[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
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.
Reviewers with methodological expertise conducted data extraction independently.
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.
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.
JAMA The Journal of the American Medical Association 03/2010; 303(12):1180-7. · 29.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate whether paediatric randomized clinical trials (RCTs) adopt recent guidance on Data Monitoring Committees (DMCs), interim analysis and early termination.
We reviewed paediatric RCTs that reported on DMCs, interim analysis or early termination, published in eight general medical and paediatric journals (2005-2007). We searched full-text databases for eligible trials and recorded predefined parameters on each item. Reported activities were compared with current scientific guidance.
A total of 110 of 648 paediatric trials (17%) reported on DMC, interim analysis or early stopping. Various approaches for convening a DMC were identified; information on DMC composition and independence was limited. Strict predefined statistical stopping 'rules' were reported in 10 of 23 trials, and interim analyses were more frequently performed on efficacy than on safety outcomes (39/45 vs 27/45). No adjustment for repeated testing was reported in 11 of 33 trials reporting monitoring methods and in 7 of 17 early terminated trials. Validity of results from early stopped trials was threatened by small sample sizes. Incomplete reporting hampered a full analysis.
Few paediatric trials report on DMCs' roles, interim analysis or early stopping. Heterogeneous practices and apparent shortcomings jeopardize the validity of trial results. Easily accessible guidelines for the design, conduct and reporting of paediatric DMCs are needed.
[Show abstract][Hide abstract] ABSTRACT: As recently demonstrated, random allocation to rosuvastatin results in large relative risk reductions for first cardiovascular events among apparently healthy men and women with low levels of low-density lipoprotein cholesterol but elevated levels of high-sensitivity C-reactive protein. However, whether the absolute risk reduction among such individuals justifies wide application of statin therapy in primary prevention is a controversial issue with broad policy and public health implications.
Absolute risk reductions and consequent number needed to treat (NNT) values were calculated across a range of end points, timeframes, and subgroups using data from Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), a randomized evaluation of rosuvastatin 20 mg versus placebo conducted among 17 802 apparently healthy men and women with low-density lipoprotein cholesterol <130 mg/dL and high-sensitivity C-reactive protein >or=2 mg/L. Sensitivity analyses were also performed to address the potential impact that alternative statin regimens might have on a similar primary prevention population. For the end point of myocardial infarction, stroke, revascularization, or death, the 5-year NNT within JUPITER was 20 (95% CI, 14 to 34). All subgroups had 5-year NNT values for this end point below 50; as examples, 5-year NNT values were 17 for men and 31 for women, 21 for whites and 19 for nonwhites, 18 for those with body mass index <or=25 kg/m(2) and 21 for those with body mass index greater than 25 kg/m(2), 9 and 26 for those with and without a family history of coronary disease, 19 and 22 for those with and without metabolic syndrome, and 14 and 37 for those with estimated Framingham risks greater or less than 10%. For the net vascular benefit end point that additionally included venous thromboembolism, the 5-year NNT was 18 (95% CI, 13 to 29). For the restricted "hard" end point of myocardial infarction, stroke, or death, the 5-year NNT was 29 (95% CI, 19 to 56). In sensitivity analyses addressing the theoretical utility of alternative agents, 5-year NNT values of 38 and 57 were estimated for statin regimens that deliver 75% and 50% of the relative benefit observed in JUPITER, respectively. All of these calculations compare favorably to 5-year NNT values previously reported in primary prevention for the use of statins among hyperlipidemic men (5-year NNT, 40 to 70), for antihypertensive therapy (5-year NNT, 80 to 160), or for aspirin (5-year NNT, >300).
Absolute risk reductions and consequent NNT values associated with statin therapy among those with elevated high-sensitivity C-reactive protein and low low-density lipoprotein cholesterol are comparable if not superior to published NNT values for several widely accepted interventions for primary cardiovascular prevention, including the use of statin therapy among those with overt hyperlipidemia.
clinicaltrials.gov. Identifier NCT00239681.
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