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Dr. Maddux: The CONVINCE study, funded by a grant from the European Union's Horizon 2020 program, is a prospective multicenter clinical trial designed to study high-volume hemodiafiltration versus high-flux hemodialysis treatments. The study is truly a collaboration between 61 centers in eight European countries with interesting results. The study assessed morbidity and all-cause mortality, as well as patient-reported outcomes and health economic outcomes.
The results were presented at the ERA conference in Milan in June of 2023. Professor Peter Blankestijn from the Department of Nephrology at the University Medical Center Utrecht in the Netherlands, is joining us today as principal investigator of the study to discuss this important research. Welcome, Peter.
Dr. Blankestijn: Thank you very much, Frank.
Dr. Maddux: Tell us about the CONVINCE study, what it's about and what's the background that led you to want to do this study?
Dr. Blankestijn: Hemodiailtration. The concept already exists for some decades, but it was only about 15 years or so that technical developments make it possible to deliver it on a, well, relatively large scale. And that was the moment that four trials in Europe started to address the question whether this has clinical benefit to our patients and indeed those four trials actually did not deliver any conclusive answer.
But we did a meta-analysis on all the individual data of all patients in these four trials, and the results showed that there was an indication that, indeed, hemodiafiltration offers benefits. And the interesting thing was that this was especially the case when high volume was delivered, and high volume was defined as 23 liters of convective volume per session.
But the critics said, well, this is very nice, but this dosage issue that you thought that afterwards that it was not an a priori a feature of the design. So actually the world, at least in Europe, was divided in believers and nonbelievers. And then the European Commission indeed launched one of their calls, in their grants system, which was titled Comparing Existing Therapies.
And that was the moment we thought, hey, wow, this is a golden opportunity to indeed compare these more or less accepted therapies. Of course, standard hemodialysis is well accepted and hemodiafiltration, at least by the believers, was accepted. So, we designed this trial, and it was funded by the European Commission. And the main difference between the previous trials was that this high volume was consistently delivered short of 23 liters and higher.
And the second new feature was that we also included a comprehensive set of patient-reported outcomes. At the time we designed the trial, that's six years or so ago, and there was an increasing awareness that this should be really a focus on the research agenda. So that is what we did.
Dr. Maddux: Described the primary endpoint that you reported in Milan. And just tell us a little bit about what we found.
Dr. Blankestijn: The primary objective of this trial was to compare this high volume hemodiafiltration versus standard high flux hemodialysis in terms of the effects on all-cause mortality. And we found a highly statistically significant, and what we think also clinically relevant, difference in the risk of mortality in favor of hemodIafiltration. Actually it was 23%, and this risk was 23% lower in the hemodiafiltration group as compared to the standard hemodialysis group. We considered that as a as a considerable effect.
Dr. Maddux: Some of the features that I think were probably important with the study where your randomization really left both groups being highly similar to each other. There were really effectively no differences between your hemodialysis group and your hemodiafiltration group with regard to their baseline characteristics. Are there other parts to the study that you think were interesting because you went through the entire pandemic. Having this study being part of the part of the story? And what do you think the impact of that was?
Dr. Blankestijn: The impact was quite big. I have to say that, of course, this Covid pandemic was not a pre-defined issue in our study for obvious reasons, and we were struck by surprise as we were globally. I think by what you just mentioned in the baseline correctors were very comparable. So, randomization was successful, but the Covid situation gave us a new cause of death.
And when we decided study for it as cause of death or covid as a reason for hospital admission was not in the protocol. So, we had to add that to the protocol and with limitations that comes with later adjustments.
Dr. Maddux: What I think was important was you had it was still a very large study, over 1300 patients, well divided by a successful randomization and a long term follow up. As you look at the all-cause mortality, which was statistically lower, can you give us some of your thoughts about what you think the impact of COVID might have been on changing some of the sub analysis on the cause-specific mortality? And how are you going to look at that in post-hoc analysis?
Dr. Blankestijn: The results on all-cause mortality. They are quite clear and we were very much interested if we could say something about the causes of death. And the a priori thinking was that the beneficial effect would be in the cardiovascular side of mortality. We looked at cardiovascular mortality as a specific group and the non-cardiovascular mortality as a specific group, and both were in favor for hemodiafiltration.
But for the cardiovascular deaths, it was not significant and for the non- cardiovascular it was. And if we looked in more detail in this non cardiovascular death, there came the suggestion that deaths due to infection also including COVID. There was a beneficial effects for hemodiafiltration. So, this I have to say, Frank, this was a total surprise for us that we had no a priori hypothesis for that finding.
We extensively discussed within the group what could be the interpretation of this, and we will do further in detail analysis of that unexpected finding. But I think it is fair to say that we should realize that it's impossible to distinguish, at least for us as a study group. It was not possible to distinguish between death due to COVID or death due to any cause in a COVID positive patient.
And because, we in Europe, as you were in the United States, we were totally overwhelmed by the Covid pandemic. it's very well possible that the attending physician marked a death in a COVID positive patient as a COVID related death, whereas it actually was a cardiovascular death. So, that is basically our interpretation.
Dr. Maddux: One of the other things that I recognized as I looked through the paper in the New England Journal of Medicine that you all published, was the fact that this study really proved that for a long period of time you could achieve consistent high volume HDF, and the level of convection that was added to diffusion, which is the nature of hemodiafiltration, was really quite remarkable and satisfying to realize that patients for a long period of time could in fact achieve these levels of convection without a lot of apparent difficulty.
Dr. Blankestijn: Yeah, that is correct. I very much agree with you. And that's the reason why I specifically mentioned that. Also as a result at the presentation in Milan, that if you carefully well think about what is needed to achieve this high volume in the vast majority of cases it you are successful actually in our trial, 92% of sessions that were scheduled as hemodiafiltration were actually also delivered as hemodiafiltration. So that is the vast, vast, vast majority.
Dr. Maddux: It strikes me that one of the greatest opportunities here is to potentially bring hemodiafiltration into North America in the United States where it effectively has not been used at all. The question that we have is what's your view on how relatable the results of the CONVINCE trial are for other populations? When we know the baseline population has more diabetics, the BMI is higher and some other things are a little bit different.
How do you approach those that might say, ‘Well, I don't know whether it's completely relatable or not?’ Personally, I think it is, but I would love to hear your perception on that.
Dr. Blankestijn: I can only give my personal opinion on that. If you add that, let's say the methodologies, the very strict, strict people, they will say, ‘Well, this is very nice, but this is a study to a European population, which is probably mainly Caucasian, and so a very low percentage of black population and no South Americans, etc., and no Asians or only a very low percentage.
So strictly speaking, you do not have the evidence in in these populations.’ Well, and that is of course true. But yeah, I'm not hesitant to say this is the best evidence there is, and there is also not a big disadvantage of delivering hemodiafiltration. So why? Why don't you do it?
Dr. Maddux: The other thing which will be fascinating to see in the coming months, you'll be releasing results on the patient-reported outcomes. if you end up seeing both a mortality gain and improvement and you see health-related quality of life issues, issues related to symptoms and other such things, if there’s a distinction there, then there’s quite an opportunity, I think, to relate this study to broader populations because of the personal experience that people have in utilizing this modality, in this type of treatment tell us a little bit about what some of the plans are over the coming months with regard to the consortium.
Dr. Blankestijn: As I mentioned in the beginning, we collected a very comprehensive set of patient reported outcomes and there is increasing awareness that that is of interest, but also the suggestion that is already in the literature that hemodiafiltration could be associated with improvement, at least in certain domains of quality of life, in certain domains of patients reported outcomes.
When we started this trial, I said, well, personally I think the patient reported outcomes are the real diamond on the cake, so to say. so we have collected 10,000 or so sets of questionnaires and the analysis is almost ready. And our ambition is to present and publish this information later this year.
Dr. Maddux: Let's talk for a second about one of the other features that I recognized as I read through the manuscript. Both groups, high flux hemodialysis and high volume HGF, had remarkable annualized mortality rates or deaths per 100 patient years compared to where we see general baselines in Europe and in other areas. I also noticed that the dose of dialysis, as we measure it through single pooled Kt/V, was very high in both groups.
It was more than what our threshold adequacy is. Any thoughts about the exceedingly low, do you think? It's from the selection of patients, the dose of dialysis, the intense follow up that everybody got, regardless of what arm they were in, in the trial? Just give me your voice over a little bit on the mortality picture.
Dr. Blankestijn: Already the baseline number on mortality was relatively good, was low, and it was somewhat lower than we expected when we started the trial. And, I think it is fair to say that some patient selection occurred because of the inclusion criteria. there were all sorts of not surprising inclusion criteria, but the two were, I think, worth mentioning.
One is the likelihood that this 23 liter could be achieved as judged by the dialysis staff. So that means, by definition, a relatively good vascular access. The second thing is the ability and the willingness to participate in these assessments of the patients-reported outcomes. So, it's inevitable to conclude that a certain level of patient selection occurred because of these inclusion criteria, and that we have a relatively good or the somewhat healthier quote unquote, part of the hemodialysis population and that probably also translates in a somewhat lower mortality rate in the control group.
Dr. Maddux: I was really pleasantly surprised that the randomization was as successful as it was, because I think that helps mitigate. Was there still a real difference? And I certainly believe that there was. A couple of things that were not studied that I would love your impression on. One is many people talk about, well, why diffusion plus convection is better than diffusion alone.
It strikes me that there's a lot of conversation around potentially larger molecules that get removed with the convective forces and the convective movement of plasma water. But I also think one of the biggest distinctions and I'd be interested in your thoughts about this is the replacement fluid of convection volume before the blood is returned to the patient.
So you have a relatively short duration of both time and distance where you have this very concentrated blood is quite different than what we do when we take high volumes of fluid through ultra filtration off patients that we know has cardiovascular impact and other problems. In that case, we're asking the body to refill the vascular space through extracellular fluid movements and so forth.
But in this case, we're replacing the convection volume directly into the venous line and, in doing that, we're making sure the patient doesn't suffer that period of time where their own intravascular space is fundamentally depleted. Do you think that plays a role?
Dr. Blankestijn: It's very well possible that that could play a role. When addressing possible mechanisms of a beneficial effect of hemodiafiltration, at multiple mechanism could be of relevance to this enhanced removal of uremic toxins. A second possible mechanism is a better or improved hemodynamic stability during session.
There are some studies showing that another mechanism could be an overall somewhat lower level of chronic inflammatory states, which has been proven multiple times. We do not really know what the mechanism is. And it's probably true that there's multiple mechanisms and
Maybe actually that is the objective. That could also be the nice thing of hemodiafiltration that it is a very general cause.
So a nonspecific IFIC intervention potentially addressing multiple mechanisms could altogether be quite strong and forceful to well ultimately give this results as a contrast to a pharmacological intervention which basically addresses usually one aspect, one mechanism. This very general nature, and potentially multiple mechanisms, could be a very nice or very important feature of this therapy.
Dr. Maddux: When I look at our own population of patients that we care for in Europe, by Fresenius Medical Care, we have a little over 57% of our patients receiving hemodiafiltration. The majority of them are receiving at least 20 liters or more of convection volume. I'm interested in your thoughts about what does the CONVINCE study do to potentially change the standard of care, not just in Europe, but obviously throughout the world as looking at what optimal therapies might look like? Do you feel that the really quite dramatic result of a 23% reduction in all-cause mortality and the disciplines of the study create an environment where we should be asking ourselves that question about is it time for the standard of care to change?
Dr. Blankestijn: That is what I'm hoping that will happen. Probably not tomorrow or the day after tomorrow, because, of course, I realize that guideline bodies, reimbursement systems, patient organizations, and other relevant stakeholders should take a look and discuss and decide on the place in the field of hemodiafiltration, and let's say in the in the in the field of kidney replacement therapy.
But my overall feeling is that the answer will be yes, because of this big results. There are also at least let's say if you have modern equipment and good, good water quality, which actually you also need for high flux hemodialysis and that is the case, then the step towards hemodiafiltration is modest.
It's only modest. You have to instruct your dialysis staff. in the beginning phase there may be a learning phase. That's all true. But as also the trial has shown 61 different centers able to perform this over prolonged period of time. That the median follow up was 2.5 years. So, in these in the 61 centers, it was not a problem. So why should it be a problem elsewhere?
Dr. Maddux: You mentioned reimbursement, briefly. Talk for a second about what you think the health economic impacts might be of moving towards this therapy from the other. Do you see it as more costly? Do you see it as one that is simply an incremental step with existing modern machinery that is developed and being deployed throughout the world? Just give me a little sense of your health economic approach.
Dr. Blankestijn: We will do an official health economic analysis that is already underway. But my personal feeling on that, and I'm not a specialist on this topic, so please realize that, is that when a center already has modern machines and has an adequate water delivery system, my sort of gut feeling is that it will be very cost effective because the incremental costs are so little and there is a clear benefit. So this balance will very easily tip over to the hemodiafiltration site. And if you first need to invest in new machinery, well then the story is different.
Dr. Maddux: Machinery will, over time, need to be turned over to new machines anyway. So, I do think it's not overnight, Any final thoughts about aspects of the study that you want to make sure this audience, some of whom had the chance to watch you in Milan and go through the details from reading the New England Journal article, but some that maybe haven't heard about it. Are there other aspects that you'd like to make sure people are aware about from the CONVINCE consortium?
Dr. Blankestijn: I think there's aspects of the patient-reported outcomes that I'm really excited and hopeful that we will be able to deliver. it's another interesting and new and innovative set of information on that aspect of the treatment, and that will be sometime in the coming months. So, in a way, we are sitting on a gold mine.
Dr. Maddux: I’d like to say congratulations to you as the PI and certainly to the whole consortium for doing what I consider to be an extraordinarily well-executed, well-designed study, and one that I think, given its name, actually is rather convincing. It's a pleasure to talk to you about this. I'm sure we'll get the chance to talk more in the future as more of the data is released.
Dr. Blankestijn: I would like to take the opportunity to thank you or Fresenius as a whole for their tremendous contribution to this study. Fresenius centers delivered the biggest portion of patients, and it was really great working with Fresenius people. So, thank you very much. without your contribution, we would not have been able to deliver this result.
Dr. Maddux: Thank you. I've been with Professor Peter Blankenstijn from the University Medical Center in Utrecht, talking about the CONVINCE study. We'll talk with him more as more data is released over the coming months. And Peter, I want to thank you so much for you being here on our Dialogues segment.
Dr. Blankestijn: Thank you very much Frank.