Digital and algorithmic strategies for guideline-directed medical therapy initiation and up-titration in adults with heart failure with reduced ejection fraction: a systematic review.

Background: Guideline-directed medical therapy (GDMT) reduces morbidity and mortality in heart failure with a reduced ejection fraction (HFrEF), yet underuse and suboptimal up-titration remain common. Digital and algorithmic strategies are increasingly being used to address these gaps, but their comparative effectiveness remains uncertain. Methods: This systematic review followed the PRISMA 2020 guidance and was prospectively registered with PROSPERO (CRD420251268580). PubMed, Embase, and Scopus were searched from inception through 26 December 2025. Randomized and comparative studies enrolling adults with HFrEF were eligible if they evaluated digital, algorithm-based, or telemonitoring strategies designed to facilitate GDMT initiation, titration, or optimization versus usual care. Results: Six randomized comparative trials involving 3706 participants were included. Interventions comprised provider-facing electronic health record alerts and digitally enabled remote titration or telemonitoring pathways. Five of the six trials showed improvements in medication-optimization outcomes; the single neutral trial was a provider-facing alert intervention that showed no difference in GDMT prescribing at hospital discharge. Remote pathway-based strategies demonstrated the largest effects, including higher titration completion (82.1% vs 53.8% at 6 months; an absolute difference of approximately 28 percentage points) and greater improvements in therapy scores. Alert-based interventions showed mixed findings, including no difference in overall GDMT class prescribing at discharge in one inpatient trial (34% vs 34%). Meta-analysis was not performed because of substantial heterogeneity in interventions, outcomes, and reporting formats. Conclusion: Digital strategies appear to improve GDMT optimization in HFrEF, particularly when embedded within structured care pathways that enable repeated reassessment and protocol-driven titration. Passive alerts alone appear less effective. Standardized outcome measures and trials evaluating clinical endpoints are needed.