Orthopaedic Trials Research Articles

Guidelines for fracture healing assessments in clinical trials. Part II: Electronic data capture and image management systems—Global Adjudicator™ system

Adjudication of outcomes helps to reduce variation in outcome assessment when clinical judgement is used. Adjudication is extremely important when the outcome being measured is subjective, as in the assessment of fracture healing. Adjudication Committees have the potential to provide a systematic, independent, and unbiased method of determining fracture healing. In order to make the adjudication process less time consuming and more efficient, Global Research Solutions™, a Contract Research Organization which specialises in orthopaedic and surgical clinical trials, developed the Global Adjudicator™, a web-based system, to serve as both an image management system and electronic data capture system. This manuscript highlights the features of the Global Adjudicator™ and demonstrates the benefits of using a web-based adjudication system.

Non-Pathogenic Anti-Heparin/PF4 Antibodies Generated by Low Molecular Weight Heparins Mediate Procoagulant Effects.

AbstractAbstract 1091 Introduction:While the incidence of symptomatic heparin-induced thrombocytopenia (HIT) is relatively low with the use of low molecular weights heparins (LMWHs), these agents do generate anti-heparin/PF4 antibodies in 10–20% of treated patients. Dosage, duration, and the pathologic predisposition of the patient influence the quantitative and qualitative nature of these antibodies. It has been suggested that these non-pathogenic antibodies (NPAs) which do not produce symptomatic HIT may, nevertheless, be biologically active and mediate thrombogenic responses. The overall pathophysiologic role of NPAs is unknown at this time. Hypothesis:NPAs generated by LMWHs cause coagulation activation and compromise the anticoagulant effects of the administered LMWH. Study Design:Blood plasma samples collected at baseline and day 10 from patients enrolled in orthopedic surgery clinical trials of LMWHs for the prophylactic management of deep vein thrombosis (Lovenox enoxaparin, sanofi-aventis, n=352; Clivarin reviparin, Abbott, n=380) were retrospectively screened for the presence of anti-heparin/PF4 antibodies using the GTI ELISA method (Waukesha, WI). Positive samples were tested by the 14C-SRA to determine if the antibodies were capable of functionally activating platelets. Both ELISA positive and negative samples were evaluated in an assay of thrombin generation (Technothrombin TGA kit, diaPharma, West Chester, OH). Result:In the enoxaparin study, the baseline pre-treatment samples only showed one patient in the heparin control group to be positive by ELISA. On day 10, 11 of 175 (6.3%) enoxaparin patients had a positive ELISA response, whereas 22 of 177 (12.4%) heparin patients were ELISA positive. None of the samples were 14C-SRA positive. In the thrombin generation assay, the ELISA positive samples showed a lesser inhibition of thrombin generation for both the enoxaparin and heparin groups (270 ± 27 nM TGA enoxaparin group; 220 ± 21 nM TGA heparin group) compared to the thrombin generation response of the ELISA negative samples (190 ± 18 nM TGA enoxaparin group; 160 ± 20 nM TGA heparin group). In the reviparin study, none of the patients were ELISA positive at baseline. On day 10, in the reviparin group 19 of 200 (9.5%) patients were ELISA positive, whereas 28 of 180 (15.6%) heparin control patients had a positive ELISA titer. None of the samples were 14C-SRA positive. In comparison to the baseline (pre-treatment), both the reviparin and heparin treated patients showed an inhibition of thrombin generation (410 ± 27 nM TGA baseline vs 180–290 nM with treatment). However, consistent with the above study, those samples that were ELISA antibody positive showed a lesser inhibition of thrombin generation (240 ± 21 nM TGA reviparin group; 210 ± 16 nM TGA heparin group) in comparison to the ELISA negative samples (190 ± 12 nM TGA reviparin group; 180 ± 14 nM TGA heparin group). Interestingly, the D-dimer levels were found to be higher in the ELISA positive samples in all groups for both studies (p<0.05). Conclusion:These studies suggest a potential pathologic role of NPAs. The results of the thrombin generation studies strongly suggest that the generation of NPAs may result in a reduction of the antithrombotic potential of both LMWH and heparin in treated patients. While the exact mechanism of this process is not clear, dosage adjustment may be useful in those patients who generate NPAs. Disclosures:No relevant conflicts of interest to declare.

Study design in clinical orthopaedic trials

This article addresses the explicit and salient aspects of clinical orthopaedic trial design for those requiring a concise overview of this topic. Planning and conducting a clinical trial requires an understanding of the key components of study design to appreciate the relative strengths and weaknesses of a particular design in answering a specific research question. At the outset of a research project a mandatory planning phase should produce an effective protocol. This should state the scientific basis of the study and utilize an appropriate study design, addressing the key concepts of validity and reliability. In the context of randomized controlled trials, one must consider how the population of interest is sampled and randomly assigned, the use of a control group and the outcome measures to be employed. In some circumstances other study designs may be preferable and it is important to note their indications so as to limit their misuse.

Outcomes Assessment in Fracture Healing Trials: A Primer

The measurement of clinical outcomes in trauma research is often problematic in that it is subjective and currently no feasible gold standard evaluation is available. Consequently, observed trial results are partly dependent on which outcome measure is used. Precise and useful estimates of treatment effects can only be obtained when using reliable, valid, and responsive instruments for measuring fracture healing. This overview outlines the concept of the validation of outcome measures and provides a summary of available and frequently used instruments in orthopaedic clinical trials. Outcome instruments can be divided into assessments by the clinician and assessments by the patient. Clinician-assessed measures are frequently used in routine practice but have often not been validated before their use in research. They include clinical and radiographic assessments. In contrast, patient-assessed measures have been designed specifically for investigational purposes and measure health on various domains. Some of them have been validated extensively. Critically evaluating established clinician-based assessments and integrating those found to be valid with patient-assessed outcomes into a composite measure of fracture healing constitute major future challenges.

Can orthopedic trials change practice?

Background and purpose The impact of large, randomized trials in orthopedic surgery on surgeons' preferences for a particular surgical approach remains unclear. We surveyed surgeons to assess whether they would change practice based upon results of a large, multicenter randomized controlled hip fracture trial.Methods We conducted a cross-sectional survey among International Hip Fracture Research Collaborative (IHFRC) surgeons and surgeons who were members of Arbeitsgemeinschaft fuer Osteosynthesefragen - Association for the Study of Internal Fixation (AO/ASIF) to determine the likelihood that they would change practice based on findings of a proposed large, multicenter randomized controlled trial (the Hip Fracture Evaluation with Alternatives of Total Hip Arthroplasty versus Hemi-Arthroplasty (HEALTH) study). We asked surgeons their current preferences for the management of displaced femoral neck fractures and whether a trial that definitively revealed a substantial improvement in function and quality of life with no difference in risk of revision surgery was important and would cause them to change practice.Results Of 883 surgeons surveyed, 210 responded from IHFRC and 586 from AO/ASIF (a response rate of 90%). Most surgeons (61%) preferred hemiarthroplasty (HA) for treating displaced femoral neck fractures. 72% of responding surgeons believed that a substantial improvement in patient function with total hip arthroplasty (THA) and no adverse effects on revision surgery would be an important finding. Moreover, of 483 surgeons who preferred hemiarthroplasty, 62% would change their practice based upon the findings of the trial.Interpretation Large clinical trials in orthopedics are worthwhile endeavors, as they have the potential to change practice among surgeons. Surgeons seem willing to adopt alternative surgical approaches if the evidence is compelling and sound.

Intention-to-Treat Analysis and Accounting for Missing Data in Orthopaedic Randomized Clinical Trials

The intention-to-treat principle implies that all patients who are randomized in a clinical trial should be analyzed according to their original allocation. This means that patients crossing over to another treatment group and patients lost to follow-up should be included in the analysis as a part of their original group. This principle is important for preserving the randomization scheme, which is the basis for correct inference in any randomized trial. In this study, we examined the use of the intention-to-treat principle in recently published orthopaedic clinical trials. We surveyed eight leading orthopaedic journals for randomized clinical trials published between January 2005 and August 2008. We determined whether the intention-to-treat principle was implemented and, if so, how it was used in each trial. Specifically, we ascertained which methods were used to account for missing data. Our search yielded 274 randomized clinical trials, and the intention-to-treat principle was used in ninety-six (35%) of them. There were significant differences among the journals with regard to the use of the intention-to-treat principle. The relative number of trials in which the principle was used increased each year. The authors adhered to the strict definition of the intention-to-treat principle in forty-five of the ninety-six studies in which it was claimed that this principle had been used. In forty-four randomized trials, patients who had been lost to follow-up were excluded from the final analysis; this practice was most notable in studies of surgical interventions. The most popular method of adjusting for missing data was the "last observation carried forward" technique. In most of the randomized clinical trials published in the orthopaedic literature, the investigators did not adhere to the stringent use of the intention-to-treat principle, with the most conspicuous problem being a lack of accounting for patients lost to follow-up. This omission might introduce bias to orthopaedic randomized clinical trials and their analysis.

Rivaroxaban in Orthopedic Surgery — A Change of Paradigm?

Two selective, orally available anticoagulant agents, although with different targets in the coagulation cascade, have recently been approved in many countries on the indication of prophylaxis against venous thromboembolism (VTE) after major joint arthroplasty. This review discusses mainly the antifactor Xa drug, rivaroxaban, with a focus on the orthopedic trials. Pharmacokinetic characteristics and other clinical development programs with rivaroxaban are briefly reviewed. Although the aim of this article is not to review the direct thrombin inhibitor, dabigatran etexilate, some comparisons are made. For clinical results, these are obviously indirect and conclusions must be drawn with caution until head-to-head comparisons are performed. Whether the introduction of rivaroxaban is a change of paradigm will ultimately be decided in the eyes and mind of the beholder.

Complication Reporting in Orthopaedic Trials

The nature and frequency of complications during or after orthopaedic interventions represent critical clinical information for safety evaluations, which are required for the development or improvement of orthopaedic care. The goal of this systematic review was to check whether essential data regarding the assessment of the prevalence, severity, and characteristics of complications related to orthopaedic interventions are consistently provided by the authors of papers on randomized controlled trials. Five major peer-reviewed orthopaedic journals were screened for randomized controlled trials published between January 2006 and July 2007. All relevant papers were obtained, anonymized, and evaluated by two external reviewers. A checklist consisting of three main parts (definition, evaluation, and reporting) was developed and applied for the assessment of complication reporting. The results were stratified into surgical and nonsurgical categories. One hundred and twelve randomized controlled trials were identified. Although complications were included as trial outcomes in two-thirds of the studies, clear definitions of anticipated complications were provided in only eight trials. In 83% of the trials, the person or group assessing the complications was not identified. No trial involved a data safety review board for assessment and classification of complications. The lack of homogeneity among the published studies that we reviewed indicates that improvement in the reporting of complications in orthopaedic clinical trials is necessary. A standardized protocol for assessing and reporting complications should be developed and endorsed by professional organizations and, most importantly, by clinical investigators.

The American Orthopaedic Association Clinical Trials Curriculum

In clinical care, high-quality, randomized controlled trials are generally acknowledged to provide the best evidence in evaluating treatment efficacy1. However, the proportion of orthopaedic publications that are clinical trials is relatively low. Although the frequency is increasing2, many surgical trials are of low quality3,4. The reasons for the low number and poor quality of surgical trials are multifactorial5-7. The design and conduct of surgical randomized trials pose unique challenges, including small numbers of patients, the heterogeneity of surgical patients, acceptability of randomization for surgical procedures, difficulty in standardizing surgical procedures, and issues of surgical proficiency such as the learning curve. Although blinded trials afford the best opportunity for unbiased assessment of outcomes, such trials are not always feasible in the surgical setting where the comparator group may be a less invasive procedure or a nonoperative approach. Despite these challenges, many questions in orthopaedics are amenable to clinical trials. In order to increase the number of trials, orthopaedic surgeons need an appreciation of a well-designed clinical trial. The objective of this article is to describe the rationale, objectives, design, and preliminary evaluation of a curriculum developed by the American Orthopaedic Association (AOA) to facilitate the conduct of clinical trials in orthopaedics. Given the many challenges posed in performing clinical trials in surgery, particular expertise is needed. Few surgeons, however, are sufficiently trained to design and conduct such trials. While surgeons or surgical groups could hire clinical research organizations or consultants to design and run clinical trials, collaborate with local experts in schools of public health or departments of clinical epidemiology, or recruit nonclinical faculty with advanced training in clinical trials methodology as would be obtained in a masters program in public health or a doctoral program in clinical epidemiology, …

Endpoint Assessment in Orthopedic Implant Trials: Current Systems and Approaches

Quality orthopedic trauma research is imperative as it provides clinical guidance in practicing evidence-based medicine. However, meaningful orthopedic trauma research, including orthopedic implant trials, is often difficult as there are very few accepted standard definitions in outcomes assessment. The unique challenges faced by investigators, especially in conducting large multi-site, multi-national randomized implant trials, can be addressed by having the adequate infrastructure in place, which includes having a central Adjudication Committee to conduct an objective outcomes assessment. While the nature of the adjudication process is complex and labor-intensive, a web-based system, such as the Global AdjudicatorTM, can greatly facilitate the adjudication process. The purpose of this manuscript is to provide an overview on the nature of orthopedic implant trials, with an emphasis on conducting reliable outcomes assessment.

Rivaroxaban (Xarelto®) : efficacité et tolérance

The oral direct Xa inhibitor rivaroxaban (Xarelto) shows great promise for prevention of venous thromboembolic events after major elective orthopedic surgery. Its consistent and predictable pharmacokinetics and pharmacodynamics across a wide range of patient populations allow administration with fixed dosing and with no coagulation monitoring. In 4 orthopaedic surgery clinical trials (12,700 patients), 10mg postoperative (6-10 hours after the end of surgery) dose, once daily, of oral rivaroxaban, achieved superior efficacy and similar safety to enoxaparin, whatever the dose of enoxaparin. Indeed, 40 mg once a day in Europe and 30 mg bid in US of enoxaparin were compared to the same dose of 10mg once daily of rivaroxaban. Furthermore, there is no difference according to liver enzymes elevation and cardio-vascular adverse events. Although the risk of spinal haematoma after neuraxial anaesthesia is rare, it is increased by concomitant use of anticoagulants. In orthopedic surgery trials with rivaroxaban to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of rivaroxaban suggests that concurrent use with neuraxial anaesthesia should require no further precautions than currently necessary with low-molecular-weight heparin.

AOA Symposium. Barriers (threats) to clinical research.

Clinical research encompasses a wide range of scientific investigations including case reports on a single patient, case series, retrospective studies, prospective studies, and multicenter randomized clinical trials. These activities aim to enhance our understanding of medical conditions with the intention of helping patients. Clinical research is time-consuming, challenging, and expensive, and with current practice pressures, it can be a daunting task. An increasing number of regulatory obstacles produce further challenges to performing clinical research. Both evidence and opinion indicate that these regulatory obstacles have adversely affected the conduct of clinical research. Ninety-one percent of the audience who attended the symposium at the 2007 Annual Meeting of the American Orthopaedic Association (AOA; a clinical meeting of senior orthopaedic surgeons) in Asheville, North Carolina, characterized this threat as moderate or severe. When the attendees were presented with three negative statements about their institutional review board, which described it as (1) cumbersome, bureaucratic, and difficult to deal with; (2) more interested in protecting the institution than the patient; and (3) causing delays and unnecessary costs, 66% felt that all three applied to their board. This reflects the deep sense of frustration many clinicians have with the current regulatory process and their belief that institutional review boards are clearly obstructive to clinical research. This symposium explores the barriers and obstacles to clinical research provided by the Health Insurance Portability and Accountability Act (HIPAA) and by institutional review boards and presents the position that change is necessary to minimize the problems and the expense they create. Clinical research requires substantial funding, particularly for large-scale multicenter trials, which limits the number and quality of these important clinical experiments. Issues related to the funding of orthopaedic trials from the perspective of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) are reviewed. Finally, high-quality clinical research needs clinician researchers trained in the methods of large clinical trials, and this type of expertise must be developed, mentored, and financially supported with protected time.

Design considerations for randomised trials in orthopaedic fracture surgery

In the hierarchy of research designs, the results of randomised controlled trials are considered the highest level of evidence. Randomisation is the only method for controlling for both known and unknown prognostic factors between comparison groups. However, there are a number of challenges to conducting trials to evaluate surgical interventions. These include patient and surgeon preferences, inability to blind surgeons and difficulties blinding patients, difficulties in obtaining adequate sample sizes, and a lack of standardisation of surgical procedures. In this paper we address these issues and offer potential solutions within the context of conducting fracture trials in orthopaedics. Careful planning can help identify methodological issues, promote adaptive study designs, and lower the risk of bias to objectively assess new or existing surgical therapies.

Management of Confounding in Controlled Orthopaedic Trials

Confounding occurs when the effect of an exposure on an outcome is distorted by a confounding factor and will lead to spurious effect estimates in clinical studies. Although confounding can be minimized at the design stage, residual confounding may remain. An argument therefore can be made for controlling for confounding during data analysis in all studies. We asked whether confounding is considered in controlled trials in orthopaedic research and hypothesized the likelihood of doing so is affected by participation of a scientifically trained individual and associated with the magnitude of the impact factor. We performed a cross-sectional study of all controlled trials published in 2006 in eight orthopaedic journals with a high impact factor. In 126 controlled studies, 20 (15.9%; 95% confidence interval, 9.5%-22.3%) studies discussed confounding without adjusting in the analysis. Thirty-eight (30.2%; 95% confidence interval, 22.2%-38.2%) controlled for confounding, although we suspect the true proportion might be somewhat higher. Participation of a methodologically trained researcher was associated with (odds ratio, 3.85) controlling for confounding, although there was no association between impact factor and controlling for confounding. The question remains to what extent the validity of published findings is affected by failure to control for confounding.

The orthopaedic trauma literature: an evaluation of statistically significant findings in orthopaedic trauma randomized trials

BackgroundEvidence-based medicine posits that health care research is founded upon clinically important differences in patient centered outcomes. Statistically significant differences between two treatments may not necessarily reflect a clinically important difference. We aimed to quantify the sample sizes and magnitude of treatment effects in a review of orthopaedic randomized trials with statistically significant findings.MethodsWe conducted a comprehensive search (PubMed, Cochrane) for all randomized controlled trials between 1/1/95 to 12/31/04. Eligible studies include those that focused upon orthopaedic trauma. Baseline characteristics and treatment effects were abstracted by two reviewers. Briefly, for continuous outcome measures (ie functional scores), we calculated effect sizes (mean difference/standard deviation). Dichotomous variables (ie infection, nonunion) were summarized as absolute risk differences and relative risk reductions (RRR). Effect sizes >0.80 and RRRs>50% were defined as large effects.Using regression analysis we examined the association between the total number of outcome events and treatment effect (dichotomous outcomes).ResultsOur search yielded 433 randomized controlled trials (RCTs), of which 76 RCTs with statistically significant findings on 184 outcomes (122 continuous/62 dichotomous outcomes) met study eligibility criteria. The mean effect size across studies with continuous outcome variables was 1.7 (95% confidence interval: 1.43–1.97). For dichotomous outcomes, the mean risk difference was 30% (95%confidence interval:24%–36%) and the mean relative risk reduction was 61% (95% confidence interval: 55%–66%; range: 0%–97%). Fewer numbers of total outcome events in studies was strongly correlated with increasing magnitude of the treatment effect (Pearson's R = -0.70, p < 0.01). When adjusted for sample size, the number of outcome events revealed an independent association with the size of the treatment effect (Odds ratio = 50, 95% confidence interval: 3.0–1000, p = 0.006).ConclusionOur review suggests that statistically significant results in orthopaedic trials have the following implications-1) On average large risk reductions are reported 2) Large treatment effects (>50% relative risk reduction) are correlated with few number of total outcome events. Readers should interpret the results of such small trials with these issues in mind.

Multicenter collaborative for orthopaedic research in India: An opportunity for global leadership

Road traffic accidents are increasing at an alarming rate and have become a major public health concern in India. In addition, there is a lack of trauma research output and reliable data from India. There are several issues and challenges that have presented an opportunity for researchers and surgeons in India to develop a collaborative aimed at improving the quality and productivity of orthopaedic trauma research. Establishing a network of surgical researchers across India is a necessary first step towards global leadership in orthopaedic surgery trials.

A Replacement for Warfarin

Vitamin K antagonists (VKAs) such as warfarin are the only oral anticoagulants currently available for clinical use. Warfarin has numerous limitations, including slow onset and offset of action, a narrow therapeutic window, and a metabolism that is affected by diet, drugs, and genetic polymorphisms.1 Because of its unpredictable dose response, warfarin requires careful coagulation monitoring to ensure that a therapeutic anticoagulant effect is achieved.2 Variable dose requirements, concern about the risk of bleeding, and the need for frequent coagulation monitoring have prompted the development of new oral anticoagulants to replace warfarin. With a predictable anticoagulant response and little potential for food or drug interactions, these new agents have been designed to be administered in fixed doses without coagulation monitoring. Consequently, these drugs have the potential to simplify long-term anticoagulant therapy. Article p 180 The features of the new oral anticoagulants in the most advanced stages of clinical development are listed in the Table and are compared with those of warfarin. Unlike warfarin, which reduces the functional levels of factors II (prothrombin), VII, IX, and X, these novel agents are directed against the active site of factor Xa or thrombin, the enzymes responsible for thrombin generation and fibrin formation, respectively (see the Figure). Rivaroxaban and apixaban target factor Xa, whereas dabigatran etexilate inhibits thrombin. View this table: Comparison of Warfarin to New Oral Anticoagulants in Advanced Stages of Clinical Development Targets of new oral anticoagulant drugs. Oral factor Xa inhibitors (rivaroxaban, apixaban) bind directly to factor Xa and prevent thrombin generation. Dabigatran etexilate, an orally active direct thrombin inhibitor, undergoes metabolic activation to dabigatran, which binds to the active site of thrombin (factor IIa) and blocks its capacity to convert fibrinogen to fibrin, to activate platelets, and to amplify its own generation by activating factors V, VIII, and XI. By blocking the …

Reporting of Outcomes in Orthopaedic Randomized Trials

Randomization, concealment of treatment allocation, and blinding are all known to limit bias in clinical research. Nonsurgical studies that fail to meet these standards have been reported to inflate the differences between treatment and control groups. While surgical trials can rarely blind surgeons or patients, they can often blind outcome assessors. The aim of this systematic review was threefold: (1) to examine the reporting of outcome measures in orthopaedic trials, (2) to determine the feasibility of blinding in published orthopaedic trials, and (3) to examine the association between the magnitude of treatment differences and the blinding of outcome assessors. We identified and reviewed thirty-two randomized, controlled trials published in The Journal of Bone and Joint Surgery (American Volume) in 2003 and 2004 for the appropriate use of outcome measures. These trials represented 3.4% of all 938 studies published during that time-period. All thirty-two trials were reviewed by two authors for (1) the outcome measures used and (2) the blinding of outcomes assessors. We calculated the magnitude of the treatment effect of the use of blinded compared with unblinded outcome assessors. Ten (31%) of the thirty-two randomized controlled trials used a modified outcome instrument. Of the ten trials, four failed to describe how the outcome instrument was modified. Nine of the ten articles did not describe how the modified instrument was validated and retested. Sixteen of the thirty-two randomized controlled trials did not report blinding of outcome assessors when blinding would have been possible. Among the studies with continuous outcome measure, unblinded outcomes assessment was associated with significantly larger treatment effects than blinded outcomes assessment (standardized mean difference, 0.76 compared with 0.25; p = 0.01). Similarly, in the studies with dichotomous outcomes, unblinded outcomes assessments were associated with significantly greater treatment effects than blinded outcomes assessments (odds ratio, 0.13 compared with 0.42; p < 0.001). The ratio of odds ratios (unblinded to blinded outcomes assessment) was 0.31, suggesting that unblinded outcomes assessment was associated with a potential for exaggeration of the benefit of the effectiveness of a treatment in our cohort of studies. In future orthopaedic randomized controlled trials, emphasis should be placed on detailed reporting of outcome measures to facilitate generalization and the outcome assessors should be blinded, when possible, to limit bias.

Reporting of Outcomes in Orthopaedic Randomized Trials

Background: Randomization, concealment of treatment allocation, and blinding are all known to limit bias in clinical research. Nonsurgical studies that fail to meet these standards have been reported to inflate the differences between treatment and control groups. While surgical trials can rarely blind surgeons or patients, they can often blind outcome assessors. The aim of this systematic review was threefold: (1) to examine the reporting of outcome measures in orthopaedic trials, (2) to determine the feasibility of blinding in published orthopaedic trials, and (3) to examine the association between the magnitude of treatment differences and the blinding of outcome assessors. Methods: We identified and reviewed thirty-two randomized, controlled trials published in The Journal of Bone and Joint Surgery (American Volume) in 2003 and 2004 for the appropriate use of outcome measures. These trials represented 3.4% of all 938 studies published during that time-period. All thirty-two trials were reviewed by two authors for (1) the outcome measures used and (2) the blinding of outcomes assessors. We calculated the magnitude of the treatment effect of the use of blinded compared with unblinded outcome assessors. Results: Ten (31%) of the thirty-two randomized controlled trials used a modified outcome instrument. Of the ten trials, four failed to describe how the outcome instrument was modified. Nine of the ten articles did not describe how the modified instrument was validated and retested. Sixteen of the thirty-two randomized controlled trials did not report blinding of outcome assessors when blinding would have been possible. Among the studies with continuous outcome measure, unblinded outcomes assessment was associated with significantly larger treatment effects than blinded outcomes assessment (standardized mean difference, 0.76 compared with 0.25; p = 0.01). Similarly, in the studies with dichotomous outcomes, unblinded outcomes assessments were associated with significantly greater treatment effects than blinded outcomes assessments (odds ratio, 0.13 compared with 0.42; p < 0.001). The ratio of odds ratios (unblinded to blinded outcomes assessment) was 0.31, suggesting that unblinded outcomes assessment was associated with a potential for exaggeration of the benefit of the effectiveness of a treatment in our cohort of studies. Conclusions: In future orthopaedic randomized controlled trials, emphasis should be placed on detailed reporting of outcome measures to facilitate generalization and the outcome assessors should be blinded, when possible, to limit bias.

Inadequate Statistical Power of Negative Clinical Trials in Urological Literature

Negative studies provide valuable information. However, conducting studies with inadequate power is unethical and an inefficient use of resources. The purpose of this study was to determine the prevalence of negative studies with inadequate power in urological literature. The Journal of Urology, Urology and BJU International (formerly British Journal of Urology) from 1982 to 2002 were searched using the Ovid MEDLINE database. All clinical trials that contained the phrase "no difference" were identified. Data necessary for power calculation were extracted from applicable studies. Of the 417 articles identified in the MEDLINE search, 127 were negative studies that contained enough information to be analyzed. There were 70 (55%) articles from The Journal of Urology, 35 (28%) from BJU International and 22 (17%) from Urology. Of the studies that used continuous variables 65% had adequate power (greater than 80%) to detect a 50% difference between groups and 32% had adequate power to detect a 25% difference. Of the studies that used dichotomous variables only 33% had adequate power to detect a 50% difference between groups and 23% had adequate power to detect a 25% difference. Levels of adequate power in negative studies did not improve over time (p = 0.258). Many negative studies in urological literature are inconclusive because they lack adequate power to detect even large differences between groups. Inadequately powered studies often result in false conclusions that alter clinical behavior and deter further research. Therefore, it is imperative to consider power when interpreting literature. When designing future investigations power calculations should be performed to ensure sufficient patient recruitment to attain clinically meaningful results.