027A/ORG 31550 (sulfated pentasaccharide [SPS]) were, respectively, 4.7 and 26 times more potent antifactor Xa inhibitory agents than CY216. They were devoid of antithrombin activity, whereas the antifactor Xa/antithrombin ratio of CY216 was 3.8. After bolus intravenous administration, the clearance (mL/kg/h) of CY216 decreased from 91 +/- 27 for the dose of 12.5 U/kg to 49 +/- 14 for the dose of 50 U/kg and then remained constant up to the highest dose tested (500 U/kg). The clearance of NPS was unrelated to the dose and comparable to that of CY216 over 50 U/kg, whereas that of SPS was 10 times lower. Consistent results were observed after continuous intravenous infusions for 9 hours and subcutaneous administration. The duration of the antithrombotic effect was compared after a single subcutaneous injection of 250 U/kg of either compound in the stasis-Wessler model using human serum as thrombogenic stimulus. Two hours after the injection, the three compounds provided a thrombus prevention of greater than 95% and mean plasma activities of 0.8, 0.9, and 1.9 U/mL for CY216, NPS, and SPS, respectively. Twelve hours after injection, the antithrombotic effects of CY216 and NPS had totally vanished, whereas that of SPS was 68%. At that time, the plasma anti-Xa activities were less than 0.06 U/mL for CY216 and NPS, but 1.1 U/mL for SPS. For the latter compound, significant antithrombotic effects and detectable anti-Xa activities were still recorded 48 hours after the injection. The antithrombotic potency of the three compounds was also compared as their ability to inhibit the growth of a standardized venous thrombosis during 4 hours. The lowest total doses providing the maximum inhibitory effect were 3,125, 1,428, and 62 micrograms/kg for CY216, NPS, and SPS, respectively. These doses generated mean steady state antifactor Xa activities of 1.06, 1.5, and 1.2 anti-Xa U/mL, respectively. These observations indicate that the amplification mechanisms triggered by thrombin bound to fibrin and leading to the generation of new thrombin are essential to ensure venous thrombosis growth and that these mechanisms may be efficiently inhibited by pure antifactor Xa targeting agents.
Venous thromboembolism is a frequent complication of total hip replacement. The pentasaccharide Org31540/SR90107A, a highly selective, indirect inhibitor of activated factor X, is the first of a new class of synthetic antithrombotic agents. To determine the optimal dose for phase 3 studies, we conducted a dose-ranging study in which Org31540/SR90107A was compared with a low-molecular-weight heparin, enoxaparin, in patients undergoing total hip replacement.
In a double-blind study, patients were randomly assigned to postoperative administration of one of five daily doses of Org31540/SR90107A, given once daily, or to 30 mg of enoxaparin, given every 12 hours. Treatment was continued for 10 days or until bilateral venography was performed after a minimum of 5 days.
Of 933 patients treated, 593 were eligible for the efficacy analysis. With Org31540/SR90107A a dose effect was observed (P=0.002), with rates of venous thromboembolism of 11.8 percent, 6.7 percent, 1.7 percent, 4.4 percent, and 0 percent for the groups assigned to 0.75 mg, 1.5 mg, 3.0 mg, 6.0 mg, and 8.0 mg of the drug, respectively, as compared with a rate of 9.4 percent in the enoxaparin group. The reduction in the risk of venous thromboembolism was 82 percent for the 3.0-mg Org31540/SR90107A group (P=0.01) and 29 percent for the 1.5-mg group (P=0.51). Enrollment in the 6.0-mg and 8.0-mg Org31540/SR90107A groups was discontinued because of bleeding complications. Major bleeding occurred 3.5 percent less frequently in the 0.75-mg group (P=0.01) and 3.0 percent less frequently in the 1.5-mg group (P=0.05) than in the enoxaparin group (in which the rate was similar to that in the 3.0-mg group).
A synthetic pentasaccharide, Org31540/SR90107A, has the potential to improve significantly the risk-benefit ratio for the prevention of venous thromboembolism, as compared with low-molecular-weight heparin.
The three low-molecular-weight heparins (LMWHs) available in the United States have been extensively evaluated for a wide array of indications. Properties associated with one LMWH cannot be assumed to be the same as those associated with another LMWH, as they are different pharmacologic entities. Therefore, therapeutic interchange of these agents is inappropriate. The pharmacokinetic and pharmacodynamic differences among LMWHs can be explained by comparing methods of preparation, molecular structures, half-lives, antithrombin- and non-antithrombin-mediated actions, effect on thrombus, and dosing interval. The Food and Drug Administration-approved indications and their respective levels of clinical evidence further differentiate these agents. A dichotomy in the results of clinical trials has been observed with the LMWHs. As the LMWHs are distinct compounds that each possess unique pharmacokinetic and pharmacodynamic profiles, treatment decisions should be based on the available safety and efficacy data for each LMWH. Agents should be prescribed only for those indications for which they have been shown to be effective and only at dosages that have been studied.
Although unfractionated heparin has been widely used for preventing and treating venous thromboembolism, low-molecular-weight heparins (LMWHs) have been extensively studied. In particular, LMWHs have been valuable in the prevention of venous thromboembolism in high-risk surgical patients, such as those undergoing total joint replacement, and in high-risk medical patients. Recent studies indicated that the extended use of LMWHs after discharge in patients undergoing total hip replacement significantly decreases the frequency of venous thrombosis compared with placebo. Furthermore, LMWHs have been shown to be as effective and safe as unfractionated heparin for the initial treatment of both deep vein thrombosis and pulmonary embolism and have extended the treatment of these conditions into the outpatient setting. New recommendations from the sixth American College of Chest Physicians Consensus Conference on Antithrombotic Therapy and the rationale for change are discussed.
Patients undergoing orthopedic surgery are at particularly high risk for venous thromboembolism (VTE) and as such often receive prophylactic low-molecular-weight heparin (LMWH) or warfarin. However, efficacy and safety limitations of these agents have prompted a search for alternative antithrombotic drugs.
A new pentasaccharide, Org31540/SR90107A, the first of a class of synthetic and highly selective Factor Xa inhibitors, was investigated in a phase II double-blind, dose-ranging study for the prevention of deep vein thrombosis in 933 patients undergoing elective total hip replacement. The assessor-blind, comparative control was the LMWH enoxaparin. Patients were randomly assigned to 1 of 5 Org31540/SR90107A treatment groups (0.75, 1.5, 3, 6, or 8 mg/d subcutaneously) or to 30 mg enoxaparin subcutaneously every 12 hours. Treatment was started after surgery and continued for 5 to 10 days. Principal outcomes, determined on the basis of standard criteria, included venographically detected deep vein thrombosis and major bleeding. The 6.0- and 8.0-mg groups were discontinued early, in accordance with a protocol-defined safety rule.
This phase II study showed improved dose-related efficacy and safety for Org31540/SR90107A versus enoxaparin and led to selection of 2.5 mg once daily as the optimal Org31540/SR90107A dose for large phase III trials in the prevention of VTE after total hip replacement, total knee replacement, and surgery for fractured hip. These studies have now been completed.
Org31540/SR90107A is a new synthetic antithrombotic agent that has demonstrated a significant efficacy and safety dose effect in VTE prophylaxis after orthopedic surgery.
ORG31540/SR90107A, a synthetic pentasaccharide, is a selective inhibitor of factor-Xa. It was hypothesized that prolonged factor-Xa inhibition with pentasaccharide may be an effective and safe antithrombotic co-therapy in acute myocardial infarction.
Patients (n=333) with evolving ST-segment elevation acute myocardial infarction were treated with aspirin and alteplase and randomized to unfractionated heparin, given intravenously during 48 to 72 h, or to a low, medium or high dose of pentasaccharide, administered daily for 5 to 7 days, intravenously on the first day, then subcutaneously. Coronary angiography was performed at 90 min and on days 5 to 7. Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 rates at 90 min were similar in the four treatment groups. Among patients with TIMI 3 flow at 90 min and who did not undergo a coronary intervention (n=155), a trend towards less reocclusion of the infarct-related vessel on days 5 to 7 was observed with pentasaccharide: 0.9% vs 7.0% with unfractionated heparin (P=0.065). Also, fewer revascularizations during the 30-day follow-up period were performed in patients given pentasaccharide (39% vs 51% for unfractionated heparin;P=0.054). The primary safety end-point, the combined incidence of intracranial haemorrhage and need for blood transfusion, was identical with pentasaccharide and unfractionated heparin (7.1%). One non-fatal intracranial haemorrhage occurred in the 241 patients given pentasaccharide (0.4%).
In this study, pentasaccharide given together with alteplase was safe and as effective as unfractionated heparin in restoring coronary artery patency. Prolonged administration of pentasaccharide was associated with a trend towards less reocclusion and fewer revascularizations. Selective factor-Xa-inhibition seems to be an attractive therapeutic concept in patients presenting with ST-segment elevation acute myocardial infarction.