Orthopaedic Trials Research Articles

Prophylaxis of postoperative thromboembolism with low molecular weight heparins.

To evaluate the thromboprophylactic use of low molecular weight heparins (LMWHs), publications from 27 orthopaedic trials and 35 studies of patients undergoing general or gynaecological surgery were scrutinized and subjected to a partial meta-analysis. In orthopaedic surgery, LMWHs were superior to placebo or dextran and at least as efficient as unfractionated heparin in the prevention of deep vein thrombosis (DVT). Compared with unfractionated heparin, one of the LMWH preparations significantly reduced the total incidence of DVT. The rate of non-fatal pulmonary embolism was 0.49 per cent in patients receiving LMWH and 1.22 per cent in controls. Seven orthopaedic patients (0.15 per cent) died from pulmonary embolism, none of whom received LMWH. In general surgery, the LMWHs were at least as efficient as unfractionated heparin, with a trend towards a lower risk of pulmonary embolism with the former. Compared with unfractionated heparin, LMWHs did not reduce the postoperative mortality rate, nor did they cause haemorrhage. LMWHs provide safe and efficient prophylaxis by administration once daily.

Multicenter Clinical Trials in Orthopaedics

Orthopaedic surgeons want what is best for their patients. Determining best practice, however, is not always straightforward. Clinicians use many sources of information to determine treatment options for their patients. Surgeons rely in large part on their training. As surgeons progress through their careers, practice learned through training is influenced by their own experience, the advice of colleagues, and their personal learning, including continuing medical education and the use of texts or the surgical literature. One of the more powerful forces in shaping best practice is, and should be, the surgical literature. The literature, however, is often contradictory. Contradictory literature leads to conflicting treatment recommendations for many conditions, and, in some situations, to a complacency among surgeons that anything goes (as surgeons can find some support for just about anything in the literature). Varying treatment recommendations in the literature and subsequent variation in practice may be acceptable if different treatments address different clinical situations, if different treatments have similar outcomes, or if different treatments address the variation in patient preferences. Barring these circumstances, if different treatments have meaningful differences in outcome, then practice variation may adversely affect patient outcomes. Why do the recommendations for treatment reported in the literature vary for many conditions? At least some of the variation in the surgical literature reflects the variation in study quality. Surgeons intuitively recognize that a more rigorous research design provides more convincing and dependable results. Study design is the basis for levels of evidence. Although critical appraisal is required to determine the merit of an individual study, according to the Levels of Evidence in The Journal of Bone and Joint Surgery 1 , randomized trials (Level I) are considered the highest quality research. Although the case series (Level IV), the predominant form of orthopaedic research, are considered a less rigorous research …

Randomization and concealment in surgical trials: a comparison between orthopaedic and non-orthopaedic randomized trials

In the hierarchy of evidence, randomized trials remain the gold standard. Critical to the limitation of bias in these studies are randomization and allocation concealment, both of which provide similar comparison groups to evaluate treatments. Despite the support of these principles through numerous studies [3], inferences from randomized trials in orthopaedic surgery have been limited due to inconsistencies in methodology [1]. Given the importance of reporting how patients were randomized and whether treatment allocation was concealed, we examined orthopaedic and non-orthopaedic randomized control trials to explore this issue.

Ximelagatran, a new oral direct thrombin inhibitor, for the prevention of venous thromboembolic events in major elective orthopaedic surgery. Efficacy, safety and anaesthetic considerations.

The oral direct thrombin inhibitor ximelagatran shows great promise for prevention of venous thromboembolic events following major elective orthopaedic 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 orthopaedic surgery clinical trials, ximelagatran was effective and well tolerated compared with standard therapy, with dose and timing relative to surgery important factors in determining its optimal profile. In European trials, an initial 3-mg postoperative dose of subcutaneous melagatran, the active form of ximelagatran, followed by oral ximelagatran 24 mg twice daily achieved similar efficacy and safety to enoxaparin. Although the risk of spinal haematoma following neuraxial anaesthesia is rare, it is increased by the concomitant use of anticoagulants. In orthopaedic surgery trials with ximelagatran to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of ximelagatran suggests that concurrent use with neuraxial anaesthesia should require no further precautions than those currently necessary with low-molecular-weight heparin.

Limiting loss to follow-up in a multicenter randomized trial in orthopedic surgery

Even the best-designed, randomized controlled trials suffer when patients are lost to follow-up. Incomplete follow-up biases the results of a trial when patients who drop out are different from those who complete follow-up. This is exaggerated further when there are differential dropout rates between study groups. Previous randomized controlled trials in orthopedic trauma have reported up to 28% loss to follow-up. Only by striving to achieve a 0% loss to follow-up rate can we be certain that this type of bias does not affect our results. In our ongoing multicenter, randomized controlled trial comparing reamed and nonreamed intramedullary nailing of tibial shaft fractures, we have implemented several innovative strategies to minimize loss to follow-up. The exclusion criteria and consent process are designed to minimize losses. Study staff are carefully trained in communication and negotiation with patients. Additionally, a central methods center monitors all patient follow-up and aids in finding lost patients. Through these primary, secondary, and tertiary interventions, we have achieved 94% complete 1-year follow-up for the first 440 patients enrolled in the trial. Eleven patients withdrew consent, and we are unable to locate 17 patients. We have successfully minimized the loss to follow-up rate in our trial by incorporating innovative prevention and retention strategies into its design and conduct. Through planning, organization, and committing time and resources to minimizing loss to follow-up, other orthopedic trauma trials can hope to achieve the same high rates of follow-up.

The risk of false-positive results in orthopaedic surgical trials.

The risk of concluding that the results of a particular study are true, when, in fact, they really are attributable to chance (or random sampling error) is underappreciated by investigators. This erroneous false-positive conclusion is designated as a Type I or alpha error. The extent to which randomized trials in surgery risk Type I errors is unclear. The current authors hand-searched four orthopaedic journals, six general surgery journals, and five medical journals to identify recently published randomized trials (within the past 2 years). Information on outcomes and statistical adjustment for multiple outcomes was recorded for each study. The risk of a Type I error was calculated for each study that did not explicitly state a primary outcome measure for the main statistical comparison. One hundred fifty-nine studies met the inclusion criteria for the study: 60 studies from orthopaedic journals, 49 studies from nonorthopaedic surgical journals, and 50 studies from medical journals. Of the trials that did not state a primary outcome measure, the risk of Type I errors (false-positive results) in orthopaedic and nonorthopaedic surgery journals (mean 37.3% +/- 13.3% and 37.6% +/- 10.5%, respectively) were significantly greater than medical journals (10.1% +/- 1.9%). In the current review of randomized trials in surgery and medicine, the following is reported: (1) reporting of primary outcomes in trials was inadequate; (2) one in three trials in surgery and one in 10 trials in medicine risked false-positive results; and (3) few trials in surgery and medicine considered adjustment for multiple comparisons.

The quality of reporting of randomized trials in the Journal of Bone and Joint Surgery from 1988 through 2000.

The purpose of this study was threefold: (1) to determine the scientific quality of published randomized trials in the American Volume of The Journal of Bone and Joint Surgery from 1988 through 2000, (2) to identify predictors of study quality, and (3) to evaluate inter-rater agreement in the scoring of study quality with use of a simple scale. Hand searches of The Journal of Bone and Joint Surgery were conducted in duplicate to identify randomized clinical trials. Of 2468 studies identified, seventy-two (2.9%) met all eligibility criteria. Two investigators each assessed the quality of the study under blinded conditions and abstracted relevant data. The mean score (and standard error) for the quality of the seventy-two randomized trials was 68.1% plus minus 1.6%; 60% (forty-three) scored <75%. Drug trials had a significantly higher mean quality score than did surgical trials (72.8% compared with 63.9%, p < 0.05). Regression analysis revealed that cited affiliation with an epidemiology department and cited funding were associated with higher quality scores. Failure to conceal randomization, to blind outcome assessors, and to describe why patients were excluded resulted in significantly lower quality scores (p < 0.05), more than the 5% decrease expected by removal of each item. A priori calculations of sample size were rarely performed in the reviewed studies, and only 2% of the studies with negative results included a post hoc power analysis. The Detsky quality scale met accepted standards of interobserver reliability (kappa, 0.87; 95% confidence interval, 0.70 to 0.95). Few studies published in The Journal of Bone and Joint Surgery were randomized trials. More than half of the trials were limited by a lack of concealed randomization, lack of blinding of outcome assessors, or failure to report reasons for excluding patients. Application of standardized guidelines for the reporting of clinical trials in orthopaedics should improve quality.

Sample size and statistical power of randomised, controlled trials in orthopaedics

Sample size and statistical power of randomised, controlled trials in orthopaedics

Type-II error rates (beta errors) of randomized trials in orthopaedic trauma.

Although an investigator may limit bias through randomization, concealment of patient allocation, and blinding, the results of randomized trials may be less convincing when the sample size is not sufficiently large to reveal a true difference between treatment groups. When the sample size is small, randomized trials are subject to beta errors (type-II errors)--that is, the probability of concluding that no difference between treatment groups exists when, in fact, there is a difference. The purpose of this study of randomized trials involving fracture care published between 1968 and 1999 was twofold: (1) to evaluate type-II error rates and study power (1 - beta) for the primary outcomes and (2) to identify whether investigators clearly identified the primary and secondary outcomes. To be eligible, studies were required to (1) be published in English, (2) be described as a randomized trial, (3) involve the care of adult patients with fractures, treated either operatively or nonoperatively, and (4) contain sufficient outcome information to enable study power to be calculated. Computer database searches were performed independently by two investigators to identify all potentially relevant study titles. Additional strategies to identify articles included (1) hand searches of selected orthopaedic journals from 1989 to 1999, (2) searches of the bibliographies of potentially relevant articles, and (3) review by content experts to identify missing studies. For each study, a standard power calculation was performed on the primary and secondary outcomes. For those studies in which the primary outcome was not explicitly reported, the most clinically relevant measure was chosen by consensus. Acceptable study power was agreed a priori to be > or = 80% (type-I error of < or = 0.20). We identified 620 potentially relevant citations from MEDLINE, of which only 187 were potentially eligible. We identified nine more articles with other searches, and application of the eligibility criteria to the 196 articles eliminated seventy-nine. Thus, we analyzed 117 studies in which a total of 19,942 patients with orthopaedic trauma had been randomized. Sample sizes ranged from ten to 662 patients (mean and standard deviation, 95 79 patients). The majority (34%) of trials involved the treatment of hip fractures. The mean overall study power among the 117 trials was 24.65% (range, 2% to 99%). The type-II error rate for primary outcomes was 90.52%. Mean type-II error rates in the orthopaedic trauma trials that we analyzed exceeded accepted standards. Investigators can reduce type-II error rates by performing power and sample-size calculations prior to conducting a trial.

Sample size and statistical power of randomised, controlled trials in orthopaedics

We reviewed all 717 manuscripts published in the 1997 issues of the British and American volumes of the Journal of Bone and Joint Surgery and in Clinical Orthopaedics and Related Research, from which 33 randomised, controlled trials were identified. The results and sample sizes were used to calculate the statistical power of the study to distinguish small (0.2 of standard deviation), medium (0.5 of standard deviation), and large (0.8 of standard deviation) effect sizes. Of the 33 manuscripts analysed, only three studies (9%) described calculations of sample size. To perform post-hoc power assessments and estimations of deficiencies of sample size, the standard effect sizes of Cohen (small, medium and large) were calculated. Of the 25 studies which reported negative results, none had adequate power (β &lt; 0.2) to detect a small effect size and 12 (48%) lacked the power necessary to detect a large effect size. Of the 25 studies which did not have an adequate size of sample to detect small differences, the average used was only 10% of the required number Our findings suggest that randomised, controlled trials in clinical orthopaedic research utilise sample sizes which are too small to ensure statistical significance for what may be clinically important results.

Sample size and statistical power of randomised, controlled trials in orthopaedics.

We reviewed all 717 manuscripts published in the 1997 issues of the British and American volumes of the Journal of Bone and Joint Surgery and in Clinical Orthopaedics and Related Research, from which 33 randomised, controlled trials were identified. The results and sample sizes were used to calculate the statistical power of the study to distinguish small (0.2 of standard deviation), medium (0.5 of standard deviation), and large (0.8 of standard deviation) effect sizes. Of the 33 manuscripts analysed, only three studies (9%) described calculations of sample size. To perform post-hoc power assessments and estimations of deficiencies of sample size, the standard effect sizes of Cohen (small, medium and large) were calculated. Of the 25 studies which reported negative results, none had adequate power (beta < 0.2) to detect a small effect size and 12 (48%) lacked the power necessary to detect a large effect size. Of the 25 studies which did not have an adequate size of sample to detect small differences, the average used was only 10% of the required number Our findings suggest that randomised, controlled trials in clinical orthopaedic research utilise sample sizes which are too small to ensure statistical significance for what may be clinically important results.

The proper sample size in clinical orthopedic trials

A determinant for the evidence of a clinical trial is the magnitude of the sample size. The proper sample size can be easily computed with the knowledge of α, power and effect size. Standard values for α and power in clinical trials are 5% and 90%, respectively. As consequence, effect size is crucial for the sample size. The effect size has to be determined by the clinician according to medical considerations.

The conduct of orthopaedic clinical trials.

The work of clinical investigators is commonly said to be a search for the truth. Many years ago, Cannon rephrased this objective in less pretentious rhetoric, saying that the investigator tries to learn whether facts that others will recognize as facts can be established and whether the facts will support some projected theory6. Today, we call a projected theory a hypothesis and we call facts clinical data. Civilized countries have established rules governing the attainment of such data, and these rules, or standards, govern the scientific and ethical conduct for clinical trials. The art of clinical trials has become more refined over the years through the application of recognized scientific principles to the interpretation of results. In addition, today's computer technology, coupled with powerful statistical methods, permits rapid evaluation of complex variables. A clinical trial to determine the safety and efficacy of an orthopaedic device represents a process in experimental therapy in which the surgeon's skill and the implant both play a major role in securing scientific evidence. The evaluation of drugs is substantially different than the evaluation of devices. For example, a dose response generally can be predicted from certain experiments conducted in animal models. Unfortunately, there are few good models for the evaluation of devices, and none, to our knowledge, for the preclinical study of orthopaedic implants. Furthermore, clinical response to pharmaceutical agents is prompt and depends partially on how the drug is administered. While a dose response to a drug is based on simple delivery to the patient, the effect of a device also depends on the skill of the user. An implanted device may immediately affect body function, but its long-term utility and potential side effects may take years to assess. The goal of any new therapy is to improve a patient's health status …

The Foot Function Index for measuring rheumatoid arthritis pain: evaluating side-to-side reliability.

The Foot Function Index is a validated and reliable instrument for measuring foot pain, disability, and activity restriction in patients with rheumatoid arthritis. For the purposes of orthopaedic studies in which one foot serves as an internal control, we assessed the side-to-side reliability of the seven-question Foot Function Index pain subscale. Thirty patients with rheumatoid arthritis completed visual analog scale pain questionnaires for both feet on two occasions 8 days apart. Internal reliability of the scale was high, with Cronbach's alphas ranging from 0.94 to 0.96, suggesting good left versus right discriminatory abilities. Principal component factor analysis segregated the questions into two large clusters containing predominantly either left or right foot items. Intraclass correlation coefficients were examined for test-retest reliability (separated by side) and for side-to-side reliability (separated by the day of test). The resultant intraclass correlation coefficients were nearly equivalent, ranging from 0.79 to 0.89. Generalizability analysis yielded similar results. Intraclass correlation coefficients and generalizability analysis demonstrate that the majority of variation is best explained by the differences within subjects or between subjects rather than by test-retest or side-to-side differences. We recommend the Foot Function Index as a reliable measurement scale for use in orthopaedic interventional trials.

Randomized trials in orthopaedics

There is increasing recognition that major new medical therapies should be rigorously evaluated before they are put into general clinical use. Randomized controlled trials provide the most unbiased assessment of the risks and benefits of such therapies. In this article, the most important aspects of the design and execution of a randomized clinical trial in orthopaedics are discussed. These include the reasons for and mechanisms of randomization, appropriate selection of patients and therapy, reasons for the blinding of therapy, types of measures of outcome that can be used, aspects of sample-size calculation and analysis of data, and ethics of randomized controlled trials.