Take the thrombin-inhibitor exam: Automatically win a million dollars if you get 100% correct!

Okay, I'm kidding. But I'd really be impressed! So here goes and good luck! You will have 10 minutes to complete the exam. There will be no "phone-a-friend, "50-50," or "let's-ask-the-audience" opportunities. No fair contacting anyone who had anything to do with the ROCKET AF or RE-LY studies. Here goes and good luck!

Mrs Jones is a 70-year-old white female with Alzheimer's disease who was brought into the ER after being involved in a MVA as a passenger. Her husband was the driver. On her list of home medications is rivaroxaban (or feel free to substitute dabigatran if you like). You plan to take her to the OR because her diagnostic peritoneal lavage came back with a little pink tinge. To make certain she is correct about not having taken one of those new direct thrombin inhibitors today, you check a ______________________. The __________________comes back within the normal range, so you call for her to come to the OR. While you are scrubbing, you get an urgent call from the ER physician that her husband, Mr Jones, is crashing. You quickly set up the OR for his arrival and spend about six hours stabilizing him. You finish the surgery, greet the family in the waiting area with the great news, and prepare to take Mrs Jones next.

You finally get Mrs Jones to the OR and realize about an hour into the surgery that she is oozing profusely. You call down to the waiting room and ask, "Did anyone see Ms Jones take any medications this morning?" and the 14-year-old granddaughter says, "You know, I saw Nana taking a pill from her purse in the ER after the doctor left her room." They quickly check her purse, and the only medication bottle present is labeled rivaroxaban (or dabigatran if you prefer). With mild sinus tachycardia and her BP in the 80s, you order four units of packed red blood cells followed by a _______________test to check her level of factor X inhibition. Furthermore, you'd like to know the remainder of time for which she'd be expected to remain anticoagulated on her last oral dose, so you order a ______________________ to see just how many packed cells she's probably going to require. You finish the surgery before any of those tests come back because they are "send-outs" and will require ________________ hours before you can get an answer. You thought about ordering: (a) an activated clotting time (ACT) test; (b) a partial thromboplastin time (PTT) test; (c) both a and b; (d) none of the above because you asked your cardiology consultant, who said, "I don't know, either."

The patient does great because you are a fabulous world-famous surgeon and on postop day 4 Mrs Jones is walking around the hospital having resumed her rivaroxaban (or dabigatran). She turns to speak to the nurse but clutches her chest and falls down in v-fib arrest. She is successfully defibrillated and taken to the cath lab by the same cardiologist who didn't know the answer to the multiple-choice question above. She has a totally occluded LAD. Since she is on rivaroxaban (or dabigatran) she receives a ______________________stent and goes home on triple therapy. She is instructed to stay on a beta blocker, a statin, an aspirin, ticagrelor, and the direct thrombin inhibitor for ___________________months, and then she will continue on with ___________________ and/or ____________________as her permanent ACS secondary-prevention regimen. Because her creatinine clearance has fallen since all of the  hypotension and acute tubular necrosis (ATN) she suffered, you consult the pharmacy, who advises you to: (a) reduce the dose of the thrombin inhibitor; (b) keep the same dose (20-mg rivaroxaban daily or dabigatran 150 bid); or (c) discontinue the medication in favor of warfarin.

On postop day 7 she is feeling great. The nurse comes in to give her the prescriptions and discharge medications as written by her physician. The nurse congratulates her because her creatinine has just come back at 0.7, having completely recovered from her ATN. Just before the cardiac monitor is removed, the nurse looks up and Mrs Jones has recurrent atrial fibrillation now with a heart rate of 150 bpm. You reconsult her cardiologist, who electrically cardioverts her the following day. Her EF is well preserved at 65%. Because she refuses to take amiodarone again, declaring it made her "feel awful last time," you give her dronedarone. You (select one of the following): (a) give the same dose of thrombin inhibitor; (b) reduce the dose of the thrombin inhibitor; or (c) switch her to warfarin at a reduced dose.

The patient finally makes it to discharge having been through a long and winding hospital admission. That afternoon, she reaches into her purse to get her "stomach medication" but bemoans the fact that her bottle is empty. When her daughter asks her why she calls it her "stomach medication" when indeed it is her blood-thinner bottle, she says, "Oh, I just put my purple pill in there because I like the size of that bottle. I ran out of my blood thinner two weeks ago."

This scenario contains almost all of the potentially nightmarish issues that one could encounter in the real world now that direct thrombin inhibitors have come to town. I've asked tons of questions to lots of different people today and so far, I've received lots of different answers. Unfortunately, the favorite answer is "We don't know yet." It's interesting to me that the very drug class we've spent a decade awaiting perhaps has suddenly become available way too soon.

I'd like to thank Dr Kenneth Mahaffey, the codirector of cardiovascular research at Duke University. He spoke to me on a separate issue of how compliance with rivaroxaban was established in the ROCKET trial and the specifics of the trial design. I didn't ask him all of my test questions but if I did, I'll bet he could have probably made a million dollars today. And after today's ROCKET AF presentation, Monopoly money at that.

See also:

Your comments

	Take the thrombin-inhibitor exam: Automatically win a million dollars if you get 100% correct!
	# 1 of 3	November 19, 2010 01:42 (EST)
	Dawn Bell	Dr. Walton-Shirley, just want to point out that rivaroxiban is a direct Xa inhibitor, not a direct thrombin inhibitor.
	# 2 of 3	November 19, 2010 10:10 (EST)
	Melissa	Dawn, Allow me to explain why I came to use this terminology.  Throughout the last four years of covering the development of these compounds, the group has been referred to in general  as thrombin inhbitors in general.  Correct or not, each time a new development occurred along the way, these drugs are all grouped together and consequently pitted against one another. Now that the games have truly begun though, I will do my  best to keep the terminolgy separate. Hematologists are shaking their heads at this I"m sure, but when you consider which of these medications you might utilize for your patients, they are all viable options and competing for the same spot held by Coumadin all these years.    Lesson learned and thanks so much reading AND for you post! Melissa
	# 3 of 3	December 2, 2010 02:09 (EST)
	Michael Creer, MD	The distinction between the mechanism of action of rivaroxiban (an anti-Xa inhibitor) and dabigatran (a direct thrombin inhibitor) is essential to try to make any reasonable attempts to "fill in the blanks" for this case.  For example, to fill in the first blank, you might consider the PT and PTT as reasonable tests to determine whether the patient is taking rivaroxaban or dabigatran.  However, while the PT and PTT are consistently prolonged in patients taking direct thrombin inhibitors (as anyone with experience using argatroban or lepirudin to treat HIT knows very well), these tests are not consistently prolonged in patients with therapeutic concentrations of rivaroxaban.  The experience using LMWH and fondaparinux (both anti-Xa inhibitors) illustrates the inconsistent effects of anti-Xa inhibitors on the PT and PTT.  So clearly, the PT and PTT could not be reliably used to determine whether the patient was receiving rivaroxaban although they would be expected to detect dabigatran. Later on in the case, questions are asked about what tests might be used to monitor for therapeutic response.  For rivaroxaban, this would be an anti-Xa assay.  Unfortunately, the anti-Xa assay routinely used to monitor LMWH or UFH can't be used directly to monitor the anti-Xa effect of rivaroxaban.  The assay conditions are not optimized for this measurement and the laboratory would have to have access to a rivaroxaban calibrator to establish the appropriate analytical response curve. Most labs are not set up to do this at this time.  As for dabigatran, the appropriate assay to use at this time would be a modification of the thrombin time.  The ecarin clotting time has been used to monitor argatroban and lepirudin but does not appear well suited for assaying dabigatran.  Here again, the assay conditions are different from the standard thrombin time used in the lab and a dabigatran calibrator is needed.  Since the blanks can't be filled, your million dollars are safe.

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