EDITORIAL
European Heart Journal (2014) 35, 2276–2278 doi:10.1093/eurheartj/ehu191
Evaluating the efficacy of mineralocorticoid receptor antagonism in patients with STEMI without heart failure Benjamin M. Scirica* TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Online publish-ahead-of-print 29 April 2014
There are three key elements to any clinical trial: study population, study intervention, and outcome. The REMINDER study1 reported by Montalescot et al., is worth considering in detail because of how the investigators ultimately decided these three questions: the choice of ST-segment elevation myocardial infarction (STEMI) patients without heart failure as the population of interest, the selection of the mineralocorticoid receptor antagonist (MRA) eplerenone as the intervention, and the use of natriuretic peptides as the principal measurement of efficacy. To summarize, the REMINDER study randomized 1012 patients presenting with STEMI but no evidence of heart failure to eplerenone or placebo within 24 h of symptoms, and followed them for 10 months. Treatment with eplerenone significantly reduced the risk of a composite endpoint of an elevated natriuretic peptide or an extended list of clinical events by .40% compared with placebo, mostly driven by lower levels of natriuretic peptides at least 1 month after randomization.
ST-segment elevation myocardial infarction without heart failure Most studies evaluating therapy to improve remodelling focus only on patients with large, anterior STEMI or an ejection fraction ,40%, which is logical given that these patients are at the highest risk of subsequent heart failure, arrhythmic events, and death. However, with more rapid reperfusion, they currently account for a small proportion of patients presenting with MI. In . 77 000 patients with STEMI enrolled in one contemporary registry, only 12% presented with heart failure and just 3.6% developed heart
failure after admission,2 a substantially lower number than earlier cohorts.3 Moreover, only 20% of patients with STEMI and no heart failure in this registry had an ejection fraction ,40%2 (Figure 1). Studies restricted to patients with the most severe presentation thus limit generalizability. The REMINDER study is therefore a example of evaluating a broader, more representative cohort, in which a therapeutic agent may have more widespread applicability. As would be expected based on the entry criteria, patients randomized into the REMINDER study were younger, had better renal function, lower rates of diabetes or prior MI, and a lower rate of anterior MI compared with studies focusing on just patients with heart failure, and a correspondingly lower risk of death or heart failure.4,5 The selection of this population is also of interest because the benefit of early initiation of inhibitors of the renin –angiotensin– aldosterone system (RAAS) in post-acute coronary syndrome (ACS) patients without any evidence of heart failure or with normal left ventricular (LV) function remains uncertain. The seminal trials of inhibitors of the RAAS excluded these healthier MI patients4 – 7 (Figure 1). Even in the ‘all-comer’ studies, the benefit of RAAS inhibition was predominately observed in patients with the largest infarcts.8 Thus early inhibition of the RAAS in patients without heart failure or depressed LV function following ACS has yet to be conclusively demonstrated in patients treated with contemporary strategies. Regardless, most patients in REMINDER were treated with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as background therapy; thus, the addition of eplerenone in this study most commonly represented ‘dual’ RAAS inhibition.
Mineralocorticoid receptor antagonists The rationale for choosing a population with smaller infarcts was necessary because of the well-established benefit of MRAs in patients with MI and heart failure or reduced LV function. It is fair to say that
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/ehu164.
* Corresponding author. Tel: +1 617 278 0145; fax: +1 617 734 7349, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 14, 2015
This editorial refers to ‘Early eplerenonetreatment inpatients with acute ST-elevation myocardial infarction without heart failure: the randomized double-blind REMINDER study’†, by G. Montalescot et al., on page 2295
Editorial
2277
MRAs have enjoyed one of the most consistent runs of proven efficacy across the cardiovascular spectrum, in particular in patients with established systolic heart failure9,10 or heart failure and reduced LV function following MI.11 In particular, after the EPHESUS study, which demonstrated clear superiority of eplerenone vs. placebo in post-MI patients with heart failure, it would not have been ethical to include patients with heart failure or reduced LV function in a placebo-controlled trial, even for a shorter duration. The proposed benefits of MRAs following MI are several-fold. First, MRAs preserve serum potassium levels and thereby may prevent arrhythmic triggers in a population vulnerable to lethal arrhythmias. More importantly, MRAs favourably influence a myriad of pathways involved in myocardial remodelling and fibrosis, and improve endothelial dysfunction and peripheral vascular compliance.12 That MRAs reduced markers of haemodynamic stress in the REMINDER Study, specifically in patients with smaller infarcts, suggests that crude measures of ventricular function such as ejection fraction and symptomatic heart failure fail to reflect the degree of myocardial damage and subsequent maladaptive remodelling in many MI patients. Eplerenone was selected as the MRA in the REMINDER study, though there is little reason to suspect that spironolactone would not have produced similar results. One notable aspect of the study was that the first dose of study drug was initiated early (,24 h of symptom onset), which was earlier than in the EPHESUS study. Moreover, there was a trend in subgroup analyses towards an even greater benefit with very early treatment (,6 h), suggesting that MRAs could play a protective role after the initial reperfusion injury following percutaneous intervention or fibrinolysis. Overall, eplerenone was well tolerated in this relatively healthy population with preserved renal function. There were few episodes of hyperkalaemia, though it occurred 2–4 times more frequently with eplerenone than with placebo. It would be informative to know the
timing of hyperkalaemia and whether patients were on other RAAS inhibitors, and at what dose? Additionally, did hyperkalaemia require treatment or lead to study drug discontinuation? Given the concerns of hyperkalaemia when MRAs are used in wider populations, a clearer evaluation of the risk of electrolyte abnormalities and renal dysfunction is necessary to balance any potential benefits in this population.
Natriuretic peptides as an outcome Elevated levels of natriuretic peptides are well-recognized markers of increased risk of heart failure and death following an MI, regardless of whether the levels were measured in the acute phase or during convalescence.13,14 However, and in contrast to patients with decompensated heart failure, identifying therapies that actually reduce levels of natriuretic peptides following an ACS has proven more challenging. Several studies have failed to demonstrate any reductions in natriuretic peptides in ACS with specific therapies.15,16 The AVANT GARDE-TIMI 43 trial, a trial similar to the REMINDER trial, randomized patients with ACS and elevated levels of natriuretic peptides (but without heart failure and with an LV ejection fraction .40%), and provides additional insight into why treatment with may have significantly reduced natriuretic peptides in the REMINDER Study.16 In AVANT GARDE-TIMI 43, there were no differences between randomization and 8 weeks in the change in natriuretic peptides between the 1101 patients assigned to valsartan, the renin inhibitor aliskiren, a combination of the two, or placebo. Active inhibition of RAAS did, however, blunt the rise in serum aldosterone levels observed in the placebo group.17 Thus, even in patients without LV dysfunction, aldosterone levels rose following an infarct, probably reflecting maladaptive remodelling and fibrosis. That even dual inhibition of RAAS with aliskiren and valsartan could just blunt the rise in
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 14, 2015
Figure 1 Summary of cardiovascular studies evaluating inhibition of the renin– angiotensin – aldosterone system in patients presenting with acute coronary syndrome. ACEi, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CHF, heart failure; DRI, direct renin inhibitor; EF, ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid antagonist; RAAS, renin– angiotensin– aldosterone system; STEMI, ST-segment elevation myocardial infarction. * - indicates studies with natriuretic peptides as an endpoint.
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Conflict of interest: B.M.S. reports research grants via the TIMI Study and Brigham and Women’s Hospital from AstraZeneca, Bristol-Myers Squibb, Daichi-Sankyo, GlaxoSmithKline, Johnson and Johnson, Bayer Healthcare, Gilead, Eisai, and Merck; and consulting fees from Gilead, Lexicon, Arena, Eisai, St. Jude’s Medical, Bristol-Myers Squibb, Forest Pharmaceuticals, Boston Clinical Research Institute, Decision Resources, University of Calgary, Elsevier Practice Update Cardiology, and Forest Pharmaceuticals.
References 1. Montalescot G, Pitt B, Lopez de Sa E, Hamm CW, Flather M, Verheught F, Shi H, Turgonyi E, Orri M, Vincet J, Zannad F. Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the randomized double-blind REMINDER study. Eur Heart J 2014;35:2295 –2302. 2. Shah RV, Holmes D, Anderson M, Wang TY, Kontos MC, Wiviott SD, Scirica BM. Risk of heart failure complication during hospitalization for acute myocardial infarction in a contemporary population: insights from the National Cardiovascular Data ACTION Registry. Circ Heart Fail 2012;5:693 –702. 3. Steg PG, Dabbous OH, Feldman LJ, Cohen-Solal A, Aumont MC, Lopez-Sendon J, Budaj A, Goldberg RJ, Klein W, Anderson FA Jr; Global Registry of Acute Coronary Events Investigators. Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004;109:494 –499.
4. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Ruherford J, Wertheimer JH, Hawkins CM, on behalf of the SAVE Investigators. 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;327:669 –677. 5. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM; 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 2003;349:1893 –1906. 6. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993;342:821–828. 7. Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995; 333:1670 –1676. 8. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998;97: 2202 –2212. 9. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. 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 – 717. 10. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. 11. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; 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;348:1309 –1321. 12. Cohn JN, Colucci W. Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiology. Am J Cardiol 2006;97:4F –12. 13. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014 –1021. 14. Morrow DA, de Lemos JA, Blazing MA, Sabatine MS, Murphy SA, Jarolim P, Fox KA, Califf RM, Braunwald E. Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. JAMA 2005;294: 2866 –2871. 15. Montalescot G, Drexler H, Gallo R, Pearson T, Thoenes M, Bhatt DL. Effect of irbesartan and enalapril in non-ST elevation acute coronary syndrome: results of the randomized, double-blind ARCHIPELAGO study. Eur Heart J 2009;30:2733 –2741. 16. Scirica BM, Morrow DA, Bode C, Ruzyllo W, Ruda M, Oude Ophuis AJ, Lopez-Sendon J, Swedberg K, Ogorek M, Rifai N, Lukashevich V, Maboudian M, Cannon CP, McCabe CH, Braunwald E. Patients with acute coronary syndromes and elevated levels of natriuretic peptides: the results of the AVANT GARDE-TIMI 43 Trial. Eur Heart J 2010;31:1993 –2005. 17. Udell JA, Morrow DA, Braunwald E, Swedberg K, Bode C, Rifai N, Brunel PC, Prescott MF, Ren F, Hoffman EB, Scirica BM. Inhibition of the renin –angiotensin system reduces the rise in serum aldosterone in acute coronary syndrome patients with preserved left ventricular function: observations from the AVANT GARDETIMI 43 trial. Clin Chem 2013;59:959–967. 18. Beygui F, Vicaut E, Ecollan P, Machecourt J, Van Belle E, Zannad F, Montalescot G. Rationale for an early aldosterone blockade in acute myocardial infarction and design of the ALBATROSS trial. Am Heart J 2010;160:642 – 648.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 14, 2015
aldosterone with no actual decline indicates the presence of an ‘extra-RAAS’ activation of aldosterone, probably at the tissue level that could only be mitigated by direct MRA. Despite a primary composite endpoint that included several clinical events, the REMINDER study should be considered a ‘proof-of-concept’ trial, driven by the ‘surrogate’ endpoint of elevated levels of natriuretic peptides, which accounted for 87% of the primary composite endpoint events. The most appropriate clinical composite endpoint of cardiovascular death, heart failure, or sustained ventricular arrhythmia occurred in 9 patients assigned to eplerenone and 16 patients in the placebo group, which is at least reassurring, but insufficient to provide any clinical guidance. A properly powered study, probably 8000–12 000 patients in size with extended follow-up, will be required before a strategy of early MRA administration could be recommended for the broader STEMI population. The ongoing, open-label 1600 patient Aldosterone Lethal effects Blocked in Acute Myocardial Infarction Treated with or without Reperfusion to Improve Outcome and Survival at Six months follow-up (ALBATROSS) trial18 will partially test this hypothesis, but is likely to be underpowered for patients without manifest heart failure and with preserved LV function. Regardless, the REMINDER trial has advanced the field of MRA and natriuretic peptides, and highlighted that direct MRAs may offer an important therapeutic target in the large population of MI patients without heart failure or depressed LV function.
Editorial
European Heart Journal (2014) 35, 2276–2278 doi:10.1093/eurheartj/ehu191
Evaluating the efficacy of mineralocorticoid receptor antagonism in patients with STEMI without heart failure Benjamin M. Scirica* TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA Online publish-ahead-of-print 29 April 2014
There are three key elements to any clinical trial: study population, study intervention, and outcome. The REMINDER study1 reported by Montalescot et al., is worth considering in detail because of how the investigators ultimately decided these three questions: the choice of ST-segment elevation myocardial infarction (STEMI) patients without heart failure as the population of interest, the selection of the mineralocorticoid receptor antagonist (MRA) eplerenone as the intervention, and the use of natriuretic peptides as the principal measurement of efficacy. To summarize, the REMINDER study randomized 1012 patients presenting with STEMI but no evidence of heart failure to eplerenone or placebo within 24 h of symptoms, and followed them for 10 months. Treatment with eplerenone significantly reduced the risk of a composite endpoint of an elevated natriuretic peptide or an extended list of clinical events by .40% compared with placebo, mostly driven by lower levels of natriuretic peptides at least 1 month after randomization.
ST-segment elevation myocardial infarction without heart failure Most studies evaluating therapy to improve remodelling focus only on patients with large, anterior STEMI or an ejection fraction ,40%, which is logical given that these patients are at the highest risk of subsequent heart failure, arrhythmic events, and death. However, with more rapid reperfusion, they currently account for a small proportion of patients presenting with MI. In . 77 000 patients with STEMI enrolled in one contemporary registry, only 12% presented with heart failure and just 3.6% developed heart
failure after admission,2 a substantially lower number than earlier cohorts.3 Moreover, only 20% of patients with STEMI and no heart failure in this registry had an ejection fraction ,40%2 (Figure 1). Studies restricted to patients with the most severe presentation thus limit generalizability. The REMINDER study is therefore a example of evaluating a broader, more representative cohort, in which a therapeutic agent may have more widespread applicability. As would be expected based on the entry criteria, patients randomized into the REMINDER study were younger, had better renal function, lower rates of diabetes or prior MI, and a lower rate of anterior MI compared with studies focusing on just patients with heart failure, and a correspondingly lower risk of death or heart failure.4,5 The selection of this population is also of interest because the benefit of early initiation of inhibitors of the renin –angiotensin– aldosterone system (RAAS) in post-acute coronary syndrome (ACS) patients without any evidence of heart failure or with normal left ventricular (LV) function remains uncertain. The seminal trials of inhibitors of the RAAS excluded these healthier MI patients4 – 7 (Figure 1). Even in the ‘all-comer’ studies, the benefit of RAAS inhibition was predominately observed in patients with the largest infarcts.8 Thus early inhibition of the RAAS in patients without heart failure or depressed LV function following ACS has yet to be conclusively demonstrated in patients treated with contemporary strategies. Regardless, most patients in REMINDER were treated with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as background therapy; thus, the addition of eplerenone in this study most commonly represented ‘dual’ RAAS inhibition.
Mineralocorticoid receptor antagonists The rationale for choosing a population with smaller infarcts was necessary because of the well-established benefit of MRAs in patients with MI and heart failure or reduced LV function. It is fair to say that
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. † doi:10.1093/eurheartj/ehu164.
* Corresponding author. Tel: +1 617 278 0145; fax: +1 617 734 7349, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 14, 2015
This editorial refers to ‘Early eplerenonetreatment inpatients with acute ST-elevation myocardial infarction without heart failure: the randomized double-blind REMINDER study’†, by G. Montalescot et al., on page 2295
Editorial
2277
MRAs have enjoyed one of the most consistent runs of proven efficacy across the cardiovascular spectrum, in particular in patients with established systolic heart failure9,10 or heart failure and reduced LV function following MI.11 In particular, after the EPHESUS study, which demonstrated clear superiority of eplerenone vs. placebo in post-MI patients with heart failure, it would not have been ethical to include patients with heart failure or reduced LV function in a placebo-controlled trial, even for a shorter duration. The proposed benefits of MRAs following MI are several-fold. First, MRAs preserve serum potassium levels and thereby may prevent arrhythmic triggers in a population vulnerable to lethal arrhythmias. More importantly, MRAs favourably influence a myriad of pathways involved in myocardial remodelling and fibrosis, and improve endothelial dysfunction and peripheral vascular compliance.12 That MRAs reduced markers of haemodynamic stress in the REMINDER Study, specifically in patients with smaller infarcts, suggests that crude measures of ventricular function such as ejection fraction and symptomatic heart failure fail to reflect the degree of myocardial damage and subsequent maladaptive remodelling in many MI patients. Eplerenone was selected as the MRA in the REMINDER study, though there is little reason to suspect that spironolactone would not have produced similar results. One notable aspect of the study was that the first dose of study drug was initiated early (,24 h of symptom onset), which was earlier than in the EPHESUS study. Moreover, there was a trend in subgroup analyses towards an even greater benefit with very early treatment (,6 h), suggesting that MRAs could play a protective role after the initial reperfusion injury following percutaneous intervention or fibrinolysis. Overall, eplerenone was well tolerated in this relatively healthy population with preserved renal function. There were few episodes of hyperkalaemia, though it occurred 2–4 times more frequently with eplerenone than with placebo. It would be informative to know the
timing of hyperkalaemia and whether patients were on other RAAS inhibitors, and at what dose? Additionally, did hyperkalaemia require treatment or lead to study drug discontinuation? Given the concerns of hyperkalaemia when MRAs are used in wider populations, a clearer evaluation of the risk of electrolyte abnormalities and renal dysfunction is necessary to balance any potential benefits in this population.
Natriuretic peptides as an outcome Elevated levels of natriuretic peptides are well-recognized markers of increased risk of heart failure and death following an MI, regardless of whether the levels were measured in the acute phase or during convalescence.13,14 However, and in contrast to patients with decompensated heart failure, identifying therapies that actually reduce levels of natriuretic peptides following an ACS has proven more challenging. Several studies have failed to demonstrate any reductions in natriuretic peptides in ACS with specific therapies.15,16 The AVANT GARDE-TIMI 43 trial, a trial similar to the REMINDER trial, randomized patients with ACS and elevated levels of natriuretic peptides (but without heart failure and with an LV ejection fraction .40%), and provides additional insight into why treatment with may have significantly reduced natriuretic peptides in the REMINDER Study.16 In AVANT GARDE-TIMI 43, there were no differences between randomization and 8 weeks in the change in natriuretic peptides between the 1101 patients assigned to valsartan, the renin inhibitor aliskiren, a combination of the two, or placebo. Active inhibition of RAAS did, however, blunt the rise in serum aldosterone levels observed in the placebo group.17 Thus, even in patients without LV dysfunction, aldosterone levels rose following an infarct, probably reflecting maladaptive remodelling and fibrosis. That even dual inhibition of RAAS with aliskiren and valsartan could just blunt the rise in
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 14, 2015
Figure 1 Summary of cardiovascular studies evaluating inhibition of the renin– angiotensin – aldosterone system in patients presenting with acute coronary syndrome. ACEi, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin receptor blocker; CHF, heart failure; DRI, direct renin inhibitor; EF, ejection fraction; MI, myocardial infarction; MRA, mineralocorticoid antagonist; RAAS, renin– angiotensin– aldosterone system; STEMI, ST-segment elevation myocardial infarction. * - indicates studies with natriuretic peptides as an endpoint.
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Conflict of interest: B.M.S. reports research grants via the TIMI Study and Brigham and Women’s Hospital from AstraZeneca, Bristol-Myers Squibb, Daichi-Sankyo, GlaxoSmithKline, Johnson and Johnson, Bayer Healthcare, Gilead, Eisai, and Merck; and consulting fees from Gilead, Lexicon, Arena, Eisai, St. Jude’s Medical, Bristol-Myers Squibb, Forest Pharmaceuticals, Boston Clinical Research Institute, Decision Resources, University of Calgary, Elsevier Practice Update Cardiology, and Forest Pharmaceuticals.
References 1. Montalescot G, Pitt B, Lopez de Sa E, Hamm CW, Flather M, Verheught F, Shi H, Turgonyi E, Orri M, Vincet J, Zannad F. Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the randomized double-blind REMINDER study. Eur Heart J 2014;35:2295 –2302. 2. Shah RV, Holmes D, Anderson M, Wang TY, Kontos MC, Wiviott SD, Scirica BM. Risk of heart failure complication during hospitalization for acute myocardial infarction in a contemporary population: insights from the National Cardiovascular Data ACTION Registry. Circ Heart Fail 2012;5:693 –702. 3. Steg PG, Dabbous OH, Feldman LJ, Cohen-Solal A, Aumont MC, Lopez-Sendon J, Budaj A, Goldberg RJ, Klein W, Anderson FA Jr; Global Registry of Acute Coronary Events Investigators. Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004;109:494 –499.
4. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Ruherford J, Wertheimer JH, Hawkins CM, on behalf of the SAVE Investigators. 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;327:669 –677. 5. Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Solomon SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM; 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 2003;349:1893 –1906. 6. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993;342:821–828. 7. Kober L, Torp-Pedersen C, Carlsen JE, Bagger H, Eliasen P, Lyngborg K, Videbaek J, Cole DS, Auclert L, Pauly NC. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995; 333:1670 –1676. 8. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998;97: 2202 –2212. 9. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. 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 – 717. 10. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. 11. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M; 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;348:1309 –1321. 12. Cohn JN, Colucci W. Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiology. Am J Cardiol 2006;97:4F –12. 13. de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, Hall C, Cannon CP, Braunwald E. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014 –1021. 14. Morrow DA, de Lemos JA, Blazing MA, Sabatine MS, Murphy SA, Jarolim P, Fox KA, Califf RM, Braunwald E. Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. JAMA 2005;294: 2866 –2871. 15. Montalescot G, Drexler H, Gallo R, Pearson T, Thoenes M, Bhatt DL. Effect of irbesartan and enalapril in non-ST elevation acute coronary syndrome: results of the randomized, double-blind ARCHIPELAGO study. Eur Heart J 2009;30:2733 –2741. 16. Scirica BM, Morrow DA, Bode C, Ruzyllo W, Ruda M, Oude Ophuis AJ, Lopez-Sendon J, Swedberg K, Ogorek M, Rifai N, Lukashevich V, Maboudian M, Cannon CP, McCabe CH, Braunwald E. Patients with acute coronary syndromes and elevated levels of natriuretic peptides: the results of the AVANT GARDE-TIMI 43 Trial. Eur Heart J 2010;31:1993 –2005. 17. Udell JA, Morrow DA, Braunwald E, Swedberg K, Bode C, Rifai N, Brunel PC, Prescott MF, Ren F, Hoffman EB, Scirica BM. Inhibition of the renin –angiotensin system reduces the rise in serum aldosterone in acute coronary syndrome patients with preserved left ventricular function: observations from the AVANT GARDETIMI 43 trial. Clin Chem 2013;59:959–967. 18. Beygui F, Vicaut E, Ecollan P, Machecourt J, Van Belle E, Zannad F, Montalescot G. Rationale for an early aldosterone blockade in acute myocardial infarction and design of the ALBATROSS trial. Am Heart J 2010;160:642 – 648.
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on November 14, 2015
aldosterone with no actual decline indicates the presence of an ‘extra-RAAS’ activation of aldosterone, probably at the tissue level that could only be mitigated by direct MRA. Despite a primary composite endpoint that included several clinical events, the REMINDER study should be considered a ‘proof-of-concept’ trial, driven by the ‘surrogate’ endpoint of elevated levels of natriuretic peptides, which accounted for 87% of the primary composite endpoint events. The most appropriate clinical composite endpoint of cardiovascular death, heart failure, or sustained ventricular arrhythmia occurred in 9 patients assigned to eplerenone and 16 patients in the placebo group, which is at least reassurring, but insufficient to provide any clinical guidance. A properly powered study, probably 8000–12 000 patients in size with extended follow-up, will be required before a strategy of early MRA administration could be recommended for the broader STEMI population. The ongoing, open-label 1600 patient Aldosterone Lethal effects Blocked in Acute Myocardial Infarction Treated with or without Reperfusion to Improve Outcome and Survival at Six months follow-up (ALBATROSS) trial18 will partially test this hypothesis, but is likely to be underpowered for patients without manifest heart failure and with preserved LV function. Regardless, the REMINDER trial has advanced the field of MRA and natriuretic peptides, and highlighted that direct MRAs may offer an important therapeutic target in the large population of MI patients without heart failure or depressed LV function.
Editorial
