April 24, 2026Journal of the American College of Cardiology23 citationsOpen Access
Sacubitril/Valsartan-Related Hypotension in Patients With Heart Failure and Preserved or Mildly Reduced Ejection Fraction
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Key Result
Sacubitril/valsartan increased the risk of hypotension compared with valsartan, particularly in patients with LVEF ≥60% who experienced substantially higher treatment-related risks (P-interaction=0.019).
Key Points
- This research aims to identify predictors of hypotension related to sacubitril/valsartan treatment and its clinical outcomes in heart failure patients.
- PARAGON-HF trial randomized chronic heart failure patients (≥45% LVEF) to sacubitril/valsartan or valsartan.
- Hypotension defined as systolic blood pressure <100 mm Hg, assessed with multivariable Cox models.
- Clinical outcomes evaluated using time-updated Cox models and Poisson regression for treatment and LVEF association.
- Out of 4,796 patients, 637 (13%) had hypotension, occurring more in the sacubitril/valsartan group (P < 0.001).
- Patients with hypotension had an increased risk of cardiovascular death (adjusted RR: 1.63; 95% CI: 1.27-2.09; P < 0.001).
- Higher LVEF correlated with a greater risk of hypotension after sacubitril/valsartan treatment.
Study Design
Type
RCT (n=4,796)
Multicenter
Yes
Structured PICO
Does sacubitril/valsartan increase the risk of hypotension compared to valsartan in patients with chronic heart failure and LVEF ≥45%, and what are the clinical implications?
P
Population
4,796 patients with chronic heart failure and left ventricular ejection fraction (LVEF) ≥45%
I
Intervention
Sacubitril/valsartan
C
Comparator
Valsartan
O
Outcome
Investigator-reported hypotension with a systolic blood pressure <100 mm Hgsafety
In patients with HF and LVEF ≥45%, sacubitril/valsartan increases the risk of hypotension compared to valsartan, particularly in those with LVEF ≥60%, which is associated with worse subsequent clinical outcomes.
Main Result
Effect estimate: RR 1.63 (95% CI 1.27-2.09)
p-value: p=<0.001
Abstract
Foà, A. et al. (2024) Sacubitril/Valsartan-related hypotension in patients with heart failure and preserved or mildly reduced ejection fraction. Journal of the American College of Cardiology , 83(18), pp. 1731-1739. (doi: 10.1016/j.jacc.2024.02.035 ) (PMID: 38537919 ) Full text not currently available from Enlighten. Background: Hypotension is a potential adverse effect of sacubitril/valsartan, but there are limited data regarding the predictors and implications of treatment-related hypotension in heart failure (HF) with mildly reduced and preserved ejection fraction. Objectives: We investigated predictors of treatment-associated hypotension, clinical outcomes after hypotension, and the relationship between left ventricular ejection fraction (LVEF) and incidence of hypotension in the PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial. Methods: PARAGON-HF randomized patients with chronic HF (≥45%) to sacubitril/valsartan or valsartan. Following randomization, hypotension was defined as investigator-reported hypotension with a systolic blood pressure <100 mm Hg. Predictors of hypotension were assessed using multivariable Cox models. Associations between hypotension and clinical outcomes were evaluated in time-updated Cox models. The relationship among treatment, LVEF, and incident rates of hypotension and clinical outcomes was estimated using Poisson regression models. Results: Of 4,796 patients in PARAGON-HF, 637 (13%) experienced hypotension, more frequently in the sacubitril/valsartan arm (P < 0.001). Following documented hypotension, patients had higher risk of cardiovascular death and total HF hospitalizations (adjusted RR: 1.63; 95% CI: 1.27-2.09; P < 0.001) and all-cause death (adjusted HR: 1.62; 95% CI: 1.28-2.05; P < 0.001). LVEF modified the association between sacubitril/valsartan and risk of hypotension (Pinteraction = 0.019) such that patients with LVEF ≥60% experienced substantially higher treatment-related risks of hypotension. Conclusions: In PARAGON-HF, a higher LVEF was associated with an increased risk of hypotension in patients treated with sacubitril/valsartan compared with valsartan. Because these subjects are also less likely to derive clinical benefit from sacubitril/valsartan, our data reinforce that the benefit/risk ratio favors the use of sacubitril/valsartan in patients with LVEF below normal, but not at higher LVEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction PARAGON-HF; NCT01920711) University Staff: Request a correction | Enlighten Editors: Update this record
Cite This Study
Foà et al. (2024) conducted an RCT in Heart failure with mildly reduced and preserved ejection fraction (n=4,796). sacubitril/valsartan vs. valsartan was evaluated on Cardiovascular death and total HF hospitalizations following documented hypotension (RR 1.63, 95% CI 1.27-2.09, p=<0.001). Sacubitril/valsartan increased the risk of hypotension compared with valsartan, particularly in patients with LVEF ≥60% who experienced substantially higher treatment-related risks (P-interaction=0.019).