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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2012  |  Volume : 23  |  Issue : 3  |  Page : 507-512
A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis


1 Isfahan Kidney Diseases Research Center/Nephrology Division, Department of Internal Medicine, Isfahan School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
2 Department of Cardiology, Isfahan School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3 Isfahan Kidney Diseases Research Center/CAPD Clinic, St. AlZahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran

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Date of Web Publication7-May-2012
 

   Abstract 

Congestive heart failure (CHF) is frequent in patients with chronic renal failure, and may contribute to high cardiovascular morbidity and mortality. There is little data in the literature about the safety and efficacy of use of spironolactone in patients with end-stage renal disease with heart failure. In this study, we evaluated the safety and efficacy of spironolactone in patients on continuous ambulatory peritoneal dialysis (CAPD) with CHF. This randomized pros­pective double-blind placebo-controlled clinical trial was performed at the St. Al-Zahra peritoneal dialysis center. Eighteen CAPD patients with New York Heart Association (NYHA) class III or IV heart failure, ejection fraction (EF) ≤45%, serum potassium level ≤5.5 mEq/L and who were eligible, were randomly assigned to taking either spironolactone (25 mg every other day) or placebo for six months. The serum potassium was measured monthly and echocardiography was repeated at the end of the study period. The serum potassium levels rose in both groups, and there was no statistically significant difference intragroup and between the groups during the study period. Only in one patient in the spironolactone group did the serum potassium level reach above the critical level (5.70 mEq/L) at the end of the second month of study, necessitating patient exclu­sion. The EF did not change significantly in the placebo group (33.3 ± 11.7 vs. 34.2 ± 11.6, F = 1, P = 0.363), but in the spironolactone group the EF rose significantly (25.7 ± 7.3 vs. 33.3 ± 7.8, F = 27.45, P = 0.002). Our study suggests that spironolactone could be used in CHF patients on CAPD to improve their cardiac function, but close monitoring of their serum potassium level is required.

How to cite this article:
Taheri S, Mortazavi M, Pourmoghadas A, Seyrafian S, Alipour Z, Karimi S. A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis. Saudi J Kidney Dis Transpl 2012;23:507-12

How to cite this URL:
Taheri S, Mortazavi M, Pourmoghadas A, Seyrafian S, Alipour Z, Karimi S. A prospective double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of spironolactone in patients with advanced congestive heart failure on continuous ambulatory peritoneal dialysis. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Jul 12];23:507-12. Available from: http://www.sjkdt.org/text.asp?2012/23/3/507/95778

   Introduction Top


About one-third to one-half of the patients with congestive heart failure (CHF) have esti­mated creatinine clearance of less than 60 mL/min. [1],[2] Spironolactone is now a standard therapy in patients with CHF. Concerns about CHF and chronic renal failure (CRF) have risen and have been examined in studies. [3],[4],[5],[6],[7],[8],[9],[10],[11] The use of spironolactone in dialysis patients also is limited because of the fear of side-effects. [10],[11] We conducted a prospective double­blind randomized placebo-controlled clinical trial to examine the safety and efficacy of spironolactone in patients on chronic ambulatory peritoneal dialysis (CAPD) with advanced heart failure.


   Subjects and Methods Top


This randomized prospective double-blind placebo-controlled clinical trial was performed from February to September 2008. A total of 125 patients who were on CAPD for a period of at least one month and aged 18 years or above, were assessed by one nephrologist in our team. Of this group, 34 patients were in the New York Heart Association (NYHA) classification III or IV and were on treatment with an angiotensin converting enzyme inhi­bitor (ACEI) or angiotensin II receptor blocking (ARB) agent, and their serum potassium level was less than 5.5 mEq/L. These patients were referred to the cardiologist to measure their heart ejection fraction (EF) by echocardiography (Vivid3, General Electric, N-3191 Horten, Sweden) using the M-mode technique. If the patients' EF was ≤45% and if they gave in­formed written consent, they were considered eligible to enter our study program. With these criteria, 18 patients was selected and randomly assigned to the drug arm (nine patients), who were administered 25 mg of spironolactone (Pars-Minoo CO.-Tehran, Iran), or placebo arm (nine patients), who were administered matching placebo every other day for six months.

The study patients' serum potassium and hemo­globin levels were measured at baseline and then monthly until the end of study. If the serum potassium level rose to >5.5 mEq/L, 10 g of oral Kayexalate was prescribed with each meal and, two weeks later, the serum potas­sium level was repeated. If the level had not dropped to ≤5.5 mEq/L, that patient was ex­cluded from the study. At the end of the study, echocardiography was repeated by the same cardiologist using the same equipment.

This study was approved and granted (research project No. 386273) by the research committee of the Isfahan Kidney Research Center, Isfahan University of Medical Sciences, and the ethics committee of Isfahan School of Medicine.


   Statistical Analysis Top


To compare the serum potassium and hemo­globin levels during time in the same group and between groups, one-way ANOVA test was used. ANOVA repeated measure analysis was used to determine statistical difference in EF during time in both groups. Independent-samples t-test and Chi-square test and Fisher's exact test were employed to compare basic characteristics and mortality between groups as indicated.


   Results Top


[Table 1] shows the baseline characteristics of both groups. As is shown, the baseline charac­teristics of the patients in both the spironolactone and the placebo groups, including age, gender, cause of renal failure, time on CAPD, daily CAPD sessions, NYHA classes, hemo­globin and serum potassium levels, were not statistically different. Although the EF was lower in the spironolactone group than in the placebo group, this difference was not statisti­cally significant.
Table 1: Baseline characteristics of the patients in the spironolactone and placebo group.

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One patient in the spironolactone group deve­loped hyperkalemia (5.7 m/mEq/L) at the end of the second month, and was treated with ion exchange resin. Because the serum potassium level did not drop to 5.5 mEq/L or less after two weeks of treatment with ion exchange resin, the patient was excluded from the study. One other patient in the same group trans­ferred to hemodialysis in the fourth month of study and, hence, was excluded. No patient in the spironolactone group died during the study period. In contrast, three patients in the pla­cebo arm died: one due to intracerebral he­morrhage and two others because of sudden cardiac death. Although there was some trend toward increased mortality in the placebo group, it did not reach statistical significance (P = 0.103).

[Figure 1] and [Figure 2] show the potassium and he­moglobin levels, respectively, at baseline and monthly thereafter in both patient-groups du­ring the study period. Although the serum potassium levels rose in both groups, there was no statistically significant difference within and between groups by one-way ANOVA test during the study period. Although the blood hemoglobin level dropped in the placebo group over six months of the study period, it was not statistically significant by the one-way way ANOVA test (P > 0.05).
Figure 1: Baseline serum and monthly serum potassium levels in patients on spironolactone and placebo during the study period. One-way ANOVA test showed no statistically significant difference in the same group and between groups during the study period (P > 0.05)

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Figure 2: Baseline and monthly blood hemoglobin levels in the spironolactone and placebo groups during the study period. One-way ANOVA test showed no statistically significant difference in the same group and between groups during the study period (P > 0.05)

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Seven patients in the spironolactone and six patients in the placebo group completed the study. The echocardiography of these patients at the end of the study period showed that the EF among patients in the placebo group did not change significantly during the six month study period (33.3 ± 11.7 vs. 34.2 ± 11.6, F = 1, P = 0.363). In contrast, in the spironolactone group, the EF rose significantly during time (25.7 ± 7.3 vs. 33.3 ± 7.8, F = 27.45, P = 0.002), and also when compared with the placebo group (F = 14.87, P = 0.003) [Figure 3].
Figure 3: Ejection fraction among the study patients in the spironolactone and placebo groups before and after six months of study

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   Discussion Top


After the report of Pitt et al on the rando­mized spironolactone evaluation study (RALES) in 1999, many patients with CHF and some degree of renal insufficiency are commonly treated with low-dose spironolactone. [12] Although the estimated creatinine clearance, by the Cockcroft-Gault formula, [13] in that study was different from the values in our study, they showed that spironolactone substantially re­duced morbidity and mortality in patients with severe CHF without causing significant hyperkalemia. Spironolactone is inexpensive and generally well tolerated, but in patients with renal failure, it can provoke life-threatening hyperkalemia, especially when combined with ACE inhibitors. [7] While spironolactone treat­ment is not recommended in patients with CRF, it may be safe in patients on dialysis. [10] In patients with end-stage renal disease (ESRD), blockade of the renin-angiotensin-aldosterone system has the potential to increase the risk of hyperkalemia due to inhibition of potassium excretion from extra-renal sites, especially the colon, and aldosterone may have some role in short- or long-term defense against hyperka-lemia in these patients. [14],[15] Hausmann et al presented a patient on peritoneal dialysis with CHF who was treated with spironolactone without significant side-effects. [16] Drugs that block the effect of aldosterone, such as spironolactone, are now used frequently in the treat­ment of hypertension or CHF. There is little information about the safety, side-effects or efficacy of these compounds in patients with CRF or ESRD. [10]

In recent years, many studies have been con­ducted to examine the safety of spironolactone in patients with ESRD on hemodialysis (HD) and peritoneal dialysis, and they showed safety of this drug in this population. [11],[16],[17],[18],[19],[20] Recently, a report that evaluated the safety and efficacy of 25 mg spironolactone thrice-weekly in pa­tients on HD, with moderate to severe heart failure, showed substantial improvement of their cardiac function and decrease in left ven­tricular mass without development of signifi­cant hyperkalemia. [18]

In the present study, we conducted a rando­mized placebo-controlled double-blind study in peritoneal dialysis patients with advanced heart failure over six months, evaluating the safety and efficacy of spironolactone in these patients. Spironolactone was generally well tolerated and, except in one case, did not cause significant hyperkalemia compared with placebo. It seems that in the dialysis population, the patients are not dependent on their kidneys to excrete their excess potassium. The EF in the placebo group remained stable, but in­creased significantly in the spironolactone group during the study period. Also, mortality due to cardiovascular causes, during the study period, was seen only in patients who received pla­cebo, although the difference did not reach statistical significance.

Our study had some limitations. The number of patients studied is small, and it may not be possible to draw definite conclusions about the safety and efficacy of spironolactone. Further studies on larger numbers of patients are nee­ded to confirm this observation.

In conclusion, our study suggests that spironolactone can be used in patients with CHF on CAPD to improve their cardiac function, but close monitoring of their serum potassium le­vels is needed.


   Acknowledgment Top


This study was approved and granted (research project No. 386273) by the research committee of Isfahan Kidney Research Center, Isfahan University of Medical Sciences and ethics committee of Isfahan School of Medicine.

 
   References Top

1.Dries DL, Exner DV, Domanski MJ, Green­berg B, Stevenson LW. The prognostic impli­cations of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol 2000; 35:681-9.  Back to cited text no. 1
    
2.Hillege HL, Girbes AR, de Kam PJ, et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation 2000;102:203-10.  Back to cited text no. 2
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3.Edwards NC, Steeds RP, Stewart PM. Effect of spironolactone on left ventricular mass and aortic stiffness in early-stage chronic kidney disease, JACC 2009;54:505-12  Back to cited text no. 3
    
4.Anton C, Cox AR, Watson RD, Ferner RE. The safety of spironolactone treatment in pa­tients with heart failure. J Clin Pharm Ther 2003;28:285-7.  Back to cited text no. 4
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5.Juurlink DN, Mamdani MM, Lee DS, et al. Rates of Hyperkalemia after Publication of the Randomized Aldacton Evaluation Study, N Engl J Med 2004;351:543-51.  Back to cited text no. 5
    
6.Berry C, McMurray JJ. Serious adverse events experienced by patients with chronic heart failure taking spironolactone. Heart 2001;85: E8.  Back to cited text no. 6
[PUBMED]  [FULLTEXT]  
7.Schepkens H, Vanholder R, Billiouw JM, 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.  Back to cited text no. 7
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8.Svensson M, Gustafsson F, Galatius S, Hilde­brandt PR, Atar D. Hyperkalaemia and im­paired renal function in patients taking spiro-nolactone for congestive heart failure: Retros­pective study. BMJ 2003;327:1141-2.  Back to cited text no. 8
    
9.Wrenger E, Muller R, Moesenthin M, Welte T, Frolich JC, Neumann KH. Interaction of spironolactone with ACE inhibitors or angiotensin receptor blockers: Analysis of 44 cases. BMJ 2003;327:147-9.  Back to cited text no. 9
    
10.McLaughlin N, Gehr TW, Sica DA. Aldosterone-receptor Antagonism and End-stage Renal Disease, Current Hypertension Reports 2004;6: 327-30.  Back to cited text no. 10
    
11.Saudan P, Mach F, Perneger T, et al. Safety of low-dose spironolactone administration in chronic haemodialysis patients. Nephrol Dial Transplant 2003;18:2359-63.  Back to cited text no. 11
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12.Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.  Back to cited text no. 12
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13.Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.  Back to cited text no. 13
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14.Knoll GA, Sahgal A, Nair RC, Graham J, van Walraven C, Burns KD. Renin-angiotensin system blockade and the risk of hyperkalemia in chronic hemodialysis patients. Am J Med 2001;112:110-4  Back to cited text no. 14
    
15.Ahmed J, Weisberg LS. Hyperkalemia in dialysis patients. Semin Dial 2001;14:348-56.  Back to cited text no. 15
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16.Hausmann MJ, Liel-Cohen N. Aldactone therapy in a peritoneal dialysis patient with decreased left ventricular function. Nephrol Dial Transplant 2002;17 : 2035-6.  Back to cited text no. 16
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17.Hussain S, Dreyfus DE, Marcus RJ, c RW, McGill RL. Is spironolactone safe for dialysis patients? Nephrol Dial Transplant 2003;18 : 2364-8.  Back to cited text no. 17
    
18.Taheri S, Mortazavi M, Shahidi S, et al. Spironolactone in chronic hemodialysis patients improves cardiac function. Saudi J Kidney Dis Transpl 2009;20:392-7.  Back to cited text no. 18
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19.Gross E, Rothstein M, Dombek S, Juknis HI. Effect of spironolactone on blood pressure and the renin-angiotensin-aldosterone system in oligo-anuric haemodialysis patients. Am J Kidney Dis 2005;46:94-101.  Back to cited text no. 19
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20.Sugarman A, Brown RS. The role of aldosterone in potassium tolerance: studies in anephric humans. Kidney Int 1988;34:397-403.  Back to cited text no. 20
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Correspondence Address:
Shahram Taheri
Nephrology Division, Internal Medicine Department, St. Al-Zahra Hospital, Soffeh Ave., Isfahan
Iran
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