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Reconsidering Sacubitril/Valsartan Dose Strategies in HFrEF: Evidence and Implications from Real-World
Kaiyuan Cen1,2,3, Juanyu Lin4,5, Fatimah Ahmedy6,7
1Cardiovascular Department, Guidong People's Hospital of Guangxi Zhuang Autonomous Region, Wuzhou, Guangxi, China. cky163163@163.com.
Insights
Real-world use of sacubitril/valsartan for heart failure with reduced ejection fraction (HFrEF) shows submaximal doses may be effective. Response-guided titration is suggested over rigid adherence to target doses for better patient outcomes.
Area of Science:
- Cardiology
- Pharmacology
- Clinical Medicine
Background:
- Sacubitril/valsartan is crucial for heart failure with reduced ejection fraction (HFrEF) management.
- Real-world application of sacubitril/valsartan faces challenges regarding optimal dosing.
- Guidelines recommend target doses, but patient comorbidities and tolerability often impede dose escalation.
Purpose of the Study:
- To analyze the gap between randomized controlled trials (RCTs) and clinical practice for sacubitril/valsartan dosing in HFrEF.
- To evaluate the effectiveness of submaximal sacubitril/valsartan doses in real-world HFrEF patient populations.
- To advocate for a shift towards response-guided titration strategies for sacubitril/valsartan therapy.
Main Methods:
- Non-systematic narrative mini-review synthesizing key real-world studies.
- Analysis of a nationwide HFrEF cohort (n=3953) examining dose tertiles and clinical outcomes.
- Evaluation of a multicenter cohort (n=652) comparing mortality across different sacubitril/valsartan dosage levels.
Main Results:
- A nationwide HFrEF cohort found no significant difference in heart failure hospitalization or all-cause mortality risk across average dose tertiles.
- A multicenter cohort indicated lower all-cause mortality when escalating from very-low to intermediate sacubitril/valsartan doses.
- Incremental benefits of sacubitril/valsartan appeared heterogeneous beyond intermediate doses.
Conclusions:
- Submaximal doses of sacubitril/valsartan may provide comparable clinical benefits to target doses in HFrEF.
- A patient-centered, response-guided titration strategy is preferable to rigid adherence to guideline-recommended doses.
- Individualized pharmacotherapy prioritizing clinical effectiveness and safety is essential for HFrEF management with sacubitril/valsartan.
Abstract:
Despite its central role in the management of heart failure with reduced ejection fraction (HFrEF), the real-world use of sacubitril/valsartan remains fraught with uncertainty-particularly regarding optimal dosing. While guidelines emphasize uptitration to trial-validated target doses, emerging evidence suggests that submaximal doses may offer comparable clinical benefit across diverse patient populations. This commentary highlights the critical gap between randomized controlled trials and everyday practice, where comorbidities and tolerability frequently limit dose escalation. We synthesize key real-world studies that demonstrate consistent outcomes at lower or intermediate doses and challenge the prevailing "as high as tolerated" paradigm. Furthermore, we argue for a shift toward response-guided titration strategies based on biomarkers and functional outcomes, rather than rigid pharmacologic benchmarks. Recognizing the limitations of guideline rigidity, we advocate for a more nuanced, patient-centered approach to heart failure pharmacotherapy-one that prioritizes clinical effectiveness, safety, and individualized care-presented as a brief non-systematic narrative mini-review. In a nationwide HFrEF cohort (n = 3953), the adjusted risk of the composite of heart failure hospitalization or all-cause mortality did not differ across average-dose tertiles (highest vs lowest: HR 0.88, 95% CI 0.74-1.06). Conversely, a multicenter cohort (n = 652) showed lower all-cause mortality at 49/51 and 97/103 mg twice daily versus 24/26 mg (24/26 vs 49/51 mg: HR 1.67, 95% CI 1.07-2.59), suggesting that the most consistent gains occur when escalating from very-low to intermediate doses, with heterogeneous incremental benefit beyond that.
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