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Objectives: The aim of this study was to examine patterns of care and clinical outcomes among patients with heart failure with reduced ejection fraction (HFrEF) in the United States and Canada., Background: In the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment) trial, the use of N-terminal pro-B-type natriuretic peptide-guided titration of guideline-directed medical therapy (GDMT) was compared with usual care alone for patients with HFrEF in the United States and Canada. It remains unknown whether the country of enrollment had an impact on outcomes or GDMT use., Methods: A total of 894 patients at 45 sites across the United States and Canada with HFrEF (ejection fraction ≤40%) were enrolled in the trial. Kaplan-Meier survival estimates stratified by country of enrollment were developed for the trial outcomes, and log-rank testing was compared between the groups. GDMT use and titration were also compared., Results: U.S. patients were more likely to be younger, to be Black, to have higher body mass index, and to have histories of defibrillator placement or sleep apnea. Use of β-blockers was significantly higher in Canada at baseline (99.3% vs. 94.0%; p = 0.01) and 6 months (99.0% vs. 94.1%; p = 0.04), and use of mineralocorticoid receptor antagonists was higher in Canada at 6 months (68.3% vs. 55.1%; p = 0.01). Canadian patients were less likely to experience the primary study endpoint (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.45 to 0.93; p = 0.01) due to decreased rates of HF hospitalization (HR: 0.57; 95% CI: 0.38 to 0.86; p = 0.003). The differences in outcomes were driven by increased heart failure hospitalization among U.S. Black patients., Conclusions: In GUIDE-IT, patients with HFrEF in Canada were significantly less likely to be hospitalized for heart failure. Differences in GDMT use, along with differences in sociodemographics and care delivery structures, may contribute to these differences, highlighting the importance of increasing diversity in clinical trials. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840)., Competing Interests: Funding Support and Author Disclosures The GUIDE-IT trial was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Additional substudies were supported by Roche Diagnostics. The sponsors had no role in the design and conduct of the present study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Dr. Januzzi is a trustee of the American College of Cardiology; has received grant support from Roche Diagnostics, Novartis Pharmaceuticals, and Applied Therapeutics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical endpoint committees and data and safety monitoring boards for Abbott, AbbVie, Amgen, CVRx, Janssen, MyoKardia, and Takeda. Dr. Desai works under contract with the Centers for Medicare and Medicaid Services to develop and maintain performance measures used for public reporting and pay-for-performance programs; and has received research grants and consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, The Medicines Company, Relypsa, Novartis, and SCPharmaceuticals. Dr. Felker has received research grants from the National Heart, Lung, and Blood Institute, the American Heart Association, Amgen, Bayer Merck, Cytokinetics, and Myokardia; has acted as a consultant to Novartis, Amgen, Bristol Myers Squibb, Cytokinetics, Medtronic, Cardionomic, Innolife, Boehringer Ingelheim, Abbott, Eidos Therapeutics, Reprieve, and Sequana; and has served on clinical endpoint committees and data and safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, and Rocket Pharma. Dr. Fiuzat has received grant support from the National Institutes of Health and Roche Diagnostics. Dr. O’Connor has received grant support from Roche Diagnostics and the National Institutes of Health. Dr. Ahmad is a consultant for Amgen, Cytokinetics, Relypsa, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)