Discontinuation of
angiotensin-converting enzyme (
ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum
creatinine after starting this
therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum
creatinine are unclear. In the ADVANCE trial (Action in Diabetes and
Vascular Disease:
Preterax and
Diamicron Modified Release Controlled Evaluation), 11 140
diabetes mellitus patients were randomly assigned to
perindopril-
indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum
creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in
creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum
creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum
creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum
creatinine increase ( P for heterogeneity=0.94). Acute increases in serum
creatinine after starting
perindopril-
indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of
angiotensin-converting enzyme inhibitor-based
therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in
creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.