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Using ARNIs for Quadruple Therapy in the Management of HFrEF

Nasrien Ibrahim, MD, considers using angiotensin receptor-neprilysin inhibitors in quadruple therapy when treating patients with heart failure with reduced ejection fraction.

James Januzzi, MD: Dr Nasrien Ibrahim, we're going to talk now about angiotensin receptor–neprilysin inhibitors [ARNIs]. How do ARNIs fit in with the current GDMT [guideline-directed medical therapy] and what do you see are the current challenges associated with their use?

Nasrien E. Ibrahim, MD: I'm glad I got the ARNIs because that is my favorite heart failure drug from 4 classes. We've worked together on several trials related to ARNIs. But sacubitril valsartan, we know it came on the market after the landmark trial PARADIGM-HF, which was in patients with chronic HFrEF [heart failure with reduced ejection fraction]. EF [ejection fraction] 40% or less that were randomized to enalapril versus the sacubitril valsartan. We saw that the patient that received sacubitril valsartan had a significant reduction in heart failure hospitalizations, and mortality. Specifically, a 20% reduction in cardiovascular death was sacubitril valsartan. If a patient is on an ACE [angiotensin-converting enzyme] inhibitor or an angiotensin receptor blocker, there is no excuse not to switch them to an ARNI because we see how beneficial the angiotensin receptor neprilysin inhibitors are. We know this in patients with chronic heart failure and then the PIONEER-HF trial gave us data in patients with decompensated heart failure, whether it was patients that had previous heart failure diagnoses, or even patients with de novo heart failure, they tolerated it well. The greatest things that I've seen with angiotensin receptor neprilysin inhibitor, which the only one we have is to sacubitril valsartan, is we know there's a reduction hospitalization and mortality, but we've seen significant improvement in quality of life. Patients feel better, their symptoms improve. We've also seen that patients that received sacubitril valsartan have had reductions in their pulmonary pressures in patients we have in the ICU [intensive care unit] that have PA [pulmonary catheter] lines that we can monitor.

I've had one case in a patient who was actually listed for transplant and had not been on a sacubitril valsartan because it was not yet approved, and we switched her to sacubitril valsartan. She had significant improvement in her LVEF [left ventricular ejection fraction] and significant improvement in her cardiopulmonary exercise testing parameters and ended up getting delisted. There’s significant cardiac reverse remodeling, and prof HF was looked at this specifically. There was remodeling up to 12 months out. Thus, I would say for patients who are not on sacubitril valsartan there really should be no excuse why they should not be switched to sacubitril valsartan for lots of reasons—reduction in morbidity and mortality, improvement in quality of life, improvement in cardiac structure and function, and overall significant benefits.

Some of the issues that we might run into starting sacubitril valsartan, potassium elevation, and there might be worsening in renal function. But one of the things I would tell clinicians is to make sure patients are not too dry because we see this all the time. Patients are on 100 mg of torsemide, or 80 mg twice a day, a few furosemides, and you start them on sacubitril valsartan. And we see this phase with dilation and increase in urination with scriptural valsartan on its own. And if patients are too dry, there might be worsening in renal function. And then clinicians end up stopping sacubitril valsartan as opposed to reducing doses of diuretic. Because of this natriuretic effect almost from the sacubitril valsartan, you could preemptively reduce doses of diuretics when you start patients on sacubitril valsartan or preferably started in wet patients, so you don't run into these issues. Always, you need to look at the rest of the medication, whether the patient is too dry, you can use natriuretic peptides if their physical exam is difficult. You can get a clue as to whether they might be too dry before stopping sacubitril valsartan when you notice the worst thing in kidney function.

James Januzzi, MD: Great answer. And I learned this from you in the clinic working side by side, initiating in patients that are somewhat on the more congested side to avoid the hypotensive effect of the drug and then titrating up, which helps the patient sort of compensate further is a really great trick, or just reducing empirically the loop diuretic.

This transcript has been edited for clarity.