Neurohormonal blockade of the renin-angiotensin-aldosterone and sympathetic nervous systems at multiple levels is “state of the art” management for patients with established cardiovascular disease (CVD) to reduce associated morbidity and mortality. However, potassium homeostasis is already impaired in patients with CVD because of associated age, diabetes mellitus (DM) and chronic kidney disease (CKD). Hyporeninemic hypoaldosteronism associated with aging and DM, maladaptive redistribution of extracellular potassium in patients with diabetes, and progressive nephron loss in CKD with hyperfunctioning distal nephron potassium excretion capacity impart vulnerability to hyperkalemia. With the increasing trend in prescribing angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β blockers, and potassium-sparing diuretics, homeostatic mechanisms are further threatened. Hyperkalemia has serious cardiotoxic effects that can be potentially lethal and difficult to diagnose given the paucity of clinical signs and symptoms. Recent reports indicate a substantial increase in 1-day odds of death in patients with hyperkalemic events compared to those with normokalemia. Clinical trials of renin-angiotensin-aldosterone system antagonists have found elevations in serum potassium levels of 0.3 to 0.6 mEq/L in 3% to 5% of patients taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and low rates of life-threatening hyperkalemia. After the Randomized Aldactone Evaluation Study (RALES), potassium-sparing diuretics were reported to increase hospitalizations for hyperkalemia by threefold to fivefold and to increase the number of hyperkalemia-related deaths by twofold. In the present investigation, risk factors for hyperkalemia (defined as serum potassium concentration >5.0 mEq/L) and all-cause mortality associated with hyperkalemia were analyzed in patients with established CVD, defined as patients with heart failure and hypertension treated with antihypertensive drugs that impair potassium homeostasis. Furthermore, risk factors for all-cause mortality were stratified in patients with CKD stages 3 to 5.

Methods

The institutional review board of the Veterans Affairs North Texas Health Care System approved the study, and all data were analyzed in aggregate without patient identifiers. The sample of patients was drawn from Veterans Affairs North Texas Health Care System electronic medical records from January 2007 to June 2010. Baseline characteristics, co-morbidities, and admission diagnoses were based on the International Classification of Disease, Ninth Revision, available from databases and associated patient encounters. Patients with ≥2 metabolic profiles performed during each year of follow-up and ≥2 clinic or provider visits performed during the follow-up year were included. Patients with missing data were excluded. A cohort of 15,803 patients was identified ( Figure 1 ). Use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β blockers, and potassium-sparing diuretics was obtained from Veterans Affairs pharmacy prescription records in the electronic medical records of the Veterans Affairs North Texas Health Care System. All-cause deaths and admission records were obtained from the electronic medical records. CKD stages 3 to 5 included patients with estimated glomerular filtration rates (eGFRs) <60 ml/min (estimated by the 4-variable Modification of Diet in Renal Disease [MDRD] equation). The National Kidney Foundation recognizes glomerular filtration rate as the best measure of overall kidney function and has set a cutoff point of <60 ml/min/1.73 m ² as a priori evidence of CKD. A hyperkalemic event was recognized as an occurrence of a serum potassium value >5.0 mEq/L. If there were 2 values of serum potassium >5.0 mEq/L, the highest value was chosen for the purpose of the study.

Exclusionary cascade of sample size.

Frequencies of baseline characteristics were compared between patients with hyperkalemia and those with normokalemia using Student’s t test for continuous variables or 2 × 2 cross tabulation chi-square tests for categorical variables. Binary logistic regression analyses were performed with hyperkalemia and death as independent variables, controlling for covariates. Subgroup analyses were performed for the CKD stages 3 to 5 population to identify predictors of hyperkalemia and all-cause mortality. Covariates used for the regression model to predict hyperkalemia were age, admissions, DM, coronary artery disease (CAD), peripheral vascular disease (PVD), hyperlipidemia, medication use, and CKD stage. Covariates used for the regression model to predict all-cause mortality were hyperkalemia and all factors described previously. Analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina). For analyses, statistical significance was set a priori at p <0.05.