New PROVE-HF Data May Reassure Clinicians of Sacubitril/Valsartan Benefit in HFrEF

PHILADELPHIA, PA—Patients who have heart failure with reduced ejection fraction (HFrEF) achieve the most benefit in terms of survival and avoiding hospitalization when N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels are lowered quickly with sacubitril/valsartan, new data from the PROVE-HF trial show. The findings extend to patients with new-onset HF, and also suggest that even a suboptimal dose of the angiotensin receptor-neprilysin inhibitor (ARNI) gets the job done.

“Those patients with a speedier reduction to lower NT-proBNP had significant reductions in mortality and HF hospitalization compared to those patients who did not,” said James L. Januzzi Jr, MD (Massachusetts General Hospital, Boston), during a late-breaking trial presentation here at the Heart Failure Society of America (HFSA) 2019 meeting. “Furthermore, those patients with a longer time spent with a low NT-proBNP had greater reverse cardiac remodeling and lower event rates.”

The analysis strengthens the overall results of PROVE-HF, which showed that reductions in NT-proBNP concentration in patients on sacubitril/valsartan (Entresto; Novartis) were weakly but significantly linked to improvements in markers of cardiac volume and function. Januzzi said the latest findings may be a step toward understanding the drug’s mechanism of action. PROVE-HF was published recently in JAMA to coincide with presentation of the main results at the European Society of Cardiology Congress 2019.

To TCTMD, Januzzi said the findings also have practical implications for managing sacubitril/valsartan therapy in daily practice. “Fundamentally, I think one thing that is really important to emphasize is that this is a study that provides information for clinicians who are seeing these patients about how to understand what the drug is doing, and how when they measure NT-proBNP what that result is telling them.”

The data Januzzi presented at HFSA are from a “time to, time in” analysis that looked at the amount of time from enrollment in the trial to achievement of a reduction in NT-proBNP of greater than 1,000 pg/mL, as well as the amount of time a patient spent over the course of the 12-month study with their levels below 1,000 pg/mL.

“What we found was that from baseline to 12 months there was a substantial and significant difference between the proportion of patients above and below 1,000 from the first visit to the end of the trial, again in keeping with the reduction seen in NT-proBNP,” he said.

Rapid and Significant Reductions in NT-proBNP

The single-group, open-label PROVE-HF study enrolled 794 patients at 78 US sites. All had HFrEF and were taking beta-blockers and ACE inhibitors or angiotensin-receptor blockers and were eligible for treatment with an ARNI. In his presentation, Januzzi pointed out that three patient subgroups were included in PROVE-HF that have not previously been assessed in other studies: patients who had new-onset HF and/or who were naive to renin-angiotensin system inhibitors, those with natriuretic peptide concentrations below the inclusion criteria for the PARADIGM-HF study, and patients who were unable to achieve top-dose sacubitril/valsartan (97 mg/103 mg twice daily) during titration. Rather than being removed from the study, this last group continued on the dose that they were able to achieve. Median NT-proBNP concentration at baseline was 816 pg/mL.

When sacubitril/valsartan was first initiated, 82% of patients received a dose of 24 mg/26 mg twice daily. By the end of the study, 65% were able to reach the target dose. Reasons for not achieving target doses included symptomatic hypotension (5.0%), kidney dysfunction (1.6%), and hyperkalemia (1.0%).

Januzzi reported that initiation and titration of sacubitril/valsartan resulted in “rapid and very significant reductions” in NT-proBNP concentrations, usually within the first 2 weeks of treatment. The quick response, he noted, occurred in most patients with the lowest dose of sacubitril/valsartan.

This is a study that provides information for clinicians who are seeing these patients about how to understand what the drug is doing, and how when they measure NT-proBNP what that result is telling them. James L. Januzzi Jr

Over 12 months, the demonstrated change in NT-proBNP concentrations also correlated with numerous measures of cardiac remodeling, including progressive improvements in LVEF, LV end-diastolic volume index, LV end-systolic volume index, left atrial volume index, and ratio of early diastolic filling/early diastolic annular velocity (P < 0.001 for all changes) within the overall cohort and the subgroups of interest.

LVEF increases averaged 5.2% by 6 months and 9.4% by 12 months. According to Januzzi, 25% of patients had an absolute increase in LVEF of 13% or greater by 12 months. In post hoc analyses, LV mass index fell from 124.77 g/m² at baseline to 107.82 g/m² at 12 months (P < 0.001).

Reverse cardiac remodeling in each of the three specified subgroups was comparable to the overall cohort. However, Januzzi pointed out that the new-onset group in particular had average LVEF increases of approximately 13% over the 12 months of treatment, higher than the average for the rest of the group. Patients with the most robust reductions in NT-proBNP and left ventricular volumes had the lowest rates of death and heart failure hospitalization, while those with suboptimal reductions in both measures had the highest event rates.

Patients Deserve Optimal Therapy

A major limitation of PROVE-HF is the lack of a control group, which leaves open the possibility that medications other than the sacubitril/valsartan either on their own or in combination with sacubitril/valsartan played a role in the reverse remodeling.

To TCTMD, Januzzi said the recently published, randomized EVALUATE trial, which has only reported outcomes to 12 weeks, has “early reverse remodeling data that suggest a step toward our 6-month and 12-month results. Investigators have 6-month results that they will be publishing soon, which will unify the two trials very nicely.”

The PROVE-HF investigators acknowledge the limitations of the lack of a control group, he added. However, seeing as sacubitril/valsartan was approved by the US Food and Drug Administration in 2015 and is widely available, “it would have been not only impractical but [also] unethical to do a randomized trial again given that we expected a long-term study out to at least year,” Januzzi explained, “and it would have provided confusing results if we had done an underpowered randomized trial and shown no differences between the two arms.”

Following the presentation, panelist Christopher O’Connor, MD (Inova Heart & Vascular Institute, Fairfax, VA), praised the “remarkable changes in NT-proBNP” and the usefulness of the data to clinicians. He then asked Januzzi: “Would you be willing to state here that the HFSA should strongly recommend a position that no device therapy should be implanted or offered until there is evidence that there is not a super response on this therapy at 6 or 12 months?”

Januzzi responded by saying that the data are an important first step toward answering a number of questions about sacubitril/valsartan’s benefits in this population.

And what was the percentage of patients in PROVE-HF who were initially eligible for an implantable cardioverter-defibrillator but then became ineligible based on reductions in their ejection fraction with sacubitril/valsartan? “Stay tuned,” Januzzi told a delighted audience. “We have those data under development, but the bottom line is, they are rather interesting and support your potential suggestion—hypothetically, maybe—that [the] Society really should start putting their big foot down about the importance of optimal medical care for our patients because they absolutely deserve it.”