AIMS: To investigate the impact of patiromer on the serum potassium level and its ability to enable specified target doses of renin-angiotensin-aldosterone system inhibitor (RAASi) use in patients with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: A total of 1642 patients with HFrEF and current or a history of RAASi-related hyperkalemia were screened and 1195 were enrolled in the run-in phase with patiromer and optimization of the RAASi therapy [≥50% recommended dose of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, and 50 mg of mineralocorticoid receptor antagonist (MRA) spironolactone or eplerenone]. Specified target doses of the RAASi therapy were achieved in 878 (84.6%) patients; 439 were randomized to patiromer and 439 to placebo. All patients, physicians, and outcome assessors were blinded to treatment assignment. The primary endpoint was between-group difference in the adjusted mean change in serum potassium. Five hierarchical secondary endpoints were assessed. At the end of treatment, the median (interquartile range) duration of follow-up was 27 (13-43) weeks, the adjusted mean change in potassium was +0.03 mmol/l in the patiromer group and +0.13 mmol/l in the placebo group [difference in the adjusted mean change between patiromer and placebo: -0.10 mmol/l (95% confidence interval, CI -0.13, 0.07); P < 0.001]. Risk of hyperkalemia >5.5 mmol/l [hazard ratio (HR) 0.63; 95% CI 0.45, 0.87; P = 0.006), reduction of MRA dose (HR 0.62; 95% CI 0.45, 0.87; P = 0.006), and total adjusted hyperkalemia events/100 person-years (77.7 vs. 118.2; HR 0.66; 95% CI 0.53, 0.81; P < 0.001) were lower with patiromer. Hyperkalemia-related morbidity-adjusted events (win ratio 1.53, P < 0.001) and total RAASi use score (win ratio 1.25, P = 0.048) favored the patiromer arm. Adverse events were similar between groups. CONCLUSION: Concurrent use of patiromer and high-dose MRAs reduces the risk of recurrent hyperkalemia (ClinicalTrials.gov: NCT03888066).

10 Université de Lorraine INSERM Centre d'Investigations Cliniques Plurithématique 1433 INSERM Unit 1116 Centre Hospitalier Régional Universitaire de Nancy Nancy France

Alexandre Aladashvili Clinic Tbilisi State Medical University Tbilisi Georgia

Almazov Federal Heart Blood and Endocrinology Centre Saint Petersburg Russia

Baylor Scott and White Research Institute Dallas TX USA

Berlin Institute of Health Center for Regenerative Therapies Berlin Germany

Cardiology ASST Spedali Civili and University Brescia Italy

Cardiology Department Hospital Universitari Germans Trias i Pujol Badalona Barcelona CIBERCV Spain

Central Michigan University College of Medicine Mount Pleasant MI USA

Charité Universitätsmedizin Berlin Germany

Clinic of Cardiology and Angiology General University Hospital Prague Prague Czech Republic

Department of Cardiology Berlin Germany

Department of Cardiology Karolinska University Hospital Stockholm Sweden

Department of Cardiology University Medical Center Groningen Groningen the Netherlands

Department of Cardiovascular Disease Saint Luke's Mid America Heart Institute Kansas City MO USA

Department of Emergency Medicine Medical University of Sofia Sofia Bulgaria

Department of Internal Medicine Göttingen Germany

Department of Medicine Duke University School of Medicine Durham NC USA

Department of Medicine Unit of Cardiology Karolinska Institutet Solna Stockholm Sweden

Department of Medicine University of Mississippi Jackson MS USA

Department of Medicine Vanderbilt University Medical Centre Nashville TN USA

Division of Cardiology University of Michigan Ann Arbor MI USA

Division of Nephrology Department of Medicine University of Maryland School of Medicine Baltimore MD USA

DZHK Göttingen partner site Göttingen Germany

Erasmus MC University Medical Center Rotterdam the Netherlands

F CRIN INI CRCT Nancy France

Faculty of Medicine and Dentistry University of Alberta Alberta Canada

Faculty of Medicine Belgrade Serbia

German Center for Cardiovascular Research partner site Berlin Berlin Germany

Hadassah Medical Centre Jerusalem Israel

Heart Institute of Queretaro Santiago de Querétaro Mexico City Mexico

Hospital Attikon Athens Greece

Hospital Oost Limburg Genk Belgium

INECO Neurociencias Oroño Rosario Santa Fe NM USA

Insitute of Heart Diseases Wroclaw Medical University Wroclaw Poland

Institute of Health and Wellbeing University of Glasgow Glasgow UK

Instituto do Coracao Hospital das Clinicas HCFMUSP Faculdade de Medicina

Klinik für Innere Medizin 3 Saarland University Homburg Saar Germany

National and Kapodistrian University of Athens School of Medicine Athens University Athens Greece

Santa Maria University Hospital CAML CCUL Faculdade de Medicina da Universidade de Lisboa Lisbon Portugal

Semmelweis University Heart and Vascular Center Budapest Hungary

Serbian Academy of Sciences and Arts Serbia

Universidade de Sao Paulo Sao Paulo SP Brazil

Université de Paris INSERM U942 APHP Hospital Lariboisiere Paris France

University Medical Center Göttingen Göttingen Germany

University of Milano Bicocca Cardiovascular Department Papa Giovanni XXIII Hospital Bergamo Italy

University of Missouri Kansas City Kansas City MO USA

University of Warwick Warwick UK

Vifor Pharma Glattbrugg Switzerland

Ziekenhuis Oost Limburg Genk and University Hasselt Belgium

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ClinicalTrials.gov
NCT03888066