Circulation October 9, 2018 Issue

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction. However, what are its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease? Well, stay tuned to find out, as we will be discussing the results of the UK Harp III Trial, right after these summaries.

                                                The first original paper this week reveals that inhibition of a long non-coding RNA may serve as a novel molecular therapy for aortic aneurysms. First author, Dr Li, corresponding author, Dr Maegdefessel from Technical University Munich, and colleagues, identified the long non-coding RNA H-19 with functional relevance in experimental aortic aneurysm progression in two mirroring models, a novel genetically mutated mini-pig model, as well as end-stage human disease. They found that H-19 mediated expression levels of the transcription factor hypoxia inducible factor 1-Alpha. Which, in the chronic hypoxic environment of an aneurysm, triggers apoptosis in aortic smooth muscle cells. This study, therefore, introduces inhibition of H-19 as a novel molecular therapy to limit smooth muscle cell death in progressing aortic aneurysms.

                                                The next study provides insights into molecular mechanisms underlying heart failure progression in chronic pressure overload. Co-first author, Dr Chiang and Alsina, co-corresponding authors, Dr Heck, from Utrecht University, and Dr Wehrens, from Baylor College of Medicine, and their colleagues developed a novel and unbiased way to comprehensively study protein phosphatase 1 or PP1 interactors in a mouse model of progressive heart failure induced by elevated afterload. This so-called PP1 interaction enabled simultaneous interrogation of multiple pathways relevant to heart failure pathogenesis. They found nine specific PP1 interactors that were strongly associated with heart failure progression. Among these, the PP1 regulatory subunit 7 was shown to play a central role by regulating the PP1 interaction, and by acting as a competitive molecular sponge of PP1.

                                                In clinical trials of direct oral anticoagulants for atrial fibrillation, patients with end stage kidney disease on dialysis were excluded. Today's study answers the question, "What are the outcomes with Apixaban in dialysis dependent end stage kidney disease patients with atrial fibrillation?"

                                                Co-corresponding authors Dr Siontis and Dr Saran from University of Michigan and their colleagues performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System from 2010-2015. All eligible patients were those with end stage kidney disease and atrial fibrillation undergoing dialysis who had initiated treatment with an oral anticoagulant.

                                                In prognostic score-matched analysis, Apixaban was associated with lower rates of major bleeding compared with Warfarin, whereas there was no difference in stroke or systemic embolism. Patients on standard dose of Apixaban of 5 mg had a lower rate of stroke and death compared to those on reduced dose Apixaban of 2.5mg. Thus, Apixaban may be associated with superior safety and comparable effectiveness outcomes as Warfarin in dialysis patients with atrial fibrillation. However, these findings require confirmation in a randomized trial setting.

                                                Does Canagliflozin have benefits in people with chronic kidney disease, including those with an Estimated Glomerular Filtration Rate, or EGFR, between 30 and 45, in whom the drug is currently not approved? First author Dr Neuen, corresponding author Dr Perkovic from the George Institute of Global Health, and their colleagues performed a secondary analysis of the CANVAS Program to describe outcomes in participants with and without chronic kidney disease, as well as according to baseline kidney function as measure by EGFR.

                                                They found that the effect of Canagliflozin on HbA1c was progressively attenuated at lower EGFR levels, but blood pressure and body weight reductions were comparable. The reduction in risk of major adverse cardiovascular events, hospitalization for heart failure and progression of kidney disease appeared similar across different levels of kidney function, down to an EGFR of 30. Safety outcomes were also mostly consistent, but the risk of hypoglycemia may increase as EGFR declines.

                                                That wraps it up for our summaries, now for our feature discussion.

                                                Cubitalis-valsartan improves outcomes in patients with heart failure with reduced ejection fraction, and we know that from the Paradigm trial, but what about its effects on kidney function and cardiac biomarkers in people with chronic kidney disease?

                                                Well, this week's feature paper provides important randomized trial data addressing this question. To discuss it, we have none other than the first and corresponding author, Dr Richard Haynes from University of Oxford, as well as our editorialist for the paper, Braden Manns and Matthew James, both from University of Calgary and in addition, we have Dr Justin Ezekowitz, associate editor who manages paper, and Justin is from University of Alberta.

                                                Welcome gentlemen, we have a full house. Richard, could you start by sharing about your trial and your findings?

Dr Richard Haynes:          So, the trial was called UK Harp-III, and it was really a pilot trial, just to work to investigate the effects of Cubitalis-valsartan on patients with chronic kidney disease, and in particular to see what it did for their kidney function in the short term, and also what it did to other measures of interest like their blood pressure and cardiac biomarkers.

                                                It was a randomized control trial double blind, among just over 400 people with chronic kidney disease, and we compared Cubitalis-valsartan with Irbesartan, which is standard of care for most of these patients. Our primary outcome was really to look at the effects of these drugs on kidney function when it was being precisely measured in hospitals. We found, actually, that Cubitalis-valsartan had very similar effects to Irbesartan on kidney function. So, there was no real difference in kidney function at any point in the trial between patients who were allocated the Cubitalis-valsartan or those allocated Irbesartan.

Dr Carolyn Lam:                Richard, the way you described it I'm sure you're prepared for this question so why Irbesartan as the control versus Valsartan?

Dr Richard Haynes:          That's a very good question and a question asked quite often. There were six of one and half a dozen of the other. We could have chosen Valsartan. The difficulty with that is that Valsartan doesn't have a license indication for the treatment of chronic kidney disease so if we found a difference people might have said we just chosen an inferior comparator, so we chose Irbesartan because that does have an indication for the treatment of proteinuria kidney disease and obviously that leaves us open for the question about how different Valsartan and Irbesartan are. My opinion is they might be subtly different, but I don't think the difference is big enough to really impact these results in any meaningful way.

Dr Carolyn Lam:                Indeed, and I know Braden and Matthew you have thought about it a lot. Congratulations on the beautiful editorial. I love the way you set the context in the heart failure world where perhaps we have noted something different with regards to kidney function. Would either of you like to start the ball rolling with discussing that?

Matthew James:              Sure, this is Matthew James. So really the Paradigm Heart Failure Trial is a very important place to start in thinking about the effect of these medications on kidney function. That was a very large trial that did report changes in estimated Glomerular Filtration Rate and did show a small but statistically significant change in kidney function between the Sacubitril-valsartan arm and the control arm. There are many potential mechanisms for that, but it is important to realize that there were limitations in the population specifically around chronic kidney disease due to the level of kidney function that the patients were enrolled in to the study. So, some of the patients with more advanced chronic kidney disease wouldn't have been included in the Paradigm Heart Failure Trial so this trial is actually giving us more information about patients with kidney disease who we would expect to be at higher risk of seeing progressive loss of kidney function or progression of their kidney disease.

Dr Carolyn Lam:                Thanks for setting that up and just to clarify for the audience here so in Paradigm EGFR went down to 30 right, and here in UK Harp we are talking about measured GFR down to 20. Am I right?

Dr Richard Haynes:          Eligibility was actually determined by the EGFR, the estimated GFR.

                                                Yeah it went down to 20, up to 60. We also had a much more proteinuria in the patients in Paradigm.

Dr Carolyn Lam:                Right, and do you have a take Richard on why the results seem different from at least the secondary analysis that Milton Packer wrote about on its effects on kidney function in Paradigm?

Dr Richard Haynes:          I do have a take. I'm really interested to hear what Braden and Matthew thought. My take was that probably when you've got heart failure one of the major determinants of how well your kidneys work is actually how well your heart is working. That is probably one of the major determinants in that setting and because we know Sacubitril-valsartan has such beneficial effects on cardiac function in people with heart failure perhaps it's not surprising that it then is protected by kidney function a little bit better than people given Enalapril in Paradigm. However, in UK Harp III, we had a group of patients whose kidney had very definite kidney disease and probably the determinants of kidney progression quite different and having any impact on their heart function probably wouldn't really be noticed because the effect of their kidney disease would outweigh that. Perhaps, Sacubitril-valsartan doesn't have any beneficial effects on the kidney itself. As far as we can tell, from what is a relatively small and a relatively short trial.

Dr Carolyn Lam:                Justin, I mean you come from the heart failure world too just like me. What was your take?

Dr Justin Ezekowitz:        I think there are a number of features here we should take a step back and think about. Number one is as Richard outlined there is a lot more proteinuria here than would typically be seen in a heart failure related population. So, the comparator between the two groups, while similar in overlap while co-manage these patients is somewhat different in terms of what the result we are looking for. So, you know, it brings to mind that what we look at in the secondary analysis in for example Paradigm, is simple EGFR creatinine changes versus here we are looking at a much more sophisticated measure of GFR plus also looking at a comparator that is known to reduce proteinuria and I would say stabilize or not change or prevent their progression of renal disease in the larger trials in the renal population. So, it's a slightly different population, a slightly different comparator as well. The importance in the choice of comparators becomes really important when we are looking for this specific effect.

                                                Now, to Richard's point, which he opened with, which is talking about this as a pilot project to a larger outcome trial, it is hard to know whether or not the effects that Richard and his team on the NT-proBNP, troponin, and other effects would play out in the larger cardiovascular outcomes trial that would be potentially different results than simply a GFR change or proteinuria change. I would be interested in Richard's thoughts on that and Matt and Braden's as well.

Matthew James:              Maybe we can also get add another question to Richard which this was a really well-done study and you talked about it being relatively small and certainly by heart standards this was a relatively small pilot study with a limited duration of follow up. By kidney standards, this is a fairly this would be a usual sized clinical trial and so getting all these patients in the trial was a wonderful result to start with and while the study wasn't directly looking at safety of these medications, there is some I think assurance we have some tolerability data at least with this medication and the challenge as Richard would well know in managing patients with chronic kidney disease once they developed more advanced chronic kidney disease GFR is less than 30 is often difficult to use medications because of side effects, high potassium, and things. The most challenging types of patients we see are patients with lower levels of kidney function and with low ejection fractions. So at least this paper provides some hope that we've got a medication that is reasonably well tolerated in that population.

                                                I think that when Richard talks about this being a pilot study where a lot of patients, in fact patients with chronic kidney disease are much more likely to die from heart disease than they are to develop end stage renal disease. For many types of patients that is true at least. So, we are often thinking about what medications could be used to improve cardiovascular outcomes. So, in that sense, again given that the majority of the structural heart disease is not necessarily reduced heart function but is left ventricular hypertrophy I'm sure, and perhaps Richard has some comments as to the next study that might be considered given this medication seemed tolerable. It didn't have the effects that were perhaps hoped on progression although in the Paradigm sub study there was only a difference of 0.5 ml per minute and they were powered to detect 3 ml per minute in this study but actually the immediate hemodynamic drop was about 3 ml per minute and then kidney function was relatively stable thereafter. So hard to imagine this study would have showed a difference in kidney function now in retrospect but potentially this opens up some additional studies to look at cardiovascular outcomes in patients with chronic kidney disease who don't have reduced ejection fraction.

Dr Richard Haynes:          I think that's a really good point. I think it would be fascinating to see the results of the Paradigm Trial with Sacubitril-valsartan in patients with heart failure and preserved ejection fraction. Nevertheless, I think this trial does raise the hypothesis that this might be a drug that could improve regardless of whether it has any effect on the kidney or not. It could be possibly be used for improving cardiac outcomes but I just don't think the trial that we've done is enough to justify that at the moment. I think it's a good indicator that it may well work, but I think before anybody could recommend that with much enthusiasm I think it would require a large outcomes trial but focusing quite rightly on cardiovascular outcomes in people with chronic kidney disease which as Matthew said is actually the major burden of disease in those patients.

Dr Justin Ezekowitz         I think the question remains though is if as a pilot trial at that time as a longer-term trial would there be any difference because the mechanism of action of Sacubitril is different from that of Irbesartan and that was also shown in the nice table you have in the supplemental file which talks about the Sacubrital lapse concentration going up with the lower GFR's. So, there is the potential for those small subgroups where the GFR is lower they may have a substantial benefit over a longer period of time, not measured necessarily by GFR but measured by clinical outcomes. I think that is where the balance of getting the pilot trial versus a longer follow-up clinical outcomes trial is really important to get.

                                                I may actually just state one other thing or two. First, it's really important to investigate or initiate a trial and this is one of critical parts of why we do clinical trials. Medicine tests the effects initially a pilot and then hopefully a larger trial.

                                                The second is the importance of randomization here. We all think that the shiny new medications are important but getting randomization in trials like this done are really advanced knowledge, so we know what to do with the medication if we are faced with it or if we want to make an important choice for a patient that we can really make a point for the patient that we will base it on the best scientific knowledge.

                                                The third point that I would just come back to something else that we have not talked about yet is this overall is a neutral trial. There are no major effects that were seen but the importance of getting a neutral trial done and published is really critical as this advances the field potentially, so others can now decide what to do and perhaps launch larger trials with cardiovascular outcomes or decide to do a different comparator or different other tasks forward. So, this one we emphasize it is critically important to get these types of trials done and then published.

Dr Carolyn Lam:                You know Justin, I couldn't have said it better and completely echo your words. We are so proud to be publishing your paper Richard and that beautiful editorial in circulation. So, I'm just going to wrap up then because in the absence of better data at the moment what is the main take home message of this trial for patients with CKD right now and their care providers. I would love to start with Braden because you wrote about it in the editorial as well. What do you think of the take home messages?

Braden Manns:                 Well again I think that we often struggle when peoples GFRs are in the 20 to 30 range with identifying a medication that's tolerable particularly in the context of people with reduced ejection fraction. I must say personally I would now be comfortable using this medication in patients with reduced ejection fraction who remain symptomatic who have GFRs in the 20 to 30 range. Those patients aren't that common but feel comfortable now using that type of medication there despite the fact that most patients weren't necessarily enrolled in the Paradigm study. A much larger population though of patients with structural heart disease but not reduced ejection fraction who have chronic kidney disease. It is not clear to me where this medication fits in the armamentarium. As Justin says it certainly wouldn't use this in preference to an ace inhibitor or an angiotensin receptor blocker at this point. So, it's hard to know where it fits without some larger studies looking at cardiac outcomes.

Matthew James:              I agree with Braden. I think we are already seeing this medication now enter practice here in Canada. There is this overlap in population between the patients with kidney disease and impaired left ventricular ejection fraction, so this is actually very helpful for us when we see these patients in practice around the appropriateness of continuing these medications in this patient population.

Dr Justin Ezekowitz:        So, I think it's critically important to remember the take home message here is to do proper clinical trials and then do again the large trial because without that would not really advance in knowledge. There could be a huge value to a newer medication or potentially the old ones are still just as good as we if we continue them safely.

Dr Richard Haynes:          I'd like to echo what everybody said already really. I mean I think what Justin just said trial is the key. We can't get away from the need for randomized control trials. I'm pleased that we've managed to deliver this one. In terms of a clinical take home message I think if I was a patient with kidney disease and heart failure, especially with reduced ejection fraction, I hope that I would feel a bit more comfortable to take this drug now knowing is it going to benefit me from a cardiovascular point of view it doesn't seem it is going to do my kidneys any harm either. So, hopefully it will reassure more patients that they can yield the benefits of a trial this drug has.

Dr Carolyn Lam:                Great stuff! Thank you so much gentlemen. This has been such an enlightening conversation.

                                                Thank you very much to audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.