title: New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: Considerations for trial design and regulatory approval.
abstract: Hyperkalemia is a common clinical problem, especially in patients with chronic kidney disease, diabetes mellitus, or heart failure. Treatment with renin angiotensin aldosterone system inhibitors exacerbates the risk of hyperkalemia in these patients. Concern about hyperkalemia can result in the failure to initiate, suboptimal dosing, or discontinuation of renin angiotensin aldosterone system inhibitor therapy in patients; effective treatments for hyperkalemia might mitigate such undertreatment. New treatments for hyperkalemia in development may offer better efficacy, tolerability and safety profiles than do existing approved treatments. These compounds might enable more eligible patients to receive renin angiotensin aldosterone system inhibitor therapy or to receive renin angiotensin aldosterone system inhibitors at target doses. The evidence needed to support a treatment claim (reduction in serum potassium) differs from that needed to support a prevention claim (preventing hyperkalemia to allow renin angiotensin aldosterone system inhibitor treatment). Thus, several issues related to clinical trial design and drug development need to be considered. This paper summarizes and expands upon a discussion at the Global Cardiovascular Clinical Trialists 2014 Forum and examines methodologic considerations for trials of new potassium binders for the prevention and management of hyperkalemia in patients with renin angiotensin aldosterone system inhibitor indications.
authors.affiliation: INSERM, Centre d'Investigation Clinique - 1433 and Unité 1116, CHU Nancy, Université de Lorraine, and F-CRIN INI-CRCT, Nancy, France. Electronic address: f.zannad@chu-nancy.fr.
authors.forename: Faiez
authors.initials: F
authors.lastname: Zannad
authors.affiliation: INSERM, Centre d'Investigations Cliniques- 1433, and Inserm U1116, CHU Nancy, Université de Lorraine, Association Lorraine pour le Traitement de l'Insuffisance Rénale, and F-CRIN INI-CRCT, Nancy, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Rossignol
authors.affiliation: Campbell University College of Pharmacy and Health Sciences, NC, United States.
authors.forename: Wendy Gattis
authors.initials: WG
authors.lastname: Stough
authors.affiliation: Division of Nephrology and Hypertension, University of Miami, Miller School of Medicine, Miami, FL, United States.
authors.forename: Murray
authors.initials: M
authors.lastname: Epstein
authors.affiliation: Scientific Advice Working Party European Medicines Agency, Medicines and Healthcare Products Regulatory Agency (MHRA), Cardiology, Imperial College Healthcare, NHS Trust, London, United Kingdom.
authors.forename: Maria de Los Angeles
authors.initials: Mde L
authors.lastname: Alonso Garcia
authors.affiliation: Department of Medicine, University of Chicago Medicine, Chicago, IL, United States.
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.affiliation: Stony Brook Heart Institute, Stony Brook University School of Medicine, Stony Brook, NY, United States.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, MO, United States.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Kosiborod
authors.affiliation: Relypsa, Redwood City, CA, United States.
authors.forename: Lance
authors.initials: L
authors.lastname: Berman
authors.affiliation: University Paris Diderot, Sorbonne Paris Cité, U942 Inserm, Paris, AP-HP, Department of Anesthesia and Critical Care, Hôpitaux Universitaires Saint Louis-Lariboisière, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
authors.affiliation: ZS Pharma, Coppell, TX, United States.
authors.forename: Henrik S
authors.initials: HS
authors.lastname: Rasmussen
authors.affiliation: Institute of Investigation and Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Ruilope
authors.affiliation: Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
authors.affiliation: Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, United States.
authors.forename: Aliza
authors.initials: A
authors.lastname: Thompson
authors.affiliation: Statistics Collaborative, Inc., Washington, D.C., United States.
authors.forename: Janet
authors.initials: J
authors.lastname: Wittes
authors.affiliation: University of Michigan School of Medicine, Ann Arbor, MI, United States.
authors.forename: Bertram
authors.initials: B
authors.lastname: Pitt
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects*; D002986:Clinical Trials as Topic; D015897:Comorbidity; D006801:Humans; D006947:Hyperkalemia / Q000188:drug therapy* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D017410:Practice Guidelines as Topic; D012084:Renin-Angiotensin System / Q000187:drug effects*; D012107:Research Design
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D011188:Potassium
keywords: Chronic; Clinical trials as topic; Heart failure; Hyperkalemia; Polymers; Renal insufficiency; Renin–angiotensin system