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| Year : 2009 | Volume
: 20
| Issue : 3 | Page : 392-397 |
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| Spironolactone in chronic hemodialysis patients improves cardiac function |
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Shahram Taheri1, Mojhgan Mortazavi1, Shahrzad Shahidi1, Ali Pourmoghadas2, Mohammad Garakyaraghi2, Shiva Seirafian1, Afrooz Eshaghian3, Maryam Ghassami3
1 Division of Nephrology, Department of Internal Medicine, Isfahan School of Medicine, Isfahan, Iran
2 Division of Cardiology, Department of Internal Medicine, Isfahan School of Medicine, Isfahan, Iran
3 Division of Students of Medicine, Department of Internal Medicine, Isfahan School of Medicine, Isfahan, Iran
Click here for correspondence address and email
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 Abstract | | |
We performed this study to assess whether low dose spironolactone could be administered in hemodialysis (HD) patients with moderate to severe heart failure to improve cardiovascular function and reduce hospitalization without inducing hyperkalemia. We enrolled 16 chronic HD patients with moderate to severe heart failure and left ventricle ejection fraction :5 45%. In a double blinded randomized placebo controlled study, one group of 8 patients received 25 mg of spironolactone after each dialysis session within six months, and the rest received a placebo. Echocardiography was performed on all the patients to assess ejection fraction and left ventricular mass during 12 hours after completion of hemodialysis at the beginning and the end of study. Serum potassium was measured predialysis every 4 weeks. The mean ejection fraction increased significantly more in spironolactone group during the study period than in the placebo group (6.2 ± 1.64 vs. 0.83 ± 4.9, P= 0.046). The mean left ventricular mass decreased in the spironolactone group, but increased significantly in the placebo group during the period (-8.4 ± 4.72 vs. 3 ± 7.97. 95%, P= 0.021). The incidence of hyperkalemia was not significantly increased in the study or controlled groups. In conclusion, we found in this study that administration of spironolactone in chronic HD patients with moderate to severe heart failure substantially improved their cardiac function and decreases left ventricular mass without development of significant hyperkalemia. Keywords: Ejection fraction (EF), Hemodialysis, Heart failure, Left ventricle (LV) mass, Spironolactone
How to cite this article:
Taheri S, Mortazavi M, Shahidi S, Pourmoghadas A, Garakyaraghi M, Seirafian S, Eshaghian A, Ghassami M. Spironolactone in chronic hemodialysis patients improves cardiac function. Saudi J Kidney Dis Transpl 2009;20:392-7 |
How to cite this URL:
Taheri S, Mortazavi M, Shahidi S, Pourmoghadas A, Garakyaraghi M, Seirafian S, Eshaghian A, Ghassami M. Spironolactone in chronic hemodialysis patients improves cardiac function. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Nov 26];20:392-7. Available from: https://www.sjkdt.org/text.asp?2009/20/3/392/50768 |
| Introduction | |  |
Cardiovascular disorders are common in chronic hemodialysis (HD) patients, [1] and cause death at 20-40 times the rate in the general population. [2],[3] The most common cardiac diseases in the HD population include coronary artery disease, hypertension, and left ventricular failure. [3],[4]
Aldosterone promotes the retention of sodium, the loss of magnesium and potassium, sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, and vascular damage and impairs arterial compliance, [5],[6],[7],[8],[9],[10],[11] induces cardiac hypertrophy, [12],[13] increases left ventricle (LV) mass index, [14] direct vascular damage, [9] and prevents the uptake of norepinephrine by myocardium. [5] The renin angiotensin system has been reported to play an important role in maintaining blood pressure in patients with end stage renal failure treated with hemodialysis. [15],[16],[17]
The RALES study showed a dramatic reduction of morbidity and mortality in patients suffering from severe heart failure, with inhibition of aldosterone by low dose spironolactone treatment (25 mg/day) associated with maximal therapy in patients with serum creatinine less than 2.5 mg/dL. [18] Safety of short term administration of spironolactone, an anti-aldosterone agent, was demonstrated in HD patients with heart failure. [1]
We aim to study prospectively the efficacy and safety of long-term use of spironolactone in hemodialysis patients with heart failure.
| Patients and Methods | | |
We studied in a double blinded randomized clinical trial the effect of spironolactone on 16 chronic HD patients with heart failure in the Isfahan University of Medical Sciences during the year of 2005. All patients were on chronic hemodialysis treatment (3sessions/ week) started at least one month before the study. M-mode echocardiography was performed on each patient during 12 hours after the hemodialysis session to record ejection fraction (EF) and LV mass. All the patients fulfilled the New York Heart Association (NYHA) class 3 and 4 heart failure criteria and ejection fraction < 45 percent, treated with at least an angiotensin converting enzyme inhibitor (ACEI)) or angiotensin receptor blocker (ARB) and erythropoietin, and revealed serum potassium concentration < 5.5 mmol/L with or without Kayaxalate therapy. All patients signed informed consent, and the ethics committee of the Department of Medicine, Isfahan University of Medical Sciences approved the study.
After the initial evaluation, the patients were randomly randomized to receive either 25mg spironolactone (Tehran Pars Mino) or a matching placebo after each dialysis session (25 mg three times/week) for 6 months. [1]
At the beginning of the study, serum potassium and hemoglobin level was measured before hemodialysis session for each patient, and repeated every four weeks during the study period. All patients were dialyzed against 1 mmol/L of potassium dialysis solution. At the end of 6 months echocardiography was performed again.
Data of electrocardiography, serum potassium concentration, times and causes of hospitalization were reviewed in a blinded fashion and compared the results between the study and control groups.
Statistical Analysis
Our study was a prospective double blinded randomized placebo control clinical trial. One way ANOVA and Fisher exact test were developed to explore the baseline characteristics on the estimated effect of spironolactone. Serum potassium concentrations were compared in the study and control groups by using the ANOVA test. Independent samples "t" test was used to compare EF, LV mass of both groups. To evaluate mortality and hospitalization we used Fisher exact test. Normal distribution of all variables defines by One Sample Kolmogrov Smirnov Test. The significance level was considered at P< 0.05. Calculations were performed using SPSS version 12.
| Results | | |
[Table 1] shows no significant differences in the baseline demographic characteristics between the spironolactone and control groups in terms of age, gender, diabetes mellitus, hyperlipidemia, hypertension, smoking, and ischemic heart disease. One patient in each group had a history of NYHA class 3 heart failure, and the rest were class 4 at the time of randomization.
[Table 2] shows that 11 patients completed the study. There was an increase of mean ejection fractions from 31.3 ± 8.76 to 41.2 ± 9.6 in the spironolactone group (P= 0.01), and from 33.7 ± 9.1 to 35.0 ± 7.7 in the placebo group (P> 0.05). The ejection fraction increased more in spironolactone group during the time than in the placebo group 6.2 ± 1.64 vs. 0.83 ± 4.9. 95% CI (0.19-6.35), P= 0.046. Left ventricular mass decreased from 158 ± 16.1g/m 2 to 142 ± 15.4 g/m 2 (P= 0.02) in the spironolactone group, while the placebo group showed a trend to increase from 158 ± 12.6 g/m 2 to 159 ± 13.5 g/m 2 (P= 0.2). The difference of mean LV mass between the spironolactone and the placebo group was statistically significant -8.4 ± 4.72, vs. 3.0 ± 7.97. 95% CI (-8.04- -3.68), P= 0.021.
Serum potassium concentrations of the placebo group was higher than those of the spironolactone group at the baseline 4.66 ± 0.41 vs. 3.86 ± 0.34, CI (-1.13- -0.47), P= 0.001, but both groups reached the same level after the second month and remained similar until the end of study. The differences of the serum potassium concentrations between both groups at the end of the study compared to the start were significant (1.02 ± 0.342 vs 0.083 ± 0.449. 95% CI (0.381-1.491), P= 0.004). The mean of potassium concentrations increased in the spironolactone group by 21%, but did not change in the placebo group during the study. Serum potassium concentrations did not change in comparison with time in each group after the first month [Figure 1]. Hyperkalemia developed in only one patient in the placebo group at the 6th month that was treated successfully by Kayaxalate.
There were 2 (25%) deaths in the placebo group due to cardiac causes and 3 (37.5%) in the spironolactone group caused by sepsis; no significant difference of the mortality was found between both groups (P> 0.05). There were 2 hospitalizations due to cardiovascular problems (ischemic heart disease and decompensated congestive heart failure) in spironolactone group but 12 hospitalizations in the control group due to the same causes (P< 0.01). On the other hand, there was more hospitalizations due to non-cardiovascular causes, mostly infectious related, in the spironolactone than in the placebo group (8 vs. 0, P< 0.01).
| Discussion | | |
Aldosterone is a potent mediator of myocardial and vascular fibrosis, and reduced levels of serum markers of cardiac fibrosis were measured after treatment with a low-dose spironolactone. [1],[19] Aldosterone is also a kaliuretic hormone, and despite concomitant treatment with angiotensin converting enzyme inhibitors (ACEIs), the use of a low dose spironolactone did not increase the prevalence of hyperkalemia in 94% of patients. [5]
Spironolactone has a bioavailability of ~90% and is metabolized rapidly by the liver. Its active metabolites, canrenone and 7 a methylspironolactone, have a long half-life (15-20 h) and 95% plasma protein binding. [20] Both metabolites are partially eliminated by the kidney (~50%), and spironolactone dosage must be decreased in ESRF. [1] Spironolactone promotes magnesium and potassium retention, increases uptake of myocardial norepinephrine, attenuates formation of myocardial fibrosis, and decreases mortality associated with both progressive ventricular dysfunction and malignant ventricular arrhythmias. [10]
Cardiac fibrosis is promoted by aldosterone and successfully suppressed by spironolactone. Local cardiac aldosterone production is increased in congestive heart failure. [21] Spironolactone blocks aldosterone effect on collagen formation, and inhibits myocardial fibrosis. [1],[19],[22] Several studies have demonstrated that dialysis patients have aldosterone levels manifold higher than normal controls. [17],[23],[24]
RALES study found that treatment with spironolactone reduced the risk of death from all causes, death from cardiac causes, hospitalization for cardiac causes, and the combined end point of death from cardiac causes or hospitalization for cardiac causes among patients who had severe heart failure as a result of left ventricular systolic dysfunction and who were receiving standard therapy including an ACEI. Spironolactone also improved the symptoms of heart failure, as measured by changes in the NYHA functional class. The reductions in the risk of death and hospitalization were observed after 2 to 3 months of treatment and persisted throughout the study. [5]
We demonstrated in our study improvement of cardiac function in the spironolactone than placebo group in ejection fraction and left ventricle mass. Spironolactone had a trend to decrease mortality due to cardiovascular causes and to increase that due to sepsis, but overall mortality was not statistically significant. Spironolactone also reduced the hospitalizations due to cardiovascular disease, but noncardiovascular hospitallization was more frequent in the spironolactone group.
In our study, serum potassium concentration increased in drug group during the 6 month study significantly, but did not reach clinical significance. The fact that our spironolactone treated group started with a lower mean potassium concentration maybe responsible for similar potassium concentrations at the end of the six months study period, despite a significant rise in the serum potassium concentration in that group.
However, during the last four months of the study period, serum potassium level of both groups was comparable. Previous studies reported the safety of spironolactone in chronic hemodialysis patients, and demonstrated that administration of 25 mg spironolactone thrice weekly is not associated with an increased frequency of hyperkalemia in hemodialysis patients when they are carefully monitored. [1],[3] These studies were non randomized, non-blinded, and over a short period of time. Our results demonstrated that cautious administration of spironolactone can be used in this population. Recently, in a case report, low dose spironolactone (25 mg) administered every day for 10 months was not found to elevate serum potassium level above 5.5 mmol/L in a patient treated by peritoneal dialysis and suffering from heart failure. [25] Considering that peritoneal dialysis is a better choice for heart failure patients, further studies in these patients will be required.
In summary, our study demonstrates spironolactone efficacy in reduction of cardiovascular complications in hemodialysis patients with moderate to severe congestive heart failure. Larger studies are needed to determine the mortality and morbidity of the patients, and lower or higher doses should be tested in future studies. Laboratory evaluation of serum potassium concentration at least every month is suggested.
| Acknowledgement | | |
The authors would like to thank Miss Parisa Afzali, Miss Narges Soltanpour, and Mr. Eshfagh Abbaskhan for their help in the preparation of this manuscript.
| References | | |
| 1. | 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.  [PUBMED] [FULLTEXT] |
| 2. | Collins AJ, Li S, Ma JZ, Herzog CA. Cardiovascular disease in end-stage renal disease patients. Am J Kidney Dis 2001;38(Suppl 1): S26-9. |
| 3. | Hussain S, Dreyfus DE, Marcus RJ, Biederman RW, McGill RL. Is spironolactone safe for dialysis patients? Nephrol Dial Transplant 2003; 18:2364-8. [PUBMED] [FULLTEXT] |
| 4. | Ritz E, Dikow R, Adamzcak M, Zeier M. Congestive heart failure due to systolic dysfunction: the Cinderella of cardiovascular management in dialysis patients. Semin Dial 2002;3: 135-40. |
| 5. | Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin converting en-zyme inhibitor in chronic congestive heart fai-lure secondary to coronary artery disease. Am J Cardiol 1995;76: 1259-65. [PUBMED] [FULLTEXT] |
| 6. | MacFadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res 1997;35:30-4. [PUBMED] [FULLTEXT] |
| 7. | Wang W. Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension 1994;24:571-5. [PUBMED] [FULLTEXT] |
| 8. | Duprez DA, De Buyzere ML, Rietzschel ER, et al. Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients. Eur Heart J 1998;19:1371-6. [PUBMED] [FULLTEXT] |
| 9. | Rocha R, Chander PN, Khanna K, Zuckerman A, Stier CT Jr. Mineralocorticoid blockade reduces vascular injury in stroke-prone hypertensive rats. Hypertension 1998;31:451-8. [PUBMED] [FULLTEXT] |
| 10. | Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: Fibrosis and renin-angiotensin-aldosterone system. Circulation 1991; 83:1849-65. [PUBMED] [FULLTEXT] |
| 11. | Brilla CG, Pick R, Tan LB, Janicki JS, Weber KT. Remodeling of the rat right and left ventricles in experimental hypertension. Circ Res 1990;67:1355-364. [PUBMED] [FULLTEXT] |
| 12. | Duprez DA, Bauwens FR, De Buyzere ML, et al. Influence of arterial blood pressure and aldosterone on left ventricular hypertrophy in moderate essential hypertension. Am J Cardiol 1993;71:17A-20A. [PUBMED] |
| 13. | Shigematsu Y, Hamada M, Okayama H, et al. Left ventricular hypertrophy precedes other target-organ damage in primary aldosteronism. Hypertension 1997;29:723-7. |
| 14. | Tanabe A, Naruse M, Naruse K, et al. Left ventricular hypertrophy is more prominent in patients with primary aldosterone than in patients with other types of secondary hypertension. Hypertens Res 1997;20:85-90. [PUBMED] |
| 15. | Igarashi Y, Suzuki H, Imafuku T, Saito I, Saruta T. Hypertension in patients of chronic hemodialysis: the role of the renin-angiotensin system. Jpn Circ J 1987;51:479-84. [PUBMED] |
| 16. | Moore J, Lazarus JM, Hakim RM. Reduced angiotensin receptors and pressor responses in hypotensive hemodialysis patients. Kidney Int 1989;36:696-701. |
| 17. | Sato A, Funder JW, Saruta T. Involvement of aldosterone in left ventricular hypertrophy of patients with end-stage renal failure treated with hemodialysis. Am J Hypertens 1999;12(9.1): 867-73. |
| 18. | 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. [PUBMED] [FULLTEXT] |
| 19. | Zannad F, Alla F, Dousset B, et al. Limitations of excessive extra-cellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure. Circulation 2000;102:2700-6. [PUBMED] [FULLTEXT] |
| 20. | Beermann B. Aspects on pharmacokinetics of some diuretics. Acta Pharmacol Toxicol 1984; 54(Suppl 1):17-129. |
| 21. | Funder J. Mineralocorticoids and cardiac fibrosis: the decade in review. Clin Exp Pharmacol Physiol 2001;28:1002-6. [PUBMED] [FULLTEXT] |
| 22. | Klug D, Robert V, Swynghedauw B. Role of mechanical and hormonal factors in cardiac remodeling and the biologic limits of myocardial adaptation. Am J Cardiol 1993;71:46A-54A. [PUBMED] |
| 23. | Clark BA, Shannon C, Brown RS, Gervino EV. Extrarenal potassium homeostasis with maximal exercise in end-stage renal disease. J Am Soc Nephrol 1996;7:1223-7. [PUBMED] [FULLTEXT] |
| 24. | Novo S, Adamo L, Giamporcaro A, et al. Changes of angiotensin converting enzyme (ACE) levels during activation of the reninangiotensin-aldosterone system (RAAs). Agents Actions Suppl 1987;22:339-47. [PUBMED] |
| 25. | Hausmann MJ, Liel-Cohen N. Aldactone therapy in a peritoneal dialysis patient with decreased left ventricular function. Nephrol Dial Transplant 2002;17:2035-6. [PUBMED] [FULLTEXT] |
Correspondence Address:
Shahram Taheri
Department of Internal Medicine, St. Al-Zahra Hospital, Soffeh Ave., Isfahan
Iran
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PMID: 19414940 
[Figure 1]
[Table 1], [Table 2] |
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