Hyperkalaemia in congestive heart failure patients using ACE inhibitors and spironolactone

Constança S. Cruz1, Álvaro A. Cruz2 and Carlos A. Marcílio de Souza1

1 Curso de Pós-graduação e Extensão em Medicina Interna da Fundação para Desenvolvimento das Ciências, Fundação Instituto Osvaldo Cruz, Salvador – Bahia, 2 Centro de Enfermidades Respiratórias da Faculdade de Medicina da Universidade Federal da Bahia, Brazil

Correspondence and offprint requests to: Constança S. Cruz, Fundação para Desenvolvimento das Ciências, Coordenação de Pós-graduação e Extensão, Av. D. João VI, 275, Pavilhão III, sala 110 – Brotas, CEP 40290-000, Salvador – Bahia, Brazil. Email: conscruz{at}ig.com.br



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Recent studies have shown a fall in global mortality with minimal side effects in severe congestive heart failure (CHF) patients receiving angiotensin-converting enzyme inhibitors (ACEI) plus spironolactone (SLN). However, the risk of hyperkalaemia due to ACEI may be increased by the concomitant use of SLN.

Methods. We conducted a retrospective cohort study by examining consecutive cases of severe decompensated CHF admitted to a university hospital in Brazil from March 1999 to March 2000, which had used ACEI with or without SLN. We reviewed charts for the 30 days following admission and assessed various therapeutic regimens used for heart failure as well as serum potassium and creatinine, before and after drug exposure. The primary end-point was the development of hyperkalaemia (K >=5.5 mEq/l). For analysis, the subjects were split into patients treated with ACEI/SLN (n = 49) and patients treated with ACEI (n = 51) by itself.

Results. Although demographical and clinical features were comparable between the two groups, ACEI/SLN patients had a higher proportion of class IV CHF. We found 16 cases of hyperkalaemia in ACE/SLN patients, but only one case in ACEI subjects. The odds ratio for developing hyperkalaemia in ACEI/SLN patients was 24. When class III CHF subjects were excluded, the odds ratio was 14.6 (95% confidence interval: 1.8–119.6). The best predictors of hyperkalaemia were class IV CHF, increases in creatinine following treatment and diabetes.

Conclusions. Patients with severe decompensated CHF using ACEI with SLN are at major risk for developing hyperkalaemia.

Keywords: angiotensin-converting enzyme inhibitors; drug-induced hyperkalaemia; heart failure; hyperkalaemia; spironolactone



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In recent years, angiotensin-converting enzyme inhibitors (ACEI) have emerged as key drugs for the management of congestive heart failure (CHF). The addition of spironolactone (SLN) as an adjuvant has been advocated following publication of the Randomized Aldactone Evaluation Study (RALES) [1], which found that subjects using ACEI/SLN had lower mortality rates than those using ACEI without SLN. Combination therapy also resulted in rare adverse events. Elderly patients, CHF patients, subjects with renal disfunction, renovascular diseases and diabetes are all more susceptible to ACEI-induced hyperkalaemia [28]. In the present work, we compared the incidence of hyperkalaemia in CHF inpatients using ACEI/SLN with those receiving ACEI without SLN.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
We performed a retrospective cohort study of decompensated New York Heart Association (NYHA) class III or IV CHF patients admitted to internal medicine wards of Santo Antônio University Hospital (Salvador, Brazil) from 1 March 1999 to 31 March 2000, which were treated with ACEI with or without SLN. A total of 139 patients fulfilled the inclusion criteria. We excluded 39 of these because four had documented hyperkalaemia at admission, nine were using concomitant potassium replacement therapy, eight were using other drugs known to induce hyperkalaemia (e.g. potassium penicillin, trimetropim, ß-blockers and non-steroidal anti-inflammatory drugs) and one presented end-stage renal failure. Seventeen additional patients were excluded because we lacked follow-up information on potassium and creatinine levels. After admission, charts were reviewed for 30 days or until hyperkalaemia (>=5.5 mEq/l), death or hospital discharge had occurred. We obtained all records of blood potassium and creatinine before and after treatment with ACEI/SLN or ACEI and registered the time of drug exposure preceding all observed cases of hyperkalaemia. All data were collected from printed charts archived at the hospital. Blood levels of creatinine and potassium were measured in all patients at admission and twice a week during the 30 day observation period. If high levels of potassium were detected, an independent blood sample was collected for confirmation and drug treatment was withdrawn. New blood samples were later taken to assure that blood potassium had returned to normal. Potassium was measured using flame photometry [9] and the Jaffé modified method [10] was used for measuring creatinine. At the day of admission, drug treatment was started immediately and patients were classified into the ACEI/SLN and ACEI groups, which were independent of other drugs used for CHF.

The cumulative risk for hyperkalaemia during the observation period was determined using Kaplan–Meier survival curves. Means and proportions were compared using Student’s t-tests, {chi}2 and Fisher’s exact tests. Odds ratios were used to compare the risk for developing hyperkalaemia associated with ACEI/SLN vs ACEI. Univariate logistic regression was used to determine the association between development of hyperkalaemia and the observed clinical and laboratory characteristics. All analyses were performed using the SPSS® version 9.0. Two-tailed statistical tests were used with an alpha level set at 0.05.



   Results
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 Abstract
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 Subjects and methods
 Results
 Discussion
 References
 
All demographic and clinical features were comparable between the two groups (Table 1), except for higher numbers of class IV CHF in the ACEI/SLN group (P < 0.005). The leading causes of CHF were cardiomyopathy secondary to Chagas’ disease (trypanosomiasis), followed by ischaemia and hypertension. Baseline potassium and creatinine did not differ between the groups.


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Table 1. Clinical and demographic characteristics of CHF patients upon admission, according to use of ACEI and SLN

 
Hyperkalaemia was observed in 16 individuals receiving ACEI/SLN, but in only one individual receiving ACEI (Table 2). The odds ratio for development of hyperkalaemia in the ACEI/SLN group was 24.24 [95% confidence interval (CI): 3.07–191.65]. We found seven cases of severe hyperkalaemia (K >6.0 mEq/l) and all of these occurred in class IV CHF patients (Table 3). When class III CHF subjects were excluded from the analysis, the odds ratio for developing hyperkalaemia among class IV CHF patients using ACEI/SLN compared with those using ACEI without SLN was 14.6 (95% CI: 1.8–119.6; Table 3). The 17 cases of hyperkalaemia are presented in Tables 4 and 5 and univariate associations between clinical/laboratory characteristics and hyperkalaemia are shown in Table 6.


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Table 2. Incidence of hyperkalaemia (K >=5.5 mEq/l) and severe hyperkalaemia (K >6.0 mEq/l) in the two groups

 

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Table 3. Incidence of hyperkalaemia (K >=5.5 mEq/l) and severe hyperkalaemia (K >6.0 mEq/l) in the two groups after excluding CHF class III patients

 

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Table 4. Characteristics of severe hyperkalaemic (serum potassium >6.0 mEq/l) patients before and after exposure and after suspension of ACEI plus SLN

 

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Table 5. Characteristics of hyperkalaemic patients without severe hyperkalaemia (5.5 mEq/l <= serum potassium <= 6.0 mEq/l) before and after exposure and after suspension of ACEI and/or SLN

 

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Table 6. Univariate associations between clinical or laboratory variables and hyperkalaemia in all patients (n = 100)

 
The average duration of treatment with ACEI/SLN was 13 ± 8 days and the average time before onset of hyperkalaemia was 15 ± 9 days (all subjects initiated treatment with ACEI/SLN simultaneously). In contrast, the average duration of treatment with ACEI was 11 ± 6 days and the only patient that developed hyperkalaemia showed a potassium level of 5.5 mEq/l on day 15 of treatment. A list of other medications and their respective doses is presented in Table 1.

Kaplan–Meier curves for hyperkalaemia are shown in Figure 1. There were no deaths during the 30 day observation period. Importantly, only 10 (20%) of 49 individuals treated with ACEI/SLN over the 30 day observation period, excluding subjects discharged before day 30, were free of hyperkalaemia.



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Fig. 1. Kaplan–Meier curves showing cumulative risk for development of hyperkalaemia (serum potassium >=5.5 mEq/l) during 30 days of drug exposure. Patients given ACEI plus SLN are shown by the lower line and patients given ACEI without SLN are shown by the upper line.

 
Figure 2 illustrates blood potassium levels in the two groups following initiation of treatment.



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Fig. 2. Serum potassium (mEq/l) after exposure to ACEI plus SLN and to ACEI without SLN. Shown are the final potassium measurements prior to hospital discharge or to suspension of medications. This box-plot represents the distribution by median, by 25 and 75% percentiles and extreme values.

 


   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The risk for hyperkalaemia was 24.2 times greater in patients using ACEI/SLN. However, the ACEI/SLN group had a greater proportion of class IV CHF patients that are at major risk for hyperkalaemia because worsening CHF stimulates the renin–angiotensin system [8,11]. We reanalysed the data after excluding class III CHF patients to minimize this potential confounding variable and found that the odds ratio for hyperkalaemia in class IV CHF patients was 14.6 (95% CI: 1.8–119.6). Although the ACEI/SLN group had higher baseline creatinine than the ACEI group (P = 0.07), exclusion of class III CHF patients resulted in a smaller difference (1.3 ± 0.6 mg/dl for ACEI/SLN patients vs 1.2 ± 0.4 mg/dl for ACEI patients; P = 0.2), suggesting that renal function deterioration and subsequent hyperkalaemia was more related to the functional class of CHF than to baseline creatinine levels. The higher post-treatment serum creatinine in the ACEI/SLN patients was probably due to more severe CHF in this group.

We found that rising creatinine after treatment with ACEI (with or without SLN), class IV CHF and diabetes were all significant predictors for the development of hyperkalaemia (Table 6). We hypothesize that the simultaneous introduction of ACEI and SLN increases the risk of hyperkalaemia because of the reduced glomerular filtration rate associated with initiation of ACEI treatment [8]. One-third (33%) of the 49 CHF patients using ACEI/SLN developed hyperkalaemia and this was severe in seven patients. Although these patients with hyperkalaemia were unskilled and socially disadvantaged, which are factors associated with trypanosomiasis, there was no evidence that hyperkalaemia occurred more frequently in CHF patients with Chagas’ disease than in patients with other conditions.

Controlled clinical trials have reported a lower incidence of hyperkalaemia in heart failure patients using ACEI/SLN [1,12,13], but these studies excluded patients with serum creatinine >2.5 mg/dl and with serum potassium >5.0 mEq/l. Moreover, these studies recruited outpatients and included a smaller proportion of subjects with class IV CHF [1]. Following a preliminary report from the RALES study [12,13], a letter by Georges et al. [14] emphasized the rising risk of hyperkalaemia in patients using ACEI/SLN for cardiologic conditions and highlighted the important difference between well-conducted clinical trials with close follow-up compared with cursory monitoring by busy clinicians. Schepkens et al. [15] reported that 25 hyperkalaemic patients using ACEI/SLN mainly for cardiologic reasons also experienced severe adverse events.

In the present retrospective study, there was potential for selection and measurement bias and the possibility for confounding variables. However, the potential for bias was reduced by consecutively including patients in the study as they had been admitted to the hospital and by verification of hyperkalaemia using two independent blood samples. Moreover, our statistical analysis has taken into consideration the most likely confounding variables.

In conclusion, treatment of decompensated severe heart failure with ACEI plus SLN was associated with frequent and severe hyperkalaemia. The major predictors of hyperkalaemia in these patients were decreased renal function, as reflected by rising serum creatinine following treatment, and the functional class of CHF. New and larger prospective studies will be necessary to verify whether simultaneous introduction of ACEI/SLN contributes to the high risk for developing hyperkalaemia in patients with recently decompensated CHF.



   Acknowledgments
 
The authors thank Prof. Luiz Sergio Silva as well as Drs Luzia Cruz and Gerald Sheehan for their assistance with manuscript preparation. Infrastructure support was provided by the Hospital Santo Antônio, Associação Obras Sociais Irmã Dulce, Salvador – Bahia, Brazil.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 2.10.02
Accepted in revised form: 28. 2.03