ACE Inhibitors reduce CV, renal, and mortality events independent of associated hyperkalemia

A new study published in Clinical Journal of American Society of Nephrology suggests that regardless of short-term changes in serum potassium levels, continuing angiotensin-converting enzyme (ACE) inhibitor-based therapy consistently reduced the risk of clinical outcomes, such as cardiovascular, renal, and mortality events.

It has been demonstrated that hyperkalemia following the initiation of renin-angiotensin system inhibitors is later linked to an increased risk of cardiovascular and renal consequences. It's uncertain, though, whether to keep taking the medication following hyperkalemia or stop. To investigate the short-term changes in serum potassium and the likelihood of subsequent vascular events and mortality, Toshiaki Ohkuma and colleagues conducted this study.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) experiment provided the information. During the run-in phase, all individuals started angiotensin-converting enzyme inhibitor-based medication (a fixed combination of perindopril and indapamide). Patients with type 2 diabetes and normokalemia (serum potassium of 3.5 to 5.0 mEq/L) at the beginning of the run-in were included in the study cohort. A total of 9694 people were divided into groups with hyperkalemia (>5.0 mEq/L), normokalemia, and hypokalemia (3.5 mEq/L) three weeks after the initial potassium measurement. Following run-in, individuals were assigned to receive angiotensin-converting enzyme inhibitor-based treatment for the next 4.4 years, or a placebo; significant macrovascular, microvascular, and mortality outcomes were assessed using Cox regression (median).

The key findings of this study were:

1. There were 556 (6%) individuals who developed hyperkalemia during the active run-in.

2. A total of 1505 patients who had been followed up on suffered the main composite outcome of significant macrovascular and microvascular incidents.

3. When compared to placebo, randomized treatment with angiotensin-converting enzyme inhibitor-based therapy dramatically reduced the risk of the main outcome.

4. The severity of the effects was the same across subgroups identified by transient variations in serum potassium during run-in.

5. All-cause mortality, major coronary events, cardiovascular death, major cerebrovascular events, and new or deteriorating nephropathy all showed consistent, comparable treatment effects.

In conclusion, these results imply that stopping [renin-angiotensin-system] inhibitor-based therapy following hyperkalemia may reduce the benefits in terms of lowering the risk of vascular events and death over the long term, though close attention to severe hyperkalemia, which can result in life-threatening arrhythmias, is required.

Reference:

Ohkuma, T., Harris, K., Cooper, M., Grobbee, D. E., Hamet, P., Harrap, S., Mancia, G., Marre, M., Patel, A., Rodgers, A., Williams, B., Woodward, M., & Chalmers, J. (2022). Short-Term Changes in Serum Potassium and the Risk of Subsequent Vascular Events and Mortality. In Clinical Journal of the American Society of Nephrology (Vol. 17, Issue 8, pp. 1139–1149). American Society of Nephrology (ASN). https://doi.org/10.2215/cjn.00180122