4. New Evidence for Angiotensin Receptor Neprilysin Inhibitors in Patients With HFpEF

HFpEF is rising in prevalence and is associated with significant morbidity and mortality.^[35],[36] Although evidence-based and mortality-reducing therapies exist for HFrEF, no therapies have shown a mortality benefit in those with an ejection fraction (EF) > 40%. In PARAMOUNT (Prospective Comparison of ARNI with ARB on Management of Heart Failure With Preserved Ejection Fraction) (NCT02371512), a phase II trial with patients with HFpEF, sacubitril/valsartan reduced N-terminal proeB-type natriuretic peptide levels and left atrial enlargement and also improved NYHA class compared with valsartan.^[37] Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) was a randomized double blind active comparator trial that tested the hypothesis that sacubitril/valsartan compared with valsartan would reduce the composite primary end point of total (first and recurrent) HF hospitalizations and cardiovascular death.^[38] After a run-in phase, patients were randomized to sacubitril/valsartan 97/103 mg twice daily vs valsartan 160 mg twice daily. Secondary end points included improvement in NYHA functional class at 8 months, changes in KCCQ clinical summary score at 8 months, time to first occurrence of worsening renal function, and time to all-cause mortality. Eligible patients were 50 years of age or older with symptomatic HF (NYHA II-IV) and an EF 45%. Inclusion criteria also specified treatment with diuretics for at least 30 days before enrollment as well as structural heart disease identified as left atrial enlargement or LV hypertrophy using echocardiography. Natriuretic peptide thresholds were stratified for the presence or absence of atrial fibrillation.^[39] In an attempt to capture the total burden of disease, the primary analysis incorporated total HF hospitalizations and cardiovascular death. In total 4822 patients were randomized, and treatment discontinuation for any reason other than death occurred in 25% of the sacubitril/valsartan arm vs 27% in the valsartan arm. The mean age in this trial was 73 years and 52% were female. Most patients had NYHA class II symptoms. Before randomization, 87% of patients in both arms were treated with either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). All baseline characteristics were balanced with the exception of mineralocorticoid receptor antagonists use, which was more common in the valsartan arm (27.1% vs 24.6%). In the PARAGON-HF trial, 1009 events were observed, equivalent to 14.6 per 100 patient-years in the valsartan arm in contrast to 894 events with a rate of 12.8 per 100 patient-years in the sacubitril/valsartan arm. This equated to a 13% relative risk reduction in the sacubitril/valsartan arm that did not meet clinical significance (95% CI, 0.75-1.01; P 1⁄4 0.06). The reduction in the primary end point was driven predominantly by a reduction in HF hospitalizations, which were reduced by 15% and also narrowly missed statistical significance (P 1⁄4 0.06). The KCCQ score was improved greater than 5 points more often in the sacubitril/valsartan group (odds ratio, 1.30; 95% CI, 1.04-1.61; P 1⁄4 0.02). Worsening renal function defined by a composite renal end point was significantly less frequent in the sacubitril/valsartan arm. A similar safety profile was seen in PARAGON-HF as was seen in previous studies of sacubitril/valsartan in patients with HFrEF.^[40] In a multivariable model of prespecified subgroups that incorporated all interaction terms, only sex and LV EF (LVEF) appeared to modify the treatment effect. Women achieved a significant 27% overall reduction in the primary end point, and patients at or below the trial median LVEF of 57% achieved a 22% reduction in primary end point. The P values for both were significant in multivariable interaction testing. In summary, in a comparison of sacubitril/valsartan with valsartan in HFpEF patients, PARAGON-HF showed a modest but nonsignificant 13% reduction in the primary outcome, which was driven by a reduction in first and recurrent HF hospitalizations. In secondary end point analysis, improvement in quality of life and renal function suggested potential benefits with sacubitril/valsartan compared with valsartan. The data further suggest heterogeneity in the treatment response with greater benefit in women and in individuals with a lower LVEF. Although these results are intriguing, they should be considered hypothesis-generating; important patient sub-groups with HFpEF might benefit from sacubitril/valsartan treatment, but further data are needed to clarify the effect of this therapy in patients with HFpEF. Key outstanding issues to be addressed include:

– More granular understanding of the biological and pathophysiological differences in HFpEF according to sex.

– Further analysis of the interaction between sex and LVEF.

– LVEF thresholds at which clinically important benefits of angiotensin receptor-neprilysin inhibition are seen.

– Possible heterogeneity of treatment effect according to etiology and/or phenotype.

The statistically negative results of the PARAGON-HF primary end point analysis preclude any recommendation for the general use of sacubitril/valsartan in patients with HFpEF. The PARAGON-HF trial has provided a number of interesting insights; further analysis and investigation might inform future specific recommendations on the management of HFpEF.