Ximelagatran and the JAMA

[Marty]

XIMELGATRAN aka EXANTA was featured in the 2/9/05 Journal of the American Medical Association with trials on deep venous thrombosis and non valvular atrial fibrillation, effectiveness in stroke prevention in afib and then a splendid editorial tying everything together. Not much new to us at vr.com. Its a very fine drug but there are questionable possibilities of liver toxicity. I was in the service with the doctor who wrote the editorial. He's a prominent Harvard cardiologist named Victor Gurewich. I specifically asked him to pronounce on the liver problems. He said out of 18000 patients in the trials there were three liver problems, one had hepatitis, one was alcoholic cirrhosis, and one may have been caused by the drug. The chance of liver toxicity is very small and Victor would like to see the drug approved for all use even valves.He notes that quick approval is unlikely as the FDA is gun shy after the COX2 inhibitor experience.

 

[RCB]

Way to go, Marty

Way to go, Marty

Thanks for the update. Did he discuss pt. compliance problem with the half like being so short? Missing one dose could put a pt. in danger of a stroke.
How about reversing effect if necessary? Have you signed up for trials?
Thanks again for the info.

 

[Guest]

The one guy who died from no apparent cause had a normal liver function test and 29 days later he was dead of liver failure. The committee was very worried that there was no way to predict who was going to have a liver problem. The bleeding from ximelagatran appears to be irreversible. The guy was given vitamin K, fresh frozen plasma, recombinant Factor VII and about 60 units of blood - nothing could stop the blood loss - evidently a real gusher.

There was also some question of a rebound effect when it was stopped. The people who took it to prevent clots after knee or hip surgery seemed to have more than the predicted number of heart attacks in the month after it was stopped. AstraZeneca was taken to task by the committee for not studying this problem beyond 24 hours.

I testified at the meeting and have my recollections on my website at http://www.warfarinfo.com/ximelagatran.htm There is also a link to the entire 414 pages of minutes from the meeting on that page. Anyone who wants to get some sleep without using a drug should try reading the entire document.

That JAMA issue also includes an article by my friend Brian Gage, MD who figures that ximelagatran at $5.00 per day will not be cost effective. His estimate of $5.00 per day is the lowest that I have heard. Another guy that I know fairly well works in public policy and healthcare. His group's estimate was that Exanta was going to be $10.00 per day.

My guess is that the time taken for the additional research will not leave enough time on the patent for AZ to recoup their expenses. They will probably just give up on marketing in the US. They had 20 years of research go down the tube in 10 hours at that committee meeting.

The drug is being marketed in the European Union, but not for valves. I don't know what has or will happen in Canada or other countries.

 

[Marty]

A better anticoagulant is needed, but I agree with Al and Victor Gurewich that Exanta will not be approved anytime soon for us valvers. Short term use after orthopedic surgery may happen first. Even if Exanta was approved I would not use it. I'm not sure they know the right dose and I would wonder how often I would need to test for elevated liver enzymes which herald liver damage.To paraphrase Churchill, warfarin is the worst anticoagulant except for all the rest!

 

[Guest]

They were going to recommend liver function tests every two months for the first six month and then every six months after that. But the one who died did so only 29 days after having a normal LFT. So there is some question as to whether or not LFTs can predict who is going to suffer liver failure with this drug.

 

[Marty]

RCB, at the next trial I will volunteer as a..........control!

 

[RCB]

aaaah...me too

aaaah...me too

RCB, at the next trial I will volunteer as a..........control!

Smart move, Marty! Now we know why the Rads make the big money

 

[Guest]

While this doesn't directly apply to valvers, it is another setback for this drug.

While this doesn't directly apply to valvers, it is another setback for this drug.

This is taken from the AstraZeneca website http://astrazeneca.com/pressrelease/4644.aspx

The European Union uses a mutual recognition procedure (MRP) to aviod duplication in drug approvals among its members. The French Regulatory Authority (AFSSAPS) has served as the Reference Member State for Exanta. Under this procedure, Exanta was approved for prevention of blood clots in people undergoing hip- or knee-replacement surgery in nine countries in May 2004. At that time AstraZeneca also requested approval for Exanta in preventing strokes among people with atrial fibrillation (AF) and venous thromboembolism (VTE). However, the regulatory authorities requested more information for giving these approvals for long-term use.

AstraZeneca?s press release of January 19, 2005 states, ?AFSSAPS requested further clinical information confirming the efficacy and demonstrating the safety of Exanta in AF to allow a definitive benefit/risk assessment to be made while, for VTE treatment, the authority does not believe the data presented in the single THRIVE Treatment study provides adequate support for this use of Exanta and is proposing a rejection for this indication.?

Dr. Hamish Cameron, AstraZeneca?s Vice President and Head of Exanta responded with comments on the unmet needs in this area and confirming that AstraZeneca remains committed to research in this area of medicine.