Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis.
Bassler D., Briel M., Montori VM., Lane M., Glasziou P., Zhou Q., Heels-Ansdell D., Walter SD., Guyatt GH., STOPIT-2 Study Group None., Flynn DN., Elamin MB., Murad MH., Abu Elnour NO., Lampropulos JF., Sood A., Mullan RJ., Erwin PJ., Bankhead CR., Perera R., Ruiz Culebro C., You JJ., Mulla SM., Kaur J., Nerenberg KA., Schünemann H., Cook DJ., Lutz K., Ribic CM., Vale N., Malaga G., Akl EA., Ferreira-Gonzalez I., Alonso-Coello P., Urrutia G., Kunz R., Bucher HC., Nordmann AJ., Raatz H., da Silva SA., Tuche F., Strahm B., Djulbegovic B., Adhikari NK., Mills EJ., Gwadry-Sridhar F., Kirpalani H., Soares HP., Karanicolas PJ., Burns KE., Vandvik PO., Coto-Yglesias F., Chrispim PP., Ramsay T.
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.