Dirk Bassler

Stopping randomized trials early for benefit and estimation of treatment effects : systematic review and meta-regression analysis

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.

Early interventions involving parents to improve neurodevelopmental outcomes of premature infants: a meta-analysis.

Objective:To determine in a systematic review, whether interventions for infant development that involve parents, improve neurodevelopment at 12 months corrected age or older.Study Design:Randomized trials were identified where an infant intervention was aimed to improve development and involved parents of preterms; and long-term neurodevelopment using standardized tests at 12 months (or longer) was reported.Result:Identified studies (n=25) used a variety of interventions including parent education, infant stimulation, home visits or individualized developmental care. Meta-analysis at 12 months (N=2198 infants) found significantly higher mental (N=2198) and physical (N=1319) performance scores favoring the intervention group. At 24 months, the mental (N=1490) performance scores were improved, but physical (N=1025) performance scores were not statistically significant. The improvement in neurodevelopmental outcome was not sustained at 36 months (N=961) and 5 years (N=1017).Conclusion:Positive clinically meaningful effects (>5 points) are seen to an age of 36 months, but are no longer present at 5 years.

Completion and publication rates of randomized controlled trials in surgery: an empirical study

OBJECTIVE To investigate the prevalence of discontinuation and nonpublication of surgical versus medical randomized controlled trials (RCTs) and to explore risk factors for discontinuation and nonpublication of surgical RCTs. BACKGROUND Trial discontinuation has significant scientific, ethical, and economic implications. To date, the prevalence of discontinuation of surgical RCTs is unknown. METHODS All RCT protocols approved between 2000 and 2003 by 6 ethics committees in Canada, Germany, and Switzerland were screened. Baseline characteristics were collected and, if published, full reports retrieved. Risk factors for early discontinuation for slow recruitment and nonpublication were explored using multivariable logistic regression analyses. RESULTS In total, 863 RCT protocols involving adult patients were identified, 127 in surgery (15%) and 736 in medicine (85%). Surgical trials were discontinued for any reason more often than medical trials [43% vs 27%, risk difference 16% (95% confidence interval [CI]: 5%-26%); P = 0.001] and more often discontinued for slow recruitment [18% vs 11%, risk difference 8% (95% CI: 0.1%-16%); P = 0.020]. The percentage of trials not published as full journal article was similar in surgical and medical trials (44% vs 40%, risk difference 4% (95% CI: -5% to 14%); P = 0.373). Discontinuation of surgical trials was a strong risk factor for nonpublication (odds ratio = 4.18, 95% CI: 1.45-12.06; P = 0.008). CONCLUSIONS Discontinuation and nonpublication rates were substantial in surgical RCTs and trial discontinuation was strongly associated with nonpublication. These findings need to be taken into account when interpreting surgical literature. Surgical trialists should consider feasibility studies before embarking on full-scale trials.

Nurses’ compliance with alarm limits for pulse oximetry: qualitative study

Objective:Monthly audits for the multicenter Canadian Oxygen Trial have shown that our neonatal team has consistently maintained study participants within the intended pulse oximetry alarm limits between 68 and 79% of the time during the first 3 days of life while infants were receiving supplemental oxygen. This good performance prompted us to explore our nurses’ perceptions of what makes them compliant with alarm limits for pulse oximetry in preterm infants.Study Design:The local neonatal research nurse interviewed all 41 staff nurses in the neonatal intensive care unit at the University Childrens Hospital in Tuebingen, Germany, for this qualitative study.Result:Nurses identified education (22/41), prompt response to alarms (22/41), a favorable patient-to-staff ratio (18/41), root cause analysis at the bedside (15/41), and the high priority given to control of oxygen therapy in the department (14/41) as the five most important determinants of their good compliance.Conclusion:These findings may be useful for other neonatal teams who struggle to improve their compliance with alarm limits for pulse oximetry.