Samuel Z. Goldhaber, MD; Christian T. Ruff, MD, MPH


May 05, 2014

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Samuel Z. Goldhaber, MD: Hello. This is Dr. Sam Goldhaber for the Clot Blog at on Medscape, speaking to you from the American College of Cardiology Scientific Sessions in Washington, DC. Today I have Dr. Christian Ruff as my guest. Christian, welcome to the Clot Blog.

Christian T. Ruff, MD, MPH: Thank you, Sam. It's my pleasure.

Dr. Goldhaber: We want to discuss the very provocative question of whether we need to measure drug levels of patients on novel oral anticoagulants (NOACs). In particular I want us to focus on the very thought-provoking study[1] that was published on the relationship between plasma dabigatran levels and subsequent bleeding and clotting (stroke) events. The reason I call it provocative is that some years back, the promise of the NOACs was that we didn't need to do any laboratory coagulation monitoring, or any monitoring at all other than renal function.

Dr. Ruff: You always ask the most provocative questions, and this is a big hanging question mark in the area of stroke prevention in atrial fibrillation. You are absolutely right. All of these drugs were developed to avoid routine blood monitoring because people wanted to get away from measuring the international normalized ratio (INR). Certainly, these drugs have a predictable effect on anticoagulation. You don't need to routinely monitor coagulation to know that they are effective at a given dose.

You ask a very interesting question because we know from the RE-LY study[1] and other data that are emerging from the other NOACs that the concentrations achieved in patients, even in patients taking the same dose, are variable. All of these drugs have different levels of clearance, mostly by the kidneys. Some of these drugs are metabolized by the liver. Even if you give the same dose to a large population of patients in these trials, there is huge variability in the actual drug concentration achieved and therefore in the level of inhibition of the coagulation factor (Xa for the Xa inhibitors or thrombin for the IIa inhibitors). So, now people are wondering whether this variability means that we should be measuring drug levels to see whether the dose should be lowered.

Dr. Goldhaber: Is the variability clinically important?

Dr. Ruff: This is an evolving field and I don't claim to have all the answers, but I think that what we find, over a broad range of exposure to drugs and levels of inhibition of the coagulation factor, is that the protection from stroke is relatively similar. You don't need to know the specific drug concentration or the level of inhibition to manage a patient's dose because there is a rather broad (or flat) range of efficacy. We realize from that very provocative study published in Journal of the American College of Cardiology that a patient with impaired clearance of the drug -- dabigatran is predominantly cleared renally -- who accumulates drugs (for example, an elderly patient with impaired renal function) can accumulate very high levels of the drug. When you have high levels of drug, you are at risk for bleeding. So, I don't know that we need to be measuring an assay, but it gives us pause to say that patients who are elderly and have impaired renal clearance are at high risk for bleeding because of high exposure to the drug, and we should be adjusting their dose down.

Dr. Goldhaber: Even in that study you referred to, wasn't age an independent risk factor for bleeding as well?

Dr. Ruff: Absolutely.

Dr. Goldhaber: And even in an elderly patient with normal renal function, didn't that patient seem to have higher drug levels, and to be more susceptible to bleeding?

Dr. Ruff: Yes, exactly. Certainly both factors elevate drug levels and the risk for bleeding, but just being elderly imparts a risk for bleeding not explained by kidney function. This is something that we intuitively know in elderly patients aged 85-90 years -- that they seem to be the patients who are often coming in with bruising and more significant bleeding.

Dr. Goldhaber: This might explain why the so-called "renal dose" for all the NOACs is given much more frequently in the real world, even to patients without renal impairment.

Dr. Ruff: Yes. This is the disconnect between the clinical trials and the real world. These drugs are approved with dose reductions, either according to how the trial was designed or to a simulation done by regulatory authorities. Practicing clinicians know which patients are at high risk for bleeding and who may benefit from a reduced dose.

Dr. Goldhaber: My last question is this: Do you think the findings with dabigatran in this study will be replicated with the other NOACs?

Dr. Ruff: That is absolutely true. We are working on that in the ENGAGE AF-TIMI 48 trial[2] and looking at drug exposure. We obviously had a very advanced dose-reduction strategy. This is going to be relevant for all of the NOACs.The more data that we have from all of the relevant agents will be a real advance in this field. It's very important because this deals with patient safety.

Dr. Goldhaber: Christian, thank you so much.

Dr. Ruff: Thank you.

Dr. Goldhaber: This is Dr. Sam Goldhaber, signing off for the Clot Blog.


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