Welcome colleagues, ladies and gentlemen, my name is Andrew Coats. I'm president of the Heart Failure Association, ESC, University of Warwick UK and it's my great pleasure to do the first talk in this Symposium.
So I'll be talking, as an introduction, about guidelines, RAAS inhibitors, hyperkalemia and the clinical dilemmas in the management of heart failure, this issue causes us.
So let's just review the clinical guidelines. And of course, we now have the foundational four classes, but two of these major drug classes are inhibitors of the renin angiotensin aldosterone system. They are fundamental to the way we manage heart failure, but part and parcel of how these drugs work is the propensity of increasing serum potassium.
If we look at the major outcome trials that led to the recommendation to use ACE inhibitors, ARNIs, mineralocorticoid receptor antagonists, they're associated with increased potassium. It's part of how these drugs work.
If we look at the RALES study of spironolactone, its substantial reduction in total mortality, as we see here, on the kaplan-meier curve, but you look at the right, the incidence of hyperkalemia, whether it's mild above 5, more significant about 5.5, above 6, was higher on the spironolactone group. That didn't prevent the major clinical benefits, the reduction in mortality. But obviously, it can be a concern if patients go to levels that normally we're a little bit uncomfortable with. Such as those higher levels of serum potassium.
We saw the same in the EMPHASIS-HF trial of eplerenone. Where also reduction in CV mortality and heart failure hospitalization, but an increase in hyperkalemia. Now, in the clinical trial, that didn't seem to matter, but when it was brought into routine practice, particularly some registry data from Canada, show the doctors were very concerned about that. There was a sudden, dramatic reduction in the use of MRAs, because of this increase in hyperkalemia events. Therefore, we have a therapeutic dilemma in managing hyperkalemia, while attempting to optimize RAASi therapy.
RAASi therapy will improve outcomes, but it'll lead to an increased risk of hyperkalemia. In managing hyperkalemia, our first natural response is, to remove the drug that might have contributed. We don't know quite what that trade off is, when we reduce the dose or even more seriously, stop that RAASi dose. Are we losing most of the benefit or all of the benefit in the case of reducing the dose entirely to zero?
When we look, this is not an uncommon problem. In real-world practice, discontinuation of RAASi therapy persist for a long time, following a single hyperkalemia event. 76% of patients who had their MRA reduced or stopped, were not reintroduced during the subsequent year. If you look at the duration in which the RAASi discontinuation persisted, in patients with chronic kidney disease, it was nearly two and a half years. In patients with heart failure, it was nearly two years. If we look at the life expectancy of a patient with significant heart failure, two years is a substantial part of their predicted future survival. Therefore this loss of protection is really a very serious risk for these patients.
So what do the guidelines tell us? Until very recently, they really weren't that helpful. What they said is guideline-recommended management of RAASi, based on serum potassium levels. They're saying with modest elevations above 5.0, don't start MRAs or ACEi/ARB, use with caution above 5.5. They're saying reduce the dose above 6, then discontinuing. It's a natural, clinical thing. When looking after a patient, you start a drug. You say: 'This can improve you. The patient comes back and you see the potassium has gone up. The natural response is to say we perhaps better stop it. We might go to a drug discontinuation, a drug dose reduction but there's a strong clinical incentive, a driver, to simply bail out and not get the drug to stop it. And that may be the very worst thing we can do.
If we look at what happens in routine practice, down-titration or complete discontinuation of RAASi therapy is very common, following a hyperkalemia event. We see 38% of patients have significant down-titration. If you look at more severe levels, the majority of patients are down-titrating or discontinuing. A very small percentage maintain a maximal, optimal dose of the RAASi. And that might mean that very few of our patients are getting optimal protection for their underlying disease. If we look at the consequence of down-titration or discontinuation of RAASi therapy, due to hyperkalemia, in both CKD, chronic kidney disease, heart failure and diabetes, we see an increase in subsequent mortality, from either discontinuing or stopping entirely. That's more than a doubling of background mortality. It's particularly strong in heart failure, where background mortality is high. We're going from 13% to 30% mortality by simply stopping the drug, because of our concern about hyperkalemia.
This is a very interesting analysis we did of the European Heart Failure Registry, looking at patients who had an episode of hyperkalemia and then looking at what happened. If you look at the bottom three lines, you see the increased hazard ratio of increased mortality. When the ACE inhibitor was discontinued or the ARB, or the MRA, showing a 7 to 13 fold increase in mortality. But if you look at what the impact of the high potassium itself was, when you account for what happened to the drug dose, there is no residual hazard of having high potassium level. It's because of our reaction that these patients do worse. It's because the high potassium leads us to stop treatment that we're getting that excess mortality.
So what we'd like to know in future is, if we can manage the elevated potassium in a way other than stopping the drug, would we get much better outcomes and of course, with the availability of novel potassium binders, we have a way of doing that. If we look now, optimizing RAASi therapy in patients, with chronic kidney disease and heart failure, we look at major outcomes, mortality and major adverse cardiovascular events. In a registry, those patients who can maintain the RAASi dose despite the hyperkalemia, they do far better for outcome. So we believe the chance is, if we can manage the potassium, alternatively to withdrawing treatment, we will get better long term outcomes. So the guideline recommended management of RAASi, in the setting of hyperkalemia, may be wrong, may be inappropriate, may be avoiding the real chance we have of maintaining the potassium balance by the extra administration of, what we would call, facilitatory therapy of managing potassium itself, as an enabler, of getting full protection from maximum recommended dose of RAASi drugs.
So we want to balance RAASi therapy with potassium levels. We want to manage the potential risk of RAASi therapy increasing potassium, versus it's absolutely substantial benefit. And we want to tip things in the favour of the patient by managing potassium independently of cessation.
So this symposium we'll go through how we can avoid the problems of reducing RAASi therapy dose, treating the hyperkalemia to optimize and maintain the RAASi therapy, versus the simple bailout procedure of saying: 'Let's stop the treatment', which may be very much the worst thing we can do.
Thank you very much.
This lecture by prof. Andrew Coats was part of the EBAC-accredited symposium "Clinical dilemmas in heart failure: Weighing the balance of RAASi and hyperkalaemia" held during the ESC Heart Failure 2022 congress.
Prof. Andrew J Stewart Coats is Dean of the Royal Australasian College of Physicians, having previously served Dean of Medicine and Deputy Vice-Chancellor of the University of Sydney and head of Cardiology at Imperial College London. He has also served as Joint Academic Vice-President of the University of Warwick, UK, and Monash University, Australia and CEO of the Norwich Research and Innovation Park. He is presently President of the Heart Failure Association of the ESC.
This recording was independently developed under auspices of PACE-cme. The views expressed in this recording are those of the individual presenter and do not necessarily reflect the views of PACE-cme.
Funding for this educational program was provided by an unrestricted educational grant from AstraZeneca.
The information and data provided in this program were updated and correct at the time of the program development, but may be subject to change.
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