Reconsidering Sacubitril/Valsartan Dose Strategies in HFrEF: Evidence and Implications from Real-World...

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.