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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Selective factor Xa inhibition with fondaparinux: from concept to clinical benefit

Alexander G.G. Turpie*

Hamilton Health Sciences, General Division, 237 Barton Street East, Hamilton, ON, Canada L8L 2X2

* Corresponding author. Tel: +1 905 528 9946; fax: +1 905 521 1551. E-mail address: turpiea{at}mcmaster.ca


   Abstract
Top
 Abstract
Introduction
 Preclinical data
 Pharmacokinetics and...
 Clinical benefit-risk ratio
 Clinical safety
 Conclusion
 References
 
Fondaparinux (Arixtra®) is a synthetic selective indirect inhibitor of activated factor X. Administered subcutaneously, the onset of action of fondaparinux is rapid, half of the maximum plasma level being reached within 30 min after injection. Furthermore, the pharmacokinetic and safety profile of fondaparinux allows once-daily subcutaneous administration without any laboratory monitoring, including platelet count. Fondaparinux exhibits a very positive benefit-risk ratio in the prevention of venous thrombo embolism in both surgical and acutely ill medical patients at risk of thrombosis. Its favourable efficacy and safety have also been demonstrated in the initial treatment of symptomatic deep-vein thrombosis and pulmonary embolism, and in patients with non-ST and ST elevation acute coronary syndromes. This review summarizes the data obtained in all phase III clinical trials with fondaparinux in the prevention and treatment of thrombo embolic disorders.

Key Words: Acute coronary syndromes • Anticoagulant • Factor Xa • Fondaparinux • Heparin • Venous thrombo embolism


   Introduction
Top
 Abstract
 Introduction
Preclinical data
 Pharmacokinetics and...
 Clinical benefit-risk ratio
 Clinical safety
 Conclusion
 References
 
Activated coagulation factor X (factor Xa) is a major target for designing anticoagulant drugs: it is located at the convergence of the intrinsic and extrinsic coagulation cascade, and activation of one molecule of factor X results in the generation of 1000 molecules of thrombin.1 Therefore, inhibition of factor Xa should theoretically be more effective for reducing fibrin formation than inactivation of thrombin.1 Fondaparinux (Arixtra®) is the only selective inhibitor of factor Xa which has been approved for use in the treatment and prevention of thrombosis worldwide. This review presents data obtained with fondaparinux across the spectrum of venous and arterial thrombo embolism in which it was tested.


   Preclinical data
Top
 Abstract
 Introduction
 Preclinical data
Pharmacokinetics and...
 Clinical benefit-risk ratio
 Clinical safety
 Conclusion
 References
 
Fondaparinux is a synthetic molecule composed of five saccharides (1728 Daltons),2 which selectively inhibits factor Xa (Figure 1). The inhibition is indirect, mediated by plasma antithrombin. By inhibiting factor Xa, fondaparinux attenuates thrombin generation and fibrin formation.


Figure 1
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  		Figure 1 Fondaparinux binds specifically to antithrombin. Bound to fondaparinux, antithrombin selectively and rapidly inhibits factor Xa. By inhibiting factor Xa, thrombin generation and fibrin formation are blocked. Fondaparinux is further released to act on other molecules of antithrombin.

 
Among the various characteristics of the drug, it is noteworthy that fondaparinux did not cross-react with sera from patients with heparin-induced thrombocytopenia, suggesting that its administration should not result in immunoallergic thrombocytopenia.3


   Pharmacokinetics and pharmacodynamics
Top
 Abstract
 Introduction
 Preclinical data
 Pharmacokinetics and...
Clinical benefit-risk ratio
 Clinical safety
 Conclusion
 References
 
Fondaparinux may be administered intravenously (Figure 2A) or subcutaneously (Figure 2B). After subcutaneous injection, fondaparinux is rapidly and completely absorbed into plasma. Time to peak plasma concentration is less than 2 h, compared with 3–5 h with low-molecular-weight heparins.4 Due to its 17 h half-life, a significant anticoagulant activity is maintained for 24 h with once-daily subcutaneous administration.4 Maximum plasma concentrations are achieved even more rapidly following intravenous bolus administration, and the half-life is unchanged when compared with the subcutaneous administration.4 The dose-response effect is highly predictable, eliminating the need for any dose adjustment or dose monitoring in practice. Like low-molecular-weight heparins, fondaparinux is excreted by the kidneys, limiting its use in patients with severe renal impairment. Importantly, fondaparinux does not interact with a number of other drugs frequently used in patients at risk of thrombosis, including aspirin, vitamin K antagonists, and digoxin.5–8


Figure 2
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  		Figure 2 Pharmacokinetic profile of 2.5 mg fondaparinux administered via intravenous (A) or subcutaneous (B) route. (A) Pharmacokinetic simulation based on a model using the demographic characteristics of the OASIS-6 patient population37 (Duane A. Boyle, personal communication). The pharmacokinetic profile was similar, regardless of whether the administration was performed using an intravenous bolus or a rapid infusion (up to 15 min). (B) Plasma concentration vs. time profile of fondaparinux sodium in healthy volunteers following a single subcutaneous dose of 2.5 mg (data derived from Donat et al.4).

 

   Clinical benefit-risk ratio
Top
 Abstract
 Introduction
 Preclinical data
 Pharmacokinetics and...
 Clinical benefit-risk ratio
Clinical safety
 Conclusion
 References
 
Prevention of venous thrombo embolism
In all phase III fondaparinux thromboprophylaxis trials, the primary efficacy outcome was a composite criterion combining documented asymptomatic and symptomatic venous thrombo embolism at the end of the study treatment. This outcome is used in the majority of anticoagulant trials in the prevention of venous thrombo embolism; it was recommended by international consensus statements and health authorities when the trials were designed.9,10 Importantly, the incidence of asymptomatic deep-vein thrombosis has been shown to correlate with the risk of clinical events, notably pulmonary embolism.11

Dose-dependent efficacy and safety
The thromboprophylactic dosage regimen of fondaparinux was chosen on the basis of the results of a randomized dose-ranging trial vs. enoxaparin in 933 patients undergoing total hip replacement.12 Fondaparinux was administered once daily at doses ranging between 0.75 and 8 mg, the first dose being given 6 ± 2 h postoperatively. Fondaparinux exerted a dose-dependent antithrombotic effect with rates of venous thrombo embolism ranging from 11.8 to 0%, at the lowest and highest dose, respectively. The rate of venous thrombo embolism was 6.7% in the 1.5 mg group, and 1.7% in the 3.0 mg group vs. 9.4% in the enoxaparin group (P = 0.01 for the comparison of 3.0 mg with enoxaparin). The incidence of major bleeding events was comparable in the 3.0 mg fondaparinux group and the enoxaparin group, whereas it tended to be lower (P = 0.05) in the 1.5 mg group. The analysis of the dose-effect relationship suggested that a once-daily 2.5 mg dose would provide an optimal benefit–risk ratio.

Major orthopaedic surgery
The benefit–risk ratio of fondaparinux after major orthopaedic surgery, the surgical procedure associated with the highest risk of thrombotic complications,9 was evaluated in four double-blind, randomized studies, two hip replacement trials, one major knee surgery trial, and one hip fracture surgery trial.13–16 Fondaparinux 2.5 mg once daily initiated 6 ± 2 h postoperatively was compared with enoxaparin, administered according to either of the two approved dosage regimens (40 mg once daily in Europe and 30 mg twice daily in North America, with an initiation either 12 h preoperatively or 12–24 h postoperatively, respectively). Both treatments were administered for 1 week. Fondaparinux was more effective than enoxaparin, irrespective of the type of orthopaedic surgery (Figure 3). A meta-analysis of these four studies including 7344 patients (mean age: 68 years) showed that, overall, fondaparinux reduced the incidence of venous thrombo embolism by 50.6% (P < 0.001), from 13.7% with enoxaparin to 6.8%.17 Fondaparinux also reduced proximal deep-vein thrombosis, considered more prone to result in pulmonary embolism, by 57.4%, from 2.9 to 1.3% (P < 0.001). In the two European studies vs. once-daily 40 mg enoxaparin in total hip replacement and hip fracture surgery, fondaparinux reduced the incidence of venous thrombo embolism by 56% (P < 0.001), from 13.2% with enoxaparin to 5.8% [risk ratio (95% confidence interval): 0.44 (0.35–0.56)]. Overall, the superior efficacy of fondaparinux was consistent, irrespective of various clinical and surgical characteristics. It is noteworthy that a single 2.5 mg dose was effective across a wide range of body weights from 36 to 169 kg.


Figure 3
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  		Figure 3 Effect of fondaparinux on the incidence of total venous thrombo embolism at the end of study treatment in various medical and surgical settings. CI, confidence interval; HFS, hip fracture surgery; LMWH, low-molecular-weight heparins; MKS, major knee surgery; THR, total hip replacement.

 
The incidence of venous thrombo embolism was not influenced by the timing of administration. However, the incidence of major bleeding was significantly (P = 0.045) lower in patients receiving the first fondaparinux dose 6 h or more after skin closure than in patients in whom fondaparinux was initiated within the 6 h following skin closure.18 Thus, when fondaparinux was used as indicated in the current recommendations on its use established after the trials were performed (i.e. at least 6 h after skin closure), the safety in terms of bleeding risk of fondaparinux was comparable to that of enoxaparin, with a 1.9% rate of major bleeding with both drugs.19 In the two European studies vs. once-daily 40 mg enoxaparin in total hip replacement and hip fracture surgery, the incidence of major bleeding was 2.6% in patients administered fondaparinux at least 6 h after skin closure and 2.5% in enoxaparin-treated patients. A further trial in patients undergoing hip fracture surgery showed that extending the once-daily administration of 2.5 mg fondaparinux from 1 to 4 weeks after hip fracture surgery was beneficial (Figure 3).20 In this trial, the incidence of symptomatic venous thrombo embolism at 1 month was also significantly reduced from 2.7% in the placebo group to 0.3% in the fondaparinux group (relative risk reduction: 88.8%; P = 0.021).20

Abdominal surgery
In a double-blind, randomized study, once-daily 2.5 mg fondaparinux was compared with placebo in 1309 patients (median age: 60 years), in whom intermittent pneumatic compression was given to all patients.21 Fondaparinux reduced the rate of venous thrombo embolism by 68.6%, from 5.3 to 1.7% (P = 0.004) (Figure 3). The rate of proximal deep-vein thrombosis was decreased by 86.1% (P = 0.037). Major bleeds were more frequent in fondaparinux-treated patients than in placebo-treated patients (1.6 vs. 0.2%, respectively; P = 0.0062), but none of the bleeds in the fondaparinux-treated group were fatal or involved a critical organ.

In a second randomized, double-blind study, once-daily 2.5 mg fondaparinux was compared with the low-molecular-weight heparin dalteparin in 2927 patients classified as being at high risk of venous thrombo embolism (median age: 66 years, 70% more than 60 years old).22 Fondaparinux was initiated 6 ± 2 h postoperatively, whereas dalteparin was started 2 h before surgery, as recommended. Compared with dalteparin, fondaparinux reduced the incidence of venous thrombo embolism by 24.6%, and was non-inferior to this low-molecular-weight heparin (Figure 3). In a subgroup analysis in cancer patients, fondaparinux reduced the incidence of venous thrombo embolism by 38.6% (P = 0.022). There were no significant differences between fondaparinux-treated patients and dalteparin-treated patients in the incidence of major bleeding, including in patients with cancer.

Acutely ill medical patients
A randomized, placebo-controlled, double-blind trial studied the efficacy and safety of once-daily 2.5 mg fondaparinux in 849 patients aged 60 years or more and expected to undergo bed rest for at least 4 days for congestive heart failure, and/or acute respiratory illness in the presence of chronic lung disease, and/or acute infection or inflammatory disease.23 Compared with other randomized trials in the same setting,24,25 inclusion criteria were chosen in order to allow a simple identification of medical patients at risk of venous thrombo embolism. The mean age of the population was 75 years, 52% of patients being 75 years old or more. Fondaparinux was administered for 6 to 14 days. At day 15, fondaparinux reduced the incidence of venous thrombo embolism by 46.7% (P = 0.029) (Figure 3). Importantly, there were five (1.5%) pulmonary embolisms, all fatal, in the placebo group, and none were reported in the fondaparinux group during administration of the study drug (P = 0.029). Fondaparinux was well tolerated with very low incidences of major bleeding (0.2%) in either study group. Of note, 34% of patients had moderate renal impairment (creatinine clearance between 30 and 50 mL/min). Interestingly, at day 32, fondaparinux tended to reduce mortality from 6.0% in the placebo group to 3.3% in the fondaparinux group (P = 0.06). Subgroup analyses showed that fondaparinux was beneficial in patients with congestive heart failure (36.0% of the population), in whom the drug significantly reduced mortality (P = 0.04) or the composite of symptomatic pulmonary embolism or mortality (P = 0.02) at day 32.26

Treatment of venous thrombo embolism
The efficacy of fondaparinux in the acute treatment of venous thrombo embolism was investigated in the two large randomized, non-inferiority MATISSE trials.27,28 The fondaparinux dosage regimen, determined on the basis of the results of a dose-finding study in patients with deep-vein thrombosis,29 was 7.5 mg once daily in patients between 50 and 100 kg, 5.0 mg in patients below 50 kg, and 10.0 mg in patients over 100 kg. In practice, the majority of patients (85%) received once-daily doses of 7.5 mg. Vitamin K antagonists were started on day 1 and study treatments were administered until the International Normalized Ratio (INR) was in the therapeutic range.

In the double-blind trial performed in 2205 patients with acute symptomatic deep-vein thrombosis (mean age: 61 years), the comparator was enoxaparin administered at the twice-daily dose of 1 mg/kg.27 Fondaparinux was at least as effective as enoxaparin: during the 3-month follow-up period, symptomatic recurrent venous thrombo embolism occurred in 3.9% of fondaparinux-treated patients, and 4.1% of enoxaparin-treated patients. Comparable data were obtained in patients treated on an outpatient basis. The rates of major bleeding during the study treatment period were comparable in the two groups (1.1% in fondaparinux-treated patients vs. 1.2% in enoxaparin-treated patients).

In the open trial in 2213 patients with acute symptomatic pulmonary embolism (mean age: 63 years), the comparator was adjusted-dose intravenous unfractionated heparin.28 Thirty-eight percent had a concurrent deep-vein thrombosis and 27% were admitted in an intensive care unit. Recurrent venous thrombo embolism occurred during the 3-month follow-up period in 3.8% of fondaparinux patients vs. 5.0% of unfractionated heparin patients. The rate of recurrent venous thrombo embolism at 3 months in patients receiving fondaparinux on an outpatient basis (14.3% of the fondaparinux population) was similar to that in patients treated with unfractionated heparin (all as inpatients), 3.2 vs. 5.0%, respectively. The rates of major bleeding were comparable in the two study groups, 1.3% in fondaparinux-treated patients and 1.1% in unfractionated heparin-treated patients. In both MATISSE trials, the overall efficacy and safety results were similar regardless of body weight (≤ or > 100 kg) or body-mass index (<30 or ≥30 kg/m2).30

Treatment of acute coronary syndromes
The efficacy and safety of fondaparinux in the treatment of acute coronary syndromes was studied in the two large OASIS-5 and OASIS-6 trials. The once-daily dose of 2.5 mg was chosen on the basis on a number of dose-ranging clinical trials in this setting.31–33

Non-ST elevation acute coronary syndromes
The OASIS-5 study was a randomized, double-blind study comparing fondaparinux 2.5 mg once daily with enoxaparin (1 mg/kg twice daily) in patients with non-ST elevation acute coronary syndromes.34 Both treatments were given for up to 8 days or discharge. Follow-up was continued for a maximum of 180 days.

A total of 20 078 patients were randomized and treated with either fondaparinux or enoxaparin for a mean duration of 5.4 and 5.2 days, respectively. Fondaparinux was non-inferior to enoxaparin in terms of the primary efficacy outcome (a composite of death, myocardial infarction, or refractory ischaemia up to day 9), which occurred in 5.8% of patients randomized to fondaparinux vs. 5.7% of patients randomized to enoxaparin. There was a trend towards a reduction in the occurrence of the composite endpoint, in favour of fondaparinux at day 30 (P = 0.13) and at 6 months (P = 0.06). Similarly, there was a significant risk reduction for death in fondaparinux-treated patients, 17% at 30 days (P = 0.02) and 11% at 6 months (P = 0.05). By day 9, the rate of major bleeding was reduced by 48% in the group of patients treated with fondaparinux (2.2 vs. 4.1% with enoxaparin; P < 0.001, Figure 4). Overall, the net clinical benefit (composite of death, myocardial infarction, refractory ischaemia, or major bleeding) at day 9 was in favour of fondaparinux (7.3 vs. 9.0%; P < 0.001); this benefit persisted up to day 180. Consistent results in favour of fondaparinux were observed in every subgroup examined, including patients undergoing percutaneous coronary intervention or patients with renal impairment.35,36


Figure 4
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  		Figure 4 Major bleeding in patients with non-ST elevation acute coronary syndromes treated with fondaparinux (2.5 mg once daily) or enoxaparin (1 mg/kg twice daily) in the randomized, double-blind OASIS-5 trial.34

 
ST-elevation acute myocardial infarction
The OASIS-6 study was a randomized, double-blind study of fondaparinux (2.5 mg once daily) vs. standard therapy (placebo or unfractionated heparin) in patients with confirmed ST elevation myocardial infarction.37 Patients were eligible, regardless of their therapeutic management, i.e. thrombolysis, primary percutaneous coronary intervention, or no reperfusion therapy. Randomization was stratified by the patient’s indication for the use of unfractionated heparin, based on the investigator’s judgment. Patients with no indication for unfractionated heparin were assigned to receive either fondaparinux or matching placebo for up to 8 days or hospital discharge if earlier. Patients with an indication for unfractionated heparin were patients in whom use of a fibrin-specific thrombolytic drug was planned, patients not eligible for thrombolysis but eligible for anticoagulants, and patients scheduled for primary percutaneous coronary intervention. Follow-up was for a maximum of 180 days.

A total of 12 092 patients were randomized. The occurrence of the primary efficacy outcome (composite of death or recurrent myocardial infarction up to day 30) was significantly reduced by 14% in patients randomized to fondaparinux (P = 0.008). This benefit was evident at day 9 and persisted up to 6 months after the event. It was marked in patients who received thrombolytics or did not receive any reperfusion therapy. Similarly, there was a significant reduction in mortality of 13% at 9 days (P = 0.04), 13% at 30 days (P = 0.03), and 12% at study-end (P = 0.03) in the fondaparinux group. A trend (P = 0.13) towards fewer severe bleeds was observed in the fondaparinux group (1.0%) compared with the control group (1.3%). Throughout the study period, the net clinical benefit, defined by the composite of death, recurrent myocardial infarction, or severe bleeding, was in favour of fondaparinux.


   Clinical safety
Top
 Abstract
 Introduction
 Preclinical data
 Pharmacokinetics and...
 Clinical benefit-risk ratio
 Clinical safety
Conclusion
 References
 
Besides the satisfactory safety in terms of bleeding risk of fondaparinux described previously, the drug was generally well tolerated concerning other safety issues.38 Although Warkentin et al.39 recently reported a case of heparin-induced thrombocytopenia in a fondaparinux-treated woman undergoing bilateral knee replacement, important information are lacking to conclusively relate this clinical event to the administration of fondaparinux. In particular, no data were reported on the effect of fondaparinux on platelet activation in this patient. Since its first marketing in 2001 and consistent with in vitro data,2,3 more than 1 million patients have been treated with fondaparinux and no proven causal association between fondaparinux and heparin-induced thrombocytopenia has been established. Moreover, a growing number of clinical reports suggest that fondaparinux may be a safe antithrombotic drug in patients with a history or an acute episode of heparin-induced thrombocytopenia caused by heparin treatment.40 Thus, laboratory monitoring of platelet count in patients administered fondaparinux is not required in Europe.41 Fondaparinux did not show any liver toxicity.38


   Conclusion
Top
 Abstract
 Introduction
 Preclinical data
 Pharmacokinetics and...
 Clinical benefit-risk ratio
 Clinical safety
 Conclusion
References
 
In all the medical and surgical settings in which the benefit–risk ratio of fondaparinux was investigated, the data of fondaparinux were positive. Thus, taking into account the results reported in the prevention of venous thrombo embolism after major orthopaedic surgery, the 2004 ACCP (American College of Chest Physicians) guidelines recommend the routine use of once-daily 2.5 mg fondaparinux (among other drugs) for at least 10 days in patients undergoing elective hip arthroplasty, elective knee arthroplasty, or hip fracture surgery (Grade 1A).42 In addition, the ACCP guidelines recommend that 2.5 mg fondaparinux be given for 28 to 35 days after surgery for hip arthroplasty (Grade 1C) or hip fracture surgery (Grade 1A).42 The value of fondaparinux was also acknowledged in the recent European and North American guidelines in patients with non-ST elevation acute coronary syndromes.43,44 The clinical trial data clearly show that fondaparinux is also an attractive drug in all medical and surgical settings in which it has been investigated.

In conclusion, due to its synthetic nature, high efficacy, acceptable safety profile, and once-daily use without any laboratory monitoring, fondaparinux represents a major therapeutic advance in the prevention and treatment of thrombotic diseases.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Preclinical data
 Pharmacokinetics and...
 Clinical benefit-risk ratio
 Clinical safety
 Conclusion
 References
 

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  4. Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H, de Greef R. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet (2002) 41(Suppl.2):1–9.[Web of Science][Medline]
  5. Lieu C, Shi J, Donat F, Van Horn R, Brian W, Newton J, Delbressine L, Vos R. Fondaparinux sodium is not metabolised in mammalian liver fractions and does not inhibit cytochrome P450-mediated metabolism of concomitant drugs. Clin Pharmacokinet (2002) 41(Suppl.2):19–26.[Medline]
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  13. Lassen MR, Bauer KA, Eriksson BI, Turpie AGG for the European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee. 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.[CrossRef][Web of Science][Medline]
  14. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, for the PENTATHLON 2000 Study Steering Committee. 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.[CrossRef][Web of Science][Medline]
  15. Bauer KA, Eriksson BI, Lassen MR, Turpie AGG, for the Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med (2001) 345:1305–1310.[Abstract/Free Full Text]
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  17. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR, for the Steering Committees of the Pentasaccharide Orthopedic Prophylactic Studies. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery. A meta-analysis of 4 randomized studies. Arch Intern Med (2002) 162:1833–1840.[Abstract/Free Full Text]
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  19. Food and Drug Administration (USA). Prescribing Information on fondaparinux. http://www.fda.gov/medwatch/SAFETY/2005/MAY_PI/Arixtra_PI.pdf.
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  21. Turpie AGG, Bauer KA, Caprini JA, Comp PP, Gent M, Muntz JE. Fondaparinux combined with intermittent pneumatic compression versus intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison. J Thromb Haemost (2007) 5:1854–1861.[CrossRef][Web of Science][Medline]
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  23. Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, Turpie AG, Egberts JF, Lensing AW, ARTEMIS Investigators. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ (2006) 332:325–329.[Abstract/Free Full Text]
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