Abstract
The two major outcome trials on the combination of angiotensin-converting enzyme (ACE) inhibitors and mineralocorticoid receptor (MR) antagonists in heart failure are RALES (Randomized Aldactone Evaluation Study) and EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study). There have also been studies in essential hypertension, and in diabetic hypertensive patients, on the cardiac and renal effects of ACE inhibitors and MR antagonists, individually and in combination. In the clinical studies on heart failure, in outcome trials and the smaller studies using surrogate end points, a combination of ACE inhibition and MR blockade is superior to ACE inhibition alone, and in the hypertension studies to either agent alone. Some insight into their distinct sites of protective action may be gained from studies on experimental animal preparations. The principal caveat in the use of combination therapy is the possibility of hyperkalemia, which should be minimal in patients with creatine clearance greater than 30 mL/min and with the low doses of MR antagonist shown to be effective in outcome trials.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References and Recommended Reading
Brilla CG, Weber KT: Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J Lab Clin Med 1992, 120:893–901.
Ikram H, Webster MWI, Nicholls MG, et al.: Combined spironolactone and converting enzyme inhibitor therapy for refractory heart failure. Aust N Z J Med 1986, 34:57–60.
Dahlstrom U, Karlsson E: Captopril and spironolactone therapy in patients with refractory congestive heart failure. Am J Cardiol 1993, 71:29A-33A.
Barr CS, Lang CC, Hanson J, et al.: Effect of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1995, 76:1259–1265.
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, 341:709–717.
Zannad F, Alla F, Dousset B, et al.: Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 2000, 102:2700–2706.
Krum H, Nolly H, Workman D, et al.: Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension 2002, 40:117–123. Showed the efficacy of eplerenone added to ACE1/ARB in terms of BP control, and the benefits in terms of plasma (K+) in titrating the eplerenone dose to effect.
Epstein M, Buckalew V, Martinez FJ, et al.: Antiproteinuric efficacy of eplerenone, enalapril and eplerenone/enalapril combination in diabetic hypertensives with microalbuminuria [abstract]. Am J Hypertens 2002, 15(suppl 1):24A. Eplerenone in combination with enalapril is clearly more effective in diabetic microalbuminuria than enalapril alone.
Pitt B, Reichek N, Willenbrock R, et al.: Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation 2003, 108:1831–1838.
Bauersachs J, Heck M, Fraccarollo D, et al.: Addition of spironolactone to angiotensin-converting enzyme inhibition in heart failure improves endothelial vasomotor dysfunction. J Am Coll Cardiol 2002, 39:351–358. Began to pry apart the overlapping and synergistic effects of ACE inhibition and MR blockade.
Schafer A, Fraccarollo D, Hildemann SK, et al.: Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction. Cardiovasc Res 2003, 58:655–662. Same as for Bauersachs et al. [10], but unexplained major differences unrelated to MR blockade in eNOS mRNA levels make eNOS changes questionable in both studies.
Farquharson CA, Struthers AD: Spironolactone increases nitric oxide bioavailability improves endothelial vasodilator function, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation 2000, 101:594–597.
Abiose AK, Mansoor GA, Barry M, et al.: Effect of spironolactone on endothelial function in patients with congestive heart failure on conventional medical therapy. Am J Cardiol 2004, 93:1564–1566. Small (n = 20) study on flow-mediated dilation showing marked (60% to 70%) improvement with spironolactone over 4 to 8 weeks in patients with NYHA class 3 to 4 heart failure on aggressive standard-of-care therapy.
Schafer A, Fraccarollo D, Hildemann SK, et al.: Inhibition of platelet activation in congestive heart failure by aldosterone receptor antagonism and ACE inhibition. Thromb Haemost 2003, 89:1024–1030.
Pitt B, Remme W, Zannad F, et al.: Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003, 348:1309–1321. What spironolactone can do on top of their standard of care in progressive CHF, eplerenone can do in patients with heart failure after myocardial infarction, the the addition of â blockers to standard of care over the intervening period notwithstanding.
Blaustein DA, Schwenk MH: Letter to Editor: Eplerenone in patients with left ventricular dysfunction. N Engl J Med 2003, 349:88–89.
Sica DA: Hyperkalemia, congestive heart failure, and aldosterone receptor antagonism. Congest Heart Fail 2003, 9:224–229.
Levy D, Rocha R, Funder JW: Distinguishing the antihypertensive and electrolyte effects of eplerenone. J Clin Endocrinol Metab 2004, 89:2736–2740. Meta-analysis of two titration-to-effect eplerenone trials, showing dissociation of BP lowering and plasma (K+) effects, and range of sensitivity to eplerenone in terms of BP.
Bozkurt B, Agoston I, Knowlton AA: Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines. J Am Coll Cardiol 2003, 41:211–214. And when prescribing doctors fail to think.
Funder JW: Is aldosterone bad for the heart? Trends Endocrinol Metab 2004, 15:139–142. A reassessment of what exactly is inappropriately activating cardiovascular MR in the context of normal aldosterone and salt levels.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Funder, J.W. ACE inhibitors and mineralocorticoid receptor blockade in patients with congestive heart failure. Curr Diab Rep 5, 36–40 (2005). https://doi.org/10.1007/s11892-005-0065-5
Issue Date:
DOI: https://doi.org/10.1007/s11892-005-0065-5