EAU Guidelines on Thromboprophylaxis in Urological Surgery - Kari Tikkinen

January 4, 2023

Ashish Kamat and Kari Tikkinen discuss guidelines on thromboprophylaxis in urological surgery. Dr. Tikkinen gives a step-by-step guide through deciding to use thromboprophylaxis, starting with demonstrating that prophylaxis works and then discussing what constitutes a need for thromboprophylaxis for the patient. They also discuss cases where the guidelines may falter and how to troubleshoot in those scenarios.

Biographies:

Kari Tikkinen, MD, Professor of Urology, University of Helsinki, Consultant Urologic Surgeon, The Department of Urology, Helsinki University Hospital, Department of Surgery, South Karelian Central Hospital, Finland

Ashish Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, Texas


Read the Full Video Transcript

Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology and cancer research at MD Anderson Cancer Center in Houston. And it's a pleasure to welcome today, Professor Kari Tikkinen, from Helsinki University Hospital. Professor Tikkinen is an expert in many things to do in urology, urologic oncology. And he also has been instrumental in guiding the guidelines, for the EAU, in thromboprophylaxis in urological surgery. We thought it'd be great to have him join us today. And he's been kind enough to accept the invitation, to share with us what are his views, and what are in the guidelines on thromboprophylaxis. So, Kari, the stage is yours.

Kari Tikkinen: Thanks very much. Thanks, Ashish, for your kind words, and thanks UroToday for the opportunity to present here. You have done an amazing job during COVID pandemic, and it's a pleasure to my small part for your work. I have no financial conflict of interest. Obviously, I have some intellectual conflict of interest. I chaired the first EAU ad hoc Guideline in 2017, which I hope we would update in upcoming years, couple of years. Also, I was a panel member for 2019 ASH guide on thromboembolism in surgical patients. And now, we are updating the European Society of Anesthesiology and Intensive Care Task Force guidelines for VTE. There's substantial practice variation in the use of thromboprophylaxis, both within and between countries. It is somewhat well documented also, but it's a common knowledge.

When you consider thromboprophylaxis, whether to give it to your patient, or whether to recommend for the patients, as a guideline member, I usually first know whether it works, and that would preferably come from a systematic review and meta-analysis of randomized contract trials.

That's what we have done. This is updated. Actually, we will soon publish this update, but it will not change our earlier estimates. Which are, that heparin roughly decreases risk of thrombosis by 50% compared, to no prophylaxis, but it also increases risk of bleeding by about 50%. This is based on thousands of patients, but it clearly shows that there's a trade-off, both benefits, and harms.

What about aspirin? Often you hear from clinicians, it doesn't make any difference. Actually, in randomized trials, it does make a little difference. The trials are on terms of the VTE prevention, they're mainly from orthopedic surgery, though. And then, from POISE-2 trial, which had different kinds of surgeries. So it shows that it little bit increases bleeding, and little bit decreases venous thromboembolism. It didn't have effect on arterial thromboembolism, though.

A couple of years ago, there was a nice trial published in the European Urology, by the colleagues from Baltimore. They randomized some 500 patients undergoing radical prostatectomy, mainly robotic. Many people consider this as a negative trial, showing no impact of VTE prophylaxis. But actually, it was underpowered to show that. Actually, the risk ratio was 0.6. Again, very much in line with our meta-analysis estimate of 50% reduction. So it was actually 60% reduction here. Although it was not statistically significant, because, in many of these patients, there was very low risk of thrombosis. So that's in many basic, radical prostatectomy, especially robotic, you probably don't need anything. But it doesn't mean that it doesn't work. It just means that you don't necessarily need it. Let's talk about that later.

This is a systematic network meta-analysis, which is just accepted to the one of the leading journals of journal medicine. I cannot comment more yet, but we published this also as a conference abstract, and here you can see somehow the results. This is a network meta-analysis, so it's a lot of indirect evidence. It's a little bit busy slide, but I can tell you, that the main message is, that direct oral anticoagulants demonstrate similar bleeding risk, in the trials so far published, among thousands of patients, mainly outside urology in other noncardiac surgery, but they may be actually a little bit better in innovative reduction. But this is network meta-analysis. This is not direct evidence. This is mainly indirect evidence. You will see this be published in upcoming weeks.

Little bit prompted by that, and a little bit prompted by other research we have done, we decided to begin. And we have now started in Finland, and then we will spread around the world. And hopefully, many will join our large pragmatic trial, where we will randomize urologic general surgery in gynecologic patients. Patients with so far, same kind of risk of thrombosis and bleeding, to either placebo or apixaban. Which is one of the most prominent, if not the most prominent, direct oral anticoagulant in VTE prophylaxis. We published a synopsis, kind of a short summary article, or kind of a short protocol article in European Urology Focus, a couple of months ago, and email me if you're interested.

So first of all, we know there's prophylaxis available, which seems to work. Do we need it? We can answer by looking for the so-called rework data, like the baseline risk in cohort studies, the natural history. We did this work. We went through hundreds of, actually thousands of our successes. Titles and action. If you find papers in urology for 14 different types of cancer procedures and 11 types of non-cancer procedures. Unfortunately, much of the evidence is not high quality, but some of it is. And what we found in this series, which we called, risk of thrombosis and bleeding in urologic surgery, rough. But we found that there's a substantial variation in risk of thrombosis by procedure. So it is maybe not so surprising for clinicians, but this is not well taken into account in many of the guidelines, which we just talk about cancer surgery as a one-hole or pelvic surgery as a one-hole.

It seems not to be the case. There seems to be clear differences between procedures. Cystectomy, no matter you to open or robotic, it's high risk. But then, different radical prostatectomies may be either lower or high. Pelvic lymph node dissection, probably four or five times higher risk with, versus without pelvic lymph node dissection, et cetera. And then many of this benign surgery, benign urologic centered procedures, are very low risk, VTE risk.

Then, what about the bleeding? This, much less variation. These rates look very small for bleeding, because they are at risk of re-operation, due to the bleeding. Meaning, a re-exploration or any embolization. If you look for transfusion rates or hemoglobin drops, they are, of course, much higher. But these were what we used here.

If you're interested in this, you can get this infograph, where you can look for the procedure, and then, based on risk factors, and then find what we suggested, whether you should use or not. You can find this from my Twitter, or for our website. This is same information that's in the EAU guidelines. This, we created based on the EAU guidelines information.

So, yes. So now we know that we have prophylaxis available for some procedures we do need, for some, we may not need. How long, and when to start? This was what we used, but now we have a little bit better information regarding risk of thrombosis. So it's actually not completely flat-lined. Let's talk about later. But the bleeding seems to be so, that if it bleeds, as you very well know, it comes very shortly after surgery. Couple of first days, majority of bleeds come during that time.

However, the thrombosis, this is a systematic review of about little more, 20 studies, which prospectively looked for risk timing of thrombosis, post-surgery. And we see that of those bleeds, which happen during the first-month post-surgery, during the first week, a little bit less than half, about two weeks, about two-thirds, or a little bit more, and at three weeks, 90%. So yes, they do happen a little bit more in the beginning. But on the other hand, if you only give prophylaxis in hospital, it's probably much too short time. Many of the thrombosis happen post-discharge. That's what we know, that for many, many studies.

So when you consider duration, if you need, you should probably give it longer time. Another aspect is, when to start? Is it before or after? Is it six hours after, or next day? Canadian colleague, Kristen McAlpine, and other colleagues from Ottawa, they published it, their systematic review, just a couple of months ago. Where they did not find any statistical differences between either before or after, but this was underpowered. There was not that much events. But we can say there's no big differences.

But what they've not surprisingly found, some suggestion, these were not statistically relevant, I'm going to say, highlight it again. But it looks like that the earlier you begin, the less thrombosis, and the later you begin, the more thrombosis. And the less earlier the begin, more bleeding, and unsurprisingly, the later you began less bleeding. So if you're very worried about bleeding, don't rush. If you're very worried about thrombosis, give it earlier.

And then, how long to give? I already little bit show that, our modeling from these 21 studies, it looks like they happen over a long time. This is abdominal and pelvic surgery. These are not urologic studies. But I don't see any difference why it would be so different in urology. This is a Cochrane review. There was clear difference in risk of thrombosis between those who gave more than two weeks, versus those who gave only in hospital. Clearly, symptomatic thromboembolism, much less, and very little, if no, impact on bleeding. Why? Because as you saw from the figure earlier, bleeds happen in the beginning. And in hospital, if you give them during the highest risk time, and if you extend it, there's not much bleeding happening after some days. So the extension doesn't make things. It's of course, a burden for patient, and it may increase costs. But it does not naturally increase bleeding. So when, you consider that this patient needs consider to give it a little bit longer than at least only the hospital time.

So now we know a little bit about the baseline response. So what about the patients? We typically have heard something about Caprini scores, or something like that. They are very burdensome. No. Basic clinicians don't use this kind of, where you have to answer more than 20 questions regarding thromboembolism. They want something more simple. We try to create that. This is not validated. So we must, and we are planning to validate. If somebody wants to validate this with their data, it would be great. We are also planning to do it.

But this is based on systematic group literature research. We identified this as a risk factor, age, BMI, and history of VTE. They are the risk factors. And then we created this some kind of guidance. But I must say, this is not yet validated, but we have been using this. And earlier, many people didn't use almost anything. Or if you use Caprini scores of those, they are not very user-friendly. And they may overestimate the risk of thrombosis.

When considering then, whether you should give or not. Of course, you should think about the quality of evidence, how certainty in urine these estimates. And think about the relative benefits and harms. Like, how bad is pulmonary embolism compared to major bleeding? Which one is worse? Which one do you want to prevent more? Or, are they equally important? Again, I'm not going, if you want to get this, all the details, go to the EAU guidelines.

Here's just a little bit, how did we do it? We gave strong recommendation. Where clearly, benefits outweigh the harms. We said, use it, favor. Or, if clearly, risks and costs outweigh the benefits, we also gave strong recommendations against. Most of the cases, we gave weak recommendations, because we were not that confident in the estimates, or, if it was a close balance.

We considered DVT and PE equally important. We consider this as a VTE. Okay. PE you can only die, but DVT can cause you long-term effects, and much more likely, like post-thrombotic syndrome, et cetera. So we considered them to be simple in a way as any VTE.

And then, bleeding. In this, we were considering re-operation risk and re-exploration risk.

And then, we considered that major, twice as bad, but it actually wouldn't make big difference, even considering it other way around. Because the estimates, in some cases, it may make some difference, but that's how we did.

Then, we looked for net benefit, and if we found that we are going to cause one person net benefit, then we gave strong in favor, et cetera.

And with all this methodology, we found that cystectomy, in all patients going under open radical cystectomy, we recommend strongly use of pharmacological prophylaxis, and we recommend extended. So in this case, we gave four weeks post, open radical cystectomy. We only gave weak that time for radical cystectomy, if you did it robotically. Not because it's lower risk, probably, but because the evidence was that time, and it still is limited. We have less evidence for risk of thrombosis post robotic. So, because the evidence was lower quality, we couldn't give strong recommendations. But our best guess is, that the risk of thrombosis is roughly the same, in whether you do open or robotics. It's not a big difference.

So then, about a robotic prostatectomy, if you do it without lymphadenectomy, actually, for those low-risk patients, we recommend not using. You can go to the guideline, you see that if you do it open, especially if you do it with lymphadenectomy, we give strong recommendation to use prophylaxis. So even though it's just radical prostatectomy, and for some, we give recommendation, for others, we didn't. Depending on patient factors and about the approach, how did you do, and whether you do lymphadenectomy, or not.

And many of these lower urinary tract and pelvic, or in prolapse, et cetera, surgery, most of them we gave against pharmacologic prophylaxis. I forgot to say, that we very often gave a recommendation, weak recommendation, to keep mechanical prophylaxis until ambulation. Why weak? Only because the evidence is very, it's, in most cases, it's a lower quality. The trials are very old, and we are really not that certain, how much does it make a difference? But it looks like being beneficial. And it seems to not to have much, if very little, harms. So, except that it's not maybe nice, and it causes burden, but patient complications are rare. But the quality of evidence is low, so we gave mainly weak recommendations.

So this is the biggest part of my presentation. It was about the thromboprophylaxis. And now, a couple of words about management of antithrombotic agents during perioperative period. These patients, we treat all the time, of course, because many cancer patients, especially they have many comorbidities. They are older people, and they have atrial fibrillation and treated, are very awesome.

So there's, in principle, four options. First of all, if possible, before surgery, until the patient doesn't need any antithrombotic agents. Okay? Quite often, they are chronic users, so you can't do that. Then, there's an option that you stop before surgery sometime and then start later. Quite often, you should actually do that. Then in some high-risk patients, you may continue through surgery, and sometimes, you bridging therapy.

This is based on pharmacologic studies. We gather guidance when to stop different molecules or different drugs. And I mean, if you're more worried about bleeding, if it's more like a very high risk of bleeding procedure, then you want to stop a little bit earlier. And if it's not that high risk bleeding procedure and the patient is more like higher, then if you stop, you maybe stop a little bit less. So for instance, this apixaban, you can stop only one, two, something between one and three days pre-surgery.

Many guidelines have preceded some major trials. Not that many more. The reason, maybe I should not talk about reason, but still, many of the earlier guidelines, which were published 2014, '15, they didn't have this information. The POISE-2 trial, in New England Journal of Medicine, showed that aspirin increases bleeding, but it did not really in arterial thrombotic events. So in many patients, it would be probably good idea to stop aspirin, actually. However, there's a clear benefit that shown in those who have a history of PCI. So in those patients, you should probably never, you should avoid stopping even aspirin. Keeps aspirin going in patients with PCI.

Then another thing, what at least here in Europe, was very, very popular was, and still is in some places, very popular. And of course, it should be used in everywhere, but maybe not that much, is bridging therapy. BRIDGE trial, also published in the New England Journal of Medicine, however, which included mostly atrial fibrillation patients with medium-risk, showed that bridging versus placebo, it didn't decrease thrombosis. But actually, bridging a little bit increased bleeding. So, that was a little bit kind of negative. And then, there has been other studies, actually replicating the result later.

So what we had, and when we have two principles, discontinue the therapy around the surgery as possible. And then, there's some patients where you want to, which are high-risk, where you want to maybe use bridging therapy, or even continue antithrombotic therapy, what they have.

So first of all, in antiplatelets, we recommend stopping, and not initiating any alternative therapy. And then, when then to start again? It depends. At least, don't go over, much over four days. I mean, of course, if it's something like aspirin for primary prevention, not really having any disease, based on just wants to use aspirin, then you can wait a longer time. Especially after TURP, which has a post, I mean this bleeding around two, three weeks. So you can, even in those very low VTE risk patients, you can postpone even longer. But in most patients, don't postpone too much, maybe one to four days, something like that, depending on the situation. Then there are some patients where you can't really stop them. So please try to delay the surgery as possible. So drug-eluting, stent placement, bare metal stent placement, recent TIA or stroke, try to delay the surgery if possible. In many patients it's possible. Of course, we have some patients where it's not possible. Then you have to operate.

There was a very nice study. This is a cohort study from US and Canada and some Europe. And more than 3000 patients, everybody had atrial fibrillation, long term direct oral anticoagulant users scheduled for elective surgery. Then they had two kind of protocols, those who they considered low-risk, and those who considered higher bleeding risk. Those who lowered, they stopped at only one day. And those with high bleeding risk, two days before surgery. And then, those who were considered low bleeding risk, they receive one day after. And those who were high, two to three days after. And every drug, it's relatively more or less the same, not very big differences. So this shows that the DOACs, you can begin always more or less. I mean, of course, if patient bleeds a lot, then it's different. But everything goes normally. If it's a high-risk, high bleeding risk, two to three days after, if it's a low, even next day. I typically personally, I'm a little bit, cautious person. Quite often, I begin two days post-surgery after DOACs. And you don't necessarily need it. I mean, you don't need bridging in these patients, typically.

So what about anticoagulants? There's, some patients which are very high risk, and I'm not talking about them now. So in those who are not very high risk, just stop it, and then initiate the same drug afterwards, don't use bridging. But then, there's of course, some patients, just as new VTE, or some with antithrombin deficiency and antiphospholipid antibody syndrome, et cetera, those you need to consult your thrombo unit, and anesthesiologian, and then think about how to do it, and maybe bridging therapy, et cetera. And so there's always these difficult cases, where not guidelines cannot answer to every agenda. You need to do some kind of compromise. Maybe you reduce one drug and leave the other one, et cetera, depending on the situation.

So, first of all, in some procedures, VTE risk is high, and bleeding low, clearly, use prophylaxis. And in those patients, please use long enough. I would not use only during short hospitalization. I would always use two, three, four weeks, if I use. And then in some patients, risk is low. So clearly no prophylaxis is needed. Often, it's not so close. So of course, it would be nice if you would even consider shared decision making also in this, and also a little bit, discuss with your patients. Often perioperative bridging is not needed. Sometimes it's needed, but often it's not needed.

And then, we are beginning a trial, and please be in touch if you want. And again, I mean, hopefully, this was useful. And thanks for this opportunity, and happy to try to discuss with Ashish now, with your questions and comments.

Ashish Kamat: Kari, that was great. You covered a lot of very important information in a very succinct manner. And of course, you know we talked about this before. I'm glad you were able to take the full time to go through your presentation.

Since you covered most of the topics, and obviously, we try to stick to a turn timeframe. I'll just restrict my questions to a few, one or two, practical viewpoints. Right? So when you have patients that have an active VTE episode, what are some of your recommendations to get these patients cleared? In other words, do you repeat CT angio? Do you repeat CT chest? Do you do VQ scans? Again, for our audience, what would you recommend as the bare minimum workup for someone who's had a recent VTE episode, in the last three to six months, before you take them to surgery?

Kari Tikkinen: Yeah. Thanks. Thanks for a very good question. First of all, if the patient has a new VTE, you should try to delay it, if possible, three months. If you're considering the patient has the VTE treatment for three months, I mean until that's over. If sometimes, you may want to even longer, that you want to postpone that. But sometimes, of course, it's a bad cancer, something you can't postpone that much. Then, I would really try to keep the full treatment of the VTE at least for one month.

So that at least, he or she would get one-month treatment of VTE, and then you would consult your thrombo unit, and do maybe, bridging and some kind of, depending, and then look for the lab and everything. And then, definitely, I would, before the surgery, I would definitely. These are not that common cases, but of course, I always do the CT scan just before the surgery, to see that the VTE is not getting bigger, and it's going to correct. And then, if it's, then I would not do surgery. But I mean, I would. Because it can be life-threatening, and the patient can die from the pulmonary embolism. So yes, that's how I would do it.

Ashish Kamat: Do you have any recommendations or experience with vena cava filters? Any opinion on those?

Kari Tikkinen: No. We have very little experience. I was fortunate to be part of the ASH guidelines, American Society of Hematology guidelines. And I learned a lot during that process. Because clearly, you guys use more filters in US than, I think, probably most of the world combined. And so yeah, I'm not an expert on them. I have just, and practically, I would say we never used them in Finland. It's almost true. And in Europe overall, so Finland is not an exception. They're very rarely used. There's no real, trial evidence showing the benefit. There's only cohort studies. I'm sure there are some cases where they could be beneficial, but they have a lot of harm also. And that's why we ended up, please, if you use them, look at the ASH guidelines. But the guidance is quite weak because we don't know really, much, whether you should use them or not.

I'm sorry. I'm not the correct person to answer. I have not experienced, and the literature is weak. I would not much recommend. I think vena cava filters should be used mostly in trials. I know that you have been using them for years, but the evidence base is weak. So I think they should be used in trials. I'm sure there could be some situation where they can be very important. I'm sure, but I'm not sure when is the case.

Ashish Kamat: I respect your candor there. I think when it comes to vena cava filters, the pendulum has swung. We used to use it too often, and now we rarely use it. And I'm sure there's a middle ground, which can only be addressed in a trial. But currently, the filters, again, as you know, come in two types. Right? Retrievable, where you can put it in, it's temporary, and you take it out, or ones that are permanent. And there are pros and cons of each. But I think, it's the highly selected patient that might benefit from it. And the paradigm where almost everybody was getting it, and that's a little bit of an exaggeration, at our center, not everybody was getting it, but many places there were. That was clearly, too much, as you appropriately recognized.

Now, moving into the thromboprophylaxis. And again, you outline each of the scenarios that we commonly do, as urologic oncologists and urologists, in what to use when. But as a generalization or simplification, would you say that a patient that is in the radical cystectomy arena should always get it? A patient that's having a prostatectomy, especially if it's robotic, should rarely get it. Would that be a appropriate simplification?

Kari Tikkinen: The simplification is, is that I think almost all, always, who undergo cystectomy for cancer, especially, but any. I mean, for cystectomy, patients should get it. Yes, definitely. And they should give extended. And I have been happy to witness that. I think in that kind of development, trend has been, that more and more cystectomy patients get actually, extended prophylaxis. That's what they should get. Then, but renal, especially when you do robotic resections, and all kinds of, where your patient is not very high risk, et cetera, I'm less sure whether they actually need it. The quality of evidence is lower, and the risks are substantially lower, probably than cystectomy. But there's more room. There's more uncertainty. It's a little bit, they are a little bit in between.

Then on the other hand, somebody like a healthy person, no risk factors, and robotic prostatectomy without a lymphadenectomy, no. They really, it's one in 500, or something, which will get. And then you need to give 500 to prevent half because you don't get... Because you know, it's 50%, maybe. You don't prevent everyone by giving heparin, there's, other reasons which you... So anyways, in those kind of patients, no, you should probably use the heparin for somebody else, than for that patient.

But then on the other hand, when you do open, especially when you do lymphadenectomy, yes, again, you should. So there's a little bit, in most of the prostatectomy should not get. Every cystectomy should get. And probably, most or half, or we don't know yet. This is interesting. We have actually, in our Arch trial, we are including, a lot of kidney cancer procedures, DOACs versus placebo, because... Not the high-risk patients who have risk factors, history of VTE, anything, not that like that. But we are including a lot of patients who go, like a robotic resection of kidney tumor, who are not high patient risk, because we really don't know what's the benefit. And so we will give them either DOAC or placebo. And I think it's ethical.

Ashish Kamat: One last question. Again, we could talk forever, but in the interest of time, let me just keep it to one more question. At our center, I've gone from using low‐molecular‐weight heparin to DOACs, because it's easier for the patient. It's more convenient, et cetera, et cetera. It tends to be more costly, at least in North America, to give them DOACs. But of course, the companies are able to subsidize it, et cetera. What's your personal recommendation of preference? Again, not ignoring the cost issues in different countries, but from an efficacy practical standpoint, what is your recommendation?

Kari Tikkinen: Okay. So first of all, this cost thing is different in different places. DOACs are cheaper in many countries than low‐molecular‐weight heparin, I was surprised. And especially, in couple of years, DOACs are getting... They already have it in many countries, but they are going generic. And so, that may also change the situation. So the cost may be a less of an issue.

Of course, I'm a little bit conflicted and biased. We are doing a trial on this because we would like to show that they work well. And then, I would hope that we could then show that people can confidently safely use DOACs. Because of course, they are more patient-friendly. Every patient who, after 10 days, when you have done your needle there, it's painful, et cetera, adherence goes down. Patients, doctors, surgeons, they believe the patients use them for four weeks. They often don't. But pills, they are more likely to use. And that would make them more efficacy in real life. But yeah, we don't have this high-quality evidence on DOACs in soft surgery. It's all more or less from orthopedic surgery. And some people are very concerned about the bleeds with DOACs, and that's why we want to do the trial and show it.

Our network meta-analysis shows that they are equally good, or even slightly better. But that's indirect evidence outside urology. So currently, I invite everybody to our trial. But of course, you can, I think more and more people are. It's off-label, but more and more people are using them. I have seen retrospective studies, also published with DOACs and with good results, and some even prospective, but not randomized. So they are becoming more popular. But currently, in the EAU guidelines, we didn't take strong recommendations on one over another, because of lack of any randomized trials with DOACs in urologic surgery. And then, because of the lack of comparative studies. But they probably all work. It's just more like a value and preference.

Probably they work, but it's more like what's your preferences? Are you more like that you want to be on the safe side, where earlier evidence is strong? But then on the other hand, you can also maybe discuss with your patient, and tell that we have these options. And this is a little bit experimental, but it's probably more patient-friendly. But I'm not very worried that they would be super harmful, because of, as you said, many leading centers are now using them, and they don't report anything super bad. Of course, they increased bleeding, DOACs, but so do heparin. And so we have to be careful, and choose carefully, and monitor the patients.

Ashish Kamat: Well said. Kari, thank you very much for taking the time and spending it with our audience this morning. I hope to be able to see you soon, hopefully, at the EAU this year. And till then, stay well and stay safe.

Kari Tikkinen: Thank you very much. Thanks for the opportunity. And stay well.

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