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Background: The contribution of clinical inertia to suboptimal guideline-directed medical therapy (GDMT) for patients with heart failure with reduced ejection fraction (HFrEF) remains unclear., Objectives: This study examined reasons for GDMT nonintensification and characterized clinical inertia., Methods: In this secondary analysis of EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction), a randomized clinical trial evaluating a patient-activation tool on GDMT utilization, we performed a sequential, explanatory mixed-methods study. Reasons for nonintensification among 4 medication classes were assigned according to an expanded published taxonomy using structured chart reviews. Audio transcripts of clinic encounters were analyzed to further characterize nonintensification reasons. Integration occurred during the interpretation phase., Results: Among 292 HFrEF patients who completed a cardiology visit, 185 (63.4%) experienced no treatment intensification, of whom 90 (48.6%) had at least 1 opportunity for intensification of a medication class with no documented contraindication or barriers (ie, clinical inertia). Nonintensification reasons varied by medication class, and included heightened risk of adverse effects (range 18.2%-31.6%), patient nonadherence (range 0.8%-1.1%), patient preferences and beliefs (range 0.6%-0.9%), comanagement with other providers (range 4.6%-5.6%), prioritization of other issues (range 15.6%-31.8%), multiple categories (range 16.5%-22.7%), and clinical inertia (range 22.7%-31.6%). A qualitative analysis of 32 clinic audio recordings demonstrated common characteristics of clinical inertia: 1) clinician review of medication regimens without education or intensification discussions; 2) patient stability as justification for nonintensification; and 3) shorter encounters for nonintensification vs intensification., Conclusions: In this comprehensive study exploring HFrEF prescribing, clinical inertia is a main contributor to nonintensification within an updated taxonomy classification for suboptimal GDMT prescribing. This approach should help target strategies overcoming GDMT underuse., Competing Interests: Funding Support and Author Disclosures This project/publication is supported in part by National Institutes of Health/NCATS Colorado CTSA Grant Number UL1 TR002535. Contents are the authors’ sole responsibility and do not necessarily represent official National Institutes of Health views. Dr Swat has received funding from the National Institutes of Health T32 Training Grant 5T32-HL-007822-22. Dr Allen has received grant funding from the American Heart Association, National Institutes of Health, and Patient-Centered Outcomes Research Institute; and has received consulting fees from Abbott, ACI Clinical, Amgen, Boston Scientific, Cytokinetics, Novartis, Quidel, and UpToDate. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)