Fondaparinux Sodium (Page 9 of 13)

14.2 Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery

In a noncomparative, unblinded manner, 737 patients undergoing hip fracture surgery were initially treated during the peri-operative period with fondaparinux sodium 2.5 mg once daily for 7 ± 1 days. Eighty-one (81) of the 737 patients were not eligible for randomization into the 3‑week double-blind period. Three hundred twenty-six (326) patients and 330 patients were randomized to receive fondaparinux sodium 2.5 mg once daily or placebo, respectively, in or out of the hospital for 21 ± 2 days. Patients ranged in age from 23 to 96 years (mean age 75 years) and were 29% men and 71% women. Patients were 99% Caucasian and 1% other races. Patients with multiple traumas affecting more than one organ system or serum creatinine level more than 2 mg/dL (180 micromol/L) were excluded from the trial. The primary efficacy endpoint, venous thromboembolism (VTE), was a composite of documented deep vein thrombosis (DVT) and/or documented symptomatic pulmonary embolism (PE) reported for up to 24 days following randomization. The efficacy data are provided in Table 8 and demonstrate that extended prophylaxis with fondaparinux sodium was associated with a VTE rate of 1.4% compared with a VTE rate of 35.0% for placebo for a relative risk reduction of 95.9% (95% CI = [98.7; 87.1], P <0.0001). Major bleeding rates during the 3-week extended prophylaxis period for fondaparinux sodium occurred in 2.4% of patients receiving fondaparinux sodium and 0.6% of placebo-treated patients [see Adverse Reactions (6.1)].

Table 8. Efficacy of Fondaparinux Sodium Injection in the Extended Prophylaxis of Thromboembolic Events Following Hip Fracture Surgery
*
N = all randomized evaluable hip fracture surgery patients. Evaluable patients were those who were treated in the post-randomization period, with an adequate efficacy assessment for up to 24 days following randomization.
P value versus placebo <0.001
P value versus placebo = 0.021.
§
P value versus placebo = NS.

Endpoint

Extended Prophylaxis

(Day 8 to Day 28 ± 2 post-surgery)

Fondaparinux Sodium

2.5 mg SC once daily

Placebo

SC once daily

n/N *

% (95% CI)

n/N *

% (95% CI)

VTE

3/208

1.4% (0.3, 4.2)

77/220

35.0% (28.7, 41.7)

All DVT

3/208

1.4%(0.3, 4.2)

74/218

33.9% (27.7, 40.6)

Proximal DVT

2/221

0.9%(0.1, 3.2)

35/222

15.8% (11.2, 21.2)

Symptomatic VTE (all)

1/326

0.3% (0.0, 1.7)

9/330

2.7% (1.3, 5.1)

Symptomatic PE

0/326

0.0%§(0.0, 1.1)

3/330

0.9% (0.2, 2.6)

14.3 Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery

In 2 randomized, double-blind, clinical trials in patients undergoing hip replacement surgery, fondaparinux sodium 2.5 mg SC once daily was compared to either enoxaparin sodium 30 mg SC every 12 hours (Study 1) or to enoxaparin sodium 40 mg SC once a day (Study 2). In Study 1, a total of 2,275 patients were randomized and 2,257 were treated. Patients ranged in age from 18 to 92 years (mean age 65 years) with 48% men and 52% women. Patients were 94% Caucasian, 4% black, <1% Asian, and 2% others. In Study 2, a total of 2,309 patients were randomized and 2,273 were treated. Patients ranged in age from 24 to 97 years (mean age 65 years) with 42% men and 58% women. Patients were 99% Caucasian, and 1% other races. Patients with serum creatinine level more than 2 mg/dL (180 micromol/L), or platelet count less than 100,000/mm3 were excluded from both trials. In Study 1, fondaparinux sodium was initiated 6 ± 2 hours (mean 6.5 hours) after surgery in 92% of patients and enoxaparin sodium was initiated 12 to 24 hours (mean 20.25 hours) after surgery in 97% of patients. In Study 2, fondaparinux sodium was initiated 6 ± 2 hours (mean 6.25 hours) after surgery in 86% of patients and enoxaparin sodium was initiated 12 hours before surgery in 78% of patients. The first post-operative enoxaparin sodium dose was given within 12 hours after surgery in 60% of patients and 12 to 24 hours after surgery in 35% of patients with a mean of 13 hours. For both studies, both study treatments were continued for 7 ± 2 days. The efficacy data are provided in Table 9. Under the conditions of Study 1, fondaparinux sodium was associated with a VTE rate of 6.1% compared with a VTE rate of 8.3% for enoxaparin sodium for a relative risk reduction of 26% (95% CI: -11%, 53%; P = NS). Under the conditions of Study 2, fondaparinux sodium was associated with a VTE rate of 4.1% compared with a VTE rate of 9.2% for enoxaparin sodium for a relative risk reduction of 56% (95% CI: 33%, 73%; P <0.001). For the 2 studies combined, the major bleeding episodes occurred in 3.0% of patients receiving fondaparinux sodium and 2.1% of enoxaparin sodium patients [see Adverse Reactions (6.1)].

Table 9. Efficacy of Fondaparinux Sodium in the Prophylaxis of Thromboembolic Events Following Hip Replacement Surgery
*
N = all evaluable hip replacement surgery patients. Evaluable patients were those who were treated and underwent the appropriate surgery (i.e., hip replacement surgery), with an adequate efficacy assessment up to Day 11.
VTE was a composite of documented DVT and/or documented symptomatic PE reported up to Day 11.
P value versus enoxaparin sodium: NS.
§
P value versus enoxaparin sodium in study 2: <0.001.
P value versus enoxaparin sodium in study 1: <0.05.
#
P value versus enoxaparin sodium in study 2: <0.01.

Endpoint

Study 1

n/N *

% (95% CI)

Study 2

n/N *

% (95% CI)

Fondaparinux Sodium

2.5 mg SC

once daily

Enoxaparin

Sodium

30 mg SC

every 12 hr

Fondaparinux Sodium

2.5 mg SC

once daily

Enoxaparin

Sodium

40 mg SC

once daily

VTE

48/787

6.1% (4.5, 8.0)

66/797

8.3% (6.5, 10.4)

37/908

4.1%§ (2.9, 5.6)

85/919

9.2% (7.5, 11.3)

All DVT

44/784

5.6% (4.1, 7.5)

65/796

8.2% (6.4, 10.3)

36/908

4.0%§ (2.8, 5.4)

83/918

9.0% (7.3, 11.1)

Proximal DVT

14/816

1.7%(0.9, 2.9)

10/830

1.2% (0.6, 2.2)

6/922

0.7%# (0.2, 1.4)

23/927

2.5% (1.6, 3.7)

Symptomatic PE

5/1,126

0.4%(0.1, 1.0)

1/1,128

0.1% (0.0, 0.5)

2/1,129

0.2%(0.0, 0.6)

2/1,123

0.2% (0.0, 0.6)

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