During optimization of RAASi therapy, SZC treatment is prescribed to a patient with HFrEF at a dose of 5 mg at alternate days. The serum potassium level of this patient is 5.5 mmol/L during monitoring. What would you consider for this patient?

• A. Adjust the frequency of dose of SZC to once daily.
• B. Increase the dose of SZC to 10 mg alternate days.
• C. Increase the dose of SZC to 10 mg once daily.
• D. Keep patient on the current dose.
• E. Consider down-titration of RAASi-based therapy.

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Hi everyone. I'm Aaron Wong from United Kingdom. It's my pleasure to be here today to share with you some of our practical experience and model of how we adopt to optimize RAAS inhibitor therapies in patients with heart failure with reduced ejection fraction. These are my disclosure.

RAAS inhibitor therapy are the foundational therapies for patients with cardiovascular disease. Previous clinical trials have demonstrated that RAAS inhibitor therapy improve clinical outcome in patient with heart and kidney failure. As a result of that, multiple organizations are now highly recommend using RAASS inhibitor therapy to treat patient with heart failure, kidney failure, and type 2 diabetes.

RAAS inhibitor therapy is important, but the dosing are equally important. There is a big gap between what is actually recommended and what is actually prescribed in the real-world setting. Many registry data have demonstrated that a lot of our patients are not on the RAAS inhibitor therapy, although indicated, or they are not on the optimal dosing of this prognostically important RAAS inhibitor therapy. This registry data also showed that sub-maximal dosing of RAAS inhibitor therapy or discontinuation of RAAS inhibitor therapy were associated with poor clinical outcomes in patients with heart failure, kidney failure, and diabetes.

If we know that RAAS inhibitor therapy are important for our patient, but why are we not putting this patient on these life-saving therapies? There are many reasons. The common one being due to high potassium levels, kidney dysfunction, the patient's blood pressure is too low, or the patient's age, and sometimes physician have perceived a thought that this patient is too frail to benefit from this class of drugs, and sometimes could be due to the physician not wanting to change the clinical practice or refuse to accept the evidence of the benefit of this agent in a particular group of patients. Some of these factors are not reversible, for example, age, and some of these factors we can easily correct such as lower pressure and kidney dysfunction. However, high potassium levels can be potentially corrected to allow us to optimize RAAS inhibitor therapy in patients with heart and kidney failure.

The presence of hyperkalemia can actually affect the confidence of how physician prescribe RAAS inhibitor therapy. Following an episode of hyperkalemia, we can see here there are 40% to 50% discontinuation or downtitration of RAAS inhibitor therapy. How can we overcome this barrier to allow our patients to benefit from this lifesaving therapy? Currently, there are two novel potassium binders. They've both been shown to be very effective to maintain potassium levels to allow optimization of RAAS inhibitor therapy. It's important to note that following a cessation of this agent, we see a rebound hyperkalemia, which indicate hyperkalemia is a persistent risk, and we need to think about a longer-term solution to treat hyperkalemia and to allow maintenance of RAAS inhibitor therapy.

I'm now going to share with you our real-world use of potassium binders to allow optimization of RAAS inhibitor therapy in patients with heart failure with reduced ejection fraction. In this retrospective analysis, we look at a 25 months' worth of data. We determine echographic parameters and biochemistry data, in particular, potassium levels, kidney function, and NT-proBNP cardiac markers. We also look at medication differences before and after putting the patient on the potassium binders, and retrospectively, we determine the reason for hospitalization and also mortality.

The 44 patients were included in this analysis. Patients with very advanced kidney disease or patients with very low blood pressure were not considered such approach. The mean age of our cohort is 75 years old, around 1/3 of them are female. These patients not just have advanced heart failure, but they also have a moderately to severe kidney impairment as well. Three-quarters of our patients have CKD stage 3b or 4, and one-third of our patients are diabetics, and half of our patients have ischemic heart disease, and 61% have hypertension. Half of these patients were in atrial fibrillation, and 10% of the patients already have a cardiac devices inserted. The mean baseline ejection fraction was 29%, and 86% of our patients were in NYHA II to III. The baseline NT-proBNP levels were just under 3,500, with a serum potassium levels of 5.7 mmol/L before initiating potassium binders, with a creatinine clearance of 48 mL/min. Only one-third of these patient with advanced heart failure were on quadruple therapy. One-third of these patients already had a hospitalization of heart failure in the preceding 24 months, indicating this cohort is a high risk population.

The following initiation of a potassium binder sodium zirconium cyclosilicate. You can see here, we have 100% of our patient were now on sacubitril/valsartan and a higher percentage being on the recommended dose. With regards to MRA, you can see here we almost double the percentage of prescription of MRA. More patients are now on the guideline recommended dose. With regards to the numbers of therapies, we've double up the number of patients being on the four pillars, heart failure therapy for reduced ejection fraction from 32% to 64%. We require 10 gram of the sodium zirconium cyclosilicate to maintain the potassium levels in half of our patients. With the use of these potassium binders, you can see here it's very effective to maintain the potassium levels while we start uptitrate and maintain RAAS inhibitor therapy.

Now, more patient are on guideline-recommended therapy. That also translates into better clinical outcomes. You can see here the ejection fraction. We observe a numeric improvement of ejection fraction from 29% to 36%. There is a significant reduction in NT-proBNP levels from 3,500 down to just over 2,000. A lot of these patient have a significant reduction in NT-proBNP. We have not observed any significant difference in kidney function or blood pressure. In terms of hospitalization and mortality, we observe a reduction in hospitalization for hyperkalemia and decompensated heart failure. There are two-fold reduction in hospitalization with a survival rate of 91%. Overall, this potassium binders are very well tolerated while the patient optimize on RAAS inhibitor therapy.

Recently, we have drafted a local guideline to empower our health care professional in the hospital and also in the community to help to monitor the potassium levels and also to dose the potassium binders. We give recommendation of how the health care professional should adjust the potassium binder dosing and RAAS inhibitor dosing based on the potassium level. We also give recommendations about how frequent potassium levels should be measured following changes of these medications. We also give guidance about putting emphasis on assessing the patient's clinical status and adjust the medication accordingly.

In summary, RAAS inhibitor therapy are the cornerstone treatment for the treatment for heart failure and kidney failure. We know that these medication are very important, but the dosing of these medication are equally important. Hyperkalemia is a potential, reversible barrier that we can overcome to allow our patients to be on this lifesaving therapy. A selective use of potassium binders in patient can allow us to optimize RAAS inhibitor therapy in patient with heart failure. Our real evidence have demonstrated that such approach is feasible, and these potassium binders are well tolerated, and that enable us to optimize RAAS inhibitor therapy which translate to improvement in clinical outcomes and cardiac biomarkers. The applicability of such approach would need to be tested by a further multicenter clinical trials such as REALIZE-K. We look forward to see the outcome of many randomized trials in this field. Thank you very much for your attention.

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