Real‐World Associations of Renin–Angiotensin–Aldosterone System Inhibitor Dose, Hyperkalemia, and Adverse Clinical Outcomes in a Cohort of Patients With New‐Onset Chronic Kidney Disease or Heart Failure in the United Kingdom

Background Dosing of renin-angiotensin-aldosterone system inhibitors (RAASi) may be modified to manage associated hyperkalemia risk; however, this approach could adversely affect cardiorenal outcomes. This study investigated real-world associations of RAASi dose, hyperkalemia, and adverse clinical outcomes in a large cohort of UK cardiorenal patients. Methods and Results This observational study included RAASi-prescribed patients with new-onset chronic kidney disease (n=100 572) or heart failure (n=13 113) first recorded between January 2006 and December 2015 in Clinical Practice Research Datalink and linked Hospital Episode Statistics databases. Odds ratios associating hyperkalemia and RAASi dose modification were estimated using logistic generalized estimating equations with normal (<5.0 mmol/L) serum potassium level as the reference category. Patients with serum potassium ≥5.0 mmol/L had higher risk of RAASi down-titration (adjusted odds ratios, chronic kidney disease: 1.79 95% CI, 1.64-1.96; heart failure: 1.33 95% CI, 1.08-1.62). Poisson models were used to estimate adjusted incident rate ratios of adverse outcomes based on total RAASi exposure (<50% and ≥50% of the guideline-recommended RAASi dose). Incidence of major adverse cardiac events and mortality was consistently higher in the lower dose group (adjusted incident rate ratios: chronic kidney disease: 5.60 95% CI, 5.29-5.93 for mortality and 1.60 95% CI, 1.55-1.66 for nonfatal major adverse cardiac events; heart failure: 7.34 95% CI, 6.35-8.48 for mortality and 1.85 95% CI, 1.71-1.99 for major adverse cardiac events). Conclusions The results of this real-world analysis highlight the potential negative impact of suboptimal RAASi dosing and the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAASi dose modification or discontinuation.