title: Risk of Bias in Systematic Reviews of Non-Randomized Studies of Adverse Cardiovascular Effects of Thiazolidinediones and Cyclooxygenase-2 Inhibitors: Application of a New Cochrane Risk of Bias Tool.
abstract: BACKGROUND
  Systematic reviews of the effects of healthcare interventions frequently include non-randomized studies. These are subject to confounding and a range of other biases that are seldom considered in detail when synthesizing and interpreting the results. Our aims were to assess the reliability and usability of a new Cochrane risk of bias (RoB) tool for non-randomized studies of interventions and to determine whether restricting analysis to studies with low or moderate RoB made a material difference to the results of the reviews.
  
  
  RESULTS
  We selected two systematic reviews of population-based, controlled non-randomized studies of the relationship between the use of thiazolidinediones (TZDs) and cyclooxygenase-2 (COX-2) inhibitors and major cardiovascular events. Two epidemiologists applied the Cochrane RoB tool and made assessments across the seven specified domains of bias for each of 37 component studies. Inter-rater agreement was measured using the weighted Kappa statistic. We grouped studies according to overall RoB and performed statistical pooling for (a) all studies and (b) only studies with low or moderate RoB. Kappa scores across the seven bias domains ranged from 0.50 to 1.0. In the COX-2 inhibitor review, two studies had low overall RoB, 14 had moderate RoB, and five had serious RoB. In the TZD review, six studies had low RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. The pooled odds ratios for myocardial infarction, heart failure, and death for rosiglitazone versus pioglitazone remained significantly elevated when analyses were confined to studies with low or moderate RoB. However, the estimate for myocardial infarction declined from 1.14 (95% CI 1.07-1.24) to 1.06 (95% CI 0.99-1.13) when analysis was confined to studies with low RoB. Estimates of pooled relative risks of cardiovascular events with COX-2 inhibitors compared with no nonsteroidal anti-inflammatory drug changed little when analyses were confined to studies with low or moderate RoB. The exception was a rise in the relative risk associated with ibuprofen from 1.07 (95% CI 0.97-1.18) to 1.14 (95% CI 1.03-1.26). The main limitation of our study was testing the instrument on a narrow range of pharmacoepidemiological studies; we cannot assume our findings extend to a broader range of interventions and settings.
  
  
  CONCLUSIONS
  The Cochrane RoB tool highlighted a wide range of risks of bias in studies included in two widely cited reviews and had the potential to change the conclusions of the reviews. Systematic reviews that incorporate non-randomized studies of medical interventions should include a detailed assessment of RoB for each included study.
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Anja
authors.initials: A
authors.lastname: Bilandzic
authors.affiliation: Ontario Strategy for Patient-Oriented Research Support Unit, Toronto, Ontario, Canada.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Fitzpatrick
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Public Health Ontario, Toronto, Ontario, Canada.|Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Rosella
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.|Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada.|Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Henry
mesh_terms: D015982:Bias; D002318:Cardiovascular Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D015986:Confounding Factors, Epidemiologic; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D019317:Evidence-Based Medicine / Q000706:statistics & numerical data; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D015201:Meta-Analysis as Topic; D015588:Observer Variation; D016017:Odds Ratio; D015203:Reproducibility of Results; D012196:Review Literature as Topic; D018570:Risk Assessment; D012307:Risk Factors; D015983:Selection Bias; D045162:Thiazolidinediones / Q000009:adverse effects*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones