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Randomized Controlled Trial
. 2025 May;27(5):779-787.
doi: 10.1002/ejhf.3515. Epub 2024 Nov 19.

Effects of sacubitril/valsartan according to background beta-blocker therapy in patients with heart failure and reduced ejection fraction: Insights from PARADIGM-HF

Sharmistha Datta Gupta  1 , Jawad H Butt  1   2   3 , Eoghan G M McMurray  1 , Atefeh Talebi  1 , Shingo Matsumoto  1 , Adel R Rizkala  4 , Alasdair D Henderson  1 , Akshay S Desai  5 , Martin Lefkowitz  2   4 , Milton Packer  6 , Jean L Rouleau  7 , Scott D Solomon  5 , Karl Swedberg  8 , Michael R Zile  9   10 , Pardeep S Jhund  1 , John J V McMurray  1 ; PARADIGM‐HF Investigators and Committees
Affiliations
Randomized Controlled Trial

Effects of sacubitril/valsartan according to background beta-blocker therapy in patients with heart failure and reduced ejection fraction: Insights from PARADIGM-HF

Sharmistha Datta Gupta et al. Eur J Heart Fail. 2025 May.

Abstract

Aims: Beta-blockers may inhibit neprilysin activity and conversely, neprilysin inhibition may have a sympatho-inhibitory action. Consequently, sacubitril/valsartan may have a greater effect in patients not receiving a beta-blocker compared to those treated with a beta-blocker.

Methods and results: We examined the effect of sacubitril/valsartan compared to enalapril on outcomes according to background beta-blocker treatment in the 8399 patients with heart failure with reduced ejection fraction enrolled in PARADIGM-HF. The primary outcome was time to first heart failure hospitalization or cardiovascular death. Compared to the 7811 patients taking a beta-blocker, the 588 patients not receiving a beta-blocker were older, more frequently female, but had a similar mean left ventricular ejection fraction and New York Heart Association class distribution, with little difference in N-terminal pro-B-type natriuretic peptide. Patients not taking beta-blockers had a higher rate of the primary endpoint than those taking beta-blockers. The benefit of sacubitril/valsartan on the primary endpoint was evident in both the no beta-blocker subgroup (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.45-0.82) and the beta-blocker subgroup (HR 0.82, 95% CI 0.75-0.90; p-interaction = 0.06). The respective HRs for cardiovascular death were 0.47 (95% CI 0.32-0.69) versus 0.84 (95% CI 0.75-0.95; p-interaction <0.01) and for HF hospitalization 0.76 (95% CI 0.51-1.12) versus 0.80 (95% CI 0.71-0.90; p-interaction = 0.73). For all-cause death, the HR in the no beta-blocker group was 0.50 (95% CI 0.36-0.71) compared to 0.89 (95% CI 0.80-0.99) in the beta-blocker group (p-interaction <0.01). Safety outcomes related to sacubitril/valsartan versus enalapril did not differ according to background beta-blocker use.

Conclusion: Sacubitril/valsartan may be more effective than enalapril in reducing the risk of death in patients not treated with a beta-blocker compared to those treated with a beta-blocker, but is effective regardless of beta-blocker use.

Clinical trial registration: ClinicalTrials.gov NCT01035255.

Keywords: Beta‐blocker; Clinical trial; Heart failure with reduced ejection fraction.

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