We evaluated how well patients taking spironolactone were monitored for hyperkalemia, as well as the association between spironolactone and hyperkalemia. Only two thirds of patients received testing for serum potassium and creatinine levels, and higher baseline serum creatinine levels predicted a high risk of hyperkalemia. These results indicate that appropriate patient selection and close monitoring are essential, especially for patients with renal impairment.
Mortality was reduced by 30% among patients with congestive heart failure (CHF) taking spironolactone in the Randomized Aldactone Evaluation Study (RALES).1 After this trial, spironolactone was widely accepted as treatment for serious systolic impairment, and an increase in prescriptions for the drug was noted. Unfortunately, morbidity and mortality rates associated with hyperkalemia have risen to levels higher than those seen prior to RALES.2
The difficulty in translating the results from a large randomized controlled trial to “real-life” clinical practice may be due to prescribing spironolactone for patients who may not be suitable candidates for the drug, based on renal function, New York Heart Association functional class, concurrent medications, and systolic function.3 Another reason for this problem may be that clinicians may not be performing sufficient testing to assess kidney function and serum potassium levels among patients receiving therapy. Therefore, we studied criteria for the selection of patients for spironolactone therapy and how well patients taking spironolactone are monitored for hyperkalemia.
Patients and methods
We examined the outpatient and inpatient electronic files of 840 CHF patients who were prescribed spironolactone between September 2, 1999, and April 1, 2004. Information on baseline serum potassium and creatinine concentrations, concurrent medications, demographic information, and ejection fractions was obtained.
We also reviewed follow-up laboratory tests for these patients. Peak serum creatinine and potassium levels within 3 months of initiating spironolactone treatment were identified. Patients with serum potassium levels ≥ 5.5 mEq/L were considered to have hyperkalemia, and those with levels ≥ 6.0 mEq/L were considered to have severe hyperkalemia, which were the same definitions used in RALES. Patients with serum creatinine levels > 2.5 mg/dL were considered to have renal dysfunction. When follow-up laboratory tests within 3 months of starting spironolactone treatment were missing, the records were examined for an explanation.
A total of 840 participants were included in the study, 66% (n = 556) of whom had laboratory tests taken following therapy initiation. No measurements were obtained for 34% (n = 284) of patients, and further examination of these records indicated that follow-up laboratory studies were not requested by the treating physician for 149 patients, and 41 patients missed appointments for scheduled tests.
Patients who received follow-up laboratory tests were more often taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-adrenergic receptor blockers, and digoxin (Lanoxin). Fifteen percent of patients developed hyperkalemia, and 6% developed severe hyperkalemia. Hyperkalemia was associated with increased serum creatinine and potassium levels at baseline. A total of 51 patients had renal failure, of which approximately one half progressed to hyperkalemia during the follow-up period. An increase in baseline serum creatinine level was directly related to an increase in the incidence of hyperkalemia.
Among patients enrolled in RALES, monitoring was strict, and creatinine and potassium levels were assessed at 1, 2, and 3 months after the start of therapy, as well as after a change in dosage. Our study showed that, in clinical practice, one third of patients did not have serum laboratory measurements taken during the follow-up period of 3 months. This significant lack of laboratory monitoring in actual practice compared with large clinical trials may explain the increased hyperkalemia-related mortality occurring after publication of RALES.
Only 2% of treated patients had severe hyperkalemia in RALES, whereas we observed a higher incidence in our study—15% of patients developed hyperkalemia, and 6% developed severe hyperkalemia. Aside from strict monitoring and frequent clinic visits in RALES, other factors may explain the increased incidence of hyperkalemia seen in our study. Our patients were at higher risk for developing hyperkalemia. They were older (70 ± 11 years in our study vs 65 ± 12 years in RALES) and thus were more likely to have lower glomerular filtration rates and a higher tendency toward potassium retention. Also, 60 high-risk patients who would have been excluded from the RALES trial (with a serum creatinine concentration of ≥ 2.5 mg/dL or a baseline serum potassium concentration of ≥ 5.0 mEq/L, or both) were included in our study.
The evidence from our study shows that the use of spironolactone should be limited in patients with renal dysfunction. Patients with increased serum creatinine levels at baseline have a greater risk of developing hyperkalemia. In fact, serum creatinine levels as low as 1.5 to 1.9 mg/dL portend a 35% risk of developing hyperkalemia. Therefore, even patients with slight renal impairment should be carefully observed.
Mineralocorticoid receptor antagonists reduce cardiac remodeling and thereby aid cardiac function and decrease mortality. The risk of hyperkalemia with spironolactone therapy, however, is greater than was shown in the RALES trial. Our study showed that monitoring for hyperkalemia among patients receiving spironolactone in actual clinical practice is not adequate. Proper selection of patients and rigorous observation for hyperkalemia after treatment begins is essential, particularly for patients with renal dysfunction. Aids such as computer reminders, patient educators, and mandatory laboratory screening schedules may help to decrease the incidence of hyperkalemia.