- Email: [email protected]
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa
Best Practice & Research Clinical Haematology Vol. 17, No. 1, pp. 89–104, 2004 doi:10.1016/j.beha.2004.03.004 available online at http://www.sciencedirect.com
6 Fondaparinux: a new synthetic and selective inhibitor of Factor Xa Kenneth A. Bauer*,1MD Associate Professor of Medicine, Harvard Medical School; Chief, Hematology Section VA Boston Healthcare System Director, Thrombosis Clinical Research, Beth, Israel, Deaconess Medical Center Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA
Fondaparinux (Arixtraw) is the first synthetic selective Factor Xa inhibitor. Its efficacy and safety in the prevention of venous thromboembolism (VTE) was first studied in patients undergoing major orthopedic surgery, a setting in the highest risk category for postoperative thrombotic complications. Low-molecular-weight heparins are frequently used in this setting, but the rates of VTE still range between 15% and 33%. In large clinical trials, fondaparinux started 6 hours postoperatively was significantly more effective than enoxaparin in preventing VTE in patients undergoing total hip replacement, total knee replacement or hip fracture surgery. The benefit of extended fondaparinux prophylaxis after hip fracture surgery was also investigated. Other trials have demonstrated that fondaparinux is efficacious in the prevention of VTE in other patient populations at risk of thrombosis and in the treatment of symptomatic VTE. Key words: fondaparinux; heparin; pentasaccharide; pharmacokinetics; thromboprophylaxis; venous thromboembolism; surgery; acute coronary syndromes.
Until very recently, pharmacological prophylaxis of thrombosis employed anticoagulants including vitamin K antagonists, unfractionated heparin (UFH) and lowmolecular-weight heparins (LMWHs) that act on a number of coagulation factors. Fondaparinux (Arixtraw) is the first of a new class of anticoagulants that inhibit Factor Xa selectively.1 – 4 Following a large clinical trials program involving more than 8000 patients, fondaparinux has been approved for use in thromboprophylaxis after major orthopedic surgery.5 – 11 Its efficacy for the prevention of venous thromboembolism (VTE) was subsequently confirmed in other surgical12 and medical13 settings. Moreover, its efficacy and safety were shown in the treatment of VTE14 – 16 and it also appears promising in patients with acute coronary syndromes.17 – 19 This chapter reviews * Tel.: þ 1-617-667-2174; Fax: þ1-617-667-2913. E-mail address: [email protected] (K.A. Bauer). 1 The author served as consultant to Sanofi-Synthelabo and NV Organon. He has no financial conflicts of interest in relation to this manuscript (no equity interests, rights to patents, royalties or payments from a company with a financial interest in the research). 1521-6926/$ - see front matter Published by Elsevier Ltd.
90 K. A. Bauer
the mechanism of action, main pharmacological characteristics and clinical development of fondaparinux.
MECHANISM OF ACTION Fondaparinux (1728 Da) is a synthetic pentasaccharide with a very high affinity for antithrombin (previously called antithrombin III, ATIII) (Kd ¼ 50 nM), as a result of a methyl group that stabilizes the anomeric end of its sequence preventing non-specific binding to plasma proteins.2,20,21 By binding to ATIII in a rapid, non-covalent and reversible manner, fondaparinux increases the ability of ATIII to inactivate Factor Xa by a factor of about 300 (Figure 1).2,4,22 Fondaparinux also inhibits clot-bound Factor Xa, but not Factor Xa within the prothrombinase complex.23 When released from ATIII, fondaparinux can exert its action again; unlike direct serine-protease inhibitors, each molecule of fondaparinux mediates the inhibition of several molecules of Factor Xa. The highest therapeutic doses of fondaparinux (which result in fondaparinux plasma concentrations up to 1.2 mM at 10 mg once daily) do not saturate plasma ATIII, the plasma concentration of which is 2– 3 mM.21 By increasing the ability of ATIII to inhibit Factor Xa, a factor situated at the junction of the intrinsic and extrinsic pathways of the coagulation cascade, fondaparinux efficiently inhibits thrombin generation.24 Its synthetic nature eliminates the theoretical risk of pathogen contamination and assures batch-to-batch consistency.
PHARMACODYNAMICS The effect of therapeutic doses of fondaparinux on routine laboratory hemostasis tests, including activated partial thromboplastin time, prothrombin time, activated clotting time and bleeding time, is very limited.25,26 When necessary, fondaparinux may be assayed in plasma using a specific anti-Factor-Xa chromogenic method.27 1
Intrinisic pathway
Extrinisic pathway
2
Intrinisic pathway
3
Extrinisic pathway
ATIII ATIII
ATIII
Xa
Xa
Xa Fondaparinux
Fondaparinux II
Fibrinogen
II
IIa
Fibrin clot
Fibrinogen
ATIII
IIa
Xa
Fibrin clot
Figure 1. Mechanism of action of fondaparinux. (1) The activation of the coagulation cascade results in the formation of thrombin and a fibrin clot. Factor Xa is located at the intersection of the intrinsic and extrinsic pathways. The inhibition of Factor Xa by antithrombin (ATIII) is very slow. (2) Fondaparinux binds specifically to ATIII. ATIII undergoes a conformational change after binding to fondaparinux. Bound to fondaparinux, ATIII inhibits Factor Xa selectively and rapidly. By inhibiting Factor Xa, thrombin generation and fibrin formation are blocked. (3) Fondaparinux is released to act on other molecules of ATIII.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 91
Unlike heparins, fondaparinux does not bind to platelets4,25 and is able to inhibit thrombin generation in the presence of platelets.24,28,29 It is insensitive to inactivation by platelet-released heparin-neutralizing proteins such as platelet factor 425 and does not cross-react with sera from patients with heparin-induced thrombocytopenia.30 – 32 Fondaparinux inhibited thrombus formation and thrombus growth in several animal models of venous thrombosis.4 Its antithrombotic effect was correlated with the exvivo inhibitory effect on Factor Xa.4,25 Complete inhibition of thrombosis induced in vivo was associated with an approximately 45 –55% inhibition of thrombin generation ex vivo.33 Thus, fondaparinux may be antithrombotic while allowing traces of thrombin to ensure hemostasis. Fondaparinux also inhibited arterial-type platelet-rich thrombus formation.4 Although fondaparinux does not in itself possess any thrombolytic activity, it enhanced thrombolysis induced by thrombolytic agents.4 At equivalent antithrombotic concentrations, fondaparinux induced less bleeding than UFH in experimental bleeding models.4,25 In cases of overdose, plasma ATIII may act as a buffer for the excess fondaparinux since, once ATIII is saturated, the addition of more molecules of fondaparinux has no further anticoagulant effect.34 In human volunteer studies, excess fondaparinux was eliminated in the urine.26 Also, recombinant activated Factor VII may be an effective drug to overcome the anticoagulant effect of fondaparinux.35
PHARMACOKINETICS Fondaparinux has a linear pharmacokinetic profile (Table 1).28,36 Administered subcutaneously, the absorption of fondaparinux is complete, rapid and independent of the dose. The distribution volume of fondaparinux is close to that of plasma and it has a17 hour half-life that allows for once-daily dosing. Fondaparinux does not undergo hepatic metabolism37 and is almost completely excreted by the kidneys as
Table 1. Main pharmacological properties of fondaparinux. Fondaparinux Source Structure Target Protein binding in plasma Administration Bioavailibility Time to peak plasma concentration (Tmax) Time to plasma concentration of Cmax/2 Half-life Pharmacokinetic profile Hepatic metabolism Elimination Monitoring of coagulation parameters Drug interactions Cross-reactivity with antibodies involved in heparin-induced thrombocytopenia
Synthetic Homogeneous Single (Factor Xa) Antithrombin only Once daily, subcutaneously 100% 2 hours 25 minutes 17 hours Linear, dose-independent No Unchanged in urine No None known No
92 K. A. Bauer
the unchanged compound. Its elimination half-life is prolonged in elderly subjects compared with young healthy subjects26, and in patients with renal insufficiency.38 The intrasubject and intersubject variability is very limited, suggesting that routine monitoring and dose adjustments are not required for the majority of the population. Fondaparinux does not undergo placental transfer in vitro.39 No interactions were observed between fondaparinux and warfarin, aspirin, piroxicam, a non-steroidal anti-inflammatory drug, and digoxin.40 – 42 These results are consistent with the fact that, in vitro, fondaparinux does not inhibit the oxidative metabolism of various cytochrome P450 substrates commonly implicated in the metabolism of drugs.37 They are also consistent with the absence of binding of fondaparinux to plasma proteins other than ATIII.21
CLINICAL TRIALS The clinical efficacy and safety of fondaparinux in the prevention and treatment of arterial and venous thrombotic disorders have been investigated in various medical and surgical settings (Table 2). The largest program so far has concerned prophylaxis of VTE after major orthopedic surgery (approximately 9000 patients up to 2003). Prevention of VTE after major orthopedic surgery Major orthopedic surgery is considered to be in the highest risk category for thrombotic complications.43 Currently, LMWHs are the most frequently used thromboprophylactic compounds in this setting, but the rates of VTE still range between 15% and 33%.43 The clinical program of fondaparinux in this setting has encompassed all types of major orthopedic surgery of the lower limbs, i.e. total hip replacement, major knee surgery and surgery for hip fracture. One phase II doseranging study5, four phase III short-term studies6 – 9 and one phase III long-term study have been conducted.11 A meta-analysis of the short-term phase III studies was also performed.10 In all trials, the primary efficacy endpoint was the incidence of venous thromboembolic events, a composite of deep vein thrombosis (DVT) detected by mandatory bilateral venography and documented symptomatic DVT or pulmonary embolism (PE) at the end of the study treatment. This endpoint, recommended by the American College of Chest Physicians (ACCP) and Health Authorities, supported the registration and use of LMWHs in all the aforementioned orthopedic prophylactic indications.43,44 The main safety endpoint was major bleeding, a composite of fatal bleeding, non-fatal bleeding in a critical organ, bleeding requiring re-operation, or overt bleeding with a bleeding index of two or more. The bleeding index was calculated as follows: (number of units of packed red blood cells or whole blood transfused) þ (prebleeding 2 post-bleeding hemoglobin levels in grams per deciliter). All efficacy and safety outcomes were adjudicated by central independent committees, the members of which were blinded with respect to the study treatments. A phase II dose-ranging study in hip replacement surgery: PENTATHLON PENTATHLON was a multicenter, randomized, double-blind, dose-ranging trial in 933 patients undergoing total hip replacement surgery.5 Fondaparinux was administered subcutaneously at doses ranging between 0.75 and 8 mg once daily, starting 6 ^ 2 hours postoperatively. The antithrombotic effect was dose-dependent with
Table 2. Clinical trials on fondaparinux. Phase
Study
Fondaparinux
Comparator
Duration of therapy
Prevention of venous thromboembolism in elective hip replacement surgery Prevention of venous thromboembolism in elective hip replacement surgery Prevention of venous thromboembolism in elective hip replacement surgery Prevention of venous thromboembolism in hip fracture surgery
II
PENTATHLON
933
EPHESUS
5–9 days
2309
III
PENTATHLON 2000
2.5 mg once daily starting postoperatively
5–9 days
2275
III
PENTHIFRA
2.5 mg once daily starting postoperatively
5–9 days
1711
Prevention of venous thromboembolism in elective knee replacement surgery Prevention of venous thromboembolism in hip fracture surgery
III
PENTAMAKS
2.5 mg once daily starting postoperatively
5–9 days
1049
III
PENTHIFRAPLUS
2.5 mg once daily
Enoxaparin, 30 mg twice daily starting postoperativelya Enoxaparin, 40 mg once daily starting preoperativelyb Enoxaparin, 30 mg twice daily starting postoperativelya Enoxaparin, 40 mg once daily starting preoperativelyb Enoxaparin, 30 mg twice daily starting postoperativelya Placebo once daily
5–9 days
III
0.75, 1.5, 3, 6 and 8 mg once daily starting postoperatively 2.5 mg once daily starting postoperatively
Prevention of venous thromboembolism in abdominal surgery in patients aged over 60 years, or over 40 years with obesity, a history of venous thromboembolism, congestive heart failure, chronic obstructive pulmonary disease, inflammatory bowel disease, or surgery for cancer
III
PEGASUS
2.5 mg once daily starting postoperatively
Dalteparin 2500 IU 2 h pre-operatively, then post-operatively on the evening of the day of surgery (212 h after the pre-operative injection) and 5000 IU once daily
21 ^ 1 days after 7 ^ 1 days of fondaparinux in both groups 5–9 days
No. of patients enrolled
656
2927
(continued on next page)
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 93
Indication
Phase
Study
Fondaparinux
Comparator
Duration of therapy
Prevention of venous thromboembolism in acutely ill medical patients aged 60 years or more and expected to undergo bed rest for at least four days for congestive heart failure and/or acute respiratory illness in the presence of chronic lung disease, and/or acute infection or inflammatory disease Treatment of venous thromboembolism Treatment of deep vein thrombosis
III
ARTEMIS
2.5 mg once daily starting postoperatively
Placebo once daily
6–14 days
849
II
REMBRANDT
453
MATISSE-DVT
Dalteparin, 100 IU/kg twice daily Enoxaparin 1 mg/kg twice daily
At least 5 days
III
At least 5 days
2200
Treatment of symptomatic pulmonary embolism with or without deep vein thrombosis
III
MATISSE-PE
Adjusted-dose continuous intravenous unfractionated heparin
At least 5 days
2213
Unstable angina or non-Q-wave myocardial infarction ST-segment-elevation acute myocardial infarction
II
PENTUA
929
PENTALYSE
Enoxaparin 1 mg/kg twice daily Unfractionated heparin intravenously 5000 U followed by 1000 U/h
2–8 days
II
5, 7.5 and 10 mg once daily 7.5 mg once daily (5.0 mg in patients ,50 kg, and 10.0 mg in patients .100 kg) 7.5 mg once daily (5.0 mg in patients ,50 kg, and 10.0 mg in patients .100 kg) 2.5, 4, 8 and 12 mg once daily 4, 8 and 12 mg once daily
Fondaparinux: 5–7 days Heparin: 2–3 days
333
a b
North-American approved regimen. Regimen approved worldwide.
No. of patients enrolled
94 K. A. Bauer
Table 2 (continued) Indication
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 95
rates of VTE by Day 11 ranging from 11.8% to 0%, at the lowest and highest doses administered, respectively. VTE rates were 6.7% in the 1.5-mg group and 1.7% in the 3.0-mg group compared with 9.4% in the 30-mg twice-daily enoxaparin group (P ¼ 0:01 for the comparison of 3.0 mg fondaparinux with enoxaparin). The incidence of major bleeding was comparable in the 3.0-mg fondaparinux and enoxaparin groups. A dose of 2.5 mg once daily was chosen for phase III trials. Phase III, short-term prophylactic studies In four phase III, randomized, double-blind, multicenter trials in major orthopedic surgery, fondaparinux 2.5 mg was administered subcutaneously, once daily, starting 6 ^ 2 hours postoperatively, for 5– 9 days. In two trials (PENTATHLON 2000 and PENTAMAKS) performed in North America, enoxaparin was administered according to the dosage regimen recommended for use by health authorities in these areas, i.e. 30 mg twice daily starting 12 – 24 hours postoperatively. In the other two studies (EPHESUS and PENTHIFRA), conducted worldwide excluding North America, the dosage regimen of enoxaparin was the other regimen recommended for use by health authorities, i.e. 40 mg once daily starting 12 hours before surgery and followed by a second injection 12– 24 hours postoperatively. Hip replacement surgery: EPHESUS AND PENTATHLON 2000. In EPHESUS, performed in 2309 patients undergoing hip replacement, fondaparinux significantly reduced the incidence of VTE by Day 11 from 9.2% with enoxaparin to 4.1%, with a relative risk reduction of 55.9% [95% confidence interval (CI): 33.1 –72.8%, P , 0:001].8 In PENTATHLON 2000, conducted in 2275 patients undergoing hip replacement, the incidence of VTE was 6.1% with fondaparinux and 8.3% with enoxaparin, with a relative risk reduction in favor of fondaparinux of 26.3% (95% CI: 2 10.8 to 52.8%, P ¼ 0:099).9 In both studies, the incidence of major bleeding did not differ significantly between the two groups. Pooling these two studies10, the relative risk reduction of VTE was 43.0% in favor of fondaparinux (95% CI: 24.6 – 57.9%, P , 0:001) (Figure 2). Major knee surgery: PENTAMAKS. In 1049 patients undergoing major knee surgery6, fondaparinux reduced the incidence of VTE from 27.8% in the enoxaparin group to 12.5%, and the relative risk reduction in favor of fondaparinux was 55.2% (95% CI: 36.2 – 70.2%, P , 0:001). Major bleeding occurred more often in the fondaparinux group, but this was solely due to an increased incidence of bleeding-index-driven events (any report of overt bleeding in association with a hemoglobin drop of 2 g/dl or a transfusion of 2 units of blood). There were no significant differences between the two groups in the incidence of bleeding leading to death or re-operation, or occurring in a critical organ. Hip fracture surgery: PENTHIFRA. In PENTHIFRA7, performed in 1711 patients undergoing surgery for hip fracture, fondaparinux significantly reduced the incidence of VTE from 19.1% with enoxaparin to 8.3%, with a relative risk reduction of 56.4% (95% CI: 39.0 –70.3%, P , 0:001). The risk of major bleeding by Day 11 did not differ significantly between the two groups. Meta-analysis of the four short-term trials. Overall, 7344 patients were randomized in the four phase III, short-term studies.10 Fondaparinux reduced the incidence of VTE by Day 11 from 13.7% with enoxaparin to 6.8%, with a relative risk reduction of 50.6% (95% CI: 40.9 –59.1%, P , 0:001) (Figure 2). Fondaparinux also reduced the incidence of proximal DVTs from 2.9% with enoxaparin to 1.3%. Using other composite efficacy endpoints suggested for superiority studies by the ACCP43 and the European Committee for Proprietary Medicinal Products44, that do not include distal DVTs,
Incidence of venous thromboembolism(%)
96 K. A. Bauer RR= 55.2% [ 70.2% to 36.2%] p<0.001
30
Fondaparinux Enoxaparin
25
RR= 56.4% [ 70.3% to 39.0%] p<0.001
20 15
RR= 50.6% [ 59.1% to 40.9%] p<0.001 RR= 43.0% [ 57.9% to 24.6%] p<0.001
10 5 0 Hip replacement Hip fracture surgery surgery (n=3411) (n=1250)
All major Major knee surgery orthopedic surgeries (n=5835) (n=724)
Figure 2. Incidence of venous thromboembolism (primary endpoint) up to Day 11 in short-term trials of fondaparinux in major orthopedic surgery.
fondaparinux was also significantly more effective than enoxaparin ðP , 0:001Þ (Table 3).45 Based on the local site’s venographic assessment, local investigators participating in trials treated significantly fewer patients ðP , 0:001Þ for VTE by Day 11 in the fondaparinux group than in the enoxaparin group (5.5% vs 9.7%, respectively). The efficacy of fondaparinux was superior to enoxaparin, irrespective of age (from 18 to 101 years), gender, body mass index (body weights between 30 and 226 kg), type of anesthesia, type of prosthesis and duration of surgery.10 The incidence of symptomatic events up to Day 49 was low in the two groups, but two therapeutic interventions are likely to have prevented their occurrence: (1) about 40% of the patients who were free of VTE at Day 11 received extended prophylaxis with anticoagulants during follow-up; and (2) most patients with a positive venography at screening were treated with therapeutic doses of anticoagulants. Table 3. Incidence of venous thromboembolism up to Day 11 according to the composite primary efficacy outcome used.
Fondaparinux studies10 ACCP Consensus43 European CPMP44
Fondaparinux n=N (%)
Enoxaparin n=N (%)
% Odds reduction (95% confidence interval) fondaparinux: enoxaparin
P
182/2682 (6.8) 47/2764 (1.7) 57/2775 (2.1)
371/2703 (13.7) 92/2780 (3.3) 108/2780 (3.9)
255.2 (263.1 to 245.8) 249.6 (265.5 to 227.3) 248.0 (263.2 to 227.3)
,0.001 ,0.001 ,0.001
n; number of patients with events; N; total number of patients assessed for this event; ACCP, American College of Chest Physicians Consensus on Antithrombotic Therapy; CPMP, Committee for Proprietary Medicinal Products.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 97
The incidence of major bleeding was only significantly higher with fondaparinux than with enoxaparin when the first dose of fondaparinux was given earlier than 6 hours after surgery, and this difference was solely due to an increased incidence of overt bleeds with a bleeding index of two or more. Whereas the incidence of VTE was similar ðP ¼ 0:57Þ between patients who received the first injection of fondaparinux less than 6 hours following skin closure and those who received the first injection at 6 hours after skin closure or later (6.4% vs 7.0%, respectively), the incidence of major bleeding was significantly related to the timing of the first fondaparinux administration ðP ¼ 0:008Þ; it was 2.1% in patients who received the first injection of active fondaparinux at 6 hours or more after skin closure.46 Overall, the rate of fatal bleeding, critical organ bleeding or bleeding leading to re-operation was low with no difference between the two groups.10 In addition, there were no differences between the two groups in wound infection or complications at the surgical site leading to prolonged hospitalization or rehospitalization. Interestingly, the overall incidence of major bleeding increased slightly with age, but age, per se, did not appear to be a risk factor for bleeding. In patients with creatinine clearance above 30 ml/min who had received injections of active fondaparinux at 6 hours or later following skin closure, the incidence of major bleeding was 1.7% in patients aged 75 years or higher compared with 2.0% in those aged less than 75 years.46 Thus, whereas high age is not a contra-indication to fondaparinux therapy, fondaparinux 2.5 mg is contra-indicated in patients with severe renal impairment (creatinine clearance below 30 ml/min). The number of deaths from any cause and the number of any other adverse events did not differ between the two treatment groups.10 Importantly, no episodes of severe thrombocytopenia and no cases of white clot syndrome or type II heparin-induced thrombocytopenia were reported as serious adverse events.10 A phase III, long-term prophylactic study in hip fracture surgery: PENTHIFRA-PLUS PENTHIFRA-PLUS11 explored whether prolongation of thromboprophylaxis with fondaparinux for up to 4 weeks after surgery for hip fracture was effective and safe. After 1 week of prophylaxis with fondaparinux, 656 patients were assigned at random to receive, in a double-blind manner, a once-daily subcutaneous injection of fondaparinux 2.5 mg or placebo for 3 additional weeks. Four weeks of fondaparinux significantly reduced the incidence of VTE compared with 1 week of fondaparinux from 35.0% to 1.4%, a relative risk reduction of 95.9% (95% CI: 87.2 –99.7%, P , 0:001) (Figure 3). Importantly, 4 weeks of fondaparinux significantly reduced the incidence of symptomatic VTE compared with 1 week of fondaparinux from 2.7% to 0.3%, a relative risk reduction of 88.8% ðP ¼ 0:021Þ: Such a statistically significant reduction in symptomatic events was suggested for LMWHs using meta-analysis techniques.47 Symptomatic VTE occurred between Days 11 and 24 after surgery, confirming the persistence of the thrombogenic risk for at least 4 weeks after surgery.48 The superior efficacy of 4 weeks of fondaparinux was observed in all patient subgroups.49 There were no differences between the two groups in the incidence of clinically relevant bleeding.11 There was no fatal bleeding or bleeding in a critical organ in either treatment group. Bleeding was associated with a need for re-operation in two patients in each group. In both the fondaparinux and placebo groups, one of these episodes led to the discontinuation of study treatment. There were six episodes of overt bleeding associated with a bleeding index of two or more in the fondaparinux group, all occurring at the surgical site. However, the clinical relevance of such bleeds
98 K. A. Bauer
40
RR= 95.9% [ 99.7% to 87.2%] p<0.001
Four-week fondaparinux One-week fondaparinux
35
Incidence (%)
30 25 20 15 RR= 88.8% [ 100.0% to 67.7%] p<0.001
10 5 0 Venous thromboembolism (n=428)
Symptomatic venous thromboembolism (N=656)
Figure 3. Incidence of venous thromboembolism (primary endpoint) and symptomatic venous thromboembolism up to Day 32 in PENTHIFRA-PLUS.
associated with a bleeding index of two or more is questionable, since they were not associated with wound infection, they did not result in re-operation and they led to permanent cessation of study treatment in only one patient. There were no differences between the two groups in the overall incidence of adverse events. In particular, no differences in platelet count were observed between the fondaparinux and placebo groups, and no patient experienced a platelet count , 100 £ 109/l.50 However, until the safety of fondaparinux concerning immune thrombocytopenia is firmly established by clinical experience, periodic blood platelet count monitoring is recommended during the course of fondaparinux therapy. Similarly, an increase in serum transaminases was rare in both groups, and variations in transaminases were comparable between the two groups.51 Finally, there was no difference in overall mortality. Prevention of VTE after high-risk abdominal surgery: PEGASUS PEGASUS was a double-blind, randomized trial conducted to investigate fondaparinux in the prevention of VTE in 2927 patients aged over 60 years, or over 40 years with at least one risk factor for VTE, such as cancer, undergoing high-risk abdominal surgery under general anesthesia.12 Once-daily fondaparinux 2.5 mg, starting postoperatively, was compared with once-daily dalteparin, a LMWH, starting pre-operatively. The incidence of VTE with fondaparinux was 4.6% compared with 6.1% with dalteparin, an odds reduction of 25.8% (95% CI: 2 49.7 to 9.5%; P ¼ 0:14) in favor of fondaparinux. Among the 1498 cancer patients analysed for efficacy, fondaparinux significantly reduced the incidence of VTE from 7.7% to 4.7%, an odds reduction of 40.5% (95% CI: 2 61.9 to 7.2%; P ¼ 0:02). There was no significant difference between the two groups in the incidence of major bleeding.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 99
Prevention of VTE in acutely ill medical patients: ARTEMIS The randomized, double-blind, placebo-controlled ARTEMIS study was conducted to study fondaparinux for the prevention of VTE in 849 acutely ill medical patients, i.e. expected to undergo bed rest for at least 4 days for congestive heart and/or acute respiratory illness in the presence of chronic lung disease, and/or acute infection or inflammatory disease.13 Fondaparinux 2.5 mg or placebo was administered subcutaneously once daily for 6– 14 days. At Day 15, fondaparinux reduced the incidence of VTE compared with placebo from 10.5% to 5.6%, an odds reduction of 49.5% ðP ¼ 0:029Þ: Importantly, there were no pulmonary emboli in the fondaparinux group compared with five, all fatal, in the placebo group (0.0% vs 1.5%, P ¼ 0:029). This benefit was maintained at the end of the follow-up period (Day 32). The incidence of major bleeding was very low with one event in each group (0.2%). Treatment of VTE A phase II, dose-ranging study: REMBRANDT The phase II, randomized, dose-ranging REMBRANDT trial investigated the optimal dose of fondaparinux for the treatment of VTE in 453 patients.14 Three doses of fondaparinux (5, 7.5 and 10 mg once daily) were compared with dalteparin (100 IU/ kg, twice daily). No differences were observed between fondaparinux and dalteparin on thrombus mass evolution measured by ultrasonography and lung perfusion scintigraphy at Day 7 ^ 1. However, the rates of recurrent thromboembolic complications were 2.4% in the fondaparinux group overall and 5.0% in the dalteparin group. The incidence of bleeding was low and similar between the groups. The 7.5-mg dose of fondaparinux once daily was selected for phase III trials. A phase III study in the treatment of DVT: MATISSE-DVT MATISSE-DVT was a multicenter, randomized, double-blind trial conducted to compare the efficacy and safety of fondaparinux with enoxaparin in the treatment of 2200 patients with DVT.15 Patients were assigned to receive either a once-daily fixed dose of fondaparinux 7.5 mg (5.0 mg in patients , 50 kg and 10.0 mg in patients . 100 kg) or twice-daily body-weight-adjusted enoxaparin (1 mg/kg). Both treatments were administered for at least 5 days and until anticoagulation with vitamin K antagonists was therapeutic [international normalized ratio (INR) of 2 –3]. In the intention-to-treat population, symptomatic recurrent thromboembolic events occurred during the 3-month follow-up period in 3.9% of fondaparinuxtreated patients compared with 4.1% of enoxaparin-treated patients. Corresponding figures for the per-protocol population were 3.4% and 4.3%, respectively, a difference in risk of 0.9% (95% CI: – 2.6 to 0.8%). The rates of major bleeding and death were comparable between the two groups. A phase III study in the treatment of PE: MATISSE-PE In the randomized, open MATISSE-PE trial, fondaparinux administered as in MATISSEDVT was compared with adjusted-dose, continuous intravenous UFH in 2213 patients with acute symptomatic PE with or without DVT.16 Patients were ineligible if
100 K. A. Bauer
thrombolysis or surgical thrombectomy was required. Both treatments were given for at least 5 days and until anticoagulation with vitamin K antagonists was therapeutic (INR ¼ 2 – 3). In the intention-to-treat population, the incidence of recurrent thromboembolic events during the 3-month follow-up period was not significantly different between the two groups; 3.8% of fondaparinux-treated patients compared with 5.0% of UFH patients. In the per-protocol population, there were 2.9% and 4.4% recurrent thromboembolic events in the fondaparinux and UFH groups, respectively, a difference in risk of 1.5% (95% CI: 2 3.3 to 0.3%). The rates of major bleeding and death were comparable between the two groups.
Treatment of acute coronary syndromes Unstable angina: PENTUA PENTUA was a phase II, randomized, double-blind study comparing four doses of fondaparinux (2.5, 4, 8 and 12 mg) with enoxaparin (1 mg/kg twice daily) in 929 patients with unstable angina or non-Q-wave myocardial infarction.19 The treatment duration ranged from 2 to 8 days with a median of 5 days. The rate of the primary efficacy outcome, a composite of death, myocardial infarction and episodes of recurrent ischemia at Day 9, was 37.0% in the fondaparinux group and 40.2% in the enoxaparin group. There was no dose-effect relationship, but the incidence of the composite primary endpoint was significantly ðP , 0:05Þ lower in patients who received fondaparinux 2.5 mg (30.0%) than in those who received enoxaparin (40.2%). This benefit was maintained at Day 30. Bleeding rates in fondaparinux- and enoxaparin-treated patients were similar. The MICHELANGELO:OASIS-5 (UA/NSTEMI) trial is a large ongoing international, randomized, double-blind study, designed to evaluate the efficacy and safety of fondaparinux compared with enoxaparin for the acute treatment of unstable angina and non-ST-segment-elevation myocardial infarction in 16 000 patients.
Myocardial infarction: PENTALYSE PENTALYSE was a phase II, randomized, open-label trial, comparing fondaparinux with UFH in 333 patients with evolving ST-segment-elevation acute myocardial infarction treated with alteplase and aspirin.17 The doses of fondaparinux were 4, 8 and 12 mg, once daily, intravenously the first day, then subcutaneously for 5– 7 days. UFH was administered at a dose of 5000 U followed by an infusion of 1000 U/hours for 48 – 72 hours. Thrombolysis In Myocardial Infarction (TIMI) flows of grade 3 at 90 minutes were similar in the four treatment groups, ranging from 60% to 68%. However, in patients with a TIMI 3 flow at 90 minutes who did not undergo a coronary intervention, a trend towards less re-occlusion of the infarct-related vessel on Days 5 –7 was observed in fondaparinux-treated patients (0.9%) compared with UFH-treated patients (7.0%, P ¼ 0:065). In addition, during the 30-day follow-up period, there were fewer revascularizations in the fondaparinux group (39%) than in the UFH group (51%, P ¼ 0:054). The incidence of bleeding was identical in the two treatment groups. The MICHELANGELO:OASIS-6 (STEMI) trial is an ongoing international, randomized, double-blind study designed to evaluate the efficacy and safety of fondaparinux compared with standard therapy in 10 000 patients with confirmed ST-segmentelevation myocardial infarction.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 101
SUMMARY Fondaparinux is the first of a new class of antithrombotic drugs, the synthetic selective inhibitors of Factor Xa. This selective action contrasts with the action of conventional anticoagulant agents in wide use. Unlike animal-sourced heparins, the chemical synthesis of fondaparinux eliminates the theoretical risk of pathogen contamination and assures batch-to-batch consistency. In plasma, it only binds to ATIII. The pharmacokinetics of fondaparinux are very predictable with little intersubject variability. Its administration requires once-daily subcutaneous injection with no monitoring of coagulation parameters. Fondaparinux has a fast onset of action and its dose-response is not subject to drug interactions. In addition, fondaparinux does not cross-react with antibodies involved in heparin-induced thrombocytopenia. Fondaparinux administered 6 h postoperatively was superior to enoxaparin in the prevention of VTE after major orthopedic surgery. With respect to major bleeding, the safety of fondaparinux was similar to enoxaparin when administered 6 – 8 hours after surgical closure, as recommended by the product labelling. Extending fondaparinux prophylaxis from 1 to 4 weeks in patients undergoing surgery for hip fracture was very effective in reducing the occurrence of late VTE to a very low absolute incidence of 1.4%. Four weeks of fondaparinux has been approved by the US Food and Drug Administration for thromboprophylaxis after hip fracture surgery. The benefit of fondaparinux was subsequently demonstrated in patients undergoing high-risk abdominal surgery and in acutely ill medical patients. Also, fondaparinux was at least as effective and safe as current heparin/LMWH treatments of acute VTE and should allow for a further simplification of the treatment of this disease. The clinical efficacy of fondaparinux in acute coronary syndromes is promising and warrants further study. Practice points † in the prevention of VTE after major orthopedic surgery, the first 2.5 mg administration of fondaparinux must be performed 6 hours after surgical closure † fondaparinux 2.5 mg is contra-indicated in patients with severe renal impairment † the clinical use of fondaparinux does not require the monitoring of its anticoagulant activity † periodic blood platelet count is recommended during the course of treatment with fondaparinux injection
Research agenda † confirmation of the safety of fondaparinux in pregnant women is required † confirmation of the safety of fondaparinux in patients with heparin-induced thrombocytopenia is required † phase III data on the benefit-to-risk ratio of fondaparinux compared with reference anticoagulants in patients with unstable angina, in patients undergoing percutaneous transluminal coronary angioplasty, and in patients with myocardial infarction are awaited
102 K. A. Bauer
REFERENCES 1. van Boeckel CAA & Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angewandte Chemie 1993; 32: 1671–1690. (international edition in English). 2. Petitou M, Lormeau JC & Choay J. Chemical synthesis of glycosaminoglycans: new approaches to antithrombotic drugs. Nature 1991; 350(supplement): 30–33. 3. Petitou M, He´rault JP, Bernat A, et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999; 398: 417–422. 4. Herbert JM, Petitou M, Lormeau JC, et al. SR 90107/Org 31540, a novel anti-factor Xa antithrombotic agent. Cardiovascular Drug Review 1997; 15: 1 –26. 5. Turpie AGG, Gallus AS & Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. The New England Journal of Medicine 2001; 344: 619 –625. * 6. Bauer KA, Eriksson BI, Lassen MR & Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. The New England Journal of Medicine 2001; 345: 1305–1310. * 7. Eriksson BI, Bauer KA, Lassen MR & Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. The New England Journal of Medicine 2001; 345: 1298–1304. * 8. Lassen MR, Bauer KA, Eriksson BI & Turpie AGG. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715–1720. * 9. Turpie AGG, Bauer KA, Eriksson BI & Lassen MR. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721–1726. * 10. Turpie AGG, Bauer KA, Eriksson BI & Lassen MR. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery. A meta-analysis of 4 randomized studies. Archives of Internal Medicine 2002; 162: 1833–1840. * 11. Eriksson BI & Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery. A multicenter, randomized, placebo-controlled, double-blind study. Archives of Internal Medicine 2003; 163: 1337–1342. 12. Agnelli G, Bergqvist D, Cohen A, et al. A randomized double-blind study to compare the efficacy and safety of fondaparinux with dalteparin in the prevention of venous thromboembolism after high-risk abdominal surgery: the PEGASUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1). Abstract OC006. 13. Cohen AT, Gallus AS, Lassen MR, et al. Fondaparinux versus placebo for the prevention of venous thromboembolism in acutely ill medical patients (ARTEMIS). Journal of Thrombosis and Haemostasis 2003; 1(supplement 1). Abstract P1915. 14. The Rembrandt Investigators, Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ORG31540) with pure anti-factor Xa activity. A phase II evaluation. Circulation 2000; 102: 2726–2731. 15. The Matisse Investigators, The MATISSE-DVT trial, a randomized, double-blind study comparing oncedaily fondaparinux (Arixtraw) with the low-molecular-weight heparin enoxaparin, twice daily, in the initial treatment of symptomatic deep vein thrombosis. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1). Abstract OC332. * 16. The Matisse Investigators, Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. The New England Journal of Medicine 2003; 349: 1695–1702. 17. Coussement PK, Bassand JP, Convens C, et al. A synthetic factor Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. European Heart Journal 2001; 22: 1716–1724. 18. Vuillemenot A, Schiele F, Meneveau N, et al. Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent. A pilot study in the setting of coronary angioplasty. Thrombosis and Haemostasis 1999; 81: 214–220. 19. Simoons M. Oral presentation on the PENTUA clinical trial. 74th Annual Scientific Sessions of the American Heart Association, Anaheim CA, USA, 14 November 2001. 20. Petitou M, Duchaussoy P, Lederman I, et al. Synthesis of heparin fragments: a alpha-methyl pentaoside with high affinity for antithrombin III. Carbohydrate Research 1987; 167: 67– 75. 21. Paolucci F, Clavies M, Donat F, et al. Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins. Clinical Pharmacokinetics 2002; 41(supplement): 11–18. 22. Olson ST, Bjo¨rk I, Sheffer R, et al. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin– proteinase reactions. Resolution of the antithrombin conformational
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 103
23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.
change contribution to heparin rate enhancement. Journal of Biological Chemistry 1992; 267: 12528–12538. He´rault JP, Bernat A, Pflieger AM, et al. Comparative effect of two direct and indirect inhibitors on free and clot-bound prothrombinase. The Journal of Pharmacology and Experimental Therapeutics 1997; 283: 16–22. Lormeau JC & He´rault JP. The effect of the synthetic pentasaccharide SR90107/ORG31540 on thrombin generation ex vivo is uniquely due to AT-mediated neutralization of factor Xa. Thrombosis and Haemostasis 1995; 74: 1474–1477. Walenga JM, Jeske WP, Bara L, et al. Biochemical and pharmacologic rationale for the development of a synthetic pentasaccharide. Thrombosis Research 1997; 86: 1–36. Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III in man. Thrombosis and Haemostasis 1995; 74: 1468– 1473. Paolucci F, van Aarle FGB, Capdevila A, et al. Two sensitive chromogenic assays of fondaparinux sodium (Arixtraw), a new synthetic and selective inhibitor of factor Xa, in plasma. Clinical Laboratory 2003; 49: 451–460. Be´guin S, Choay J & Hemker HC. The action of a synthetic pentasaccharide on thrombin generation in whole plasma. Thrombosis and Haemostasis 1989; 61: 397 –401. Lormeau JC & He´rault JP. Comparative inhibition of extrinsic and intrinsic thrombin generation by standard heparin, a low molecular weight heparin and the synthetic AT-III-binding pentasaccharide. Thrombosis and Haemostasis 1993; 69: 152–156. Elalamy I, Lecrubier C, Potevin F, et al. Absence of in vitro cross-reaction of pentasaccharide with the plasma heparin dependent factor of twenty-five patients with heparin associated thrombocytopenia. Thrombosis and Haemostasis 1995; 74: 1384–1385. Ahmad S, Jeske WP, Walenga JM, et al. Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies. Clinical and Applied Thrombosis/Hemostasis 1999; 5: 259–266. Amiral J, Lormeau JC, Marfaing-Koka A, et al. Absence of cross-reactivity of SR90107A/ORG31540 pentasaccharide with antibodies to heparin-PF4 complexes developed in heparin-induced thrombocytopenia. Blood Coagulation and Fibrinolysis 1997; 8: 114– 117. Walenga JM, Bara L, Petitou M, et al. The inhibition of the generation of thrombin and the antithrombotic effect of a pentasaccharide with sole anti-factor Xa activity. Thrombosis Research 1988; 51: 23– 33. Walenga JM, Hoppensteadt D, Mayuga M, et al. Functionality of pentasaccharide depends on endogenous antithrombin levels. Blood 2000; 96: 817a. Bijsterveld NR, Moons AH, Boekholdt M, et al. Ability of recombinant activated factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550– 2554. Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clinical Pharmacokinetics 2002; 41: 1–9. Lieu C, Shi J, Donat F, et al. Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs. Clinical Pharmacokinetics 2002; 41(supplement): 19–26. Faaij RA, Burggraaf J, Schoemaker HC, et al. The influence of renal function on the pharmacokinetics and pharmacodynamics of ORG31540/SR90107A. Thrombosis and Haemostasis 1997; 77(supplement): 379. Lagrange F, Vergnes C, Brun JL, et al. Absence of placental transfer of pentasaccharide (fondaparinux Arixtraw) in the dually perfused cotyledon in vitro. Thrombosis and Haemostasis 2002; 87: 831–835. Faaij RA, Burggraaf J, Schoemaker RC, et al. The synthetic pentasaccharide fondaparinux sodium does not interact with oral warfarin. Clinical Pharmacokinetics 2002; 41(supplement): 27–29. Ollier C, Santoni A, Faaij RA, et al. Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers. Clinical Pharmacokinetics 2002; 41(supplement): 31 –37. Mant T, Fournie´ P, Ollier C, et al. Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers. Clinical Pharmacokinetics 2002; 41(supplement): 39–45. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001; 119(supplement): 132S–175S. Committee for Proprietary Medicinal Products. Points to consider on clinical investigation of medicinal products for prophylaxis of intra- and postoperative venous thromboembolic risk. London: The European Agency for the Evaluation of Medicinal Products, 29 June 2000, CPMP/EWP/707/98. Bauer KA, Eriksson BI, Lassen MR, Turpie AGG., Consistency of fondaparinux superiority over enoxaparin in prevention of venous thromboembolism in orthopaedic surgery according to different composite efficacy endpoints. Seventh Annual Meeting of the European Haematology Association. Bologna, Italy: Monduzzi Editore, 2002, pp. 289–292.
104 K. A. Bauer 46. Turpie AGG, Bauer KA, Eriksson BI & Lassen MR. Effect on efficacy and safety of the timing of the first pentasaccharide (fondaparinux Arixtraw) administration in the prevention of venous thromboembolism (VTE) after major orthopedic surgery. Thrombosis and Haemostasis 2003; 90: 364 –366. 47. Eikelboom JW, Quinlan DJ & Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomized trials. Lancet 2001; 358: 9–15. 48. Eriksson BI & Lassen MR. Persistence of the risk of venous thromboembolism for at least four weeks after hip fracture surgery: evidence from the fondaparinux hip fracture surgery database. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2080. 49. Lassen MR & Eriksson BI. Efficacy of fondaparinux (Arixtraw) in extended thromboprophylaxis in hip fracture surgery is irrespective of patient and surgical characteristics: subgroup analyses of the PENTHIFRA-PLUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2062. 50. Bauer KA, Eriksson BI, Lassen MR & Turpie AGG. No episode of thrombocytopenia after four-week administration of fondaparinux, a new synthetic and selective inhibitor of factor Xa, in the PENTHIFRAPLUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2050. 51. Lassen MR & Eriksson BI. Absence of transaminase increase after four-week administration of fondaparinux (Arixtraw), a new synthetic and selective inhibitor of factor Xa, in the PENTHIFRA-PLUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2052.
6 Fondaparinux: a new synthetic and selective inhibitor of Factor Xa Kenneth A. Bauer*,1MD Associate Professor of Medicine, Harvard Medical School; Chief, Hematology Section VA Boston Healthcare System Director, Thrombosis Clinical Research, Beth, Israel, Deaconess Medical Center Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA
Fondaparinux (Arixtraw) is the first synthetic selective Factor Xa inhibitor. Its efficacy and safety in the prevention of venous thromboembolism (VTE) was first studied in patients undergoing major orthopedic surgery, a setting in the highest risk category for postoperative thrombotic complications. Low-molecular-weight heparins are frequently used in this setting, but the rates of VTE still range between 15% and 33%. In large clinical trials, fondaparinux started 6 hours postoperatively was significantly more effective than enoxaparin in preventing VTE in patients undergoing total hip replacement, total knee replacement or hip fracture surgery. The benefit of extended fondaparinux prophylaxis after hip fracture surgery was also investigated. Other trials have demonstrated that fondaparinux is efficacious in the prevention of VTE in other patient populations at risk of thrombosis and in the treatment of symptomatic VTE. Key words: fondaparinux; heparin; pentasaccharide; pharmacokinetics; thromboprophylaxis; venous thromboembolism; surgery; acute coronary syndromes.
Until very recently, pharmacological prophylaxis of thrombosis employed anticoagulants including vitamin K antagonists, unfractionated heparin (UFH) and lowmolecular-weight heparins (LMWHs) that act on a number of coagulation factors. Fondaparinux (Arixtraw) is the first of a new class of anticoagulants that inhibit Factor Xa selectively.1 – 4 Following a large clinical trials program involving more than 8000 patients, fondaparinux has been approved for use in thromboprophylaxis after major orthopedic surgery.5 – 11 Its efficacy for the prevention of venous thromboembolism (VTE) was subsequently confirmed in other surgical12 and medical13 settings. Moreover, its efficacy and safety were shown in the treatment of VTE14 – 16 and it also appears promising in patients with acute coronary syndromes.17 – 19 This chapter reviews * Tel.: þ 1-617-667-2174; Fax: þ1-617-667-2913. E-mail address: [email protected] (K.A. Bauer). 1 The author served as consultant to Sanofi-Synthelabo and NV Organon. He has no financial conflicts of interest in relation to this manuscript (no equity interests, rights to patents, royalties or payments from a company with a financial interest in the research). 1521-6926/$ - see front matter Published by Elsevier Ltd.
90 K. A. Bauer
the mechanism of action, main pharmacological characteristics and clinical development of fondaparinux.
MECHANISM OF ACTION Fondaparinux (1728 Da) is a synthetic pentasaccharide with a very high affinity for antithrombin (previously called antithrombin III, ATIII) (Kd ¼ 50 nM), as a result of a methyl group that stabilizes the anomeric end of its sequence preventing non-specific binding to plasma proteins.2,20,21 By binding to ATIII in a rapid, non-covalent and reversible manner, fondaparinux increases the ability of ATIII to inactivate Factor Xa by a factor of about 300 (Figure 1).2,4,22 Fondaparinux also inhibits clot-bound Factor Xa, but not Factor Xa within the prothrombinase complex.23 When released from ATIII, fondaparinux can exert its action again; unlike direct serine-protease inhibitors, each molecule of fondaparinux mediates the inhibition of several molecules of Factor Xa. The highest therapeutic doses of fondaparinux (which result in fondaparinux plasma concentrations up to 1.2 mM at 10 mg once daily) do not saturate plasma ATIII, the plasma concentration of which is 2– 3 mM.21 By increasing the ability of ATIII to inhibit Factor Xa, a factor situated at the junction of the intrinsic and extrinsic pathways of the coagulation cascade, fondaparinux efficiently inhibits thrombin generation.24 Its synthetic nature eliminates the theoretical risk of pathogen contamination and assures batch-to-batch consistency.
PHARMACODYNAMICS The effect of therapeutic doses of fondaparinux on routine laboratory hemostasis tests, including activated partial thromboplastin time, prothrombin time, activated clotting time and bleeding time, is very limited.25,26 When necessary, fondaparinux may be assayed in plasma using a specific anti-Factor-Xa chromogenic method.27 1
Intrinisic pathway
Extrinisic pathway
2
Intrinisic pathway
3
Extrinisic pathway
ATIII ATIII
ATIII
Xa
Xa
Xa Fondaparinux
Fondaparinux II
Fibrinogen
II
IIa
Fibrin clot
Fibrinogen
ATIII
IIa
Xa
Fibrin clot
Figure 1. Mechanism of action of fondaparinux. (1) The activation of the coagulation cascade results in the formation of thrombin and a fibrin clot. Factor Xa is located at the intersection of the intrinsic and extrinsic pathways. The inhibition of Factor Xa by antithrombin (ATIII) is very slow. (2) Fondaparinux binds specifically to ATIII. ATIII undergoes a conformational change after binding to fondaparinux. Bound to fondaparinux, ATIII inhibits Factor Xa selectively and rapidly. By inhibiting Factor Xa, thrombin generation and fibrin formation are blocked. (3) Fondaparinux is released to act on other molecules of ATIII.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 91
Unlike heparins, fondaparinux does not bind to platelets4,25 and is able to inhibit thrombin generation in the presence of platelets.24,28,29 It is insensitive to inactivation by platelet-released heparin-neutralizing proteins such as platelet factor 425 and does not cross-react with sera from patients with heparin-induced thrombocytopenia.30 – 32 Fondaparinux inhibited thrombus formation and thrombus growth in several animal models of venous thrombosis.4 Its antithrombotic effect was correlated with the exvivo inhibitory effect on Factor Xa.4,25 Complete inhibition of thrombosis induced in vivo was associated with an approximately 45 –55% inhibition of thrombin generation ex vivo.33 Thus, fondaparinux may be antithrombotic while allowing traces of thrombin to ensure hemostasis. Fondaparinux also inhibited arterial-type platelet-rich thrombus formation.4 Although fondaparinux does not in itself possess any thrombolytic activity, it enhanced thrombolysis induced by thrombolytic agents.4 At equivalent antithrombotic concentrations, fondaparinux induced less bleeding than UFH in experimental bleeding models.4,25 In cases of overdose, plasma ATIII may act as a buffer for the excess fondaparinux since, once ATIII is saturated, the addition of more molecules of fondaparinux has no further anticoagulant effect.34 In human volunteer studies, excess fondaparinux was eliminated in the urine.26 Also, recombinant activated Factor VII may be an effective drug to overcome the anticoagulant effect of fondaparinux.35
PHARMACOKINETICS Fondaparinux has a linear pharmacokinetic profile (Table 1).28,36 Administered subcutaneously, the absorption of fondaparinux is complete, rapid and independent of the dose. The distribution volume of fondaparinux is close to that of plasma and it has a17 hour half-life that allows for once-daily dosing. Fondaparinux does not undergo hepatic metabolism37 and is almost completely excreted by the kidneys as
Table 1. Main pharmacological properties of fondaparinux. Fondaparinux Source Structure Target Protein binding in plasma Administration Bioavailibility Time to peak plasma concentration (Tmax) Time to plasma concentration of Cmax/2 Half-life Pharmacokinetic profile Hepatic metabolism Elimination Monitoring of coagulation parameters Drug interactions Cross-reactivity with antibodies involved in heparin-induced thrombocytopenia
Synthetic Homogeneous Single (Factor Xa) Antithrombin only Once daily, subcutaneously 100% 2 hours 25 minutes 17 hours Linear, dose-independent No Unchanged in urine No None known No
92 K. A. Bauer
the unchanged compound. Its elimination half-life is prolonged in elderly subjects compared with young healthy subjects26, and in patients with renal insufficiency.38 The intrasubject and intersubject variability is very limited, suggesting that routine monitoring and dose adjustments are not required for the majority of the population. Fondaparinux does not undergo placental transfer in vitro.39 No interactions were observed between fondaparinux and warfarin, aspirin, piroxicam, a non-steroidal anti-inflammatory drug, and digoxin.40 – 42 These results are consistent with the fact that, in vitro, fondaparinux does not inhibit the oxidative metabolism of various cytochrome P450 substrates commonly implicated in the metabolism of drugs.37 They are also consistent with the absence of binding of fondaparinux to plasma proteins other than ATIII.21
CLINICAL TRIALS The clinical efficacy and safety of fondaparinux in the prevention and treatment of arterial and venous thrombotic disorders have been investigated in various medical and surgical settings (Table 2). The largest program so far has concerned prophylaxis of VTE after major orthopedic surgery (approximately 9000 patients up to 2003). Prevention of VTE after major orthopedic surgery Major orthopedic surgery is considered to be in the highest risk category for thrombotic complications.43 Currently, LMWHs are the most frequently used thromboprophylactic compounds in this setting, but the rates of VTE still range between 15% and 33%.43 The clinical program of fondaparinux in this setting has encompassed all types of major orthopedic surgery of the lower limbs, i.e. total hip replacement, major knee surgery and surgery for hip fracture. One phase II doseranging study5, four phase III short-term studies6 – 9 and one phase III long-term study have been conducted.11 A meta-analysis of the short-term phase III studies was also performed.10 In all trials, the primary efficacy endpoint was the incidence of venous thromboembolic events, a composite of deep vein thrombosis (DVT) detected by mandatory bilateral venography and documented symptomatic DVT or pulmonary embolism (PE) at the end of the study treatment. This endpoint, recommended by the American College of Chest Physicians (ACCP) and Health Authorities, supported the registration and use of LMWHs in all the aforementioned orthopedic prophylactic indications.43,44 The main safety endpoint was major bleeding, a composite of fatal bleeding, non-fatal bleeding in a critical organ, bleeding requiring re-operation, or overt bleeding with a bleeding index of two or more. The bleeding index was calculated as follows: (number of units of packed red blood cells or whole blood transfused) þ (prebleeding 2 post-bleeding hemoglobin levels in grams per deciliter). All efficacy and safety outcomes were adjudicated by central independent committees, the members of which were blinded with respect to the study treatments. A phase II dose-ranging study in hip replacement surgery: PENTATHLON PENTATHLON was a multicenter, randomized, double-blind, dose-ranging trial in 933 patients undergoing total hip replacement surgery.5 Fondaparinux was administered subcutaneously at doses ranging between 0.75 and 8 mg once daily, starting 6 ^ 2 hours postoperatively. The antithrombotic effect was dose-dependent with
Table 2. Clinical trials on fondaparinux. Phase
Study
Fondaparinux
Comparator
Duration of therapy
Prevention of venous thromboembolism in elective hip replacement surgery Prevention of venous thromboembolism in elective hip replacement surgery Prevention of venous thromboembolism in elective hip replacement surgery Prevention of venous thromboembolism in hip fracture surgery
II
PENTATHLON
933
EPHESUS
5–9 days
2309
III
PENTATHLON 2000
2.5 mg once daily starting postoperatively
5–9 days
2275
III
PENTHIFRA
2.5 mg once daily starting postoperatively
5–9 days
1711
Prevention of venous thromboembolism in elective knee replacement surgery Prevention of venous thromboembolism in hip fracture surgery
III
PENTAMAKS
2.5 mg once daily starting postoperatively
5–9 days
1049
III
PENTHIFRAPLUS
2.5 mg once daily
Enoxaparin, 30 mg twice daily starting postoperativelya Enoxaparin, 40 mg once daily starting preoperativelyb Enoxaparin, 30 mg twice daily starting postoperativelya Enoxaparin, 40 mg once daily starting preoperativelyb Enoxaparin, 30 mg twice daily starting postoperativelya Placebo once daily
5–9 days
III
0.75, 1.5, 3, 6 and 8 mg once daily starting postoperatively 2.5 mg once daily starting postoperatively
Prevention of venous thromboembolism in abdominal surgery in patients aged over 60 years, or over 40 years with obesity, a history of venous thromboembolism, congestive heart failure, chronic obstructive pulmonary disease, inflammatory bowel disease, or surgery for cancer
III
PEGASUS
2.5 mg once daily starting postoperatively
Dalteparin 2500 IU 2 h pre-operatively, then post-operatively on the evening of the day of surgery (212 h after the pre-operative injection) and 5000 IU once daily
21 ^ 1 days after 7 ^ 1 days of fondaparinux in both groups 5–9 days
No. of patients enrolled
656
2927
(continued on next page)
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 93
Indication
Phase
Study
Fondaparinux
Comparator
Duration of therapy
Prevention of venous thromboembolism in acutely ill medical patients aged 60 years or more and expected to undergo bed rest for at least four days for congestive heart failure and/or acute respiratory illness in the presence of chronic lung disease, and/or acute infection or inflammatory disease Treatment of venous thromboembolism Treatment of deep vein thrombosis
III
ARTEMIS
2.5 mg once daily starting postoperatively
Placebo once daily
6–14 days
849
II
REMBRANDT
453
MATISSE-DVT
Dalteparin, 100 IU/kg twice daily Enoxaparin 1 mg/kg twice daily
At least 5 days
III
At least 5 days
2200
Treatment of symptomatic pulmonary embolism with or without deep vein thrombosis
III
MATISSE-PE
Adjusted-dose continuous intravenous unfractionated heparin
At least 5 days
2213
Unstable angina or non-Q-wave myocardial infarction ST-segment-elevation acute myocardial infarction
II
PENTUA
929
PENTALYSE
Enoxaparin 1 mg/kg twice daily Unfractionated heparin intravenously 5000 U followed by 1000 U/h
2–8 days
II
5, 7.5 and 10 mg once daily 7.5 mg once daily (5.0 mg in patients ,50 kg, and 10.0 mg in patients .100 kg) 7.5 mg once daily (5.0 mg in patients ,50 kg, and 10.0 mg in patients .100 kg) 2.5, 4, 8 and 12 mg once daily 4, 8 and 12 mg once daily
Fondaparinux: 5–7 days Heparin: 2–3 days
333
a b
North-American approved regimen. Regimen approved worldwide.
No. of patients enrolled
94 K. A. Bauer
Table 2 (continued) Indication
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 95
rates of VTE by Day 11 ranging from 11.8% to 0%, at the lowest and highest doses administered, respectively. VTE rates were 6.7% in the 1.5-mg group and 1.7% in the 3.0-mg group compared with 9.4% in the 30-mg twice-daily enoxaparin group (P ¼ 0:01 for the comparison of 3.0 mg fondaparinux with enoxaparin). The incidence of major bleeding was comparable in the 3.0-mg fondaparinux and enoxaparin groups. A dose of 2.5 mg once daily was chosen for phase III trials. Phase III, short-term prophylactic studies In four phase III, randomized, double-blind, multicenter trials in major orthopedic surgery, fondaparinux 2.5 mg was administered subcutaneously, once daily, starting 6 ^ 2 hours postoperatively, for 5– 9 days. In two trials (PENTATHLON 2000 and PENTAMAKS) performed in North America, enoxaparin was administered according to the dosage regimen recommended for use by health authorities in these areas, i.e. 30 mg twice daily starting 12 – 24 hours postoperatively. In the other two studies (EPHESUS and PENTHIFRA), conducted worldwide excluding North America, the dosage regimen of enoxaparin was the other regimen recommended for use by health authorities, i.e. 40 mg once daily starting 12 hours before surgery and followed by a second injection 12– 24 hours postoperatively. Hip replacement surgery: EPHESUS AND PENTATHLON 2000. In EPHESUS, performed in 2309 patients undergoing hip replacement, fondaparinux significantly reduced the incidence of VTE by Day 11 from 9.2% with enoxaparin to 4.1%, with a relative risk reduction of 55.9% [95% confidence interval (CI): 33.1 –72.8%, P , 0:001].8 In PENTATHLON 2000, conducted in 2275 patients undergoing hip replacement, the incidence of VTE was 6.1% with fondaparinux and 8.3% with enoxaparin, with a relative risk reduction in favor of fondaparinux of 26.3% (95% CI: 2 10.8 to 52.8%, P ¼ 0:099).9 In both studies, the incidence of major bleeding did not differ significantly between the two groups. Pooling these two studies10, the relative risk reduction of VTE was 43.0% in favor of fondaparinux (95% CI: 24.6 – 57.9%, P , 0:001) (Figure 2). Major knee surgery: PENTAMAKS. In 1049 patients undergoing major knee surgery6, fondaparinux reduced the incidence of VTE from 27.8% in the enoxaparin group to 12.5%, and the relative risk reduction in favor of fondaparinux was 55.2% (95% CI: 36.2 – 70.2%, P , 0:001). Major bleeding occurred more often in the fondaparinux group, but this was solely due to an increased incidence of bleeding-index-driven events (any report of overt bleeding in association with a hemoglobin drop of 2 g/dl or a transfusion of 2 units of blood). There were no significant differences between the two groups in the incidence of bleeding leading to death or re-operation, or occurring in a critical organ. Hip fracture surgery: PENTHIFRA. In PENTHIFRA7, performed in 1711 patients undergoing surgery for hip fracture, fondaparinux significantly reduced the incidence of VTE from 19.1% with enoxaparin to 8.3%, with a relative risk reduction of 56.4% (95% CI: 39.0 –70.3%, P , 0:001). The risk of major bleeding by Day 11 did not differ significantly between the two groups. Meta-analysis of the four short-term trials. Overall, 7344 patients were randomized in the four phase III, short-term studies.10 Fondaparinux reduced the incidence of VTE by Day 11 from 13.7% with enoxaparin to 6.8%, with a relative risk reduction of 50.6% (95% CI: 40.9 –59.1%, P , 0:001) (Figure 2). Fondaparinux also reduced the incidence of proximal DVTs from 2.9% with enoxaparin to 1.3%. Using other composite efficacy endpoints suggested for superiority studies by the ACCP43 and the European Committee for Proprietary Medicinal Products44, that do not include distal DVTs,
Incidence of venous thromboembolism(%)
96 K. A. Bauer RR= 55.2% [ 70.2% to 36.2%] p<0.001
30
Fondaparinux Enoxaparin
25
RR= 56.4% [ 70.3% to 39.0%] p<0.001
20 15
RR= 50.6% [ 59.1% to 40.9%] p<0.001 RR= 43.0% [ 57.9% to 24.6%] p<0.001
10 5 0 Hip replacement Hip fracture surgery surgery (n=3411) (n=1250)
All major Major knee surgery orthopedic surgeries (n=5835) (n=724)
Figure 2. Incidence of venous thromboembolism (primary endpoint) up to Day 11 in short-term trials of fondaparinux in major orthopedic surgery.
fondaparinux was also significantly more effective than enoxaparin ðP , 0:001Þ (Table 3).45 Based on the local site’s venographic assessment, local investigators participating in trials treated significantly fewer patients ðP , 0:001Þ for VTE by Day 11 in the fondaparinux group than in the enoxaparin group (5.5% vs 9.7%, respectively). The efficacy of fondaparinux was superior to enoxaparin, irrespective of age (from 18 to 101 years), gender, body mass index (body weights between 30 and 226 kg), type of anesthesia, type of prosthesis and duration of surgery.10 The incidence of symptomatic events up to Day 49 was low in the two groups, but two therapeutic interventions are likely to have prevented their occurrence: (1) about 40% of the patients who were free of VTE at Day 11 received extended prophylaxis with anticoagulants during follow-up; and (2) most patients with a positive venography at screening were treated with therapeutic doses of anticoagulants. Table 3. Incidence of venous thromboembolism up to Day 11 according to the composite primary efficacy outcome used.
Fondaparinux studies10 ACCP Consensus43 European CPMP44
Fondaparinux n=N (%)
Enoxaparin n=N (%)
% Odds reduction (95% confidence interval) fondaparinux: enoxaparin
P
182/2682 (6.8) 47/2764 (1.7) 57/2775 (2.1)
371/2703 (13.7) 92/2780 (3.3) 108/2780 (3.9)
255.2 (263.1 to 245.8) 249.6 (265.5 to 227.3) 248.0 (263.2 to 227.3)
,0.001 ,0.001 ,0.001
n; number of patients with events; N; total number of patients assessed for this event; ACCP, American College of Chest Physicians Consensus on Antithrombotic Therapy; CPMP, Committee for Proprietary Medicinal Products.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 97
The incidence of major bleeding was only significantly higher with fondaparinux than with enoxaparin when the first dose of fondaparinux was given earlier than 6 hours after surgery, and this difference was solely due to an increased incidence of overt bleeds with a bleeding index of two or more. Whereas the incidence of VTE was similar ðP ¼ 0:57Þ between patients who received the first injection of fondaparinux less than 6 hours following skin closure and those who received the first injection at 6 hours after skin closure or later (6.4% vs 7.0%, respectively), the incidence of major bleeding was significantly related to the timing of the first fondaparinux administration ðP ¼ 0:008Þ; it was 2.1% in patients who received the first injection of active fondaparinux at 6 hours or more after skin closure.46 Overall, the rate of fatal bleeding, critical organ bleeding or bleeding leading to re-operation was low with no difference between the two groups.10 In addition, there were no differences between the two groups in wound infection or complications at the surgical site leading to prolonged hospitalization or rehospitalization. Interestingly, the overall incidence of major bleeding increased slightly with age, but age, per se, did not appear to be a risk factor for bleeding. In patients with creatinine clearance above 30 ml/min who had received injections of active fondaparinux at 6 hours or later following skin closure, the incidence of major bleeding was 1.7% in patients aged 75 years or higher compared with 2.0% in those aged less than 75 years.46 Thus, whereas high age is not a contra-indication to fondaparinux therapy, fondaparinux 2.5 mg is contra-indicated in patients with severe renal impairment (creatinine clearance below 30 ml/min). The number of deaths from any cause and the number of any other adverse events did not differ between the two treatment groups.10 Importantly, no episodes of severe thrombocytopenia and no cases of white clot syndrome or type II heparin-induced thrombocytopenia were reported as serious adverse events.10 A phase III, long-term prophylactic study in hip fracture surgery: PENTHIFRA-PLUS PENTHIFRA-PLUS11 explored whether prolongation of thromboprophylaxis with fondaparinux for up to 4 weeks after surgery for hip fracture was effective and safe. After 1 week of prophylaxis with fondaparinux, 656 patients were assigned at random to receive, in a double-blind manner, a once-daily subcutaneous injection of fondaparinux 2.5 mg or placebo for 3 additional weeks. Four weeks of fondaparinux significantly reduced the incidence of VTE compared with 1 week of fondaparinux from 35.0% to 1.4%, a relative risk reduction of 95.9% (95% CI: 87.2 –99.7%, P , 0:001) (Figure 3). Importantly, 4 weeks of fondaparinux significantly reduced the incidence of symptomatic VTE compared with 1 week of fondaparinux from 2.7% to 0.3%, a relative risk reduction of 88.8% ðP ¼ 0:021Þ: Such a statistically significant reduction in symptomatic events was suggested for LMWHs using meta-analysis techniques.47 Symptomatic VTE occurred between Days 11 and 24 after surgery, confirming the persistence of the thrombogenic risk for at least 4 weeks after surgery.48 The superior efficacy of 4 weeks of fondaparinux was observed in all patient subgroups.49 There were no differences between the two groups in the incidence of clinically relevant bleeding.11 There was no fatal bleeding or bleeding in a critical organ in either treatment group. Bleeding was associated with a need for re-operation in two patients in each group. In both the fondaparinux and placebo groups, one of these episodes led to the discontinuation of study treatment. There were six episodes of overt bleeding associated with a bleeding index of two or more in the fondaparinux group, all occurring at the surgical site. However, the clinical relevance of such bleeds
98 K. A. Bauer
40
RR= 95.9% [ 99.7% to 87.2%] p<0.001
Four-week fondaparinux One-week fondaparinux
35
Incidence (%)
30 25 20 15 RR= 88.8% [ 100.0% to 67.7%] p<0.001
10 5 0 Venous thromboembolism (n=428)
Symptomatic venous thromboembolism (N=656)
Figure 3. Incidence of venous thromboembolism (primary endpoint) and symptomatic venous thromboembolism up to Day 32 in PENTHIFRA-PLUS.
associated with a bleeding index of two or more is questionable, since they were not associated with wound infection, they did not result in re-operation and they led to permanent cessation of study treatment in only one patient. There were no differences between the two groups in the overall incidence of adverse events. In particular, no differences in platelet count were observed between the fondaparinux and placebo groups, and no patient experienced a platelet count , 100 £ 109/l.50 However, until the safety of fondaparinux concerning immune thrombocytopenia is firmly established by clinical experience, periodic blood platelet count monitoring is recommended during the course of fondaparinux therapy. Similarly, an increase in serum transaminases was rare in both groups, and variations in transaminases were comparable between the two groups.51 Finally, there was no difference in overall mortality. Prevention of VTE after high-risk abdominal surgery: PEGASUS PEGASUS was a double-blind, randomized trial conducted to investigate fondaparinux in the prevention of VTE in 2927 patients aged over 60 years, or over 40 years with at least one risk factor for VTE, such as cancer, undergoing high-risk abdominal surgery under general anesthesia.12 Once-daily fondaparinux 2.5 mg, starting postoperatively, was compared with once-daily dalteparin, a LMWH, starting pre-operatively. The incidence of VTE with fondaparinux was 4.6% compared with 6.1% with dalteparin, an odds reduction of 25.8% (95% CI: 2 49.7 to 9.5%; P ¼ 0:14) in favor of fondaparinux. Among the 1498 cancer patients analysed for efficacy, fondaparinux significantly reduced the incidence of VTE from 7.7% to 4.7%, an odds reduction of 40.5% (95% CI: 2 61.9 to 7.2%; P ¼ 0:02). There was no significant difference between the two groups in the incidence of major bleeding.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 99
Prevention of VTE in acutely ill medical patients: ARTEMIS The randomized, double-blind, placebo-controlled ARTEMIS study was conducted to study fondaparinux for the prevention of VTE in 849 acutely ill medical patients, i.e. expected to undergo bed rest for at least 4 days for congestive heart and/or acute respiratory illness in the presence of chronic lung disease, and/or acute infection or inflammatory disease.13 Fondaparinux 2.5 mg or placebo was administered subcutaneously once daily for 6– 14 days. At Day 15, fondaparinux reduced the incidence of VTE compared with placebo from 10.5% to 5.6%, an odds reduction of 49.5% ðP ¼ 0:029Þ: Importantly, there were no pulmonary emboli in the fondaparinux group compared with five, all fatal, in the placebo group (0.0% vs 1.5%, P ¼ 0:029). This benefit was maintained at the end of the follow-up period (Day 32). The incidence of major bleeding was very low with one event in each group (0.2%). Treatment of VTE A phase II, dose-ranging study: REMBRANDT The phase II, randomized, dose-ranging REMBRANDT trial investigated the optimal dose of fondaparinux for the treatment of VTE in 453 patients.14 Three doses of fondaparinux (5, 7.5 and 10 mg once daily) were compared with dalteparin (100 IU/ kg, twice daily). No differences were observed between fondaparinux and dalteparin on thrombus mass evolution measured by ultrasonography and lung perfusion scintigraphy at Day 7 ^ 1. However, the rates of recurrent thromboembolic complications were 2.4% in the fondaparinux group overall and 5.0% in the dalteparin group. The incidence of bleeding was low and similar between the groups. The 7.5-mg dose of fondaparinux once daily was selected for phase III trials. A phase III study in the treatment of DVT: MATISSE-DVT MATISSE-DVT was a multicenter, randomized, double-blind trial conducted to compare the efficacy and safety of fondaparinux with enoxaparin in the treatment of 2200 patients with DVT.15 Patients were assigned to receive either a once-daily fixed dose of fondaparinux 7.5 mg (5.0 mg in patients , 50 kg and 10.0 mg in patients . 100 kg) or twice-daily body-weight-adjusted enoxaparin (1 mg/kg). Both treatments were administered for at least 5 days and until anticoagulation with vitamin K antagonists was therapeutic [international normalized ratio (INR) of 2 –3]. In the intention-to-treat population, symptomatic recurrent thromboembolic events occurred during the 3-month follow-up period in 3.9% of fondaparinuxtreated patients compared with 4.1% of enoxaparin-treated patients. Corresponding figures for the per-protocol population were 3.4% and 4.3%, respectively, a difference in risk of 0.9% (95% CI: – 2.6 to 0.8%). The rates of major bleeding and death were comparable between the two groups. A phase III study in the treatment of PE: MATISSE-PE In the randomized, open MATISSE-PE trial, fondaparinux administered as in MATISSEDVT was compared with adjusted-dose, continuous intravenous UFH in 2213 patients with acute symptomatic PE with or without DVT.16 Patients were ineligible if
100 K. A. Bauer
thrombolysis or surgical thrombectomy was required. Both treatments were given for at least 5 days and until anticoagulation with vitamin K antagonists was therapeutic (INR ¼ 2 – 3). In the intention-to-treat population, the incidence of recurrent thromboembolic events during the 3-month follow-up period was not significantly different between the two groups; 3.8% of fondaparinux-treated patients compared with 5.0% of UFH patients. In the per-protocol population, there were 2.9% and 4.4% recurrent thromboembolic events in the fondaparinux and UFH groups, respectively, a difference in risk of 1.5% (95% CI: 2 3.3 to 0.3%). The rates of major bleeding and death were comparable between the two groups.
Treatment of acute coronary syndromes Unstable angina: PENTUA PENTUA was a phase II, randomized, double-blind study comparing four doses of fondaparinux (2.5, 4, 8 and 12 mg) with enoxaparin (1 mg/kg twice daily) in 929 patients with unstable angina or non-Q-wave myocardial infarction.19 The treatment duration ranged from 2 to 8 days with a median of 5 days. The rate of the primary efficacy outcome, a composite of death, myocardial infarction and episodes of recurrent ischemia at Day 9, was 37.0% in the fondaparinux group and 40.2% in the enoxaparin group. There was no dose-effect relationship, but the incidence of the composite primary endpoint was significantly ðP , 0:05Þ lower in patients who received fondaparinux 2.5 mg (30.0%) than in those who received enoxaparin (40.2%). This benefit was maintained at Day 30. Bleeding rates in fondaparinux- and enoxaparin-treated patients were similar. The MICHELANGELO:OASIS-5 (UA/NSTEMI) trial is a large ongoing international, randomized, double-blind study, designed to evaluate the efficacy and safety of fondaparinux compared with enoxaparin for the acute treatment of unstable angina and non-ST-segment-elevation myocardial infarction in 16 000 patients.
Myocardial infarction: PENTALYSE PENTALYSE was a phase II, randomized, open-label trial, comparing fondaparinux with UFH in 333 patients with evolving ST-segment-elevation acute myocardial infarction treated with alteplase and aspirin.17 The doses of fondaparinux were 4, 8 and 12 mg, once daily, intravenously the first day, then subcutaneously for 5– 7 days. UFH was administered at a dose of 5000 U followed by an infusion of 1000 U/hours for 48 – 72 hours. Thrombolysis In Myocardial Infarction (TIMI) flows of grade 3 at 90 minutes were similar in the four treatment groups, ranging from 60% to 68%. However, in patients with a TIMI 3 flow at 90 minutes who did not undergo a coronary intervention, a trend towards less re-occlusion of the infarct-related vessel on Days 5 –7 was observed in fondaparinux-treated patients (0.9%) compared with UFH-treated patients (7.0%, P ¼ 0:065). In addition, during the 30-day follow-up period, there were fewer revascularizations in the fondaparinux group (39%) than in the UFH group (51%, P ¼ 0:054). The incidence of bleeding was identical in the two treatment groups. The MICHELANGELO:OASIS-6 (STEMI) trial is an ongoing international, randomized, double-blind study designed to evaluate the efficacy and safety of fondaparinux compared with standard therapy in 10 000 patients with confirmed ST-segmentelevation myocardial infarction.
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 101
SUMMARY Fondaparinux is the first of a new class of antithrombotic drugs, the synthetic selective inhibitors of Factor Xa. This selective action contrasts with the action of conventional anticoagulant agents in wide use. Unlike animal-sourced heparins, the chemical synthesis of fondaparinux eliminates the theoretical risk of pathogen contamination and assures batch-to-batch consistency. In plasma, it only binds to ATIII. The pharmacokinetics of fondaparinux are very predictable with little intersubject variability. Its administration requires once-daily subcutaneous injection with no monitoring of coagulation parameters. Fondaparinux has a fast onset of action and its dose-response is not subject to drug interactions. In addition, fondaparinux does not cross-react with antibodies involved in heparin-induced thrombocytopenia. Fondaparinux administered 6 h postoperatively was superior to enoxaparin in the prevention of VTE after major orthopedic surgery. With respect to major bleeding, the safety of fondaparinux was similar to enoxaparin when administered 6 – 8 hours after surgical closure, as recommended by the product labelling. Extending fondaparinux prophylaxis from 1 to 4 weeks in patients undergoing surgery for hip fracture was very effective in reducing the occurrence of late VTE to a very low absolute incidence of 1.4%. Four weeks of fondaparinux has been approved by the US Food and Drug Administration for thromboprophylaxis after hip fracture surgery. The benefit of fondaparinux was subsequently demonstrated in patients undergoing high-risk abdominal surgery and in acutely ill medical patients. Also, fondaparinux was at least as effective and safe as current heparin/LMWH treatments of acute VTE and should allow for a further simplification of the treatment of this disease. The clinical efficacy of fondaparinux in acute coronary syndromes is promising and warrants further study. Practice points † in the prevention of VTE after major orthopedic surgery, the first 2.5 mg administration of fondaparinux must be performed 6 hours after surgical closure † fondaparinux 2.5 mg is contra-indicated in patients with severe renal impairment † the clinical use of fondaparinux does not require the monitoring of its anticoagulant activity † periodic blood platelet count is recommended during the course of treatment with fondaparinux injection
Research agenda † confirmation of the safety of fondaparinux in pregnant women is required † confirmation of the safety of fondaparinux in patients with heparin-induced thrombocytopenia is required † phase III data on the benefit-to-risk ratio of fondaparinux compared with reference anticoagulants in patients with unstable angina, in patients undergoing percutaneous transluminal coronary angioplasty, and in patients with myocardial infarction are awaited
102 K. A. Bauer
REFERENCES 1. van Boeckel CAA & Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angewandte Chemie 1993; 32: 1671–1690. (international edition in English). 2. Petitou M, Lormeau JC & Choay J. Chemical synthesis of glycosaminoglycans: new approaches to antithrombotic drugs. Nature 1991; 350(supplement): 30–33. 3. Petitou M, He´rault JP, Bernat A, et al. Synthesis of thrombin-inhibiting heparin mimetics without side effects. Nature 1999; 398: 417–422. 4. Herbert JM, Petitou M, Lormeau JC, et al. SR 90107/Org 31540, a novel anti-factor Xa antithrombotic agent. Cardiovascular Drug Review 1997; 15: 1 –26. 5. Turpie AGG, Gallus AS & Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. The New England Journal of Medicine 2001; 344: 619 –625. * 6. Bauer KA, Eriksson BI, Lassen MR & Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. The New England Journal of Medicine 2001; 345: 1305–1310. * 7. Eriksson BI, Bauer KA, Lassen MR & Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. The New England Journal of Medicine 2001; 345: 1298–1304. * 8. Lassen MR, Bauer KA, Eriksson BI & Turpie AGG. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715–1720. * 9. Turpie AGG, Bauer KA, Eriksson BI & Lassen MR. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721–1726. * 10. Turpie AGG, Bauer KA, Eriksson BI & Lassen MR. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery. A meta-analysis of 4 randomized studies. Archives of Internal Medicine 2002; 162: 1833–1840. * 11. Eriksson BI & Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery. A multicenter, randomized, placebo-controlled, double-blind study. Archives of Internal Medicine 2003; 163: 1337–1342. 12. Agnelli G, Bergqvist D, Cohen A, et al. A randomized double-blind study to compare the efficacy and safety of fondaparinux with dalteparin in the prevention of venous thromboembolism after high-risk abdominal surgery: the PEGASUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1). Abstract OC006. 13. Cohen AT, Gallus AS, Lassen MR, et al. Fondaparinux versus placebo for the prevention of venous thromboembolism in acutely ill medical patients (ARTEMIS). Journal of Thrombosis and Haemostasis 2003; 1(supplement 1). Abstract P1915. 14. The Rembrandt Investigators, Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ORG31540) with pure anti-factor Xa activity. A phase II evaluation. Circulation 2000; 102: 2726–2731. 15. The Matisse Investigators, The MATISSE-DVT trial, a randomized, double-blind study comparing oncedaily fondaparinux (Arixtraw) with the low-molecular-weight heparin enoxaparin, twice daily, in the initial treatment of symptomatic deep vein thrombosis. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1). Abstract OC332. * 16. The Matisse Investigators, Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. The New England Journal of Medicine 2003; 349: 1695–1702. 17. Coussement PK, Bassand JP, Convens C, et al. A synthetic factor Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. European Heart Journal 2001; 22: 1716–1724. 18. Vuillemenot A, Schiele F, Meneveau N, et al. Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent. A pilot study in the setting of coronary angioplasty. Thrombosis and Haemostasis 1999; 81: 214–220. 19. Simoons M. Oral presentation on the PENTUA clinical trial. 74th Annual Scientific Sessions of the American Heart Association, Anaheim CA, USA, 14 November 2001. 20. Petitou M, Duchaussoy P, Lederman I, et al. Synthesis of heparin fragments: a alpha-methyl pentaoside with high affinity for antithrombin III. Carbohydrate Research 1987; 167: 67– 75. 21. Paolucci F, Clavies M, Donat F, et al. Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins. Clinical Pharmacokinetics 2002; 41(supplement): 11–18. 22. Olson ST, Bjo¨rk I, Sheffer R, et al. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin– proteinase reactions. Resolution of the antithrombin conformational
Fondaparinux: a new synthetic and selective inhibitor of Factor Xa 103
23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.
change contribution to heparin rate enhancement. Journal of Biological Chemistry 1992; 267: 12528–12538. He´rault JP, Bernat A, Pflieger AM, et al. Comparative effect of two direct and indirect inhibitors on free and clot-bound prothrombinase. The Journal of Pharmacology and Experimental Therapeutics 1997; 283: 16–22. Lormeau JC & He´rault JP. The effect of the synthetic pentasaccharide SR90107/ORG31540 on thrombin generation ex vivo is uniquely due to AT-mediated neutralization of factor Xa. Thrombosis and Haemostasis 1995; 74: 1474–1477. Walenga JM, Jeske WP, Bara L, et al. Biochemical and pharmacologic rationale for the development of a synthetic pentasaccharide. Thrombosis Research 1997; 86: 1–36. Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III in man. Thrombosis and Haemostasis 1995; 74: 1468– 1473. Paolucci F, van Aarle FGB, Capdevila A, et al. Two sensitive chromogenic assays of fondaparinux sodium (Arixtraw), a new synthetic and selective inhibitor of factor Xa, in plasma. Clinical Laboratory 2003; 49: 451–460. Be´guin S, Choay J & Hemker HC. The action of a synthetic pentasaccharide on thrombin generation in whole plasma. Thrombosis and Haemostasis 1989; 61: 397 –401. Lormeau JC & He´rault JP. Comparative inhibition of extrinsic and intrinsic thrombin generation by standard heparin, a low molecular weight heparin and the synthetic AT-III-binding pentasaccharide. Thrombosis and Haemostasis 1993; 69: 152–156. Elalamy I, Lecrubier C, Potevin F, et al. Absence of in vitro cross-reaction of pentasaccharide with the plasma heparin dependent factor of twenty-five patients with heparin associated thrombocytopenia. Thrombosis and Haemostasis 1995; 74: 1384–1385. Ahmad S, Jeske WP, Walenga JM, et al. Synthetic pentasaccharides do not cause platelet activation by antiheparin-platelet factor 4 antibodies. Clinical and Applied Thrombosis/Hemostasis 1999; 5: 259–266. Amiral J, Lormeau JC, Marfaing-Koka A, et al. Absence of cross-reactivity of SR90107A/ORG31540 pentasaccharide with antibodies to heparin-PF4 complexes developed in heparin-induced thrombocytopenia. Blood Coagulation and Fibrinolysis 1997; 8: 114– 117. Walenga JM, Bara L, Petitou M, et al. The inhibition of the generation of thrombin and the antithrombotic effect of a pentasaccharide with sole anti-factor Xa activity. Thrombosis Research 1988; 51: 23– 33. Walenga JM, Hoppensteadt D, Mayuga M, et al. Functionality of pentasaccharide depends on endogenous antithrombin levels. Blood 2000; 96: 817a. Bijsterveld NR, Moons AH, Boekholdt M, et al. Ability of recombinant activated factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550– 2554. Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clinical Pharmacokinetics 2002; 41: 1–9. Lieu C, Shi J, Donat F, et al. Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs. Clinical Pharmacokinetics 2002; 41(supplement): 19–26. Faaij RA, Burggraaf J, Schoemaker HC, et al. The influence of renal function on the pharmacokinetics and pharmacodynamics of ORG31540/SR90107A. Thrombosis and Haemostasis 1997; 77(supplement): 379. Lagrange F, Vergnes C, Brun JL, et al. Absence of placental transfer of pentasaccharide (fondaparinux Arixtraw) in the dually perfused cotyledon in vitro. Thrombosis and Haemostasis 2002; 87: 831–835. Faaij RA, Burggraaf J, Schoemaker RC, et al. The synthetic pentasaccharide fondaparinux sodium does not interact with oral warfarin. Clinical Pharmacokinetics 2002; 41(supplement): 27–29. Ollier C, Santoni A, Faaij RA, et al. Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers. Clinical Pharmacokinetics 2002; 41(supplement): 31 –37. Mant T, Fournie´ P, Ollier C, et al. Absence of interaction of fondaparinux sodium with digoxin in healthy volunteers. Clinical Pharmacokinetics 2002; 41(supplement): 39–45. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001; 119(supplement): 132S–175S. Committee for Proprietary Medicinal Products. Points to consider on clinical investigation of medicinal products for prophylaxis of intra- and postoperative venous thromboembolic risk. London: The European Agency for the Evaluation of Medicinal Products, 29 June 2000, CPMP/EWP/707/98. Bauer KA, Eriksson BI, Lassen MR, Turpie AGG., Consistency of fondaparinux superiority over enoxaparin in prevention of venous thromboembolism in orthopaedic surgery according to different composite efficacy endpoints. Seventh Annual Meeting of the European Haematology Association. Bologna, Italy: Monduzzi Editore, 2002, pp. 289–292.
104 K. A. Bauer 46. Turpie AGG, Bauer KA, Eriksson BI & Lassen MR. Effect on efficacy and safety of the timing of the first pentasaccharide (fondaparinux Arixtraw) administration in the prevention of venous thromboembolism (VTE) after major orthopedic surgery. Thrombosis and Haemostasis 2003; 90: 364 –366. 47. Eikelboom JW, Quinlan DJ & Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomized trials. Lancet 2001; 358: 9–15. 48. Eriksson BI & Lassen MR. Persistence of the risk of venous thromboembolism for at least four weeks after hip fracture surgery: evidence from the fondaparinux hip fracture surgery database. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2080. 49. Lassen MR & Eriksson BI. Efficacy of fondaparinux (Arixtraw) in extended thromboprophylaxis in hip fracture surgery is irrespective of patient and surgical characteristics: subgroup analyses of the PENTHIFRA-PLUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2062. 50. Bauer KA, Eriksson BI, Lassen MR & Turpie AGG. No episode of thrombocytopenia after four-week administration of fondaparinux, a new synthetic and selective inhibitor of factor Xa, in the PENTHIFRAPLUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2050. 51. Lassen MR & Eriksson BI. Absence of transaminase increase after four-week administration of fondaparinux (Arixtraw), a new synthetic and selective inhibitor of factor Xa, in the PENTHIFRA-PLUS study. Journal of Thrombosis and Haemostasis 2003; 1(supplement 1): P2052.