Key result
Higher sacubitril/valsartan doses linked to ~75% lower mortality versus low doses in HFrEF.
Why the study?
Real-world dosing of sacubitril/valsartan in HFrEF often falls below guideline recommendations, motivating an evaluation of the association between sacubitril/valsartan dose categories and clinical prognosis.
Does achieving higher or target doses of sacubitril/valsartan reduce heart failure hospitalization and mortality compared to lower doses in patients with HFrEF?
Systematic Review (n=7,814)
Yes
Does achieving higher or target doses of sacubitril/valsartan reduce heart failure hospitalization and mortality compared to lower doses in patients with HFrEF?
Real-world evidence across 7,814 HFrEF patients demonstrates that achieving higher or target doses of sacubitril/valsartan is consistently associated with reduced mortality and heart failure hospitalization rates compared to lower doses, supporting individualized dose optimization.
Supports higher sacubitril/valsartan dosing in HFrEF; extends observational data but leaves open randomized confirmation of benefit.
Heart failure with reduced ejection fraction (HFrEF) remains a major cause of mortality and hospitalizations. While sacubitril/valsartan is essential, real-world dosing often falls below guideline recommendations. This systematic review evaluated the association between sacubitril/valsartan dose categories and clinical prognosis across seven observational studies (N=7,814). Research findings indicate that variations in sacubitril/valsartan dosage are associated with differences in clinical outcomes, influenced by tolerability and treatment preferences. High-dose therapy (400 mg daily) was associated with a 75% lower all-cause mortality and 77% lower cardiovascular mortality compared with low doses. Conversely, the lowest dose (24/26 mg twice daily) exhibited a 2.56-fold higher mortality risk versus target doses. Reaching ≥50% of the target dose was associated with a 70% lower mortality risk in patients aged <65 years (HR 0.30) and 49% in those aged 65–74 years (HR 0.51). Target doses were also associated with a 66% lower rate of composite death and hospitalization across hemodynamic profiles. Initiating therapy at a very low dose (25 mg twice daily) in high-risk patients appeared well-tolerated, yielding outcomes comparable to standard initiation. Real-world evidence demonstrates that higher sacubitril/valsartan doses are consistently associated with improved survival and reduced hospitalization rates, underscoring the importance of individualized dose optimization.
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Putri et al. (2026) conducted a systematic review in Heart failure with reduced ejection fraction (HFrEF) (n=7,814). Sacubitril/valsartan dose optimization (target/high or intermediate doses) vs. Low or sub-target dose (24/26 mg BID or <200 mg/day) or discontinuation was evaluated on Heart failure hospitalization, rehospitalization, and mortality across dose categories (qualitative synthesis; no pooled meta-analysis performed). Higher sacubitril/valsartan doses (400 mg/day) were associated with up to 75% lower all-cause mortality (HR 0.25) and 66% lower composite death/HF hospitalization (HR 0.34) versus low doses in HFrEF.
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