Dianne Bryant

Validity of composite end points in clinical trials

Use of composite end points as the main outcome in randomised trials can hide wide differences in the individual measures. How should you apply the results to clinical practice? Improvements in medical care over the past two decades have decreased the frequency with which patients with common conditions such as myocardial infarction develop subsequent adverse events. Although welcome for patients, low event rates provide challenges for clinical investigators, who consequently require large sample sizes and long follow up to test the incremental benefits of new treatments. Clinical trialists have responded to these challenges by relying increasingly on composite end points, which capture the number of patients experiencing any one of several adverse events—for example, death, myocardial infarction, or hospital admission.1 Use of composite end points is usually justified by the assumption that the effect on each of the components will be similar and that patients will attach similar importance to each component.1 But this is not always the case. In this article we provide a strategy to interpret the results of clinical trials when investigators measure the effect of treatment on an aggregate of end points of varying importance. Consider a 76 year old man who has disabling angina despite taking β blockers, nitrates, aspirin, an angiotensin converting enzyme inhibitor, and a statin. His doctor suggests cardiac catheterisation and possible revascularisation. The patient is reluctant to have invasive management, and wonders how much benefit he might expect from surgery. The trial of invasive versus medical therapy in elderly patients (TIME) is relevant.2 The study randomised 301 patients aged 75 years or older with resistant angina to optimised drug treatment or cardiac catheterisation and possible revascularisation. Although the groups showed no difference in quality of life at 12 months, the frequency of a composite end point (death, non-fatal …

Problems with use of composite end points in cardiovascular trials: systematic review of randomised controlled trials

Objective To explore the extent to which components of composite end points in randomised controlled trials vary in importance to patients, the frequency of events in the more and less important components, and the extent of variability in the relative risk reductions across components. Design Systematic review of randomised controlled trials. Data sources Cardiovascular randomised controlled trials published in the Lancet, Annals of Internal Medicine, Circulation, European Heart Journal, JAMA, and New England Journal of Medicine, from 1 January 2002 to 30 June 2003. Component end points of composite end points were categorised according to importance to patients as fatal, critical, major, moderate, or minor. Results Of 114 identified randomised controlled trials that included a composite end point of importance to patients, 68% (n=77) reported complete component data for the primary composite end point; almost all (98%; n=112) primary composite end points included a fatal end point. Of 84 composite end points for which component data were available, 54% (n=45) showed large or moderate gradients in both importance to patients and magnitude of effect across components. When analysed by categories of importance to patients, the most important components were associated with lower event rates in the control group (medians of 3.3-3.7% for fatal, critical, and major outcomes; 12.3% for moderate outcomes; and 8.0% for minor outcomes). Components of greater importance to patients were associated with smaller treatment effects than less important ones (relative risk reduction of 8% for death and 33% for components of minor importance to patients). Conclusion The use of composite end points in cardiovascular trials is frequently complicated by large gradients in importance to patients and in magnitude of the effect of treatment across component end points. Higher event rates and larger treatment effects associated with less important components may result in misleading impressions of the impact of treatment.

Operative versus Nonoperative Treatment of Acute Achilles Tendon Ruptures A Multicenter Randomized Trial Using Accelerated Functional Rehabilitation

BACKGROUND To date, studies directly comparing the rerupture rate in patients with an Achilles tendon rupture who are treated with surgical repair with the rate in patients treated nonoperatively have been inconclusive but the pooled relative risk of rerupture favored surgical repair. In all but one study, the limb was immobilized for six to eight weeks. Published studies of animals and humans have shown a benefit of early functional stimulus to healing tendons. The purpose of the present study was to compare the outcomes of patients with an acute Achilles tendon rupture treated with operative repair and accelerated functional rehabilitation with the outcomes of similar patients treated with accelerated functional rehabilitation alone. METHODS Patients were randomized to operative or nonoperative treatment for acute Achilles tendon rupture. All patients underwent an accelerated rehabilitation protocol that featured early weight-bearing and early range of motion. The primary outcome was the rerupture rate as demonstrated by a positive Thompson squeeze test, the presence of a palpable gap, and loss of plantar flexion strength. Secondary outcomes included isokinetic strength, the Leppilahti score, range of motion, and calf circumference measured at three, six, twelve, and twenty-four months after injury. RESULTS A total of 144 patients (seventy-two treated operatively and seventy-two treated nonoperatively) were randomized. There were 118 males and twenty-six females, and the mean age (and standard deviation) was 40.4 ± 8.8 years. Rerupture occurred in two patients in the operative group and in three patients in the nonoperative group. There was no clinically important difference between groups with regard to strength, range of motion, calf circumference, or Leppilahti score. There were thirteen complications in the operative group and six in the nonoperative group, with the main difference being the greater number of soft-tissue-related complications in the operative group. CONCLUSIONS This study supports accelerated functional rehabilitation and nonoperative treatment for acute Achilles tendon ruptures. All measured outcomes of nonoperative treatment were acceptable and were clinically similar to those for operative treatment. In addition, this study suggests that the application of an accelerated-rehabilitation nonoperative protocol avoids serious complications related to surgical management.

Lateral trunk lean explains variation in dynamic knee joint load in patients with medial compartment knee osteoarthritis

OBJECTIVE To test the hypothesis that selected gait kinematics, particularly lateral trunk lean, observed in patients with medial compartment knee osteoarthritis explain variation in dynamic knee joint load. METHOD In this cross-sectional observational study, 120 patients with radiographically confirmed varus gonarthrosis underwent three-dimensional gait analysis at their typical walking speed. We used sequential (hierarchical) linear regression to examine the amount of variance in dynamic knee joint load (external knee adduction moment) explained by static lower limb alignment (mechanical axis angle) and gait kinematics determined a priori based on their proposed effect on knee load (walking speed, toe-out angle, and lateral trunk lean angle). RESULTS Approximately 50% of the variation in the first peak external knee adduction moment was explained by mechanical axis angle (25%), Western Ontario and McMaster Universities Osteoarthritis Index pain score (1%), gait speed (1%), toe-out angle (12%), and lateral trunk lean angle (13%). There was no confounding or interaction with Kellgren and Lawrence grade of severity. CONCLUSIONS Gait kinematics, particularly lateral trunk lean, explain substantial variation in dynamic knee joint load in patients with medial compartment knee osteoarthritis. While largely ignored in previous gait studies, the effect of lateral trunk lean should be considered in future research evaluating risk factors and interventions for progression of knee osteoarthritis.

How Many Patients? How Many Limbs? Analysis of Patients or Limbs in the Orthopaedic Literature: A Systematic Review

BACKGROUND Clinical studies assessing orthopaedic interventions often include data from two limbs or multiple joints within single individuals. Without appropriate design or statistical approaches to address within-individual correlations, this practice may contribute to false precision and possible bias in estimates of treatment effect. We conducted a systematic review of the orthopaedic literature to determine the frequency of inappropriate inclusion of nonindependent limb or joint observations in clinical studies. METHODS We identified seven orthopaedic journals with high Science Citation Index impact factors and retrieved all clinical studies for 2003 for any intervention on any limb or joint. RESULTS We identified 288 clinical studies, 143 of which involved two limbs or multiple joint observations from single individuals. These studies included nineteen randomized clinical trials (13%) fifty-eight two-group cohort studies (41%), and sixty-six one-group cohort studies (46%). Seventy-six (53%) of the 143 studies involved statistical comparisons between patient groups with use of tests of association, and an additional sixty studies (42%) presented estimates of proportions without statistical comparisons. Only sixteen of the seventy-six studies involving statistical comparisons involved the use of any technique or methodological approach to account for multiple, nonindependent observations. A median of approximately 13% of the patients in these studies contributed more than one observation. The median proportion of nonindependent observations to total observations (the unit of analysis) was approximately 23%. CONCLUSIONS Our findings suggest that a high proportion (42%) of clinical studies in high-impact-factor orthopaedic journals involve the inappropriate use of multiple observations from single individuals, potentially biasing results. Orthopaedic researchers should attend to this issue when reporting results.

Systematic review to determine whether participation in a trial influences outcome

Abstract Objective To systematically compare the outcomes of participants in randomised controlled trials (RCTs) with those in comparable non-participants who received the same or similar treatment. Table 1 Summary of studies included in sensitivity analysis Number of comparisons Number of similar results Number better in RCT Number worse in RCT Selection bias: Low risk 6 6 — — No imbalance 22 19 1 2 Adjusted results 12 7 4 2 Partially controlled 18 15 2 1 Poorly controlled 33 30 3 — Detection bias: Low risk* 78 66 8 3 Partially met, similarly measured 5 3 2 1 High risk 8 8 — — Exclusion bias: No losses to follow up 38 32 4 2 1 person to 20% lost to follow up 33 30 2 1 > 20% loss to follow up 11 10 — 1 Unclear 9 4 4 1 Reasons for non-participation: Refused 27 18 7 2 Refused because of preference 23 20 1 2 RCT versus preference trial 16 15 — 1 Not invited 8 8 — — Treated by non-participating clinicians 1 1 — — Different skills required for treatment: Surgery and procedures 28 25 1 2 Drug treatment 22 17 4 1 Radiology 14 12 1 1 Usual care 9 8 1 — Counselling and education 8 8 — — Watchful waiting 7 6 — 1 Different clinical area: Oncology 28 23 3 2 Obstetrics and gynaecology 14 12 2 1 Cardiology 13 10 2 1 Other internal medicine 11 9 2 — Psychology and drug misuse 9 9 — — Paediatrics 8 7 — 1 Respiration 2 2 — — RCT=randomised controlled trial. * Outcomes were measured in same way. Data sources Bibliographic databases, reference lists from eligible articles, medical journals, and study authors. Review methods RCTs and cohort studies that evaluated the clinical outcomes of participants in RCTs and comparable non-participants who received the same or similar treatment. Results Five RCTs (six comparisons) and 50 cohort studies (85 comparisons) provided data on 31 140 patients treated in RCTs and 20 380 comparable patients treated outside RCTs. In the five RCTs, in which patients were given the option of participating or not, the comparisons provided limited information because of small sample sizes (a total of 412 patients) and the nature of the questions considered. 73 dichotomous outcomes were compared, of which 59 reported no statistically significant differences. For patients treated within RCTs, 10 comparisons reported significantly better outcomes and four reported significantly worse outcomes. Significantly heterogeneity was found (I2 = 89%) among the comparisons of 73 dichotomous outcomes; none of our a priori explanatory factors helped explain this heterogeneity. The 18 comparisons of continuous outcomes showed no significant differences in heterogeneity (I2 = 0%). The overall pooled estimate for continuous outcomes of the effect of participating in an RCT was not significant (standardised mean difference 0.01, 95% confidence interval −0.10 to 0.12). Conclusion No strong evidence was found of a harmful or beneficial effect of participating in RCTs compared with receiving the same or similar treatment outside such trials.

Medial opening wedge high tibial osteotomy: A prospective cohort study of gait, radiographic, and patient-reported outcomes

OBJECTIVE To evaluate the effect of medial opening wedge high tibial osteotomy on gait, radiographic, and patient-reported outcomes over a 2-year postoperative period in patients with varus alignment and medial compartment knee osteoarthritis, and to identify significant predictors of outcome. METHODS We used an observational cohort study design and prospectively administered 3-dimensional quantitative gait analysis, hip to ankle weight-bearing radiographs, and patient-reported outcomes preoperatively and 6, 12, 18, and 24 months postoperatively. Observed changes with 95% confidence intervals (95% CIs) were calculated. Multivariate linear regression and cluster analysis were used to evaluate associations between patient characteristics and 2-year outcomes in dynamic knee joint load (external knee adduction moment during gait) and Knee Injury and Osteoarthritis Outcome Scores (KOOS). RESULTS A total of 126 patients (mean age 47.48 years) were included in the study. Mean changes suggested clinically important improvements in malalignment (change in mechanical axis angle 8.04 degrees [95% CI 7.16 degrees , 8.93 degrees ]), medial compartment load during gait (change in knee adduction moment -1.38 [95% CI -1.53, -1.22] percentage body weight x height), and all KOOS domain scores (change in pain 23.19 [95% CI 19.49, 26.89] KOOS points). A small (13%) increase in knee adduction moment was observed from 6 to 24 months postoperatively. Few preoperative clinical and/or gait characteristics assessed at baseline were significantly associated with 2-year outcomes. CONCLUSION A medial opening wedge high tibial osteotomy with correction to approximately neutral alignment produces substantial and clinically important changes in dynamic knee joint load and patient-reported measures of pain, function, and quality of life 2 years postoperatively. Changes in knee adduction moment observed in the first 2 years postoperatively should be explored as potential predictors of longer-term success and subgroups of patients with poor outcomes.

Lateral Extra-articular Tenodesis Reduces Rotational Laxity When Combined With Anterior Cruciate Ligament Reconstruction: A Systematic Review of the Literature.

PURPOSE To determine whether the addition of lateral extra-articular tenodesis (LET) to anterior cruciate ligament (ACL) reconstruction would provide greater control of rotational laxity and improved clinical outcomes compared with ACL reconstruction alone. METHODS Two independent reviewers searched 9 databases for randomized and nonrandomized clinical studies comparing ACL reconstruction plus LET versus ACL reconstruction alone in a human adult population. All years and 5 languages were included. Animal and cadaveric studies, revision or repair surgical techniques, and studies focused on biomechanical outcomes were excluded. Quality assessment of the included studies was performed with the Cochrane Collaboration tool. Outcomes of interest included the pivot-shift test, KT-1000/-2000 measurements (MEDmetric, San Diego, CA), and International Knee Documentation Committee scores. RESULTS The literature search yielded 3,612 articles. After titles and abstracts were reviewed, 106 articles were selected for full-text review, of which 29 studies met the inclusion criteria (8 randomized and 21 nonrandomized studies). Of the 8 randomized studies, 3 concluded that the results were nonsignificant between treatment groups, 4 were in favor of the extra-articular tenodesis, and 1 was in favor of the ACL reconstruction alone. The Cochrane Collaboration tool showed an unclear to high risk of bias for most articles. A meta-analysis showed a statistically significant difference for the pivot-shift test (P = .002, I2 = 34%) in favor of ACL reconstruction with LET. No difference was found between the groups for International Knee Documentation Committee scores (P = .75, I2 = 19%) and KT-1000/-2000 measurements (P = .84, I2 = 34%). CONCLUSIONS Meta-analysis showed a statistically significant reduction in pivot shift in favor of the combined procedure. Studies lacked sufficient internal validity, sample size, methodologic consistency, and standardization of protocols and outcomes. LEVEL OF EVIDENCE Level III, systematic review of Level I, II, and III studies.

A Randomized Controlled Trial Comparing the Effectiveness of Functional Knee Brace and Neoprene Sleeve Use After Anterior Cruciate Ligament Reconstruction

Background Despite a lack of evidence for their effectiveness, functional knee braces are commonly prescribed to patients after anterior cruciate ligament (ACL) reconstruction. Purpose This trial was conducted to compare postoperative outcomes in patients using an ACL functional knee brace and patients using a neoprene knee sleeve. Hypothesis Patients using a brace will have superior outcomes than those using a sleeve. Study Design Randomized controlled clinical trial; Level of evidence, 1. Methods One hundred fifty patients were randomized to receive a brace (n = 76) or neoprene sleeve (n = 74) at their 6-week postoperative visit after primary ACL reconstruction with hamstring autograft. Patients were assessed preoperatively, then 6 weeks and 6, 12, and 24 months postoperatively. Outcome measures included disease-specific quality of life (Anterior Cruciate Ligament–Quality of Life [ACL-QOL] Questionnaire), anterior tibial translation (KT-1000 arthrometer side-to-side difference), the single-limb forward hop test (limb symmetry index), and Tegner Activity Scale. Outcomes at 1 and 2 years were compared after adjusting for baseline scores. Subjective ratings of how patients felt while using the brace/sleeve were also collected for descriptive purposes using a questionnaire. Four a priori directional subgroup hypotheses were evaluated using tests for interactions. Results There were no significant differences between brace (n = 62) and sleeve (n = 65) groups for any of the outcomes at 1- and 2-year follow-ups. Adjusted mean differences at 2 years were as follows: −0.94 (95% confidence interval [CI], −7.52 to 5.64) for the ACL-QOL Questionnaire, −0.10 mm (95% CI, −0.99 to 0.81) for KT-1000 arthrometer side-to-side difference, −0.87% (95% CI, −8.89 to 7.12) for hop limb symmetry index, and −0.05 (95% CI, −0.72 to 0.62) for the Tegner Activity Scale. Subjective ratings of confidence in the knee provided by the brace/sleeve were higher for the brace group than the sleeve group. Subgroup findings were minimal. Adverse events were few and similar between groups. Conclusions A functional knee brace does not result in superior outcomes compared with a neoprene sleeve after ACL reconstruction. Current evidence does not support the recommendation of using an ACL functional knee brace after ACL reconstruction.

Development and validation of the short form of a urinary quality of life questionnaire: SF-Qualiveen.

PURPOSE The 30-item Qualiveen is a specific health related quality of life questionnaire for urinary disorders in patients with neurological conditions, such as multiple sclerosis and spinal cord injury. Previous studies have demonstrated the reliability, validity and responsiveness of Qualiveen. However, to address the needs of large clinical trials and long-term monitoring, in which efficiency may compete with precision of measurement, we developed the 8-item self-administered SF-Qualiveen. MATERIALS AND METHODS A total of 180 English speaking and French speaking outpatients with multiple sclerosis at multiple sclerosis clinics and departments of rehabilitation in Canada and France completed the entire Qualiveen, the Multiple Sclerosis Quality of Life-54 questionnaire or its French version (SEP-59) as well as urinary function assessments at study enrollment and 2 to 10 weeks later. At visit 2 patients also made global ratings of change in urinary health related quality of life. SF-Qualiveen development and testing used this data set. RESULTS Correlations of SF-Qualiveen with its original form were high (r = 0.70 to 0.92). SF-Qualiveen proved reliable (ICC 0.83 to 0.93). Its responsiveness was similar to that of the long form (SRM 0.75 to 1.62). Correlations with other measures were consistent with our a priori predictions (weighted kappa 0.55 for cross-sectional correlations and 0.66 for correlations of change), supporting the cross-sectional and longitudinal construct validity of SF-Qualiveen. CONCLUSIONS SF-Qualiveen has excellent measurement properties, similar to those of the long form. The new instrument is likely to perform well in the clinical and research context.