Results of the PARAGON HF study, which were presented at ESC Congress 2019, reveal no significant benefit of sacubitril-valsartan compared to valsartan for heart failure with preserved ejection fraction in more than 4,500 patients.
Scott Solomon, MD
The results of the PARAGON-HF study presented at ESC Congress 2019 are shedding new light on the efficacy of sacubitril-valsartan for the prevention of heart failure (HF) and death from cardiovascular diseases in patients with HF with preserved ejection fraction.
While the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan had previously been shown to reduce risk of hospitalization for HF or death from cardiovascular causes among patients with HF and reduced ejection fraction the findings of the study, which was presented at the European Society of Cardiology (ESC) Congress 2019, revealed sacubitril-valsartan did not significantly reduce rate of total hospitalizations from HF and death from cardiovascular causes.
The Prospective Comparison of ARNI with Angiotensin-Receptor Blockers Global Outcomes in HF with Preserved ejection trial was a randomized, double-blind, active-comparator trial that included 4822 patients. Patients included in the study were at least 50 years of age, ejection fraction of 45% or higher, elevated natriuretic peptides, structural heart disease, and class II to IV HF — as defined by the New York Heart Association.
Patients included in the study were randomized in a 1:1 ratio to receive either sacubitril-valsartan (97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (160 mg twice daily). Investigators evaluated patients at trial visits every 4 to 16 weeks.
The primary outcome measure of the trial was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Secondary outcome measures included change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary, change from baseline to 8 months in NYHA class, the first occurrence of decline in renal function in a time-to-event analysis, and death from any cause in a time-to-first-event analysis.
Investigators noted renal decline was defined as a decrease in the estimated glomerular filtration of 50% or more, development of end-stage renal disease, or death due to renal failure.
During the course of the study, which had a median follow-up duration of 35 months, a total of 895 primary events (690 hospitalizations for HF and 204 deaths from cardiovascular causes) occurred in 526 patients in the sacubitril-valsartan group. In the valsartan group, a total of 1009 primary events (797 hospitalizations for HF and 212 deaths for cardiovascular causes) in 557 patients occurred (rate ratio, 0.87; 95% CI, 0.75 to 1.01 P=0.06).
Incidence of death from cardiovascular causes in the sacubitril-valsartan group was 8.5% and 8.9% in the valsartan group (HR, 0.95; 95% CI, 0.79 to 1.16).
Investigators pointed out NYHA class improved in 15% of patients in the sacubitril-valsartan group and in 12.6% in the valsartan group (OR, 1.45; 95% CI, 1.13 to 1.86) at 8 months. In regard to mean change in KCCQ score at 8 months, those in the sacubitril-valsartan group scored 1.0 point higher than those in the valsartan group.
Renal function worked in 1.4% of the sacubitril-valsartan group compared to 2.7% of the valsartan group (HR, 0.50; 95% CI, 1.13 to 1.86). Additionally, investigators noted patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema, but a lower incidence of hyperkalemia.
In 12 prespecified subgroup analyses, investigators noted evidence suggesting heterogeneity with the possible benefit of sacubitril-valsartan in those with lower ejection fraction and in women.
This study, “While the angiotensin receptor-neprilysin inhibitor sacubitril had previously been shown to reduce risk of hospitalization for HF or death from cardiovascular causes among patients with HF and reduced ejection fraction,” is published online in The New England Journal of Medicine and was presented at ESC Congress 2019.