eMJA: The direct thrombin inhibitor melagatran/ximelagatran

Luke R Bereznicki,* Shane L Jackson,^† Gregory M Peterson^‡

* PhD Candidate, ^† Research Fellow, ^‡ Professor of Pharmacy, Unit for Medication Outcomes Research and Education, University of Tasmania, Private Bag 26, Hobart, Tasmania 7001. lberezniATutas.edu.au

To the Editor: If a new drug such as ximelagatran is to be considered as a replacement for warfarin in preventing the thromboembolic complications associated with atrial fibrillation (AF), drug cost becomes an important issue. Brighton’s recent article in the Journal, 1 while comprehensive, does not discuss the cost-effectiveness of ximelagatran treatment. Ximelagatran was approved in several European countries for the prevention of venous thromboembolism associated with orthopaedic surgery. The cost of the drug for this indication (24 mg given twice daily) is 4.5 euros (A$7.7) per day.2 This represents the best available estimate of the cost of using ximelagatran for AF, although the dose is higher in AF (36 mg twice daily), and there are limitations in applying the drug cost in one country to another country.

Routine monitoring of the antithrombotic effect of ximelagatran (ie, international normalised ratio [INR] testing) was not conducted in clinical trials. While this is potentially advantageous, frequent testing of alanine aminotransferase (ALT) levels is recommended at baseline and monthly for the first 6 months of therapy, every second month for the remainder of the first year, and every third month thereafter, for safety reasons.3 This is because some patients taking ximelagatran will develop elevated ALT levels (about 6.1% of patients to greater than threefold normal, and 3.4% to greater than fivefold normal) when ximelagatran therapy is commenced.3

The costs of INR and ALT tests are very similar (about $25 and $22, respectively). Although INR monitoring may be more frequent with warfarin than ALT testing with ximelagatran, the cost difference associated with therapeutic monitoring would remain far less than the likely cost of ximelagatran. We estimate the cost associated with treating 1000 patients with AF with ximelagatran instead of warfarin for 1 year, taking into account drug costs, monitoring costs and the slight difference in major bleeding rates, to be about $2.4 million (Box).

A United States Food and Drug Administration advisory committee has recently raised concerns about the safety of ximelagatran (after episodes of severe liver damage), and has recommended that it not be granted any indication for use without further safety data. In particular, ALT monitoring did not prevent 3 deaths attributable to ximelagatran-associated hepatocellular necrosis.3 In light of the recent withdrawal of rofecoxib (Vioxx; Merck Sharp & Dohme), warfarin carries the intangible benefits of a long and proven track record. It certainly requires careful management and ongoing monitoring, but healthcare resources might be better spent on improving the use of warfarin rather than paying substantially increased costs for a drug with similar efficacy and an uncertain safety profile.

Estimated costs of treating 1000 patients with atrial fibrillation (AF) with ximelagatran or warfarin for the first year of therapy.

	Ximelagatran*	Warfarin^†

Total cost	$2 803 821.00	$106 800.00
Cost per patient	$2 803.82	$106.80
Monitoring
Test (frequency/year)	ALT (10)^‡	INR (20)^§
Total cost	$217 000.00	$507 000.00
Cost per patient	$217.00	$507.00
Major bleeding¶
Annual incidence**	1.6%	2.2%
No. of expected events	16	22
Total cost	$38 730.00	$53 253.00
Ischaemic stroke^†^†
Annual incidence^‡^‡	1.6%	1.6%
No. of expected events	16	16
Total cost	$101 936.00	$101 936.00
Overall cost
Total	$3 161 487.00	$768 989.00
Per patient	$3 161.49	$768.99
Cost difference compared with warfarin
Total	$2 392 498.00	—
Per patient	$2 392.50	—

ALT = Alanine aminotransferase. INR = International normalised ratio. * Cost of giving ximelagatran (24 mg twice-daily) to prevent venous thromboembolism post-surgery (German data; the dose for prevention of thromboembolism in AF is 36 mg twice-daily).3^† Cost of warfarin taken from the Australian Pharmaceutical Benefits Scheme, December 2004. ^‡ Monitoring cost derived from the cost of conducting ALT testing (Medicare Benefits Schedule, December 2004) according to the manufacturer’s directions (tests at baseline, monthly for the first 6 months, 2-monthly for remainder of the first year). ^§ Cost derived from Medicare Benefits Schedule (December 2004) based on a frequency of 20 tests per annum. ¶ The cost of a hospital admission caused by a major bleed was $2420.60 in Australia for the years 2002–2003 (estimate based on 2002–2003 public hospital data).4 Intracranial haemorrhage may be associated with significant ongoing costs, but a smaller proportion of major bleeding incidents. ** No significant difference between warfarin and ximelagatran in either SPORTIF III5 or V;6 statistically significant when data from both trials were combined at P < 0.05. ^†^† Cost ($6371) taken from the NEMESIS study7 and covers acute admission to an Australian hospital with ischaemic stroke only; this is an underestimate of the ongoing costs associated with ischaemic stroke. ^‡^‡ No significant difference between warfarin and ximelagatran in SPORTIF III5 and V;6 no significant difference when data from both trials were combined at P < 0.05.