Arixtra® administered the morning after orthopedic surgery prevented venous thromboembolism with low risk of bleeding

New Study Published in The Journal of Arthroplasty

Philadelphia, PA, February 3, 2006–Results from a new study of Arixtra® (fondaparinux sodium) called FLEXTRA (Flexibility in Administration of Fondaparinux for Prevention of Symptomatic Venous Thromboembolism in Orthopaedic Surgery) showed the anti-thrombotic drug was generally well tolerated and effective in the prevention of symptomatic venous thromboembolism (VTE) when administered to patients the morning after orthopedic surgery. The study, which was published in the January 2006 issue of The Journal of Arthroplasty, evaluated the tolerability and efficacy of Arixtra following total joint arthroplasty. Study results demonstrated that delayed initiation of Arixtra prophylaxis may provide an alternative dosage regimen for preventing VTE after total joint arthroplasty.

“Many factors, such as patient status and a hospital’s routine dosing schedule, can delay the administration of anti-thrombotics,” said lead author Clifford W. Colwell Jr., MD, with the Division of Orthopedic Surgery at Scripps Clinic, La Jolla, California. “These results showed that administration of Arixtra the morning after surgery was just as effective in decreasing the risk of symptomatic VTE as administered 6 to 10 hours post-operation the day of surgery.”

Venous thromboembolism is a common complication of total knee or hip replacement surgery. The routine use of VTE prophylaxis is recommended for patients who undergo these types of orthopedic surgery.1 All anti-thrombotics carry some risk for bleeding, however, and the timing of administration of the first dose following orthopedic surgery has been shown to influence both tolerability and efficacy. The recommended timing for initiation of VTE prophylaxis may depend on the unique pharmacology of each anti-thrombotic agent.2-5

Arixtra is the first selective inhibitor of Factor Xa, a protein central to the coagulation process. Arixtra is approved in the United States (U.S.) for the prevention of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing surgery for hip fracture (including extended prophylaxis), knee replacement, hip replacement, and in abdominal surgery patients who are at risk for thromboembolic complications. Additionally, Arixtra is indicated for the treatment of acute DVT when administered in conjunction with warfarin sodium and for the treatment of acute PE when administered in conjunction with warfarin sodium, when initial therapy is administered in the hospital.

Study Design

The primary endpoint of the study was the comparison of tolerability and efficacy of Arixtra (2.5 mg) in patients using two different dosing schedules. Patients were randomized into two groups: a standard dosing schedule (first postoperative dose 8 ± 2 hours after surgery) and an alternate dosing schedule (first postoperative dose between 7:00 a.m.and 9:00 a.m.the morning after surgery). Subsequent doses were administered once daily between 7 a.m.and 9 a.m.for a total of 7 to 10 days.

The study included 2,046 patients, 2,000 of whom were evaluated for efficacy (1,003 in the standard-regimen group and 997 in the alternate-regimen group). Both groups were similar for baseline, surgical, and post-surgical characteristics.

Efficacy was similar between the treatment groups in the study. When evaluated 6 ± 2 weeks following surgery, the incidence of VTE, including symptomatic DVT or PE, concurrent DVT and PE, or fatal PE, was similar for both groups (P ≥ .81). In the standard-regimen group, 19 patients (1.9 percent) experienced VTE compared with 18 patients (1.8 percent) in the alternate-regimen group (P = .89). PE occurred in 9 patients (0.9 percent) in both treatment groups, and no PE-related fatalities occurred. Two patients in the alternate-regimen group experienced both DVT and PE. The median time to first occurrence of VTE following surgery was also similar between groups: 5 days in the standard-regimen group and 7 days in the alternate-regimen group (P = .96).


Additionally, safety results were similarly low for both groups. At 6 ± 1 weeks after surgery, 12 patients (1.2 percent) in the standard-regimen group and 7 patients (0.7 percent) in the alternate-regimen group had a major bleeding episode (P = .24). The incidence of minor bleeding was also low (1.4 percent versus 1.9 percent in the standard-regimen and alternate-regimen groups, respectively; P = .41). Bleeding into a critical organ or death from bleeding did not occur in either group.

VTE

Up to two million cases of VTE develop in the United Stateseach year.6 It is estimated that about one-third of patients with symptomatic VTE manifest PE7. According to the American Heart Association, VTE can be fatal; the mortality rate is about six percent in DVT cases and 12 percent in PE cases.

Important Safety Information

Contraindications

Arixtra is contraindicated in patients with severe renal impairment, patients with active major bleeding, bacterial endocarditis, and patients with hypersensitivity to fondaparinux sodium. In the United States, Arixtra is also contraindicated in patients weighing less than 50kg (less than 110 lbs) who are undergoing major surgery of the lower limbs and abdominal surgery.

Warnings

When epidural/spinal anaesthesia or spinal puncture is employed, patients anticoagulated with low–molecular-weight heparins, heparinoids or fondaparinux sodium are at risk of developing an epidural or spinal haematoma, which can result in long-term or permanent paralysis. The risk of these events may be higher with postoperative use of indwelling epidural catheters or concomitant use of drugs affecting haemostasis. Spinal/epidural anaesthesia should not be used concurrently with Arixtra for the treatment of VTE (see BOXED Warning in the US Prescribing Information).

Arixtra is not intended for intramuscular administration.

Arixtra should be used with caution in all patient groups with increased risk of bleeding. This includes the elderly, patients with moderate renal or severe hepatic impairment. In the EU, Arixtra should be used with caution in those patients weighing less than 50kg (less than 110lbs). Arixtra should not be co-administered with drugs that may increase the risk of bleeding.

The efficacy and safety of Arixtra in patients with heparin induced thrombocytopenia type II has not been studied. Thrombocytopenia can occur with Arixtra. If the platelet count falls below 100,000/mm3, Arixtra should be discontinued.

About GlaxoSmithKline

GlaxoSmithKline is one of the world’s leading research-based pharmaceutical and healthcare companies. GlaxoSmithKline is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information visit www.gsk.com.

Cautionary statement regarding forward-looking statements

Under the safe harbor provisions of the US Private Securities Litigation Reform Act of 1995, the company cautions investors that any forward-looking statements or projections made by the company, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect the Group’s operations are described under ’Risk Factors’ in the Operating and Financial Review and Prospects in the company’s Annual Report on Form 20-F for 2004.

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References

1. Haake DA, Berkman SA: Venous thromboemolic disease after hip surgery. Risk factors, prophylaxis, and diagnosis. Clin Orthop Relat Res 242:212-31. 1989 May.

2. Shaieb MD, Watson BN, Atkinson RE: Bleeding complications with enoxaparin for deep venous thrombosis prophylaxis. J Arthroplasty 14:432, 1999.

3. Raskob GE, Hirsh J: Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest 124:379S, 2003.

4. Hull RD, Pineo GF, Stein PD, et al: Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med 161:1952, 2001.

5. Kwong LM, Muntz JE: Thromboprophylaxis dosing: the relationship between timing of first administration, efficacy, and safety. Am J Orthop 31:16, 2002.

6. Goldhaber SZ, Fanikos J. Cardiology patient pages. Prevention of deep vein thrombosis and pulmonary embolism. Circulation. 2004 Oct 19;110(16):e445-7. Venous Thromboembolism — Statistics. American Heart Association. www.americanheart.org/downloadable/heart/1111612689370FS29VTE5.REVdoc.doc Accessed May 13th, 2005.

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