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Gerald Gartlehner speaking at the Symposium on the 10th Anniversary of the German Cochrane Centre

Gerald Gartlehner speaking at the Symposium on the 10th Anniversary of the German Cochrane Centre

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Systematic reviews of adverse effects and other topics not – yet – covered by the Cochrane Collaboration Systematic reviews of adverse effects and other topics not – yet – covered by the Cochrane Collaboration Presentation Transcript

  • Systematic Reviews of Adverse Effects and Other Topics Not Yet Covered by Cochrane Reviews Gerald Gartlehner Donau-Universität Krems, Department für Evidenzbasierte Medizin und Klinische Epidemiologie Symposium anlässlich des 10-jährigen Bestehens des Deutschen Cochrane Zentrums 2. April 2008
  • Objectives
    • To further the discussion on two important issues currently left incomplete by many Cochrane reports:
        • Adverse effects
        • Applicability of findings
  • Benefits Harms A systematic review emphasizing only benefits is likely to lead to biased conclusions
  • Cochrane Reviews Underemphasize Adverse Effects
    • Of 138 Cochrane reviews with data from at least 4000 participants, only 18% included data on clearly defined adverse effects
    • (Papanikolaou et al. Am J Med 2004;117:582-589)
    • Most Cochrane reviews focus on data from RCTs
    • 213 out of 5053 records mention “observational” OR “non-randomized” in the abstract
  • RCTs and Adverse Effects – Major Issues
    • 1. Assessment and reporting of harms is often inadequate
    • 2. Methodological issues limit the detection of certain adverse effects
    • 3. Publication bias
  • Inadequate Assessment and Reporting
    • Review of 7 interventions (Ioannidis et al. JAMA 2001;285:437-443)
      • 61% had inadequate reporting of adverse effects and 71% of laboratory-determined toxicity
      • Space devoted to safety was the same or less than the space given for the names of authors and their affiliations
    • Reporting may be worse for non-pharmacologic vs. pharmacologic interventions
    • (Ethgen et al. Ann Intern Med 2005;143:20-25)
  • Example: Second-generation Antidepressants
    • Sexual adverse events are common but frequently underreported
    • Assessment in RCTs varied greatly
    • Most studies did not use targeted questions
    Gartlehner et al. Comparative Effectiveness Review No 7: Agency for Healthcare Research and Quality. January 2007
  • Reporting of Sexual Adverse Events in RCTs of Antidepressants
  • Mean Incidence of Sexual Adverse Events in RCTs
  • Mean Incidence of Sexual Adverse Events in Observational Studies
  • Methodological Limitations of RCTs to Assess Harms
    • Sample size
    • Limited duration
    • Lack of applicability (homogeneous, healthy populations)
  • Methodological limitations of RCTs to assess adverse effects
    • RCTs are a good primary source to assess harms, if adverse effects :
      • are distinctive
      • occur frequently
      • have a close temporal association with the intervention
    • RCTs provide an incomplete picture of the risk of harms if adverse effects are:
      • infrequent
      • have a long latency
      • or affect only subgroups of patients
  • Publication Bias: Antidepressants in Children
    • Systematic review of published RCTs
    • Favorable risk benefit profiles for the treatment of depressive disorders in children
    • Inclusion of unpublished trials reversed conclusions for most antidepressants
    (Whittington et al. Lancet 2004; 363: 1341-45)
  • How can the limitations be overcome?
    • Observational studies may provide useful supplemental information for assessing adverse effects
      • Often larger than RCTs
      • Cover longer time periods
      • Examine less selected populations
  • “ Observational studies” refers to a broad range of study designs
    • Controlled observational studies (often derived from large databases)
      • Cohort studies
      • Case-control studies
    • Hypothesis-generating observational studies
      • Case series, case reports
      • Data-mining
  • Case reports
    • 30% of primary published literature on adverse drug events is in the form of case reports (Aronson et al.Fundam Clin Pharacol 2004;57:616-21)
        • Suicidality and SSRIs
        • Reye syndrome and aspirin
  • Observational Studies and Confounding
    • Systematic error (unmeasured differences between groups) is always possible
    • Adverse effects are often unexpected and unpredictable
    • Confounding by indication is often not relevant
  • Asymptomatic Carotid Artery Surgery Trial (ACAS)
      • From Rothwell, Lancet 2005;365;82-93
  • Applicability - What Decision Makers Need To Know
    • Can it work?
    • Will it work?
      • In this patient?
      • In this setting?
    • Is it worth it?
      • Do benefits outweigh harms/costs/inconvenience?
      • Does it offer important advantages over existing alternatives?
        • ( adapted from Brian Haynes
        • ACP Journal Club)
  • APPLICABILITY ( external validity, generalizability) Can I apply results to my population of interest? Can it work (under ideal circumstances)? Will it work (in real life)?
  • How can we facilitate the assessment of applicability?
    • Better reporting of factors that may affect applicability
      • Population characteristics
      • Intervention and comparisons
      • Intended and Unintended Outcomes
      • Adverse effects
      • Differences between trial protocol and routine practice
      • (Rothwell, Lancet 2005;365;82-93)
    • Standardized approach to distinguish efficacy from pragmatic studies
  • Criteria to distinguish efficacy from pragmatic trials
    • Population in primary care
    • Less stringent eligibility criteria
    • Health outcomes
    • Clinically relevant study duration and treatment modalities
    • Assessment of adverse events
    • Adequate power to detect a minimally important difference from a patient perspective
    • ITT-analysis
    (Gartlehner et al. A simple and valid tool distinguished efficacy from effectiveness studies. J Clinical Epidemiology 2006; 56:1040-1048)
  • Summary
    • Balanced systematic reviews should assess both benefits and harms
    • Broader range of data sources may be required
    • More emphasis on the applicability of findings