Considerations for initiating sacubitril/valsartan as de novo therapy in patients naïve to angiotensin-converting enzyme inhibitors or angiotensin receptor blocker therapies as per the 2021 update of the expert consensus decision pathway document.
James Januzzi, MD: What do we know about de novo treatment with patients? This is an important change in the 2021 Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment document. In this document, we now say you don’t need to pretreat with an ACE [angiotensin-converting enzyme] inhibitor or an ARB [angiotensin receptor blocker], and part of that has to do with the fact that delaying initiation of a superior therapy like sacubitril/valsartan exposes the patient to potential risk. But what about efficacy? Do we know anything about the initiation of sacubitril/valsartan in de novo patients?
Javed Butler, MD, MPH, MBA: Yes. This is the constant struggle when you’re making recommendations between empiricism and pragmatism between science and art. On one hand, you can make a genuine comment that if you were to give a de novo heart failure patient 6 weeks of an ACE inhibitor before you switched them over, what has changed in the biology? You’re basically delaying the use of a good medical therapy, and you’re putting a patient at a higher risk. So you can make a very good case that there’s no biologic reason to delay. On the other hand, the empiricists would say, “Well, but where are the data? What about safety?” Because that is not how the PARADIGM-HF trial was done, so we’ve really needed the data. The problem is, how do you generate these data? There were other things. Can you start it in the hospital setting? It was another issue. PARADIGM-HF was a large trial, but it was a global trial. It was the only trial. There were all of these questions out there about what to do, such as with patients not on a RAS [renin-angiotensin system] inhibitor therapy in the background. But the problem in conducting that trial is that now you have a drug that is a class 1 recommended therapy, and how can you give somebody anything else in a randomized fashion for 2, 3, or 4 years to look at the clinical end point? That’s the struggle.
So a trial was done called PIONEER-HF that tried to answer all of these questions, but remain within the ethical bounds. It was an 8-week therapy, NT-proBNP [N-terminal pro-B-type natriuretic peptide level] was the primary end point. Clinical end points were exploratory end points, to at least start getting a sense of whether the drug was beneficial in all of these cases. It was about an 800 or 900 patient study, and NT-proBNP was the primary end point. There was a large proportion of patients with new onset of heart failure, 30% or more, a large proportion of patients not on RAS inhibitor therapy, a large proportion of African American patients, all patients who were in the hospital with decompensated heart failure for at least 24 hours. So, not the emergency department crash and burn, but still getting IV [intravenous] diuretics, still in their acute phase or early phase.
The results were fascinating. First of all, the primary end point was usually in favor of valsartan/sacubitril because of the further reduction in NT-proBNP. For all of these subgroups that we were asking if the valsartan/sacubitril was more beneficial, whether it’s new onset of heart failure, whether it is African American patients in hospital settings, and so on, it was very well tolerated. The adverse effect profile again was comparable to the standard of care. What was fascinating was that while we were trying to look for trends in the clinical outcome, because it was an 8-week study, there was a 44% reduction in rehospitalization rates. Everything was statistically significant. Granted, it was exploratory analysis, but the benefits and clinical benefits were huge. That took away all of these concerns that we had about not having any data, to having data now where we feel more comfortable in recommending ARNIs [angiotensin receptor-neprilysin inhibitors] as a preferable therapy.
James Januzzi, MD: Yes, and subsequent to PIONEER-HF, the TRANSITION study also included a large percentage of patients who were de novo initiation. Then we did a mechanistic study together looking at the effect of sacubitril/valsartan on left ventricular reverse remodeling and improvement in ejection fraction [EF]. Folks, this is something that we see when we initiate therapies of benefit in chronic heart failure with reduced EF. Reverse remodeling is improvement in the ejection fraction, which is something that everyone loves to see, but importantly is related to the benefit. In other words, as the ejection fraction improves, the risk for complications such as heart failure events or sudden death go down.
In this study that we performed, we included patients with new onset or untreated chronic heart failure with reduced EF. What we found was that the people who were de novo initiation on sacubitril/valsartan had the largest improvements in ejection fraction and the greatest reductions in NT-proBNP, really illustrating that this concept of a pretreatment phase was more a manifestation of us getting tied in knots about the clinical design. And once we put some clinical logic in place, it is quite clear that delaying initiation of a favorable therapy like sacubitril/valsartan would not be justifiable. In this regard, the 2021 Expert Consensus Decision Pathway document takes a so-called ARNI-first approach, which is to say for patients with heart failure with reduced EF, regardless of the chronicity, patients should be initiated on an evidence-based β-blocker, carvedilol or metoprolol succinate, and sacubitril/valsartan as the first 2 foundational therapies.
Transcript Edited for Clarity