Background/Aims: Spironolactone may be hazardous in heart failure (HF) patients with renal dysfunction due to risk of hyperkalemia and worsened renal function. We aimed to evaluate the effect of spironolactone on all-cause mortality in HF outpatients with renal dysfunction in a propensity-score-matched study. Methods: A total of 2,077 patients from the Norwegian Heart Failure Registry with renal dysfunction (eGFR <60 mL/min/1.73 m2) not treated with spironolactone at the first visit at the HF clinic were eligible for the study. Patients started on spironolactone at the outpatient HF clinics (n = 206) were propensity-score-matched 1:1 with patients not started on spironolactone, based on 16 measured baseline characteristics. Kaplan-Meier and Cox regression analyses were used to investigate the independent effect of spironolactone on 2-year all-cause mortality. Results: Propensity score matching identified 170 pairs of patients, one group receiving spironolactone and the other not. The two groups were well matched (mean age 76.7 ± 8.1 years, 66.4% males, and eGFR 46.2 ± 10.2 mL/min/1.73 m2). Treatment with spironolactone was associated with increased potassium (delta potassium 0.31 ± 0.55 vs. 0.05 ± 0.41 mmol/L, p < 0.001) and decreased eGFR (delta eGFR -4.12 ± 12.2 vs. -0.98 ± 7.88 mL/min/1.73 m2, p = 0.006) compared to the non-spironolactone group. After 2 years, 84% of patients were alive in the spironolactone group and 73% of patients in the non-spironolactone group (HR 0.59, 95% CI 0.37-0.92, p = 0.020). Conclusion: In HF outpatients with renal dysfunction, treatment with spironolactone was associated with improved 2-year survival compared to well-matched patients not treated with spironolactone. Favorable survival was observed despite worsened renal function and increased potassium in the spironolactone group.

Keywords:
Heart failure, Reduced renal function, Spironolactone, Prognosis
1.
Damman K, Valente MA, Voors AA, O'Connor CM, van Veldhuisen DJ, Hillege HL: Renal impairment, worsening renal function, and outcome in patients with heart failure: an updated meta-analysis. Eur Heart J 2014;35:455-469.
2.
Waldum B, Westheim AS, Sandvik L, Flonaes B, Grundtvig M, Gullestad L, Hole T, Os I: Renal function in outpatients with chronic heart failure. J Card Fail 2010;16:374-380.
3.
van Deursen VM, Urso R, Laroche C, Damman K, Dahlstrom U, Tavazzi L, Maggioni AP, Voors AA: Co-morbidities in patients with heart failure: an analysis of the European Heart Failure Pilot Survey. Eur J Heart Fail 2014;16:103-111.
4.
Hallan SI, Coresh J, Astor BC, Asberg A, Powe NR, Romundstad S, Hallan HA, Lydersen S, Holmen J: International comparison of the relationship of chronic kidney disease prevalence and ESRD risk. J Am Soc Nephrol 2006;17:2275-2284.
5.
Coca SG, Krumholz HM, Garg AX, Parikh CR: Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease. JAMA 2006;296:1377-1384.
6.
Klungel OH, Martens EP, Psaty BM, Grobbee DE, Sullivan SD, Stricker BH, Leufkens HG, de Boer A: Methods to assess intended effects of drug treatment in observational studies are reviewed. J Clin Epidemiol 2004;57:1223-1231.
7.
McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, et al: ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803-869.
8.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, et al: 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013;128:1810-1852.
9.
Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA: Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. New Engl J Med 2004;351:543-551.
10.
Svensson M, Gustafsson F, Galatius S, Hildebrandt PR, Atar D: How prevalent is hyperkalemia and renal dysfunction during treatment with spironolactone in patients with congestive heart failure? J Card Fail 2004;10:297-303.
11.
Clark H, Krum H, Hopper I: Worsening renal function during renin-angiotensin-aldosterone system inhibitor initiation and long-term outcomes in patients with left ventricular systolic dysfunction. Eur J Heart Fail 2014;16:41-48.
12.
Damman K, Navis G, Voors AA, Asselbergs FW, Smilde TD, Cleland JG, van Veldhuisen DJ, Hillege HL: Worsening renal function and prognosis in heart failure: systematic review and meta-analysis. J Card Fail 2007;13:599-608.
13.
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;35:681-689.
14.
Maeder MT, Rickli H, Pfisterer ME, Muzzarelli S, Ammann P, Fehr T, Hack D, Weilenmann D, Dieterle T, Kiencke S, et al: Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy. Am Heart J 2012;163:407-414, 414.e401.
15.
Remme WJ, Swedberg K, Task Force for the D, Treatment of Chronic Heart Failure ESoC: Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527-1560.
16.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, et al: A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-612.
17.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. New Engl J Med 1999;341:709-717.
18.
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B: Eplerenone in patients with systolic heart failure and mild symptoms. New Engl J Med 2011;364:11-21.
19.
Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. New Engl J Med 2003;348:1309-1321.
20.
Lund LH, Svennblad B, Melhus H, Hallberg P, Dahlstrom U, Edner M: Association of spironolactone use with all-cause mortality in heart failure: a propensity scored cohort study. Circ Heart Fail 2013;6:174-183.
21.
Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B, Solomon SD: 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;60:2082-2089.
22.
Niederseer D, Thaler CW, Niederseer M, Niebauer J: Mismatch between heart failure patients in clinical trials and the real world. Int J Cardiol 2013;168:1859-1865.
23.
Rossignol P, Cleland JG, Bhandari S, Tala S, Gustafsson F, Fay R, Lamiral Z, Dobre D, Pitt B, Zannad F: Determinants and consequences of renal function variations with aldosterone blocker therapy in heart failure patients after myocardial infarction: insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study. Circulation 2012;125:271-279.
24.
Brunner-La Rocca HP, Knackstedt C, Eurlings L, Rolny V, Krause F, Pfisterer ME, Tobler D, Rickenbacher P, Maeder MT: Impact of worsening renal function related to medication in heart failure. Eur J Heart Fail 2015;17:159-168.
25.
Austin PC: An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399-424.
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2017
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