Abstract Body (Do not enter title and authors here): Introduction: Since individual adherence/persistence studies for heart failure (HF) guideline-directed medical therapy (GDMT) have mainly focused on single classes or had limited sample sizes, providing inconclusive estimates, a comprehensive analysis is needed to understand the magnitude of the problem.

Hypothesis: Adherence and persistence to HF GDMT are suboptimal and are associated with increased risks of HF admission and mortality.

Aims: To generate estimates of real-world HF medication adherence and persistence and associated clinical outcomes.

Methods: We conducted a systematic review and meta-analysis, searching PubMed, EMBASE, and CINAHL for observational studies on adherence and persistence in HF GDMT from inception to 9/25/23. We evaluated bias using the Newcastle-Ottawa Scale. Primary outcomes were adherence and persistence rates using a restricted maximum-likelihood model. Adherence was summarized as the mean proportion of days covered (PDC) and medication possession ratio (MPR), proportion of patients with good adherence (PDC/MPR≥80%), and persistence. Secondary outcomes were all-cause mortality and HF readmission with summary hazard ratios (HRs) and 95% confidence intervals (CI) estimated. Heterogeneity and publication bias were assessed using Cochran’s Q, I squared statistics, funnel plots, and Egger's tests, while subgroup analyses explored variations across studies.

Results: The 48 studies included comprised 1,614,985 patients (mean age 71; 57% men). The overall mean PDC/MPR was 76%, with good adherence of 54%, and persistence rates of 60%. Renin-angiotensin-aldosterone system inhibitors had the highest mean PDC/MPR of 78%, good adherence of 56%, and persistence of 64%, while mineralocorticoid receptor antagonists (MRAs) had the lowest at 71%, 47%, and 49% respectively. Nonadherence/nonpersistence to GDMT was associated with a higher rate of mortality (HR 1.27 [95% CI 1.19–1.35]) and HF admission (HR 1.25 [95% CI 1.14-1.37]).

Conclusions: Suboptimal adherence/persistence to HF GDMT is common, with only half of patients showing good adherence. Given the association with worse clinical outcomes, clinicians should prioritize identifying barriers to and addressing nonadherence/nonpersistence to HF GDMT, particularly with MRAs.