James Januzzi, MD: The PROVE-HF Trial

In new data from the PROVE-HF trial presented at the Heart Failure Society of America (HFSA) 2019 Scientific Sessions in Philadelphia, PA, sacubitril/valsartan (Entestro) was shown to benefit patients with reduced ejection fraction heart failure (HFrEF), regardless of dosing titration, over 1 year.

The findings, which included patients from PARADIGM-HF as well as those who did not qualify, changes the scope of understanding as to how the angiotensin receptor/neprilysin inhibitor therapy affects patients.

In an interview with MD Magazine®, investigator James Januzzi, MD, professor of medicine, Harvard Medical School, and of the Cardiology Division at Massachusetts General Hospital, explained his team’s findings.

MD Mag: What was the makeup of the PROVE-HF trial?

Januzzi: This is a prospective analysis of the effects of sacubitril/valsartan, a widely-used heart failure medication, on cardiac remodeling. So, the reasoning for the study was that—although we recognized that sacubitril/valsartan is a drug used for patients with heart failure and reduced ejection fraction—it reduces risk for heart failure, hospitalization, cardiovascular death, and other outcomes.

The mechanism of benefit remains really uncertain. In fact, there’s an open question as to how exactly this medication exerted its benefits. So to study this, we actually looked at how the drug seems to affect our patients when we initiated. And one of the things that we saw in early studies is that there's a rather significant reduction in n-terminal proBNP concentrations.

This is a biomarker of myocardial stress, and higher concentrations of NT-proBNP are associated with risk, but mechanistically, the reason why these concentrations are high in our patients is because their ventricles are remodeling so the ventricles are becoming larger and weaker.

It was our hypothesis that these anti-proBNP concentration reductions seen in patients treated with the sacubitril/valsartan were related to reverse cardiac remodeling. So to study this, we took 800 patients with reduced ejection fraction heart failure, initiated them on sacubitril/valsartan, did an echocardiogram at baseline, 6 ,and 12 months, and during the years time of treatment we sampled their blood frequently for measurements of n-terminal proBNP.

One other very important thing that we did in this study was we included patients that had not previously been studied in the PARADIGM-HF trial—including people with new-onset heart failure, people not taking an ACE inhibitor or angiotensin receptor blocker before starting sacubitril/valsartan, people with low concentrations of n-terminal proBNP, as well as people who could not be titrated up to the target doses.

So, the idea was to try to fill in some mechanistic understanding and also filling data on patients where data did not yet exist.

MD Mag: What is the significance of including that second patient population?

Januzzi: So we designed the study to look at certain patient populations that are not currently being treated with sacubitril/valsartan, in part because of the way that the Food and Drug Administration approved the use of the drug, number 1, but also, how the guidelines are written.

So, for example, the guidelines state that patients with new onset heart failure should be treated for at least a month with an ACE inhibitor or angiotensin receptor blocker. And we've wished to really examine whether that absolutely is all that necessary. So we studied those patients treatment-naive patients, with the goal of really trying to understand number 1, how the drug is tolerated—but also how it affects the cardiac performance in these patients.

MD Mag: What were the findings?

Januzzi: So we initiated sacubitril/valsartan and titrated. About two-thirds of the patients got to the target dose, but one-third did not. So that's important. We were able to study those patients who didn't reach the highest dose of the drug.

Within 2 weeks of initiating the drug we saw a rapid sustained reduction in NT-proBMP concentrations. Really, by 2 weeks, most of the reduction that we saw had already occurred, with a maximal 37% reduction in NT-proBMP out to a year after initiation and titration.

From baseline to 6 months, we observed a significant correlation between the reduction in NT-proBMP and changes in cardiac remodeling parameters. And from 6-12 months, across the whole year, that relationship became even stronger. So, given the fact that NT-proBMP went down, and there was this very strong relationship with cardiac remodeling.

With the reduction in NT-proBMP on the echocardiogram, we saw from baseline to 6 months an absolute 5% increase in ejection fraction. And by a year, there was an absolute 9.5% increase in ejection. Along with this, there was reverse cardiac remodeling, with reduction in left ventricular volumes, reductions in left atrial volume, and improvement in diastolic function.

So these data really provide useful information about how the drug exerts its benefits. These reductions in NT-proBMP are essentially reflecting the reverse cardiac remodeling that comes along with the drug.

Importantly, the subgroups of interest—patients that were new-onset heart failure patients that had lower concentrations before treatment, as well as those not reaching the highest doses of the drug—all had similar, if not greater reverse remodeling, really implying that patients where there was some degree of uncertainty about how the drug works benefit just as much. And that I think that’s really useful for clinicians to understand.