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Why is fondaparinux contraindicated in low body weight surgery patients but not in other low weight patients?
Background
According to the prescribing information for fondaparinux (Arixtra by GlaxoSmithKline), venous thromboembolism (VTE) prophylactic therapy is contraindicated in patients with a body weight of <50 kg undergoing hip fracture surgery, hip replacement or knee replacement surgery, and abdominal surgery.1 Use of fondaparinux is not contraindicated; however, in other low weight patients (<50 kg) who are not undergoing surgery. Pharmacokinetic data have shown that total clearance of fondaparinux is decreased by approximately 30% in patients weighing <50 kg. Therefore, one might ask, what is the rationale behind the contraindication for surgical patients only?
VTE prophylaxis data reviewed
The ARTEMIS study was a randomized, multicenter, double-blind, placebo controlled trial that evaluated the efficacy and safety of fondaparinux for the prevention of VTE in older acutely ill medical patients expected to remain in bed for at least 4 days.2 Patients were randomized to fondaparinux 2.5 mg once daily (n=429) or placebo (n=420) for 6 to 14 days. Detection of VTE by routine bilateral venography on days 6 to 15 and symptomatic VTE up to day 15 were evaluated as the primary composite efficacy endpoint. Major bleeding events and death were assessed for safety. Treatment with fondaparinux resulted in a 46.7% relative risk reduction for the primary composite endpoint. A total of 5.6% of fondaparinux-treated patients and 10.5% of placebo-treated patients had VTE detected by bilateral venography and symptomatic VTE up to day 15 (p=0.029). The incidence of major bleeding events were similar between the 2 groups (0.2% in each group), and no significant difference was noted in death rates at 1 month (3.3% in the fondaparinux group and 6.0% in the placebo group; p=0.06).
A subanalysis of the ARTEMIS trial revealed that 7.9% (n=25) of patients receiving fondaparinux 2.5 mg once daily and 10.3% (n=33) assigned to placebo weighed <50 kg.3
Of these patients, a total of 2 in the fondaparinux and 3 in the placebo group experienced a VTE. From a safety perspective, an analysis of bleeding events failed to identify a relationship between these events and patient weight. The manufacturer points out; however, that the number of bleeding events in the overall primary efficacy population was small.
According to GlaxoSmithKline, an analysis of low weight patients (<50 kg) from randomized clinical trials who were given fondaparinux in the perioperative period following hip fracture, hip replacement, or knee replacement surgery showed that the occurrence of major bleeding was doubled in low weight patients (5.4%) as compared to patients who weighed 50 kg or more (2.1%).1 In addition, the same increased rate of major bleeding was also noted in low weight patients (<50 kg) who had undergone abdominal surgery compared with those who weighed 50 kg or more (5.3% versus 3.3%). Unfortunately, these analyses have not been published in the medical literature as of September 2008 and GlaxoSmithKline could not comment on the exact studies used to compile these rates of major bleeding observed in low weight patients.
It is important to note that fondaparinux is not currently approved by the Food and Drug Administration (FDA) to be used as prophylactic therapy in acutely ill medical patients.1 It is only indicated as VTE prophylactic therapy in patients undergoing hip, knee, or abdominal surgical procedures, and for the treatment of VTE (deep vein thrombosis and pulmonary embolism) when used in conjunction with warfarin.
Incidence of major bleeding in relation to timing of initial fondaparinux dose
In 2003, Turpie and colleagues published a paper describing the safety of fondaparinux in major orthopedic surgery according to the timing of its first administration.4 The investigators used the fondaparinux phase III study database to identify patients 18 years or older who were scheduled for elective major hip surgery, elective major knee surgery, or standard surgery for fracture of the upper third of the femur. The investigators did not exclude any patients based on age (range 17 to 97 years old) or weight (range 30 to 166 kg). A total of 3471 patients were included in the analysis, and incidence of major bleeding episodes was compared for patients who received fondaparinux <6 hours after surgery (n=1300) or ≥6 hours postoperatively (n=2171). In addition, the investigators analyzed a subgroup of high-risk patients defined as those who weighed <50 kg, and/or ≥75 years old, and/or had a creatinine clearance between 30 and 50 mL/min (n=1253).
The overall incidence of major bleeding was 2.5% (n=88/3471).4 The incidence of major bleeding was significantly lower in patients who received fondaparinux 6 hours or longer after skin closure compared with those who received the drug <6 hours postoperatively (2.1% versus 3.2%). In addition, the investigators noted that the impact of the timing of the first fondaparinux dose on risk of major bleeding was particularly evident in the subgroup of high-risk patients analyzed (table 1).
Table 1. Incidence of major bleeding up to day 11 according to fondaparinux administration time. 4
| Postoperative initiation of fondaparinux |
< 6 hours |
≥ 6 hours |
p value |
| All major bleeding episodes |
|
| All patients |
42/1300
(3.2%) |
46/2171
(2.1%) |
0.045 |
| High-risk patients a |
21/484
(4.3%) |
18/769
(2.3%) |
0.065 |
| Major bleeding episodes reported after injection of active fondaparinux |
|
| All patients |
33/1300
(2.5%) |
40/2171
(1.8%) |
0.18 |
| High-risk patients a |
19/484
(3.9%) |
14/769
(1.8%) |
0.03 |
a High-risk patients defined as those who weighed <50 kg, and/or ≥75 years old, and/or had a creatinine clearance between 30 and 50 mL/min
Where do we go from here?
It is evident that the risk of major bleeding with fondaparinux appears to be increased in high-risk patients undergoing surgical procedures, including those who are low weight (<50 kg).1,4 The study by Turpie and colleagues has shed some light on the risk of major bleeding in high-risk patients in relation to the administration time of fondaparinux postoperatively.4 An individual analysis assessing the risk of major bleeding in low weight patients in relation to administration time of fondaparinux postoperatively is needed before firm conclusions can be drawn.
In Europe, the use of fondaparinux in low weight patients (<50 kg) undergoing surgery is not a contraindication.5,6 European prescribing guidelines recommend that particular attention be paid to the timing of its administration in this patient population.
References
- Arixtra [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.
- Cohen AT, Davidson BL, Gallus AS, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomized placebo controlled trial. BMJ. 2006;332(7537):325-329.
- Data on file. Use of Arixtra in Medically Ill Patients Weighing <50 kg. GlaxoSmithKline; Research Triangle Park, NC.
- Turpie A, Bauer K, Eriksson B, et al. Efficacy and safety of fondaparinux in major orthopedic surgery according to the timing of its first administration. Thromb Haemost. 2003;90(2):364-366.
- Turpie A. The safety of fondaparinux for the prevention and treatment of venous thromboembolism. Expert Opin Drug Saf. 2005;4(4):707-721.
- European Medicines Agency. Scientific discussion. Available at:
http://www.emea.europa.eu/humandocs/PDFs/EPAR/arixtra/011502en6.pdf. Accessed August 26, 2008.
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