Blockade of Renin–Angiotensin–Aldosterone System in Elderly Patients with Heart Failure and Chronic Kidney Disease: Results of a Single-Center, Observational Cohort Study

  • Juan Martínez-MillaEmail author
  • Marcelino Cortés García
  • Mikel Taibo Urquía
  • Marta López Castillo
  • Ana Devesa Arbiol
  • Ana Lucía Rivero Monteagudo
  • María Luisa Martín Mariscal
  • Sem Briongos Figuero
  • Juan Antonio Franco-Pelaéz
  • José Tuñón
Original Research Article



Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEis/ARBs) and mineralocorticoid receptor antagonists (MRAs) have been shown to benefit patients with heart failure with reduced ejection fraction (HFrEF). However, there is a lack of information on the advantages of these drugs for patients with chronic kidney disease (CKD), and this gap is especially pronounced in elderly patients.


The objective of this study was to assess the role of treatment consisting of ACEi/ARBs and MRAs in patients ≥ 75 years of age with CKD.


From January 2008 to July 2014, 390 consecutive patients ≥ 75 years of age with an ejection fraction ≤ 35% and a glomerular filtration rate (GFR) ≤ 60 mL/min/1.73 m2 were included. We analyzed the relationship between treatment with ACEi/ARBs and MRAs and mortality or cardiovascular events.


Three hundred and ninety patients were included, with a mean age of 82.6 ± 4.1 years. Mean ejection fraction was 27.9 ± 6.5%. Renal dysfunction was mild (GFR 45–60 mL/min/1.73 m2) in 50.3% of patients, moderate (GFR 30–44 mL/min/1.73 m2) in 37.4%, and severe (GFR < 30 mL/min/1.73 m2) in 12.3%. After 32 ± 23 months, 68.7% of patients were receiving ACEi/ARBs and 40% were receiving MRAs; 65.9% developed a cardiovascular event and 54.4% had died. After multivariate Cox regression analysis, ACEi/ARB treatment was independently associated with a decreased rate of cardiovascular events (hazard ratio 0.71 [95% confidence interval 0.50–0.98]) and MRAs were not associated with a decrease in cardiovascular events or total mortality.


Treatment with ACEi/ARBs in elderly patients with HFrEF and CKD was associated with a lower rate of cardiovascular events, though MRA treatment failed to reduce the risk of morbidity and mortality in our population.



The authors would like to acknowledge Oliver Shaw for editing the manuscript for aspects related to English language usage and style.

Compliance with Ethical Standards


No external funding was used in the preparation of this manuscript.

Conflict of interest

Juan Martínez-Milla, Marcelino Cortés García, Mikel Taibo Urquía, Marta López Castillo, Ana Devesa Arbiol, Ana Lucía Rivero Monteagudo, María Luisa Martín Mariscal, Sem Briongos Figuero, Juan Antonio Franco-Pelaéz, and José Tuñón declare that they have no potential conflicts of interest that might be relevant to the contents of this article.


  1. 1.
    Ma TK-W, Szeto C-C. Mineralocorticoid receptor antagonist for renal protection. Renal Fail. 2012;34(6):810–7.CrossRefGoogle Scholar
  2. 2.
    Eckhart AD. Mineralocorticoid receptors, corticosteroids and the heart. Where do we stand? J Hypertens. 2010;28(5):889–91.CrossRefGoogle Scholar
  3. 3.
    The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.CrossRefGoogle Scholar
  4. 4.
    The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–35.CrossRefGoogle Scholar
  5. 5.
    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.CrossRefGoogle Scholar
  6. 6.
    Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309–21.CrossRefGoogle Scholar
  7. 7.
    Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.CrossRefGoogle Scholar
  8. 8.
    Tamirisa KP, Aaronson KD, Koelling TM. Spironolactone-induced renal insufficiency and hyperkalemia in patients with heart failure. Am Heart J. 2004;148:971–8.CrossRefGoogle Scholar
  9. 9.
    Navis G, Faber HJ, de Zeeuw D, de Jong PE. ACE inhibitors and the kidney. A risk-benefit assessment. Drug Saf. 1996;15(3):200–11.CrossRefGoogle Scholar
  10. 10.
    Komajda M, Hanon O, Hochadel M, Lopez-Sendón JL, Follath F, Pinokowski P, et al. Contemporary management of octogenarians hospitalized for heart failure in Europe: Euro Heart Failure Survey II. Eur Heart J. 2009;30:478–86.CrossRefGoogle Scholar
  11. 11.
    Massie BM, Armstrong PW, Cleland JG, et al. Toleration of high doses of angiotensin-converting enzyme inhibitors in patients with chronic heart failure: results from the ATLAS trial. The assessment of treatment with lisinopril and survival. Arch Intern Med. 2001;161:165–71.CrossRefGoogle Scholar
  12. 12.
    Granger CB, McMurray JJV, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-alternative trial. Lancet. 2003;362(9386):772–6.CrossRefGoogle Scholar
  13. 13.
    Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129–200.CrossRefGoogle Scholar
  14. 14.
    Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 2013;62(2013):e147–239.CrossRefGoogle Scholar
  15. 15.
    Kottgen A, Russell SD, Loehr LR, et al. Reduced kidney function as a risk factor for incident heart failure: the atherosclerosis risk in communities (ARIC) study. J Am Soc Nephrol. 2007;18(4):1307–15.CrossRefGoogle Scholar
  16. 16.
    Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart. 2007;93(9):1137–46.CrossRefGoogle Scholar
  17. 17.
    Vidan MT, Blaya-Novakova V, Sanchez E, Ortiz J, Serra-Rexach JA, Bueno H. Prevalence and prognostic impact of frailty and its components in non-dependent elderly patients with heart failure. Eur J Heart Fail. 2016;18(7):869–75.CrossRefGoogle Scholar
  18. 18.
    Heywood JT, Fonarow GC, Yancy CW, et al. Influence of renal function on the use of guideline-recommended therapies for patients with heart failure. Am J Cardiol. 2010;105:1140–6.CrossRefGoogle Scholar
  19. 19.
    Hawwa N, Schreiber MJ Jr, Tang WH. Pharmacologic management of chronic reno-cardiac syndrome. Curr Heart Fail Rep. 2013;10:54–62.CrossRefGoogle Scholar
  20. 20.
    McMurray JJ, Pfeffer MA. Heart failure. Lancet. 2005;365:1877–1889K.CrossRefGoogle Scholar
  21. 21.
    K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39:S1–266.Google Scholar
  22. 22.
    Damman K, Tang WH, Felker GM, Lassus J, Zannad F, Krum H, et al. Current evidence on treatment of patients with chronic systolic heart failure and renal insufficiency: practical considerations from published data. J Am Coll Cardiol. 2014;63:853–71.CrossRefGoogle Scholar
  23. 23.
    Pfeffer MA, Braunwald E, Moye LA, Basta L. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the survival and ventricular enlargement trial. N Engl J Med. 1992;327(10):669–77.CrossRefGoogle Scholar
  24. 24.
    Ahmed A, Love TE, Sui X, Rich MW. Effects of ACE inhibitors in systolic heart failure patients with chronic kidney disease: a propensity score analysis. J Cardiac Fail. 2006;12(7):499–506.CrossRefGoogle Scholar
  25. 25.
    The Digitalis Investigation Group. Rationale, design, implementation, and baseline characteristics of patients in the DIG trial: a large, simple, long-term trial to evaluate the effect of digitalis on mortality in heart failure. Control Clin Trials. 1996;17:77–97.CrossRefGoogle Scholar
  26. 26.
    Edner M, Benson L, Dahlström U, Lund LH. Association between renin-angiotensin system antagonist use and mortality in heart failure with severe renal insufficiency: a prospective propensity score-matched cohort study. Eur Heart J. 2015;36(34):2318–26.CrossRefGoogle Scholar
  27. 27.
    Higuchi S, Kohsaka S, Shiraishi Y, et al. Association of renin-angiotensin system inhibitors with long-term outcomes in patients with systolic heart failure and moderate-to-severe kidney function impairment. Eur J Intern Med. 2019;62:58–66.CrossRefGoogle Scholar
  28. 28.
    Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374:1840–8.CrossRefGoogle Scholar
  29. 29.
    Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362(9386):772–6.CrossRefGoogle Scholar
  30. 30.
    Vardeny O, Wu DH, Desai A, 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.CrossRefGoogle Scholar
  31. 31.
    Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11–21.CrossRefGoogle Scholar
  32. 32.
    Beattie JN, Soman SS, Sandberg KR, Yee J, Borzak S, Garg M, McCullough PA. Determinants of mortality after myocardial infarction in patients with advanced renal dysfunction. Am J Kidney Dis. 2001;37(6):1191–200.CrossRefGoogle Scholar
  33. 33.
    McCullough PA, Sandberg KR, Borzak S, Hudson MP, Garg M, Manley HJ. Benefits of aspirin and beta-blockade after myocardial infarction in patients with chronic kidney disease. Am Heart J. 2002;144(2):226–32.CrossRefGoogle Scholar
  34. 34.
    Lien CT, Gillespie ND, Struthers AD, McMurdo ME. Heart failure in frail elderly patients: diagnostic difficulties, co-morbidities, polypharmacy and treatment dilemmas. Eur J Heart Fail. 2002;4:91–8.CrossRefGoogle Scholar
  35. 35.
    Komajda M, Hanon O, Hochadel M, Follath F, Swedberg K, Gitt A, et al. Management of octogenarians hospitalized for heart failure in Euro Heart Failure Survey II. Eur Heart J. 2009;30(4):478–86.CrossRefGoogle Scholar
  36. 36.
    Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P, et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol. 2006;47:1987–96.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Juan Martínez-Milla
    • 1
    Email author
  • Marcelino Cortés García
    • 1
  • Mikel Taibo Urquía
    • 1
  • Marta López Castillo
    • 1
  • Ana Devesa Arbiol
    • 1
  • Ana Lucía Rivero Monteagudo
    • 1
  • María Luisa Martín Mariscal
    • 2
  • Sem Briongos Figuero
    • 3
  • Juan Antonio Franco-Pelaéz
    • 1
  • José Tuñón
    • 1
  1. 1.Department of CardiologyHospital Universitario Fundación Jiménez Díaz-QuirónsaludMadridSpain
  2. 2.Department of CardiologyHospital Universitario Ruber-QuirónsaludMadridSpain
  3. 3.Department of CardiologyHospital Universitario Infanta LeonorMadridSpain

Personalised recommendations