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

Abstract

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.

Keywords: ACE inhibitors; discontinuation; hyperkalemia; randomized controlled trials; renin angiotensin system.

Graphical abstract

Figure 1.

Study design and identification of the study cohort. Participants were followed until the earliest of the first study event, death, or the end of follow-up.

Figure 2.

The association between short-term changes in serum potassium after initiating angiotensin-converting enzyme (ACE) inhibitor–based therapy and subsequent risk of major clinical outcomes. Short-term changes in serum potassium were defined on the basis of the measurement made 3 weeks after initiating ACE inhibitor–based therapy. Models were adjusted for age, sex, region of residence, duration of diabetes mellitus, history of macrovascular diseases, smoking habit, alcohol drinking habit, body mass index, hemoglobin A1c, total cholesterol, log-transformed triglyceride, systolic BP, eGFR, log-transformed urine albumin-creatinine ratio, randomized BP-lowering intervention, and randomized glucose control intervention (n=9190). 95% CI, 95% confidence interval; HR, hazard ratio.

Figure 3.

Modification of randomized treatment effects of ACE inhibitor–based therapy on the risk of major clinical outcomes according to short-term changes in serum potassium after treatment initiation. Short-term changes in serum potassium were defined on the basis of the measurement made 3 weeks after initiating ACE inhibitor–based therapy. White diamonds indicate the HRs for subgroups defined by short-term change in serum potassium. Black diamonds indicate the HRs of overall randomized participants of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial (n=11,140). Active indicates perindopril-indapamide.