Welcome to Katie. Go conversations in Nephrology. This episode is titled benefits of rassi utilization. For disclosure information. Please go to KD. Go dot org slash podcasts here's your host dr. Roberto perk aphelion. Hello and welcome to the que digo conversations in The Prodigy. I am dr. Herbert Pavilions, senior research, scientist at Arbor research collaborative for
health. Now professor of medicine at the pontifical Catholic University of paranoia joining me to discuss the benefits of drugs, that block the reigning and to Tenzin aldosterone system is dr. Catherine Clays, dr. Clays is a nephrologist and a professor of medicine at McMaster, University in the editor-in-chief of the Canadian Journal of Kidney Health and disease. Katherine and I share the passion for this area of our specialty and I had the privilege of co-chairing.
The que digo controversies conference on the management of this Colony has in kidney disease with her Catherine. Welcome to the program. Thank you, Roberto. It's great to participate in this to be working with you again and to participate in this discussion on West blockade. All right, so let's get started. Seems like ass time goes by the renin-angiotensin-aldosterone Inhibitors or rassi as I will
refer from. Now on in this episode are still very important Therapies in kidney and cardiovascular disease. She's actually emphasized by the current revised guidelines in frolla G and Cardiology. Now what's the main evidence based represents to the use of rassi as a cardio? A protective therapy. I think that's a great place to start with Ewing the randomized
evidence here. So when I think about the strongest or perhaps the most prevalent indication or Reason to use grassy, it would be cardiovascular protection in people with cardiovascular disease or when people who have diabetes and evidence of end organ damage. So high risk vascular population. Looking at a cardioprotective outcome and this goes back to the Hope Study 20 years ago in which grassy would used major cardiovascular. Switch.
I'm going to call him mace by three percent over five years. So it's a large effect, high certainty directly applicable to people with CKD G1 G2 G3, who have established cardiovascular disease, or high risk diabetes. So, in summary for cardio protection, strong evidence, large effect. This is a great summary about the benefits of rassi from a general perspective. Now, it seems that there is also a robust evidence in heart failure. Specifically. Right now, such guide.
So that evidence is actually our ruined even more compelling. It's specific to heart. Failure with wood used ejection fraction and a good example here would be say the save trial, 30 years ago and this trial where I see reduced cardiovascular events, but actually would use death for all causes by 5%, which was a nominated tweet of 20. So that's really the strongest indication based on the
magnitude of the effect. And because we have here, Effect on all-cause mortality, which is relatively unusual in Trials, even Trials of cardiovascular outcomes. Interesting. So can you go Revisited the raw of rassi in patients with diabetic and non-diabetic kidney
disease? There's something new in this area when I think about this area, I'm really going back again to evidence that was generated some time ago, think about the gifts and study, I think about the prolific a senior property study and fortunately There's a wonderful meta-analysis that individual patient meta-analysis of those
studies. And what they show is that the for people with put new a kidney disease, there was a reduction in kidney replacement therapy, that's dialysis or transplant. That's the really clinically important outcome in this area. But having said that, these were Trials of Port Newark patients, most of those studies. Had main put new at Baseline of one gram a day or more and in a subgroup analysis within the study, the benefit, in terms of kidney.
And Sarah P was limited to people who had waistline proteinuria with more than 500. So that's why we have a recommend, a strongest level of recommendation in the Katie go. Blood pressure guidelines for 2021, and this is why we think that we have very clear evidence to use, whereas inhibition to prevent kidney failure in people who have CK D & A 3 up in the new area. In people with diabetes. The evidence is comes from different trials.
Yes. But it's similar so we have id&t and we're now looking at people with microalbuminuria or case we as we call it now, looking at outcomes of doubling of creatinine or kidney replacement therapy, and then when we think about people with diabetes and a to album in your area or microalbuminuria, we can go back to the Hope Study and look at the cardiovascular outcome, which was reduced.
So, for this reason, people with a three-album Anew and CKD, Or a two of them in your area or above and diabetes. These again are recommend when we look at the que digo guidelines. So in this area of the block pressure management and CKD, there has been some controversies in the final report of the guidelines prepare by KD go, can you comment on the decision?
Absolutely. So the biggest area of controversy I think is the use of last blockade in people with a CK D, we can say that somebody with CKD and a 2 is at high cardiovascular risk. We can say that most of these patients or perhaps all of these patients are at sufficiently high risk that we should consider them like participants in the Hope Study and that they should be taking last blockade because of the cardiovascular benefit.
And I think that's a very good argument, but it's not the same kind of directness of evidence that we have seen when we talked about the previous categories of reasons. To use last blockade when we look at the kidney progression. Again, the data that we have on much less clear, we have some evidence from the transcend, study some evidence from the
aask study. But again, we do not have that consistency of direct evidence that leads to the highest level of recommendation, and TD will reflect this controversy by using the word suggests quite appropriately in my mind. The other thing that Katie goes And with of course, is hypertension in people who don't have CKD or who have a one C KD in that setting. It's not known really. Whether there's a special role or a special benefit for us
blockade. But we can certainly work at Nuys. That arsenic mission is going to be a useful tool in our toolbox. When we're treating people with hypertension, particularly when we start to apply the results of the Sprint study, we're looking at a blood pressure Target of less than 120. Why are we doing that? And because Cardiovascular outcomes were reduced by point five percent in the Sprint study. That's a number needed to treat a 200 bigger than the numbers.
We've talked about before but if you and your patient come together and make a patient-centered decision that you're going to go for Sprint Target, the next thing that you need to know is that that's going to take about 3 minutes on average rather than to meds and then we're using three different classes of medication having grasped locators. One of those classes of medication is obviously going to
be very useful. This further Evidence now about a lower blood pressure Target from the recently published step study out of China. They have composite outcome of maize, heart failure and atrial fibrillation, but they found that over three years that was would use by fully 1% and kidney outcomes. Long-term kidney outcomes were equivalent. So we now have two studies pushing us towards that lower blood pressure Target.
And what I tend to do is approach this in a patient-centered way, I tend to say you've prepared to take more drugs to have your blood pressure lower because Gets better. Well, thanks for that Catherine. Let's change from the evidence and guidelines to the real world. Clinical practice, always strike by the under utilization of Rossi that we see in different real world, the cards. For instance, in the u.s. seems like 50% of people. This continue rassi within five
years of starting. What do you think are the challenges in applying this evidence? I think that's really a very Important point that people are starting and then they're stopping. We know from a recent study that when we look at prevalent patients in the u.s. again, only 50% of people with putting your ex e KD, for example, are actually actively on worse
inhibition. And when we look at the risk factors for being in that situation, they are past Aki past hyperkalemia and not being under the care of a nephrologist. For those just tuning in, you are listening to the key. Eagle conversations in frolla G. Our topic today is the benefits of Rossi utilization and October took the cloth video, and I'm speaking with dr. Katherine Clays. Catherine, coming back to the discussion about the under realization of Rossi in the real
world. What do you think of the Practical challenges of using this class of drugs in 2021? The first thing to say is I don't think this is a knowledge issue was just quoting some evidence that suggests that though, only 50% of people. Well, with put new Acadia on last blockade, 90% of been on in the past. I think that people have got the message.
I think that there are challenges facing maintaining people on West blockade, and those challenges are changes in the creatinine levels, hyperkalemia and Aki. So I'm going to start just by talking about hyperkalemia when we look at while data only small proportions of people develop hyperkalemia, but in Clinical practice and routine care studies. It tends to be higher. So for example, in a Danish cohort 16% of people started on
grassy developed hyperkalemia. In the first six months, in five percent of people had Piper collinear greater than 6 and is 6% of people. There was recurrent hyperkalemia. The other thing is that potassium in patients at high, vascular risk seems to drift up
over time. So in the Queen's study for example, when Most people would know, I think that in the Queen's study people were optimized on West blockade at Baseline. So this is a study of people who tolerate last locate the potassium level in Creedence over the 42 months of the study, just drifts up slowly by an average of .3 millimoles per liter, which suggests that over time, it may be harder to keep somebody on grass block head.
So what can we do about the problem of hyperkalemia, in the context of us blockade, there are obvious things like looking for Do non-prescribed supplements and salt substitutions. Look at Co existing medications. Like potassium sparing are you addicts? And look at Mrs. Unless they're being used for specific indication and consider stopping those things. Very important to my mind is the use of a diuretic in this
context. Usually I'll use it Loop diuretic if the GFR is less than 30 and a thiazide. If the GFR is above 30, I want to talk a bit about sigh aside because I think the key there's a very strong evidence for You're using thiazide in hypertension in general, we have meta-analyses showing reductions in cardiovascular outcomes and immortality. I also want to promote the use of cloth valadon particularly in this indication to lower potassium. The blood pressure lowering was
closed. Saladin is superior to the blood pressure lowering of hydrochlorothiazide and so is the potassium lowering. Probably by about point to looked at another way. The odds ratio for hypokalemia was 2.7 times that of hydrochlorothiazide in a u.s. cohort so 2.7 times as much hypokalemia with close salad own as with Hydrochlorothiazide suggesting that it's a much more potent work when it comes to lowering potassium.
So whereas, this might be a caution for you, if you are using it as monotherapy, when you are using it to reduce serum potassium chloride. Solid own is undoubtedly, a better drug to use. The other thing is that for many A of these patients. If you're going for Sprint Target, you're going to need to prescribe more than one antihypertensive in any case. And in that case the combination of arson ambition with a thiazide diuretic is a very useful and evidence-based, way to approach this.
And you'll notice that I'm coming to the whole question of diet really right at the end because I think these other things should be thought about first. And the reason for that is because we don't really have trials showing the effectiveness of diet and we You actually have evidence showing that people's dietary potassium intake doesn't really call it with their levels. However, using diet to using dietary restrictions to be
specific to control. Potassium is standard of care, and moving away from this is going to be challenging and needs to be done safely. So, what I'm doing is I'm thinking very much about substituting vegetables, not eliminating them, so the people can still have the health benefits of eating vegetables and Yeti. Eat vegetables that are lower in potassium content. I also talked about the meat content in the potassium content
of meat as well. We know, for example, in hemodialysis patients, that fall out of the top five sources of potassium in their diet are actually made products. Even unprocessed made often contains injected additives and processed meat is even worse. So, I would say, if you're discussing diet to put the holder on the table, and not to convey the impression that vegetables are particularly the demons when it comes. To dietary content of potassium, right? Are there any developments here
that you would like to mention? What are your thoughts, for example, and passing binders, quite well, most of our listeners will be aware that there are new potassium, binders on the market. So, let's just talk about the evidence base that we have here. The first thing to say is that for none of the potassium binders, do we have outcome studies that include outcomes that are important to patients or way. I used to cop clinically important outcomes for our old binder, STS or kayexalate.
As it's often called, we have a small trial showing efficacy for potassium outcomes and then we have huge post-marketing experience for homes. We have two very large well-conducted, observation studies. Looking at the magnitude of severe GI consequences of taking SPS and though it looks like there is a signal there. My general take home from those studies is actually one of reassurance. Because the absolute numbers are very small. We turn to the new binders, we
have a different situation. We have Trials of several hundred patients. We don't have patient important outcomes but we have lots of data showing, potassium outcomes and also showing non discontinuation of gasp. Okay, that it's possible to keep people on whereas blockade by using these binders. We also know that the adverse effects in those trials though they're not negligible or
probably acceptable. But of course what we don't have here is the face for experience that post marketing experience about the way homes. So in my own practice, I continue to use SPSS over time. I think we'll need to look at the observational evidence, that's emerging about harms, and we'll also need to look at cost and cost Effectiveness.
So that's one new area. And then the other thing that I find really exciting is literally just published this month on sglt2 Inhibitors and I'm grateful to you for pointing this evidence out. Many populations that benefit from u.s. inhibition of now being shown to also benefit from sglt2 Inhibitors ssion and the New Evidence is that in Credence, at least with Canada Frozen. There was a reduction in a variety of different potassium related, adverse outcomes by 22 to 34 percent.
So, that's quite a big risk reduction we're seeing in potassium in a high potassium related outcomes. An Really, you're not almost magically. There's no difference in mean, potassium and there's no increase in hypokalemia. So really, it's possible that when we add an sglt2 Inhibitors, and I wouldn't add it for potassium alone, but if you add it, for one of the many indications for sglt2 inhibition, that that is going to make it easier to avoid these upwards.
Excursions of potassium that lead to a patient being identified as hyperkalemic and that lead to as blockade. Stop interesting to hear that there are multiple strategies other than diet that we can use for controlling potassium. I think our patients would also be happy to hear about that. Are there any other particular challenges in keeping people on
rassi? Yes, there are two other things that I'd like to mention the first is acute kidney injury, so we aren't certain based on observational data when we have an episode of acute kidney injury, We should restart people aren't as blockade, but given this uncertainty and given the wealth of randomized evidence that we have for benefit in. Those specific situations, I was talking about my personal preference is to assess the risk for recurrent Aki.
If it's truly extreme, if a patient is coming into emergency with a high-output early ostomy and recurrent hypovolemic shock, then I might not restarted. But if there were 64, Aki are the same as their risks for Progressive, kidney disease, and for cardiovascular disease. Then I do tend to restart West located after Aki. The second issue is changing creatinine, particularly changing creatinine with starting. We've all come to recognize that the idea that we should stop us blockade.
If there's a change of more than thirty percent is actually not evidence based for sure a large Excursion in creatinine. A large change in creatinine. Like, that is a bad prognostic marker. Multiple studies show this. But what we don't have is evidence that that change is then associated with a reduced ability to benefit from the last
blockade itself. The other thing we know is that in general for rasp locate Associated changes, when we repeat the creatinine in another couple of weeks, it tends to go back towards Base Line and about 50%.
So unless the change in creatinine is truly extreme What I suggest is following the trajectory stop the last placate, only if it's Progressive, and when you stop it, if the creatinine doesn't improve and your hypothesis, doesn't look as if it's correct, then that's another great situation where you can consider, restarting grasp. Okay, it's a great Point. Catherine there, any final message you'd like to leave with our listeners. I'd like to go back to when you're prescribing this.
Think about what the indications are the magnitude of the benefit. And remember that for many of the patients that were treating cardiovascular outcomes are more numerous than kidney outcomes, even fun of artists.
And then the second thing is to think about the residual risk, even though these are quite drugs and they would use risk, consistently and biologic fact, we know the risk is still high for many patients and we now have strong evidence to use additional therapies like, sglt2 Inhibitors, and Mrs, for many of the same indications as well as see as add-ons Therapies. So I'm always thinking about that.
It's a great way to round out our discussion today when you think my guest dr. Katherine glaze for joining me. Catherine was great. Having you on the program? Thank you for having me. It's been an honor to participate. I am dr. Herbert I'll see you soon to access this and other episodes of the series. Visit Kate evil.org, Clash podcast, thanks for listening. This episode was provided by KD go. Go and supported by V for farming. Go and supported by V for farming.