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(Circulation. 2007;115:2976-2982.)
© 2007 American Heart Association, Inc.

Controversies in Cardiovascular Medicine

Should aldosterone antagonists be considered as primary therapy for prevention of sudden cardiac death?

Added Benefit of Mineralocorticoid Receptor Blockade in the Primary Prevention of Sudden Cardiac Death

Bertram Pitt, MD; Geoffrey S. Pitt, MD, PhD

From the University of Michigan School of Medicine, Ann Arbor (B.P.); and Departments of Pharmacology and Medicine, Division of Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY (G.S.P).

Correspondence to Bertram Pitt, MD, University of Michigan School of Medicine, Division of Cardiology, University Hospital, 1500 East Medical Center Dr, Ann Arbor, MI 48109–0366. E-mail bpitt{at}umich.edu

	Introduction

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Sudden cardiac death (SCD) is a major public health issue. In patients with heart failure (HF) of various origins, including ischemia post-myocardial infarction (MI), successful development of pharmacological therapies that target neurohormonal abnormalities and modulate disease progression has changed the major cause of death from progressive pump failure to SCD from cardiac arrhythmias. Conditions such as hypertension, hypertrophic cardiomyopathy, aortic stenosis, diabetes mellitus, and aging are accompanied by hypertrophy and fibrosis, increasing the risk of SCD. Also affected are patients with inherited arrhythmogenic disorders such as long-QT syndrome and Brugada syndrome (BrS). Although the mechanisms responsible for SCD, its epidemiology, and treatment have recently been reviewed,^1–4 1 aspect of therapy that deserves further emphasis for the prevention of SCD is the role of aldosterone blockade (AB) or, more precisely, mineralocorticoid receptor blockade (MRB).

Response by Kloner and Cannom p 2982

As with any pharmacological approach to reduce SCD, including MRB, implantable cardioverter-defibrillators (ICDs) and/or cardiac resynchronization therapy (CRT) will remain central in the secondary prevention of SCD in high-risk individuals. Rather, we hypothesize that MRB may have an important role in the primary prevention of SCD in high-risk individuals both with and without systolic left ventricular dysfunction (SLVD) and as an adjunct to ICDs and/or CRT, both in the primary and secondary prevention of SCD. In this article, we will briefly review the current experience with MRB in the prevention of SCD in patients with severe chronic HF and SLVD and in patients with SLVD and HF post-MI. We will discuss the potential mechanisms by which MRB may reduce SCD. Finally, we will propose opportunities for further reducing SCD in high-risk individuals without SLVD or HF.

	The Role of MRB in Reducing SCD in Patients With Severe Chronic HF Associated With SLVD and in Patients With SLVD and HF Post-MI

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MRB with spironolactone 12.5 to 50 mg/d was shown to be effective in reducing SCD by 29% (P=0.02) and total mortality by 30% (P<0.001) in patients with severe HF due to SLVD associated with either ischemic heart disease or idiopathic dilated cardiomyopathy when added to standard therapy that included an angiotensin-converting enzyme inhibitor (ACEI), β-adrenergic blocking agent (BB), diuretics, and digoxin in the Randomized Aldactone Evaluation Study (RALES).⁵ Because this study was initiated before the positive results of trials with BB in severe HF were published,⁶ only 10% to 11% of patients randomized in RALES were on BB.

In a subsequent study, the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), the more selective MRB eplerenone, at 25 to 50 mg/d, was also associated with a 21% (P=0.02) reduction in SCD and a 15% (P=0.008) reduction in total mortality in patients with HF and SLVD post-MI.⁷ In EPHESUS, 83% of patients were on an ACEI and/or angiotensin receptor blocker (ARB) and 75% of patients on a BB before hospital discharge. Eplerenone was also effective in reducing SCD in patients on "optimal therapy" that included aspirin, reperfusion, a statin, an ACEI and/or an ARB, and a BB, suggesting that MRB adds to the efficacy of the standard therapy of HF in reducing SCD and total mortality. It should be noted that the definition of SCD in EPHESUS included death occurring within 1 hour of new symptoms, unwitnessed death with no new symptoms within the previous 72 hours, or cardiac arrest with death within 28 days thereafter; it is therefore possible that not all the deaths classified as SCD were due to an arrhythmia. Nevertheless, the significant reduction in total mortality in RALES and EPHESUS suggests a beneficial effect of MRB on SCD.

	Role of MRB in the First 30 Days After MI

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In patients with SLVD and/or HF, the first 30 days has been shown to be the period of highest risk for SCD.⁸ In EPHESUS, eplerenone 25 mg/d, equivalent to approximately 12.5 mg/d of spironolactone, was effective in reducing both SCD (by 37%; P=0.051) and total mortality (by 31%; P=0.004) during this high-risk period.⁹ It is possible that eplerenone may be even more effective in reducing SCD if therapy is initiated earlier. In EPHESUS,⁷ eplerenone was administered between 3 to 14 days post-MI (mean=7 days). Elevated plasma aldosterone levels for patients with ST-segment elevation MI on admission to the hospital predicted an increase risk of death and resuscitated cardiovascular death independent of the patients’ age, reperfusion status, or the presence of HF.¹⁰ Of importance, 83% of the patients in this study did not have evidence of HF on admission, suggesting an important role for the early administration of an AB to patients post-MI regardless of the presence of clinical HF. In another study, Hayashi et al randomized patients with their first anterior ST-segment–elevation MI after primary percutaneous coronary intervention on day 1 post-MI to an AB strategy consisting of intravenous canreonate, an injectable MRB, followed by oral spironolactone for 30 days.¹¹ They found that the AB strategy was well tolerated and was associated with a significant improvement in ventricular remodeling and collagen formation. The potential benefits of initiating AB therapy on day 1 post-MI will, however, require further testing, especially because of the negative experience with the early administration of intravenous ACEI post-MI.¹²

AB during the first 30 days post-MI should be considered because early ICD implantation may be detrimental.¹³ The role of ICDs in reducing SCD in patients with SLVD after 30 days post-MI is not in dispute, as established by the results of the Second Multicenter Automatic Defibrillator Implantation Trial (MADIT-II).¹⁴ Yet in MADIT-II, in which the mean time of ICD implantation was 81 months post-MI, no reduction in SCD occurred during the first year post implantation. Moreover, The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), which tested the hypothesis that ICD placement during this early vulnerable period would be protective, found an excess of deaths due to an increase in noncardiovascular deaths during 1 year of follow up.¹³ Thus, while further exploration of the role of ICDs in the early post-MI setting continues, current guidelines do not recommend the insertion of an ICD in patients post-MI with SLVD before 30 days. The reason for the apparent failure of an ICD to reduce SCD during this early phase is unclear. On the basis of these observations, it would, however, appear prudent to treat patients with SLVD post-MI who otherwise qualify for implantation of an ICD with optimum pharmacological therapy, including a BB, ACEI and/or ARB, an MRB, and an ICD to provide both early and late protection from SCD.

In patients with chronic HF and SLVD associated with ventricular asynchrony, CRT has also been shown to be effective in reducing SCD.¹⁵ However, as yet no evidence exists for the effectiveness of CRT in reducing SCD early post-MI because such a study has not yet been performed. Given the beneficial effects of MRB on ventricular remodeling post-MI,¹⁰ we believe that the early administration of an MRB to prevent persistent SLVD and thus the need for an ICD and/or a CRT in many patients should be evaluated. The development of promising stratification algorithms to determine which patients are most likely to benefit from ICDs, such as microvolt T-wave alternans,¹⁶ presents opportunities to test this hypothesis.

	The Role of MRB in Reducing SCD in Patients With New York Heart Association Class II HF and SLVD

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The role of MRB in reducing SCD in patients with mild HF and SLVD is less certain than in those with severe HF (New York Heart Association class III and IV). The role of the MRB eplerenone in patients with New York Heart Association class II HF and SLVD is currently being evaluated in a large scale, prospective, blinded, multicenter trial, the Effect of Eplerenone versus Placebo on Cardiovascular Mortality and Heart Failure Hospitalization in Subjects With NYHA Class II Chronic Systolic Heart Failure (EMPHASIS-HF).¹⁷

	The Role of MRB in Reducing SCD in Patients With HF and Preserved Left Ventricular Systolic Function

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Mounting evidence suggests that the incidence of HF associated with preserved left ventricular systolic function (HFPSF) is rising as a result of the aging of the population and the increasing epidemic of obesity and diabetes mellitus.¹⁸ In contrast to patients with chronic HF and SLVD, patients with HFPSF have not been shown to receive a reduction in either total mortality or SCD from pharmacological therapy. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity in Patients with Preserved Systolic function (CHARM–Preserved Trial)¹⁹ suggested that the ARB candesartan may provide a benefit in reducing hospitalization for HF in these patients, but not in reducing total mortality or SCD. The role of the ARB irbesartan in patients with HFPSF is currently being explored in the Irbesartan in Patients with Heart Failure and Preserved Systolic Function trial (IPRESERVE).²⁰ Whereas no data currently exist on the effectiveness of an MRB in reducing SCD in patients with HFPSF, spironolactone has been shown to improve diastolic function in patients with HFPSF²¹ and is currently being evaluated in a large-scale, prospective randomized multicenter trial sponsored by the National Heart, Lung, and Blood Institute, the Treatment of Preserved Systolic function in Cardiac Failure with an Aldosterone Antagonist (TOPCAT).²² The resultant effects on SCD in this patient population will be eagerly awaited.

	The Role of MRB in the Prevention of SCD in Patients Without SLVD or HF

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The role of MRB in preventing SCD in patients without SLVD, such as those with essential hypertension accompanied by myocardial fibrosis and/or hypertrophy, is also promising but as yet unproven. Both myocardial fibrosis and hypertrophy predispose to SCD. MRB, as noted above, has been shown to be effective in reducing myocardial fibrosis and hypertrophy in experimental animal models as well as in patients with essential hypertension. Myocardial fibrosis increases electrical inhomogeneity of conduction and alters gap junction function. Ventricular hypertrophy as well as myocardial fibrosis is associated with a decrease in coronary flow reserve,²³ which predisposes to myocardial ischemia and therefore SCD. Whereas, as yet, no large scale studies exist that demonstrate a benefit of MRB on SCD in patients with hypertension without SLVD or HF, an analysis of the EPHESUS data has suggested that almost all of the benefit of eplerenone in reducing SCD in patients with SLVD and HF post-MI may have occurred in those patients with a history of hypertension, even though they were not hypertensive at the time of their MI.²⁴ The explanation for the benefit of MRB in these patients is uncertain but may relate to prevention of detrimental electrical remodeling associated with an increase in MR activity (see Mechanisms by Which MRB Reduces SCD below).

MRB may also play a role in preventing SCD in patients with obstructive coronary artery disease but without structural abnormalities of the ventricle. MRB has been shown to improve endothelial function in an experimental model of hyperlipidemia,²⁵ and MRB has been shown to be effective in preventing the development of experimental atherosclerosis in the ApoE knockout mouse as well as in a primate model of atherosclerosis.^26,27 Thus, although not as yet proven, the effectiveness of MRB in the primary prevention of SCD can be postulated both for patients without SLVD but with structural abnormalities of the ventricle (such as fibrosis and hypertrophy) and for patients with obstructive coronary artery disease or ischemia without structural abnormalities of the ventricle.

	Mechanisms by Which MRB Reduces SCD

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Although MRB affects a number of mechanisms associated with SCD, it is unlikely that any single mechanism explains its benefits in reducing SCD in patients with chronic HF and SLVD, as well as in patients with SLVD and HF post-MI. Under certain circumstances, one or another of the mechanisms reviewed below may be of particular importance.

Aldosterone has been shown to increase tissue ACE expression and to upregulate the AT1 receptor.²⁸ Thus, in HF or in the post-MI setting, an increase in serum aldosterone levels may lead to an increase in the concentration and effect of angiotensin II on the AT1 receptor, resulting in a vicious cycle, with activation of the renin-angiotensin-aldosterone system and a further production of aldosterone by the adrenal gland. Because angiotensin II is a major stimulus for the production of aldosterone from the adrenal gland, one might conclude that the use of an ACEI and/or ARB would decrease aldosterone levels and eliminate the need for an MRB. Other stimuli, such as the extracellular concentration of potassium, are also of importance. For example, in angiotensinogen knock-out mice, in which no angiotensin II is present, an increase in serum sodium with a consequent decrease in serum potassium significantly raises aldosterone levels.²⁹ Although an ACEI and/or ARB may transiently suppress the production of aldosterone, over time aldosterone production "escapes" and the serum aldosterone level increases.³⁰

Whereas activation of MR is important in regulating renal sodium, potassium, and magnesium concentration in the distal renal tubule, it is also of importance in a number of other tissues that express MR, including the myocardium, vascular wall, glomerulus, and brain.^31,32 In HF, expression of MR in the myocardium increases.³³ Furthermore, cortisol may also activate the MR in several tissues, such as the renal tubule and vascular wall. These tissues, however, express the enzyme 11 β-hydroxysteroid dehydrogenase-2 that regulates the conversion of cortisol to cortisone, which cannot stimulate the MR.^34,35 In situations in which reactive oxygen species increases, such as in HF and hypertension, 11 β-hydroxysteroid dehydrogenase-2 may be downregulated, thereby preventing the conversion of cortisol to cortisone. The consequent increase in cortisol may activate the MR. In the cardiomyocyte, which does not express 11 β-hydroxysteroid dehydrogenase-2, the MR may be normally occupied but not activated by cortisol. With increased reactive oxygen species generation, however, the cortisol-MR complex is activated through unknown mechanisms.³⁵ Aldosterone has also been shown to downregulate the enzyme glucose-6-phosphate dehydrogenase, resulting in a decrease in antioxidant reserve and an increase in reactive oxygen species,³⁶ which could result in activation of the MR.

Activation of the MR also may directly affect the electrical properties of the ventricle, providing a substrate for arrhythmias and SCD. In a mouse model, conditional cardiac-specific overexpression of the MR led to fatal arrhythmias.³⁷ Several factors may contribute. In these mice, the ventricular action potential was prolonged, a harbinger of arrhythmogenesis and an independent risk factor for SCD in HF patients.² In a rat post-MI model, canrenone, the active metabolite of spironolactone, decreased the ventricular fibrillation threshold.³⁸ At the tissue level, activation of the MR results in potassium loss, as well as apoptosis, fibrosis, hypertrophy, and central sympathetic nervous system activation.^39–41 The increase in myocardial fibrosis and resultant ventricular remodeling could promote electrical inhomogeneity and a propensity to ventricular arrhythmias. At the cellular level, aldosterone has been demonstrated to alter the expression of several different ion channels that contribute to the regulation of the cardiac action potential. These resultant changes in the cardiac action potential may also be important contributors to arrhythmogenesis. For example, aldosterone has been shown to cause a dose-dependent increase in the expression of the gap junction protein connexin-43 in cultured rat ventricular myocytes and a concomitant change in conduction velocity.⁴² Aldosterone also affects the levels of several different ionic currents in a manner that consistently results in prolongation of the ventricular action potential. Activation of the MR has been shown to cause an increase in the inward calcium channel current, I_Ca.⁴³ These changes occur within 1 week of MI, before any morphological changes in the ventricle, and can be prevented by MRB. Aldosterone also decreases I_to, the transient outward K⁺ current.⁴³ Interestingly, a decrease in I_to has consistently been found in myocytes from HF patients or in animal models of HF.² Either of these changes, an increase in the calcium current or a decrease in I_to—or both together—would prolong the cardiac action potential. Consistent with these findings, MR overexpression in cardiac myocyte causes ion channel remodeling, resulting in prolonged ventricular repolarization that is associated with an upregulation of I_Ca and a downregulation of I_to, resulting in severe ventricular arrhythmias.³⁷ Administration of aldosterone also increases the expression of cardiac sodium channels.⁴⁴ Whereas the mechanism by which this mode of regulation could contribute to arrhythmogenesis is not clear, it offers a hint of what might underlie the arrhythmogenesis of BrS, an inheritable disorder characterized in many individuals by a haploinsufficiency of SCN5A, the gene for the major cardiac sodium channel.⁴⁵ Interestingly, these patients usually do not experience SCD until adulthood, suggesting the contribution of additional factors to arrhythmogenesis. Thus, the report that SCD in these individuals may be associated with the development of myocardial fibrosis⁴⁶ and an animal model which showed that myocardial fibrosis can be associated with a loss of function of SCN5A⁴⁷ raises the intriguing possibility that sodium channel expression and aldosterone levels may be linked in a feedback loop so that the decrease in sodium channels in BrS patients leads to a compensatory increase in aldosterone production and consequent fibrosis.⁴⁸ Thus, although the effect is not as yet proven, it can be postulated that early administration of an MRB to an individual with BrS will protect against the subsequent development of myocardial fibrosis and thus SCD.

Activation of the MR has also been shown to block norepinephrine uptake into the myocardium, which is associated with an increase in circulating norepinephrine levels and ventricular arrhythmias.⁴⁹ MRB, in contrast, improves the uptake of norepinephrine into the myocardium and decreases ventricular arrhythmias. MRB also improves parasympathetic activity, as indicated by improved heart rate variability, QT dispersion, and baroreceptor function.^39,50,51 These changes are also associated with an increase in NO availability, which can affect the release of norepinephrine from sympathetic nerve terminals and parasympathetic activity as well as endothelial and platelet function.^52,53 MRB has also been shown to decrease plasminogen activator inhibitor-1 levels, improve fibrinolysis, and prevent thrombosis.^54,55 Depending on circumstances, one or another of these mechanisms may be of particular importance in preventing SCD. The benefits of MRB in terms of preventing SCD early post-MI are more likely due to their effects on electrical remodeling of the myocardium, whereas the effects on ventricular remodeling, collagen formation, and hypertrophy may be of equal or greater importance in preventing SCD in patients with HF and SLVD over the long term.

	The Risk of MRB Causing Hyperkalemia

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Whereas MRB has been proven to reduce SCD in patients with severe HF and SLVD, as well as in patients post-MI with SLVD and HF, many clinicians have been reluctant to use an MRB because of the fear of inducing serious hyperkalemia. In both the RALES⁵ and EPHESUS⁷ studies, patients randomized to an MRB had a reduction in SCD and total mortality without any deaths attributable to hyperkalemia. However, since publication of RALES,⁵ a number of reports have appeared showing that the use of spironolactone in clinical practice resulted in a marked increase in the incidence of hyperkalemia associated in some circumstances with renal failure and/or death.^56–59 A review of these reports reveals that many of these episodes of hyperkalemia were due to the use of higher doses of spironolactone than the 12.5 to 50 mg/d used in RALES⁵ and that many deaths occurred in patients with severe renal dysfunction (estimated GFR <30 mL/min) and/or a serum potassium >5.0 mEq/L. A solution to this problem may be to encourage physicians to measure serum potassium either before starting a patient on spironolactone and/or during follow up. In both RALES⁵ and EPHESUS,⁷ serum potassium was measured before considering the use of an MRB, and if serum potassium was >5.0 mEq/L the MRB was withheld. Serum potassium was measured during the first week after starting an MRB, at 1 month, and every 3 to 6 months thereafter. In patients with chronic kidney disease, monitoring of serum potassium should be more frequent. Similarly, if a change in serum electrolyte status is suspected, such as after an episode of vomiting or diarrhea or after adding a drug that might affect potassium excretion, serum potassium should be remeasured. If serum potassium is >5.5 mEq/L, the dose of the MRB should be halved, and if >6.0 mEq/L in a nonhemolyzed sample, the MRB should be withheld until the serum potassium returns to <5.0 mEq/L.

It should be pointed out that hyperkalemia (defined as a serum potassium >5.5 mEq/L) and especially "serious" hyperkalemia (serum potassium >6.0 mEq/L), although a matter of concern, may not necessarily be associated with any serious consequences. Recent data emphasize that serum potassium concentration is not a good indicator of myocardial tissue potassium levels.⁶⁰ In patients with HF treated with drugs affecting the transport of potassium into the myocardial tissues such as digoxin, ACEI, ARBs, BBs, or non-steroidal antiinflammatory agents there may be a defect in transporting potassium into tissues. In some cases, a serum potassium concentration of >7.0 mEq/L may not be accompanied by any ECG or clinical manifestations of hyperkalemia if the tissue potassium concentration, as reflected by red blood cell potassium concentration and ionized calcium concentration, are normal.⁶⁰ Because the determination of red blood cell potassium concentration is not yet routinely available, it would be prudent to minimize the potential risks of hyperkalemia associated with MRB by eliminating, if possible, any drugs such as potassium supplements or nonsteroidal anti-inflammatory agents that could contribute to hyperkalemia, to prescribe a low-potassium diet, to monitor serum potassium and the ECG serially, and to discontinue the MRB if any ECG and/or clinical manifestations of hyperkalemia appear.

The situation with regard to the use of an MRB to prevent SCD and the risk of hyperkalemia may be analogous to the use of warfarin in a patient to prevent thromboembolism and the risk of serious bleeding. When the international normalized ratio is closely monitored during the initiation of warfarin and the dose adjusted periodically according to this ratio, the risk of serious bleeding can be minimized while preventing thromboembolism. One would consider it malpractice if a patient had a serious bleeding episode while on warfarin and the international normalized ratio had not been measured. Similarly, physicians who elect to prescribe an MRB should be obligated to monitor serum potassium and the ECG.

In conclusion, MRB has been shown to play an important role in the primary prevention of SCD in patients with severe chronic HF and SLVD, as well as in patients with SLVD and HF post-MI. It is likely, but not as-yet proven, that MRB will also prevent SCD in patients with mild HF and SLVD or HFPSF, as well as in patients without SLVD or HF, including those with hypertension and myocardial fibrosis and/or hypertrophy and ischemic heart disease, as well as in other conditions associated with myocardial fibrosis and/or hypertrophy, such aortic stenosis, diabetes mellitus, and BrS. Although hyperkalemia is a potential risk, with careful patient selection on the basis of renal function, serial monitoring of serum potassium and the ECG, and appropriate adjustment of the dose of the MRB in response to these factors, it is likely that the benefits of MRB in reducing SCD should far outweigh its potential risks. This hypothesis will, however, require further prospective evaluation in large scale randomized trials.

	Acknowledgments

 
Sources of Funding

Dr G. Pitt is the Esther Aboodi Assistant Professor of Medicine. This work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant R01 HL71165 and an American Heart Association Established Investigator Award (Dr G. Pitt).

Disclosures

Dr B. Pitt has received honoraria from Pfizer (>$10,000) and serves on the consultant/advisory boards for Pfizer and Novartis.

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Response to Pitt and Pitt

Robert A. Kloner, MD, PhD, and David S. Cannom, MD

The 2 MADIT trials that we described in our article unequivocally show that patients with remote myocardial infarctions (>3 to 4 weeks) and reduced left ventricular ejection fraction demonstrated a reduction in total mortality and sudden death with automatic implantable cardioverter-defibrillators. In contrast, in the DINAMIT study patients with recent acute myocardial infarctions (6 to 40 days) and reduced left ventricular function did not demonstrate a reduction in total mortality but did demonstrate a decrease in sudden cardiac death with implantable cardioverter-defibrillator therapy. In the EPHESUS study, eplerenone given early after myocardial infarction (3 to 14 days after myocardial infarction, with an average of 7 days) reduced total mortality (but only by 15%) and decreased sudden cardiac death in patients with compromised ventricles. We agree with Pitt and Pitt that in the early post–myocardial infarction phase, patients with reduced cardiac function benefited from an aldosterone antagonist. However, existing data do not yet support the administration of this agent specifically to postinfarction patients with left ventricular dysfunction after 2 weeks of infarction with or without concomitant implantable devices. Thus, beyond this time, while it is known that implantable cardioverter-defibrillators reduce total mortality and can be considered first line therapy for preventing sudden death, information on administration of aldosterone antagonists starting during the later phase of myocardial infarction is missing, and therefore these agents cannot be considered primary therapy for preventing sudden cardiac death. It is clear that more research into the interaction (or lack of interaction) between implantable cardioverter-defibrillator and/or cardiac resynchronization devices and pharmacological agents such as aldosterone antagonists is needed, both in the early and late phases after acute infarction. Furthermore, the same type of research on device–drug interaction is needed for patients with congestive heart failure due to any cause, including nonischemic dilated cardiomyopathy.

	Footnotes

 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

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