Correspondence
Eplerenone in Patients with Left Ventricular Dysfunction
N Engl J Med 2003; 349:88-89July 3, 2003
- Article
To the Editor:
The results of the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), reported by Pitt et al. (April 3 issue),1 yield evidence of a benefit from selective aldosterone blockade with eplerenone in patients with acute myocardial infarction complicated by left ventricular dysfunction, beyond the benefit achieved with optimal medical therapy including angiotensin-converting–enzyme (ACE) inhibitors and beta-blockers. In patients with severe heart failure, aldosterone blockade with spironolactone has previously been demonstrated to provide meaningful reductions in morbidity and mortality as well.2 One point of contention is that the authors began randomization in the EPHESUS trial in December 1999, more than two months after the results of the Randomized Aldactone Evaluation Study (RALES) were published. Would it not have been more meaningful if the authors had used an active-control–equivalence design involving the use of spironolactone?3 I am left in a quandary about whether to use a “designer” agent that is purported to be specific for the aldosterone receptor or another agent that is much cheaper, although it is associated with a 10 percent incidence of gynecomastia, in a population of patients with ischemic left ventricular dysfunction who are already taking multiple medications.
3 ReferencesAtul Aggarwal, M.D.
University of Vermont College of Medicine, Burlington, VT 05401
atul.aggarwal@vtmednet. org 1
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
Full Text | Web of Science | Medline2
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
Full Text | Web of Science | Medline3
Temple R ,Ellenberg SS . Placebo-controlled trials and active-control trials in the evaluation of new treatments. 1. Ethical and scientific issues. Ann Intern Med 2000;133:455-463
Web of Science | Medline
To the Editor:
In the trial reported by Pitt et al., the incidence of serious hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001). Although the reduction in mortality has been ascribed largely to nonrenal mechanisms, the difference in the incidence of hypokalemia, which most likely results from aldosterone blockade, may be the reason for the 21 percent reduction in the rate of sudden death from cardiac causes, since hypokalemia frequently leads to ventricular arrhythmias.1
1 ReferencesSteven G. Coca, D.O.
Gregory K. Buller, M.D.
St. Mary's Hospital, Waterbury, CT 067061
Nordrehaug JE ,von der Lippe G . Hypokalaemia and ventricular fibrillation in acute myocardial infarction. Br Heart J 1983;50:525-529
CrossRef | Web of Science | Medline
To the Editor:
Pitt et al. report that in their study, the incidence of serious hyperkalemia was greater in the eplerenone group than in the placebo group, but they do not specifically state the base-line creatinine clearances for the patients with hyperkalemia nor the clearances at the time of hyperkalemia. We have recently described fatal hyperkalemia in patients with heart failure who were treated with mineralocorticoid antagonist spironolactone; these patients had base-line serum creatinine concentrations of less than 2.5 mg per deciliter and were receiving concomitant therapy with ACE inhibitors or angiotensin-receptor blockers.1 Other groups have also confirmed the occurrence of serious hyperkalemia with this form of therapy.2,3
We believe that eplerenone therapy, like spironolactone therapy, is contraindicated when the creatinine clearance is less than 30 ml per minute4 and that simple measurement of the serum creatinine concentration will not provide an adequate measure of renal function in elderly or malnourished patients. In addition, monitoring of renal function and potassium levels may not be as rigorous in routine clinical practice as in a study, renal function may suddenly deteriorate, or drug interactions (with erythromycin or ketoconazole) may impair eplerenone clearance.
4 ReferencesDaniel A. Blaustein, M.D.
Long Island College Hospital, Brooklyn, NY 11201Michael H. Schwenk, Pharm.D.
New York Hospital Medical Center of Queens, Flushing, NY 11355
mhschwen@nyp.org 1
Blaustein DA ,Babu K ,Reddy A ,Schwenk MH ,Avram MM . Estimation of glomerular filtration rate to prevent life-threatening hyperkalemia due to combined therapy with spironolactone and angiotensin-converting enzyme inhibition or angiotensin receptor blockade. Am J Cardiol 2002;90:662-663
CrossRef | Web of Science | Medline2
Schepkens H ,Vanholder R ,Billiouw J ,Lameire N . Life threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases. Am J Med 2001;110:438-441
CrossRef | Web of Science | Medline3
Berry C ,McMurray J . Life threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone. Am J Med 2001;111:587-587
Web of Science | Medline4
Boudoulas H, Leier CV. Renal disorders and cardiovascular disease. In: Braunwald E, Zipes DP, Libby P, eds. Heart disease: a textbook of cardiovascular medicine. 6th ed. Vol. 2. Philadelphia: W.B. Saunders, 2001:2280-97.
Author/Editor Response
At the time EPHESUS was initiated, no information was available on the effect of spironolactone on mortality or morbidity among patients with acute myocardial infarction. Since the pathophysiology of acute infarction may differ from that of chronic heart failure, we see no compelling ethical reason that we should have used an active-control–equivalence design for our study.
The decision about which aldosterone blocker to use in patients with systolic left ventricular dysfunction after an acute myocardial infarction should, in our opinion, be based on the results of our study and several other factors. It is as yet uncertain whether the greater relative binding of spironolactone to androgen and progesterone receptors in comparison with eplerenone will have a relative beneficial or detrimental effect on mortality or morbidity. Furthermore, because of its metabolite canrenoate, the half-life of spironolactone is considerably longer than that of eplerenone. This difference could have important implications for the relative risks of hyperkalemia associated with these two treatments. This possibility is, however, speculative, since it has not, as yet, been examined prospectively. It should be emphasized that neither spironolactone nor eplerenone is currently approved by the Food and Drug Administration for use in patients with acute myocardial infarction complicated by systolic left ventricular dysfunction or heart failure.
A preliminary analysis of data from EPHESUS reveals a significant reduction in the risk of sudden death from cardiac causes, which is independent of the effects of eplerenone in preventing hypokalemia, and thus does not support the hypothesis proposed by Coca and Buller.
We agree with Blaustein and Schwenk that one should be cautious in using an aldosterone blocker in a patient with a creatinine clearance of less than 30 ml per minute, and we urge clinicians to adhere to the dose recommendations in RALES and EPHESUS, the exclusion criteria, the strategy for monitoring serum potassium, and the adjustment of the dose of the aldosterone blocker on the basis of the serum potassium and creatinine values. Most episodes of serious hyperkalemia associated with aldosterone blockade described in the literature have occurred in patients in whom these recommendations were not followed. Aldosterone blockade in a patient with systolic left ventricular dysfunction that is treated with an ACE inhibitor and a beta-blocker poses a risk of hyperkalemia. However, RALES and EPHESUS demonstrate that if one follows the recommendations in these studies, there is a significant benefit in terms of mortality and morbidity that is not associated with excess risk.
Bertram Pitt, M.D.
University of Michigan Medical Center, Ann Arbor, MI 48109-0366
bpitt@umich.edu for the EPHESUS Investigators
- Citing Articles (2)
Citing Articles
1
Steven G. Coca, Mark A. Perazella, Gregory K. Buller. (2005) The cardiovascular implications of hypokalemia. American Journal of Kidney Diseases 45:2, 233-247
CrossRef2
John W. Funder. (2005) ACE inhibitors and mineralocorticoid receptor blockade in patients with congestive heart failure. Current Diabetes Reports 5:1, 36-40
CrossRef
