title: Is randomization to placebo safe? Risk in placebo-controlled angina trials: angina risk meta-analysis.
abstract: OBJECTIVE
  It was the aim of this study to document the risks of symptomatic patients with angina in placebo-controlled, anti-anginal drug development trials in which symptom-limited exercise testing was used as the primary endpoint.
  
  
  METHODS
  The original case report forms submitted to the United States Food and Drug Administration in support of approval of new or supplemental new drug applications between 1973 and 2001 were identified and subjected to a by-patient meta-analysis, utilizing both a maximum likelihood analysis and classical Mantel-Haenszel methods.
  
  
  RESULTS
  There were 63 placebo-controlled, clinical trials that randomized 10,865 patients, with 1,047 patient-years of observation time. The trials involved 21 different chemical entities from 4 different drug classes. The relative risk (RR) for withdrawal (placebo compared to drug-treated patients) was not increased [RR = 0.92, 95% confidence interval (CI) 0.78-1.08; p = 0.28]. Of interest, a RR of 0.54 (95% CI 0.26-1.04; p < 0.068) for irreversible harm (a combination of cerebrovascular accidents, myocardial infarction and death) and a RR of 0.89 (95% CI 0.61-1.30; p = 0.56) for serious cardiovascular events (myocardial infarction, congestive heart failure, cerebrovascular accidents) both non-statistically significantly favored being randomized to placebo.
  
  
  CONCLUSIONS
  For the development of current or future drugs for the treatment of angina, there is no obvious contraindication to the use of placebo controls and exercise tolerance testing.
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL 35202, USA. sglasser@uab.edu
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Glasser
authors.forename: James
authors.initials: J
authors.lastname: Willard
authors.forename: Albert
authors.initials: A
authors.lastname: Defelice
authors.forename: John
authors.initials: J
authors.lastname: Lawrence
authors.forename: James
authors.initials: J
authors.lastname: Hung
authors.forename: Evelyn
authors.initials: E
authors.lastname: Obot
authors.forename: John
authors.initials: J
authors.lastname: Girton
authors.forename: Shari
authors.initials: S
authors.lastname: Targum
authors.forename: Douglas
authors.initials: D
authors.lastname: Throckmorton
authors.forename: Dennis
authors.initials: D
authors.lastname: Mangano
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Lipicky
mesh_terms: D000083:Acetanilides / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000787:Angina Pectoris / Q000188:drug therapy*; D000789:Angina, Unstable / Q000188:drug therapy; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000139:chemically induced; D017277:Drug Approval; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D008499:Medical Records / Q000706:statistics & numerical data; D008875:Middle Aged; D009566:Nitrates / Q000627:therapeutic use; D015588:Observer Variation; D010352:Patient Dropouts / Q000706:statistics & numerical data; D061214:Patient Safety; D010879:Piperazines / Q000627:therapeutic use; D010919:Placebos / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic / Q000009:adverse effects*; D000069458:Ranolazine; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D017211:Treatment Failure
chemical_list: D000083:Acetanilides; D000319:Adrenergic beta-Antagonists; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D009566:Nitrates; D010879:Piperazines; D010919:Placebos; D000069458:Ranolazine