Frequency and Predictors of Hyperkalemia in Patients >60 Years of Age With Heart Failure Undergoing Intense Medical Therapy

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1 Frequency and Predictors of Hyperkalemia in Patients >60 Years of Age With Heart Failure Undergoing Intense Medical Therapy Stefano Muzzarelli, MD a,b, *, Micha Tobias Maeder, MD c, Stefan Toggweiler, MD d, Hans Rickli, MD c, Fabian Nietlispach, MD a, Barbara Julius, MD e, Thilo Burkard, MD a, Matthias Emil Pfisterer, MD a, and Hans-Peter Brunner-La Rocca, MD a,f, for the TIME-CHF Investigators Hyperkalemia is a concern in heart failure (HF), especially in older patients with comorbidities. Previous studies addressing this issue have focused mainly on younger patients. This study was aimed at determining the frequency and predictors of hyperkalemia in older patients with HF undergoing intense medical therapy. Frequency and predictors of hyperkalemia were defined in patients (n 566) participating in the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure, in which patients >60 years of age were randomized to a standard versus an intensified N-terminal brain natriuretic peptide-guided HF therapy. During an 18-month follow-up 76 patients (13.4%) had hyperkalemia (>5.5 mmol/l) and 28 (4.9%) had severe hyperkalemia (>6.0 mmol/l). Higher baseline serum potassium (odds ratio [OR] 2.92 per mmol/l), baseline creatinine (OR 1.11 per 10 mol/l), gout (OR 2.56), New York Heart Association (NYHA) class (compared to NYHA class II, IV OR 3.08), higher dosage of spironolactone at baseline (OR 1.20 per 12.5 mg/day), and higher dose changes of spironolactone (compared to no dose change: 12.5 mg, OR 1.45; 25 mg, OR 2.52; >25 mg, OR 3.24) were independent predictors for development of hyperkalemia (p <0.05 for all comparisons). In conclusion, hyperkalemia is common in patients >60 years of age with HF undergoing intense medical therapy. Risk is increased in patients treated with spironolactone, in addition to patient-specific risk factors such as chronic kidney disease, higher serum potassium, advanced NYHA class, and gout. Careful surveillance of serum potassium and cautious use of spironolactone in patients at risk may help to decrease the incidence of potentially hazardous complications caused by hyperkalemia Elsevier Inc. All rights reserved. (Am J Cardiol 2012;109: ) Several studies have described the incidence and risk factors of hyperkalemia in patients with heart failure (HF). 1,2 However, these studies typically have focused on younger patients with a lower prevalence of relevant comorbidities known to interfere with potassium homeostasis compared to older patients who represent most patients with HF. Therefore, we aimed to describe the frequency and a Department of Cardiology, University Hospital Basel, Basel, Switzerland; b Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland; c Department of Cardiology, Kantonsspital St. Gallen, St. Gallen, Switzerland; d Department of Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland; e Department of Cardiology, Kantonsspital Aarau, Aarau, Switzerland; f Department of Cardiology, Maastricht University Medical Center (MUMC), Maastricht, Netherlands. Manuscript received September 22, 2011; revised manuscript received and accepted October 25, This study was sponsored by the Horten Research Foundation, Lugano, Switzerland and by smaller unrestricted grants from AstraZeneca Pharma, Zug, Switzerland, Novartis Pharma, Basel, Switzerland, Menarini Pharma, Zürich, Switzerland, Pfizer Pharma, Zürich, Switzerland, Servier, Roche Diagnostics, Basel, Switzerland, Roche Pharma, Basel, Switzerland, and Merck Pharma, Luzern, Switzerland. *Corresponding author: Tel: ; fax: address: stefano.muzzarelli@cardiocentro.org (S. Muzzarelli). predictors of hyperkalemia in patients 60 years of age with HF taking part in the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF). 3 Methods Patients participating in the TIME-CHF were considered for this analysis. Details of the study have been described previously. 3,4 In brief, patients 60 years of age with New York Heart Association (NYHA) class II, a history of HF hospitalization within the previous year, and an N-terminal brain natriuretic peptide (NT-BNP) level 2 times the upper limit of normal were included in the study. Patients with dyspnea not mainly caused by HF, valvular heart disease needing surgery, acute coronary syndrome within 10 days, angina pectoris documented as ischemia by Canadian Cardiovascular Society class II, percutaneous coronary intervention within the previous month, coronary artery bypass graft surgery within the previous 3 months, body mass index 35 kg/m 2, life expectancy 3 years for diseases other than cardiovascular, and serum creatinine level 220 mol/l were excluded. The ethics committee of each center approved the study and each patient gave written informed consent before entering the study (trial registration at: isrctn.org, identifier ISRCTN ) /12/$ see front matter 2012 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 694 The American Journal of Cardiology ( The TIME-CHF was a prospective randomized controlled multicenter trial addressing the therapeutic management of patients 60 years of age with HF. A standard symptom-guided therapy and an intensified NT-BNP guided medical therapy were compared. After baseline assessment patients were treated according to the study protocol and followed for 18 months with visits after 1 month and 3, 6, 12, and 18 months. Treatments were adjusted at all but the last visit with the attempt to achieve therapeutic goals by the 6-month visit followed by 12 months of outcome observation. Details about therapy uptitration as recommended by the study protocol have been described previously. 4 Detailed clinical and laboratory assessments including measurement of serum potassium concentration were performed per protocol at each follow-up visit. Noncardiac co-morbidities were identified based on medical and hospital case histories. Hyperkalemia and severe hyperkalemia were defined as serum potassium concentrations 5.5 and 6.0 mmol/l, respectively. Estimated glomerular filtration rate was calculated according to the simplified Modified Diet in Renal Disease study equation. 5 Of the 622 patients included in TIME-CHF, 566 patients who had 2 study visits were included in this analysis. Of the remaining 56 patients, 18 died (none owing to known hyperkalemia; 9 because of circulatory failure, 5 because of sudden cardiac death, 2 from a noncardiovascular cause, and 2 from an unknown cause), 37 withdraw consent, and 1 was excluded by investigator decision. Dosages of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and blockers at baseline and follow-up were expressed as percent recommended target dosages (e.g., for a target dosage of ramipril 10 mg/day, 5 mg/day represents 50% of the target dose). For the combination of ACE inhibitors and ARBs, the relative dosages were added and expressed as a combined dosage (e.g., 75% of target dosage of ACE inhibitors and 50% of target dosage of ARBs would produce a combined dosage of 125%). Target dosages of the used ACE inhibitors, ARBs, and blockers as recommended by the guidelines are listed in Table 1. 6 Although not based on large trials, similar target doses were used for patients with preserved systolic left ventricular function. Dosages of loop diuretics are expressed as equivalent dosages of oral furosemide, where torsemide 10 mg was defined as furosemide 40 mg. This recalculation of dosages was necessary because different ACE inhibitors, ARBs, blockers, and loop diuretics were used at the discretion of participating investigators. In contrast, spironolactone was the only mineralocorticoid receptor antagonist used in this study and the dosage, therefore, is expressed as milligrams per day. Information on drug treatment and doses was available for every single day throughout the study. Because changes in serum potassium levels were more relevant during the early course of the study, when most therapy adjustments were carried out, we performed a specific analysis focused on the impact of drug uptitration during the first 6 months on changes in serum potassium levels. For the present analysis, maximal dose, maximal dose increase, and mean dose for each class of drugs (i.e., renin angiotensin aldosterone inhibitors, blocker, loop diuretic, spironolactone) were calculated and tested. Table 1 Target dosages of heart failure therapy as recommended by guidelines Drug Angiotensin-converting enzyme inhibitors Benazepril Captopril Enalapril Lisinopril Quinapril Perindopril Ramipril Cilazapril Fosinopril Trandolapril Angiotensin receptor blockers Losartan Valsartan Irbesartan Candesartan cilexetil Telmisartan Eprosartan Blockers Bisoprolol Metoprolol succinate Carvedilol Nebivolol Aldosterone antagonist Spironolactone Target Maintenance Dose 10 mg 2 times/day 50 mg 3 times/day 10 mg 2 times/day 20 mg 1 time/day 10 mg 2 times/day 4 mg 1 time/day 5 mg 2 times/day 2.5 mg 1 time/day 20 mg 1 time/day 4 mg 1 time/day 100 mg 1 time/day 160 mg 1 time/day 150 mg 1 time/day 16 mg 1 time/day 40 mg 1 time/day 800 mg 1 time/day 10 mg 1 time/day 200 mg 1 time/day 25 mg 2 times/day 10 mg 1 time/day mg 1 time/day Continuous data are presented as mean SD or median (interquartile range) as appropriate. Categorical data are presented as number (percentage). The univariate association between the tested variables and incident hyperkalemia was tested by t test for continuous variables with normal distribution, Mann Whitney U test for ordinal variables or continuous variables without normal distribution, and by Fisher s test for nominal variables. Independent predictors of hyperkalemia were identified by including variables with a p value 0.1 in univariable analysis in a multivariable logistic regression using forward and backward procedures, which provided similar results. A p value 0.05 was considered statistically significant (2-sided). Analyses were performed using SPSS 15.0 (SPSS, Inc., Chicago, Illinois). Results Baseline characteristic of patients included in this study are listed in Table 2. Notably, the median age was 75 years, and the prevalence of co-morbidities potentially interfering with potassium homeostasis was frequent, with 1 of2patients having a history of chronic renal failure and 1 of3 having diabetes mellitus. During the entire study period, 76 patients (13.4%) had hyperkalemia ( 5.5 mmol/l) and 28 (4.9%) had severe hyperkalemia ( 6.0 mmol/l). Figure 1 illustrates the frequency of hyperkalemia during the 18-month course of the study, showing some increase in hyperkalemia early after intensifying therapy and late during the study course. Results of univariable analysis to identify predictors at baseline for development of hyperkalemia are presented in Table 2. Patients developing hyperkalemia were more likely to

3 Heart Failure/Hyperkalemia in Older Patients With HF 695 Table 2 Baseline characteristics and univariable predictors of hyperkalemia Variable Hyperkalemia p Value No Yes (n 490) (n 76) Age (years) Men 285 (58%) 53 (70%) 0.06 Randomization to N-terminal brain natriuretic peptideguided 252 (51%) 33 (43%) 0.22 therapy Body mass index (kg/m 2 ) Systolic blood pressure (mm Hg) New York Heart Association Classes II/III/IV 129/306/55 (26%/62%/11%) 15/44/17 (20%/58%/22%) 0.02 Left ventricular ejection fraction (%) Heart failure with preserved left ventricular ejection fraction 90 (18%) 14 (18%) 1.00 Coronary artery disease 250 (51%) 44 (58%) 0.27 Atrial fibrillation 158 (33%) 27 (36%) 0.60 Hypertension 365 (75%) 55 (72%) 0.67 Diabetes mellitus 158 (32%) 35 (46%) 0.03 Hypercholesterolemia 237 (48%) 43 (57%) 0.22 Peripheral occlusive artery disease 93 (19%) 18 (24%) 0.35 Cerebrovascular disease 76 (16%) 14 (18%) 0.50 Chronic obstructive pulmonary disease 91 (19%) 19 (25%) 0.21 Kidney disease 257 (52%) 57 (75%) Anemia 126 (26%) 29 (38%) 0.03 Gout 36 (7%) 13 (17%) 0.01 Cancer 71 (15%) 8 (11%) 0.48 Osteoarthritis 138 (28%) 21 (28%) 1.00 N-terminal brain natriuretic peptide (pg/ml) 3,555 (1,829 6,520) 4,854 (2,367 7,467) 0.02 Creatinine (mmol/l) Estimated glomerular filtration rate (ml/min/1.73 m 2 ) Urea (mmol/l) Potassium (mmol/l) Sodium (mmol/l) Hemoglobin (mmol/l) Blockers 383 (78%) 57 (75%) 0.55 Angiotensin-converting enzyme inhibitors or angiotensin 457 (93%) 70 (92%) 0.63 receptor blockers Spironolactone 176 (36%) 37 (49%) 0.04 Loop diuretics 451 (92%) 72 (95%) 0.49 Dose of blockers, median (interquartile range of target 25 ( ) 25 ( ) 0.30 dosage) Dose of angiotensin-converting enzyme inhibitors or 50 (25 67) 50 (25 67) 0.97 angiotensin receptor blockers, median (interquartile range of target dosage) Dose of spironolactone, median (interquartile range of target 0 (0 25) 0 (0 25) 0.01 dosage) Dose of loop diuretics, median (interquartile range of furosemide equivalents) 60 (40 80) 80 (40 120) 0.02 Data are presented as number (percentages), mean SD, or median (interquartile range) as appropriate. Noncardiac co-morbidities were identified based on medical and hospital case histories. be in NYHA class III or IV and to have a history of diabetes mellitus, gout, and renal failure, higher serum concentrations of creatinine, urea, potassium, and NT-BNP, and a lower estimated glomerular filtration rate. At baseline dosages of spironolactone and loop diuretics were higher in patients developing hyperkalemia than in those who did not. In the 76 patients developing hyperkalemia, the average estimated glomerular filtration rate at the time of hyperkalemia was significantly lower compared to visits when the same patients did not have hyperkalemia (34 12 vs ml/min/1.73 m 2, p 0.001). In a multivariable logistic regression model, serum potassium and creatinine, history of gout, NYHA class, and dose of spironolactone at baseline were independent predictors of hyperkalemia (Table 3). Figure 2 depicts frequencies of hyperkalemia according to presence of renal failure, serum potassium levels, NYHA class, history of gout, and dosage of spironolactone prescribed at baseline. Maximal and mean doses and maximal dose changes of ACE inhibitors, ARBs, and blockers were very similar in patients developing hyperkalemia compared to those not developing hyperkalemia (p 0.2 for all comparisons, detailed data not shown). Doses and dose change of loop diuretics were higher in patients developing hyperkalemia compared to those not doing so (maximal dose: median 120 mg, interquartile

4 696 The American Journal of Cardiology ( Table 4 Maximal dose, maximal dose change, and mean dose of spironolactone during first six months of study (or until end of follow-up) in patients developing hyperkalemia compared to patients not doing so Hyperkalemia No Hyperkalemia p Value Figure 1. Frequency of hyperkalemia and severe hyperkalemia during the 18-month course of the study. Maximal dose (mg) 25 (0 25), 75% 25 (0 25), 56% Maximal dose 25 (3 25), 64% 25 (0 25), 42% change (mg) Mean dose (mg) 13.3 (0 24.3), 75% 3.2 (0 22.5), 56% Data are presented as median spironolactone doses (interquartile range), proportion of patients with dose 0 mg. Table 3 Multivariable baseline predictors of hyperkalemia Variable OR 95% CI p Value Potassium (per mmol/l) Gout New York Heart Association 0.02 class vs class II Class III Class IV Creatinine (per 10 mol/l) Dose of spironolactone (per 12.5 mg) Figure 3. Overall prevalence of hyperkalemia ( 5.5 mmol/l) (white bars) and severe hyperkalemia ( 6.0 mmol/l) (black bars) in relation to maximal (Max) change of spironolactone dosage during the first 6 months. Abbreviation as in Figure 2. Figure 2. Frequency of hyperkalemia in selected subgroups of patients according to presence of chronic renal failure, serum potassium (K) levels at baseline, symptoms of heart failure, history of gout, and dosage of spironolactone at baseline. egfr estimated glomerular filtration rate; pts patients. range 80 to 200, vs 80 mg, interquartile range 40 to 200, p 0.008; maximal change in dose: 80 mg, interquartile range 40 to 124, vs 60 mg, interquartile range 20 to 120, p 0.11; mean dose: 80 mg, interquartile range 43 to 110, vs 56 mg, interquartile range 31 to 97, p 0.008). However, this was related to more severe HF. In fact, in multivariable logistic regression analysis including relevant baseline predictors of hyperkalemia (see earlier in Table 3), higher doses of loop diuretics showed a nonsignificant trend toward less hyperkalemia (maximum dose: odds ratio [OR] 0.92 per furosemide 40 mg equivalent, 95% confidence interval [CI] 0.84 to 1.01; maximum dose change: OR 0.92, 95% CI 0.85 to 1.00; mean dose: OR 0.94, 95% CI 0.80 to 1.10). As presented in Table 4, doses of spironolactone were higher in patients developing hyperkalemia. Figure 3 depicts rates of developing hyperkalemia depending on maximal dose change of spironolactone during the first 6 months. Risk for developing hyperkalemia increased with higher dose changes (overall p 0.002; compared to no dose change: 12.5 mg, OR 1.45, 95% CI 0.48 to 4.44; 25 mg, OR 2.52, 95% CI 1.45 to 4.35; 25 mg, OR 3.24, 95% CI 1.52 to 6.91). Importantly, influence of maximal dose of spironolactone (OR 1.36 per 12.5 mg, 95% CI 1.14 to 1.63), maximal dose changes (OR 1.28 per 12.5 mg, 95% CI 1.07 to 1.52), and mean dose (OR 1.59 per 12.5 mg, 95% CI 1.19 to 2.14) during the first 6 months remained independent predictors of hyperkalemia. Development of hyperkalemia was not associated with worse outcome (p 0.4 for all comparisons). Discussion Hyperkalemia was frequent in this HF population 60 years of age taking part in TIME-CHF. During a period of

5 Heart Failure/Hyperkalemia in Older Patients With HF months of intense HF therapy hyperkalemia was observed in almost 1 of 7 patients. Hyperkalemia was more frequent in patients with a history of gout, more advanced HF symptoms, and higher serum creatinine and potassium levels at baseline. Start and larger changes in spironolactone dose increased the risk of hyperkalemia, whereas other renin angiotensin aldosterone inhibitors and blockers did not. Loop diuretics were also associated with hyperkalemia, but this was related to HF severity. After publication of the Randomized Aldactone Evaluation Study (RALES), Eplerenone Post- Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF), which showed the beneficial effects of spironolactone and eplerenone on outcome in patients with HF, the prescription of aldosterone blockers has increased substantially in patients with HF Notably, in contrast to RALES, which showed a low incidence of hyperkalemia in the active-treatment group (2%), EPHESUS and multiple other studies carried out in less selected populations of patients with HF reported much higher rates of hyperkalemia related to the use of aldosterone blockers. 7,11 16 Results of the present study strongly reinforce the evidence that spironolactone, more than other inhibitors of the renin angiotensin aldosterone system, increases the risk of hyperkalemia in patients with HF, indicating that its use needs particular prudence. In fact, in this population of older patients with HF, hyperkalemia was more common than previously described, particularly when spironolactone was used. Thus, 1 in 5 patients developed hyperkalemia (i.e., 5.5 mmol/l) when the spironolactone dose was increased by 25 mg, and severe hyperkalemia (i.e., 6 mmol/l) occurred in 10% of patients when spironolactone was increased by 25 mg over a time frame of 6 months, suggesting that appropriate monitoring is of utmost importance because it may decrease the risk related to hyperkalemia, 17 particularly in patients having other risk factors for the development of hyperkalemia. The dose of spironolactone may have to be decreased in such patients at risk. 18 The frequency of hyperkalemia increased considerably from baseline to the 1-month visit and again after the 6-month visit. The explanation for this phenomenon is speculative only. The first relevant increase may, however, be related to important intensification of the medical HF treatment at the beginning of the study, whereas the second increase may have been a consequence of the less intensive monitoring of patients owing to a longer gap between the follow-up visits from month 6 and to month 12 and from month 12 to month 18, respectively. This underscores the importance of regular clinical surveillance of patients with HF. 17,19 In the Studies of Left Ventricular Dysfunction (SOLVD) trial, incidences of hyperkalemia ( 5.5 mmol/l) and severe hyperkalemia ( 6.0 mmol/l) of 6% and 1%, respectively, were described during a follow-up of 2.7 years. 1 This is considerably lower than in the present study but may be explained by the use of ACE inhibitors only. Furthermore, prevalence of diabetes mellitus and chronic renal failure was relatively low in the SOLVD population. Chronic renal failure, diabetes mellitus, NYHA class, atrial fibrillation, higher serum potassium levels at baseline, and randomization to ACE inhibitors were identified as predictors of hyperkalemia, which is comparable to the present study. 1 In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study, Desai et al 2 reported clinically relevant hyperkalemia, defined as hyperkalemia leading to study drug decrease or discontinuation, hospitalization, or death, in 1.8% of patients on standard HF treatment (including ACE inhibitors and spironolactone) and in 5.2% on additional therapy with candesartan. Rates of hyperkalemia based on prespecified thresholds of serum potassium levels are not given in this report, impeding a direct comparison with hyperkalemia rates noted in the present population, but they were certainly lower. 2 The patient collectives of these 2 studies were substantially younger, and the prevalence of co-morbidities with a potential to interfere with potassium homeostasis was lower compared to the present population. This may be of particular interest because studies carried out in older, although relatively small, collectives of patients with HF reported a higher incidence of hyperkalemia. 11,12,20 The TIME-CHF population therefore offered the opportunity to analyze rates and predictors of hyperkalemia in a distinctive collective of patients 60 years of age aggressively treated with multiple renin angiotensin aldosterone inhibitors including spironolactone as recommended by the most recent guidelines for treatment of HF. 21 There are limitations to this study. The study was not designed to test the effects of modern HF drug treatment on development of hyperkalemia and the present analysis was conducted post hoc. In addition, patients dying early had less chance to develop hyperkalemia, and as a consequence the potential effects of hyperkalemia on outcome cannot be properly tested. However, it portrays an excellent opportunity to analyze the risk of hyperkalemia in a well-defined and characterized HF population that is quite comparable with the general HF population. Furthermore, patients were closely monitored and changes in medication were recorded meticulously. Thus, our patients received more controls than patients usually receive in daily practice. The increase in the incidence of hyperkalemia after intensifying medical therapy early in the study underscores the importance of such monitoring. It can be speculated that this regular control prevented patients from developing serious consequences of hyperkalemia. 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