Take two ximelegatran and call me in the morning

[Addendum, 2/14/05: as has been pointed out by commenters, ximelagatran was turned down for approval by an FDA panel in September, 2004, because of concerns about hepato-toxicity. Whether it will ever be marketed in the US is very much in doubt. The following post has been slightly edited with this in mind.]

Coumadin is such a source of headaches for patients and physicians. Patients have their lives medicalized and mildly disrupted by the frequent blood tests necessary to monitor anticoagulation. Physicians have to deal with the constant, low-level anxiety inherent in steering between hemorrhage and thrombosis.

Enter ximelagatran, an oral thrombin inhibitor whose anticoagulant effect is not significantly influenced by diet, body-weight and drug interactions. A drug that can be given at a fixed dose without monitoring anticoagulant effect. In last week’s JAMA are three articles looking at this medication.

Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis reports on the results of the THRIVE study of 2,489 patients with documented DVT, one third of whom also had pulmonary emboli. Patients were double-blind randomized to either ximelagatran or LMWH / coumadin and were followed for six months. There was no difference in the rates of recurrent thrombosis; major bleeding was also not statistically different (trend towards lower bleeding in ximelagatran group). Liver enzymes exceeded 3 times normal in about 10% of ximelagatran patients, vs. 2% on warfarin.

Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation reported on the results of the SPORTIF V trial. Here, patients with nonvalvular atrial fibrillation were randomized to ximelegatran or placebo. Mean follow-up was 20 months. In this trial too, there was no significant difference between the two therapies, although the primary endpoint, all-cause stroke per year, was 1.6% with ximelegatran vs 1.2 % with coumadin. Elevated liver enzymes occurred in 6% of ximelagatran patients. Among the 1,960 patients assigned to ximelagatran, there was one death that seemed to be the result of drug-related liver toxicity and one that was the result of gastrointestinal hemorrhage in a patient who had developped elevated liver enzymes.

Finally, costs and effectiveness of ximelagatran for stroke prophylaxis in chronic atrial fibrillation looked at a computer model of the problem and concluded that ximelegatran only marginally improves QALY over warfarin, at a fairly high cost per QALY.

Several points occur to me in looking at these articles:

  • If it were not for the liver toxicity, ximelagatran would be a real winner. But liver toxicity, including a fatality rate on the order of one per 5,000 patients, is a very definite limiting factor. Because of this, I don’t think ximelagatran is likely to become a substitute for coumadin.
  • The coumadin monitoring that goes on in trials such as these is clearly better that that which occurs in real life, which skews the results slightly against ximelagatran.
  • Some patients are clearly problematic coumadin patients, such as those who are frequently non-compliant or have to spend prolonged periods of time away from medical care. For these patients, ximelagatran, or a similar drug, may prove to be extremely useful.
  • The cost-effectiveness article is a computer simulation of the problem and, as such, is of very limited value. Articles of this sort make multiple assumptions about the problem at hand and then plug them into a computer model. Numbers go in, the computer grinds and grinds, and out come some neatly packaged QALY’s. Common sense beats the Markov model any day, in my opinion.

3 replies on “Take two ximelegatran and call me in the morning”