Challenges in the Analysis of Longitudinal Pain Data: Practical Lessons from a Randomized Trial of Annular Closure in Lumbar Disc Surgery.

Senol Jadik,Charlotte Flüh,Sandro Eustacchio,Gerrit J. Bouma,Larry E. Miller,Richard Bostelmann,Martin Barth

doi:10.1155/2019/3498603

Abstract

Purpose. To analyze leg pain severity data from a randomized controlled trial (RCT) of lumbar disc surgery using integrated approaches that adjust pain scores collected at scheduled follow-up visits for confounding clinical events occurring between visits. Methods. Data were derived from an RCT of a bone-anchored annular closure device (ACD) following lumbar discectomy versus lumbar discectomy alone (Control) in patients with large postsurgical annular defects. Leg pain was recorded on a 0 to 100 scale at 6 weeks, 3 months, 6 months, 1 year, and 2 years of follow-up. Patients with pain reduction ≥20 points relative to baseline were considered responders. Unadjusted analyses utilized pain scores reported at follow-up visits. Since symptomatic reherniation signifies clinical failure of lumbar discectomy, integrated analyses adjusted pain scores following a symptomatic reherniation by baseline observation carried forward for continuous data or classification as nonresponders for categorical data. Results. Among 550 patients (272 ACD, 278 Control), symptomatic reherniation occurred in 10.3% of ACD patients and in 21.9% of controls (p < 0.001) through 2 years. There was no difference in leg pain scores at the 2-year visit between ACD and controls (12 versus 14; p = 0.33) in unadjusted analyses, but statistically significant differences favoring ACD (19 versus 29; p < 0.001) in integrated analyses. Unadjusted nonresponder rates were 6.0% with ACD and 6.7% with controls (p = 0.89), but 15.7% and 27.8% (p = 0.001) in integrated analyses. The probability of nonresponse was 16.4% with ACD and 18.3% with controls (p = 0.51) in unadjusted analysis, and 23.7% and 31.2% (p = 0.04) in integrated analyses. Conclusion. In an RCT of lumbar disc surgery, an integrated analysis of pain severity that adjusted for the confounding effects of clinical failures occurring between follow-up visits resulted in different conclusions compared to an unadjusted analysis of pain scores reported at follow-up visits only.

Highlights

Long-term follow-up in clinical trials is mandatory for monitoring the safety and efficacy of chronic pain treatments
Data were derived from a multicenter randomized controlled trial intended to determine whether implantation of a bone-anchored annular closure device (ACD) in patients with a large annular defect following lumbar discectomy reduced the risk of recurrent herniation compared to lumbar discectomy alone
The frequency of symptomatic reherniation was lower with ACD versus controls (10.3% versus 21.9%; p < 0.001) through 2 years

Summary

Introduction

Long-term follow-up in clinical trials is mandatory for monitoring the safety and efficacy of chronic pain treatments. Longer follow-up periods increase the likelihood for missing data, patient withdrawal, and clinical events that may confound data interpretation. Numerous analytic approaches are available to deal with missing data (e.g., multiple imputation, last observation carried forward, baseline observation carried forward [BOCF], and nonresponder imputation) and their comparative performance and recommendations for use are well-documented [1,2,3]. Methods to adjust existing data for confounding clinical events have received considerably less attention. For example, a clinical trial of lumbar disc surgery with annual follow-up visits for 5 years.

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