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. This 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).

Prespecified secondary outcomes included the individual components of the composite, QOL as assessed by KCCQ, improvement in NYHA Class, a renal composite outcome (renal death, ESRD, reduction in 50% of GFR) and all cause death) there was improvement in NYHA class; 15% in the sacubitril—valsartan group versus 12.6% in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86) and reduction in renal outcomes but not in quality of life or all cause death. In addition, of the 12 prespecified subgroups, 2 showed a possible treatment effect, with a suggestion of benefit in patients with an ejection fraction in the lower part (45 to 57%) of the range studied, and in women, who represent a high proportion of patients with heart failure with preserved ejection fraction. They made up 51.6% of the patients in this trial. In regard to the safety profile, patients in the sacubitril–valsartan group were more likely to have hypotension, however less likely to have increases in the creatinine/potassium levels than those in the valsartan group. In addition, angioedema occurred in 14 patients in the sacubitril–valsartan group and in 4 patients in the valsartan group after randomization had occurred.

Overall, Sacubitril–valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. However, there is a trend towards benefit observed by a non-significant reduction in hospitalizations from heart failure, and an improvement of NYHA class in the sacubitril—valsartan group as compared to the valsartan group.

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). This was an Important population – HFpEF comprises 50% of heart failure in the world today and has high rates of morbidity and mortality. To date no pharmacotherapy has shown improvement in HFpEF clinical outcomes. Inclusions of the patient reported outcome of quality of life using KCCQ which is a well validated tool. Women represented 51% of the study.

Study Weaknesses

The study patient population had a very low proportion of African American patients (2% in both groups) and therefore the extrapolation of data to this subset of patients is limited. Sacubitril–valsartan was tested against an active comparator, valsartan, since most patients were receiving a renin–angiotensin system inhibitor before enrollment. The potential benefit of angiotensin-receptor blockers in patients with heart failure with preserved ejection fraction (as suggested in prior trials) may have contributed to the smaller-than-anticipated treatment difference between groups. Interesting they did not use enalapril like PARADIGM-HF. Irbesartan and candesartan have been studied with some suggestion of benefit. More patients in the valsartan group were on spironolactone which may have biased towards the null hypothesis.

Next Steps/Clinical Perspective

This was a difficult population to study given number of comorbid conditions and heterogeneity among patients. Given these results it is possible that the guidelines for sacubitril-valsartan use should extend for patients with intermediate EF of 40-50%, where there is currently a lack of guidance to direct our therapies. The trend towards benefit seen in women indicates the need for further evaluation.