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(Chest. 2003;124:371S-378S.)
© 2003 American College of Chest Physicians

New Pentasaccharides for the Prophylaxis of Venous Thromboembolism*

Clinical Studies

Alexander G. G. Turpie, MD; Bengt I. Eriksson, MD; Kenneth A. Bauer, MD and Michael R. Lassen, MD

* From the Hamilton Health Sciences (Dr. Turpie), Hamilton General Hospital, Hamilton, ON, Canada; Sahlgrenska University Hospital/OSTRA (Dr. Eriksson), Goteborg, Sweden; VA Boston Healthcare System and Beth Israel Deaconess Medical Center (Dr. Bauer), Boston, MA; and University of Copenhagen Hillerod (Dr. Lassen), Hillerod, Denmark.

Correspondence to: Alexander G. G. Turpie, MD, Department of Medicine, Hamilton Health Sciences-General Hospital, 237 Barton St East, Hamilton, ON, L8L 2X2 Canada; e-mail: turpiea{at}mcmaster.ca


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

Key Words: deep-vein thrombosis • enoxaparin • fondaparinux • low-molecular-weight heparin • orthopedic surgery • pentasaccharide • thromboprophylaxis • venous thromboembolism


   Introduction
TOP
 Abstract
 Introduction
Phase II Dose-Ranging Study...
 Phase III, Randomized, Double...
 Duration of Thromboprophylaxis...
 Conclusion
 References
 
Synthetic pentasaccharides are a new class of antithrombotic compounds.1 The first, fondaparinux, has been approved for use in thromboprophylaxis after major orthopedic surgery, and its clinical development is ongoing. The second, idraparinux, is currently in clinical development. Both selectively target a single factor of the coagulation cascade, namely activated factor X (factor Xa).2 3 They differ mainly in their pharmacokinetic characteristics. Administered subcutaneously, fondaparinux has a dose-independent elimination half-life of 17 h allowing once-daily administration.4 Idraparinux has a longer half-life that allows once-weekly subcutaneous administration.3 In a recent phase II trial,5 idraparinux showed promising results in secondary prevention of deep-vein thrombosis. The benefit-to-risk ratio of fondaparinux has been investigated in a number of completed trials6 7 8 9 10 11 12 13 14 15 in orthopedic surgery, and is being investigated in a number of ongoing trials encompassing arterial and venous thromboembolism disorders. This article presents an overview of the results obtained with fondaparinux in the prophylaxis of venous thromboembolism in patients undergoing major orthopedic surgery of the lower limbs. The clinical program of fondaparinux in thrombosis prophylaxis currently includes approximately 9,000 patients (Table 1 ).


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  		Table 1. Trials on Fondaparinux in Major Orthopedic Surgery

 
Major orthopedic surgery represents one of the highest-risk surgical procedures for thrombotic complications. Despite progress in pharmacologic thromboprophylaxis,16 17 the incidence of venous thromboembolism has remained relatively constant since the 1980s.18 19 Based on the results of contrast venography, the rates of venous thromboembolism in patients receiving low-molecular-weight heparins, among the most widely used agents in this surgical setting, still range between 15% and 33%.16 More effective and safe thromboprophylactic drugs are therefore needed.

The efficacy and safety of fondaparinux in the prevention of venous thromboembolism in major orthopedic surgery has been studied in six trials6 7 8 9 10 11 , including one phase II dose-ranging study, four phase III studies involving various major orthopedic settings, and one trial of extended duration prophylaxis in hip fracture surgery. In all these studies, the primary efficacy end point was the incidence of venous thromboembolic events consisting of a composite of deep-vein thrombosis detected by mandatory bilateral venography, documented symptomatic deep-vein thrombosis, or pulmonary embolism. Bilateral venography is the standard recommended method for the evaluation of new antithrombotic drugs in patients undergoing major orthopedic procedures, as it is considered to be the most accurate and reliable method of detecting deep-vein thrombosis in asymptomatic patients.20 21 It is noteworthy that asymptomatic deep-vein thrombosis carries a substantial risk of pulmonary embolism,22 and that in several meta-analyses of data from trials23 24 25 26 27 28 performed in various clinical settings, including major orthopedic surgery, the reduction in asymptomatic venographically proven deep-vein thrombosis with anticoagulants was associated with a reduction in symptomatic pulmonary embolism. Thus, venographically detected deep-vein thrombosis is widely accepted as an appropriate surrogate for important clinical outcomes.

The main safety end point of the fondaparinux trials6 7 8 9 10 11 in major orthopedic surgery was major bleeding. Major bleeding was a composite of fatal bleeding, nonfatal bleeding in a critical organ, bleeding requiring reoperation, or overt bleeding with a bleeding index of two or more. The bleeding index was calculated as follows: (number of units of packed RBCs or whole blood transfused) + (prebleeding-postbleeding hemoglobin values in grams per deciliter). All efficacy and safety outcomes were adjudicated by a central independent committee, the members of which were unaware of treatment assignment.


   Phase II Dose-Ranging Study of Fondaparinux in Elective Hip Replacement Surgery
TOP
 Abstract
 Introduction
 Phase II Dose-Ranging Study...
Phase III, Randomized, Double...
 Duration of Thromboprophylaxis...
 Conclusion
 References
 
The thromboprophylactic dosage regimen of fondaparinux in orthopedic surgery was determined from a large phase II, multicenter, randomized, parallel, double-blind, dose-ranging trial6 in patients undergoing surgery for elective total hip replacement, the PENTATHLON trial. Fondaparinux was administered subcutaneously once daily at five different doses, starting 4 h to 8 h postoperatively. The comparator was the low-molecular-weight heparin enoxaparin administered at a dose of 30 mg bid, starting postoperatively. Both drugs were administered for a minimum of 5 days and a maximum of 10 days. The primary efficacy end point was the incidence of venous thromboembolic events determined by bilateral ascending venography performed at day 10 or at hospital discharge (whichever came first), but not before day 5.

A total of 933 patients were treated. Approximately 85% of the surgical procedures were primary hip replacements, and 56% of the treated patients received cemented prostheses. Sixty-four percent of the treated patients (593 patients) were eligible for the efficacy analysis. Doses of fondaparinux > 3 mg were associated with significant bleeding risk and were discontinued in accordance with prespecified termination protocols.

Fondaparinux showed a statistically significant dose-dependent effect for both efficacy and safety (p = 0.002 and p < 0.001, respectively) [Fig 1 ]. The rate of venous thromboembolism was significantly lower in the fondaparinux 3.0 mg group than in the enoxaparin group (p = 0.01), and the incidence of major bleeding was comparable. The optimal dose of fondaparinux for further phase III trials was determined on the basis of statistical calculations from logit modeling for efficacy and safety. A subcutaneous regimen of 2.5 mg of fondaparinux qd, starting 6 h postoperatively, was selected.



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  		Figure 1. PENTATHLON trial.6 Efficacy and safety dose dependence. RRR = relative risk reduction; NS = nonsignificant.

 

   Phase III, Randomized, Double-Blind Studies of Fondaparinux in the Prevention of Venous Thromboembolism in Major Orthopedic Surgery
TOP
 Abstract
 Introduction
 Phase II Dose-Ranging Study...
 Phase III, Randomized, Double...
Duration of Thromboprophylaxis...
 Conclusion
 References
 
The thromboprophylactic efficacy and safety of fondaparinux were studied in four multicenter prospective, randomized, double-blind, comparative, parallel-group studies.7 8 9 10 These four trials were designed in parallel for a preplanned meta-analysis to be done.29 Two studies, EPHESUS (European Pentasaccharide Hip Elective Surgery Study)9 and PENTATHLON 2000,10 were conducted in elective hip replacement surgery patients; one study (PENTAMAKS [Pentasaccharide in Major Knee Surgery])7 was in elective major knee surgery patients; and one study (PENTHIFRA [Pentasaccharide in Hip Fracture Surgery])8 was in patients undergoing surgery for hip fracture (Table 1) . In all these trials, fondaparinux was administered subcutaneously at the dose of 2.5 mg qd, starting 6 ± 2 h postoperatively. In the PENTATHLON 2000 and PENTAMAKS trials,7 10 fondaparinux was compared to the 30 mg bid regimen of enoxaparin (starting 12 to 24 h postoperatively); in the two other studies,8 9 fondaparinux was compared to the 40 mg qd regimen of enoxaparin (starting 12 h before surgery and followed by a second injection 12 to 24 h postoperatively). Throughout the treatment period, intermittent pneumatic compression, dextran, and thrombolytic or anticoagulant agents were prohibited. The primary efficacy outcome was venous thromboembolism up to day 11 after surgery. The duration of follow-up was 6 weeks. The adjudication committee was the same for the four studies (Fig 2 ).7 8 9 10



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  		Figure 2. A meta-analysis of four trials7 8 9 10 of fondaparinux in major orthopedic surgery, with incidence of venous thromboembolism up to day 11 (primary efficacy), and odds reduction per study and estimated common odds reduction (percent and 95% confidence intervals) with fondaparinux relative to enoxaparin. p = 0.068, homogeneity test for elective hip replacement studies; p = 0.058, homogeneity test for all studies; p = 0.16, homogeneity test for the three types of surgery.

 
Fondparinux in Elective Hip Replacement Surgery
The EPHESUS study9 enrolled 2,309 patients undergoing hip replacement surgery, and 1,827 patients (79%) were included in the efficacy analysis. Fondaparinux significantly reduced the incidence of venous thromboembolism from 9.2% (85 of 919 patients) with enoxaparin to 4.1% (37 of 908 patients), a relative risk reduction of 55.9% (95% confidence interval, - 72.8 to - 33.1%; p < 0.001). There was no difference between the two groups in the incidence of major bleeding or death.

A total of 2,275 hip replacement surgery patients were recruited in the PENTATHLON 2000 study.10 Among 1,584 patients (69.6%) evaluable for primary efficacy, 6.1% (48 of 787 patients) in the fondaparinux group and 8.3% (66 of 797 patients) in the enoxaparin group acquired venous thromboembolism, a relative risk reduction of 26.3% (95% confidence interval, - 52.8 to + 10.8%; p = 0.099). Again, there was no difference between the two groups in the incidence of major bleeding or death.

When the results of these two studies in elective hip replacement surgery were pooled (MR Lassen, AGG Turpie, KA Bauer; unpublished data; 2003) fondaparinux reduced the incidence of venous thromboembolism from 8.8% (151 of 1,716 patients) in the enoxaparin group to 5.0% (85 of 1,695 patients). The relative risk reduction of 43.0% in favor of fondaparinux was highly significant (p < 0.001; 95% confidence interval, - 57.9 to - 24.6%). Overall, fondaparinux was superior to enoxaparin irrespective of age, gender, obesity (body-mass index >= 30), type of anesthesia (general/regional only), type of prosthesis (cemented vs noncemented), and duration of surgery. Bleeding associated with a bleeding index of at least 2 occurred in 60 of the 2,268 fondaparinux-treated patients (2.6%) and in 37 of the 2,262 enoxaparin-treated patients (1.6%, p = 0.026). However, the rate of clinically important bleeding, ie, fatal bleeding, critical organ bleeding, or bleeding leading to reoperation, was low with no difference between the two groups. 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. Of note, in patients in whom fondaparinux therapy was initiated >= 6 h after surgical closure, the rate of major bleeding was 2.0% (29 of 1,434 patients). Finally, the incidence of death was low and comparable in the two treatment groups.

Fondaparinux in Hip Fracture Surgery
In the PENTHIFRA study,8 1,711 patients undergoing surgery for fracture of the upper third of the femur were recruited. Primary efficacy analysis was assessed in 1,250 patients (73.1%). The incidence of venous thromboembolism by day 11 was 8.3% (52 of 626 patients) in the fondaparinux group and 19.1% (119 of 624 patients) in the enoxaparin group, a relative risk reduction of 56.4% (95% confidence interval, - 70.3 to - 39.0%; p < 0.001). There was no difference between the two groups in the incidence of major bleeding or death.

Fondaparinux in Elective Major Knee Surgery
The PENTAMAKS trial,7 performed in patients undergoing knee replacement surgery, involved 1,049 patients; the primary efficacy outcome was analyzed in 724 patients (69.0%). The incidence of venous thromboembolism was 12.5% (45 of 361 patients) and 27.8% (101 of 363 patients) in the fondaparinux and enoxaparin groups, respectively. Fondaparinux significantly reduced the incidence of venous thromboembolism compared with enoxaparin, with a relative risk reduction of 55.2% (95% confidence interval, - 70.2 to - 36.2%; p < 0.001). There were 11 major bleeding episodes in the fondaparinux group (including 9 episodes of overt bleeding with a bleeding index of >= 2) and one in the enoxaparin group (p = 0.006), but there were no significant differences between the two groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ. Finally, there was no difference in mortality between the two groups.

Fondaparinux in Major Orthopedic Surgery: a Meta-analysis of the Four Randomized Studies
A preplanned meta-analysis29 of the four studies was performed. Overall, 7,344 patients undergoing major orthopedic surgery of the lower limbs were randomized into the four phase III studies. Their ages ranged from 18 to 101 years, and their body weight varied from 30 to 226 kg. The patient population was 59% female. General anesthesia was used in 51.6% of the patients, epidural or spinal anesthesia was used in 45.1% of the patients, and a combination of both was used in 3.4%.

A total of 5,385 patients (73.3%) were included in the analysis of primary efficacy. Fondaparinux reduced the incidence of venous thromboembolism by day 11 from 13.7% in the enoxaparin-treated group to 6.8% (Fig 2) . The common odds reduction was 55.2% (95% confidence interval, - 63.1 to - 45.8%; p < 0.001). Importantly, the superior efficacy of fondaparinux over enoxaparin was also demonstrated for proximal deep-vein thromboses (Table 2 ), which are more prone to embolize30 31 32 with a common odds reduction of 57.4% (95% confidence interval, - 72.3 to - 35.6%). The incidences of fatal and nonfatal pulmonary embolism up to day 49 were low (< 1%) and did not differ between the two groups. However, the incidence of symptomatic events during follow-up should be interpreted with caution because most patients who had an abnormal venogram finding were treated with therapeutic doses of anticoagulants. In addition, approximately 40% of the remaining patients who were free of venous thromboembolism at day 11 received extended prophylaxis with low-molecular-weight heparins or vitamin K antagonists during follow-up. Since venography is not performed routinely in orthopedic surgical patients and many are not treated with extended prophylaxis, the rates of venous thromboembolism observed during follow-up are likely to be lower than would have been observed in clinical practice. The number of patients treated for a venous thromboembolic event by day 11, based on the local site assessment of primary efficacy, was significantly lower in the fondaparinux group (5.5%, 199 of 3,616 patients) than in the enoxaparin group (9.7%, 351 of 3,621 patients; p < 0.001), consistent with the lower rates of venous thromboembolism observed. Overall, fondaparinux showed superior efficacy relative to enoxaparin in primary prophylaxis irrespective of age, gender, obesity (body mass index >= 30), type of anesthesia (general/regional only), type of prosthesis (cemented vs noncemented), and duration of surgery. Elastic stockings were used in 71.6% of the patients. Their use did not influence the rates of venous thromboembolic events or the superiority of fondaparinux over enoxaparin with respect to the primary efficacy outcome.33


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  		Table 2. Incidence of Efficacy and Safety Outcomes Up to Day 11 in the Meta-analysis of Four Trials on Fondaparinux in Major Orthopedic Surgery*

 
Safety analysis was performed in 7,237 patients (98.5% of the randomized population; Table 2 ). There were more adjudicated episodes of major bleeding in the fondaparinux group (96, 2.7%) than in the enoxaparin group (63, 1.7%). In both treatment groups, major bleeding occurred mostly within the first 5 days after surgery.34 Beyond 5 days after surgery, the incidence was 0.4% in the fondaparinux group and 0.3% in the enoxaparin group. Importantly, the difference in major bleeding between the two treatment groups was mainly accounted for by an excess of bleeding with a bleeding index of >= 2. The clinical relevance of these bleeding events is uncertain because they did not reflect in a difference in fatal bleeding, critical organ bleeding, bleeding leading to reoperation, wound infection, or complications at the surgical site leading to prolonged hospitalization or rehospitalization between the two groups. Minor bleeding events occurred in 3.0% of patients in the fondaparinux group and in 2.7% in the enoxaparin group. Finally, the number of deaths from any cause and the number of any other adverse events did not differ between the two treatment groups.

Role of the Timing of the First Administration of Fondaparinux
The influence of the timing of the first administration of thromboprophylactic treatments relative to the surgical procedure on their benefit-to-risk ratio is still debated,16 particularly with respect to low-molecular-weight heparins.35 36 37 38 In the phase II and III trials of fondaparinux in major orthopedic surgery, fondaparinux therapy was to be initiated 6 ± 2 h postoperatively. A post hoc analysis of the phase III trials showed that in patients who received the first injection of fondaparinux >= 6 h after skin closure, the incidence of venous thromboembolism was comparable to that observed in patients who received this injection < 6 h after skin closure (p = 0.57).39 In contrast, the incidence of major bleeding was significantly lower when the first injection was administered >= 6 h after skin closure (46 of 2171 patients, 2.1%) rather than earlier (42 of 1,300 patients, 3.2%; p = 0.045). Based on these observations, health authorities recommend initiating fondaparinux treatment at least 6 h after orthopedic surgery.

Role of the Duration of Administration of Fondaparinux
The duration of pharmacologic thromboprophylaxis in patients undergoing surgical procedures is important to consider.16 This point was confirmed in four trials of fondaparinux in orthopedic surgery.34 In these four trials, fondaparinux and enoxaparin were administered for a duration from 5 to 11 days after surgery. Logistic regression analyses showed that the efficacy of both fondaparinux and enoxaparin in preventing venous thromboembolism was significantly increased by longer treatment duration (p < 0.001 for fondaparinux and p = 0.0025 for enoxaparin) and that the incidence of venous thromboembolism was higher in patients treated for <= 5 days than in patients treated for > 5 days. Thus, when fondaparinux was administered for < 5 days, the incidence of venous thromboembolism was 8.7%, as compared to 5.2% when it was administered for 9 to 11 days. Respective figures in enoxaparin-treated patients were 17.0% and 11.7%. The optimal duration of thromboprophylaxis beyond 10 days after surgery was further addressed in the PENTHIFRA-Plus trial in hip fracture surgery patients.11


   Duration of Thromboprophylaxis With Fondaparinux in Hip Fracture Surgery
TOP
 Abstract
 Introduction
 Phase II Dose-Ranging Study...
 Phase III, Randomized, Double...
 Duration of Thromboprophylaxis...
Conclusion
 References
 
While the benefit of thromboprophylaxis for up to 4 weeks after surgery has now been well established in elective hip replacement surgery,16 40 41 42 extended prophylaxis has not been investigated in hip fracture surgery, a group of patients in the highest risk category for postoperative venous thromboembolism.16 17 In the PENTHIFRA trial8 in patients undergoing hip fracture surgery, a 1-week treatment with fondaparinux reduced the risk of venous thromboembolism by > 55% compared with enoxaparin to an absolute rate of 8.3%. It was uncertain whether a 4-week fondaparinux regimen would provide additional benefit over the already very substantial gain with 1-week prophylaxis. In the randomized, double-blind PENTHIFRA-Plus trial,11 after an initial 1-week prophylaxis with fondaparinux, patients undergoing hip fracture surgery were assigned to an additional 3 weeks of treatment with a once-daily subcutaneous injection of either 2.5 mg of fondaparinux or placebo. The primary efficacy outcome was venous thromboembolism occurring during the 3 additional weeks of treatment. The main safety outcome was major bleeding.

A total of 656 patients were randomized, and the primary efficacy outcome was assessed in 428 patients (65.2%). Fondaparinux reduced the incidence of venous thromboembolism from 35.0% (77 of 220 patients) in the placebo group to 1.4% (3 of 208 patients), with a relative reduction in risk of 95.9% (95% confidence interval, - 99.7 to - 87.2%; p < 0.001) [Fig 3 ]. Importantly, the incidence of symptomatic venous thromboembolism was also significantly lower with fondaparinux (0.3%, 1 of 326 patients) than with placebo (2.7%, 9 of 330 patients; relative reduction in risk, 88.8%; p = 0.021). Extended prophylaxis with fondaparinux was well tolerated. Although there was a trend toward more major bleeding in the fondaparinux group (2.4%, eight patients) compared with placebo (0.6%, two patients; p = 0.063), there were no differences between the two groups in the incidence of clinically important bleeding. No fatal bleeding or bleeding in a critical organ occurred in either treatment group. Bleeding was associated with a need for reoperation in two patients in each group. In both the fondaparinux and placebo groups, one of these episodes led to the discontinuation of study treatment. Furthermore, there were no differences between the two groups in the overall incidence of other adverse events and in overall mortality.



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  		Figure 3. PENTHIFRA-Plus trial11 : incidence of adjudicated venous thromboembolism up to day 32. RR = reduction in risk.

 

   Conclusion
TOP
 Abstract
 Introduction
 Phase II Dose-Ranging Study...
 Phase III, Randomized, Double...
 Duration of Thromboprophylaxis...
 Conclusion
References
 
Clinical trials evaluating fondaparinux, the first of a new class of synthetic antithrombotic agents, in patients undergoing major orthopedic surgery, demonstrated that at the subcutaneous dose of 2.5 mg qd, fondaparinux was more effective than enoxaparin in preventing venous thromboembolism without increasing the risk of clinically relevant bleeding. Overall, fondaparinux achieved optimal efficacy and safety when treatment was initiated >= 6 h after the surgical procedure. In patients undergoing hip fracture surgery, the optimal duration of treatment with fondaparinux was shown to be 4 weeks postoperatively.

The beneficial effect of fondaparinux may be explained by its specific mechanism of action, ie, selective factor Xa inhibition, and/or by its pharmacologic properties, including a rapid onset of action, optimal half-life, and highly reproducible and predictable linear pharmacokinetics.4 Fondaparinux has been approved for the prevention of venous thromboembolism following major orthopedic surgery in various countries, including the United States of America, European countries, and Australia. The benefit-to-risk ratio of fondaparinux in other thromboprophylactic indications remains to be evaluated.


   Footnotes
 
The authors have served as consultants to Sanofi-Synthelabo and NV Organon.

Dr. Turpie has received an honorarium from the American College of Chest Physicians for the preparation of this article.


   References
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 Abstract
 Introduction
 Phase II Dose-Ranging Study...
 Phase III, Randomized, Double...
 Duration of Thromboprophylaxis...
 Conclusion
 References
 

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