Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality: Results from a Randomized Controlled Trial of ACE Inhibitors

Toshiaki Ohkuma, Katie Harris, Mark Cooper, Diederick E. Grobbee, Pavel Hamet, Stephen Harrap, Giuseppe Mancia, Michel Marre, Anushka Patel, Anthony Rodgers, Bryan Williams, Mark Woodward, John Chalmers, on behalf of the ADVANCE Collaborative Group

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BACKGROUND AND OBJECTIVES: Hyperkalemia after starting renin-angiotensin system inhibitors has been shown to be subsequently associated with a higher risk of cardiovascular and kidney outcomes. However, whether to continue or discontinue the drug after hyperkalemia remains unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data came from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial, which included a run-in period where all participants initiated angiotensin-converting enzyme inhibitor-based therapy (a fixed combination of perindopril and indapamide). The study population was taken as patients with type 2 diabetes with normokalemia (serum potassium of 3.5 to <5.0 mEq/L) at the start of run-in. Potassium was remeasured 3 weeks later when a total of 9694 participants were classified into hyperkalemia (≥5.0 mEq/L), normokalemia, and hypokalemia (<3.5 mEq/L) groups. After run-in, patients were randomized to continuation of the angiotensin-converting enzyme inhibitor-based therapy or placebo; major macrovascular, microvascular, and mortality outcomes were analyzed using Cox regression during the following 4.4 years (median). RESULTS: During active run-in, 556 (6%) participants experienced hyperkalemia. During follow-up, 1505 participants experienced the primary composite outcome of major macrovascular and microvascular events. Randomized treatment of angiotensin-converting enzyme inhibitor-based therapy significantly decreased the risk of the primary outcome (38.1 versus 42.0 per 1000 person-years; hazard ratio, 0.91; 95% confidence interval, 0.83 to 1.00; P=0.04) compared with placebo. The magnitude of effects did not differ across subgroups defined by short-term changes in serum potassium during run-in (P for heterogeneity =0.66). Similar consistent treatment effects were also observed for all-cause death, cardiovascular death, major coronary events, major cerebrovascular events, and new or worsening nephropathy (P for heterogeneity ≥0.27). CONCLUSIONS: Continuation of angiotensin-converting enzyme inhibitor-based therapy consistently decreased the subsequent risk of clinical outcomes, including cardiovascular and kidney outcomes and death, regardless of short-term changes in serum potassium. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE), NCT00145925.

Original languageEnglish
Pages (from-to)1139-1149
Number of pages11
JournalClinical Journal of the American Society of Nephrology
Issue number8
Publication statusPublished - Aug 2022


  • ACE inhibitors
  • discontinuation
  • hyperkalemia
  • randomized controlled trials
  • renin angiotensin system

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