The Role of Aldosterone Blockade in Patients with Heart Failure Due to Systolic Left Ventricular Dysfunction

Login or register to view PDF.
Citation
US Cardiology 2004;2004:1(1):1-6

Pages

The therapy of patients with chronic heart failure (HF) due to systolic left ventricular dysfunction (SLVD) continues to evolve. There is agreement that all patients with HF due to SLVD should be treated with an angiotensin converting enzyme inhibitor (ACE-I) and a beta-adrenergic receptor blocking agent (BB) unless contraindicated or not tolerated. The role of angiotensin receptor blocking agents (ARBs) is more problematical. ARBs in comparison with an ACE-I appear similar in effectiveness but, as yet, have not been shown to be statistically equivalent in patients with chronic HF. It is likely however, based upon the results of the Valsartan in Acute Myocardial Infarction Trial (VALIANT1) study in patients with HF or SLVD post myocardial infarction (MI), that when used at an effective dose, such as valsartan 160mg bid, they are equivalent. However, until further studies are available, ACE-I remains the strategy of choice to inhibit the effect of angiotensin II in patients with chronic HF due to SLVD. The situation with regard to adding an ARB to an ACE-I and a BB, is controversial. In Valsartan Heart Failure Trial (Val-HeFT2), the addition of valsartan to standard therapy, which could include an ACE-I and a BB, failed to improve cardiovascular mortality although it did reduce hospitalizations for HF. In contrast, in the CHARM-Added trial,3 the addition of candesartan resulted in a reduction in cardiovascular mortality as well as hospitalization for HF. Therefore, further study will be required to determine whether the benefits of candesartan seen in the CHARM-Added trial3 are unique to candesartan or are common to other ARBs such as valsartan and whether adding an ARB to an ACE-I and a BB in a patient with HF due to SLVD is beneficial. Increasing data suggests, however, that adding an aldosterone blocker (AB) to an ACE-I and a BB reduces total and cardiovascular mortality in patients with SLVD. Further data will be required before AB can be recommended in all patients with HF due to SLVD current guidelines both in the US and Europe, which recommend AB in patients with severe heart failure due to SLVD based upon the Randomized Aldactone Evaluation Study (RALES) trial.4

RALES4 evaluated the AB spironolactone at an initial dose of 25mg daily in over 1,600 patients with severe HF (New York Heart Association (NYHA) Class III-IV with a history of being in Class IV HF). Patients with a baseline serum potassium 5.0meq/L or a creatinine 2.5mg/dl were excluded. The study was prematurely stopped at a mean follow-up of two years when patients randomized to spironolactone were found to have a 30% reduction in all cause mortality in comparison with placebo. The reduction in death associated with spironolactone was attributed both to a reduction in sudden cardiac death (SCD) and death due to progressive HF. In addition, there was a 35% reduction in the incidence of hospitalization for HF. The beneficial effect of spironolactone on mortality was seen in both males and females - ischemic and non-ischemic ideologies of HF, whether or not patients were on an ACE-I and/or a BB.

Pages

References
  1. Pfeffer M A, MCMurray J J V,Velazquez E J, Rouleau J-L, K├©ber L, Maggioni A P, Soloman S D, Swedberg K,Van de Werf F, White H, Leimberger J D, Henis M, Edwards S, Zelenkofske S, Sellers M A and Califf R M, "for the Valsartan in Acute Myocardial Infarction Trial Investigators.Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both", N. Engl. J. Med. (2004), 349 (20): pp. 1,893-1,906.
    Crossref
  2. Cohn J N and Tognoni G,"A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure", N. Engl. J. Med. (2001), 345: pp. 1,667-1,675.
    Crossref | PubMed
  3. Pfeffer M A, Swedberg, Granger C B, Held P, MCMurray J J V, Michelson E L, Olofsson B, Östergren J and Yusuf S, "for the CHARM investigators and Committees", Lancet (2003), 362: pp. 759- 781.
    Crossref | PubMed
  4. Pitt B, Zannad F, Remme W J, Cody R, Castaigne A, Perez A, Palensky J and Wittes J, "for the Randomized Aldactone Evaluation Study Investigators.The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure", N. Engl. J. Med. (1999), 341 (10): pp. 709-716.
    Crossref | PubMed
  5. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J and Gatlin M, "for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction", N. Engl. J. Med. (2003), 348 (14): pp. 1,309-1,321.
    Crossref | PubMed
  6. Pitt B, "Escape" of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitors: implications for therapy", Cardiovascular Drugs Therapy (1995), 99: pp. 145-149.
    Crossref | PubMed
  7. Okubo S, Niimura F, Nishimura H,Takemoto F, Fogo A, Matsusaka T and Ichikawa I,"Angiotensin-independent mechanism for aldosterone synthesis during chronic extracellular fluid volume depletion", Journal of Clinical Investigation (1997), 99: pp. 855-860.
    Crossref | PubMed
  8. Swedberg K, Eneroth P, Kjekshus J and Wilhelmsen L, "Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality, Circulation (1990), 82: pp. 1,730-1,760.
    Crossref | PubMed
  9. Bocchi B, Kenouch S, Lamarre-Clich├® M, et al.,"Impaired 11-├ş Hydroxysteroid Dehydrogenase Type 2 Activity in Sweat Gland Ducts in Human Essential Hypertension", Hypertension (2004), 43: pp. 803-808.
    Crossref | PubMed
  10. Funder J W, Pearce P T, Smith R and Campbell J and "Vascular type I aldosterone binding sites are physiological mineralocorticoid receptors", Endocrinology (1989), 125: pp. 2,224-2,226.
    Crossref | PubMed
  11. Lombes M, Oblin M E, Gasc J M, Baulieu E E, Farman N and Bonvalet J P,"Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor", Circ. Res. (1992), 71: pp. 503-510.
    Crossref | PubMed
  12. Rajagopalan S, Duquaine D, King S, Pitt B and Patel P, "Mineralocorticoid Receptor Antagonism in Experimental Atherosclerosis", Circulation (2002), 105: pp. 2,212-2,216.
    Crossref | PubMed
  13. Luft F C,"Mechanisms and cardiovascular damage in hypertension", Hypertension (2001), 37: pp. 594-598.
    Crossref | PubMed
  14. Mazak I, Fiebler A, Dominik N, et al., "Aldosterone Potentiates Angiotensin II-Induced Signaling in Vascular Smooth Muscle Cells", Circulation (2004), 109: pp. 2,792-2,800.
    Crossref | PubMed
  15. Harada E,Yoshimura M,Yasue H, Nakagawa O, Nakagawa M, Harada M, Mizuno Y, Nakayama M, Shimasaki Y, Ito T, Nakamura S, Kuwahara K, Saito Y, Nakao K and Ogawa H, "Aldosterone Induces Angiotensin-Converting-Enzyme Gene Expression in Cultured Neonatal Rat Cardiocytes", Circulation (2001), 104: pp. 137-139.
    Crossref | PubMed
  16. Michel F,Ambroisine M L, Duriez M, et al.,"Aldosterone enhances ischemia-induced neovascularization through angiotensin IIdependent pathway", Circulation (2004), 109: pp. 1,933-1,937.
    Crossref | PubMed
  17. Hatakeyama H, Miyamori I,Takeda Y,Yamamoto H and Mabuchi H, "The expression of steroidogenic enzyme genes in human vascular cells", Biochemistry & Molecular Biology International (1996), 40: pp. 639-645.
    Crossref | PubMed
  18. Moss A J,Vyas A, Greenberg H, et al.,"Temporal aspects of improved survival with the implanted defibrillator (MADIT-II)", Am. J. Cardiol. (2004), 109: pp. 2,792-2,800.
    Crossref | PubMed
  19. Pitt B, Reichek N,Willenbrock R, et al., "Effect of Eplerenone, Enalapril, and Eplerenone/Enalapril in Patients with Essential Hypertension and Left ventricular Hypertrophy Study", Circulation (2003), 108: pp. 1,831-1,838.
    Crossref | PubMed
  20. Yusuf S, Sleight P, Pogue J, et al.,"Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in highrisk patents,The Heart Outcomes Prevention Evaluation Study Investigators", New Engl. J. Med. (2000), 342: pp. 145-153.
    Crossref | PubMed
  21. Keidar S, Kaplan M, Pavlotsky E, et al., "Aldosterone Administration to Mice Stimulates Macrophage NADPH Oxidase and Increases Atherosclerosis Development: A Possible Role for Angiotensin-Converting Enzyme and the Receptors for Angiotensin II and Aldosterone", Circulation (2004), 109: pp. 2,213-2,220.
    Crossref | PubMed
  22. Hulley S, Grady D, Bush T, Furberg C, Herrington D, et al., "Effects of estrogen replacement on the progression of coronary - artery atherosclerosis", N. Engl. J. Med. (2000), 343: pp. 522-529.
    Crossref | PubMed
  23. Oelkers W,"Effect of a new oral contraceptive containing an antimineralocorticoid progestogen, drospirenone, on the renin-aldosterone system, body weight, blood pressure, glucose tolerance, and lipid metabolism", J. Clin. Endocrinol. Metab. (1995), 80: pp. 1,861-1,821.
    Crossref | PubMed
  24. Krattenmacher R,"Drospirenone: pharmacology and pharmacokinetics of a unique progestogen", Contraception (2000), 62: pp. 29-38.
    Crossref | PubMed