The thrombin inhibitor melagatran/ximelagatran (MELAGATRAN ASTRAZENECA/EXANTA) has been on the market since June and is the first oral anticoagulant to be launched since the introduction of coumarins. Germany is the first market for this drug in the world. As yet the licence is restricted to short-term postoperative prevention of thromboembolism following elective hip or knee replacement (1,2). This is controversial: in the mutual recognition procedure, the UK and Ireland signalled their refusal to grant a licence, whereupon AstraZeneca withdrew its application there (3). The licence for long-term thromboembolism prophylaxis claimed by the company also seems questionable to us because of the hepatotoxicity of the drug: in clinical trials, liver transaminases rose to more than three times the upper limit of normal in 6% to 13% of patients (4,5).

CHARACTERISTICS: The orally administered prodrug ximelagatran is metabolised rapidly into melagatran after ingestion. Melagatran itself is available for subcutaneous injection for initiating prophylaxis. The bioavailability of melagatran after ingestion of ximelagatran is 23%. Peak plasma levels are reached 30 minutes after subcutaneous injection and two hours after oral administration. Melagatran is eliminated unchanged with a half-life of 2-3 hours (s.c.) and 4-5 hours (oral), mainly via the kidneys. It is contraindicated for patients with severe renal impairment(1,2).

Like hirudins, melagatran directly inhibits the clotting factor IIa (thrombin). It blocks both free and fibrin-bound thrombin. Coagulation tests such as the activated partial thromboplastin time (APTT) are unsuitable for monitoring treatment with the low dosages recommended for prophylactic purposes. Melagatran has no known antidote (1,2).

CLINICAL EFFICACY: The licence is based on the METHRO* III trial, a double-blind comparison of the new drug with the low molecular weight heparin enoxaparin (CLEXANE). 2,788 patients with an average age of 66, who were to undergo elective hip or knee replacement surgery, were randomly allocated to receive the following: either 3 mg melagatran subcutaneously four to 12 hours postoperatively, then - if oral administration was possible - 24 mg ximelagatran orally twice a day; or, starting 12 hours before the operation, 50 mg enoxaparin once a day (European dosage) for eight to 11 days. The primary endpoint of this trial, which was designed to prove superiority of ximelagatran, was the rate of venous thromboembolisms, including fatal or non-fatal pulmonary embolisms and unexplained deaths. Systematic phlebography screening was performed to diagnose deep vein thromboses (6).

Proof of superiority was not achieved. With a rate of 31% on ximelagatran compared with 27.3% on enoxaparin, there is a clear trend in favour of heparin with regard to the primary endpoint (difference 3.7%; 95% confidence interval [CI] 0.0% to 7.4%). No difference was found in proximal (5.7% vs. 6.2%) and symptomatic (1.3% vs. 1.2%) thromboembolisms. There was also no difference with regard to severe bleeding events (1.4% vs. 1.7%). Seven of the eight deaths in the follow-up observation period of up to six months were in the ximelagatran arm. After post-hoc analyses, the rate of venous thromboembolisms was in the order of size of that found with enoxaparin, provided that the first injection of melagatran took place no later than eight hours after surgery (6). This time window established after the trial is now specified in the Summary of Product Characteristics (1,2).

Starting prophylaxis with melagatran pre-operatively is explicitly not licensed but was tested in a phase III trial involving 2,835 patients. It was in fact associated with fewer thromboses detected by phlebography screening in comparison with enoxaparin. The incidence of symptomatic venous thromboembolisms did not differ at 0.6% vs. 0.9%. However there was a significant increase in severe bleeding from 1.2% on enoxaparin to 3.3%. Five patients on ximelagatran died, in comparison with one death on enoxaparin (7).

There are no published data on risk and benefit of post-hospitalisation continuation of prophylaxis with ximelagatran which - as it has been reported to us - the company's medical reps are already supposed to be promoting in rehabilitation clinics. A duration of use for more than 11 days is expressly not recommended in the SPC (1,2).

The hitherto unlicensed use of ximelagatran for thromboembolism prophylaxis of atrial fibrillation is compared with warfarin (COUMADIN) anticoagulation (target INR** 2-3) in two similarly designed phase III trials. Only one of these has been fully published. In addition to atrial fibrillation, the participating patients had at least one other risk factor, such as hypertension or advanced age. In the published, open SPORTIF* III study with a total of 3,410 patients, the non-inferiority of 36 mg ximelagatran twice daily (1.6%) to warfarin (2.3%) is demonstrated in terms of the annual rate of stroke or systemic embolism (difference -0.7%; 95% CI -1.4 to +0.1). There is also no difference in the number of deaths (3.2% annual rate for both drugs) or severe hemorrhage. However, significantly more patients in the ximelagatran group were additionally taking low-dose aspirin (4). Non-inferiority is also likely to be demonstrated in the double-blind SPORTIF V study, which has still not been fully published. This trial is thought to show a trend towards warfarin performing better (8). Bias caused by the open design of the SPORTIF III study is discussed as a possible reason for the discrepancies in these results (9).

ADVERSE EVENTS: Available safety data on ximelagatran appear to be totally inadequate. The SPC only lists very roughly the adverse events from the licensing trial, while complications that are unrelated to bleeding are only mentioned if their incidence is over 2%. These include dizziness and headaches, gastrointestinal disorders, rash and pruritus as well as abnormal liver enzyme values (1,2).

The hepatotoxicity of the drug is entirely unclear. Information about this is almost exclusively based on the published trials involving the manufacturer. We feel that the prescribed terminology in these trials plays down the relevance of this problem. During administration of ximelagatran for longer periods, liver transaminases were elevated to more than three times the upper limit of normal in 6% to 13% of patients (4,5). In the unpublished SPORTIF V study, one patient reportedly died from the sequels of hepatitis in connection with ximelagatran (8).

Concomitant administration of erythromycin (e.g. MONOMYCIN) increases the bioavailability of melagatran. The interaction may be based on inhibition of transporting proteins such as p-glycoprotein and might also apply to other p-glycoprotein inhibitors such as azithromycin (ZITHROMAX), clarithromycin (KLACID and others) or cyclosporin (SANDIMMUN and others). Concurrent use of p-glycoprotein inducers such as rifampicin (RIFA, etc.) may be expected to reduce the bioavailability of melagatran (1,2).

COSTS: Ximelagatran is only supplied to hospital pharmacies. In relation to hospital purchase prices*** (without VAT), the thrombin inhibitor increases the cost of thromboembolism prophylaxis as much as three-fold: ximelagatran 4.50 €/day compared with low molecular weight heparins such as enoxaparin (CLEXANE 40, ready-to-use prefilled syringe approx. 2.30 €/day, multidose approx. 1.40 €/day) or certoparin (MONOEMBOLEX, ready-to-use prefilled syringe approx. 1.60 €/day).

	The oral thrombin inhibitor ximelagatran (EXANTA) is licensed only for short-term postoperative prevention of thromboembolism after elective hip or knee replacement.
	Equivalence with standard treatment, a low molecular weight heparin such as enoxaparin (CLEXANE), has not been proven for the licensed indication. The licence is largely based on retrospective subgroup analyses of a single phase III trial.
	There are absolutely no published data about benefit and safety for prolonged (e.g. post-hospitalisation) thromboembolism prophylaxis, which remains explicitly non recommended in the SPC.
	Hepatotoxicity is observed in a high proportion of patients during long-term use, but cannot be judged at present because of the lack of safety data that are independent of the manufacturer. There should be a specific warning against any longer-term use - for post-hospitalisation prophylaxis of thromboembolism, for instance.
	Given current knowledge, we advise against the use of the drug, which is up to three times more expensive than the standard.

(R = randomised study)

1

AstraZeneca: Summary of Product Characteristics MELAGATRAN ASTRAZENECA, dated June 2004

2

AstraZeneca: Summary of Product Characteristics EXANTA, dated June 2004

3

Scrip 2004; No. 2949/50: 25

4

Executive Steering Committee on Behalf of the SPORTIF-III-Investigators: Lancet 2003; 362: 1691-8

5

WALLENTIN, L. et al.: Lancet 2003; 362: 789-97

6

ERIKSSON, B.I. et al.: Thromb. Haemost. 2003; 89: 288-96

7

ERIKSSON, B.I. et al.: J. Thromb. Haemost. 2003; 1: 2490-6

8

Scrip 2003; No. 2902: 24

9

EIKELBOOM, J.W., HANKEY, G.J.: MJA 2004; 180: 549-51

METHRO = MElagatran THRombosis prophylaxis in Orthopaedic surgery; SPORTIF = Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation

INR = International Normalized Ratio (a-t 1993; No. 7: 70)

The hospital purchase prices are told by hospital pharmacies and pharmacies supplying hospitals.