title: Combined oral positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure.
abstract: OBJECTIVE
  We sought to assess the effects of combined oral positive inotropic and beta-blocker therapy in patients with severe heart failure.
  
  
  BACKGROUND
  Patients with severe, class IV heart failure who receive standard medical therapy exhibit a 1-year mortality rate >50%. Moreover, such patients generally do not tolerate beta-blockade, a promising new therapy for chronic heart failure. Positive inotropes, including phosphodiesterase inhibitors, are associated with increased mortality when administered over the long term in these patients. The addition of a beta-blocker to positive inotropic therapy might attenuate this adverse effect, although long-term oral inotropic therapy might serve as a bridge to beta-blockade.
  
  
  METHODS
  Thirty patients with severe heart failure (left ventricular ejection fraction [LVEF] 17.2+/-1.2%, cardiac index 1.6+/-0.1 liter/min per m2) were treated with the combination of oral enoximone (a phosphodiesterase inhibitor) and oral metoprolol at two institutions. Enoximone was given at a dose of < or = 1 mg/kg body weight three times a day. After clinical stabilization, metoprolol was initiated at 6.25 mg twice a day and slowly titrated up to a target dose of 100 to 200 mg/day.
  
  
  RESULTS
  Ninety-six percent of the patients tolerated enoximone, whereas 80% tolerated the addition of metoprolol. The mean duration of combination therapy was 9.4+/-1.8 months. The mean length of follow-up was 20.9+/-3.9 months. Of the 23 patients receiving the combination therapy, 48% were weaned off enoximone over the long term. The LVEF increased significantly, from 17.7+/-1.6% to 27.6+/-3.4% (p=0.01), whereas the New York Heart Association functional class improved from 4+/-0 to 2.8+/-0.1 (p=0.0001). The number of hospital admissions tended to decrease during therapy (p=0.06). The estimated probability of survival at 1 year was 81+/-9%. Heart transplantation was performed successfully in nine patients (30%).
  
  
  CONCLUSIONS
  Combination therapy with a positive inotrope and a beta-blocker appears to be useful in the treatment of severe, class IV heart failure. It may be used as a palliative measure when transplantation is not an option or as a bridge to heart transplantation. Further study of this form of combined therapy is warranted.
authors.affiliation: Department of Medicine, University of Colorado Health Sciences Center, Denver 80262, USA.
authors.forename: S F
authors.initials: SF
authors.lastname: Shakar
authors.forename: W T
authors.initials: WT
authors.lastname: Abraham
authors.forename: E M
authors.initials: EM
authors.lastname: Gilbert
authors.forename: A D
authors.initials: AD
authors.lastname: Robertson
authors.forename: B D
authors.initials: BD
authors.lastname: Lowes
authors.forename: L S
authors.initials: LS
authors.lastname: Zisman
authors.forename: D A
authors.initials: DA
authors.lastname: Ferguson
authors.forename: M R
authors.initials: MR
authors.lastname: Bristow
mesh_terms: D000284:Administration, Oral; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D017335:Enoximone / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011446:Prospective Studies; D015996:Survival Rate; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000150:complications; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D017335:Enoximone; D008790:Metoprolol