Stopping Randomized Trials Early for Benefit and Estimation of Treatment Effects&lt;subtitle&gt;Systematic Review and Meta-regression Analysis&lt;/subtitle&gt;

Bassler, Dirk

doi:10.1001/jama.2010.310

Cited by 560 publications

(364 citation statements)

References 21 publications

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“…Therefore, the results presented here are exploratory and should be interpreted with caution. However, the results from the pooled studies are unlikely to overestimate a treatment effect as occurred in other trials that were terminated early [3,14].…”

Section: Discussionmentioning

confidence: 78%

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Bhandari

Jin

See

et al. 2016

Clinical Orthopaedics &Amp; Related Research

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Background There is a medical need for therapies that improve hip fracture healing. Teriparatide (Forteo 1 / Forsteo 1 , recombinant human parathyroid hormone) is a bone anabolic drug that is approved for treatment of osteoporosis and glucocorticoid-induced osteoporosis in men and postmenopausal women at high fracture risk. Preclinical and preliminary clinical data also suggest that teriparatide may enhance bone healing.Questions/purposes We wished to test the hypotheses that treatment with teriparatide versus placebo would improve femoral neck fracture healing after internal fixation as measured by (1) frequency of revision surgery, (2) radiographic fracture healing, and (3) other outcomes including pain control, gait speed, and safety. Methods We initiated two separate, but identically designed, clinical trials to meet FDA requirements to provide substantial evidence to support approval of a new indication. The two prospective, randomized double-blind, placebo-controlled Phase III studies were designed to evaluate the effect of subcutaneous teriparatide (20 lg/day) for 6 months versus placebo on fracture healing at 24 months. The trials were conducted concurrently with a planned enrollment of 1220 patients per trial. However, enrollment was stopped owing to very slow patient accrual, and an a priori decision was made to pool the results of those studies for statistical analyses before study completion; pooling was specified in both protocols. Randomization was stratified by fixation (sliding hip screw or multiple cancellous screws) and fracture type (displaced or nondisplaced). An independent Central Adjudication Committee reviewed revision surgical procedures and radiographs. A total of 159 patients were randomized in the two trials (81 placebo, 78 teriparatide). The combined program had very low power to detect the originally This study was sponsored by Eli Lilly and Company. The institutions of authors (MB, NG, RW) have received, during the study period, funding from Eli Lilly and Company. One author (MB), or a member of his or her immediate family, has or may receive payments or benefits, during the study period, an amount of less than USD 10,000 from Eli Lilly and Company. One or more of the authors (LJ, KS, RB, KDK, MRW, BM) are employees of Eli Lilly and Company, that provided funding for this study. One of the authors (QIA) was an employee of Eli Lilly and Company at the time of the study but he no longer is employed by them. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board members are on file with the publication and can be viewed on request. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This study was conducted at the authors' various institutions. Clinical Orthopaedics and Related Research ®A Publication of The ...

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Section: Discussionmentioning

confidence: 78%

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Bhandari

Jin

See

et al. 2016

Clinical Orthopaedics &Amp; Related Research

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“…[38][39][40] The magnitude of bias is inversely related to the number of events. 38 A recent study of 91 trials 38 suggests that the correction factor multiplier would be close to 1 at 1231 events as in the ACCOMPLISH trial and would likely equal 1 when at 3837 events as in the ALLHAT CTDN-doxazosin trial. Regardless of the above controversy, early terminations were not involved in the ACE inhibitor network, for which CTDN was superior to HCTZ.…”

Section: Discussionmentioning

confidence: 99%

Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events

2012

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Abstract-Hydrochlorothiazide (HCTZ) is widely used for hypertension, and prescriptions for HCTZ outnumber those for chlorthalidone (CTDN) by Ͼ20-fold in 2 recent surveys. Some have recently expressed a preference for CTDN. However, head-to-head trials testing the effect of the 2 drugs on cardiovascular events (CVEs) are lacking. We conducted a systematic review of randomized trials in which 1 arm was based on either HCTZ or CTDN followed by 2 types of network meta-analyses, a drug-adjusted analysis and an office systolic blood pressure-adjusted analysis. Nine trials were identified: 3 based on HCTZ and 6 based on CTDN. In the drug-adjusted analysis (nϭ50 946), the percentage of risk reduction in congestive heart failure for CTDN versus HCTZ was 23 (95% CI, 2-39; Pϭ0.032); and in all CVEs was 21 (95% CI, 12-28; PϽ0.0001). In the office systolic blood pressure-adjusted analysis (nϭ78 350), the percentage of risk reduction in CVEs for CTDN versus HCTZ was 18 (95% CI, Pϭ0.024). When the reduction in office systolic blood pressure was identical in the 2 arms, the risk for CVEs in HCTZ arms was 19% higher than in its nondiuretic comparator arms (Pϭ0.021). Relative to HCTZ, the number needed to treat with CTDN to prevent 1 CVE over 5 years was 27. In conclusion, CTDN is superior to HCTZ in preventing cardiovascular events. This cannot be attributed entirely to the lesser effect of HCTZ on office systolic blood pressure but may be attributed to the pleomorphic effects of alternative medications or to the short duration of action of HCTZ. Pharmaceutical preparations of the 2 drugs differ. HCTZ is available in 12.5-mg and 25.0-mg tablets and in 19 combination tablets, whereas CTDN is commonly available only in an unscored 25-mg tablet, an excessive dose in many patients, and in only 3 combination tablets, including atenolol, clonidine, and azilsartan. In light of the practical features of HCTZ, 2 there were 134 million prescriptions (solo or as a combination tablet) in 2007. 3 HCTZ is the 10th most commonly prescribed drug in the United States, with 48 million solo prescriptions annually from 2006 through 2010. 4 In 2 recent surveys, one in the United States and the other in Germany, HCTZ prescriptions outnumbered those for CTDN by Ͼ20-fold. 5,6 In the last several years, some have compared the drugs pharmacologically and have recommended CTDN rather than HCTZ. 3,[7][8][9][10][11][12] Two recent reanalyses of Multiple Risk Factor Intervention Trial (MRFIT) data have found CTDN to be superior to HCTZ in reducing cardiovascular events (CVEs) 13 and left ventricular hypertrophy. 14 However, no randomized, controlled trials have compared the 2 medications head to head with respect to CVEs. To examine whether 1 drug was superior over the other in reducing CVEs, we undertook a systematic review of randomized, controlled trials with either HCTZ or CTDN as the step 1 agent and then conducted 2 different types of network analyses. MethodsPreferred Reporting Items for Systematic Reviews and MetaAnalyses guidelines were followed th...

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“…Bassler et al observe that the risk of overestimating treatment benefit for truncated RCTs is increased in studies with fewer than 500 events. On the contrary, the methodological quality and the presence of defined statistical stopping rules fail to predict the magnitude of the bias of RCTs stopped early for benefit [5].…”

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confidence: 97%

“…Recent studies observe that truncated RCTs have different biases leading to implausible large treatment effects and misleading estimates of the benefit [5]. Use of well defined statistical procedures may obviate the problem of multiple repeated interim analyses at the same unadjusted level of significance.…”

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confidence: 99%

Can we trust in trials stopped early for benefit?

Casazza

Casella²,

Metodologica

2012

Intern Emerg Med

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

Abstract: 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.

Cited by 560 publications

References 21 publications

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Does Teriparatide Improve Femoral Neck Fracture Healing: Results From A Randomized Placebo-controlled Trial

Chlorthalidone Compared With Hydrochlorothiazide in Reducing Cardiovascular Events

Can we trust in trials stopped early for benefit?

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