Entresto Halves Renal Events in Preserved EF Heart Failure Patients

Mitchel L. Zoler, PhD

October 14, 2020

Patients with heart failure with preserved ejection fraction (HFpEF) who received sacubitril/valsartan in the PARAGON-HF trial had significant protection against progression of renal dysfunction in a prespecified secondary analysis.

The 2419 patients with HFpEF who received sacubitril/valsartan (Entresto) had half the rate of the primary adverse renal outcome compared with the 2403 patients randomized to valsartan alone in the comparator group, a significant difference, according to the results published online September 29 in Circulation by Finnian R. McCausland, MBBCh, and colleagues.

In absolute terms, sacubitril/valsartan treatment, an angiotensin-receptor/neprilysin inhibitor (ARNI), cut the incidence of the combined renal endpoint — renal death, end-stage renal disease, or at least a 50% drop in estimated glomerular filtration rate (eGFR) — from 2.7% in the control group to 1.4% in the sacubitril/valsartan group during a median follow-up of 35 months.

The absolute difference of 1.3% equated to a number needed to treat of 51 to prevent one of these events.

Also notable was that renal protection from sacubitril/valsartan was equally robust across the range of baseline kidney function.

"An Important Therapeutic Option"

The efficacy "across the spectrum of baseline renal function" indicates treatment with sacubitril/valsartan is "an important therapeutic option to slow renal-function decline in patients with heart failure," write McCausland, a nephrologist at Brigham and Women's Hospital in Boston, Massachusetts, and colleagues.

The authors' conclusion is striking, as currently no drug class has produced clear evidence for efficacy in HFpEF.

On the other hand, the PARAGON-HF trial that provided the data for this new analysis was statistically neutral for its primary endpoint — a reduction in the combined rate of cardiovascular death and hospitalizations for heart failure — with a P value of 0.06 and 95% confidence interval of 0.75 - 1.01.

"Because this difference [in the primary endpoint incidence between the two study group] did not meet the predetermined level of statistical significance, subsequent analyses were considered to be exploratory," noted the authors of the primary analysis of PARAGON-HF (N Engl J Med. 2019;381:1609-1620), as reported by Medscape Medical News.

Despite this limitation in interpreting secondary outcomes from the trial, the new report of a significant renal benefit "opens the potential to provide evidence-based treatment for patients with HFpEF," comment Sheldon W. Tobe, MD, and Stephanie Poon, MD, in an editorial accompanying the latest analysis (Circulation. 2020;142:1246-1248).

"At the very least, these results are certainly intriguing and suggest that there may be important patient subgroups with HFpEF who might benefit from using sacubitril/valsartan," they emphasize.

First Large Trial to Show Renal Improvement in HFpEF

The editorialists' enthusiasm for the implications of the new findings relate in part to the fact that "PARAGON-HF is the first large trial to demonstrate improvement in renal parameters in HFpEF," they note.

"The finding that the composite renal outcome did not differ according to baseline eGFR is significant and suggests that the beneficial effect on renal function was indirect, possibly linked to improved cardiac function," say Tobe, a nephrologist, and Poon, a cardiologist, both at Sunnybrook Health Sciences Centre in Toronto, Ontario, Canada.

PARAGON-HF enrolled 4822 HFpEF patients at 848 centers in 43 countries, and the efficacy analysis included 4796 patients.

The composite renal outcome was mainly driven by the incidence of a 50% or greater drop from baseline in eGFR, which occurred in 27 patients (1.1%) in the sacubitril/valsartan group and 60 patients (2.5%) who received valsartan alone.  

The annual average drop in eGFR during the study was 2.0 mL/min/1.73m2 in the sacubitril/valsartan group and 2.7 mL/min/1.73m2 in the control group.

Although the heart failure community was disappointed that sacubitril/valsartan failed to show a significant benefit for the study's primary outcome in HFpEF, the combination has become a mainstay of treatment for patients with HFpEF based on its performance in the PARADIGM-HF trial (N Engl J Med. 2014;371:993-1004).  

And despite the unqualified support sacubitril/valsartan now receives in guidelines and its label as a foundational treatment for HFpEF, the formulation has had a hard time gaining traction in US practice, often because of barriers placed by third-party payers.

PARAGON-HF was sponsored by Novartis, which markets sacubitril/valsartan (Entresto). McCausland had reported no relevant financial relationships. Tobe has reported participating on a steering committee for Bayer Fidelio/Figaro studies and being a speaker on behalf of Pfizer and Servier. Poon has reported being an advisor to Novartis, Boehringer Ingelheim, and Servier.

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