Sacubitril/valsartan for HFpEF reduces NT-proBNP, but no effect on functional outcomes
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The PARALLAX trial of sacubitril/valsartan for HF with preserved ejection fraction met one of its two co-primary endpoints, showing a reduction in NT-proBNP, but no additional benefit on 6-minute walk distance and functional class.
PARALLAX was a prospective, 24-week, randomized, active-controlled, double-blind trial that enrolled 2,572 patients with symptomatic HF with mid-range or preserved EF and elevated NT-proBNP levels. The mean age was 73 years, 51% were women, 87% were white and mean left ventricular EF at baseline was 56%. Patients were randomly assigned to sacubitril/valsartan (Entresto, Novartis) or optimal individualized medical therapy, which could consist of enalapril, valsartan or placebo if they were not taking a renin-angiotensin system inhibitor.
Main results
The co-primary endpoints — change in NT-proBNP from baseline to 12 weeks and change in 6-minute walk distance from baseline to 24 weeks — were chosen to assess HF severity and functional capacity.
After 12 weeks, sacubitril/valsartan significantly reduced NT-proBNP compared with individualized medical therapy (adjusted geometric mean ratio = 0.84; 95% CI, 0.8-0.88; P < .0001), according to results reported during a Hot Line session at the European Society of Cardiology Congress.
Sacubitril/valsartan did not significantly impact 6-minute walk distance from baseline to 24 weeks compared with individualized medical therapy (adjusted mean change from baseline, 9.7 m vs. 12.2 m, respectively; adjusted mean difference, 2.5 m; 95% CI, 8.53 to 3.53; P = .42).
“We did miss this key component of the primary endpoint, but still I do consider that the consistent reduction in NT-proBNP is promising,” Burkert Pieske, MD, director of the department of internal medicine-cardiology at Charité University Medicine and German Heart Center in Berlin, said during a press conference.
“A biomarker is, in principle, not enough to decide on whether or not to treat a patient with this specific disease with a drug, but in the light that we have no specific therapies for HFpEF after years and years of investigations, we should take all information that we can get into consideration. Here, this is a large trial with 2,500 patients, extremely well characterized, and with this study we can see the significant and impressive reduction in NT-proBNP, an established marker for heart failure disease severity and prognosis,” Pieske said.
“That adds to a large number of previous studies where, despite proven outcome benefit, no improvements on 6-minute walk distance could be demonstrated with other drugs and medications for heart failure, specifically for HFpEF,” Pieske told Healio. “The discussion here at the moment is that 6-minute walk distance may not be a good readout for HFpEF trials, at least not for pharmacological interventions.”
Treatment with sacubitril/valsartan had no additional benefit on NYHA functional class at 24 weeks from baseline to 24 weeks (OR for sacubitril/valsartan vs. individualized medical therapy = 1.01; 95% CI, 0.75-1.37).
Researchers observed a significant improvement in Kansas City Cardiomyopathy Questionnaire score after 4 weeks in the sacubitril/valsartan group compared with the individualized medical therapy group, but this difference decreased over time and was no longer significant at 24 weeks (least square means change from baseline, 12.4 vs. 11.8, respectively; least square means of difference, 0.52; 95% CI, 0.93 to 1.97; P = .48).
In a post-hoc analysis of adverse events, patients assigned sacubitril/valsartan had a significant reduction in first HF hospitalization at 24 weeks compared with the individualized medical therapy group (HR = 0.49; 95% CI, 0.3-0.81).
“This is an interesting signal in this patient population,” Pieske said during the press conference.
The researchers also observed a reduction in the composite of time of death from cardiac failure or HF hospitalization with sacubitril/valsartan (HR = 0.64; 95% CI, 0.42-0.97).
Further evidence in HFpEF
Pieske said the PARALLAX results “are consistent with the findings from PARAGON-HF and provide further evidence for the potential benefits of sacubitril/valsartan in patients with HF and mid-range or preserved ejection fraction.”
As Healio previously reported, in PARAGON-HF, which was presented at the 2019 ESC Congress, sacubitril/valsartan did not reduce the primary outcome of hospitalizations for HF and death from CV causes, but secondary endpoints showed improvements in NYHA functional class, KCCQ score and worsening renal function.
“The inclusion and exclusion criteria [in PARALLAX] were very similar to the PARAGON-HF study,” Pieske said during the press conference. “The main exception was that [PARALLAX] recruited patients with an ejection fraction higher than 40% and in PARAGON-HF, the outcomes study, it was 45% or higher. Another difference was that PARAGON-HF tested the effects of sacubitril/valsartan vs. valsartan.”
Further, Pieske told Healio, “[this] correlates, confirms and expands knowledge from PARAMOUNT, the early phase 2 study, that there is a clear reduction in NT-proBNP as early as after 4 weeks of treatment initiation, which continues over 6 months with sacubitril/valsartan. That was irrespective of the comparator. ... We are now confident that irrespective of the previous medication, if you take that surrogate marker for outcomes, sacubitril/valsartan may [be beneficial].
HFpEF remains a challenging condition that lacks approved treatments.
“PARALLAX adds to the growing body of evidence highlighting the potential benefits of Entresto in HFpEF, a life-threatening condition that affects about 3 million people in the U.S. and lacks approved treatments,” David Soergel, MD, global head of cardiovascular, renal and metabolic drug development for Novartis, stated in a company press release.
During a discussion of the trial, Rudolf De Boer, MD, cardiologist and head of experimental cardiology at University of Groningen in the Netherlands, emphasized this “difficult-to-manage” patient population.
“If one intends to use a [renin–angiotensin system] blocker in patients with HFpEF or HF [with midrange] EF, then sacubitril/valsartan is likely the most effective agent,” De Boer said.
Additional analyses of the PARALLAX trial are planned, Pieske told Healio.
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Pieske B. Hot Line 2. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 1, 2020 (virtual meeting).
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