New Pooled Data Can Help Guide Implementation of Sacubitril/Valsartan, with Muthiah Vaduganathan, MD, MPH

The heart failure community welcomed new insight into the effects of sacubitril/valsartan (Entresto) on NT-proBNP and potential benefit on clinical outcomes with the release of data from the PARAGLIDE-HF trial at the European Society of Cardiology (ESC)’s 2023 Heart Failure Association (HFA) meeting.

Results of the trial, which were presented on May 21, 2023, demonstrated use of sacubitril/valsartan (Entresto) was associated with greater reduction in plasma NT-proBNP levels (ratio of change, 0.85 [95% CI, 0.73-0.999]; P=.049), but was also associated with increased risk of symptomatic hypotension (Odds Ratio, 1.73 [95% CI, 1.09-2.76]). Analysis of a secondary hierarchal outcome from the trial indicated the win ratio favored sacubitril/valsartan but failed to reach statistical significance (unmatched win ratio, 1.19 [95% CI, 0.93-1.52]; P = .16).¹

Following the formal debut of trial results in the meeting’s late-breaking session was a presentation of pooled data from the PARAGLIDE-HF and PARAGON-HF trials by Muthiah Vaduganathan, MD, MPH, cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital.

In the presentation, Vaduganathan offered insight a respecified primary analysis of participants from PARAGLIDE-HF and a “PARAGLIDE-like” subset from the PARAGON-HF trial, which was defined as those hospitalized for heart failure within the 30 days preceding initiation. Overall, the primary pooled analysis included 1088 patients and the pooled analysis of all participants included 5262 patients.²

"I think that the totality of evidence really helps guide implementation of sacubitril/valsartan, now, with a second randomized clinical trial showing clinical benefits not only on cardiovascular but also on kidney disease endpoints in this high-risk population who have heart failure with preserved [ejection fraction]," said Vaduganathan, in an interview with HCPLive.

In the primary pooled analysis, use of sacubitril/valsartan was associated with a significant reduction in total worsening heart failure events and cardiovascular death relative to valsartan for both the primary pooled analysis (Rate ratio [RR], 0.78 [95% CI, 0.61-0.99]; P = .042) and in the pooled analysts of all trial participants (RR, 0.86 [95% CI, 0.75-0.98]; P = .027).²

When assessing time to first nominal statistical significance, results indicated significance was reached by day 9 after randomization in apparent treatment benefits were greater in those with an ejection fraction equal to or less than 60% (RR, 0.78 [95% CI, 0.66-0.91]) relative to those with an ejection fraction greater than 60% (RR, 1.09 [95% CI, 0.86-1.40]; P = .021). Results also indicated use of sacubitril/valsartan was assize with a reduced rate of the renal composite endpoint in both the primary pooled analysis (Hazard ratio [HR], 0.67 [95% CI, 0.43-1.05]; P = .08) and the pooled analysis of all trial participants (HR, 0.60 [95% CI, 0.44-0.83]; P = .002).²

As part of our coverage of the ESC HFA meeting, our editorial team sat down with Vaduganathan, who is the co-host of HCPLive Cardiology’s Don’t Miss a Beat podcast, to learn more about PARAGLIDE-HF and the pooled analysis.

References:

1. Campbell P. Paraglide-HF offers further insight into Sacubitril/Valsartan in heart failure with elevated EF. HCP Live. May 22, 2023. Accessed May 22, 2023. https://www.hcplive.com/view/paraglide-hf-offers-further-insight-into-sacubitril-valsartan-in-heart-failure-with-elevated-ef.
2. Vaduganathan M, Mentz RJ, Claggett BL, et al. Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: a pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF [published online ahead of print, 2023 May 21]. Eur Heart J. 2023;ehad344. doi:10.1093/eurheartj/ehad344

Disclosures: Vaduganathan reports having received funding for consulting or research grants from Novartis, Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Cytokinetics, Lexicon, and others.