Using MRAs for Quadruple Therapy in the Management of HFrEF


Javed Butler, MD, discusses the class of mineralocorticoid receptor antagonists used within quadruple therapy for patients with heart failure with reduced ejection fraction.

James Januzzi, MD: Dr Javed Butler, let's talk about mineralocorticoid receptor antagonists [MRAs], another older class that is time tested and time honored, where do they fit in with the current guideline-directed medical therapy? And what are the challenges that you see with this class?

Javed Butler, MD: I think MRAs are probably the most neglected heart failure medication. There are all of these fears related to hyperkalemia; and I certainly don't want to make light off [an adverse] effect profile, and we have to [be concerned]. But remember being overly cautious and not giving an incredibly effective therapy is a problem. Also, if you look at the heart failure trials, 30% reduction in mortality if you're a high-risk [very] sick patient, even milder patients, substantial mortality benefit, early certain cardiac death benefit in patients….who have congestion or heart failure. Lots of benefit with these agents. The problem is that they have a contraindication for eGFR [estimated glomerular filtration rate] less than 30, primarily because of the concerns of risk for hyperkalemia, and that you should not give it to patients with potassium levels that are over 5, and that you have to titrate the dose down if somebody on therapy develops a potassium concentration greater than 5.5. Now, the problem is that not many patients develop necessarily a potassium level of more than 5.5. The issue is a psychological fear that you will put these drugs on somebody where they live far away. They're not going to be coming for regular medical checkup. Maybe they won't get their blood tests. A lot of the time proactively is these drugs are not given, but otherwise, they are fairly well tolerated. The good thing, however, is that the guidelines give a pretty good map of how to measure and monitor potassium levels. And if you do that, these drugs are incredibly safe and very, very efficacious.

If you look at what's happening in therapy for heart failure with reduced ejection fraction, RAS [renin-angiotensin system] inhibitor using a beta-blocker continue to have improved at the community level. Certainly, in patients who come into clinical trials, but there still is a bigger lab for MRA, which is just absolutely not deserved because these are incredibly effective therapies. Now, the good thing is that despite following all the recommendations for electrolyte follow-up and management, if a person does develop hyperkalemia or your concern for that, there are novel potassium binders, such as sodium zirconium, cyclosilicate, or patiromer, which are very well tolerated and can manage [a patient’s] potassium levels. You can enable this in those few patients where this will be a big issue.

There are 2 leftover questions. First, what about eGFR less than 30? Because, presumably, those patients are at an even higher risk of cardiovascular adverse outcomes. Can you give it, second, and what about patients who have heart failure with preserved ejection fraction? We'll talk about preserved ejection fraction later, but for less than 30, there are actually trials going on. We will get some idea, but, today, we should consider it as a contraindication. We should give it to patients with eGFR greater than 30. And then lastly, there are these selective nonsteroidal MRAs that are also coming in the market, not approved for heart failure, not tested in heart failure, but nevertheless, the hyperkalemia risk is much lower than things like spironolactone. And they have been tested in chronic kidney disease with some very good results, and they are being tested and heart failure with preserved ejection fraction as well. Thus, the field continues to evolve.

James Januzzi, MD: It's exciting to see an older class of drug have some new life to it and maybe improve the safety profile.

This transcript has been edited for clarity.

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