Using Sacubitril/Valsartan in Heart Failure Treatment 

James Januzzi, MD: You’ve listed a bunch of important therapies, and I’m going to reorder some of them. Let’s address where we stand right now with respect to our GDMT, or guideline-directed medical therapy, and how we implement it. You’ve mentioned the successes with β-blockers, with a tremendous benefit in heart failure. They’re perhaps one of the most important therapies we give, particularly when adjusted to higher doses. We have mineralocorticoid receptor antagonists, ACE [angiotensin-converting enzyme] inhibitors, and ARBs [angiotensin receptor blockers], and then along comes sacubitril/valsartan.

The way sacubitril/valsartan was studied was actually a head-to-head against enalapril, so it is in the list of therapies that we give in heart failure with reduced ejection fraction. It’s the first switch that we’ve had to contend with, which creates some anxieties among clinicians about how to do it, when to do it, and why to do it. You’ve addressed to some extent how the drug works. It’s got an angiotensin receptor blocker, but it also raises the concentration of numerous vasoactive peptides with favorable effect on heart failure because of its neprilysin inhibition. Can you tell me a little about the efficacy and safety profile in the clinical trials that have looked at sacubitril/valsartan? Why would we be talking about this as a new therapy ahead of an ACE inhibitor or ARB?

Javed Butler, MD, MPH, MBA: Yes. The fundamental concept here was if you look at the PARADIGM-HF trial, there’s 1 word missing in the trial’s schema: placebo. This was comparing against the standard of care with the idea of not adding something, but replacing the existing standard of care. This was a completely different concept, and that has some benefits to it. If you win, then you have 2 benefits. You have a better standard of care. Also, polypharmacy is a complex issue and we’ll get into that a little bit, and by replacing a drug, you’re not adding yet another drug, but replacing another drug’s pill count, and that complexity remains a little more stable. Those are on the plus side.

The perceived negative side is that it requires you to take some time out, talk to the patient. The patient is saying, “I’ve been taking this medicine for such a long time, why do you want to switch? Why do I have to come back to take another blood test?” Having said that, we are not talking about some minor benefit. We’re talking about 20% relative risk reduction in both components of the primary end point: cardiovascular death by itself and heart failure hospitalization risk. This is a pretty substantial risk reduction, on top of standard of care and high-dose ACE inhibitors that we don’t even give in the clinical setting. So even in this idealized setting, there was a 20% increase. You can slice and dice the outcomes any which way. If you look at the secondary end points—the risk of sudden cardiac death, progressive heart failure-related death—all of these outcomes were improved. Quality of life improved, the scores got better, people feel better as well. All of these were subsequently also shown in registries and real-life data about improvement in quality of life.

When it comes to the safety profile, if we do a large trial, there will always be some wiggle, right? You have thousands of patients numerically, but overall, the safety profile was pretty comparable. If anything, stopping the drug for adverse effects occurred more in the enalapril arm than the valsartan/sacubitril arm. There was a little bit more cough with one drug, a little more hypokalemia with the other, and some decreasing blood pressure with the other, give or take. All in all, it was a very comparable safety profile with a lot of additional benefits.

James Januzzi, MD: This is really remarkable. In the original 2017 Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment document, we incorporated sacubitril/valsartan, but there was an important nuance to how we recommended it, which very much aligned with the current clinical practice guidelines for heart failure. We recognized that because in the PARADIGM-HF study, all patients were treated with an ACE inhibitor before being switched to sacubitril/valsartan, we had this important recommendation that the preferred strategy would be to have patients stable on an ACE or an ARB before being switched on to sacubitril/valsartan.

Transcript Edited for Clarity