More About Oral Anticoagulants

Question from a colleague: My 92-YO dad has atrial fibrillation and is on warfarin. He is well controlled and since he is independent and drives, getting monitored is not a big deal…while the pavement is dry. However, I am worried that he will venture out when he should not during the winter when he has an appointment. So, we are exploring whether to switch him to one of the new drugs that does not require monitoring. He took Xarelto after his knee replacement and did not have any reaction.

So…
1) We chose warfarin therapy due to its good track record and the fact that the Xa inhibitors were relatively new to the US market. Some data do suggest that they are superior to warfarin for stroke prevention. Do you have any hesitations about them for someone who is 92 years old with good kidney and liver function?
2) Do you have a good simple explanation for a lay person as to why monitoring isn’t needed event hough there is risk of bleeding?

From George: Hi, I am just back from the Quest conference in DC,where I had the privilege of hearing Drs Adam Cuker from University of Pennsylvania and Jeff Dlottfrom Quest. Dr. Cuker suggests the phrase “targeted specific oral anticoagulants (TSOACs)” in place of “New Oral Anticoagulants (NOACs)” on the premise that the oral anticoagulants won’t be “new” for much longer.

Anyway, to continue with Dr. Cuker and Dlott’s recommendations, mixed with some facts I’ve gathered over the months. if a patient is successfully controlled on Coumadin and doesn’t mind the monthly trips to the lab, don’t change. Coumadin is cheaper and has 50-year track record. If your Dad is inclined to go out in the snow for his INR, convince him he can postpone for a few days until the weather clears without consequence. There is in fact a current study that shows compliant patients can go once every three months with no loss of time in therapeutic range.

The TSOACs  have better efficacy and safety records than Coumadin, and can be safely substituted. Of course in the US they cost more (by about 30X) and if the patient skips a dose he becomes at risk for thrombosis in about 24 hours, unlike Coumadin, where the anticoagulant effect takes at least 48 hours to diminish.

In clinical trials, pharmaceutical houses establish preliminary safety and efficacy in phase I and II trials, respectively, and then run big phase III trials using the dosages established in Phases I and II, but they do not monitor plasma levels. The dose-response relationship is stable for all, just like, for instance, Prilosec or Crestor, so there is no need for a lab assay, and to include one in a clinical trial implies the opposite.

Of course, the day a drug is FDA-released, physicians phone to ask that labs measure (not monitor, which implies dose adjustment) to test for compliance, overdose, renal effects, effects of obesity or extreme slimness, unstable coagulation such as in cancer and pregnancy, and many more reasons, often emergent.

So the IVD manufacturers are scrambling to develop assays. For the anti-Xa’s like rivaroxaban (Xarelto), apixaban (Eliquis) and more on the way, it looks like the chromogenic anti-Xa assays will win the market share when FDA-cleared. They are identical to the assay for heparin, low molecular weight heparin, and fondaparinux, except they require specific calibrators and controls and use different specimen dilutions that can be easily programmed into coag instruments.

For the only oral direct thrombin inhibitor, dabigatran (Pradaxa) there is the ecarin chromogenic assay, and the plasma-diluted thrombin time, both are linear and reproducible, except at very low ranges. Since everything is RUO, however, the current stop-gap measures are PT for the anti-Xa’s and the PTT for the DTI’s They are semiquantitative and prone to variation, but at least can tell you something. Also, the thrombin time may be used for a binary (rule in-rule out) DTI determination.

Here’s the limitation. We have no target therapeutic ranges, and it will take years to develop them, since prospective double-blind placebo controlled randomized trials are impossible when people show up in the ER bleeding or clotting. The best we can hope for is that someone establishes a registry where ER personnel can send in symptoms and plasma levels. After a few years we may have something reasonably valid. One additional wrinkle is that the plasma levels vary widely from peak to trough, so the time of collection after dosing must be pinpointed, thus relying on patient self-reporting.

By the way, don’t buy the lawyer-inspired denigration of rivaroxaban (Pradaxa), 1-800-BAD-DRUG. Initial reports reflected “early reporting bias,” but all current data show Pradaxa to be as safe or safer than Coumadin.

From my friend: So the simple answer to my question about why no monitoring perhaps is, in time, we may actually BE monitoring…but we need a therapeutic range, which we don’t have. But it does look like stroke prevention may be better with the new drugs.

George’s response: Probably measuring, not monitoring, and yes, if the expense can be met, one could certainly argue the improved efficacy and safety is worth the switch. One thing to keep in mind, no 92-YO subjects were included in the clinical trials! Also, while all tend to say that because of a 12-hour half-life, patients lose most anti-thrombotic effect after missing only one dose. However, although the drug level drops 50% in 12 hours, it takes factor X at least another 12 hours to regenerate, owing to it’s long half-life. So although the drug is below therapeutic range, its effect lingers because the inactivated Xa hangs around. Nevertheless, the patient should take the next pill on schedule to avoid an adverse event.

One other thing, rivaroxaban tables are hygroscopic, so they have to stay sealed with a desiccant pouch. If you leave the lid off or dole them out into those daily pill boxes, they lose their efficacy, a particular problem for folks with chronic disorders who are taking 4 or 5 pills a day. Geo.