<![CDATA[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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