EMPIRICAL APPLICATION OF DIFFERENT STATISTICAL METHODS FOR ANALYZING CONTINUOUS OUTCOMES IN RANDOMIZED CONTROLLED TRIALS

Abstract

<p>Background: Post-operative pain management in total joint replacement surgery remains to be ineffective in up to 50% of patients and remains to have overwhelming impacts in terms of patient well-being and healthcare burden. The MOBILE trial was designed to assess whether the addition of gabapentin to a multimodal perioperative analgesia regimen can reduce morphine consumption or improve analgesia of patients following total joint arthroplasty. We present here empirical application of these various statistical methods to the MOBILE trial.</p> <p>Methods: Part 1: Analysis of covariance (ANCOVA) was used to adjust for baseline measures and to provide an unbiased estimate of the mean group difference of the one year post-operative knee flexion scores in knee arthroplasty patients. Robustness test were done by comparing ANCOVA to three comparative methods: i) the post-treatment scores, ii) change in scores, iii) percentage change from baseline.</p> <p>Part 2: Morphine consumption, taken at 4 time periods, of both the total hip and total knee arthroplasty patients was analyzed using linear mixed-effects model (LMEM) to provide a longitudinal estimate of the group difference. Repeated measures ANOVA and generalized estimating equations were used in a sensitivity analysis to compare robustness of the methods. Additionally, robustness of different covariance matrix structures in the LMEM were tested, namely first order auto-regressive compared to compound symmetry and unstructured.</p> <p>Results: Part 1: All four methods showed similar direction of effect, however ANCOVA (-3.9, 95% CI -9.5, 1.6, p=0.15) and post-treatment score (-4.3, 95% CI -9.8, 1.2, p=0.12) method provided the highest precision of estimate compared to change score (-3.0, 95% CI -9.9, 3.8, p=0.38) and percent change (-0.019, 95% CI -0.087, 0.050, p=0.58).</p> <p>Part 2: There was no statistically significant difference between the morphine consumption in the treatment group and the control group (1.0, 95% CI -4.7, 6.7, p=0.73). The results remained robust across different longitudinal methods and different covariance matrix structures.</p> <p>Conclusion: ANCOVA, through both simulation and empirical studies, provides the best statistical estimation for analyzing continuous outcomes requiring covariate adjustment. More wide-spread of the use of ANCOVA should be recommended amongst not only biostatisticians but also clinicians and trialists. The re-analysis of the morphine consumption aligns with the results of the MOBILE trial that gabapentin did not significantly reduce morphine consumption in patients undergoing major replacement surgeries. More work in area of post-operative pain is required to provide sufficient management for this patient population.</p>