title: A Review of the External Validity of Clinical Trials with Beta-Blockers in Heart Failure.
abstract: BACKGROUND
  Beta-blockers (BBs) are the mainstay prognostic medication for all stages of chronic heart failure (CHF). There are many classes of BBs, each of which has varying levels of evidence to support its efficacy in CHF. However, most CHF patients have one or more comorbid conditions such as diabetes, renal impairment, and/or atrial fibrillation. Patient enrollment to randomized controlled trials (RCTs) often excludes those with certain comorbidities, particularly if the symptoms are severe. Consequently, the extent to which evidence drawn from RCTs is generalizable to CHF patients has not been well described. Clinical guidelines also underrepresent this point by providing generic advice for all patients. The aim of this review is to examine the evidence to support the use of BBs in CHF patients with common comorbid conditions.
  
  
  METHODS
  We searched MEDLINE, PubMed, and the reference lists of reviews for RCTs, post hoc analyses, systematic reviews, and meta-analyses that report on use of BBs in CHF along with patient demographics and comorbidities.
  
  
  RESULTS
  In total, 38 studies from 28 RCTs were identified, which provided data on six BBs against placebo or head to head with another BB agent in ischemic and nonischemic cardiomyopathies. Several studies explored BBs in older patients. Female patients and non-Caucasian race were underrepresented in trials. End points were cardiovascular hospitalization and mortality. Comorbid diabetes, renal impairment, or atrial fibrillation was detailed; however, no reference to disease spectrum or management goals as a focus could be seen in any of the studies. In this sense, enrollment may have limited more severe grades of these comorbidities.
  
  
  CONCLUSIONS
  RCTs provide authoritative information for a spectrum of CHF presentations that support guidelines. RCTs may provide inadequate information for more heterogeneous CHF patient cohorts. Greater Phase IV research may be needed to fill this gap and inform guidelines for a more global patient population.
authors: Cardiologist and Senior Lecturer, Northern Territory School of Medicine, Flinders University, Bedford Park, South Australia.
authors: Pupalan
authors: P
authors: Iyngkaran
authors: Department of Cardiology, Austin Health, Heidelberg, Victoria, Australia.
authors: Samia R
authors: SR
authors: Toukhsati
authors: Professor, NHMRC Senior Research Fellow, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors: Merlin C
authors: MC
authors: Thomas
authors: Professor, Department of Cardiology, St. Vincent's Hospital, Melbourne, Victoria, Australia.
authors: Michael V
authors: MV
authors: Jelinek
authors: Professor, Coordinator, Cardiovascular Research, University of Melbourne; Director of Heart Failure Services, Austin Health, Melbourne, Victoria, Australia.
authors: David L
authors: DL
authors: Hare
authors: Professor of Cardiology, Director, Cardiology Unit, Discipline of Medicine, Cardiology Research Laboratory, The Basil Hetzel Institute, Woodville South, South Australia, Australia.
authors: John D
authors: JD
authors: Horowitz
keywords: beta-blockers; chronic heart failure; comorbidity; external validity; review