Introduction

Fondaparinux is the first synthetic, selective Factor Xa inhibitor. Factor Xa is an important coagulation factor located at the junction of the extrinsic and intrinsic coagulation pathways [11]. Consequently, inhibition of Factor Xa results in effective inhibition of the coagulation cascade and inhibition of thrombin generation. Unlike unfractionated heparin (UFH) and low molecular weight heparin (LMWH), fondaparinux is a single chemical entity (1728 Dalton) comprising five saccharides designed specifically to bind to antithrombin [8]. In experimental animal models, fondaparinux was associated with less bleeding than was UFH, at an equivalent antithrombotic concentration [8]. In humans, a therapeutic dose of fondaparinux did not prolong bleeding time [2].

A dose-ranging study in total hip replacement (THR) [16] demonstrated a statistically significant dose-response for the prevention of venous thromboembolism (VTE) in the range from 0.75 mg to 8.0 mg. Moreover, the results suggested that fondaparinux had the potential to improve significantly the risk-benefit ratio for VTE prophylaxis compared with LMWH. Based on the results, a 2.5 mg, once-daily dosage of fondaparinux was selected for the following four phase 3 studies. And these studies [1, 3, 10, 17] demonstrated that a once-daily fondaparinux 2.5 mg significantly improved the risk–benefit ratio for VTE prophylaxis in major orthopaedic surgery of the lower limbs. Eriksson BI et al. [4] reported that 4-week fondaparinux treatment was superior to 1-week fondaparinux in VTE prophylaxis for the patients with hip fracture surgery.

In the United States and Europe, a once-daily subcutaneous dose of 2.5 mg fondaparinux is indicated and used as VTE prophylaxis in fracture surgery, hip/knee replacement surgery and abdominal surgery [12, 15]. In the Seventh American College of Chest Physicians (ACCP) Guidelines on Prevention of VTE [7], fondaparinux, along with LMWH and vitamin K antagonists, was recommended with a Grade 1A rating for VTE prophylaxis in TKR and THR. Fondaparinux were the only anticoagulant recommended with a Grade 1A rating for hip-fracture surgery.

In Japan, UFH and warfarin are indicated for VTE prophylaxis, but there is no randomised clinical trial (RCT) in Japanese patients. LMWH has no indication for VTE prophylaxis. Therefore, no established active control is available in Japan.

These studies was conducted to compare the efficacy and safety of fondaparinux with a placebo, and to evaluate the dose-response relationship between 0.75 mg, 1.5 mg, 2.5 mg, and 3.0 mg of fondaparinux and the incidence of VTE, in TKR or THR surgery.

Methods

Patients

Patients of either gender were eligible if their age was 20 years or greater, and they were scheduled for TKR or THR surgery or revision surgery for TKR or THR. Exclusion criteria were: (a) active, clinically significant bleeding, (b) bleeding tendency/disorder (e.g., ulcer of the digestive tract, diverticulitis of the digestive tract, colitis, acute bacterial endocarditis, severe hypertension, or severe diabetes), (c) severe hepatic disorder, (d) hypersensitivity to UFH or LMWH, (e) requirement of an indwelling intrathecal or epidural catheter during the treatment period (after the first dose of test drug, until the completion of venography), or (f) brain, spine, or ophthalmologic surgery within the 3 months preceding enrollment. Patients with: (g) a body weight less than 40 kg (88 lb), or (h) severe renal disorder (serum creatinine concentration >2.0 mg/dL [180 μmol/L]) were also excluded.

The use of UFH, LMWH, heparinoids, antithrombin agents (argatroban), oral anticoagulants (warfarin), fibrinolytic agents and dextrans was prohibited, beginning 1 week before the first dose of study drug and study period. Nonsteroidal anti-inflammatory drugs (NSAIDs) and antiplatelet medications were also strongly discouraged during the treatment period, but were allowed, if necessary, in a condition of unchanged regimen. During the study, the use of intermittent pneumatic compression or a venous foot pump was prohibited during surgery, and continuous spinal and epidural anaesthesia (intrathecal or epidural catheterisation) were prohibited, beginning 2 hours before the first dose of study drug and study period.

Study design

There are two studies described in this paper, Study 1 for TKR and Study 2 for THR, both of which are multicentre, randomised, double-blind, placebo-controlled, parallel-group, dose–response studies of subcutaneous fondaparinux.

The studies were conducted according to the provisions of the revised Declaration of Helsinki and the guidelines for Good Clinical Practice. The study protocols were approved by the institutional review board (IRB) at each centre. Written informed consent was obtained from each patient before enrollment in the trial. A Central Independent Adjudication Committee for Efficacy (CIACE) evaluated diagnostic images in a blind manner for the incidence of VTE. A Central Independent Adjudication Committee for Safety (CIACS) evaluated all reported bleeding events and adverse events (AEs), also in a blind manner.

Outcome measures

The primary efficacy outcome was assessed by the rate of VTE [defined as deep vein thrombosis (DVT), pulmonary embolism (PE), or both] up to day 11. Patients were examined for deep-vein thrombosis by systematic bilateral ascending venography of the legs between day 11 and day 17, but no more than 2 days after the last injection of study drug, or earlier if thrombosis was clinically suspected. Symptomatic PE was confirmed by a lung scan indicating a high probability of PE, pulmonary angiography, or helical computed tomography, or at autopsy.

The primary safety outcome was the incidence of major bleeding, which included fatal bleeding; bleeding that was retroperitoneal, intracranial, or intraspinal or that involved any other critical organ; bleeding leading to reoperation; and overt bleeding with a bleeding index of 2 or more. The bleeding index was calculated as the number of units of packed red cells or whole blood transfused plus the haemoglobin values before the bleeding episode minus the haemoglobin values after the episode (in grams per decilitre).

Treatment and regimen

Patients were assigned to receive a once-daily subcutaneous injection of fondaparinux (0.75 mg, 1.5 mg, 2.5 mg, or 3.0 mg) or placebo. Treatment was scheduled from Day 2 to Days 11–15 (at least 10 days, with the day of surgery defined as Day 1).

The first dose of study drug was administered at 24 ± 2 h after surgery, before 11:00 pm on Day 2; subsequent doses were administered at 9:00 am ± 2 h, from Days 3 to 15. The first dose on Day 2 and the second dose on Day 3 were at least 12 hours apart.

Disposable pre-filled syringes containing 0.75 mg, 1.5 mg, 2.5 mg, or 3.0 mg of fondaparinux or placebo were supplied by Sanofi-Winthrop Industrie (Notre Dame de Bondeville, France). Fondaparinux and placebo were provided as isotonic solutions in 0.25 ml, and placebo was isotonic sodium chloride. All pre-filled syringes were indistinguishable from one another.

Results

Disposition of patients

Study 1

Study 1 was conducted from October 2001 to August 2003 at 56 centres in Japan. A total of 432 patients were enrolled and randomised. Six of the 432 patients did not receive any study drug and were excluded from further analyses, with 426 patients remaining in the “all treated patients” (ATP) population (339 in the fondaparinux groups and 87 in the placebo group). A total of 29 (6.8%) withdrew. There were no statistically significant differences in values for demographic variables (Table 1) among the five treatment groups. The physical prophylaxis during the study is summarised in Table 2.

Table 1 Summary of demographic characteristics: all-treated-patients population
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Table 2 Summary of patients who used physical methods for DVT prophylaxis from surgery to end of treatment: all-treated-patients population
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Study 2

Study 2 was conducted from October 2001 to June 2003 at 57 centers in Japan. A total of 411 patients were enrolled and randomised. Five out of 411 patients did not receive any study drug and were excluded from further analyses, with 406 patients remaining in the ATP population (324 in the fondaparinux groups and 82 in the placebo group). A total of 25 (6.2%) withdrew. There were no statistically significant differences in the values for demographic variables (Table 1) among the five treatment groups. The use of physical prophylaxis is summarised in Table 2.

Efficacy

Study 1 (TKR)

In the intent to treat (ITT) population, 65.3%, 34.2%, 21.3%, 16.2% and 9.5% of the patients showed VTE in the groups given placebo, 0.75 mg, 1.5 mg, 2.5 mg, and 3.0 mg of fondaparinux respectively. The Cochran-Armitage trend test demonstrated a statistically significant difference (P < 0.001) in VTE incidence by fondaparinux, compared with placebo (Fig. 1). VTE incidence in all groups receiving fondaparinux was significantly lower (P < 0.001) than in the group receiving placebo, by Fisher’s exact probability tests. The calculated relative risk reductions (RRR) of VTE with 0.75 mg, 1.5 mg, 2.5 mg and 3.0 mg of fondaparinux, compared with placebo, were 47.6%, 67.4%, 75.2%, and 85.5% respectively.

Fig. 1
figure 1

Venous thromboembolism: incidence in all groups. VTE: venous thromboembolism; TKR: total knee replacement; THR: total hip replacement; RRR: relative risk reduction * P < 0.001, † P < 0.01, ‡ P = 0.007 (Fisher’s exact probability test)

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Study 2 (THR)

In the ITT population, 33.8%, 24.2%, 4.6%, 7.4% and 14.3% of the patients showed VTE in the groups receiving placebo, 0.75 mg, 1.5 mg, 2.5 mg, and 3.0 mg of fondaparinux respectively. The Cochran-Armitage trend test demonstrated a statistically significant reduction (P < 0.001) in VTE incidence by fondaparinux, compared with placebo (Fig. 1). The groups receiving 1.5 mg, 2.5 mg, or 3.0 mg fondaparinux were significantly lower (P < 0.01, P < 0.01 and P = 0.007 respectively) from the placebo group by Fisher’s exact probability tests. RRR of VTE with 0.75 mg, 1.5 mg, 2.5 mg and 3.0 mg of fondaparinux were 28.4%, 86.4%, 78.1%, and 57.7% respectively, compared with placebo.

Safety evaluation

The incidences of major and minor bleeding are presented Table 3. In the studies, major bleeding during the treatment period was the primary safety endpoint.

Table 3 The proportion of patients with bleeding by treatment group: all-treated-patients population, Study 1 (TKR)
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In Study 1 (TKR), the incidence of major bleeding was 1.1% with placebo and 0%, 0%, 1.2%, and 1.2% with 0.75 mg, 1.5 mg, 2.5 mg, and 3.0 mg of fondaparinux respectively. The incidences of major or minor bleeding among the treatment groups were not statistically significant; there was no fatal bleeding, bleeding in a critical organ, or bleeding leading to re-operation. All of the patients who experienced major bleeding received >2 units of blood. Two patients treated with fondaparinux had bleeding at the surgical site. One patient in the placebo group had major bleeding in the gastrointestinal tract.

There were no deaths during the study; three severe AEs were reported in two patients. One patient (receiving fondaparinux 3.0 mg) experienced skin necrosis that was not considered by the investigator to be related to the study drug; another patient (receiving placebo) developed a gastric ulcer and had a gastrointestinal hemorrhage. Both patients recovered without sequelae from these events.

There was no statistically significant difference in drug-related AEs among treatment groups.

In Study 2 (THR), there were no statistically significant differences in major or minor bleeding events between the fondaparinux groups and the placebo group. The incidences of major and minor bleeding events by fondaparinux were not dose-dependent. Three cases of major bleeding included a reduction in haemoglobin of >2 g/dL in one patient (receiving fondaparinux 2.5 mg) and transfusion of more than two units of blood in two patients (receiving fondaparinux 0.75 mg, 2.5 mg). No fatal bleeding occurred. Furthermore, although clinically abnormal blood loss occurred in more patients in the 2.5 mg fondaparinux group, all abnormal blood loss in this group was considered to be associated with surgery and not related to fondaparinux treatment.

There were no deaths during the study; however, three severe AEs were reported in two patients. One patient (0.75 mg fondaparinux) had hepatic dysfunction on Day 4 that was not related to test drug. The second patient (0.75 mg fondaparinux) experienced a cerebral infarction and supraventricular tachycardia on Day 5 but recovered; both events were considered possibly related to the test drug.

Discussion

In both studies, fondaparinux groups demonstrated significant dose-dependent effect in VTE incidence. 1.5 mg and 2.5 mg fondaparinux respectively reduced risk of VTE by 67.4% and 75.2% in the THR study, and that of VTE by 86.4% and 78.1% in the TKR study, compared with placebo. Fondaparinux also showed a good safety profile, in terms of bleeding complication, and the incidences of bleeding events by fondaparinux were not dose-dependent in both the TKR and THR studies.

In the United States, VTE is recognised as a silent, life-threatening disease and VTE prophylaxis is considered critical in a variety of medical settings, not only in postsurgical patients but also in acutely ill medical patients [7]. It is estimated that there are approximately 2 million cases of DVT and 600,000 cases of PE—including 60,000 fatal cases—per year in the United States [9]. In contrast, in Japan, 3,492 PE cases were estimated in 1996, based on surveillance by the Japanese Government [13, 14]. Because of the reported lower incidence of VTE in Japan, the importance of VTE prophylaxis has not been well-recognised by Japanese physicians.

Recently, Fujita et al. reported that, similar to Western data, VTE incidences of 48.6% and 22.6% followed TKR and THR surgery respectively, in Japanese patients [5].

According to the Sixth ACCP Guidelines [6], overall RRR of VTE following TKR surgery was 33% with low-dose UFH (two studies) and 52% with LMWH (13 studies), and the overall RRR of VTE following THR surgery was 45% with low dose UFH (11 studies) and 70% with LMWH (30 studies).

In Study 2 for THR, the incidence of VTE in both the 2.5 mg and 3.0 mg fondaparinux groups was slightly higher than that of the 1.5 mg group. However, there were no statistically significant differences among these groups; therefore, these differences could be observed by chance. There were no differences in demographic or VTE risk factors among the groups; however, there were more patients with ischaemic heart disease or diabetes in the 3.0 mg group, and it is speculated that these disorders may affect the efficacy of anticoagulant therapy. The incidences of VTE with 1.5 mg to 2.5 mg of fondaparinux in Study 2 for THR are similar to those in other published reports [1, 3, 10, 17].

The efficacies of these studies were completely equal to that in the United States and Europe. Major bleeding associated with fondaparinux was reported in 2.1% (11/517) of patients undergoing TKR [1], and 1.8% [17] and 4.1% [10] in THR; however, fatal bleeding or critical organ bleeding was not reported in Western studies. In the present studies, major bleeding occurred in one patient (0.6%) in the placebo group, one patient (0.6%) at 0.75 mg, 3 (1.8%) at 2.5 mg, and one patient (0.6%) at 3.0 mg of fondaparinux. The incidences of major bleeding in Japanese studies were somewhat lower than in the United States and Europe. It is considered that lower incidence of major bleeding could be due to the initial administration fondaparinux 24 hours after operation. Compared with overseas data, the efficacy and safety findings in this study support a once-daily dose of 2.5 mg fondaparinux is favorable for VTE prophylaxis in Japanese patients undergoing TKR or THR.

Finally, our study demonstrated that fondaparinux effectively prevents VTE without increasing the risk of bleeding or other AEs in patients undergoing TKR or THR. Fondaparinux could be a promising option for the prevention of VTE major orthopedic surgery of the lower limbs.

Conclusion

  1. 1)

    The incidence of VTE in Japanese TKR and THR patients are similar to Western data.

  2. 2)

    Once-daily, subcutaneous doses of 1.5 mg to 2.5 mg fondaparinux have a favourable risk (bleeding and other AEs) to benefit (VTE prevention) ratio in these patients.

  3. 3)

    Fondaparinux, the first in a new class of anticoagulants, could be one of the best options for managing the risk of VTE in patients at major orthopaedic surgery of the lower limbs.

In order to define optimal daily dose of fondaparinux for Japanese patients, further clinical study is needed.