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

Abstract

Background Dosing of renin–angiotensin–aldosterone system inhibitors ( RAAS i) may be modified to manage associated hyperkalemia risk; however, this approach could adversely affect cardiorenal outcomes. This study investigated real‐world associations of RAAS i dose, hyperkalemia, and adverse clinical outcomes in a large cohort of UK cardiorenal patients. Methods and Results This observational study included RAAS i‐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 RAAS i 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 RAAS i 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 RAAS i exposure (<50% and ≥50% of the guideline‐recommended RAAS i 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 RAAS i dosing and the need for strategies that allow patients to be maintained on appropriate therapy, avoiding RAAS i dose modification or discontinuation.