Cardiac 'Shrinkage' on Sacubitril/Valsartan May Rival CRT in Reduced-EF Heart Failure: PROVE-HF

September 11, 2019

PARIS — A lot of the clinical benefit from sacubitril/valsartan (Entresto, Novartis) seen in its major heart failure trials likely stems from the drug's salutary effects on cardiac remodeling, which shows up as improved left ventricular (LV) structure and function.

That was one take from a yearlong observational study that also showed steep declines in natriuretic peptides that correlated with modest reverse-remodeling effects in its patients with heart failure and reduced ejection fraction (HFrEF).

The study, based on almost 800 patients put on sacubitril/valsartan for at least a year, "fills in necessary information that was lacking with respect to how the drug exerts its benefits," observed James L. Januzzi Jr, MD, Massachusetts General Hospital, Boston.

That is, he told | Medscape Cardiology, it strongly suggests that reverse cardiac remodeling was the likely mechanism behind the main findings of the randomized PARADIGM-HF study in 2014 comparing sacubitril/valsartan to enalapril in HFrEF.

In that trial, the newer drug was associated with reductions in levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP), the biomarker linked to myocardial stretch, and in the risk of cardiovascular (CV) death or heart failure hospitalization.

"Reverse cardiac remodeling underlies the benefits of most of the therapies that we deliver for patients with heart failure and reduced ejection fraction," Januzzi said.

The magnitude of the reverse-remodeling effect in PROVE-HF "is really quite substantial — almost half of the patients had a double-digit absolute percentage rise in ejection fraction."

Januzzi presented the results of the study, called PROVE-HF, here at ESC Congress 2019 and is lead author on its simultaneous publication September 2 in the Journal of the American Medical Association.

Importantly in the nonrandomized study, patients took sacubitril/valsartan on top of good guideline-recommended medical therapy, including beta blockers in 95% of the population. The 75% of patients on ACE inhibitors or angiotensin-receptor blockers (ARBs) at baseline went off those drugs before they started sacubitril/valsartan, which is the lone approved member of the angiotensin receptor–neprilysin inhibitor (ARNI) drug class.

Still, the mean left-ventricular ejection fraction (LVEF) improved by 5.2 absolute percentage points at 6 months and 9.4 at 12 months compared to the baseline average of about 28%.

"This is far and away more than what has been seen with other drugs," Januzzi said. On average, he said, medical therapies for HFrEF raise LVEF by only 3% to 5% in absolute points. But the much higher LVEF improvement on sacubitril/valsartan is similar to what can be expected from cardiac resynchronization therapy (CRT), "and CRT is the reverse-remodeling champion."

The current findings "strongly suggest that ARNI therapy can promote cardiac reverse remodeling in patients with HFrEF," observes Mark H. Drazner, MD, University of Texas Southwestern Medical Center, Dallas, in an accompanying editorial.

"As with beta-blockers and ACE inhibitors, it thus appears that the benefits of ARNI therapy on clinical outcomes in patients with HFrEF are mediated, at least in part, by their favorable effects on the adverse cardiac remodeling that characterizes this condition," he writes.

Still, "the absence of a control group remains a notable limitation and allows the possibility that some component of the reverse remodeling in PROVE-HF was due to another therapy, such as beta-blockers, started prior to study enrollment," he cautions.

While PROVE-HF "provides some insight on the mechanism of action regarding benefit, some of the findings were not as significant as one would have expected," Adrian F. Hernandez, MD, MHS, Duke University School of Medicine, Durham, North Carolina, told | Medscape Cardiology by email.

"This indicates that there are still other potential mechanisms that contribute to the benefits observed for sacubitril/valsartan, and why it's critical to have combination of evidence with outcomes," said Hernandez, who wasn't involved in PROVE-HF.

Sacubitril/valsartan in the study's 794 patients with HFrEF, of whom only 28.5% were women and virtually all of whom were in NYHA class 2-3, was uptitrated over about 60 days to a target dose of 97 mg sacubitril/103 mg valsartan twice daily as tolerated. The drug is a binary molecule that releases its constituent medications after administration.

The median NT-proBNP level was 816 pg/mL and 455 pg/mL at baseline and 12 months, respectively (P < .001), with overwhelmingly most of the drop taking place within the first 2 weeks.

The study's primary endpoint consisted of correlations between changes in log2–NT-proBNP concentrations and 12-month cardiac structural changes by echocardiography, specifically LV and left atrial measures of volume and function as well as E/e′, which quantifies diastolic function.

Coefficients of correlation for all measures were modest but significant at 12 months, in the approximate range of 0.26 to 0.40.

Table. Echocardiographic Changes on Sacubitril/Valsartan and Correlation with Natriuretic Peptide Levels


Change at 6 mo

Change at 12 mo

Correlation* (r) w/log2–NT-proBNP levels

LVEF (%)




LVEDVI (mL/m2)




LVESVI (mL/m2)




LAVI (mL/m2)




E/e′ ratio




*all significant at P <.001

LVEF = left ventricular ejection fraction

LVEDVI = left ventricular end-diastolic volume index

LVESVI = left ventricular end-systolic volume index

LAVI = left atrial volume index

E/e′ = ratio of early transmitral Doppler velocity to early diastolic annular velocity

In prespecified PROVE-HF analyses of several subgroups of patients that had been excluded from PARADIGM-HF — a limitation of that earlier study, some have said — correlations between NT-proBNP levels and cardiac structural and functional changes were similar to those seen in the entire cohort.

Those subgroups included the 24% of patients who entered the study with new-onset heart failure (9.8% of the total population) — that is, the diagnosis had been made within the past 60 days — or who were otherwise not on ACE inhibitors or ARBs before the study started.

"Those patients had an average absolute improvement in ejection fraction of 13%, so compared to the group as a whole, the new-onset patients reverse-cardiac-remodeled quite vigorously," Januzzi said.

The subgroups also included patients with baseline NT-proBNP levels below the threshold required for entry into PARADIGM-HF, and those who didn't reach the sacubitril/valsartan target dose at uptitration due to intolerance.

In all three subgroups, representing patients seen every day in clinical practice, Januzzi said, "We actually show comparable if not even greater reverse cardiac remodeling."

A separate study looking at the reverse-remodeling effects of sacubitril/valsartan compared with enalapril in 464 patients with HFrEF accompanied the PROVE-HF publication in JAMA. No significant change was observed over 12 weeks in aortic characteristic impedance (Zc), an index of central aortic stiffness based on carotid arterial tonometry and Doppler-echo readings of ventricular output.

But sacubitril/valsartan was associated with significant improvements, compared with enalapril, in some of the same echocardiographic remodeling measures that were tracked in PROVE-HF, although LVEF wasn't one of them, reported Akshay S. Desai, MD, MPH, Brigham and Women's Hospital, Boston, here at ESC Congress 2019.

Desai is also lead author on the simultaneous publication of the study, called EVALUATE-HF.

The purely mechanistic study, along with PROVE-HF, suggests that the functional benefits of sacubitril/valsartan are primarily cardiac rather than vascular, Januzzi said.

"There are clinical implications from these 2 studies," writes Drazner.

"Guidelines recommend that patients with new-onset HFrEF should have an implantable cardioverter-defibrillator [ICD] only after a trial of guideline-directed medical therapy," he observes. So, given PROVE-HF and EVALUATE-HF, "it stands to reason that ARNI should be implemented before determining a patient's eligibility for an implantable cardioverter-defibrillator."

For perspective, many initially ICD-eligible patients with HFrEF who achieve a 9.4-point improvement in LVEF as seen in PROVE-HF would no longer be suitable for a device. But how many?

Januzzi said such an analysis based on PROVE-HF patients is currently in the works. "The percentage of patients that went from ICD-eligible to ineligible was quite eye-opening, and we're in the process of developing those data for publication."

PROVE-HF was funded by Novartis Pharmaceuticals. Januzzi reports receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Disclosures for the other PROVE-HF authors are in the report. Desai reports receipt of research support from Alnylam, AstraZeneca, and Novartis; and consulting fees from AstraZeneca, Abbott, Alnylam, Biofourmis, Boehringer Ingelheim, Boston Scientific, DalCor Pharma, Novartis, and Regeneron.

Drazner has disclosed no relevant financial relationships.

JAMA . Published online September 2, 2019. PROVE-HF, EVALUATE-HF, Editorial

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