Effects of spironolactone on extrasystoles and heart rate variability in haemodialysis patients: a randomised crossover trial

  • Michael Eklund Department of Internal Medicine, School of Medical Sciences, Örebro University, Örebro, Sweden https://orcid.org/0000-0001-7706-1758
  • Olof Hellberg Department of Internal Medicine, School of Medical Sciences, Örebro University, Örebro, Sweden
  • Hans Furuland Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden http://orcid.org/0000-0002-9001-614X
  • Yang Cao Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden; and Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden http://orcid.org/0000-0002-3552-9153
  • Erik Nilsson Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; and School of Medical Sciences, Örebro University, Örebro, Sweden http://orcid.org/0000-0001-6968-6934
Keywords: haemodialysis, spironolactone, clinical trial, long-term ECG, arrhythmias, heart rate variability


Background: Spironolactone treatment reduces mortality in haemodialysis (HD) patients. The objective of this study was to evaluate if spironolactone affects cardiac electric activity in this population.

Methods: Participants were randomised to start with spironolactone 50 mg daily or observation (12 weeks) with subsequent washout (6 weeks) and crossover to the other intervention (12 weeks). Long-term electrocardiograms were recorded and assessed with blinding to treatment. The primary outcome was premature ventricular complexes (PVC), and secondary outcomes were atrial premature contractions (APC) and heart rate variability (HRV).

Results: Thirty participants were recruited, and data for 16 participants were included in the analysis. Treatment was associated with an increase in PVCs by 9.7 [95% confidence interval (CI): 1.5 to 18] h−1. HRV time-domain variables increased during treatment, the standard deviation of all beat-to-beat intervals by 18 (95% CI: 3.3 to 32) milliseconds (ms) and the standard deviation of the averages of beat-to-beat intervals in all 5-min segments of the entire recording by 16 (95% CI: 1.5 to 30) ms. There were no significant differences in other variables.

Conclusion: Spironolactone treatment increases PVCs in HD, indicating a possible proarrhythmic effect. However, improved cardiac autonomic function, as indicated by an increased HRV, may contribute to the survival benefit from spironolactone treatment in HD patients.


Download data is not yet available.


  1. Sarnak MJ, Levey AS, Schoolwerth AC, Coresh J, Culleton B, Hamm LL, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Hypertension. 2003;42:1050–65. doi: 10.1161/01.HYP.0000102971.85504.7c

  2. Lin C, Zhang Q, Zhang H, Lin A. Long-term effects of low-dose spironolactone on chronic dialysis patients: a randomized placebo-controlled study. J Clin Hypertens (Greenwich). 2016;18:121–8. doi: 10.1111/jch.12628

  3. Matsumoto Y, Mori Y, Kageyama S, Arihara K, Sugiyama T, Ohmura H, et al. Spironolactone reduces cardiovascular and cerebrovascular morbidity and mortality in hemodialysis patients. J Am Coll Cardiol. 2014;63:528–36. doi: 10.1016/j.jacc.2013.09.056

  4. Chung YW, Yang YH, Wu CK, Yu CC, Juang JM, Wang YC, et al. Spironolactone is associated with reduced risk of new-onset atrial fibrillation in patients receiving renal replacement therapy. Int J Cardiol. 2016;202:962–6. doi: 10.1016/j.ijcard.2015.05.167

  5. Kimura S, Ito M, Tomita M, Hoyano M, Obata H, Ding L, et al. Role of mineralocorticoid receptor on atrial structural remodeling and inducibility of atrial fibrillation in hypertensive rats. Hypertens Res. 2011;34:584–91. doi: 10.1038/hr.2010.277

  6. Ouvrard-Pascaud A, Sainte-Marie Y, Bénitah JP, Perrier R, Soukaseum C, Nguyen Dinh Cat A, et al. Conditional mineralocorticoid receptor expression in the heart leads to life-threatening arrhythmias. Circulation. 2005;111:3025–33. doi: 10.1161/circulationaha.104.503706

  7. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Circulation. 1996;93:1043–65. doi: 10.1161/01.CIR.93.5.1043

  8. Hillebrand S, Gast KB, de Mutsert R, Swenne CA, Jukema JW, Middeldorp S, et al. Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose-response meta-regression. Europace. 2013;15:742–9. doi: 10.1093/europace/eus341

  9. Inohara T, Kohsaka S, Okamura T, Watanabe M, Nakamura Y, Higashiyama A, et al. Long-term outcome of healthy participants with atrial premature complex: a 15-year follow-up of the NIPPON DATA 90 cohort. PLoS One. 2013;8:e80853. doi: 10.1371/journal.pone.0080853

  10. Lin CY, Chang SL, Lin YJ, Lo LW, Chung FP, Chen YY, et al. Long-term outcome of multiform premature ventricular complexes in structurally normal heart. Int J Cardiol. 2015;180:80–5. doi: 10.1016/j.ijcard.2014.11.110

  11. Qureshi W, Shah AJ, Salahuddin T, Soliman EZ. Long-term mortality risk in individuals with atrial or ventricular premature complexes (results from the Third National Health and Nutrition Examination Survey). Am J Cardiol. 2014;114:59–64. doi: 10.1016/j.amjcard.2014.04.005

  12. Chong BH, Pong V, Lam KF, Liu S, Zuo ML, Lau YF, et al. Frequent premature atrial complexes predict new occurrence of atrial fibrillation and adverse cardiovascular events. Europace. 2012;14:942–7. doi: 10.1093/europace/eur389

  13. Meyerfeldt U, Wessel N, Schütt H, Selbig D, Schumann A, Voss A, et al. Heart rate variability before the onset of ventricular tachycardia: differences between slow and fast arrhythmias. Int J Cardiol. 2002;84:141–51. doi: 10.1016/s0167-5273(02)00139-0

  14. Santoro F, Di Biase L, Hranitzky P, Sanchez JE, Santangeli P, Perini AP, et al. Ventricular fibrillation triggered by PVCs from papillary muscles: clinical features and ablation. J Cardiovasc Electrophysiol. 2014;25:1158–64. doi: 10.1111/jce.12478

  15. Barr CS, Lang CC, Hanson J, Arnott M, Kennedy N, Struthers AD. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995;76:1259–65. doi: 10.1016/s0002-9149(99)80353-1

  16. Gao X, Peng L, Adhikari CM, Lin J, Zuo Z. Spironolactone reduced arrhythmia and maintained magnesium homeostasis in patients with congestive heart failure. J Card Fail. 2007;13:170–7. doi: 10.1016/j.cardfail.2006.11.015

  17. Ramires FJ, Mansur A, Coelho O, Maranhão M, Gruppi CJ, Mady C, et al. Effect of spironolactone on ventricular arrhythmias in congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy. Am J Cardiol. 2000;85:1207–11. doi: 10.1016/s0002-9149(00)00729-3

  18. Sica DA. Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev. 2005;10:23–9. doi: 10.1007/s10741-005-2345-1

  19. Rodríguez-Liñares L, Méndez AJ, Lado MJ, Olivieri DN, Vila XA, Gómez-Conde I. An open source tool for heart rate variability spectral analysis. Comput Methods Programs Biomed. 2011;103:39–50. doi: 10.1016/j.cmpb.2010.05.012

  20. Senn S. Cross-over trials in clinical research. Chichester, UK: John Wiley & Sons; 2002. doi: 10.1002/0470854596

  21. Nordeen SK, Bona BJ, Beck CA, Edwards DP, Borror KC, DeFranco DB. The two faces of a steroid antagonist: when an antagonist isn’t. Steroids. 1995;60:97–104. doi: 10.1016/0039-128x(94)00001-s

  22. Massaad C, Lombès M, Aggerbeck M, Rafestin-Oblin ME, Barouki R. Cell-specific, promoter-dependent mineralocorticoid agonist activity of spironolactone. Mol Pharmacol. 1997;51:285–92. doi: 10.1124/mol.51.2.285

  23. Lincevicius GS, Shimoura CG, Nishi EE, Perry JC, Casarini DE, Gomes GN, et al. Aldosterone contributes to sympathoexcitation in renovascular hypertension. Am J Hypertens. 2015;28:1083–90. doi: 10.1093/ajh/hpu300

  24. Kienzle MG, Ferguson DW, Birkett CL, Myers GA, Berg WJ, Mariano DJ. Clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive heart failure. Am J Cardiol. 1992;69:761–7. doi: 10.1016/0002-9149(92)90502-p

  25. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol. 1995;26:1257–63. doi: 10.1016/0735-1097(95)00332-0

  26. Musch MW, Lucioni A, Chang EB. Aldosterone regulation of intestinal Na absorption involves SGK-mediated changes in NHE3 and Na+ pump activity. Am J Physiol Gastrointest Liver Physiol. 2008;295:G909–19. doi: 10.1152/ajpgi.90312.2008

  27. Shah NC, Pringle SD, Donnan PT, Struthers AD. Spironolactone has antiarrhythmic activity in ischaemic cardiac patients without cardiac failure. J Hypertens. 2007;25:2345–51. doi: 10.1097/HJH.0b013e3282e9a72d

  28. Wei J, Ni J, Huang D, Chen M, Yan S, Peng Y. The effect of aldosterone antagonists for ventricular arrhythmia: a meta-analysis. Clin Cardiol. 2010;33:572–7. doi: 10.1002/clc.20762

  29. Karaboyas A, Zee J, Brunelli SM, Usvyat LA, Weiner DE, Maddux FW, et al. Dialysate potassium, serum potassium, mortality, and arrhythmia events in hemodialysis: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2017;69:266–77. doi: 10.1053/j.ajkd.2016.09.015

  30. Flevari P, Kalogeropoulou S, Drakou A, Leftheriotis D, Panou F, Lekakis J, et al. Spironolactone improves endothelial and cardiac autonomic function in non heart failure hemodialysis patients. J Hypertens. 2013;31:1239–44. doi: 10.1097/HJH.0b013e32835f955c

  31. 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. doi: 10.1016/s0008-6363(97)00091-6

  32. Yee KM, Pringle SD, Struthers AD. Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol. 2001;37:1800–7. doi: 10.1016/s0735-1097(01)01243-8

  33. Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B, et al. Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol. 2012;60:2082–9. doi: 10.1016/j.jacc.2012.07.048

  34. Quach K, Lvtvyn L, Baigent C, Bueti J, Garg AX, Hawley C, et al. The safety and efficacy of mineralocorticoid receptor antagonists in patients who require dialysis: a systematic review and meta-analysis. Am J Kidney Dis. 2016;68:591–8. doi: 10.1053/j.ajkd.2016.04.011

How to Cite
Eklund, M., Hellberg, O., Furuland, H., Cao, Y., & Nilsson, E. (2021). Effects of spironolactone on extrasystoles and heart rate variability in haemodialysis patients: a randomised crossover trial. Upsala Journal of Medical Sciences, 126(1). https://doi.org/10.48101/ujms.v126.5660
Original Articles