Orthopedic Surgery Study Details for the Prophylaxis of Venous Thromboembolism (VTE)

ARIXTRA in prophylaxis of venous thromboembolism (VTE) in orthopedic surgery [4]

The meta-analysis of the orthopedic surgery excluding extended hip-fracture data was done using the following studies: PENTAMAKS, PENTHIFRA, PENTATHLON 2000, and EPHESUS.

Knee surgery [6]

PENTAMAKS was a double-blind study in which 1,049 patients undergoing elective major knee surgery were assigned to receive 2.5 mg of ARIXTRA SC once-daily or 30 mg of enoxaparin twice-daily, with both treatments initiated postoperatively.

The primary efficacy outcome was DVT detected by mandatory bilateral venography or documented symptomatic DVT or PE up to postoperative Day 11. The primary safety outcome was major bleeding.

The group treated with ARIXTRA had a significantly lower incidence of DVT/PE by Day 11 (12.5%; 45/361) vs the enoxaparin group (27.8%; 101/363). The relative reduction in risk was 55.2% (95% CI, 36.2-70.2; P<0.001). Major bleeding (including overt bleeding with a bleeding index of 2 or more) occurred more frequently in the group treated with ARIXTRA, 2.1% (11/517) vs the enoxaparin group, 0.2% (1/517) (P=0.006), but there were no significant differences between the 2 groups in the incidence of bleeding leading to death or reoperation or occurring in a critical organ.

Hip fracture surgery [5]

PENTHIFRA was a double-blind study in which 1,711 patients undergoing hip fracture surgery received either ARIXTRA 2.5 mg SC once-daily, initiated postoperatively, or 40 mg of enoxaparin once-daily, initiated preoperatively, for at least 5 days. The primary efficacy outcome was DVT detected by mandatory bilateral venography, documented symptomatic DVT, or documented symptomatic PE up to postoperative Day 11.

The main safety outcomes were major bleeding and mortality from all causes. The duration of follow-up was 6 weeks.

The incidence of DVT/PE by Day 11 was 8.3% (52/626) in the group treated with ARIXTRA vs 19.1% (119/624) in the enoxaparin group (P<0.001). The relative reduction in risk with ARIXTRA was 56.4% (95% CI, 39.0-70.3). ARIXTRA cut proximal DVT by 78.7% vs enoxaparin (0.9%, 6/650 for ARIXTRA vs 4.3%, 28/646 for enoxaparin). Major bleeding episodes occurred in 2.2% (18/831) of patients receiving ARIXTRA and 2.3% (19/842) of patients receiving enoxaparin. There were no significant differences between the 2 groups in the incidence of death or clinically relevant bleeding.

Hip replacement surgery [7,8]

PENTATHLON 2000 was a double-blind study in which 2,275 patients undergoing elective hip replacement surgery received postoperative SC injections of either ARIXTRA 2.5 mg once-daily or enoxaparin 30 mg BID.

The primary efficacy outcome was DVT detected by mandatory bilateral venography, documented symptomatic DVT, or documented symptomatic PE to Day 11. The main safety outcomes were bleeding and death. Patients were followed up for 6 weeks.

By Day 11, the incidence of DVT/PE was 6% (48/787) for ARIXTRA vs 8% (66/797) for enoxaparin. The relative reduction in risk was 26.3% (95% CI, -10.8-52.8; P=0.099). Bleeding leading to reoperation in patients was 0.2% (2/1,128) in the group treated with ARIXTRA and 0.2% (2/1,129) in the enoxaparin group. Bleeding with a bleeding index of =2 occurred in 2% (18/1,128) in the group treated with ARIXTRA and 0.7% (8/1,129) of the enoxaparin group. The rate of death did not differ between the 2 groups: 0.5% (6/1,128) for the group treated with ARIXTRA and 0.3% (6/1,129) for the enoxaparin group.

In the EPHESUS double-blind study, 2,309 patients undergoing elective hip replacement surgery received SC once-daily injections of either ARIXTRA 2.5 mg starting postoperatively, or 40 mg enoxaparin, starting preoperatively.

The primary efficacy outcome was DVT detected by mandatory bilateral venography, documented symptomatic DVT, or documented symptomatic PE to Day 11. The main safety outcomes were bleeding and death. By Day 11, the incidence of DVT/PE was 4% (37/908) for ARIXTRA vs 9% (85/919) for enoxaparin (difference -5.2% [95% CI, -8.1 to -2.7]), (P<0.0001). The relative reduction in risk was 55.9% (95% Cl, 33.1-72.8). Patients with bleeding leading to reoperation was <1% (5/1,140) in the group receiving ARIXTRA and <1% (3/1,133) in the enoxaparin group. Bleeding with a bleeding index of ≥2 occurred in 4% (42/1,140) of patients receiving ARIXTRA and 3% (29/1,133) of patients receiving enoxaparin. The rate of death did not differ between the 2 groups, with 0.2% (2/1,140) for the group treated with ARIXTRA and 0.4% (4/1,133) for the enoxaparin group.

WARNING: SPINAL/EPIDURAL HEMATOMAS

Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH), heparinoids, or fondaparinux sodium and are receiving neuraxial anesthesia or undergoing spinal puncture.

These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

• use of indwelling epidural catheters
• concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants
• a history of traumatic or repeated epidural or spinal puncture
• a history of spinal deformity or spinal surgery

Monitor patients frequently for signs and symptoms of neurologic impairment. If neurologic compromise is noted, urgent treatment is necessary. Consider the benefit and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

INDICATIONS AND USAGE
Prophylaxis of Deep Vein Thrombosis
ARIXTRA is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patients undergoing:

• hip fracture surgery, including extended prophylaxis;
• hip replacement surgery;
• knee replacement surgery;
• abdominal surgery who are at risk for thromboembolic complications.

Treatment of Acute Deep Vein Thrombosis
ARIXTRA is indicated for the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium.

Treatment of Acute Pulmonary Embolism
ARIXTRA is indicated for the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital.

CONTRAINDICATIONS
ARIXTRA is contraindicated in the following conditions:

• Severe renal impairment (creatinine clearance <30 mL/min) in prophylaxis or treatment of venous thromboembolism.
• Active major bleeding.
• Bacterial endocarditis.
• Thrombocytopenia associated with a positive in vitro test for anti-platelet antibody in the presence of fondaparinux sodium.
• Body weight <50 kg (venous thromboembolism prophylaxis only).

WARNINGS AND PRECAUTIONS

• Use with caution in patients who have conditions or who are taking concomitant medications that increase risk of hemorrhage.
• Bleeding risk is increased in renal impairment and in patients with low body weight <50 kg.
• Thrombocytopenia can occur with administration of ARIXTRA.
• Periodic routine complete blood counts (including platelet counts), serum creatinine level, and stool occult blood tests are recommended.
• The packaging (needle guard) contains dry natural rubber and may cause allergic reactions in latex sensitive individuals.