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The Burden of Hyperkalemia in Patients With Cardiovascular and Renal Disease
Jeffrey D. Dunn, PharmD, MBA; Wade W. Benton, PharmD; Ernesto Orozco-Torrentera, MD; and Robert T. Adamson, PharmD, FASHP

The Burden of Hyperkalemia in Patients With Cardiovascular and Renal Disease

Jeffrey D. Dunn, PharmD, MBA; Wade W. Benton, PharmD; Ernesto Orozco-Torrentera, MD; and Robert T. Adamson, PharmD, FASHP
Hyperkalemia is a potentially serious condition that can result in life-threatening cardiac arrhythmias and is associated with an increased mortality risk. Patients older than 65 years who have an advanced stage of chronic kidney disease (stage 3 or higher), diabetes, and/or chronic heart failure are at higher risk for hyperkalemia. To reduce disease progression and improve outcomes in these groups of patients, modulation of the renin-angiotensinaldosterone system (RAAS) is recommended by guidelines. One limiting factor of RAAS inhibitors at proven doses is the increased risk for hyperkalemia associated with their use. Although there are effective therapeutic options for the short-term, acute management of hyperkalemia, the available strategies for chronic control of high potassium levels have limited effectiveness. The management of high potassium in the long term often requires withdrawing or reducing the doses of drugs proven to reduce cardiovascular and renal outcomes (eg, RAAS inhibitors) or implementing excessive and often intolerable dietary restrictions. Furthermore, withholding RAAS inhibitors may lead to incremental healthcare costs associated with poor outcomes, such as end-stage renal disease, hospitalizations due to cardiovascular causes, and cardiovascular mortality. As such, there is an important unmet need for novel therapeutic options for the chronic management of patients at risk for hyperkalemia. Potential therapies in development may change the treatment landscape in the near future.

Am J Manag Care. 2015;21:S307-S315

For author information and disclosures, see end of text.
Hyperkalemia: Mechanisms, Patient Populations at Risk, and Prevalence
Potassium is an essential dietary mineral that is the main intracellular cation required for the maintenance of cell membrane potential, ion and solute transport, and the regulation of cell volume. Hyperkalemia is a potentially life-threatening condition that is defined as a serum potassium level above a reference range, usually greater than 5.0 mEq/L; severe hyperkalemia is often defined as a level greater than 6.0 mEq/L.1 Elevation of plasma potassium concentration decreases the ratio of intracellular to extracellular potassium, leading to partial depolarization of the cell membrane. These physiologic effects of hyperkalemia can result in muscle weakness, paralysis, life-threatening effects on cardiac conduction (eg, QRS widening), arrhythmias such as ventricular fibrillation, and sudden death.2,3

Hyperkalemia can be caused by an abnormal net release of potassium from cells, often due to trauma, metabolic acidosis, hemolytic states, or other cell degradations, usually in the setting of suboptimal kidney function. If not treated rapidly, the mortality rate for patients with severe hyperkalemia can be over 30%.4 Hyperkalemia may also result from impaired distribution between the intracellular and extracellular spaces due to other causes, as well as increased potassium intake, reduced renal excretion, or a combination of several of these factors.5
Those at greatest risk for hyperkalemia are persons older than 65 years who have an advanced stage of chronic kidney disease (CKD) (ie, stage 3-5), chronic heart failure (CHF), and/or diabetes and/or are taking medications known to increase serum potassium levels, notably inhibitors of the renin-angiotensin-aldosterone system (RAAS).1,5-9 In patients with diabetes, the presence of a constellation of multiple risk factors that interfere with potassium excretion—including hyporeninemic hypoaldosteronism, and renal tubular acidosis type IV—explains why the incidence of hyperkalemia is higher than in the general population.10

CKD is the most common risk factor for hyperkalemia due to the intrinsic pathophysiological effects of kidney dysfunction on potassium homeostasis and the superimposing cluster of cardiometabolic comorbidities—and their associated treatments—that frequently are present in patients with CKD.5 As the number and severity of comorbidities increase and further decline in renal function ensues, the prevalence of hyperkalemia and the number of recurrent episodes increases.

Although the incidence and prevalence of hyperkalemia in the general population is unknown, some studies in hospitalized patients have reported incidence rates between 1 and 10 per 100 patients.11 In a Canadian retrospective population-based study, 2.6% of patients 66 years and older who presented to the emergency department were hyperkalemic, defined as a serum potassium level greater than 5.5mEq/L.12 Some retrospective US analyses have reported incidences between 2.5% and 3.2% in populations with diverse risk factors.9,13 Among those risk factors, the presence of CKD is significantly associated with higher frequencies of hyperkalemia, depending on the studied population and on the definition of hyperkalemia.9

Among the medications that can cause hyperkalemia, the most relevant in clinical practice are RAAS inhibitors because while they have been shown to confer mortality and morbidity benefits in patients with CKD, diabetes, and cardiovascular disease (CVD),14-17 the development of hyperkalemia frequently hinders their utilization at optimal doses for chronic cardiorenal protection.18 The interaction between the presence of CKD and the administration of RAAS inhibitors is highlighted by data from clinical trials showing how the incidence of hyperkalemia associated with RAAS inhibitors increases from less than 2% in patients without CKD to between 5% and 10% with dual inhibition of the RAAS in patients with CKD.19

Because randomized clinical trials typically exclude individuals with advanced cardiorenal comorbidities and the patients included in these trials are carefully monitored, reports from randomized clinical trials may underestimate the true burden of hyperkalemia, which is probably much higher in routine clinical practice. For instance, a study at a Veterans Administration clinic revealed that 11% of outpatients prescribed angiotensinconverting enzyme (ACE) inhibitors developed hyperkalemia over the 2-year study period.20 In addition, whereas the Randomized Aldactone Evaluation (RALES) study17 in patients with heart failure (HF) and serum creatinine less than 2.5 mg/dL reported only a 2% rate of hyperkalemia, subsequent analyses in unselected patients treated with ACE inhibitors who had recently been hospitalized for HF showed a significant increase in hyperkalemiarelated hospitalizations and deaths.21 This correlated with an increase in the prescription rate for spironolactone used in addition to ACE inhibitors following the publication of the RALES study.21 Bozkurt et al documented that 24% of patients with HF treated with spironolactone in clinical practice developed a serum potassium level greater than 5.2 mEq/L; of these, 12% had a serum potassium level greater than 6.0 mEq/L.22 Shah et al reported that hyperkalemia developed in 35% of patients with HF also treated with spironolactone and who had a baseline creatinine of 1.5 mg/dL or greater; and in 63% with a baseline creatinine of 2.5 mg/dL or greater, punctuating the clear trend toward increased hyperkalemia risk with declining kidney function.23

Consequences of Hyperkalemia
Hyperkalemia is often a silent condition that goes undetected until a patient exhibits serious consequences, such as ventricular arrhythmias, or may be detected incidentally upon laboratory testing. In patients with cardiorenal comorbidities, the risk for developing hyperkalemia is an ongoing concern. Hyperkalemia is associated with both clinical and economic consequences, including increased emergency department (ED) visits, hospitalizations, and mortality. These have a direct bearing on the overall cost of managing patients, especially in a managed care setting.

In 2011, approximately 67,000 visits to the ED were a direct result of elevated potassium levels.24 Of patients who visited the ED, 50% were admitted to the hospital, with an average length of stay of 3.2 days and mean inhospital charges of $24,178 per stay. A total of 84% of individuals hospitalized were older than 45 years. Thus, persons older than 45 years who are at risk for hyperkalemia should be monitored closely. The estimated total annual hospital charges for Medicare admissions with hyperkalemia as the primary diagnosis were approximately $697 million (US) in 2011.24

Clinical evidence shows that increases in serum potassium above the normal range are associated with higher mortality rate, especially as an individual ages and in patients with comorbidities (Figure 18).7,8 Other studies have noted that hyperkalemia is one of the greatest risk factors associated with all-cause mortality in patients with pre-existing CVD, advanced CKD,6 patients without CKD,9 and patients undergoing dialysis (Figure 226).25,26 A retrospective analysis of 15,803 patients with CKD and CVD treated with antihypertensive drugs revealed that patients with hyperkalemia had higher rates of hospital admissions and mortality compared with normokalemic patients.6 The association of mortality risk with hyperkalemia was also studied in a retrospective analysis conducted in a large national cohort including more than 240,000 US Veterans with at least 1 hospitalization and at least 1 serum potassium measurement during a year.9 The authors determined the risk of death (odds ratio) within 1 day of a hyperkalemic event in patients with CKD compared with normokalemic non-CKD patients. This study showed that patients with CKD were significantly more likely to experience a hyperkalemic event than those without CKD, but also that hyperkalemia increased the odds of death within 1 day regardless of kidney function. The risk of death correlated incrementally with severity of hyperkalemia (moderate hyperkalemia defined as serum potassium level ≥5.5 mg/dL and <6.0 mg/dL and severe hyperkalemia defined as ≥6.0 mg/dL).9

Current Management of Hyperkalemia
Both acute and chronic treatment strategies are critical for the management of patients at risk of hyperkalemia. The currently available treatment strategies mainly focus on emergency and intermediate care, and limited options are available for chronic management of patients at risk of recurrent hyperkalemia. Interventions for chronic management are limited to reducing or eliminating exacerbating factors, including RAAS inhibitors. Table 13,5,18,19,48,50,51 shows the list of interventions commonly used for the management of hyperkalemia.3,5,19 

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