title: 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.
abstract: OBJECTIVE
  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.
  
  
  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 < or = 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.
  
  
  CONCLUSIONS
  Although low-dose enoximone appears to be safe in patients with advanced HF, major clinical outcomes are not improved.
authors.affiliation: Cardiology, Department of Experimental and Applied Medicine, c/o Spedali Civili, University of Brescia, P.zza Spedali Civili, 25100 Brescia, Italy. metramarco@libero.it
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.forename: Eric
authors.initials: E
authors.lastname: Eichhorn
authors.forename: William T
authors.initials: WT
authors.lastname: Abraham
authors.forename: Jennifer
authors.initials: J
authors.lastname: Linseman
authors.forename: Michael
authors.initials: M
authors.lastname: Böhm
authors.forename: Ramon
authors.initials: R
authors.lastname: Corbalan
authors.forename: David
authors.initials: D
authors.lastname: DeMets
authors.forename: Teresa
authors.initials: T
authors.lastname: De Marco
authors.forename: Uri
authors.initials: U
authors.lastname: Elkayam
authors.forename: Michael
authors.initials: M
authors.lastname: Gerber
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Peter
authors.initials: P
authors.lastname: Liu
authors.forename: Vyacheslev
authors.initials: V
authors.lastname: Mareev
authors.forename: Sergio V
authors.initials: SV
authors.lastname: Perrone
authors.forename: Philip
authors.initials: P
authors.lastname: Poole-Wilson
authors.forename: Ellen
authors.initials: E
authors.lastname: Roecker
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stewart
authors.forename: Karl
authors.initials: K
authors.lastname: Swedberg
authors.forename: Michal
authors.initials: M
authors.lastname: Tendera
authors.forename: Brian
authors.initials: B
authors.lastname: Wiens
authors.forename: Michael R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000502:physiology; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D002908:Chronic Disease; D004311:Double-Blind Method; D017335:Enoximone / Q000008:administration & dosage*; D015444:Exercise / Q000502:physiology*; D017079:Exercise Tolerance; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006339:Heart Rate / Q000502:physiology; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D055815:Young Adult
chemical_list: D002316:Cardiotonic Agents; D017335:Enoximone
references.citation: N Engl J Med. 2002 Oct 31;347(18):1397-402
references.pmid: 12409541
references.citation: Eur Heart J. 1999 Jan;20(2):136-9
references.pmid: 10099910
references.citation: Eur Heart J. 2005 Apr;26(8):778-93
references.pmid: 15774495
references.citation: Circulation. 2004 Dec 21;110(25):3760-5
references.pmid: 15583079
references.citation: Circulation. 2000 Sep 5;102(10):1126-31
references.pmid: 10973841
references.citation: J Card Fail. 2005 Dec;11(9):659-69
references.pmid: 16360960
references.citation: J Am Coll Cardiol. 1997 Oct;30(4):992-6
references.pmid: 9316529
references.citation: J Am Coll Cardiol. 2003 May 21;41(10):1797-804
references.pmid: 12767667
references.citation: Circulation. 2005 May 31;111(21):2837-49
references.pmid: 15927992
references.citation: J Am Coll Cardiol. 2000 Aug;36(2):501-8
references.pmid: 10933364
references.citation: J Card Fail. 2001 Jun;7(2 Suppl 1):8-12
references.pmid: 11605160
references.citation: N Engl J Med. 1998 Dec 17;339(25):1810-6
references.pmid: 9854116
references.citation: Br Heart J. 1994 Sep;72(3):226-30
references.pmid: 7946771
references.citation: Eur J Heart Fail. 2007 Jun-Jul;9(6-7):684-94
references.pmid: 17481947
references.citation: Circulation. 1990 Sep;82(3):774-80
references.pmid: 2144216
references.citation: J Am Coll Cardiol. 2002 Oct 2;40(7):1248-58
references.pmid: 12383572
references.citation: J Am Coll Cardiol. 1998 Sep;32(3):686-92
references.pmid: 9741512
references.citation: Circulation. 2006 Feb 21;113(7):1020-7; discussion 1033
references.pmid: 16490837
references.citation: Can Med Assoc J. 1985 Apr 15;132(8):919-23
references.pmid: 3978515
references.citation: N Engl J Med. 1991 Nov 21;325(21):1468-75
references.pmid: 1944425
references.citation: Int J Cardiol. 2001 Dec;81(2-3):141-9
references.pmid: 11744130
references.citation: Lancet. 2003 May 31;361(9372):1843-8
references.pmid: 12788569
references.citation: J Am Coll Cardiol. 1999 Mar 15;33(4):943-50
references.pmid: 10091820
references.citation: J Cardiovasc Pharmacol. 1998;32 Suppl 1:S36-45
references.pmid: 9731694
references.citation: J Am Coll Cardiol. 2003 Jun 4;41(11):2029-35
references.pmid: 12798577
references.citation: N Engl J Med. 2002 May 2;346(18):1357-65
references.pmid: 11986409
references.citation: Arch Intern Med. 2004 Apr 12;164(7):769-74
references.pmid: 15078647
references.citation: Am Heart J. 1991 May;121(5):1471-9
references.pmid: 1826806