Study Summary

The angiotensin receptor–neprilysin inhibitor sacubitril-valsartan has been shown to reduce risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure with reduced ejection fraction (HFrEF) compared to ACE inhibitors and angiotensin receptor blockers, however its effect on patients with heart failure with preserved ejection fraction (HFpEF) is unclear. The PARAGON-HF study randomly assigned patients with ejection fraction of 45% or higher and NYHA class II to IV heart failure symptoms to receive sacubitril—valsartan versus valsartan alone. The primary outcome was a composite of hospitalizations for heart failure and death from cardiovascular causes, and patients on sacubitril-valsartan did not experience a statistically significant reduction in this composite compared to patients on valsartan HR 0.87 (95% confidence interval [CI], 0.75 to 1.01; P=0.06).

However, in this pre-specified subgroup analysis, the team examined outcomes according to sex in the PARAGON-HF trial. Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. When compared to the male subgroup, women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction=0.017. The main benefit from sacubitril-valsartan was due to reduction in heart failure hospitalization. The improvement in NYHA class and renal function with sacubitril-valsartan was similar in women and men, however the improvement in KCCQ-CSS was less in women than in men.

As compared with valsartan alone, sacubitril – valsartan seemed reduce the risk of heart failure hospital admissions in woman. This benefit was not seen in men. This study does not provide a mechanism for this disparity of finding.

Commentary

Study Strengths

The study was a randomized multicenter double-blind trial. It has a Clear definition of HFpEF – (50 years or older with signs and symptoms of heart failure, NYHA class II to IV, an ejection fraction of 45% or higher within the previous 6 months, elevated level of natriuretic peptides, evidence of structural heart disease and on diuretic therapy). The sub-group analysis was an important population – HFpEF comprises 50% of heart failure in the world today and has high rates of morbidity and mortality, with women representing over half of those with heart failure and preserved ejection fraction. To date, no pharmacotherapy has shown improvement in HFpEF clinical outcomes, and given the clinically significant reduction in heart failure hospitalizations for women, treatment with this medication seems appropriate.

Study Weaknesses

This is a subgroup analysis and therefore the randomization may not have been preserved between the two study groups. In addition, when compared to the male sub-group, women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men, which could confound the conclusion that these affects were gender specific. Also, the specific reason for this apparent benefit in woman is unknown and therefore needs further study to evaluate whether the sacubitril-valsartan medicine is beneficial over valsartan alone.

Next Steps/Clinical Perspective

Given these results, it is possible that the guidelines for sacubitril-valsartan use should extend for women with heart failure and preserved ejection fraction, where there is currently a lack of guidance to direct our therapies. In addition, further studies to strengthen the observed results during this trial need to be analyzed. Lastly, this study indicates that our treatments for heart failure may need to be tailored based on gender. It provides an avenue for further investigation into this arena.