Dear colleagues, ladies, and gentlemen, my name is Dan Atar, professor of Cardiology at the University of Oslo, Norway. The topic today is the importance of optimal RAAS inhibitor therapy in heart failure. This is embedded in a symposium dealing with hyperkalemia. These are my disclosures.

We are all very aware of the level of recommendations, both in the 2021 ESC heart failure guideline, as well as in the AHA/ACC 2022 guidelines regarding the implementation of ACE inhibition, MRA, sacubitril/valsartan, ARB. All the elements of RAAS inhibition in modern heart failure therapy. Now, to just focus on today's topic, I'd like to show you this delicate balance where you see that, of course, guidelines recommend optimizing RAAS inhibitor therapy, and it is known and the entire background for this recommendation that RAAS inhibitors improve outcomes. That is morbidity, mortality, and in fact, also, the progression of kidney disease. Then, on the other hand, you have the challenge of hyperkalemia. It may prevent patients from achieving target RAAS inhibitor doses, which I will show you in the next slide, and it actually leads to a RAAS inhibitor dose reduction or even discontinuation.

Let us look at some epidemiologic data. This is from the Swede-HF registry, nationwide registry, where you see on the y-axis the incidence of hyperkalemic events during one year. The dark blue bar is the overall heart failure population and it is clear that one out of four heart failure patients is actually experiencing one or more episodes with the potassium over 5.0. If we look at the potassium of about 5.5, it is 10% to 11% do have such an episode, so it is really very common. If we look at the declining GFRs from left to right on the x-axis and look at whether worsening chronic kidney disease triggers hyperkalemia, we see very clearly that it does relate to each other. We see the dark blue bars with those heart failure patients that also have concomitant chronic kidney disease, and the light blue bars are those who have only chronic kidney disease. For each deterioration, as we go from left to the right of GFR, we see that the incidence of hyperkalemic event is rising.

Let's look at the real world of RAAS inhibitor prescription. These are a number of the typical drugs that we give in heart failure. The guideline recommended drugs on the left, ACE inhibitors, ARB, then the ARNI, beta-blockers, and MRA. We see for the blue part of the cake that these are sub-optimal dosing or even no medication, and together with the yellow bar, which is the discontinuation or dose decrease part of the patients, we are close to 90% of heart failure patients who are not optimally dosed with an ACE inhibitor or ARB. Very much so to the right, the numbers for MRA, mineralocorticoid receptor antagonists, and that is accounting for about 72% or 73% non-achieving target dose. This is really a 12-month real-world view on how prevalent this situation is in a heart failure population.

I'd like also to show you that this, of course, has a direct impact on mortality. We have on the y-axis the mortality rates, and if we look at the right panel for heart failure, it is stratified according to less than 50% of the target dose of a RAAS inhibitor, and the dark green bar is from over 50 to 100% of the target dose. As you see, mortality is more than doubled for those who don't achieve half of the target dose. MACE is doubled in heart failure. Exactly the same pattern is visible to the left when we look at chronic kidney disease patients.

How does it play a role whether we completely discontinue a RAAS inhibitor therapy or if we do not achieve a maximum dose? This is a very interesting data from a American database that looked at mortality to the left. You see the panel in the middle that is saying heart failure, you see the gray bar being completely discontinued patients, the middle bar is a sub-maximum dose, and to the left, the bar showing 13.7%, it is those who did achieve a maximum dose of RAAS inhibitor therapy. What the simple message from this slide is, the doubling of mortality again when sub-optimal doses are present in these patients, but stunningly, as a matter of fact, the sub-maximum dose is very close to diverse outcome with the completely discontinued therapy.

Now, what is the reason for such discontinuation or down titration of dosing? This is a study from a single center in Turkey which looked at one year of kidney patients and the reasons were noted why RAS inhibitor therapy was not started at the first visit. You see that on the left panel. There was no clear reason obvious from the chart review but if you look at the hyperkalemia, the dark green panel, it shows that it is one important reason for not starting RAAS inhibitor therapy. Other reasons are hypotension, very low GFR, and acute deterioration of renal failure. Very understandable. Interestingly, when we look at the follow-up for these 12 months, hyperkalemia trumps all the other courses for discontinuation of RAAS inhibitor therapy.

How is the relationship between hyperkalemia and poor renal function? This is very clearly shown on this slide which, on the left, on the y-axis, shows increasing potassium levels from four to six, and you see on the x-axis those patients who actually are not on an MRA at all. We call that MRA avoidance. If you look at those patients with the light blue bars that have normal kidney function, the MRA avoidance is not so severe at the low potassium levels but sets in clearly after 5.0 of potassium and above, and very manifest when you come to potassium levels above 5.5 or 6.0. However, for the patients who have compromised GFR, the dark blue bars, you see that, already, at the normal potassium levels, half of them are not on an MRA, and this increases dramatically when potassium reaches 5.5 or above. In real world, that is leading to a duration of RAAS inhibitor therapy discontinuation for heart failure patients after a hyperkalemia event, almost two years. In chronic kidney disease patients, even more. 2.4 years. On the other hand, we can say three out of four patients, heart failure patients, who had a hyperkalemic event, were not reintroduced to MRA therapy during the subsequent year.

For the last slide, I'd like to present a type of paradigm shift to you. I call it rethinking heart failure therapy. You have chronic kidney disease and/or heart failure on the top. We know that is leading to increasing morbidity and mortality, and there comes in hyperkalemia. This is manifesting the problem of increased morbidity and mortality and, actually, via the suboptimal RAAS inhibitor therapy. The rethinking would be that we have now potassium binders. They may break the cycle, they may lead to normokalemia, they may have an influence on RAAS inhibitor therapy optimization, and ultimately, lead to reduced mortality and morbidity in heart failure and chronic kidney disease.

I thank you very much for your attention.

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