Patients with an ejection fraction (EF) greater than 40% who were stabilized after recent worsening or de novo heart failure (HF) had a greater reduction in natriuretic peptides and less worsening renal function, but a higher rate of hypotension over 8 weeks with sacubitril-valsartan (Entresto) versus valsartan (Diovan) in the PARAGLIDE-HF trial.
A subgroup analysis showed evidence of a larger treatment effect among those with an EF of 60% or less, said Robert Mentz, MD, of the Duke Clinical Research Institute, Durham, N.C.
Dr. Robert J. Mentz
Dr. Mentz presented the findings at the Heart Failure Association of the European Society of Cardiology (HFA-ESC) scientific sessions. The study was also published online simultaneously in the Journal of the American College of Cardiology.
“Next steps will involve further assessment of the cardiovascular and renal benefits, as well as further exploration of the symptomatic hypotension that we observed,” Dr. Mentz said in an interview.
Meanwhile, he said, “clinicians should be aware of these new data – specifically, the incremental reduction in natriuretic peptide level, compared with valsartan, and potential benefits on cardiovascular and renal events,” particularly in those with an EF greater than 40% to 60% or less.
Larger benefit for EF > 40% to < 60%
PARAGLIDE-HF was a double-blind, randomized controlled trial with 466 patients with EF greater than 40% enrolled within 30 days of a worsening HF event. The median age was 71 years, 52% were women, and 22% were Black.
The trial was a follow-up to PARAGON-HF, which had shown that, in patients with an EF of at least 45%, sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for HF or death from cardiovascular causes, compared with valsartan.
The primary endpoint for PARAGLIDE was the time-averaged proportional change in N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) from baseline through weeks 4 and 8, as in the PIONEER-HF trial. That trial showed that among patients hospitalized for acute decompensated HF with reduced EF (< 40%), the angiotensin receptor/neprilysin inhibitor (ARNI) led to a greater reduction in NT-proBNP concentration than the angiotensin receptor blocker (ARB).
Similarly, for PARAGLIDE, the time-averaged reduction in NT-proBNP was greater with sacubitril-valsartan, with a change ratio of 0.85 (15% greater reduction).
A secondary hierarchical outcome for PARAGLIDE, using the win ratio, consisted of time to cardiovascular death, number and timing of HF hospitalizations, number and timing of urgent HF visits, and time-averaged proportional change in NT-proBNP from baseline to weeks 4 and 8.
The hierarchical outcome favored sacubitril-valsartan, but was not significant (unmatched win ratio, 1.19).
As noted, sacubitril-valsartan reduced worsening renal function, compared with valsartan (odds ratio, 0.61), but increased symptomatic hypotension (OR, 1.73).
“We will work to better characterize the hypotension events that were observed to help identify those patients at greater risk and to provide further clarity around the timing and implications of these events,” Dr. Mentz said in an interview.
The team hypothesized that such events may be prevented by optimizing volume status and background therapies commonly used to treat hypertension in these patients.
“For instance,” Dr. Mentz suggested, “calcium channel blockers like amlodipine could be dose reduced or discontinued in patients with lower baseline blood pressures to better support sacubitril/valsartan initiation and titration.”
He highlighted the subgroup analysis showing evidence of a larger treatment effect in study patients with an EF of 60% or less for the NT-proBNP change (0.78) and the hierarchical outcome (win ratio, 1.46).
“These data may influence future guidance for sacubitril-valsartan in HF with EF greater than 40%, regardless of HF chronicity [acute or chronic vs. de novo] and treatment setting [hospital vs. clinic],” Dr. Mentz concluded.