Randomized trials stopped early for benefit: a systematic review

Context  Randomized clinical trials (RCTs) that stop earlier than planned because of apparent benefit often receive great attention and affect clinical practice. Their prevalence, the magnitude and plausibility of their treatment effects, and the extent to which they report information about how investigators decided to stop early are, however, unknown. Objective  To evaluate the epidemiology and reporting quality of RCTs involving interventions stopped early for benefit. Data Sources  Systematic review up to November 2004 of MEDLINE, EMBASE, Current Contents, and full-text journal content databases to identify RCTs stopped early for benefit. Study Selection  Randomized clinical trials of any intervention reported as having stopped early because of results favoring the intervention. There were no exclusion criteria. Data Extraction  Twelve reviewers working independently and in duplicate abstracted data on content area and type of intervention tested, reporting of funding, type of end point driving study termination, treatment effect, length of follow-up, estimated sample size and total sample studied, role of a data and safety monitoring board in stopping the study, number of interim analyses planned and conducted, and existence and type of monitoring methods, statistical boundaries, and adjustment procedures for interim analyses and early stopping. Data Synthesis  Of 143 RCTs stopped early for benefit, the majority (92) were published in 5 high-impact medical journals. Typically, these were industry-funded drug trials in cardiology, cancer, and human immunodeficiency virus/AIDS. The proportion of all RCTs published in high-impact journals that were stopped early for benefit increased from 0.5% in 1990-1994 to 1.2% in 2000-2004 (P<.001 for trend). On average, RCTs recruited 63% (SD, 25%) of the planned sample and stopped after a median of 13 (interquartile range [IQR], 3-25) months of follow-up, 1 interim analysis, and when a median of 66 (IQR, 23-195) patients had experienced the end point driving study termination (event). The median risk ratio among truncated RCTs was 0.53 (IQR, 0.28-0.66). One hundred thirty-five (94%) of the 143 RCTs did not report at least 1 of the following: the planned sample size (n = 28), the interim analysis after which the trial was stopped (n = 45), whether a stopping rule informed the decision (n = 48), or an adjusted analysis accounting for interim monitoring and truncation (n = 129). Trials with fewer events yielded greater treatment effects (odds ratio, 28; 95% confidence interval, 11-73). Conclusions  RCTs stopped early for benefit are becoming more common, often fail to adequately report relevant information about the decision to stop early, and show implausibly large treatment effects, particularly when the number of events is small. These findings suggest clinicians should view the results of such trials with skepticism.      

Halofuginone inhibits collagen deposition in fibrous capsules around implants

Fibrous capsule formation around implants remains a difficult problem that has been studied for decades. The etiology is elusive, but the end result is the deposition of a dense collagenous capsule around implanted materials. The purpose of this study was to determine the effects of a type I collagen synthesis inhibitor, halofuginone, on fibrous capsule formation around implanted materials. Silastic disks were implanted subcutaneously into 4 groups of adult male rats for up to 8 weeks. Group 1 received drug throughout the study, group 2 received drug during the first half only, group 3 received drug during the second half only, and the control group received no drug. Implants were removed and histology of the capsules was examined. A collagen index score was calculated from digital images of trichrome-stained histologic sections, which permitted semiquantitative comparison of collagen content among the 4 groups. The collagen index values clearly indicate that halofuginone effectively inhibited collagen deposition within the capsule around the implanted disks. Halofuginone treatment also resulted in a decrease in the collagen index score in rat skin, indicating that halofuginone may affect preexisting collagenous structures. The ability of halofuginone to inhibit collagen deposition in new and preexisting fibrous capsules suggests that it may be a useful adjunct to minimize the formation of capsules around implantable prostheses.     

Balloon occlusion technique to cannulate angulated and tortuous coronary sinus branches in cardiac resynchronization therapy

We present two cases that demonstrate a new technique to cannulate angulated and tortuous coronary sinus branches during left ventricular lead placement for cardiac resynchronization therapy. The technique uses an occlusive pulmonary artery balloon just beyond the takeoff of the coronary sinus branch to assist in the cannulation of the branch.     

Unemployment and the disabled

An analysis of Employment Services Division statistics show a close relationship between the levels of unemployment in the disabled rehabilitated at the Employment Rehabilitation Centres (ERCs) and the rates of unemployment in the general population in the whole of Great Britain (r = 0.90) or in the local areas of the Centres (r = 0.66). There is also a significant association between the levels of unemployment in 749 rehabilitees passing through one ERC and the rates of unemployment in their home areas. The results have practical implications for both the employment and medical rehabilitation services.