Prof. John Eikelboom: Again, a wealth of new data, having considered the two dabigatran trials, we also have a couple of trials with Xa inhibitors and the first is the COMPASS trial. This is really changing gear from atrial fibrillation to chronic atherothrombosis, patients with stable coronary or peripheral artery disease. We know that in this population during long term treatment there is a substantial residual risk, and the goal of COMPASS was to try and address this residual risk by testing rivaroxaban-based therapy as an alternative to aspirin. The trial included 27,395 patients, there were three arms, one the combination of rivaroxaban 2.5 milligrams twice daily and aspirin. Two, rivaroxaban 5 milligrams twice daily, and then the control arm was aspirin 100 milligrams once daily. These two rivaroxaban arms, the doses were selected based on the results of the ATLAS trial. What did the results show? A clear-cut result, the combination of rivaroxaban and aspirin, shown in the black line, reduced the risk of the primary outcome cardiovascular death, stroke and myocardial infarction, compared with aspirin in the red line by 24-percent, a highly significant reduction. Rivaroxaban alone produced an intermediate result a 10-percent risk reduction, which was not statistically significant. In addition to the primary outcome there are several important additional outcomes to focus on. One is that there was a reduction in major adverse limb events or MALE. This was reduced by about 50-percent and likewise amputations were reduced by about 50-percent. There was a cost to pay in terms of bleeding, a 70-percent increase in major bleeding. So, the clinicians will say, how do we integrate the benefits and the risks of treatment? The ultimate measure of net benefit is mortality, because in the end if you are going to compromise your efficacy with bleeding and you do not see a mortality reduction, you might say it is a wash. In COMPASS there was an 18-percent reduction in mortality. This is the first long term antithrombotic that shows a total mortality reduction. We have not seen that since aspirin, we have not seen that with clopidogrel or clopidogrel and aspirin, or ticagrelor and aspirin, we have not seen that with warfarin and aspirin or warfarin alone, it is the first time. I think the combination of 24-percent risk reduction, a reduction in the devastating complications of stroke and amputation, and the mortality benefit will be attractive.

The second study and the equally exciting study also from the last year is the Hokusai-VTE cancer study. The leads on this study have shown this was a study that was also lead substantially here from the Netherlands. What is the issue with cancer and VTE? We know that historically when we treat these people with heparin followed by warfarin that there is a very high recurrence rate, maybe 10 or 20-percent per year. We know this is a highly problematic group. In the CLOT study, patients treated with dalteparin instead of warfarin had a large reduction in recurrent thrombotic events. This lead to the adoption of dalteparin as the standard of care. Patients do take dalteparin and reasonably well, but these are cancer patients and it is an additional burden, they do not like doing it and they are tired doing it. After three to six months quite a number drop out. If we could have a simpler treatment that was as effective and safe, I think it would be a major advance. In the Hokusai study there was a comparison between edoxaban based therapy with a lead-in of five days of low molecular weight heparin, and the control group was dalteparin given in the CLOT regiment, and patients were followed out to one year. The primary outcome was a composite of thrombotic and bleeding events and the two treatments were essentially the same in terms of this primary outcome. What does this mean? There was actually somewhat of a lower rate of venous and a somewhat higher rate of bleeding in this study, but overall very similar results, and I think that this will lead to the adoption of edoxaban based therapy as a very attractive alternative to the current standard of care.

Dr. Hanna Pohjantähti-Maaroos: Let us talk about the COMPASS trial first. You, John, mentioned about the net clinical benefit. Will you shortly say again, how do you trust the net clinical benefit? There was a decrease in ischemic events which was really meaningful, but also an increase in bleeding events.

Prof. John Eikelboom: I think we can look at net clinical benefit in various ways. One way is to do one of these composite net clinical outcomes and we prespecified in COMPASS a net clinical benefit outcome that included ischemic events and the most serious bleeding events. When evaluated in this manner there was a about a 20-percent reduction in the net clinical benefit outcome, by the use of combination of rivaroxaban and aspirin, compared with aspirin. I think that most clinicals look at these net clinical benefit outcomes with some uncertainty because they are not sure what it means. The beauty I think of the COMPASS result is that this was paralleled by a similar magnitude reduction in mortality. I personally think that the best measure of net benefit is mortality. The consistent results, I think, are very reassuring.

Dr. Hanna Pohjantähti-Maaroos: Okay, but in what kind of patients should we use this combination therapy with low dose rivaroxaban and aspirin? To all patients with stable cardiovascular disease, or how can we choose the right patients?

Prof. John Eikelboom: That is a very important question translating trials to the practice. I think the trial shows us that it can work. I think that as clinicians we start by treating those who are gonna get the most bang for the bucks. The higher risk people and certainly starting with the peripheral artery disease patients that are very high risk and there are very large absolute benefits. We also did some risk scoring for the coronary disease patients and those at highest risk obviously got the most benefit. I would say that as we translate the practice we start with the higher risk population. Overtime, as we get confidence, we may move towards the intermediate risk, whereas the lowest risk people we do not need to use it in those people.

Dr. Hanna Pohjantähti-Maaroos: Just one question about the COMPASS trial. It is quite interesting that we do not get rid of aspirin. What do you think is the effect behind the combination of rivaroxaban and aspirin, did you for example access the atrial fibrillation burden on the patients?

Prof. John Eikelboom: I think you make a good point and we have just seen in the RE-DUAL trial, we can eliminate aspirin, we think, for many patients, certainly for all the stable PCI patients and a certain portion of the post ACS patients. There we get rid of aspirin, but here in COMPASS it seems that aspirin provides a valuable addition to rivaroxaban. The atrial fibrillation population, there was a probably three or 400 people diagnosed with AF during the trial and there was a large stroke reduction in COMPASS, but I do not think that atrial fibrillation explains that result. It is a complicated story because the large reduction in stroke makes us again reevaluate the dose of rivaroxaban that is effective for thromboembolism prevention at 2.5 milligrams twice daily. We did not expect such a large reduction in stroke.

Prof. Saskia Middeldorp: It is also going to be quite complex to dose rivaroxaban in the correct way, or at least I think that is also something that we–and it is not getting any easier. Whereas the NOACs were meant to become–to make the lives of everybody easier.

Prof. John Eikelboom: Yes and no, I guess on the one hand they certainly still do make life easier. As we start to expand the indications we are going to have–

Prof. Saskia Middeldorp: Fine tuning basically.

Prof. John Eikelboom: –and learn all the doses, yes indeed.

Prof. Saskia Middeldorp: If we then move on to the edoxaban cancer trial, which of course is close to my heart, will the edoxaban cancer trial change your clinical practice, will it change your practice John?

Prof. John Eikelboom: For me personally, without question. I think this trial very elegant study. I know not the perfect study and it is not the largest study, but managing people with cancer and thrombosis, this is a real problem, it is a real challenge and I think this is going to be highly attractive for the patients. I am certainly going to think about this in every cancer patient who has venous thrombosis. I may not treat every cancer patient because there are some very high risk with the metastatic adenocarcinoma, where I am very worried about the thrombosis risk, but I think in the vast majority of people I will use it.

Prof. Saskia Middeldorp: we just discussed net clinical benefit for the COMPASS trial but for the Hokusai cancer trial you show to primary composite endpoint. I think it was done primarily because overall oncologists and patients would value a recurrent clot as much or as bad as a recurrent major bleeding. That is the rationale behind that composite endpoint, and of course a smaller trial not 27,000 but 1050, I think this is valid al as a priori find but if you would look at the components well then it was a little bit less VTE and a little bit more major bleeding.

Dr. Hanna Pohjantähti-Maaroos: And there was no difference in the number of pulmonary embolisms.

Prof. John Eikelboom: That is true–

Prof. Saskia Middeldorp: It was not inferiority of course because the idea of course, it would be so much more friendly to the patient with no injections and so on. Is there still not a little bit more to learn in this particular population?

Prof. John Eikelboom: I think there is definitely more to learn, I am reassured also by the fact that there were no fatal pulmonary emboli, there were no fatal bleeds in the edoxaban group, and the investigators were clever in their evaluation of bleeding in that they very carefully looked at the severity of bleeding. In fact, the slight excess of bleeds with edoxaban was confined to the less severe bleeds.

Prof. Saskia Middeldorp: Yes, that is true. I think it is though still important thing to consider because for instance, the Select-D study that was recently also presented in abstract form still with rivaroxaban in the same type of population, during that trial the investigator or the steering committee decided to not include any gastrointestinal cancers anymore because of the fear of the increase in bleeding. What are your thoughts about that?

Prof. John Eikelboom: I am aware that in the Hokusai cancer study there was a slightly excessive GI bleeding which seemed to be confined to those with GI cancers, and I think it is a pity that the Select-D study did not include these people. We need more data and I am not put off by what we have seen in Hokusai cancer, and I would even treat my GI cancer patients with edoxaban, of course discussing it with them. I think your point is very well taken, we need more data and I am delighted that we have got a number of other studies ongoing in this area.

Dr. Hanna Pohjantähti-Maaroos: I agree it is not wise to exclude patients with GI cancer because those are mainly adenocarcinomas which are really thromboembolic as well.

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