Hi, there. I'm Shelley Zieroth, Professor of Medicine from Winnipeg, Canada. I am very pleased to be speaking to you today about continuing foundational therapy in symptomatic heart failure, the key role of RAASi-based therapy.
Now, you all know that there have been many landmark trials in heart failure in particular. It started off with landmark trials in ACE inhibitors, which became our first-line therapy, and then we added MRAs. And finally came angiotensin receptor-neprilysin inhibitors, which then really replaced ACE inhibitors as the cornerstone of GDMT in HFrEF therapy. What's the trouble with all of these RAASi therapies? They improve outcomes in our patients with heart failure, but there is a significant barrier in initiating them, and one of those barriers is hyperkalemia. We're going to talk more about that today.
Now, RAASi therapy is a cornerstone of all of our international heart failure guidelines. I'm showing you here the ESC guidelines which were published in 2021, and, of course, there are Canadian guidelines and American guidelines as well, all of them use RAASi therapy as a component of GDMT for HFrEF therapy, however, they also recommend getting to target doses. The paradigm has shifted. We have four foundational therapies for HFrEF. We start low, but always remember to up-titrate to the maximally targeted dose. Here are the American HFrEF guidelines. You can see on the left-hand side of the slide that these are our four foundational therapies and they all have a class 1 indication, that means high priority. Start them, up-titrate to target doses.
Now, RAASi therapy is also a component of other guideline recommendations as well, but to a lower level, and I just wanted to briefly mention them for you. This is the American guidelines for heart failure with mildly reduced ejection fraction, and you can see elements of RAASi therapy have a 2B recommendation here, and for heart failure with preserved ejection fraction, once again, RAASi therapy is recommended, but at a 2B recommendation level. For the remainder of this talk, I'm going to speak to you about HFrEF because that's where all of the class 1 indications are for RAASi therapy.
Despite proven benefits of RAASi therapy, many patients with HFrEF are not at the target doses, and CHAMP-HF was one of the first ones for us to really recognize this major gap in prescribing. Not only were patients not getting prescribed guideline-directed medical therapy, but very few of them were achieving target doses, and you can see the dark portion of the rings represents that small percentage of patients that actually made it to target dose. With the CHAMP-HF registry. Then we also had Professor Savarese publish a registry of patients from the US, Sweden, and the UK. This is an international problem.
Achieving target doses of RAASi therapy is a challenge for us in clinical practice, and hyperkalemia is one of the reasons why. You can see anywhere from about 10% to up to 23% of patients achieve target doses depending on the registry, this is by far a major gap in our therapeutic inertia.
This is a landmark paper, in my opinion. It was led by Professor Rosano, and it's a product of the ESC Heart Failure Association and it generated 11 different HFrEF phenotypes. They recommended prescribing practices or various medications to prescribe based on four challenges in the management of HFrEF patients. That being blood pressure, the presence or absence of atrial fibrillation, heart rate, and, of course, CKD and hyperkalemia are there as well.
This is a real-life challenge for clinicians caring for those patients living with HFrEF. Hyperkalemia can be a barrier to target dose RAASi therapy, as we just saw in that last phenotype presentation. Now, the presence of hyperkalemia actually increases as we move from ACE, ARB to MRA, which is an important element of GDMT in patients with HFrEF.
What's interesting as well is the proportion of patients with recurrent hyperkalemic events is real. Once they've had hyperkalemia, they may have it again, and the gap between episodes of hyperkalemia reduces as well. In this slide, I'm also introducing to you the CKD patient population. This is also a very relevant comorbidity in our patients living with HFrEF.
Optimizing RAASi therapy in patients with CKD and heart failure is associated with decreased mortality and MACE. On the left-hand side of this slide, you see chronic kidney disease patients, and on the right-hand side, heart failure patients, and the difference between prescribing less than 50% of guideline-directed medical therapy or RAASi therapy versus target doses results in substantial reductions in mortality and MACE. In both of these patient populations, getting to target dose really matters.
Furthermore, we know that discontinuation or down-titration of RASi therapy after an episode of hyperkalemia is more likely to occur when higher levels of hyperkalemia have occurred. This is a great paper from Cecilia Linde. What happens when discontinuation happens?
Well, it's not a great trajectory after that. 76% of patients were not reintroduced to MRA therapy during the subsequent year, and the mean duration of RAASi discontinuation was 2.4 years in those patients with chronic kidney disease, and 1.9 year in patients with heart failure. The down-titration or discontinuation of RAASi therapy is associated with a doubling of mortality across patient subtypes. You can see those patients who are at maximum dose in the green bars have substantially lower mortality in comparison to those patients who are at a down-titrated dose or have been discontinued. This is important for patient outcomes that we get to target therapy.
As a clinician caring for patients with HFrEF and prescribing GDMT, it's important to recognize some benefits of elements of these four foundational therapies. For instance, in clinical trials, those patients who are randomized to SGLT2 inhibitors were less likely to have hyperkalemia or require potassium binders. This meant you may be able to up-titrate sacubitril/valsartan or their MRA. Furthermore, sacubitril/valsartan, in comparison to enalapril in clinical trials, was also associated with less hyperkalemia, thus potentially facilitating up-titration of your MRA.
Nevertheless, hyperkalemia remains a significant challenge for clinicians prescribing RAASi therapy. RAASi should be initiated and titrated to the highest approved dose that is tolerated to improve patient outcomes in those with heart failure and even CKD. Despite the proven benefits of RAASi therapy, hyperkalemia can be a barrier to achieving and maintaining optimal RAASi therapy and management of hyperkalemia with potassium binders may allow for RAASi optimization.
