Ryan Haumschild, PharmD, MS, MBA: As we start to transition into our discussion about heart failure, it’s important for us to talk about some of the treatments. Dr Anderson, I’m going to look to you here, as I’d like for you to touch on this. What are considered the 4 pillars of quadruple therapy for patients with heart failure, maybe with reduced ejection fraction [EF] and preserved ejection fraction? As you’re answering the question, maybe talk to us a little about the rationale behind each of them.

John E. Anderson, MD: Thanks, Ryan. There are 4 pillars. Let’s go back to the ones we’ve had for years: RAS [renin-angiotensin system] inhibition. That’s the use of maximally tolerated ACEs [angiotensin-converting enzyme inhibitors] or ARBs [angiotensin receptor blockers]. But now the recommendation is for angiotensin receptor-neprilysin inhibitors [ARNIs] to be the preferred RAS inhibitor. Traditionally, beta blockers, perhaps vasodilating beta blockers, have always been a pillar of therapy. A mineralocorticoid receptor antagonist, such as spironolactone, has also been one of the pillars of therapy. And now with both reduced ejection fraction and preserved ejection fraction is the SGLT2 inhibition, which is the fourth mainstay of therapy. That has some of the more recent data as well—some of the ARNI data—and we could get into that a little more as we look at some of the studies. Then there’s plus or minus the use of a loop diuretic. It’s the balancing of all 4 of these pillars that are maximizing the treatment for heart failure.

Ryan Haumschild, PharmD, MS, MBA: Yes. Going through some of those therapies, some are tried and true, but we’re seeing that emerging, how do we start to complement each other? How do we consider diversity, equity, and inclusion in a patient-specific background? Are they salt sensitive, are they not, as we treat not only the blood pressure but the reduced ejection fraction. There are also newer medications emerging. Dr Januzzi, I’m going to slide back to you, being someone who’s familiar with the updated 2022 guidelines. Talk to us a little about some of those new medications. When we think about those with preserved ejection fraction, we think of SGLT2s. We’ve started to see it for heart failure as well as for diabetes and metabolic syndrome. Now we have aldosterone receptor antagonists, otherwise known as MRAs [mineralocorticoid receptor antagonists], and we have ARNIs. How does this recommendation impact the clinical outcomes for patients with heart failure? What are the benefits that you see by inhibiting RAS in patients with heart failure with preserved ejection fraction [HFpEF]?

Jim Januzzi, MD: Thank you for the question. Let’s take a step back and first remember the categorization of reduced, mildly reduced, and preserved ejection fraction. Because the treatments largely extend across that spectrum of ejection fraction but with different benefits and effects. We talk about the foundational treatments of an evidence-based beta blocker, a mineralocorticoid receptor antagonist, an inhibitor of the renin-angiotensin system, in particular sacubitril/valsartan, the prototypical angiotensin receptor-neprilysin inhibitor. Sacubitril/valsartan is one of the newer kids on the block that has been put to the forefront. Then there are SGLT2 inhibitors. Those are the 4 main classes that we’re focusing on.

By and large, until we get to a very normal ejection fraction up well closer to 60%, the treatment is pretty much the same for most patients, with some important nuances. If you look at the guidelines, there are varying levels of recommendation. But largely, the treatments will extend regardless of ejection fraction until you get down to 40% and less, where everything gets much firmer. When you’re at an EF of 40% or less, it’s class 1 for those 4 drugs. When you’re in the mildly reduced category, it’s still very heavily recommended for these patients with an impaired ejection fraction to be on all 4 classes. There are reasons why this is, but by and large, patients with reduced ejection fraction have activation of their sympathetic nervous system and their renin-angiotensin-aldosterone system, much like folks with an EF of 40% or less.

When you get up to the normal range of ejection fraction, things start to get a little more qualified. The guidelines give a class 2a recommendation for SGLT2 inhibitors in individuals with a preserved ejection fraction. This was on the basis of the EMPEROR-Preserved study looking at randomized treatment with 10 mg of empagliflozin vs placebo in patients with preserved ejection fraction heart failure. It’s important to recognize that in EMPEROR-Preserved, we included people with ejection fractions of 40% or greater. We included mildly reduced patients, and they did very well on SGLT2 inhibitors. But even in people with EFs of 50% or greater, the so-called classical HFpEF, the treatment with empagliflozin in particular reduced heart failure hospitalization. As a result, the guidelines give a 2-way recommendation, essentially recommending treatment with an SGLT2 inhibitor, even when you’re up into that normal range.

The recent DELIVER study hasn’t been presented, but the top-line data were reported as being positive for dapagliflozin in preserved ejection fraction. We now have 2 studies with 2 different drugs in this previously challenging-to-treat population showing benefit. In this population, there’s also qualified recommendations for use of spironolactone, particularly in women with a normal ejection fraction. But at the lower range of normal, down to an EF of 55% or less, we start seeing benefits. Also, sacubitril/valsartan is recommended in women at the lower range of normal. By and large, the treatments are pretty similar unless you get to the higher range of normal ejection fraction, where it’s mainly focused on SGLT2 inhibitor therapy.

Ryan Haumschild, PharmD, MS, MBA: That’s a good overview. It’s exciting that we have more agents to treat our patients with. At the end of the day, that’s a great thing. These guidelines are some of the most exciting because they’ve incorporated a lot of new treatments.

Transcript edited for clarity.