|
||
|
American Journal of Medicine
|
|
|
||
|
American Journal of Medicine
|
It is critical for anyone writing prescriptions for these new anticoagulants to understand the key differences from warfarin. For this, the first thing to remember is that warfarin blocks all of the vitamin K-dependent factors, ie, factors II, VII, IX, and X. On the other hand, the new anticoagulants are target specific, meaning that they are focused on only one particular molecule; for dabigatran that target is thrombin, or factor II, whereas the 3 other new agents (rivaroxaban, apixaban, edoxaban) all inhibit factor Xa.
Looking at Figure 14 the next fact to note is that the time-to-maximum effect, the Tmax, for the new agents is very short, so when using these agents the peak effect is reached within hours – unlike warfarin with its very delayed effect.[8] This is critically important because it means that the anticoagulant effect is going to be reached in a much shorter time period On the other hand, it is also true that after surgery or in any vascular field with an intervention, it will be important to have achieved hemostasis, because these new agents will begin providing an anticoagulant effect within hours and physicians will not want to contribute to any oozing from the wound by starting one of these agents too soon.
Regarding the biologic half-life [T1/2], the average T1/2 of warfarin is about 40 hours, meaning it takes 40 hours for 50% of warfarin to be metabolized. This is again a dramatic difference for the new agents compared to warfarin; on the other hand, when compared with each other, it appears that dabigatran has a longer T1/2 on average than the others, but for all of these NOACs the T1/2 is effectively around 10 to 12 hours.
The next important thing is dosing: dabigatran and apixaban are dosed twice a day, rivaroxaban is once daily (and I will emphasize one difference with rivaroxaban when we get to acute treatment). In addition the newest agent, edoxaban, is being tested in clinical trials as a once-daily medication.
Another absolute departure from warfarin with these NOACs is renal clearance. Warfarin is exclusively or nearly exclusively dependent on the liver for clearance; in contrast dabigatran is 80% cleared by the kidney. About 36% of rivaroxaban is cleared by the kidneys (actually 60% of rivaroxaban is cleared renally, but rivaroxaban metabolism results in a portion of the drug being changed and a portion unchanged, and the critical proportion cleared renally is closer to 36%). Finally renal clearance with apixaban is about 25% and for edoxaban it is about 35%.
Finally these breakthrough agents have fewer drug–drug interactions than warfarin, but there are a few interactions that should be borne in mind. One is P-glycoprotein (P-GP) interference, seen with all of these agents; in addition, for the factor Xa inhibitors there is an interaction with the cytochrome P450 hepatic enzymes, specifically CYP3A4, which largely is seen with the protease inhibitor drugs that are used in human immunodeficiency virus (HIV) disease. Hylek E. Am J Med 2013; published on-line at http://education.amjmed.com/00000.
[8] Franchini M, Mannucci PM. New anticoagulants for treatment of venous thromboembolism. Eur J Intern Med. 2012;23:692-695.