Background: An acute increase in serum creatinine (AICr) after starting ACE inhibitor is frequently observed, and consideration of discontinuation has been recommended if creatinine values increased 30% or more. However, the long term effect of continuation or discontinuation of that therapy is unclear.

Objective: To examine the association of AICr after starting a fixed combination of perindopril-indapamide and its continuation or discontinuation, with clinical outcomes using data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial.

Research Design and Methods: A total of 11,140 diabetes patients were randomly assigned to a fixed combination of perindopril-indapamide or placebo after a 6-week active run-in period. These analyses included 11,066 patients with 2 measurements of serum creatinine, before and during the active run-in period (3 weeks apart). AICr was determined using these 2 measurements, classified into 4 groups: <10%, 10-19%, 20-29%, and ≥30%.

Results: AICr after starting perindopril-indapamide in the run-in period was subsequently associated with an increased risk of a composite of major macrovascular events, new or worsening nephropathy, all-cause mortality, in both randomized groups (P for trend <0.for each). However, a consistent benefit of randomized treatment for the outcome was observed across subgroups defined by AICr, with no heterogeneity in the magnitude of the effects (P for heterogeneity = 0.94). Similar results were observed for major macrovascular events alone, new or worsening nephropathy alone, and all-cause mortality alone.

Conclusions: AICr after starting ACE inhibitor was associated with an increased risk of clinical outcomes, irrespective of continuation or discontinuation of the therapy. However, randomized treatment effects are consistent and beneficial across subgroups defined by AICr.


T. Ohkuma: None. M. Jun: None. M. Woodward: None. J. Chalmers: Research Support; Self; Servier. Other Relationship; Self; Servier. V. Perkovic: Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Consultant; Self; AbbVie Inc.. Advisory Panel; Self; Janssen Global Services, LLC.. Speaker's Bureau; Self; Novo Nordisk Inc.. Advisory Panel; Self; Novartis Pharmaceuticals Corporation, AstraZeneca, Gilead Sciences, Inc.. Consultant; Self; Servier. Speaker's Bureau; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Eli Lilly and Company. A. Rodgers: Other Relationship; Self; George Health Enterprises.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at