New approaches to hyperkalemia in patients with indications for renin angiotensin aldosterone inhibitors: Considerations for trial design and regulatory approval.

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.