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Background Loss to follow-up from randomised trials (RCTs) can affect the reliability of results. Objectives To quantify the effect of strategies to improve retention in RCTs, explore their use, and develop best practice guidance. Methods Systematic review: including retention RCTs nested in RCTs. Qualitative study: in-depth interviews with RCT personnel. Consensus development: workshops with RCT personnel. Results Systematic review: 38 RCTs evaluated RCT retention strategies. Most aimed to improve questionnaire response. Questionnaire response was improved by: adding monetary incentives (RR 1.18;1.09-1.28), higher value monetary incentives (RR 1.12;1.04-1.22) and offering monetary incentives (RR 1.25;1.14-1.38). There is some evidence that recorded delivery (RR 2.08;1.11-3.87), a specialised postal strategy (RR 1.43;1.22-1.67) and an open RCT design (RR 1.37;1.16-1.63) also improve questionnaire response. There is no clear evidence that, when compared to usual follow-up procedures, questionnaire response / retention is improved by: sending questionnaires early, more disease-relevant questionnaires, shorter, or long and clear questionnaires, offering charity donations, giving or offering gifts, "enhanced" letters, priority post, additional reminders, questionnaire order, reminders to sites, behavioural or case management strategies. There was no clear effect for monetary incentives when compared to offering entry into a prize draw, or telephone surveys when compared to a monetary incentive with a questionnaire. Qualitative study: Communication and incentive strategies are routinely used to improve retention / response. There was uncertainty about their effectiveness. Non-monetary incentives, although used, were not thought to be effective. Efforts are made to improve questionnaire layout. Other strategies are seldom used. Factors thought to impact upon retention were identified. Consensus development: Best practice guidance was agreed for monetary incentives and postage. Conclusion Giving and offering small monetary incentives can be used to improve questionnaire response in RCTs. Second class postage can also be used. Application of the results would depend on RCT context and follow-up procedures.

Covariate adjustment is common in the analysis of randomised trials, and can increase statistical power without increasing sample size. Published research on covariate adjustment, and guidance for choosing covariates, focusses on trials where individuals are randomised to treatments. In cluster randomised trials (CRTs) clusters of individuals are randomised. Valid analyses of CRTs account for the structure imposed by cluster randomisation. There is limited published research on the e ects of covariate adjustment, or guidance for choosing covariates, in analyses of CRTs. I summarise existing guidance for choosing covariates in individually randomised trials and CRTs, and review the methods used to investigate the e ects of covariate adjustment. I review the use of adjusted analyses in published CRTs. I use simulation, analytic methods, and analyses of trial data to investigate the e ects of covariate adjustment in mixed models. I use these results to form guidance for choosing covariates in analyses of CRTs. Guidance to choose covariates a priori and adjust for covariates used to stratify randomisation is also applicable to CRTs. I provide guidance speci c to CRTs using linear and logistic mixed models. Cluster size, the intra-cluster correlations (ICCs) of the outcome and covariate, and the strength of the relationship between the outcome and covariate in uence the power of adjusted analyses and the precision of treatment e ect estimates. An a priori estimate of the product of cluster size and the ICC of the outcome can be used to assist choosing covariates. When this product is close to one, adjusting for a cluster level covariate or a covariate with a negligible ICC provide similar increases in power. For smaller values of this product, adjusting for a cluster level covariate gives minimal increases in power. The use of separate withincluster and contextual covariate e ect parameters may increase power further in some circumstances.

<b>Background:</b> Comparative assessments of the vascular and upper gastrointestinal risks of different regimens of non-steroidal anti-inflammatory drugs (NSAIDs) are required. <b>Methods:</b> Meta-analyses were conducted, using individual participant data where possible, of placebo-controlled trials of a selective cyclo-oxygenase [COX]-2 inhibitor ('coxib') or traditional NSAID, or randomised trials of a coxib versus traditional NSAIDs. A prespecified subdivision of traditional NSAID regimens of those with antiplatelet activity (mainly naproxen) and those without (mainly diclofenac) was made. Primary outcomes were major vascular events (MVEs; nonfatal myocardial infarction, nonfatal stroke or vascular death) and upper gastrointestinal complications (UGICs; perforation, obstruction or bleed). <b>Findings:</b> Searches identified 788 trials: 200 comparisons of a coxib vs placebo (88,604 participants, mean follow-up 0.60 years), 206 comparisons of a traditional NSAID vs placebo (43,482 participants, 0.46 years) and 149 comparisons of a coxib vs traditional NSAID (137,466 participants, mean follow-up 0.95 years). Compared to placebo, allocation to a coxib increased the risk of MVEs (rate ratio 1.38, 95&percnt; CI 1.14-1.66), vascular mortality (1.58, 1.11-2.24) and UGICs (1.81, 1.17-2.81). Overall, in the population studied, coxibs were associated with three additional major vascular events (one fatal) and two (rarely fatal) upper gastrointestinal complications per 1000 person-years exposure. There was no evidence of heterogeneity by duration of follow-up, coxib type, dose (other than for celecoxib), or patient characteristics, for the primary outcomes. The risk of MVEs for traditional NSAIDs without antiplatelet activity (mostly diclofenac 75mg bd or ibuprofen 800mg tds) were comparable to coxibs (1.40, 1.15-1.72); but the risk of UGICs (1.98, 1.39-2.84) was significantly greater. For traditional NSAIDs with antiplatelet activity (mostly naproxen 500mg bd) there were no significant excess of MVEs (0.84, 0.66-1.08), but UGICs were substantially increased (4.06, 2.85-5.78). Both coxibs and traditional NSAIDs increased risk of hospitalisation for heart failure by about two-fold. <b>Interpretation:</b> The vascular and upper gastrointestinal risks of coxibs and high-dose tNSAID regimens can be predicted, allowing the choice of analgesia to be tailored for particular patients.