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How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure?
Journal of Cardiac Failure Vol. 10 No. 4 2004
How Prevalent Is Hyperkalemia and Renal Dysfunction During Treatment With Spironolactone in Patients With Congestive Heart Failure? MORTEN SVENSSON, MD,1 FINN GUSTAFSSON, MD, PhD,1 SØREN GALATIUS, MD, DMSci,1 PER R. HILDEBRANDT, MD, DMSci,1 AND DAN ATAR, MD, DMSci2 Copenhagen, Denmark; Oslo, Norway
ABSTRACT Background: Treatment with spironolactone (SPL) is beneficial in patients with severe congestive heart failure (CHF). In the Randomized Aldactone Evaluation Study SPL was well tolerated, particularly with regard to renal function and serum K⫹ levels. Our aim was to investigate whether the reported low frequency of adverse effects during SPL treatment in a heart failure study population could be confirmed in an unselected heart failure outpatient cohort and to identify potential predictors of harmful effects. Methods and Results: We investigated 125 consecutive patients with CHF recruited from our heart failure clinic. Inclusion criteria were LVEF (left ventricular ejection fraction) ⱕ45% and treatment with SPL. Blood tests were performed bimonthly or more frequently if necessary. Outcomes measures were (1) increases in serum K⫹ to ⬎5,0, 5.5, 6.0, or 6.5 mmol/L, respectively, and (2) rise in serum creatinine to 120%, 150%, and 200% of baseline, respectively. Mean age was 72.9 years (range 46.5 to 90.6 years); 27% were women. The New York Heart Association class distribution was: I, 6%; II, 44%; III, 46%; and IV, 4%. Mean LVEF was 29 ⫾ 5%. Other medication included angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 86% and β-blockers in 39%. At baseline, serum creatinine levels were 117.6 ⫾ 6.5 (mean ⫾ standard deviation; µmol/L, normal ⬍130) and serum K⫹ was 4.2 ⫾ 0.3 mmol/L. The mean follow-up period was 11 months, and the cumulative observation period was 73 SPL treatment years. Mean peak serum-creatinine was 167.6 µmol/L ⫾ 11.9 (45% increase from baseline) and mean peak serum K⫹ was 5.0 ⫾ 0.4 mmol/L (21% increase from baseline). Sixty patients were already on SPL when admitted to the CHF clinic. The remainder were initiated on SPL. During the follow-up period 36% of the patients developed hyperkalemia (⬎5 mmol/L), with 10% having serum K⫹ ⬎6 mmol/L. An increase in serum creatinine of ⬎20% was seen in 55%, and in 24% an increase of ⬎50% was found. These alterations in serum creatinine and serum K⫹ were not significantly more frequent in patients treated with angiotensin-converting enzyme inhibitors or β-blockers or different doses of SPL. Conclusion: SPL adverse effects (impaired renal function, increase in serum K⫹) are much more prevalent in our elderly CHF patient population than previously reported. The recommendations from our study are that (1) particular caution is mandated in elderly patients with an LVEF ⬍20%, (2) potassium supplementation should be discontinued, (3) changes in body weight should raise concern, and (4) a doseadjustment of the concomitant conventional diuretic regime should be considered. Care should be given to the frequent monitoring of electrolytes and renal parameters. Key Words: Spironolactone, Hyperkalemia, Adverse effects, Heart failure, Dyspnea, Human, Renal function.
From the 1Frederiksberg University Hospital, Department of Cardiology and Endocrinology, Frederiksberg-Copenhagen, Denmark, and 2Aker University Hospital, Division of Cardiology, Oslo, Norway Manuscript received April 28, 2003; revised manuscript received October 6, 2003; revised manuscript accepted October 24, 2003. Reprint requests: Dan Atar, MD, Professor and Head of Cardiology, Aker University Hospital, Division of Cardiology, Trondheimsvn 235, NO0514 Oslo, Norway. E-mail: [email protected].
Supported by grants from Merck Co., Denmark; F. Hoffmann-La Roche Ltd., Denmark; The Research Fund of the Copenhagen Hospital Corporation; the Elisabeth M Schlinsog’s Fund; the Danish Hospital Foundation for Medical Research (Region of Copenhagen, the Faroe Islands and Greenland) (to D.A.); and the Danish Heart Foundation (to D.A.). 1071-9164/$ - see front matter 쑕 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2003.10.012
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A multitude of large intervention studies has shown that pharmacologic treatment of congestive heart failure (CHF) convincingly reduces morbidity and mortality.1,2 Among the more recent trials, the Randomized Aldactone Evaluation Study (RALES)3 has established a beneficial effect on mortality and morbidity of spironolactone (SPL) in patients with severe CHF (New York Heart Association [NYHA] class III-IV). Importantly, SPL was well tolerated in the RALES trial, particularly with regard to renal function and serum potassium levels. Subsequently, the addition of SPL to angiotensin-converting enzyme (ACE) inhibitor and β-blocker therapy has been implemented into the guidelines for treatment of CHF NYHA III-IV patients both in Europe and North America.4,5 Notwithstanding, it is well known that severe renal dysfunction or hyperkalemia may occur during SPL treatment, and the intuitive impression from daily clinical practice is that hyperkalemia is not a rare event in CHF patients. Series of hyperkalemic episodes in CHF patients treated with SPL have previously been reported,6 but no studies on the incidence of hyperkalemia and renal dysfunction in nontrial CHF patients are available. We therefore embarked on a systematic examination of the frequency of adverse renal effects during SPL treatment in a consecutive outpatient heart failure population with the goal of possibly identifying predictors of these potentially harmful effects. Methods The Heart Failure Outpatient Clinic The study was carried out at the heart failure outpatient clinic at Frederiksberg University Hospital, Copenhagen, Denmark. Since September 1999, a heart failure clinic has been in operation at this institution, covering a metropolitan area of Copenhagen of 125,000 inhabitants. The clinic was designed with both a diagnostic and a therapeutic unit. The diagnostic unit offers open access to all patients with suspected heart failure, either through referral from general practitioners or from the medical departments of the hospital. In case of confirmed systolic heart failure dysfunction (defined by a left ventricular ejection fraction [LVEF] ⱕ45%), the patient is referred to the therapeutic unit for (1) uptitration and optimization of medical therapy and (2) comprehensive information and education. In addition, the unit offers a rapid access track and the possibility of intravenous diuretic treatment. All clinical data, blood test results, and drug treatment are recorded prospectively in an electronic database. Details regarding the organization of the clinic and the database have recently been published.7 Treatment With Spironolactone Spironolactone was used according to the international recommendations for heart failure patients.4,5 Initiation and uptitration of ACE inhibitors was attempted in all patients before SPL was considered. The target dose of SPL was 25 mg once daily; however, the dose could be diminished (to 12.5 mg/d) or increased if hypokalemia was present. In the local treatment guidelines it was clearly suggested that potassium supplementation should be discontinued when SPL was initiated and only added again if hypokalemia developed despite SPL treatment. Furthermore, SPL should not be
started in patients with creatinine higher than 150 µmol/L. Beyond these suggestions, the treatment plan in the individual patient was left up to 1 of the 4 senior physicians serving the clinic. Analysis of blood electrolytes was scheduled to take place 1 week after initiation of SPL, and was thereafter performed bimonthly or more frequently if necessary. Data Collection The inclusion period for the current study started on September 1, 1999, and ended on August 30, 2001. During these 24 months information on all patients who were treated with SPL (both for shorter or longer periods) was recorded in the database of the heart failure clinic. Measurements of serum K⫹ and serum creatinine were also recorded in the database. To search for measurements that were not available through the database (for instance, during a hospital admission), the central laboratory computer system of the hospital was interrogated as well. Being a “real-world scenario,” some patients were on and off treatment with SPL during the course in the clinic. For all patients, a “SPL period” was defined as the time from the first prescription to final discontinuation. For patients already on SPL at the time of referral to the clinic, the SPL period was set to begin at the time of referral, because clinical data from the time preceding the course in the heart failure clinic were not available. In all patients treated with SPL, the peak values of serum K⫹ and serum creatinine during the SPL period were traced. Furthermore, the maximum dose of SPL was recorded, as were a number of clinical characteristics noted at the time of entry into the heart failure clinic. Ethics The study was approved by the ethics committee of the Frederiksberg and Copenhagen communities. The funding sources did not have any role in study design, collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the manuscript. Statistics Chi-square tests were used to compare independent groups with categoric data. Continuous baseline data were compared using Student’s t-test. To investigate which baseline characteristics were associated with an increased risk of hyperkalemia or renal dysfunction during SPL treatment, logistic regression analysis was performed. All tests were computed using the SPSS 10.5 software (SPSS Inc, Chicago, IL). P values ⬍.05 were considered significant.
Results During the study period 309 CHF patients with LVEF ⱕ 0.45 were enrolled into the heart failure clinic. Of these, 125 consecutive patients underwent treatment with SPL. Sixty of the 125 patients were on SPL before referral to our clinic, whereas 65 started later during their course. The patients treated with SPL were elderly, with a mean age of 72.9 years (range 46.5 to 90.6 years), and 27% were women. Table 1 shows the baseline characteristics of the study population. Of the 125 patients, 48 were at some time treated with 50 mg of SPL daily. As suggested in the treatment guidelines, most of the patients (71%) that
Spironolactone in Heart Failure Table 1. Baseline Characteristics of the Heart Failure Population Studied Age (y) Female (%) LVEF (%) Creatinine (µmol/L) S-K⫹ (mmol/L) NYHA-cl. I, II, III, IV (%) ACE-I or ARB (%) Potassium suppl (%) Digitalis (%) ß-blockers (%)
72.9 (range 46.5–90.6) 27.4 28.8 ⫾ 4.5 117.6 ⫾ 6.5 4.2 ⫾ 0.3 5.7, 43.9, 46.3, 4.1 86 74 38 39
LVEF, left ventricular ejection fraction; S-K⫹, serum-potassium; NYHA-cl., New York Heart Association dyspnea class; ACE-I, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker; Potassium suppl., potassium supplementation. Data are mean ⫾ SD except where annotated.
were initiated on SPL had their potassium supplementation discontinued or reduced, whereas the remainder (29%) stayed on supplementation therapy, most often because of an observed tendency to hypokalemia. Loop diuretic mean dose among the 125 spironolactone patients was 144 mg (⫾107 mg) (expressed as furosemide equivalent). Noncardiac medications were also recorded. For example, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was very restricted in this population: only 2 of 125 patients took any NSAIDs during SPL treatment. Overall 6 of 125 patients had taken any NSAID at any time point while enrolled in the heart failure clinic. The 125 patients on SPL were observed over a mean period of 370 days (range 1 to 696 days) comprising 201 days on treatment with SPL (range 1 to 658 days), resulting in a total (combined) observation time of 73.0 patient years. Each patient was seen in the outpatient clinic on average 11.1 times (range 1 to 45 times) with a mean interval of 22.9 days (range 0.5 to 165 days) between each visit. The pattern of follow-up was characterized by a mandatory weekly visit at the initial weeks 1 through 8 and increasing time intervals after week 12. Approximately 7% of the contacts were either managed solely by telephone and therefore not followed by a blood sample or there was a genuine consultation without a blood sample. Most patients (91.2%) had 1 continuous period of SPL treatment, whereas the remainder started and stopped treatment with SPL more than once. To contrast the SPL-treated population to the patients not treated with SPL, baseline characteristics of the latter group are shown in Table 2. The major difference was the high
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percentage of NYHA class I and II patients (75%). The explanation of why these 184 patients did not receive SPL is that they did not meet the established treatment criteria for SPL. At baseline, the mean serum creatinine concentration was 117.6 ⫾ 6.5 µmol/L. Thirty-seven patients (29.6%) had serum creatinine levels ⬎130 µmol/L (upper normal reference value) and 3 had levels ⬎220 µmol/L. The mean serum K⫹ concentration was 4.2 ⫾ 0.3 mmol/L at baseline, and 7 patients (6%) had a serum K⫹ ⬎5 mmol/L. These 7 patients (and the 3 patients mentioned with serum creatinine levels ⬎220 µmol/L) belonged to the group that had started SPL before referral to the heart failure clinic. SPL would not have been initiated in such patients according to the guidelines of the clinic. At the end of the observation period 23 patients (18%) had died and 35% of the patients had been referred back to their general practitioner because their heart failure symptoms were regarded stable and their medication had been optimized. The peak serum creatinine concentration in the 125 patients treated with SPL was 167.6 ⫾ 11.9 µmol/L (mean ⫾ standard deviation). In 72 patients (58%) serum creatinine exceeded 130 µmol/L; 23 of these (18% of the total cohort) reached serum creatinine levels ⬎220 µmol/L. Figure 1A depicts the increase in serum creatinine relative to the baseline value. The mean percent increase in serum creatinine in the SPL treatment period was 45%. The peak serum K⫹ concentration was 5.0 ⫾ 0.4 mmol/ L (up from baseline serum K⫹ 4.2 ⫾ 0.3 mmol/L). A total of 45 patients (36%) reached serum K⫹ concentrations ⬎5 mmol/L, and serum K⫹ exceeded 6 mmol/L in 12 patients (9.6%). Figure 1B shows the percentage of patients encountering at least 1 episode of hyperkalemia.
Table 2. Baseline Characteristics of the Heart Failure Population (n ⫽ 184) Not Receiving Spironolactone Age (y) LVEF (%) NYHA III-IV (n; %) Creatinine (µmol/L) S-K⫹ (mmol/L)
Female (%)
72.2 ⫾ 11.5 29.5 ⫾ 8.9 46 (25) 112 ⫾ 68
4.0 ⫾ 0.4 27
LVEF, left ventricular ejection fraction; S-K⫹, serum-potassium; NYHA-cl., New York Heart Association dyspnea class. Data are mean ⫾ SD except where annotated.
Fig. 1. (a) Graph depicting the percent of distribution of patients and their respective increase in creatinine encountered in the heart failure population studied. (b) Graph showing the percent of distribution of patients and their respective peak serum potassium measured during their observation period in the heart failure clinic.
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Because a substantial fraction of patients was already taking SPL when entering this study, we analyzed this subgroup (n ⫽ 60) and the patients newly initiated on SPL (n ⫽ 65) separately. The incidence of severe hyperkalemia (serum K⫹ ⬎6.0 mmol/L) in the on-treatment group was 8.3% and in the start-up group 10.8% (an absolute difference of 2.5%, which was nonsignificant (95 confidence interval [CI]: ⫺7.0 to 12.5%; P ⫽ .63). For the development of renal dysfunction (50% increase in serum creatinine from baseline), the incidence was 23.3% in the on-treatment group and 24.6% in the start-up group (absolute difference 1.3% [95 CI: ⫺9% to 12%, P ⫽ .81; not significant]). Table 3 shows a stratification of patients developing hyperkalemia according to baseline creatinine and loop diuretic dose. There is a nonsignificant trend to higher creatinine in those patients who develop episodes of hyperkalemia. Changes in body weight were analyzed in the subgroup of patients with newly initiated SPL therapy: 44 of 65 patients had body weight data available both at baseline and at an early follow-up time point arbitrarily defined at 1 to 3 weeks after baseline. The mean weight loss was 1.3 ⫾ 2.7 kg. Among the 12 patients that had episodes of hyperkalemia with a serum K⫹ level ⬎6.0 mmol/L, 8 died while being enrolled at the heart failure clinic; however, 5 of them previously had had their spironolactone discontinued, which left 3 patients dying during the spironolactone follow-up. None of the patients needed renal replacement or had acute renal failure. To identify potential predictors of creatinine increase during SPL treatment, a multivariate logistic regression analysis was performed including the following variables: age, gender, NYHA class, LVEF, ACE inhibitor treatment at baseline, and β-blocker treatment at baseline. There were no missing data in the analysis. In this model, only age emerged as a potent independent risk factor for developing a 50% increase in creatinine during treatment with SPL (risk ratio [RR] 1.74 (1.03 to 2.91) per higher age decade). Furthermore, decreased LVEF was a weak, but significant independent risk factor for developing a 50% increase in creatinine (RR 0.94 [0.89–0.99] per 10% increase in LVEF). Similarly a model was created to identify predictors of severe hyperkalemia (serum K⫹ ⬎6.0 mmol/L). In addition
Table 3. Stratification of Patients Developing Hyperkalemia According to Baseline Creatinine and Loop Diuretic Dose
Baseline creatinine (µmol/L) Mean loop diuretic dose (expressed as furosemide equivalent; mg)
No Hyperkalemia
Patients with Episode of S-K⫹ ⬎6.0 mmol/L
115 ⫾ 43
136 ⫾ 48 (P ⫽ .17)
143 ⫾ 107
146 ⫾ 108 (P ⫽ NS)
Data are mean ⫾ SD. S-K⫹, serum-potassium; NS, not significant.
to the parameters mentioned previously, this model included baseline creatinine and the use of potassium supplementation at baseline. In this model decreased LVEF emerged as most predictive of hyperkalemia (RR 0.37 [0.15–0.85] per 10% increase in LVEF). NYHA class was also associated with a significantly increased risk of serious hyperkalemia (RR 3.36 [1.17 to 9.69] per NYHA class increase). None of the other covariates displayed an independent influence on the risk of developing hyperkalemia. Discussion We found that treatment with SPL in CHF patients resulted in side effects including hyperkalemia and renal dysfunction, which were considerably more frequently than the previously reported figures from the RALES study but—in the case of hyperkalemia—similar to those reported in smaller reports. Age, decreased LVEF, and higher NYHA class emerged as predictors of harmful effects. In the context of hyperkalemia and SPL therapy, one mandatory piece of evidence and comparison is the preRALES pilot study of 1996.8 The investigation consisted of 214 patients, revealing a dose-response in the incidence of hyperkalemia defined as serum K⫹ ⬎5.5 mmol/L in the 4 SPL treatment groups of 12.5 mg, 25 mg, 50 mg, and 75 mg, respectively. The incidence of hyperkalemia here was 5%, 13%, 20%, and 24%, respectively, and predictors for the development of hyperkalemia were the use of ACE inhibitors and a baseline elevation of potassium or creatinine. The treatment was considered safe provided that serum K⫹ levels were monitored closely. More recently Vanpee et al reported 4 cases of severe hyperkalemia in CHF patients,9 with a SPL dose regimen that exceeded the recommended SPL dosages for CHF. The authors emphasized the need for correct dosage and close monitoring of frail, elderly CHF patients. In 2001 several publications reported small casuistic series of CHF patients with side effects from SPL treatment (eg, Berry et al documenting 4 cases of hyperkalemia in CHF patients).10 Another recent study reported on 25 CHF patients who had developed severe hyperkalemia, but 16 of the 25 patients had received 50 mg SPL or more per day.11 In the RALES study comprising 1663 patients, the baseline characteristics portrayed a 7-year younger population than our 125 nontrial patients.3 The proportion of females was equal (27%), whereas the proportion of NYHA III-IV class was 51% in our cohort as compared with almost 100% in RALES. This is partly because SPL initiation—60 of our patients were already on SPL when admitted to the heart failure clinic—and the evaluation of NYHA class were not done simultaneously. Furthermore, a slightly higher LVEF in our population (29% versus 26% in RALES) and a significantly lower proportion of patients treated with ACE inhibitors (64%) or angiotensin receptor blockers (20%) (taken together 84% versus 95% ACE inhibitors in RALES) were recorded. The latter difference is probably
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explained by the decreasing creatinine clearance detected in the advanced age population of our study, and hence a higher proportion of patients intolerant of ACE inhibitors. Digitalis was used in 31% versus 75% in RALES, a difference that might be explained on grounds of geographic differences in treatment traditions. With regard to potassium supplementation, 74% of our cohort received this type of medication versus 29% in RALES, reflecting that one of the indications for SPL initiation in our clinic was refractory hypokalemia as well as edema or deteriorating heart failure in otherwise maximally treated patients (requiring additional use of highceiling diuretics and potassium supplementation). Also, a considerably higher proportion of patients in our cohort was treated with β-blockers (39% versus 11% in RALES), which again is presumably a matter of age, but may also be explained by the lower proportion of patients treated with ACE inhibitors. In fact, 11% of our population received β-blockers and no ACE inhibitors, whereas 28% received both. Further, some of the major β-blocker trials in heart failure had not been published at the time of enrollment into the RALES study. Although these patient baseline characteristics clearly show differences between our cohort and the one enrolled in the RALES study, it is still noteworthy how large a proportion of our patients (36%) developed hyperkalemia (serum K⫹ ⬎5 mmol/L) or severe hyperkalemia with serum K⫹ ⬎6 mmol/L (10% versus 2% in RALES) even though they were meticulously followed with regular laboratory workups. In line with these findings, the development of renal dysfunction in our population was striking, with 55% encountering a rise in serum creatinine to ⬎120% of their baseline, 24% suffering from a rise to ⬎150% of baseline, and 9% of the patients doubling their serum creatinine level. In contrast, the reported mean creatinine increase in RALES was as low as 9 µmol/L. Fifty percent of our patients were in NYHA class II (or I), which is also different from the RALES population. When scrutinizing this subpopulation it turns out that only 25 of the 65 patients were actually initiated on SPL at our heart failure clinic (ie, a substantial fraction of the patients were already on treatment with SPL before admission). Of these, 17 (68%) also received potassium supplementation, which likely means that the caregivers aimed at counteracting diuretic-induced hypokalemia. In fact—and importantly—this is in line with the European Society of Cardiology guidelines for the use of SPL in CHF. This idea is further supported by the fact that among all NYHA I and II patients, there was a (yet nonsignificant) tendency to lower potassium levels in the SPL-treated as compared with the non–SPL-treated patients. In other words, one rationale in this subpopulation was to omit large quantities of potassium supplements. One further point of consideration is that CHF patients will often be treated with SPL in case of worsening heart failure (even if their baseline NYHA class is II), and individual indications according to how different treating doctors perceive the patients’ complaints may vary in such cases. This does not mean that the treatment protocol of the heart
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failure clinic is not in accordance with international guidelines. In fact, we believe that our data very much mirror daily clinical practice, which made us use the term “real life.” Moreover, given the difference of our patients from the RALES population in terms of NYHA class, the patients should not be more prone to electrolyte disturbances; one would rather expect the opposite. In this context, the use of aldosterone antagonism in milder forms of cardiomyopathy has gained further support through the recent Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) trial.12 Although the current study was not a placebo-controlled, blinded trial, baseline characteristics of the patients not treated with spironolactone can be informative contrasting the study group per se. These characteristics were therefore compiled (Table 2), showing the major difference between these 2 populations being the higher percentage (75%) of NYHA class I and II patients in the non-SPL patients. Because the treatment algorithm of the heart failure clinic was established according to international guidelines, the explanation why the 184 patients did not receive SPL is, simply, that they did not meet the established treatment criteria for SPL. Excessive diuresis with prerenal uremia might be a potentially important cause of renal dysfunction during SPL treatment. When analyzing weight data of our cohort, a slight weight loss of 1.3 kg (mean) was recorded, in contrast to the RALES study, in which there was reported to be no weight loss in the SPL treatment group. Also, the loop diuretic mean dose among our 125 SPL patients was considerably higher than in RALES (144 mg versus 80 mg). This may reflect that RALES investigators had cut back on conventional diuretic doses when renal disturbances were noted. Hence an effective way of dealing with renal dysfunction secondary to SPL may be to cut back the dose of conventional diuretic therapy, a recommendation that cautiously may be deducted from our findings. One potential confounder and promoter of renal and electrolyte disturbances is polypharmacy in our elderly CHF population. In many cardiovascular studies, concomitantly administered noncardiac drugs are escaping the rigorous scrutiny of the investigators, even though they may contribute significantly to recorded side effects. One such class of compounds are the NSAIDs, whose utilization in elderly populations often is inappropriately excessive. We found that the concomitant administration of any NSAID and SPL was negligibly small (occurring in 2 of 125 SPL patients). This may underscore that contraindications arising from known drug-drug interactions are taken seriously when treating the severely ill CHF population in our specialized outpatient clinic. It is important, however, to keep in mind that our study was not a placebo-controlled trial. Hence one cannot directly attribute the side effects found to the use of spironolactone. The scope of the article was to evaluate the side effects in CHF patients treated with spironolactone rather than to evaluate the side effects of spironolactone per se—this needs
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to be addressed using a placebo-controlled design. Furthermore, because this study has no control group, it is difficult to know whether SPL actually contributes to either the hyperkalemia or the increased creatinine levels. Even further, conceptually one cannot just imply that SPL causes increased creatinine levels, as the natural history of CHF is that renal function deteriorates steadily. One does not even know whether small changes in creatinine are relevant, because previous trials such as CONSENSUS13 have taught us the opposite. In fact, creatinine is a very poor marker of renal function, and increases in creatinine levels are far from irreversible but may simply represent overdiuresis. Nevertheless, and taking all these considerations into account, the main message of the study is still that electrolyte profiles should be monitored very carefully in elderly patients based on the findings of our study. With regard to the high mortality (66%) during our observation period of the 12 patients that had episodes of hyperkalemia with a serum K⫹ level ⬎6.0 mmol/L, one cannot deduct any causality from these numbers (ie, mortality is not directly attributable to hyperkalemia). With regard to declining renal function, none of the patients needed renal replacement or had acute renal failure. This may be due in part to the close monitoring of creatinine. Importantly, as a result of trials measuring human serum aldosterone levels, it has recently been argued that also patients suffering from mild dyspnea (NYHA II) could benefit from SPL treatment.14 More advanced drugs such as canrenone or eplerenone may become important substitutes of SPL for future CHF treatment indications, yet their side effect profiles still await full elucidation. In fact, the recently published EPHESUS trial12 has shown that eplerenone reduces both mortality and cardiovascular hospitalizations in postinfarction patients with left ventricular dysfunction. Patients with elevated serum creatinine concentration or serum K⫹ ⬎5 mmol/L were excluded from the study. Follow-up measurements of potassium and creatinine were performed frequently. Interestingly, the rate of serious hyperkalemia was 5.5% in the eplerenone group and 3.9% in the placebo group. EPHESUS patients had substantially less impaired left ventricular function and less severe heart failure than did patients in RALES and were much more likely to be receiving other recommended medications, yet still they benefited from aldosterone blockade. Nevertheless eplerenone appears to be as likely as SPL to cause hyperkalemia and renal insufficiency. In our search for potential predictors of creatinine increase and severe hyperkalemia during SPL treatment, we did not find baseline serum K⫹, baseline serum creatinine, SPL dosing, nor discontinuation of potassium supplementation as predictors of hyperkalemia. Only age and decreased LVEF emerged as independent risk factors for developing renal dysfunction, and decreased LVEF and higher NYHA class emerged as most predictive of hyperkalemia. During the follow-up course presented in the present study (comprising an average work-up every 23rd day for a mean
period of 11 months), the adverse effects were not satisfactorily avoided. The conclusions from our study are that (1) particular caution is mandated in elderly patients with an LVEF ⬍20%, (2) potassium supplementation should be discontinued, (3) changes in body weight should raise additional concern, and (4) a dose-adjustment of the concomitant conventional diuretic regime should be considered. Even though our data do not pinpoint decreased renal function as a predicting factor (see Table 3), we concur with the recently published suggestions of Blaustein et al15 stating that patients with severe underlying chronic renal failure should not be considered eligible for SPL therapy, even if they fulfill the inclusion criteria according to the RALES study. An estimation of creatinine clearance in each patient, using the Cockcroft and Gault formula,16 which computes both serum creatinine and body weight, age, gender, and muscle mass, may be a means to identify patients at particularly high risk. Conclusion Taken together, SPL adverse effects, in particular impaired renal function and hyperkalemia, are much more prevalent in an elderly CHF patient population as described in the present study than previously reported. Elderly patients with poor systolic function or low functional class appear to be particularly at risk, yet this population does have the greatest potential benefit because of the high baseline risk. Again this serves as a reminder that care should be given to the frequent monitoring of electrolytes and renal parameters. Above and beyond this conclusion, these findings shed an ambiguous light on the recurrent, yet unexplained observation that patients participating in placebo-controlled, international, multicenter, randomized, double-blind trials differ from those admitted to an outpatient clinic “in the real world,” even though the formal inclusion/exclusion criteria are comparable.
Acknowledgments We are indebted to the staff of the heart failure clinic: Per H. Nielsen, RN; Hanne Bartholdy, RN; Ingelise Henriksen, RN; and Louise Flye Jensen, RN.
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11. Schepkens H, Vanholder R, Billiouw J-M, Lameire N. Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med 2001;110:438–41. 12. Pitt B, Remme W, Zannad F, Neaton J, Gatlin M, Roniker B, et al. EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study): a double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of eplerenone in patients with heart failure following acute myocardial infarction. N Engl J Med 2003; 348:1309–21. 13. Ljungman S, Kjekshus J, Swedberg K. Renal function in severe congestive heart failure during treatment with enalapril (the Cooperative North Scandinavian Enalapril Survival Study [CONSENSUS] Trial). Am J Cardiol 1992;70:479–87. 14. Zannad F, Dousset B, Alla F. Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension 2001;38:1227–32. 15. Blaustein D, Babu K, Reddy A, Schwenk M, Avram M. Estimation of glomerular filtration rate to prevent life-threatening hyperkalemia due to combined therapy with spironolactone and angiotensin-converting enzyme inhibition or angiotensin receptor blockade. Am J Cardiol 2002;90:662–3. 16. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.
How Prevalent Is Hyperkalemia and Renal Dysfunction During Treatment With Spironolactone in Patients With Congestive Heart Failure? MORTEN SVENSSON, MD,1 FINN GUSTAFSSON, MD, PhD,1 SØREN GALATIUS, MD, DMSci,1 PER R. HILDEBRANDT, MD, DMSci,1 AND DAN ATAR, MD, DMSci2 Copenhagen, Denmark; Oslo, Norway
ABSTRACT Background: Treatment with spironolactone (SPL) is beneficial in patients with severe congestive heart failure (CHF). In the Randomized Aldactone Evaluation Study SPL was well tolerated, particularly with regard to renal function and serum K⫹ levels. Our aim was to investigate whether the reported low frequency of adverse effects during SPL treatment in a heart failure study population could be confirmed in an unselected heart failure outpatient cohort and to identify potential predictors of harmful effects. Methods and Results: We investigated 125 consecutive patients with CHF recruited from our heart failure clinic. Inclusion criteria were LVEF (left ventricular ejection fraction) ⱕ45% and treatment with SPL. Blood tests were performed bimonthly or more frequently if necessary. Outcomes measures were (1) increases in serum K⫹ to ⬎5,0, 5.5, 6.0, or 6.5 mmol/L, respectively, and (2) rise in serum creatinine to 120%, 150%, and 200% of baseline, respectively. Mean age was 72.9 years (range 46.5 to 90.6 years); 27% were women. The New York Heart Association class distribution was: I, 6%; II, 44%; III, 46%; and IV, 4%. Mean LVEF was 29 ⫾ 5%. Other medication included angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in 86% and β-blockers in 39%. At baseline, serum creatinine levels were 117.6 ⫾ 6.5 (mean ⫾ standard deviation; µmol/L, normal ⬍130) and serum K⫹ was 4.2 ⫾ 0.3 mmol/L. The mean follow-up period was 11 months, and the cumulative observation period was 73 SPL treatment years. Mean peak serum-creatinine was 167.6 µmol/L ⫾ 11.9 (45% increase from baseline) and mean peak serum K⫹ was 5.0 ⫾ 0.4 mmol/L (21% increase from baseline). Sixty patients were already on SPL when admitted to the CHF clinic. The remainder were initiated on SPL. During the follow-up period 36% of the patients developed hyperkalemia (⬎5 mmol/L), with 10% having serum K⫹ ⬎6 mmol/L. An increase in serum creatinine of ⬎20% was seen in 55%, and in 24% an increase of ⬎50% was found. These alterations in serum creatinine and serum K⫹ were not significantly more frequent in patients treated with angiotensin-converting enzyme inhibitors or β-blockers or different doses of SPL. Conclusion: SPL adverse effects (impaired renal function, increase in serum K⫹) are much more prevalent in our elderly CHF patient population than previously reported. The recommendations from our study are that (1) particular caution is mandated in elderly patients with an LVEF ⬍20%, (2) potassium supplementation should be discontinued, (3) changes in body weight should raise concern, and (4) a doseadjustment of the concomitant conventional diuretic regime should be considered. Care should be given to the frequent monitoring of electrolytes and renal parameters. Key Words: Spironolactone, Hyperkalemia, Adverse effects, Heart failure, Dyspnea, Human, Renal function.
From the 1Frederiksberg University Hospital, Department of Cardiology and Endocrinology, Frederiksberg-Copenhagen, Denmark, and 2Aker University Hospital, Division of Cardiology, Oslo, Norway Manuscript received April 28, 2003; revised manuscript received October 6, 2003; revised manuscript accepted October 24, 2003. Reprint requests: Dan Atar, MD, Professor and Head of Cardiology, Aker University Hospital, Division of Cardiology, Trondheimsvn 235, NO0514 Oslo, Norway. E-mail: [email protected].
Supported by grants from Merck Co., Denmark; F. Hoffmann-La Roche Ltd., Denmark; The Research Fund of the Copenhagen Hospital Corporation; the Elisabeth M Schlinsog’s Fund; the Danish Hospital Foundation for Medical Research (Region of Copenhagen, the Faroe Islands and Greenland) (to D.A.); and the Danish Heart Foundation (to D.A.). 1071-9164/$ - see front matter 쑕 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2003.10.012
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A multitude of large intervention studies has shown that pharmacologic treatment of congestive heart failure (CHF) convincingly reduces morbidity and mortality.1,2 Among the more recent trials, the Randomized Aldactone Evaluation Study (RALES)3 has established a beneficial effect on mortality and morbidity of spironolactone (SPL) in patients with severe CHF (New York Heart Association [NYHA] class III-IV). Importantly, SPL was well tolerated in the RALES trial, particularly with regard to renal function and serum potassium levels. Subsequently, the addition of SPL to angiotensin-converting enzyme (ACE) inhibitor and β-blocker therapy has been implemented into the guidelines for treatment of CHF NYHA III-IV patients both in Europe and North America.4,5 Notwithstanding, it is well known that severe renal dysfunction or hyperkalemia may occur during SPL treatment, and the intuitive impression from daily clinical practice is that hyperkalemia is not a rare event in CHF patients. Series of hyperkalemic episodes in CHF patients treated with SPL have previously been reported,6 but no studies on the incidence of hyperkalemia and renal dysfunction in nontrial CHF patients are available. We therefore embarked on a systematic examination of the frequency of adverse renal effects during SPL treatment in a consecutive outpatient heart failure population with the goal of possibly identifying predictors of these potentially harmful effects. Methods The Heart Failure Outpatient Clinic The study was carried out at the heart failure outpatient clinic at Frederiksberg University Hospital, Copenhagen, Denmark. Since September 1999, a heart failure clinic has been in operation at this institution, covering a metropolitan area of Copenhagen of 125,000 inhabitants. The clinic was designed with both a diagnostic and a therapeutic unit. The diagnostic unit offers open access to all patients with suspected heart failure, either through referral from general practitioners or from the medical departments of the hospital. In case of confirmed systolic heart failure dysfunction (defined by a left ventricular ejection fraction [LVEF] ⱕ45%), the patient is referred to the therapeutic unit for (1) uptitration and optimization of medical therapy and (2) comprehensive information and education. In addition, the unit offers a rapid access track and the possibility of intravenous diuretic treatment. All clinical data, blood test results, and drug treatment are recorded prospectively in an electronic database. Details regarding the organization of the clinic and the database have recently been published.7 Treatment With Spironolactone Spironolactone was used according to the international recommendations for heart failure patients.4,5 Initiation and uptitration of ACE inhibitors was attempted in all patients before SPL was considered. The target dose of SPL was 25 mg once daily; however, the dose could be diminished (to 12.5 mg/d) or increased if hypokalemia was present. In the local treatment guidelines it was clearly suggested that potassium supplementation should be discontinued when SPL was initiated and only added again if hypokalemia developed despite SPL treatment. Furthermore, SPL should not be
started in patients with creatinine higher than 150 µmol/L. Beyond these suggestions, the treatment plan in the individual patient was left up to 1 of the 4 senior physicians serving the clinic. Analysis of blood electrolytes was scheduled to take place 1 week after initiation of SPL, and was thereafter performed bimonthly or more frequently if necessary. Data Collection The inclusion period for the current study started on September 1, 1999, and ended on August 30, 2001. During these 24 months information on all patients who were treated with SPL (both for shorter or longer periods) was recorded in the database of the heart failure clinic. Measurements of serum K⫹ and serum creatinine were also recorded in the database. To search for measurements that were not available through the database (for instance, during a hospital admission), the central laboratory computer system of the hospital was interrogated as well. Being a “real-world scenario,” some patients were on and off treatment with SPL during the course in the clinic. For all patients, a “SPL period” was defined as the time from the first prescription to final discontinuation. For patients already on SPL at the time of referral to the clinic, the SPL period was set to begin at the time of referral, because clinical data from the time preceding the course in the heart failure clinic were not available. In all patients treated with SPL, the peak values of serum K⫹ and serum creatinine during the SPL period were traced. Furthermore, the maximum dose of SPL was recorded, as were a number of clinical characteristics noted at the time of entry into the heart failure clinic. Ethics The study was approved by the ethics committee of the Frederiksberg and Copenhagen communities. The funding sources did not have any role in study design, collection, analysis, and interpretation of data; in the writing of the report; nor in the decision to submit the manuscript. Statistics Chi-square tests were used to compare independent groups with categoric data. Continuous baseline data were compared using Student’s t-test. To investigate which baseline characteristics were associated with an increased risk of hyperkalemia or renal dysfunction during SPL treatment, logistic regression analysis was performed. All tests were computed using the SPSS 10.5 software (SPSS Inc, Chicago, IL). P values ⬍.05 were considered significant.
Results During the study period 309 CHF patients with LVEF ⱕ 0.45 were enrolled into the heart failure clinic. Of these, 125 consecutive patients underwent treatment with SPL. Sixty of the 125 patients were on SPL before referral to our clinic, whereas 65 started later during their course. The patients treated with SPL were elderly, with a mean age of 72.9 years (range 46.5 to 90.6 years), and 27% were women. Table 1 shows the baseline characteristics of the study population. Of the 125 patients, 48 were at some time treated with 50 mg of SPL daily. As suggested in the treatment guidelines, most of the patients (71%) that
Spironolactone in Heart Failure Table 1. Baseline Characteristics of the Heart Failure Population Studied Age (y) Female (%) LVEF (%) Creatinine (µmol/L) S-K⫹ (mmol/L) NYHA-cl. I, II, III, IV (%) ACE-I or ARB (%) Potassium suppl (%) Digitalis (%) ß-blockers (%)
72.9 (range 46.5–90.6) 27.4 28.8 ⫾ 4.5 117.6 ⫾ 6.5 4.2 ⫾ 0.3 5.7, 43.9, 46.3, 4.1 86 74 38 39
LVEF, left ventricular ejection fraction; S-K⫹, serum-potassium; NYHA-cl., New York Heart Association dyspnea class; ACE-I, angiotensinconverting enzyme inhibitor; ARB, angiotensin receptor blocker; Potassium suppl., potassium supplementation. Data are mean ⫾ SD except where annotated.
were initiated on SPL had their potassium supplementation discontinued or reduced, whereas the remainder (29%) stayed on supplementation therapy, most often because of an observed tendency to hypokalemia. Loop diuretic mean dose among the 125 spironolactone patients was 144 mg (⫾107 mg) (expressed as furosemide equivalent). Noncardiac medications were also recorded. For example, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) was very restricted in this population: only 2 of 125 patients took any NSAIDs during SPL treatment. Overall 6 of 125 patients had taken any NSAID at any time point while enrolled in the heart failure clinic. The 125 patients on SPL were observed over a mean period of 370 days (range 1 to 696 days) comprising 201 days on treatment with SPL (range 1 to 658 days), resulting in a total (combined) observation time of 73.0 patient years. Each patient was seen in the outpatient clinic on average 11.1 times (range 1 to 45 times) with a mean interval of 22.9 days (range 0.5 to 165 days) between each visit. The pattern of follow-up was characterized by a mandatory weekly visit at the initial weeks 1 through 8 and increasing time intervals after week 12. Approximately 7% of the contacts were either managed solely by telephone and therefore not followed by a blood sample or there was a genuine consultation without a blood sample. Most patients (91.2%) had 1 continuous period of SPL treatment, whereas the remainder started and stopped treatment with SPL more than once. To contrast the SPL-treated population to the patients not treated with SPL, baseline characteristics of the latter group are shown in Table 2. The major difference was the high
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percentage of NYHA class I and II patients (75%). The explanation of why these 184 patients did not receive SPL is that they did not meet the established treatment criteria for SPL. At baseline, the mean serum creatinine concentration was 117.6 ⫾ 6.5 µmol/L. Thirty-seven patients (29.6%) had serum creatinine levels ⬎130 µmol/L (upper normal reference value) and 3 had levels ⬎220 µmol/L. The mean serum K⫹ concentration was 4.2 ⫾ 0.3 mmol/L at baseline, and 7 patients (6%) had a serum K⫹ ⬎5 mmol/L. These 7 patients (and the 3 patients mentioned with serum creatinine levels ⬎220 µmol/L) belonged to the group that had started SPL before referral to the heart failure clinic. SPL would not have been initiated in such patients according to the guidelines of the clinic. At the end of the observation period 23 patients (18%) had died and 35% of the patients had been referred back to their general practitioner because their heart failure symptoms were regarded stable and their medication had been optimized. The peak serum creatinine concentration in the 125 patients treated with SPL was 167.6 ⫾ 11.9 µmol/L (mean ⫾ standard deviation). In 72 patients (58%) serum creatinine exceeded 130 µmol/L; 23 of these (18% of the total cohort) reached serum creatinine levels ⬎220 µmol/L. Figure 1A depicts the increase in serum creatinine relative to the baseline value. The mean percent increase in serum creatinine in the SPL treatment period was 45%. The peak serum K⫹ concentration was 5.0 ⫾ 0.4 mmol/ L (up from baseline serum K⫹ 4.2 ⫾ 0.3 mmol/L). A total of 45 patients (36%) reached serum K⫹ concentrations ⬎5 mmol/L, and serum K⫹ exceeded 6 mmol/L in 12 patients (9.6%). Figure 1B shows the percentage of patients encountering at least 1 episode of hyperkalemia.
Table 2. Baseline Characteristics of the Heart Failure Population (n ⫽ 184) Not Receiving Spironolactone Age (y) LVEF (%) NYHA III-IV (n; %) Creatinine (µmol/L) S-K⫹ (mmol/L)
Female (%)
72.2 ⫾ 11.5 29.5 ⫾ 8.9 46 (25) 112 ⫾ 68
4.0 ⫾ 0.4 27
LVEF, left ventricular ejection fraction; S-K⫹, serum-potassium; NYHA-cl., New York Heart Association dyspnea class. Data are mean ⫾ SD except where annotated.
Fig. 1. (a) Graph depicting the percent of distribution of patients and their respective increase in creatinine encountered in the heart failure population studied. (b) Graph showing the percent of distribution of patients and their respective peak serum potassium measured during their observation period in the heart failure clinic.
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Because a substantial fraction of patients was already taking SPL when entering this study, we analyzed this subgroup (n ⫽ 60) and the patients newly initiated on SPL (n ⫽ 65) separately. The incidence of severe hyperkalemia (serum K⫹ ⬎6.0 mmol/L) in the on-treatment group was 8.3% and in the start-up group 10.8% (an absolute difference of 2.5%, which was nonsignificant (95 confidence interval [CI]: ⫺7.0 to 12.5%; P ⫽ .63). For the development of renal dysfunction (50% increase in serum creatinine from baseline), the incidence was 23.3% in the on-treatment group and 24.6% in the start-up group (absolute difference 1.3% [95 CI: ⫺9% to 12%, P ⫽ .81; not significant]). Table 3 shows a stratification of patients developing hyperkalemia according to baseline creatinine and loop diuretic dose. There is a nonsignificant trend to higher creatinine in those patients who develop episodes of hyperkalemia. Changes in body weight were analyzed in the subgroup of patients with newly initiated SPL therapy: 44 of 65 patients had body weight data available both at baseline and at an early follow-up time point arbitrarily defined at 1 to 3 weeks after baseline. The mean weight loss was 1.3 ⫾ 2.7 kg. Among the 12 patients that had episodes of hyperkalemia with a serum K⫹ level ⬎6.0 mmol/L, 8 died while being enrolled at the heart failure clinic; however, 5 of them previously had had their spironolactone discontinued, which left 3 patients dying during the spironolactone follow-up. None of the patients needed renal replacement or had acute renal failure. To identify potential predictors of creatinine increase during SPL treatment, a multivariate logistic regression analysis was performed including the following variables: age, gender, NYHA class, LVEF, ACE inhibitor treatment at baseline, and β-blocker treatment at baseline. There were no missing data in the analysis. In this model, only age emerged as a potent independent risk factor for developing a 50% increase in creatinine during treatment with SPL (risk ratio [RR] 1.74 (1.03 to 2.91) per higher age decade). Furthermore, decreased LVEF was a weak, but significant independent risk factor for developing a 50% increase in creatinine (RR 0.94 [0.89–0.99] per 10% increase in LVEF). Similarly a model was created to identify predictors of severe hyperkalemia (serum K⫹ ⬎6.0 mmol/L). In addition
Table 3. Stratification of Patients Developing Hyperkalemia According to Baseline Creatinine and Loop Diuretic Dose
Baseline creatinine (µmol/L) Mean loop diuretic dose (expressed as furosemide equivalent; mg)
No Hyperkalemia
Patients with Episode of S-K⫹ ⬎6.0 mmol/L
115 ⫾ 43
136 ⫾ 48 (P ⫽ .17)
143 ⫾ 107
146 ⫾ 108 (P ⫽ NS)
Data are mean ⫾ SD. S-K⫹, serum-potassium; NS, not significant.
to the parameters mentioned previously, this model included baseline creatinine and the use of potassium supplementation at baseline. In this model decreased LVEF emerged as most predictive of hyperkalemia (RR 0.37 [0.15–0.85] per 10% increase in LVEF). NYHA class was also associated with a significantly increased risk of serious hyperkalemia (RR 3.36 [1.17 to 9.69] per NYHA class increase). None of the other covariates displayed an independent influence on the risk of developing hyperkalemia. Discussion We found that treatment with SPL in CHF patients resulted in side effects including hyperkalemia and renal dysfunction, which were considerably more frequently than the previously reported figures from the RALES study but—in the case of hyperkalemia—similar to those reported in smaller reports. Age, decreased LVEF, and higher NYHA class emerged as predictors of harmful effects. In the context of hyperkalemia and SPL therapy, one mandatory piece of evidence and comparison is the preRALES pilot study of 1996.8 The investigation consisted of 214 patients, revealing a dose-response in the incidence of hyperkalemia defined as serum K⫹ ⬎5.5 mmol/L in the 4 SPL treatment groups of 12.5 mg, 25 mg, 50 mg, and 75 mg, respectively. The incidence of hyperkalemia here was 5%, 13%, 20%, and 24%, respectively, and predictors for the development of hyperkalemia were the use of ACE inhibitors and a baseline elevation of potassium or creatinine. The treatment was considered safe provided that serum K⫹ levels were monitored closely. More recently Vanpee et al reported 4 cases of severe hyperkalemia in CHF patients,9 with a SPL dose regimen that exceeded the recommended SPL dosages for CHF. The authors emphasized the need for correct dosage and close monitoring of frail, elderly CHF patients. In 2001 several publications reported small casuistic series of CHF patients with side effects from SPL treatment (eg, Berry et al documenting 4 cases of hyperkalemia in CHF patients).10 Another recent study reported on 25 CHF patients who had developed severe hyperkalemia, but 16 of the 25 patients had received 50 mg SPL or more per day.11 In the RALES study comprising 1663 patients, the baseline characteristics portrayed a 7-year younger population than our 125 nontrial patients.3 The proportion of females was equal (27%), whereas the proportion of NYHA III-IV class was 51% in our cohort as compared with almost 100% in RALES. This is partly because SPL initiation—60 of our patients were already on SPL when admitted to the heart failure clinic—and the evaluation of NYHA class were not done simultaneously. Furthermore, a slightly higher LVEF in our population (29% versus 26% in RALES) and a significantly lower proportion of patients treated with ACE inhibitors (64%) or angiotensin receptor blockers (20%) (taken together 84% versus 95% ACE inhibitors in RALES) were recorded. The latter difference is probably
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explained by the decreasing creatinine clearance detected in the advanced age population of our study, and hence a higher proportion of patients intolerant of ACE inhibitors. Digitalis was used in 31% versus 75% in RALES, a difference that might be explained on grounds of geographic differences in treatment traditions. With regard to potassium supplementation, 74% of our cohort received this type of medication versus 29% in RALES, reflecting that one of the indications for SPL initiation in our clinic was refractory hypokalemia as well as edema or deteriorating heart failure in otherwise maximally treated patients (requiring additional use of highceiling diuretics and potassium supplementation). Also, a considerably higher proportion of patients in our cohort was treated with β-blockers (39% versus 11% in RALES), which again is presumably a matter of age, but may also be explained by the lower proportion of patients treated with ACE inhibitors. In fact, 11% of our population received β-blockers and no ACE inhibitors, whereas 28% received both. Further, some of the major β-blocker trials in heart failure had not been published at the time of enrollment into the RALES study. Although these patient baseline characteristics clearly show differences between our cohort and the one enrolled in the RALES study, it is still noteworthy how large a proportion of our patients (36%) developed hyperkalemia (serum K⫹ ⬎5 mmol/L) or severe hyperkalemia with serum K⫹ ⬎6 mmol/L (10% versus 2% in RALES) even though they were meticulously followed with regular laboratory workups. In line with these findings, the development of renal dysfunction in our population was striking, with 55% encountering a rise in serum creatinine to ⬎120% of their baseline, 24% suffering from a rise to ⬎150% of baseline, and 9% of the patients doubling their serum creatinine level. In contrast, the reported mean creatinine increase in RALES was as low as 9 µmol/L. Fifty percent of our patients were in NYHA class II (or I), which is also different from the RALES population. When scrutinizing this subpopulation it turns out that only 25 of the 65 patients were actually initiated on SPL at our heart failure clinic (ie, a substantial fraction of the patients were already on treatment with SPL before admission). Of these, 17 (68%) also received potassium supplementation, which likely means that the caregivers aimed at counteracting diuretic-induced hypokalemia. In fact—and importantly—this is in line with the European Society of Cardiology guidelines for the use of SPL in CHF. This idea is further supported by the fact that among all NYHA I and II patients, there was a (yet nonsignificant) tendency to lower potassium levels in the SPL-treated as compared with the non–SPL-treated patients. In other words, one rationale in this subpopulation was to omit large quantities of potassium supplements. One further point of consideration is that CHF patients will often be treated with SPL in case of worsening heart failure (even if their baseline NYHA class is II), and individual indications according to how different treating doctors perceive the patients’ complaints may vary in such cases. This does not mean that the treatment protocol of the heart
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failure clinic is not in accordance with international guidelines. In fact, we believe that our data very much mirror daily clinical practice, which made us use the term “real life.” Moreover, given the difference of our patients from the RALES population in terms of NYHA class, the patients should not be more prone to electrolyte disturbances; one would rather expect the opposite. In this context, the use of aldosterone antagonism in milder forms of cardiomyopathy has gained further support through the recent Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) trial.12 Although the current study was not a placebo-controlled, blinded trial, baseline characteristics of the patients not treated with spironolactone can be informative contrasting the study group per se. These characteristics were therefore compiled (Table 2), showing the major difference between these 2 populations being the higher percentage (75%) of NYHA class I and II patients in the non-SPL patients. Because the treatment algorithm of the heart failure clinic was established according to international guidelines, the explanation why the 184 patients did not receive SPL is, simply, that they did not meet the established treatment criteria for SPL. Excessive diuresis with prerenal uremia might be a potentially important cause of renal dysfunction during SPL treatment. When analyzing weight data of our cohort, a slight weight loss of 1.3 kg (mean) was recorded, in contrast to the RALES study, in which there was reported to be no weight loss in the SPL treatment group. Also, the loop diuretic mean dose among our 125 SPL patients was considerably higher than in RALES (144 mg versus 80 mg). This may reflect that RALES investigators had cut back on conventional diuretic doses when renal disturbances were noted. Hence an effective way of dealing with renal dysfunction secondary to SPL may be to cut back the dose of conventional diuretic therapy, a recommendation that cautiously may be deducted from our findings. One potential confounder and promoter of renal and electrolyte disturbances is polypharmacy in our elderly CHF population. In many cardiovascular studies, concomitantly administered noncardiac drugs are escaping the rigorous scrutiny of the investigators, even though they may contribute significantly to recorded side effects. One such class of compounds are the NSAIDs, whose utilization in elderly populations often is inappropriately excessive. We found that the concomitant administration of any NSAID and SPL was negligibly small (occurring in 2 of 125 SPL patients). This may underscore that contraindications arising from known drug-drug interactions are taken seriously when treating the severely ill CHF population in our specialized outpatient clinic. It is important, however, to keep in mind that our study was not a placebo-controlled trial. Hence one cannot directly attribute the side effects found to the use of spironolactone. The scope of the article was to evaluate the side effects in CHF patients treated with spironolactone rather than to evaluate the side effects of spironolactone per se—this needs
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to be addressed using a placebo-controlled design. Furthermore, because this study has no control group, it is difficult to know whether SPL actually contributes to either the hyperkalemia or the increased creatinine levels. Even further, conceptually one cannot just imply that SPL causes increased creatinine levels, as the natural history of CHF is that renal function deteriorates steadily. One does not even know whether small changes in creatinine are relevant, because previous trials such as CONSENSUS13 have taught us the opposite. In fact, creatinine is a very poor marker of renal function, and increases in creatinine levels are far from irreversible but may simply represent overdiuresis. Nevertheless, and taking all these considerations into account, the main message of the study is still that electrolyte profiles should be monitored very carefully in elderly patients based on the findings of our study. With regard to the high mortality (66%) during our observation period of the 12 patients that had episodes of hyperkalemia with a serum K⫹ level ⬎6.0 mmol/L, one cannot deduct any causality from these numbers (ie, mortality is not directly attributable to hyperkalemia). With regard to declining renal function, none of the patients needed renal replacement or had acute renal failure. This may be due in part to the close monitoring of creatinine. Importantly, as a result of trials measuring human serum aldosterone levels, it has recently been argued that also patients suffering from mild dyspnea (NYHA II) could benefit from SPL treatment.14 More advanced drugs such as canrenone or eplerenone may become important substitutes of SPL for future CHF treatment indications, yet their side effect profiles still await full elucidation. In fact, the recently published EPHESUS trial12 has shown that eplerenone reduces both mortality and cardiovascular hospitalizations in postinfarction patients with left ventricular dysfunction. Patients with elevated serum creatinine concentration or serum K⫹ ⬎5 mmol/L were excluded from the study. Follow-up measurements of potassium and creatinine were performed frequently. Interestingly, the rate of serious hyperkalemia was 5.5% in the eplerenone group and 3.9% in the placebo group. EPHESUS patients had substantially less impaired left ventricular function and less severe heart failure than did patients in RALES and were much more likely to be receiving other recommended medications, yet still they benefited from aldosterone blockade. Nevertheless eplerenone appears to be as likely as SPL to cause hyperkalemia and renal insufficiency. In our search for potential predictors of creatinine increase and severe hyperkalemia during SPL treatment, we did not find baseline serum K⫹, baseline serum creatinine, SPL dosing, nor discontinuation of potassium supplementation as predictors of hyperkalemia. Only age and decreased LVEF emerged as independent risk factors for developing renal dysfunction, and decreased LVEF and higher NYHA class emerged as most predictive of hyperkalemia. During the follow-up course presented in the present study (comprising an average work-up every 23rd day for a mean
period of 11 months), the adverse effects were not satisfactorily avoided. The conclusions from our study are that (1) particular caution is mandated in elderly patients with an LVEF ⬍20%, (2) potassium supplementation should be discontinued, (3) changes in body weight should raise additional concern, and (4) a dose-adjustment of the concomitant conventional diuretic regime should be considered. Even though our data do not pinpoint decreased renal function as a predicting factor (see Table 3), we concur with the recently published suggestions of Blaustein et al15 stating that patients with severe underlying chronic renal failure should not be considered eligible for SPL therapy, even if they fulfill the inclusion criteria according to the RALES study. An estimation of creatinine clearance in each patient, using the Cockcroft and Gault formula,16 which computes both serum creatinine and body weight, age, gender, and muscle mass, may be a means to identify patients at particularly high risk. Conclusion Taken together, SPL adverse effects, in particular impaired renal function and hyperkalemia, are much more prevalent in an elderly CHF patient population as described in the present study than previously reported. Elderly patients with poor systolic function or low functional class appear to be particularly at risk, yet this population does have the greatest potential benefit because of the high baseline risk. Again this serves as a reminder that care should be given to the frequent monitoring of electrolytes and renal parameters. Above and beyond this conclusion, these findings shed an ambiguous light on the recurrent, yet unexplained observation that patients participating in placebo-controlled, international, multicenter, randomized, double-blind trials differ from those admitted to an outpatient clinic “in the real world,” even though the formal inclusion/exclusion criteria are comparable.
Acknowledgments We are indebted to the staff of the heart failure clinic: Per H. Nielsen, RN; Hanne Bartholdy, RN; Ingelise Henriksen, RN; and Louise Flye Jensen, RN.
References 1. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293–302. 2. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA 2000;283:1295–302. 3. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients
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