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Angiotensin Receptor Neprilysin Inhibition and Cardiovascular Outcomes Across the Kidney Function Spectrum: The
Finnian R Mc Causland1, Muthiah Vaduganathan2, Brian Claggett2
1Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA; Harvard Medical School, Boston, Massachusetts, USA.
Insights
Sacubitril/valsartan demonstrated greater benefits in reducing cardiovascular death and heart failure hospitalizations compared to valsartan, particularly in patients with lower estimated glomerular filtration rate (eGFR) and ejection fraction. These findings highlight the efficacy of sacubitril/valsartan in managing heart failure with preserved ejection fraction (HFpEF) across varying kidney function levels.
Area of Science:
- Cardiology
- Nephrology
- Pharmacology
Background:
- Reduced estimated glomerular filtration rate (eGFR) can impede the initiation of effective therapies for patients with heart failure (HF).
- Understanding treatment efficacy across different levels of kidney function is crucial for optimizing HF management.
Purpose of the Study:
- To evaluate whether the cardiovascular benefits of sacubitril/valsartan versus valsartan differ based on baseline kidney function in patients with HF with preserved ejection fraction (HFpEF).
- To identify specific patient subgroups within HFpEF who may experience the greatest benefit from sacubitril/valsartan therapy.
Main Methods:
- Analysis of the PARAGON-HF trial data, a global study involving 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45%.
- Patients were randomized to receive either sacubitril/valsartan or valsartan.
- Cox regression models were used to assess treatment effects on cardiovascular outcomes, stratified by region, and to examine differential effects based on baseline eGFR and LVEF.
Main Results:
- The mean eGFR at randomization was 67 mL/min/1.73 m²; 41% of participants had an eGFR <60 mL/min/1.73 m².
- Sacubitril/valsartan showed a greater reduction in the primary composite outcome (cardiovascular death and total HF hospitalizations) compared to valsartan, especially in patients with lower baseline eGFR (P-interaction = 0.07).
- The most pronounced treatment effect was observed in patients with eGFR ≤45 mL/min/1.73 m² and in those with LVEF ≤57% and eGFR ≤45 mL/min/1.73 m².
Conclusions:
- The PARAGON-HF trial demonstrated that sacubitril/valsartan provides significant benefits in reducing HF hospitalizations and cardiovascular death.
- These benefits were most evident in patients with lower baseline estimated glomerular filtration rate (eGFR) and lower ejection fraction.
- The findings support the use of sacubitril/valsartan in patients with HFpEF, including those with impaired kidney function.
Background:
Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF).
Objectives:
This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction.
Methods:
The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the effect of treatment on cardiovascular outcomes using Cox regression models, stratified by region, and assessed for differential treatment effects according to the baseline eGFR and ejection fraction.
Results:
At randomization, mean eGFR was 67 ± 19 mL/min/1.73 m2; 1,955 (41%) participants had an eGFR <60 mL/min/1.73 m2. Compared with valsartan, sacubitril/valsartan reduced the primary cardiovascular outcome (cardiovascular death and total HF hospitalizations) to a greater extent among those with lower baseline eGFR (P interaction = 0.07 for continuous eGFR), and was most pronounced for those with eGFR ≤45 mL/min/1.73 m2 (RR: 0.69; 95% CI: 0.51-0.94). The influence of eGFR on the treatment effect for cardiovascular death was nonlinear, with the most pronounced treatment effect for those with baseline eGFR <45 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.97). In further subgroup analyses according to LVEF and eGFR, the treatment effect for the primary outcome was most pronounced among those with LVEF ≤57% and eGFR ≤45 mL/min/1.73 m2 (HR: 0.66; 95% CI: 0.45-0.97).
Conclusions:
In the PARAGON-HF trial, the benefits of sacubitril/valsartan to reduce the frequency of HF hospitalizations and cardiovascular death were most apparent in patients with lower baseline eGFR and lower ejection fraction. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).
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