European Heart Journal Advance Access published online on August 22, 2009
European Heart Journal, doi:10.1093/eurheartj/ehp338
Effects of low-dose oral enoximone administration on mortality, morbidity, and exercise capacity in patients with advanced heart failure: the randomized, double-blind, placebo-controlled, parallel group ESSENTIAL trials
1 Cardiology, Department of Experimental and Applied Medicine, c/o Spedali Civili, University of Brescia, P.zza Spedali Civili, 25100 Brescia, Italy
2 Medical City, Dallas, TX, USA
3 Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH, USA
4 Myogen/Gilead Inc., Westminster, CO, USA
5 Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg, Germany
6 Departamento de Enfermedades Cardiovasculares, Hospital Clinico Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
7 Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI, USA
8 San Francisco Medical Center, University of California, San Francisco, California
9 Division of Cardiovascular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
10 Department of Cardiology, La Pitié-Salpétrière Hospital, Paris, France
11 Cardiovascular Research Program, University of Toronto, Ontario, Canada
12 Myasnikov Institute of Cardiology, Moscow, Russia
13 Instituto FLENI, Buenos Aires, Argentina
14 National Heart and Lung Institute, Imperial College London, London, UK
15 Department of Emergency and Cardiovascular Medicine, Institute of Medicine, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
16 III Division of Cardiology, Medical University of Silesia, Katowice, Poland
17 Cardiovascular Institute, University of Colorado, Denver, CO, USA
Received 25 March 2008; revised 23 May 2009; accepted 28 July 2009 * Corresponding author. Tel: +39 030 3995572, Fax: +39 030 3700359, Email: metramarco{at}libero.it
Aims: Use of inotropic agents in patients with heart failure (HF) has been limited by adverse effects on outcomes. However, administration of positive inotropes at lower doses and concomitant treatment with beta-blockers might increase benefit–risk ratio. We investigated the effects of low doses of the positive inotrope enoximone on symptoms, exercise capacity, and major clinical outcomes in patients with advanced HF who were also treated with beta-blockers and other guideline-recommended background therapy.
Methods and results: The Studies of Oral Enoximone Therapy in Advanced HF (ESSENTIAL) programme consisted of two identical, randomized, double-blind, placebo-controlled trials that differed only by geographic location (North and South America: ESSENTIAL-I; Europe: ESSENTIAL-II). Patients with New York Heart Association class III–IV HF symptoms, left ventricular ejection fraction 
30%, and one hospitalization or two ambulatory visits for worsening HF in the previous year were eligible for participation in the trials. The trials had three co-primary endpoints: (i) the composite of time to all-cause mortality or cardiovascular hospitalization, analysed in the two ESSENTIAL trials combined; (ii) the 6 month change from baseline in the 6 min walk test distance (6MWTD); and (iii) the Patient Global Assessment (PGA) at 6 months, both analysed in each trial separately. ESSENTIAL-I and -II randomized 1854 subjects at 211 sites in 16 countries. In the combined trials, all-cause mortality and the composite, first co-primary endpoint did not differ between the two treatment groups [hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.80–1.17; and HR 0.98; 95% CI 0.86–1.12, respectively, for enoximone vs. placebo]. The two other co-primary endpoints were analysed separately in the two ESSENTIAL trials, as prospectively designed in the protocol. The 6MWTD increased with enoximone, compared with placebo, in ESSENTIAL-I (P = 0.025, not reaching, however, the pre-specified criterion for statistical significance of P < 0.020), but not in ESSENTIAL-II. No difference in PGA was observed in either trial.
Conclusion: Although low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.
Key Words: Advanced heart failure • Inotropic agents • Enoximone