Fondaparinux (Arixtra®) – prevention of venous thromboembolism after orthopedic surgery

Findings by SBU Alert

Version: 1

Technology and target group

Deep vein thrombosis (DVT) is a common complication following major orthopedic surgery involving the lower extremities (hip replacement surgery, knee replacement surgery, and hip fracture surgery). Annually, nearly 60 000 patients in Sweden have surgery of this type. Most of these patients receive prophylactic therapy with drugs to reduce the risk for DVT.

Fondaparinux (Arixtra®) is a drug that inhibits the formation of blood clots in a more selective way than low-molecular-weight heparins (earlier the most commonly used group of drugs). Fondaparinux was initially approved for 5 to 9 days of use following surgery, but was later approved for extended treatment (up to 29 days) after hip fracture surgery. On May 11, 2004, the Pharmaceutical Benefits Board rendered a decision to include fondaparinux in the pharmaceutical reimbursement scheme in Sweden.

Patient benefit and risks

All studies assessing the effects of fondaparinux therapy used DVT, diagnosed by lower limb venography (contrast x-ray examination of veins), as an endpoint. The benefit to patients of identifying these blood clots is not clear since most of these clots would not have resulted in clinical symptoms.

Four randomized trials investigated fondaparinux as an alternative to low-molecular-weight heparin in short-term (5-9 days) therapy. These trials included just over 7 000 patients who underwent hip replacement surgery, knee replacement surgery, or hip fracture surgery. The combined results of the four trials showed that the prevalence of DVT, as identified by lower extremity venography, was 6.8 percent in the fondaparinux group compared to 13.7 percent in the group that received low-molecular-weight heparin (enoxaparin). However, no differences were found between the groups in mortality or in the prevalence of the severe type of venous thromboembolism (VTE) involving blood clots in the lungs. There was a tendency toward a somewhat greater number of bleedings among patients treated with fondaparinux.

Extended prophylaxis (up to 29 days) with fondaparinux was compared to placebo in a randomized trial of just over 700 patients who received surgery for hip fracture. Those treated with fondaparinux during the entire period had a lower rate of venography-verified thromboses/emboli (1.4 percent) compared to the placebo group (35 percent). Symptomatic thromboses/emboli occurred in 0.3 percent and 2.7 percent of the cases, respectively. There are no studies of extended prophylaxis (up to 29 days) that compare fondaparinux versus low-molecular-weight heparin.

Economic aspects

The cost of fondaparinux for 5 to 9 days is approximately 450 to 800 Swedish kronor (SEK), while the corresponding cost for enoxaparin is approximately 170 to 300 SEK. For therapy extending up to 29 days, the cost difference is approximately 1 600 SEK. A general change to fondaparinux would substantially increase the cost for drugs, although the benefit to patients is uncertain. Model studies in health economics have simulated the costs and effects. Reliable conclusions on cost effectiveness cannot be drawn from these model studies as long as there are no data showing that prophylaxis with fondaparinux – compared to enoxaparin – leads to fewer cases of symptomatic VTE and thereby lower consumption of healthcare resources.

Scientific evidence

Fondaparinux therapy for 5 to 9 days shows a lower risk for DVT, as diagnosed by lower extremity venography, compared to low-molecular-weight heparin (Evidence grade 1)*. The patient benefit of this is, however, uncertain. Studies of cost effectiveness in short-term treatment are limited to analytical models that build on the premise of an association between DVT (as detected by venography) and serious events.

There is some documentation showing that extended prophylaxis (up to 4 weeks) with fondaparinux – as with low-molecular-weight heparin – reduces the risk for VTE compared to no treatment (Evidence grade 2)*. No studies have been published on the cost effectiveness of long-term prophylaxis with fondaparinux.

*Grading of the level of scientific evidence for conclusions. The grading scale includes four levels;
Evidence grade 1 = strong scientific evidence,
Evidence grade 2 = moderately strong scientific evidence,
Evidence grade 3 = limited scientific evidence,
Evidence grade 4 = insufficient scientific evidence.

This summary is based on a report prepared at SBU in collaboration with Christer Andersson, MD, Linköping University Hospital, Linköping. It has been reviewed by Bengt Ljungberg, MD, Medical Products Agency and Prof. David Bergqvist, Uppsala University Hospital, Uppsala.

The complete report is available in Swedish only.

SBU Alert is a service provided by SBU in collaboration with the Medical Products Agency, the National Board of Health and Welfare, and the Federation of Swedish County Councils.

References

1. Turpie AG, Bauer KA, Eriksson BI, Lassen MR; PENTATHLON 2000 Study Steering Committee. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002;359(9319):1721-6.
2. Lassen MR, Bauer KA, Eriksson BI, Turpie AG; European Pentasaccharide Elective Surgery Study (EPHESUS) Steering Committee. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002;359(9319):1715-20.
3. Bauer KA, Eriksson BI, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Major Knee Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001;345(18):1305-10.
4. Eriksson BI, Bauer KA, Lassen MR, Turpie AG; Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001;345(18):1298-304.
5. Eriksson BI, Lassen MR; Pentasaccharide in Hip-Fracture Surgery Plus Investigators. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003;163(11):1337-42.
6. SBU Rapport nr 158. Blodpropp - förebyggande, diagnostik och behandling av venös tromboembolism: Statens beredning för medicinsk utvärdering, Stockholm; 2002.
7. Turpie AG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med 2002;162(16):1833-40.
8. Gordois A, Posnett J, Borris L, Bossuyt P, Jonsson B, Levy E et al. The cost-effectiveness of fondaparinux compared with enoxaparin as prophylaxis against thromboembolism following major orthopedic surgery. J Thromb Haemost 2003;1(10):2167-74.
9. Spruill WJ, Wade WE, Leslie RB. A cost analysis of fondaparinux versus enoxaparin in total knee arthroplasty. Am J Ther 2004;11(1):3-8.
10. Wade WE, Spruill WJ, Leslie RB. Cost analysis: fondaparinux versus preoperative and postoperative enoxaparin as venous thromboembolic event prophylaxis in elective hip arthroplasty. Am J Orthop 2003;32(4):201-5.
11. Lundkvist J, Bergqvist D, Jönsson B. Cost-effectiveness of fondaparinux vs enoxaparin as venous thromboembolism prophylaxis in Sweden. Eur J Health Econ 2003;4:254-62.