Prof. John Eikelboom: Yes, I think all clinicians, all of those in the audience, you all are familiar with dealing with emergencies in people on anticoagulants, and bleeding remains our number one concern as clinicians. There is some very good news because the recent trials of reversal therapy now give us the ability, at least in relation to dabigatran to instantaneously, completely, and permanently reverse anticoagulation. I would suggest that never before in the history of anticoagulation have we had such an ability to control anticoagulation. We give a pill now to stop coagulation, a simple pill with no monitoring and when we want to switch it off we squirt in a little bit of idarucizumab and we are done. I think it is a dramatic advance. What other principles of bleeding management in anticoagulation? The common things apply we hold the drug, we use local measures, we resuscitate, there are some general hemostatic measures, we can use PCC or recombinant VIIa and other interventions. Despite these types of measures, there are people on anticoagulants who we cannot control. In patients on a NOAC the good news is that they have a short half-life, so they wear off fairly rapidly. The time of their wearing off is about the time that it takes vitamin K to work, so it is almost as though we have got an inbuilt vitamin K type reversal of the NOACs, at least if kidney function is preserved. In theory we can give charcoal, but who gives charcoal in this day and age. In theory we can try some PCCs or hemodialysis, for dabigatran not very palatable. There are certain critical clinical situations where we absolutely want to reverse and I think with a life-threatening bleed of intracranial bleed. A pericardial bleed you mentioned early, the ablation patient, there are these types of patients where we absolutely instantaneously want to get rid of the anticoagulant, and then of course the renal failure patient who comes into the ER, they have got acute kidney injury, they have got a drug on board and they need to go to the operating for a fracture or acute abdomen or something, you want to get control there.

There are two reversal agents in development, one is idarucizumab and this is not approved around the world for reversal of dabigatran, based on the REVERSE AD study, which was published just in the last year. This is a humanized antibody fragment, it is specific for dabigatran, it binds very tightly, and it works very rapidly.

Andexanet alfa is the reversal agent for the Xa inhibitors. This is a human recombinant factor Xa variant, it binds competitively and it is given as a bolus followed by an infusion. In that trial, the trial testing this is currently ongoing, that is called the ANNEXA trial.

A little bit about the REVERSE AD design, this was a cohort study included people with bleeding and those requiring emergency surgery, 503 subjects. After informed consent all subjects got 5 grams of idarucizumab then we serially measured reversal with blood tests and during longer term follow up evaluated hemostasis. We also collected thrombotic events, we collected mortality, we measured drug levels, and we evaluated the restart of anticoagulation. The results can be summarized on one slide very simply. If you look at the left-hand side of this slide this is reversal as measured by fancy unbound dabigatran assay. So this is actually measuring the drug in the system. On the left-hand side of that graph you see block and whisker plot that represents the range of concentrations of dabigatran prior to administration of the reversal. On the X-axis is time and there are two big blue arrows, these are the two 2.5 gram doses of idarucizumab. You will see on the slidethat there is immediate reversal, even after the first bolus of idarucizumab there is immediate reversal, and it is pretty much everyone who get reversed. That reversal is sustained. If you have think of the ideal reversal therapy in the ER, I would suggest to you this is it. On the right-hand side of this slide is reversal as measured by the poor man’s assay, the aPTT, it is actually remarkably versatile and useful measure of dabigatran, it is not perfect, it is not specific, but it is relatively sensitive. You can measure reversal also with the aPTT. Was hemostasis achieved? It is hard to evaluate that rigorously in a cohort study, but the time to cessation GI bleeding was three and a half hours, of non-GI, non-intracranial hemorrhage was four and a half hours. In those going to the operating room the surgeons, of all people, said over 90-percent of people there was no access bleedings, so that is incredibly reassuring, and thromboembolic event rates were low at 30 and 90 days. A dramatic result in my opinion.

The second study, the ANNEXA-4 study, this was also a cohort study, this is restricted, it is ongoing, it is restricted to major bleeding patients. Having provided consent these people get an intravenous bolus of andexanet alfa, and because it is a very short acting drug and it works competitively, we follow with a two-hour infusion and then the infusion is stopped. There is again serial measurement of reversal plus there is clinical follow up in terms of hemostasis and thrombotic events, mortality, etcetera. The results are also impressive but not quite as impressive as the idarucizumab data. Here we have on the left-hand side reversal of rivaroxaban, on the right-hand side reversal of apixaban. The Box-and-Whisker plot to the left-hand side of each of the graphs represents the range of concentrations prior to administration of the bolus. After the bolus is administered there is a reduction in levels, that reduction is sustained for about two hours during the infusion, the infusion is stopped, there is recovery of anticoagulant activity. So that most people are again fully anticoagulated. It seems that andexanet alfa works, but its reversal that it produces is incomplete and it is not sustained. The good news is that despite the incomplete and short acting effect of andexanet alfa, hemostasis was deemed to be excellent or good in the majority of people 79-percent. The thromboembolism rate was a little higher than we would have liked, 12-percent at 30 days. There are today about 250 people in this study, so it is ongoing. Andexanet alfa is not approved for clinical use. We do not yet know what is going to happen, it is currently being considered by the regulators while we finished the study, but idarucizumab is now on every shelf in every major teaching hospital, in pretty much every European country. That is good news for clinicians and patients. There are some unresolved issues and perhaps I will skip those for the moment and we may be able to get to those in the discussion. The ESC guidelines have already adopted the recommendation for the use of idarucizumab in people with life-threatening bleeding who was treated with dabigatran.

Dr. Hanna Pohjantähti-Maaroos: Okay, extremely interesting data. It is really important to have this data, but I want to go back a bit to the time before we have the bleeding. How can we decrease the risk of bleeding in patients before we need the anticoagulation, how can we evaluate and reduce the risk?

Prof. John Eikelboom: Well I think obviously prevention better than curing the problem, and prevention is difficult but I think there are some sensible measures we can take firstly. I think we can address reversible bleeding risk factors, and I would emphasis control the blood pressure, control the blood pressure, could probably say that three times because it is something that is so obvious and simple to address, but we often ignore that. I think we should avoid the concomitant use of aspirin and nonsteroidal anti-inflammatory drugs, and if a patient is on warfarin or vitamin K antagonist and they have got poor INR control, get them off the vitamin K antagonist and put them on NOAC, and that is another way to reduce the risk of bleeding. Then perhaps in people with a history of GI bleeding you could prophylactically put them on a proton pump inhibitor, although that is not quite proven as of yet.

Dr. Hanna Pohjantähti-Maaroos: In addition to hypertension that we should treat before initiation of anticoagulation. There are two things that we quite often forget, one is anemia which regardless of the reason for anemia is a significant risk factor for bleeding. Another thing is the patient information, I have realized that the patients do not, for example know that black feces means melena it is a sign of gastrointestinal bleeding. We should better inform the patients why we start anticoagulation so that they adhere better to the treatment and also about the signs of bleeding. Of course, the follow up after patient is extremely important.

Prof. Saskia Middeldorp: We will get to that also a little bit later I hope, but we will never get rid of anticoagulant related bleeding no matter how much we try up front. I think it is interesting because let us say in the development phase of the NOACs, I think as least you and I we were saying we do not really need an antidote, we have PCCs if it all goes wrong and supportive measures and we just have to plug something in the hole that is causing the bleed, right? Now that we have an antidote we are really happy, and I think if would have had to first make the antidotes available we would never had gotten into this progress in anticoagulation management with NOACs. Now that they are there we find them important again, and I think that is clear, I mean we all have now the clinical practice of bleeding patients and bleeding is a bit higher in the practice-based populations than in trial-based populations, sure we see those patients. There is more and more of them now that we have more and more patients on the DOACs. I fully agree of course that we need to try to prescribe wisely and use them wisely.

Dr. Hanna Pohjantähti-Maaroos: What we have to remember on antidotes is that we often think about bleeding, we have to treat the bleeding, but we also in clinical practice most of the patients who has got the antidote, who has needed the antidote are those patients who are going to emergency operation. For example, old patients with a hip fracture, it is known that the mortality increases if we delay the operation, so it is really important to reverse the effect of the anticoagulation and treat the fracture, for example, immediately.

Prof. John Eikelboom: I think you raise a really important point, and in Canada certainly what we found is we know that in the REVERSE AD trial it was a three to two ratio of bleeding to surgery, but in clinical practice it is actually the other way around it is three to one or four to one emergency surgery versus bleeding.

Prof. Saskia Middeldorp: Of procedures, yeah.

Prof. John Eikelboom: It is an incredible relief, it is an incredibly empowering situation to be able to say to a patient, yes you are fully anticoagulated. To be able to say to a surgeon, yes, your patient is fully anticoagulated but give me three minutes and I will squirt this stuff and it will be gone and you can have your surgery.

Prof. Saskia Middeldorp: I think you are always raising something that is a big difference between the idarucizumab and the andexanet, and we know that one is not available to most of you, your hospitals, because it is only done yet in the context of research. The idarucizumab has massive difference in practical issues. You already showed the effect that it only works if you give it. So, for surgery we would even have to wait that cohort study where they will decide probably a continuous infusion, but we also have the thrombosis risk, and I think the trials do not show us, but we really need also to make sure that we have the most beneficial way of reintroducing anticoagulants in those patients who have been reversed.

Prof. John Eikelboom: Absolutely right, I think one of the other challenges with andexanet alfa is while you are infusing this drug it is non-specific in its competition with the anticoagulants. If you try to run heparin and say you are going to bypass surgery, in theory even though it only competes it with the Xa inhibitory part, in theory it is going to interfere with other things like heparin.

Prof. Saskia Middeldorp: It is much more complicated than the idarucizumab.

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