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Stopping Randomized Trials Early for Benefit and Estimation of Treatment Effects Systematic Review and Meta-regression Analysis

Dirk Bassler, MD, MSc; Matthias Briel, MD, MSc; Victor M. Montori, MD, MSc; Melanie Lane, BA; Paul Glasziou, MBBS, PhD; Qi Zhou, PhD; Diane Heels-Ansdell, MSc; Stephen D. Walter, PhD; Gordon H. Guyatt, MD, MSc; and the STOPIT-2 Study Group
JAMA. 2010;303(12):1180-1187. doi:10.1001/jama.2010.310.
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Context Theory and simulation suggest that randomized controlled trials (RCTs) stopped early for benefit (truncated RCTs) systematically overestimate treatment effects for the outcome that precipitated early stopping.

Objective To compare the treatment effect from truncated RCTs with that from meta-analyses of RCTs addressing the same question but not stopped early (nontruncated RCTs) and to explore factors associated with overestimates of effect.

Data Sources Search of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify truncated RCTs up to January 2007; search of MEDLINE, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects to identify systematic reviews from which individual RCTs were extracted up to January 2008.

Study Selection Selected studies were RCTs reported as having stopped early for benefit and matching nontruncated RCTs from systematic reviews. Independent reviewers with medical content expertise, working blinded to trial results, judged the eligibility of the nontruncated RCTs based on their similarity to the truncated RCTs.

Data Extraction Reviewers with methodological expertise conducted data extraction independently.

Results The analysis included 91 truncated RCTs asking 63 different questions and 424 matching nontruncated RCTs. The pooled ratio of relative risks in truncated RCTs vs matching nontruncated RCTs was 0.71 (95% confidence interval, 0.65-0.77). This difference was independent of the presence of a statistical stopping rule and the methodological quality of the studies as assessed by allocation concealment and blinding. Large differences in treatment effect size between truncated and nontruncated RCTs (ratio of relative risks <0.75) occurred with truncated RCTs having fewer than 500 events. In 39 of the 63 questions (62%), the pooled effects of the nontruncated RCTs failed to demonstrate significant benefit.

Conclusions Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.

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Figure 1. Selection Process for Study Inclusion
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RCT indicates randomized controlled trial; RR, relative risk.

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Figure 2. Pooled Ratio of Relative Risks (RRs) and 95% Confidence Intervals (CIs) for Truncated vs Nontruncated Randomized Controlled Trials (RCTs)
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First column indicates number associated with the question addressed by each review that included 1 or more truncated and matching nontruncated RCTs. Results ordered by P values associated with results of nontruncated RCTs; size of the data markers indicates weight of review questions in meta-analysis.

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Figure 3. Weighted Bubble Plot Showing the Ratio of Relative Risks (RRs) vs the Total Number of Outcome Events in Truncated Randomized Controlled Trials (RCTs)
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The size of each bubble is proportional to the magnitude of the inverse of the variance of the ratio of RR in the log scale. The dashed line indicates a ratio of RR of 0.71; the dotted line, a ratio of RR of 1.00. The shaded areas numbered 1 through 3 correspond to different degrees of overestimates of effect (ratios of RRs, 0.05-0.5; 0.5-0.75; 0.75-1.00): in area 1, very large overestimation (ratio of RR, 0.37; 95% confidence interval [CI], 0.31-0.44; P < .001) occurred in truncated trials with fewer than 200 events. In area 2, large overestimation (ratio of RR, 0.65; 95% CI, 0.56-0.77; P < .001) occurred in truncated trials stopped between 200 and 500 events. In area 3, truncated trials with more than 500 events led to moderate overestimation (ratio of RR, 0.88; 95% CI, 0.80-0.96; P = .003).



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