Hello everyone, my name is Aaron Wong. I am one of the consultant cardiologists working in South Wales, United Kingdom. It is my honour to be here today to share with you our experience of using potassium binders to enable optimization of RAASi therapy.

So these are my disclosures.

We have now learned that hyperkalemia is highly prevalent in patients with heart failure, kidney failure, diabetes and those who require RAASi therapy. There is a U-shaped relationship curve between the potassium levels and mortality, and recurrent episodes of hyperkalemia often lead to discontinuation or down titration of prognostically important RAASi therapy, particularly in heart failure, kidney failure, with shorter duration between these recurrent episodes of hyperkalemia. Hyperkalemia on its own is associated with an increased risk in mortality, which has been observed in patients with heart failure, kidney failure, and diabetes.

We all know that RAASi therapy is the cornerstone treatment for patients with cardiovascular disease. Studies have shown that sub-maximal dosing of RAASi therapy or discontinuation of RAASi therapy are associated with poor outcome in patients with kidney failure, heart failure, and diabetes. Hyperkalemia can alter our prescribing habit of RAASi therapy. Following an episode of mild hyperkalemia, 38% of the patients would have a reduction or discontinuation of RAASi therapy. Following a moderate to severe episode of hyperkalemia, almost half of these patients would have a down titration or discontinuation of this important RAASi therapy. In recent years, we have got many guidelines, giving the recommendation of how we can manage RAASi therapy in the context of hyperkalemia. ESC expert consensus was published back in 2018, recommending using a potassium lowering agent to allow continuation of RAASi therapy.

So we now have two novel effective potassium binders we can use to allow continuation of RAASi therapy. One is called patiromer and the other one is called sodium zirconium cyclosilicate. Patiromer, according to the AMETHYST diabetic nephropathy study, is very effective for normalizing potassium levels in the acute setting, and also throughout the maintenance phase of the study. Following the discontinuation of patiromer, we see a rebound of hyperkalemia. Sodium zirconium cyclosilicate, in the HARMONIZE trial, has demonstrated its effectiveness to normalize potassium levels in the acute setting and also throughout the maintenance phase of the study. And again, we've seen a rebound hyperkalemia following discontinuation of the potassium binding agent. So, in the long term sodium zirconium cyclosilicate clinical study, we've seen that the majority of the patients were able to remain on RAASi therapy. According to the Crystalize program, 9 out of 10 patients were able to continue on RAASi therapy with the use of sodium zirconium cyclosilicate.

So, ladies and gentlemen, I'm now going to share with you our own experience of using sodium zirconium cyclosilicate to enable optimization of RAASi therapy in patients with heart failure with reduced ejection fraction. In the last two years, we started using this agent to optimize heart failure treatment in patients with ongoing heart failure symptoms with extremely high NTproBNP levels and low ejection fraction. We captured our data from February 2020 until March 2022. We captured baseline echographic data and also blood tests, particularly serum potassium levels, NTproBNP and kidney function. And we also captured background, have they had therapy prior to the initiation of sodium zirconium cyclosilicate. We then look back, looking at the hospitalization rate, and also the mortality rate of this cohort of patients. So 29 patients were initiated on sodium zirconium cyclosilicate throughout the study period. With a mean age of 76 and 1/3 being a female. The baseline ejection fraction is 29% and all of our patients are symptomatic. One third of our patients already had a hospitalization for heart failure and also with cardiovascular hospitalizations in the preceding 12 months.

You can see here, this group of patient has severe heart failure, as reflected by the very high NTproBNP level of over 5,000. The serum potassium levels were 5.7 prior to initiation of the potassium binders. The creatinine clearance was 44 ml per minute. Just under one third of these patient were on quadruple therapy for heart failure with reduce ejection fraction and just over half were on mineralocorticoid receptor agonists.

So with the use of the potassium binding agent we can see there's a marked improvement in RAASi therapy. Our prescription of ARNI increased from 90% to 100%, and the MRA prescription has also increased from 52% to 90%. And more patients were able to be on the guideline recommended dose. In terms of quadruple therapy we've significantly increased the number of patients who were able to be on quadruple therapy. It increases from 28% to 59%. Sodium zirconium cyclosilicate were licensed to use as a maintenance therapy up to 10 grams. So half of our patients needed 10 grams to maintain normal potassium levels, to allow optimization of RAASi therapy.

The mean potassium level was 5.7 prior to the initiation of this potassium binding agent. You can see here sodium zirconium cyclosilicate were very effective for maintaining normal potassium levels, throughout the study period. We also look at episodes of hyperkalemia, prior to the initiation of this potassium binding agents. We've observed each of our patients would have an average of 9 episodes of mild hyperkalemia and just over 2 episodes of moderate hyperkalemia, prior to starting on potassium binders. The highest potassium levels were 6.1 prior to the initiation of this potassium binder.

With the use of the potassium binder, we observe a numeric improvement in ejection fraction from 29% to 36%. And there was significant reduction in NTproBNP levels. Over two-thirds of our patients had a reduction of NTproBNP levels, and two thirds of them had a significant reduction of over 800 nanogram per liter. We did not see any significant change in renal function and also in blood pressure.

In terms of hospitalization and mortality 17 of our patients needed to be emitted due to worsening renal function or hyperkalemia that required a temporary adjustment of the diuretic dose, RAASi therapy and adjustment of the dose of the potassium binder. In terms of heart failure hospitalization, we observe a 14% heart failure hospitalization, which is relatively low, considering the severity of heart failure in this cohort of patients. The survival rate was 90%. Sodium zirconium cyclosilicate in this setting was well tolerated and almost all of our patient can continue on this treatment.

So the conclusion for our study, we demonstrated that potassium binder, sodium zirconium cyclosilicate, was very well tolerated and effective for maintaining normokalemia while allowing us to optimize RAASi therapy. We also observe improvement in ejection fraction and NTproBNP levels.

So in summary, hyperkalemia is highly prevalent in patients with heart failure, kidney failure, and diabetes. Recurrent episodes of hyperkalemia often lead to discontinuation or down titration of this prognostically important RAASi therapy. We now have novel potassium binders to enable us to initiate and also to optimize RAASi therapy.

Our real world data have shown that sodium zirconium cyclosilicate was well tolerated and also effective for maintaining normal potassium levels, allowing optimization of RAASi therapy in patients with heart failure with reduced ejection fraction. Further randomized control trials are urgently needed to fully assess the clinical impact of such intervention in the broader group of patients.

I would like to thank my team for not just capturing the data, but also helping to improve heart failure care in Wales in the United Kingdom.

Thank you for your attention.

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