Antistolling 2017: de belangrijkste lessen en implicaties van recente klinische studies (1)

Prof. Saskia Middeldorp: It is my big pleasure to be here and to cohost this session together with–

Dr. Hanna Pohjantähti-Maaroos: Hello everyone I am Hanna Pohjantähti-Maaroos. I work as a cardiologist in the Kuopio University Hospital in Finland.

Prof. Saskia Middeldorp: My name is Saskia Middeldorp and I work as a vascular internist in the Academic Medical Center in Amsterdam. It is our big pleasure to have professor John Eikelboom from Hamilton, Canada here to give this webcast and to share the latest evidence on anticoagulation therapy with us and with you behind your computer screens.

Prof. John Eikelboom: It has been an exciting decade in anticoagulant therapy with the advent of the NOACs. We have seen a lot of trial information in the public domain and we have seen the approval of four NOACs, but 2017 has been another exceptional year. I am going to review firstly two very important trials with dabigatran. The first trial that I would like to share with you is a trial called RE-CIRCUIT. This was a 700-patient trial in patients undergoing ablation for atrial fibrillation. Why was this trial done? We know that anticoagulant therapy is important around the time of ablation because patients are at risk of stroke, and we certainly want to avoid stroke. In the past, if a patient was treated with a NOAC prior to ablation we would interrupt that treatment and then we would either bridge with heparin or some people would switch to warfarin, because warfarin has been tested and used in an uninterrupted fashion during ablation. That is a real nuisance, switching to warfarin is a nuisance, and starting and stopping is inconvenient and also associated with risk. In the RE-CIRCUIT trial the question was wither dabigatran could be given in an uninterrupted fashion compared with warfarin given uninterrupted in patients undergoing ablation. The primary outcome was a bleeding outcome. The results are very clear and compelling, in this trial patients who are randomized to uninterrupted dabigatran had a large and important 5-percent absolute reduction in major bleeding, a more than 70-percent relative reduction in major bleeding. On the efficacy side there is was no difference in thromboembolic events so we did not compromise efficacy in anyway, we would not expect too. What are the implications of this result? Well already in the same year that these results were presented the guidelines have adopted uninterrupted dabigatran as a Class IA indication in patients undergoing ablation. This is the first major trial of dabigatran that I want to share with you.

There is a second important trial of dabigatran, this is called the RE-DUAL trial. RE-DUAL was a trial performed in patients with atrial fibrillation, but this time atrial fibrillation patients were undergoing stenting. This is one of the most challenging and problematic areas in antithrombotic therapy in patients with acute coronary syndromes, because in the past these people have been treated with triple therapy, with warfarin, aspirin and a P2Y12 receptor antagonist. We know that that is associated with a large increase in bleeding. A very important study was done in the Netherlands called WOEST, which suggested that if we treated patients with warfarin plus clopidogrel instead of warfarin plus dual antiplatelet therapy that we could substantially reduce bleeding and even achieve an efficacy benefit. The NOACs have not been tested up until recently in this same manner. We did see last year the PIONEER study which tested rivaroxaban in this setting, and now we have RE-DUAL with dabigatran. The design is shown here. Two doses of dabigatran tested and importantly, both of these doses are known to be effective and safe for stroke prevention in atrial fibrillation. In the two dabigatran arms, the dabigatran was combined with the P2Y12 receptor antagonist and then in the control arm we tested triple therapy. The results once again very clear cut, no difference in efficacy but a large reduction in bleeding with dabigatran. This is another trial that I think will impact clinical practice, particularly because of this very large reduction in intracranial bleeding with dabigatran. The two trials that I have just shared with you, RE-CIRCUIT and RE-DUAL fit very nicely with a program of research with dabigatran showing that it is effective, safer than warfarin in patient with atrial fibrillation.

Dr. Hanna Pohjantähti-Maaroos: How do you think the patients who are using Factor X inhibitors, should they switch to dabigatran for example before catheter ablation?

Prof. John Eikelboom: I think that is a key question. We have these really very compelling data from RE-CIRCUIT and it is difficult to avoid the conclusion that all patients undergoing ablation should be switch to dabigatran. There are some centers that already have adopted this practice where there was routine switching to dabigatran. I think that is very reasonable. There are other that suggest, well could this be a class effect, do we simply assume that the other NOACs will perform in the same attractive manner. There is always extrapolation in medicine, the purest would say no, stick to the highest quality evidence. I think this is an evolving field but certainly one thing we can be sure about, that with the use of dabigatran we are certainly going to achieve at least as good results as with warfarin and clearly with RE-CIRCUIT it shows that it is likely to be a substantially safer, and this is a very attractive option.

Dr. Hanna Pohjantähti-Maaroos: Another important point is also that we have an antidote for dabigatran if there is some serious bleeding during the catheter ablation or afterwards.

Prof. John Eikelboom: I am glad you mention that because indeed that is a major concern for people doing ablation. It is an uncommon complication to get tamponade but when it happens you want to get rapid control and we are going to come to the REVERSE AD study, but this antidote is certainly attractive in that setting.

Prof. Saskia Middeldorp: 90-percent, almost 91-percent of the respondents actually think RE-DUAL PCI data will change clinical practice. That is, I think a massive. Had you expected that as a cardiologist Hanna?

Dr. Hanna Pohjantähti-Maaroos: Not actually, not that high percentage. It is a great data I think, it shows the efficacy of double treatment in prevention of bleeding, but how about the–can we say anything about the efficacy in preventing ischemic events?

Prof. John Eikelboom: It is interesting this poll result because certainly I would endorse this opinion. We have actually been using the NOACs in general, in fact, dabigatran in particular now for over five years in this setting because we adopted the results from RE-LY already, but I think this is a very powerful endorsement of the use of NOACs in place of warfarin in the context of recent stenting. What can we say about efficacy, yes, ideally we needed a larger trial to show that indeed the efficacy is equivalent, but when we look at the combined results, the curves are superimposed on one another. I think that is very reassuring. You are right we were not powered for efficacy, but we can take a lot of reassurance from these results.

Prof. Saskia Middeldorp: Yes, and how does–because you have mentioned the WOEST trial, but when you look at the data in a critical way and you see the study design and you say it is almost a no brainer that if you give three antithrombotic drugs and, in the comparator here warfarin plus dual platelet antitherapy including aspirin and then have two dabigatran arms that have only one platelet inhibitor added to that. Any good way of telling me that I should not be so critical?

Prof. John Eikelboom: No, no, I think it is important to critically consider all of the data, and you are absolutely right, it would be surprising if there was not a reduction in bleeding. As you know, predicting in medicine is challenging and we want to see the evidence. I think that clinicians will be very assured, not only by the reduction in bleeding, but by the very similar thromboembolic rates. I do think that this will transform together with the other proceeding data the WOEST trial, then we have the PIONEER and now RE-DUAL, I think practice is gonna change–

Prof. Saskia Middeldorp: Yes.

Prof. John Eikelboom: –and NOACs will become the first line combination therapy post PCI.

Dr. Hanna Pohjantähti-Maaroos: We have more potent antiplatelets nowadays for patients with ACS, for example ticagrelor that has not been used in patients with anticoagulation. In the RE-DUAL PCI there were only 12-percent of patients on ticagrelor. What do you think can we apply this data of the RE-LY PCI also on patients on ticagrelor? Is it safe to use ticagrelor together with dabigatran?

Prof. John Eikelboom: I think the testing of ticagrelor is not as advanced, that there are at least a few hundred patients now, is it enough to change practice I suspect that it will still be a strong leaning towards the use of clopidogrel in this setting. By dropping one antiplatelet drug I think it does give some possibility of intent to finding antiplatelet therapy, and certainly the next trial I would hope would be able to test ticagrelor. There are a couple of trials ongoing, one is call AUGUSTUS with apixaban and one is called ENTRUST with edoxaban, and I do not know whether either of those trials are including ticagrelor. Perhaps in the highest risk patient one might combine dabigatran with ticagrelor, based on the RE-DUAL results.

Prof. Saskia Middeldorp: It is an interesting field where basically finally I would say as an internist, the cardiologists have gotten a true interest in major bleeding complications, knowing that major bleeding complications are very important for the cardiac or overall prognoses of a patient. I think that is excellent that we get more data on the other hand older trials you are being called up by the varying clinical practice where it is sort of difficult to extrapolate all the trial data in an ever-changing clinical landscape I believe. You agree?

Prof. John Eikelboom: Absolutely and I think that is a very important point.

Dr. Hanna Pohjantähti-Maaroos: It is really important that in the group of ticagrelor and dabigatran that results were quite the same as in the whole RE-DUAL PCI study.

Prof. Saskia Middeldorp: Do these results apply for patients on hemodialysis, and I think this is too important to just slip by.

Prof. John Eikelboom: Yes. Very important question, thank you for this. The answer is very simple and the results do not apply to chronic renal failure patients on hemodialysis, because the NOACs in general and dabigatran also is at least partly renally cleared and it should not be used in end-stage kidney disease.

Prof. Saskia Middeldorp: Yes, and I think that this question also stresses always the fact for us clinicians that if you read a trial that it is important to make sure that you understand what the patient population that has been included in this study looks like. Not just looking and inclusion and exclusion criteria, although that is a great first step, but also look at the baseline characteristics making sure that to see whether your patient is or is not part of that trial, and you can generalize the data to your patients and for hemodialysis patients. They are excluded from all these trials.

Dr. Hanna Pohjantähti-Maaroos: We do not have studies on warfarin in hemodialysis patients either, but we do know that warfarin is not eliminated by kidneys so I guess it is safer.

Prof. John Eikelboom: I was gonna say yes, we certainly base on the pharmacologic properties of warfarin use it in end-stage kidney disease, but we do so with trepidation because there is a very high rate of bleeding. I guess the bottom line is, we desperately need alternatives to–

Prof. Saskia Middeldorp: Yes.

Prof. John Eikelboom: –warfarin.

Prof. Saskia Middeldorp: We desperately need studies in this particular vulnerable patient group.