The effects of excluding patients from the analysis in randomised controlled trials: meta-epidemiological study
Eveline Nüesch, Sven Trelle, Stephan Reichenbach, Anne W S Rutjes, Elizabeth Bürgi, Martin Scherer, Douglas G Altman, Peter Jüni, Eveline Nüesch, Sven Trelle, Stephan Reichenbach, Anne W S Rutjes, Elizabeth Bürgi, Martin Scherer, Douglas G Altman, Peter Jüni
Abstract
Objective: To examine whether excluding patients from the analysis of randomised trials are associated with biased estimates of treatment effects and higher heterogeneity between trials.
Design: Meta-epidemiological study based on a collection of meta-analyses of randomised trials.
Data sources: 14 meta-analyses including 167 trials that compared therapeutic interventions with placebo or non-intervention control in patients with osteoarthritis of the hip or knee and used patient reported pain as an outcome.
Methods: Effect sizes were calculated from differences in means of pain intensity between groups at the end of follow-up, divided by the pooled standard deviation. Trials were combined by using random effects meta-analysis. Estimates of treatment effects were compared between trials with and trials without exclusions from the analysis, and the impact of restricting meta-analyses to trials without exclusions was assessed.
Results: 39 trials (23%) had included all patients in the analysis. In 128 trials (77%) some patients were excluded from the analysis. Effect sizes from trials with exclusions tended to be more beneficial than those from trials without exclusions (difference -0.13, 95% confidence interval -0.29 to 0.04). However, estimates of bias between individual meta-analyses varied considerably (tau(2)=0.07). Tests of interaction between exclusions from the analysis and estimates of treatment effects were positive in five meta-analyses. Stratified analyses indicated that differences in effect sizes between trials with and trials without exclusions were more pronounced in meta-analyses with high between trial heterogeneity, in meta-analyses with large estimated treatment benefits, and in meta-analyses of complementary medicine. Restriction of meta-analyses to trials without exclusions resulted in smaller estimated treatment benefits, larger P values, and considerable decreases in between trial heterogeneity.
Conclusion: Excluding patients from the analysis in randomised trials often results in biased estimates of treatment effects, but the extent and direction of bias is unpredictable. Results from intention to treat analyses should always be described in reports of randomised trials. In systematic reviews, the influence of exclusions from the analysis on estimated treatment effects should routinely be assessed.
Conflict of interest statement
Competing interests: None declared.
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References
- Tierney JF, Stewart LA. Investigating patient exclusion bias in meta-analysis. Int J Epidemiol 2005;34:79-87.
- Juni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001;323:42-6.
- Sackett DL, Gent M. Controversy in counting and attributing events in clinical trials. N Engl J Med 1979;301:1410-2.
- Coronary Drug Project Research Group. Influence of adherence to treatment and response of cholesterol on mortality in the coronary drug project. N Engl J Med 1980;303:1038-41.
- Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 1999;319:670-4.
- Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12.
- Sterne JA, Juni P, Schulz KF, Altman DG, Bartlett C, Egger M. Statistical methods for assessing the influence of study characteristics on treatment effects in ‘meta-epidemiological’ research. Stat Med 2002;21:1513-24.
- Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2001;135:982-9.
- Balk EM, Bonis PA, Moskowitz H, Schmid CH, Ioannidis JP, Wang C, et al. Correlation of quality measures with estimates of treatment effect in meta-analyses of randomized controlled trials. JAMA 2002;287:2973-82.
- Gluud LL, Thorlund K, Gluud C, Woods L, Harris R, Sterne JA. Correction: reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med 2008;149:219.
- Juni P, Egger M. Commentary: empirical evidence of attrition bias in clinical trials. Int J Epidemiol 2005;34:87-8.
- Wood L, Egger M, Gluud LL, Schulz KF, Juni P, Altman DG, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ 2008;336:601-5.
- Montori VM, Wilczynski NL, Morgan D, Haynes RB. Optimal search strategies for retrieving systematic reviews from Medline: analytical survey. BMJ 2005;330:68.
- Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 2002;31:140-9.
- Juni P, Reichenbach S, Dieppe P. Osteoarthritis: rational approach to treating the individual. Best Pract Res Clin Rheumatol 2006;20:721-40.
- Reichenbach S, Sterchi R, Scherer M, Trelle S, Burgi E, Burgi U, et al. Meta-analysis: chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 2007;146:580-90.
- DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
- Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Lawrence Earlbaum, 1988.
- Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials and health-care evaluation. Chichester: Wiley, 2004.
- Fransen M, McConnell S, Bell M. Exercise for osteoarthritis of the hip or knee. Cochrane Database Syst Rev 2003(3):CD004286.
- Lo GH, LaValley M, McAlindon T, Felson DT. Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. JAMA 2003;290:3115-21.
- Chodosh J, Morton SC, Mojica W, Maglione M, Suttorp MJ, Hilton L, et al. Meta-analysis: chronic disease self-management programs for older adults. Ann Intern Med 2005;143:427-38.
- Towheed TE, Maxwell L, Anastassiades TP, Shea B, Houpt J, Robinson V, et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database Syst Rev 2005(2):CD002946.
- Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006(1):CD004257.
- Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch Intern Med 2006;166:1899-906.
- Avouac J, Gossec L, Dougados M. Efficacy and safety of opioids for osteoarthritis: a meta-analysis of randomized controlled trials. Osteoarthritis Cartilage 2007;15:957-65.
- Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis 2007;66:433-9.
- Bjordal JM, Johnson MI, Lopes-Martins RA, Bogen B, Chow R, Ljunggren AE. Short-term efficacy of physical interventions in osteoarthritic knee pain. A systematic review and meta-analysis of randomised placebo-controlled trials. BMC Musculoskelet Disord 2007;8:51.
- Bjordal JM, Klovning A, Ljunggren AE, Slordal L. Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: a meta-analysis of randomised placebo-controlled trials. Eur J Pain 2007;11:125-38.
- Manheimer E, Linde K, Lao L, Bouter LM, Berman BM. Meta-analysis: acupuncture for osteoarthritis of the knee. Ann Intern Med 2007;146:868-77.
- Pildal J, Hrobjartsson A, Jorgensen K, Hilden J, Altman D, Gotzsche P. Impact of allocation concealment on conclusions drawn from meta-analyses of randomized trials. Int J Epidemiol 2007;36:847-57.
- Gravel J, Opatrny L, Shapiro S. The intention-to-treat approach in randomized controlled trials are authors saying what they do and ng what they say? Clin Trials 2007;4:350-6.
- Altman DG, Schulz KF, Moher D, Egger M, Davidoff F, Elbourne D, et al. The revised CONSORT statement for reporting randomized trials: explanation and elaboration. Ann Intern Med 2001;134:663-94.
- Egger M, Juni P, Bartlett C. Value of flow diagrams in reports of randomized controlled trials. JAMA 2001;285:1996-9.
- Huwiler-Muntener K, Juni P, Junker C, Egger M. Quality of reporting of randomized trials as a measure of methodologic quality. JAMA 2002;287:2801-4.
- Soares HP, Daniels S, Kumar A, Clarke M, Scott C, Swann S, et al. Bad reporting does not mean bad methods for randomised trials: observational study of randomised controlled trials performed by the Radiation Therapy Oncology Group. BMJ 2004;328:22-4.
- Melander H, Ahlqvist-Rastad J, Meijer G, Beermann B. Evidence b(i)ased medicine—selective reporting from studies sponsored by pharmaceutical industry: review of studies in new drug applications. BMJ 2003;326:1171-3.
- Fergusson D, Aaron SD, Guyatt G, Hébert P. Postrandomisation exclusions: the intention to treat principle and excluding patients from analysis. BMJ 2002;325:652-4.
- Moher D, Schulz KF, Altman DG. The CONSORT statement: revised recommendations for improving the quality of reports of parallel-group randomized trials. Ann Intern Med 2001;134:657-62.
- Baron G, Boutron I, Giraudeau B, Ravaud P. Violation of the intent-to-treat principle and rate of missing data in superiority trials assessing structural outcomes in rheumatic diseases. Arthritis Rheum 2005;52:1858-65.
- Kim M. Statistical methods in Arthritis & Rheumatism: current trends. Arthritis Rheum 2006;54:3741-9.
- Julious SA, Mullee MA. Issues with using baseline in last observation carried forward analysis. Pharm Stat 2008;7:142-6.
- Streiner DL. The case of the missing data: methods of dealing with dropouts and other research vagaries. Can J Psychiatry 2002;47:68-75.
- Baron G, Ravaud P, Samson A, Giraudeau B. Missing data in randomized controlled trials of rheumatoid arthritis with radiographic outcomes: a simulation study. Arthritis Rheum 2008;59:25-31.
Source: PubMed