Surgical versus Nonsurgical Treatment for Lumbar Degenerative

Surgical versus Nonsurgical Treatment for Lumbar Degenerative Spondylolisthesis James N. Weinstein, D.O., Jon D. Lurie, M.D., Tor D. Tosteson, Sc.D., Brett Hanscom, M.S., Anna N.A. Tosteson, Sc.D., Emily A. Blood, M.S., Nancy J.O. Birkmeyer, Ph.D., Alan S. Hilibrand, M.D., Harry Herkowitz, M.D., Frank P. Cammisa, M.D., Todd J. Albert, M.D., Sanford E. Emery, M.D., M.B.A., Lawrence G. Lenke, M.D., William A. Abdu, M.D., Michael Longley, M.D., Thomas J. Errico, M.D., and Serena S. Hu, M.D.* From the Departments of Orthopaedics (J.N.W., B.H., E.A.B., W.A.A.), Medicine (J.D.L., A.N.A.T.), and Community and Family Medicine (J.N.W., T.D.T., A.N.A.T.), Dartmouth Medical School, Lebanon, NH; the University of Michigan, Ann Arbor (N.J.O.B.); the Rothman Institute at Thomas Jefferson University, Philadelphia (A.S.H., T.J.A.); William H. Beaumont Hospital, Royal Oak, MI (H.H.); the Hospital for Special Surgery, New York (F.P.C.); the University Hospitals of Cleveland and Case Western Reserve University, Cleveland (S.E.E.); Washington University, St. Louis (L.G.L.); the Nebraska Foundation for Spinal Research, Omaha (M.L.); the Hospital for Joint Diseases, New York (T.J.E.); and the University of California at San Francisco, San Francisco (S.S.H.). Abstract BACKGROUND—Management of degenerative spondylolisthesis with spinal stenosis is controversial. Surgery is widely used, but its effectiveness in comparison with that of nonsurgical treatment has not been demonstrated in controlled trials. METHODS—Surgical candidates from 13 centers in 11 U.S. states who had at least 12 weeks of symptoms and image-confirmed degenerative spondylolisthesis were offered enrollment in a randomized cohort or an observational cohort. Treatment was standard decompressive laminectomy (with or without fusion) or usual nonsurgical care. The primary outcome measures were the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) bodily pain and physical function scores (100-point scales, with higher scores indicating less severe symptoms) and the modified Oswestry Disability Index (100-point scale, with lower scores indicating less severe symptoms) at 6 weeks, 3 months, 6 months, 1 year, and 2 years. RESULTS—We enrolled 304 patients in the randomized cohort and 303 in the observational cohort. The baseline characteristics of the two cohorts were similar. The one-year crossover rates were high in the randomized cohort (approximately 40% in each direction) but moderate in the observational cohort (17% crossover to surgery and 3% crossover to nonsurgical care). The intention-to-treat analysis for the randomized cohort showed no statistically significant effects for the primary outcomes. The as-treated analysis for both cohorts combined showed a significant advantage for surgery at 3 months that increased at 1 year and diminished only slightly at 2 years. The treatment effects at 2 years were 18.1 for bodily pain (95% confidence interval [CI], 14.5 to 21.7), 18.3 for physical function (95% CI, 14.6 to 21.9), and −16.7 for the Oswestry Disability Index (95% CI, −19.5 to −13.9). There was little evidence of harm from either treatment. CONCLUSIONS—In nonrandomized as-treated comparisons with careful control for potentially confounding baseline factors, patients with degenerative spondylolisthesis and spinal stenosis treated Address reprint requests to Dr. Weinstein at SPORT@dartmouth.edu.. *Other investigators participating in the Spine Patient Outcomes Research Trial (SPORT) are listed in the Appendix NIH Public Access Author Manuscript N Engl J Med. Author manuscript; available in PMC 2008 September 26. Published in final edited form as: N Engl J Med. 2007 May 31; 356(22): 2257–2270. doi:10.1056/NEJMoa070302. N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript surgically showed substantially greater improvement in pain and function during a period of 2 years than patients treated nonsurgically. (ClinicalTrials.gov number, NCT00000409.) Degenerative spondylolisthesis is the slipping forward of one lumbar vertebra on another with an intact neural arch. It rarely occurs before the age of 50 years, and it disproportionately affects women, particularly black women, with a male:female ratio of approximately 1:6.1 Slippage most commonly occurs at the L4–L5 level and rarely exceeds 30% of vertebral width.1 Degenerative spondylolisthesis is generally asymptomatic, but it can be associated with symptomatic spinal stenosis.1 Spinal stenosis, the most common reason for lumbar surgery in adults over the age of 65, is a narrowing of the spinal canal with encroachment on the neural structures by surrounding bone and soft tissue. Patients typically present with neurogenic claudication — pain in the buttocks or legs with walking or standing that resolves with sitting or lumbar flexion. However, anatomical spinal stenosis is frequently detected by imaging studies in asymptomatic patients; thus, clinical correlation between symptoms and imaging is critical.2 Two studies have compared surgery with non-surgical treatment for spinal stenosis, but both of these studies included patients with and those without degenerative spondylolisthesis.3-5 Several studies have compared surgical techniques in cohorts with degenerative spondylolisthesis; however, these studies had small samples with limited geographic participation and lacked nonsurgical controls and validated outcome measures.6-8 The optimal treatment strategy for symptomatic degenerative spondylolisthesis remains unclear. The Spine Patient Outcomes Research Trial (SPORT) was designed to compare the effectiveness of surgical and nonsurgical treatment among participants with confirmed diagnoses of intervertebral disk herniation,9,10 spinal stenosis, and degenerative spondylolisthesis.11 Here we report the 2-year outcomes of patients with degenerative spondylolisthesis. METHODS STUDY DESIGN The SPORT was conducted in 11 states at 13 medical centers in the United States that have multidisciplinary spine practices. The SPORT included both a randomized cohort and a concurrent observational cohort with identical selection criteria and outcomes assessment.12 The standardized protocol was approved by human subjects committees at each participating institution, and an independent data and safety monitoring board monitored the results of the trial. The principal investigator had full access to all the data in the study and takes responsibility for the accuracy and integrity of the data analysis. Additional background information has been published previously.9-11,13 PATIENT POPULATION All patients had neurogenic claudication or radicular leg pain with associated neurologic signs, spinal stenosis shown on cross-sectional imaging, and degenerative spondylolisthesis shown on lateral radiographs obtained with the patient in a standing position. The patients had had persistent symptoms for at least 12 weeks and had been confirmed as surgical candidates by their physicians. Patients with adjacent levels of stenosis were eligible; patients with spondylolysis and isthmic spondylolisthesis were not. The nature of non-surgical care before enrollment was not prespecified but included physical therapy in 68% of patients, epidural injections in 55%, chiropractic treatment in 25%, antiinflammatory agents in 63%, and opioid analgesic agents in 30%. Weinstein et al. Page 2 N Engl J Med. Author manuscript; available in PMC 2008 September 26. N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript Research nurses at each site identified potential participants and verified their eligibility. The patients were offered enrollment in either cohort and gave written informed consent after viewing videotapes explaining the expected benefits, risks, and uncertainties of the treatments. 14,15 Participants in the randomized cohort received computer-generated random treatment assignments blocked according to center; those in the observational cohort chose their treatment with their physician. Enrollment began in March 2000 and ended in February 2005. STUDY INTERVENTIONS The protocol surgery consisted of a standard posterior decompressive laminectomy with or without bilateral single-level fusion (iliac crest bone grafting with or without posterior pedicle- screw instrumentation).11 The nonsurgical protocol was usual care, recommended to include at least active physical therapy, education or counseling including instructions for exercising at home, and nonsteroidal antiinflammatory agents if tolerated.11,13 STUDY MEASURES The primary end points were the Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) bodily pain and physical function scores16-19 and the Oswestry Disability Index (American Academy of Orthopaedic Surgeons/Modems version)20 measured at 6 weeks and at 3, 6, 12, and 24 months after enrollment. Secondary outcomes included patient-reported improvement, satisfaction with current symptoms and care,21 the Stenosis Bothersomeness Index,22,23 and the Low Back Pain Bothersomeness Scale.3 The SF-36 scores range from 0 to 100, with higher scores indicating less severe symptoms; the Oswestry Disability Index ranges from 0 to 100, with lower scores indicating less severe symptoms; the Stenosis Bothersomeness Index ranges from 0 to 24, with lower scores indicating less severe symptoms; and the Low Back Pain Bothersomeness Scale ranges from 0 to 6, with lower scores indicating less severe symptoms. STATISTICAL ANALYSIS A sample size of 150 patients in each treatment group for the randomized cohort was determined as sufficient on the basis of a two-sided t-test with a power of 0.85 to detect a 10- point difference in the SF-36 bodily pain and physical function scores or a similar effect size in the Oswestry Disability Index. The sample size allowed for up to 20% of the data to be missing but did not account for any specific levels of nonadherence. Initial analyses compared baseline characteristics of the patients between the randomized cohort and the observational cohort and between the treatment groups of the combined randomized cohort and the observational cohort. The extent of missing data and the percentage of patients undergoing surgery were calculated for each scheduled follow-up. Baseline predictors of time until surgical treatment in both cohorts (including treatment crossovers) were determined by a stepwise proportional-hazards regression model with an inclusion criterion of P<0.1 to enter and P>0.05 to exit. Predictors of missing follow-up visits at 1 year were determined by stepwise logistic regression with entry and exit criteria of P<0.1 and P>0.05, respectively. Primary analyses compared surgical and non-surgical treatments using changes from baseline at each follow-up time for SF-36 bodily pain and physical function and for the Oswestry Disability Index. The randomized cohort was initially analyzed on an intention-to-treat basis. However, because of the extent of crossover, subsequent analyses combined the randomized cohort and the observational cohort and were based on treatments actually received. In these as-treated analyses, the treatment indicator was a time-varying covariate, allowing for variable times to surgery. Before the time of surgery, all changes from baseline were included in the estimates of the nonsurgical treatment effect. After surgery, subsequent changes in outcomes Weinstein et al. Page 3 N Engl J Med. Author manuscript; available in PMC 2008 September 26. N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript were assigned to the surgical group with follow-up measured from the date of surgery. The randomized cohort and the observational cohort were each analyzed to produce separate as- treated estimates of treatment effect. These results were compared with the use of a Wald test to simultaneously test all follow-up visit times for differences in estimated treatment effects between the randomized and observational groups.24 Subsequent analyses combined the two cohorts. To adjust for potential confounding effects, baseline variables associated with missing data or treatment received were included as covariates in longitudinal regression models.24 A random effect was specified to account for the correlation between the repeated measurements of individual patients. Computations were performed with the use of SAS software (PROC MIXED for continuous data with normal random effects and PROC GENMOD for binary and non-normal secondary outcomes). Statistical significance was defined as P<0.05 on the basis of a two-sided hypothesis test (SAS software, version 9.1). Data for these analyses were collected through October 3, 2006. RESULTS Overall, 607 of 892 eligible participants were enrolled in the SPORT (304 in the randomized cohort and 303 in the observational cohort). A total of 601 patients (99%) completed at least one follow-up visit and were included in the analysis; between 83% and 95% of enrollees supplied data at each follow-up visit (Fig. 1). In the randomized cohort, 159 patients were assigned to surgery and 145 to nonsurgical treatment. Of those assigned to surgery, 57% underwent surgery by 1 year and 64% by 2 years. In the group assigned to nonsurgical care, 44% underwent surgery by 1 year and 49% by 2 years. In the observational cohort, 173 patients initially chose surgery and 130 initially chose nonsurgical care. Of those initially choosing surgery, 97% underwent surgery by 1 year, and one additional patient underwent surgery between 1 and 2 years from the time of enrollment. Of those initially choosing nonsurgical treatment, 17% underwent surgery by 1 year and 25% by 2 years. In both cohorts combined, 372 patients underwent surgery within the first 2 years and 235 received only non-surgical treatment. PATIENT CHARACTERISTICS Table 1 shows the baseline characteristics and clinical findings of participants in the randomized and the observational cohorts. The cohorts were remarkably similar; however, patients in the observational cohort had more L4–L5 involvement, less involvement of L3–L4, and less lateral recess stenosis. Summary statistics for the combined cohorts are also shown in Table 1 according to treatment received; the mean age was 66 years. Eighty-five percent of patients had neurogenic claudication, and 77% had associated dermatomal pain radiation. Most of the degenerative slips and associated stenoses were at L4–L5. On imaging, stenosis was graded as severe in 60% of patients, and 35% had multiple levels of stenosis. At baseline, patients in the group undergoing surgery from the combined randomized and observational cohorts were younger and more likely to be receiving compensation (e.g., workers' compensation or social security) than those receiving nonsurgical treatment. They had worse pain, function, disability, and symptoms than patients in the nonsurgical group. Patients in the surgery group were more dissatisfied with their symptoms and at enrollment more often rated their symptoms as worsening. This observation highlights the need to control for baseline differences in the adjusted models. The final model controlled for the following covariates, selected as described in the Methods section: age, sex, work status, depression, Weinstein et al. Page 4 N Engl J Med. Author manuscript; available in PMC 2008 September 26. N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript osteoporosis, joint problems, duration of current symptoms, reflex deficit, number of moderate or severe stenotic levels, baseline score (for the SF-36, the Oswestry Disability Index, and the Stenosis Bothersomeness Index), and the center where the patient was treated. SF-36 and the Oswestry Disability Index scores were also adjusted for the baseline Stenosis Bothersomeness Index score. Lateral radiographs obtained with the patient in a neutral standing position were available for independent review for 169 patients. The percentage of slip as measured by the method of Morgan and King25 ranged from 1 to 37% (median, 15%; interquartile range, 10 to 21%). Eighty-six percent of patients had grade 1 slip and 14% had grade 2. NONSURGICAL TREATMENTS Nonsurgical treatments used during the SPORT included physical therapy (42%), epidural steroid injections (45%), nonsteroidal antiinflammatory drugs (51%), and opioids (34%). Nonsurgical treatments were similar in the randomized cohort and the observational cohort, though more patients in the randomized cohort reported visits to a surgeon (44% vs. 34%, P = 0.04), receiving injections (49% vs. 37%, P = 0.02), and narcotics use (40% vs. 26%, P = 0.007). SURGICAL TREATMENT AND COMPLICATIONS The median surgical time was 199 minutes, with a mean blood loss of 589 ml (Table 2). There were no significant differences between the cohorts in rates of intraoperative blood replacement, but there was a difference in the postoperative transfusion rates (16% in the randomized cohort vs. 26% in the observational cohort, P = 0.04). The most common surgical complication was dural tear (10%). The 2-year reoperation rate was 12%. MAIN TREATMENT EFFECTS The intention-to-treat analysis of the randomized cohort showed no statistically significant effects for the primary outcomes, on the basis of a global hypothesis test for differences in mean changes from baseline between the treatment groups including all time periods. Treatment effects at 2 years were 1.5 for SF-36 bodily pain (95% confidence interval [CI], −4.2 to 7.3; P = 0.52), 1.9 for physical function (95% CI, −3.7 to 7.5; P = 0.71), and 2.2 for the Oswestry Disability Index (95% CI, −2.3 to 6.8; P = 0.68). As-treated effects for the combined cohorts were statistically significant in favor of surgery for all primary and secondary outcomes (Table 3 and Fig. 2). Treatment effects were stable for 2 years and were significant for all time periods, with treatment effects at 2 years of 18.1 for SF-36 bodily pain (95% CI, 14.5 to 21.7), 18.3 for physical function (95% CI, 14.6 to 21.9), and −16.7 for the Oswestry Disability Index (95% CI, −19.5 to −13.9). The results of the intention-to-treat and the as-treated analyses of the randomized and the observational cohorts are compared in Figure 2. The as-treated treatment effects at 2 years were nearly identical in the randomized and the observational cohorts. For SF-36 bodily pain, the effect was 17.8 (95% CI, 12.5 to 23.0) in the randomized cohort as compared with 18.5 (95% CI, 13.4 to 23.6) in the observational cohort; for SF-36 physical function, the effect was 16.7 (95% CI, 11.4 to 22.1) in the randomized cohort as compared with 19.9 (95% CI, 14.8 to 24.9) in the observational cohort; and for the Oswestry Disability Index, the effect was −15.9 (95% CI, −20.2 to −11.7) in the randomized cohort as compared with −17.7 (95% CI, −21.6 to −13.7) in the observational cohort. The global hypothesis test comparing the treatment effects in the randomized and the observational cohorts over all time periods revealed no significant difference between the cohorts: P = 0.29 for SF-36 bodily pain, P = 0.28 for SF-36 physical function, and P = 0.97 for the Oswestry Disability Index. Weinstein et al. Page 5 N Engl J Med. Author manuscript; available in PMC 2008 September 26. N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript SUBGROUP ANALYSES Models fitted for selected subgroups were examined for evidence of modification of treatment efficacy. Participants less than 65 years old at baseline had larger treatment effects in favor of surgery at 3 months (21.3 vs. 14.6 for bodily pain, P = 0.02) but not at 1 or 2 years. The treatment effect for a degenerative spondylolisthesis level of L3–L4 was larger than that for a level of L4–L5 (33.1 vs. 16.8 for SF-36 bodily pain, P = 0.01) at