Friday, December 17, 2010


These two years, and the years ahead will see a proliferation of drugs to fine tune anticoagulation. Last year, we saw the release of the Re-Ly data, showing that dabigatran was superior to warfarin in preventing strokes in patients with Atrial Fibrillation ( more later ). This year, we see a well orchestrated presentation, on 15th Nov in AHA Chicago, of the data on the ROCKET-AF trial ( nothing to do with DAP ), comparing Rivaroxaban with Warfarin, for stroke prevention in patients with Atrial Fibrillation. Rivaroxaban was non-inferior to warfarin in this aspect, in ROCKET-AF. Well, obviously good drugs attract imitators. There is a whole host of "-xabans" on the way. Trials are under way with Apixaban, Edoxaban, TAK-442 ( only a Jap company will do this name ), Betrixaban, and Darexaban. These are the few in the pipeline that I could find. Of course, Dabigatran had a predecessor called ximelagatran, which which was studied and then withdrawn, in view of a hepato-toxic side effect. Dabigatran remains the sole member now of the "-gatran" family. For how long we do not know. There are a few problems with dabigatran. More of that later.
It must be noted that the dabigatran is a competitive thrombin inhibitor, quite unlike the "-xabans" which are direct Factor Xa inhibitors. They are both anti-coagulants but working on different pathways.
Dabigatran in Re-Ly was shown to be superior to warfarin, in preventing strokes. That is the gist of the results of the Re-Ly trial. But a closer look at the analysis, revealed that both in the warfarin arm and the dabigatran arm of Re-Ly, the optimal PT-INR was achieved in the minority of the patients. Basically, proper anti-coagulation, may not have been achieved. If we sub-analyse the population with optimal PT-INR in both arms, dabigatran anti-coagulation was no longer superior to warfarin. But then this is a subgroup analysis. Also, the other troubling thought about dabigatran seemed to be a slight increase in the number of heart attacks in the dabigatran arm, although the total cardiac mortality was the same. An increase in heart attack rates is worrying. There is also the 10% side effects of dyspepsia with dabigatran. Of course, as always, there is the issue of cost. Dabigatran costs much more than warfarin. However, in a costing analysis, if you take into account closer monitoring with warfarin, intra-cranial bleeds and repeat hospitalisation with warfarin, the total cost analysis seem to favour dabigatran. At least that is what the Re-Ly investigators will have us believe. Obviously, they managed to persuade the FDA, as dabigatran is FDA approved for use in Atrial Fibrillation and DVT.
Rivaroxaban, dont seem to have some of the dabigatran problems. Dyspepsia is less, and heart attack rates are the same in the rivaroxaban arm and warfarin arm. However, the ROCKET-AF study is a smaller one, and may not be as definitive as the Re-Ly study.
It is true that good old warfarin ( rat poison ), is a very fussy drug. It is cheap ( that is about its only selling point ) and it is effective. But it does have significant side effects, the worse of which is intra-cranial hemorrhage. It also interacts with hundreds of other drugs and also veges, fruits and meat. It is rather difficult to maintain a good and reliable therapeutic level, avoiding bleeding at the same time. But it can be done, and the cost savings are substantial.
I would like to spend a few lines to dwell into this issue of cost. Can a developing nation like ours afford to use a drug that cost RM 15 daily, for lifelong to replace a drug that cost about RM 2 daily?, in an attempt to prevent a stroke for every 1-2000 treated? Of course ( as always ), if you are the one stroked out, you will say yes. but if you are those well controlled, you will probably count the RM 450 monthly expenditure on dabigatran, and tell me no ( as some of my patients have ). A tough one. I wonder what the UK NICE will decide. Will they make dabigatran available for NHS patients?
Anyway, there are more "-xabans " coming. Maybe that will bring the price down.
For the moment, all my AF patients are still on warfarin and close monitoring.

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