“Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction”

N Engl J Med. 2019 Oct 24;381(17):1609-1620 [Full text]

Summary by Ravi Masson, MD


In PARADIGM-HF, Angiotensin and Neprilysin Inhibition (ARNI) was shown to be beneficial in heart failure with reduced ejection fraction (HFrEF).

Heart failure with preserved ejection fraction (HFpEF) is responsible for nearly half of all cases of heart failure in the United States. In contrast to HFrEF, data from clinical trials do not support any class I recommendations for medication therapy in HFpEF. The only medication to demonstrate positive phase II results in HFpEF was sacubitril/valsartan in the 2012 PARAMOUNT-HF trial. This study found that sacubitril/valsartan reduced NT-proBNP to a greater extent than valsartan at 12 weeks and was associated with improvement in NYHA class at 36 weeks. The PARAGON-HF trial sought to build on these results by analyzing the effectiveness of sacubitril/valsartan versus valsartan alone at improving clinical outcomes in HFpEF.

The study randomly assigned 4822 patients from 43 countries aged 50 and older with New York Heart Association (NYHA) class II to IV heart failure, left ventricular ejection fraction (LVEF) of 45% or higher, elevated level of natriuretic peptides, and structural heart disease (left ventricular hypertrophy or left atrial enlargement) to receive sacubitril–valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily).

Outcomes and Design

Primary Outcome

  • Composite of cardiovascular death and first and recurrent heart failure hospitalizations.

Secondary Outcomes, selected:

  • NYHA class change.
  • Worsening of renal function (development of end-stage renal disease or 50% decrease in glomerular filtration rate).
  • Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score.

Key Baseline Characteristics:

  • Average age: 73 years old
  • Female: 52%
  • NYHA Class II: 80%
  • Beta-blockers: 80%
  • ACE Inhibitor/ARB: 87%
  • Mineralocorticoid receptor antagonist: 26%


Primary Outcome:

There were 894 primary events in 526 patients in the sacubitril/valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.059). Given that the primary endpoint did not meet the predetermined cutoff for statistical significance, secondary outcomes were considered exploratory.

Secondary Outcomes:

There was a mean decrease in the KCCQ clinical summary score of 1.6 points in the sacubitril–valsartan group and 2.6 points in the valsartan group (between-group difference, 1.0 point; 95% CI, 0.0 to 2.1). Although there was a mean decrease in scores for both groups (lower score is worse), there was a higher percentage of patients in the sacubitril-valsartan group that had an improvement in the KCCQ score of 5 or more points.

With regards to NYHA class, more patients in the sacubitril/valsartan group showed improvement and less showed worsening of NYHA class at the prespecified 8 months of follow-up. Less patients in the sacubitril/valsartan group had worsening of renal function.

Prespecified subgroup Analysis:

Findings from the subgroup analysis suggested heterogeneity of treatment effect with possible benefit in women and patients with lower ejection fraction. There was a relative risk reduction of the primary endpoint in 27% in females and 22% in patients with ejection fraction between 45-57%.  


Patients randomized to sacubitril/valsartan were less likely to have worsening kidney function and hyperkalemia. However, they were more likely to have hypotension (systolic blood pressure less than 100 mmHg) and angioedema. Of note, there was no occurrence of airway compromise.


The primary composite outcome of total hospitalizations for heart failure and death from cardiovascular causes did not differ significantly between sacubitril/valsartan and valsartan, though there was a trend toward significance. There was a lower rate of hospitalizations for heart failure with sacubitril/valsartan than with valsartan but this difference was not statistically different. There was no statistically significant difference in the risk of death from cardiovascular causes.

Within the subgroup analysis, the authors reported a possible benefit in women and patients with an ejection fraction in the lower part (45 to 57%) of the range included in the study. The latter findings are consistent with post-hoc analyses of several other trials of medications with proven efficacy in HFrEF in which patients with mild systolic dysfunction (ejection fraction 40-55%) were observed to have lower rates of hospitalization events. Prior studies have shown that women have a higher left ventricular ejection fraction than men secondary to a higher stroke volume for a given end-diastolic volume. Proposed differences in maladaptive cardiac remodeling between genders may contribute to the heterogeneity observed in the subgroup analysis and warrants further investigation.

In their discussion, the authors hypothesized that the potential benefit of angiotensin receptor blockers (ARBs) in reducing heart failure hospitalizations (demonstrated in the CHARM-preserved trial) may have attenuated differences in outcomes between sacubitril/valsartan and valsartan. This trial was an active comparator study and not placebo controlled given the ethical implication of discontinuing valsartan in patients before randomization.


Although there was no significant difference in the primary composite endpoint, findings from this study warrant future research on the potential role of ARNI in patients with heart failure with ejection fractions that are below normal but not severely reduced.

Further reading:

1. Maladaptive left ventricular remodeling in women: An analysis from the Women’s Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction study
4. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.
5. Candesartan in Heart Failure—Preserved – CHARM-Preserved