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Mineralocorticoid Receptor Antagonists for Heart Failure with Reduced Ejection Fraction: Integrating Evidence Into Clinical Practice

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Mineralocorticoid Receptor Antagonists for Heart Failure with Reduced Ejection Fraction: Integrating Evidence Into Clinical Practice European Heart Journal Advance Access published August 31, 2012 European Heart Journal REVIEW doi:10.1093/eurheartj/ehs257 Novel Therapeutic Concepts Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice Faiez Zannad1*, Wendy Gattis Stough2,PatrickRossignol1, Johann Bauersachs3, John J.V. McMurray4,KarlSwedberg5,AllanD.Struthers6, Adriaan A. Voors7, Luis M. Ruilope8,GeorgeL.Bakris9, Christopher M. O’Connor10, Mihai Gheorghiade11, Downloaded from Robert J. Mentz10, Alain Cohen-Solal12,AldoP.Maggioni13, Farzin Beygui14, Gerasimos S. Filippatos15,ZiadA.Massy16, Atul Pathak17, Ileana L. Pin˜a18, Hani N. Sabbah19, Domenic A. Sica20, Luigi Tavazzi21, and Bertram Pitt22 http://eurheartj.oxfordjournals.org/ 1INSERM, Centre d’Investigation Clinique 9501 and Unite´ 961, Centre Hospitalier Universitaire, and the Department of Cardiology, Nancy University, Universite´ de Lorraine, Nancy, France; 2Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA; 3Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany; 4Western Infirmary and the British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK; 5Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 6University of Dundee, Ninewells Hospital and Medical School, Dundee, UK; 7University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 8Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain; 9ASH Comprehensive Hypertension Center, The University of Chicago Medicine, Chicago, IL, USA; 10Duke University Medical Center, Durham, NC, USA; 11Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; 12Service de Cardiologie, Hoˆpital Lariboisiere, Faculte´ de Me´decine Paris Diderot, INSERM U942, Paris, France; 13Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy; 14Institute of Cardiology, CHU La Pitie´-Salpetie`re, Paris, France; 15Athens University Hospital Attikon, Athens, Greece; 16Institut National de la Sante´ et de la Recherche Me´dicale, U-1088, Universite´ de Picardie Jules Verne, Centre Hospitalier Universitaire, Amiens, France; 17Faculte´ de Me´decine et CHU Toulouse, Unite´ de Pharmacologie Cardiovasculaire et Autonome, Service de Pharmaco-logie et Cardiologie, INSERM U 1048, Universite´ Paul Sabatier, Toulouse, France; 18Montefiore Einstein Center for Heart and Vascular Care, New York, NY, USA; 19Henry Ford Health System, Detroit, MI, USA; 20Virginia 21 22 Commonwealth University, Richmond, VA, USA; Maria Cecilia Hospital, GVM Care and Research, E.S. Health Science Foundation, Cotignola, Italy; and University of by guest on September 9, 2013 Michigan School of Medicine, Ann Arbor, MI, USA Received 25 April 2012; revised 2 July 2012; accepted 27 July 2012 Mineralocorticoid receptor antagonists (MRAs) improve survival and reduce morbidity in patients with heart failure, reduced ejection frac- tion (HF–REF), and mild-to-severe symptoms, and in patients with left ventricular systolic dysfunction and heart failure after acute myocardial infarction. These clinical benefits are observed in addition to those of angiotensin converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers. The morbidity and mortality benefits of MRAs may be mediated by several proposed actions, including antifi- brotic mechanisms that slow heart failure progression, prevent or reverse cardiac remodelling, or reduce arrhythmogenesis. Both eplere- none and spironolactone have demonstrated survival benefits in individual clinical trials. Pharmacologic differences exist between the drugs, which may be relevant for therapeutic decision making in individual patients. Although serious hyperkalaemia events were reported in the major MRA clinical trials, these risks can be mitigated through appropriate patient selection, dose selection, patient education, mon- itoring, and follow-up. When used appropriately, MRAs significantly improve outcomes across the spectrum of patients with HF–REF. ----------------------------------------------------------------------------------------------------------------------------------------------------------- Keywords Heart failure † Aldosterone antagonist spironolactone † Mineralocorticoid receptors Introduction ejection fraction (HF–REF or ‘systolic heart failure’). These agents have demonstrated morbidity and mortality benefits across the Mineralocorticoid receptor antagonists (MRAs), often referred to as spectrum of HF–REF, including patients with mild1 to severe2 aldosterone antagonists, are a key component of evidence-based heart failure symptoms, as well as in patients with signs and symp- therapy for patients with heart failure and reduced left ventricular toms of heart failure after acute myocardial infarction (AMI).3 * Corresponding author: Centre d’Investigation Clinique Plurithe´matique Pierre Drouin, INSERM 9501 CHU de Nancy, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, 4, rue du Morvan, 54500 Vandoeuvre-les-Nancy, France. Tel: +33 3 83 15 73 20, Fax: +33 3 83 15 73 24, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected] Page 2 of 16 F. Zannad et al. This paper provides both state-of-the-art and practical informa- symptoms within 6 months before enrolment and NYHA class III tion regarding the optimal use of MRAs in patients with heart or IV symptoms at the time of enrolment were randomized to spir- failure. This topic was discussed among a panel of heart failure onolactone 25 mg per day or placebo. After 8 weeks of treatment, experts, cardiovascular clinical trialists, biostatisticians, National the dose could be increased to 50 mg once daily if the patient Institutes of Health (NIH) scientists, US and European government showed signs or symptoms of heart failure progression without regulators, and pharmaceutical industry researchers during the evidence of hyperkalaemia. It is important to note that strict eligi- Eighth Global Cardiovascular Clinical Trialists Forum held in bility criteria and laboratory monitoring were used in RALES and all of Paris, France in December 2011. This review summarizes the the subsequent MRA heart failure trials (Table 1). The primary end- current body of knowledge pertaining to MRAs in heart failure, point was all-cause mortality. After a mean follow-up of 24 months, targets for future research, and strategies practicing clinicians can the study was stopped after the data monitoring committee advised employ to optimize MRA use in appropriate patients, thereby ul- the Steering Committee that the pre-specified efficacy boundary timately improving clinically relevant outcomes. for mortality had been crossed. Patients randomized to spironolac- tone had a lower risk of death from any cause when compared with placebo (RR 0.70, 95% CI 0.60–0.82, P , 0.001) (Figure 1).2 Spir- Review of the evidence and onolactone also significantly reduced cause-specific mortality. current indications Sudden death was reduced by 29% (RR 0.71, 95% CI 0.54–0.95, P ¼ 0.02), and death due to progressive heart failure was reduced Downloaded from Primary evidence from randomized by 36% (RR 0.64, 95% CI 0.51–0.8, P , 0.001). Beta-blocker use controlled trials was low (11%). As anticipated in a population receiving background Severe heart failure ACE-inhibition, patients randomized to spironolactone had an in- Recognition of aldosterone as an important neurohormonal modu- crease in median potassium concentration of 0.3 mmol/L, but the in- cidence of serious hyperkalaemia (serum potassium ≥ 6 mmol/L) lator of heart failure progression dates back more than six http://eurheartj.oxfordjournals.org/ decades.4 –6 These early data led to the conceptual framework was not significantly different between the spironolactone and that combining an angiotensin converting enzyme (ACE) inhibitor placebo groups [14 spironolactone patients (2%) vs. 10 placebo ¼ and spironolactone may achieve more complete inhibition of the patients (1%), P 0.42]. Treatment discontinuation due to any renin–angiotensin–aldosterone system (RAAS) and may produce adverse event occurred in 8% of patients randomly assigned to spir- further clinical benefits. The findings of a pilot study6,7 led to the onolactone and in 5% of the placebo group. design and conduct of the Randomized Aldactone Evaluation Study (RALES), which was the first large, prospective, randomized Left ventricular systolic dysfunction and heart failure mortality trial of an MRA in patients with heart failure.2 The RALES after acute myocardial infarction data have been widely discussed in the literature. Briefly, 1663 The recognition of aldosterone as a mediator of ventricular re- by guest on September 9, 2013 patients with LVEF ≤35% and NYHA class IV heart failure modelling and fibrosis led to its investigation in patients with LV Table 1 Key exclusion criteria and monitoring procedures in major mineralocorticoid receptor antagonist heart failure trials Trial Major exclusions Monitoring schedule Dose adjustment ........................................................................ Renal Potassium Other relevant exclusions exclusions exclusions ..............................................................................................................................................................................
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