RESEARCH HUMAN CLINICAL STUDIES

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1 TOPIC RESEARCH HUMAN CLINICAL STUDIES RESEARCH HUMAN CLINICAL STUDIES Jau-Ching Wu, MD* Laura Liu, MD Wen-Cheng Huang, MD, PhD* Yu-Chun Chen, MD, MSc Chin-Chu Ko, MD* Ching-Lan Wu, MD # Tzeng-Ji Chen, MD, PhD** Henrich Cheng, MD, PhD* Tung-Ping Su, MD *Department of Neurosurgery, Neurological Institute; #Department of Radiology; Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine; Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan; kdepartment of Ophthalmology, Chang-Gung Memorial Hospital, Linko, Taiwan; Department of Medical Informatics, Institute for Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany; **Institute of Hospital and Health Care Administration, School of Medicine, National Yang-Ming University,Taipei, Taiwan Correspondence: Yu-Chun Chen, MD, MSc, Institute for Medical Biometry and Informatics, Department of Medical Informatics, Heidelberg University, Im Neuenheimer Feld 305, Heidelberg 69120, Germany. cbrain@self.twmail.cc or Yu-Chun.Chen@med.uni-heidelberg.de Received, November 8, Accepted, July 13, Published Online, August 19, Copyright ª 2011 by the Congress of Neurological Surgeons The Incidence of Adjacent Segment Disease Requiring Surgery After Anterior Cervical Diskectomy and Fusion: Estimation Using an 11-Year Comprehensive Nationwide Database in Taiwan BACKGROUND: The incidence of symptomatic adjacent segment disease (ASD) after anterior cervical diskectomy and fusion (ACDF) was reported as 2.9%/y in a previous cohort of 374 patients. Few other data corroborate the incidence and natural history of ASD. OBJECTIVE: To calculate the incidence of ASD after ACDF that required secondary fusion surgery. METHODS: The retrospective study used an 11-year nationwide database to analyze the incidences. All patients who underwent ACDF for cervical disk diseases were identified through diagnostic and procedure codes. Kaplan-Meier and Cox regression analyses were performed. RESULTS: From 1997 to 2007, covering person-years, patients received ACDF and 568 had $ 2 ACDF operations. The incidence of secondary ACDF operations was 7.6 per 1000 person-years. At the end of the 10-year cohort, 94.4% of patients who had received 1 ACDF remained free from secondary ACDF. The average time interval between the first and second ACDF was 23.3 months. After adjustment for comorbidities and socioeconomic status, secondary ACDF operations were more likely performed on male patients (hazard ratio = 1.27; P =.008) 15 to 39 years of age (hazard ratio = 1.45; P =.009) and 40 to 59 years of age (hazard ratio = 1.41, P =.002, respectively). CONCLUSION: Repeat ACDF surgery for ASD cumulated steadily in an annual incidence of approximately 0.8%, much lower than the reported incidence of symptomatic ASD. However, at the end of this 10-year cohort, a considerable portion of patients (5.6%) received a second operation. Younger and male patients are more likely to receive such second operations. KEY WORDS: Adjacent segment disease (ASD), Anterior cervical diskectomy and fusion (ACDF), Incidence Neurosurgery 70: , 2012 DOI: /NEU.0b013e318232d4f2 Adjacent segment disease (ASD) after anterior cervical diskectomy and fusion (ACDF) has gained attention in the past decades, although ACDF remains the gold standard surgical treatment of choice. 1-4 Hilibrand et al 5 retrospectively studied 374 patients with 409 ABBREVIATIONS: ACDF, anterior cervical diskectomy and fusion; ASD, adjacent segment disease; NHIRD, National Health Insurance Research Database ACDF operations and reported that repeat surgical intervention was required in 2.9% of patients per year for symptomatic ASD in 10 years. 5 Furthermore, they predicted that 10 years after ACDF, 25.6% of patients would develop ASD, more than two-thirds of whom failed conservative treatment and required additional surgery. Goffin et al 6 followed up 180 patients after ACDF for. 60 months and found that adjacent segment degeneration occurred in 92% of patients. In addition, the severity of deterioration correlated with the time since surgery, but there 594 VOLUME 70 NUMBER 3 MARCH

2 INCIDENCE OF ASD AFTER ACDF was no difference in the incidence of adjacent segment degeneration between patients who underwent ACDF for trauma and those with degenerative disease. 6 In a cadaveric study, intradisk pressures increased in both adjacent segments after simulated experimental C5-C6 fusion. 7 These findings suggest that adjacent segment degeneration is less likely secondary to natural history but is a consequence of altered cervical biomechanics after fusion. Such findings and inferences have led to the popularity of cervical arthroplasty in recent years despite a paucity of evidence supporting its beneficial effect on cervical ASD However, the natural history and actual incidence rate of ASD remain uncertain and lack epidemiologic studies. 1 The National Health Insurance Research Database (NHIRD), as provided by the National Health Research Institutes of Taiwan, is a national database containing 26 million administered insurants accumulated from January 1997 to December Covering 99% of the population, this unique system finances health care for the entire population and offers unrestricted access to any healthcare provider of the patient s choice. Therefore, the statistics gathered represent a sound epidemiologic investigation of disease incidence and use of medical intervention because of its universal coverage. This report used the nationwide data to estimate the incidence of ASD after ACDF in those who received refusion surgery. To date, this is the largest cohort to investigate such an issue. MATERIALS AND METHODS Database The NHIRD included all claims data from Taiwan s National Health Insurance program. This study was exempted from full review by the Institutional Review Board because the NHIRD consisted of deidentified secondary data released to the public for research purposes. Study Sample For the entire 11 years, from January 1, 1997, to December 31, 2007, all inpatient data from the NHIRD were collected for analysis. The total National Health Insurance enrollees consisted of people, and the total observation span included person-years. All subjects who received ACDF were followed up until death or the end of the study period (December 31, 2007). The follow-up for these subjects only was censored at the first occurrence of either of the above 2 events. Identification of ACDF Surgery Diagnosis of every admission was recorded in the NHIRD with the International Classification of Disease, 9th revision. Any hospitalization discharge with the diagnostic code of cervical disk diseases (722.0, 722.4, or ) combined with surgical procedures coded for cervical diskectomy (80.51) in conjunction with anterior spinal fusion (81.00, 81.02, 81.30, 81.32) was considered to be for a patient who received ACDF surgery during the specific admission. Incidences of hospitalization for ACDF surgery were identified as subjects who were followed up for. 1 year and those newly hospitalized with the aforementioned discharge codes within the study period. Those with a documented ACDF surgery before the start of the up-to-standard database follow-up or during its first year were excluded to ensure the first event of ACDF. The date of admission was designated the date of the ACDF incidence. The incidence rates in the study were calculated by the incidence density. Secondary ACDF (Reoperations) In all subjects identified as receiving ACDF surgery, those who received multiple but similar diagnostic and procedure codes with an interval of. 3 months were calculated as receiving a secondary ACDF procedure. Multiple ACDF operations within 3 months were excluded to avoid overestimation of reoperations made for complications or other interferences. Secondary ACDF surgeries at least 3 months apart were considered secondary ACDFs for ASD. Adjustment of Covariates Comorbidities were determined by diagnosis codes of records between 6 weeks before and after the operation date (International Classification of Disease, 9th revision, clinical modification, codes 250.x, 790.2x, or for diabetes mellitus; for hypertension; 391.x, , , or for diseases of the heart; and for cerebrovascular diseases). In addition to demographic factors and comorbidities, socioeconomic factors were considered. The income level of patients (through incomerelated insurance premiums as a proxy for income) was grouped into 4 categories by the premium paid (New Taiwan dollars $ $ , , , and fixed amount). In the National Health Insurance of Taiwan, premiums are determined mostly by the insured wage and premium rate. Thus, a higher premium implies a higher income. Those without salaries such as the unemployed, students, children, and the elderly were designated fixed amount (dependents) by the Bureau of National Health Insurance, and the government or their foster families covered their insurance premiums. According to previous reports using the NHIRD, 14 urbanization levels in Taiwan were divided into 7 strata. Level 1 was referred to as the most urbanized and level 7 as the least urbanized; levels 5 through 7 were combined into a single group and hereafter are referred to as level 5. Statistical Analysis All data were calculated with SPSS software for descriptive statistics and contingency tables (SPSS, Inc, Chicago, Illinois). Kaplan-Meier survival analysis and Cox regression were used. A value of P =.05 was considered statistically significant. RESULTS Incidences During the decade of observation, events of ACDF surgery were identified. Among the primary ACDF surgeries, (58.4%) were in male patients and 8072 (41.6%) were in female patients. By age, patients (55.6%) received the first ACDF surgery at 40 to 59 years of age, whereas 5989 patients (30.9%) were. 60 years of age and 2620 patients (13.5%) were 15 to 39 years of age. Among the ACDF surgeries, 568 patients received a secondary ACDF and 29 received $ 3 ACDFs. Among those with secondary surgery, 367 (64.6%) were male and 201 (35.4%) were female, with 335 (59.0%) 40 to 59 NEUROSURGERY VOLUME 70 NUMBER 3 MARCH

3 WU ET AL TABLE 1. Anterior Cervical Diskectomy and Fusion Events a First ACDF (n = ), n (%) Second ACDF (n = 568), n (%) Sex Female 8072 (41.64) 201 (35.39) Male (58.36) 367 (64.61) Age, y (13.52) 92 (16.20) (55.59) 335 (58.98) $ (30.90) 141 (24.82) a ACDF, anterior cervical diskectomy and fusion. years of age, 141 (24.8%). 60 years of age, and 92 (16.2%) 15 to 39 years of age (Table 1). The overall incidence of cervical disk diseases receiving 1 ACDF was per 1000 person-years. The male specific incidence of the first ACDF surgery was per 1000 person-years, whereas it was 0.081for female patients. The age group. 60 years had the highest incidence of receiving the first ACDF at per 1000 personyears, whereas the age groups of 40 to 59 and 15 to 39 years had lower incidences (0.178 and 0.024, respectively; Table 2). The overall incidence of secondary ACDF in those who received an ACDF was per 1000 person-years (approximately 0.8%). The sex-specific incidence was higher for male than female patients (8.309 vs per 1000 person-years). Moreover, in the 3 age categories, the youngest age group (15-39 years old) had the highest incidence of secondary ACDF at a rate of per 1000 person-years. Those 40 to 59 years of age had an incidence of 8.022, whereas those. 60 years of age had per 1000 person-years (Table 2). Estimated Disease-Free Rate After ACDF Surgery Kaplan-Meier analysis demonstrated that the cumulative incidence of multiple ACDF events increased gradually without abrupt fluctuations, regardless of sex or age (Figure 1). At the end of the 10-year cohort, 94.4% of patients who received 1 ACDF did not need a secondary ACDF operation. The TABLE 2. Incidences of Anterior Cervical Diskectomy and Fusion a Age, Incidence b of First ACDF Incidence c of Second ACDF y Female Male Both Female Male Both All $ a ACDF, anterior cervical diskectomy and fusion. b Per 1000 person-years of the entire population. c Per 1000 person-years of those who received 1 ACDF surgery. average time from the first to the secondary ACDF operation was 23.3 months (Figure 1A). Among patients who received a secondary ACDF, 90.4% did not require a third, and the mean time from the secondary to the third was 19.7 months (Figure 1B). When specified by sex, at the end of the 10-year cohort, the percentage of patients without a secondary ACDF surgery was 94.8% for male and 94.1% for female patients. The percentages were 94.5%, 93.7%, and 95.8% in the age groups 15 to 39, 40 to 59, and. 60 years, respectively (Figures 2A and 2B). Influences of Age and Sex on the Incidence of Secondary ACDF Operations The incidence of a secondary ACDF operation varied by age and sex in this cohort. Multivariate Cox regression analysis showed that secondary ACDF operations were more likely for male patients (adjusted hazard ratio = 1.27) than for female patients with statistical significance (P =.008). Patients 15 to 39 and 40 to 59 years of age were more likely to receive a secondary operation than those. 60 years of age (hazard ratio = 1.45 and 1.41; P =.009 and.002, respectively; Table 3 and Figure 3). Adjustment of Other Systemic Diseases and Socioeconomic Factors Comorbid systemic diseases, including diabetes mellitus, hypertension, cerebrovascular disease, and disease of the heart, had no significant influence on the incidence of a secondary ACDF operation. (hazard ratio = 1.10, 1.17, 1.39, and 1.40; P = 0.523, 0.213, 0.064, and 0.134, respectively). The socioeconomic factors of the patients were analyzed by looking at the insurance amount and urbanization levels. No significant influences on the incidence of a secondary ACDF operation were found among the groups (Table 3). Despite insignificance, a few comorbidities yielded relatively large hazard ratios, which might be worth further studies. DISCUSSION The present report used the largest series of patients to date who were followed up to investigate the reoperation rate after ACDF. Of patients, 568 received repeat ACDF for cervical disk disease. This nationwide retrospective cohort shows a secondary ACDF operation incidence of 7.6 per 1000 person-years. This incidence can be considered the incidence of ASD that required surgical treatment based on repeated diagnosis and procedure codes. Compared with the historical study by Hilibrand et al, 5 which quoted a rate of 2.9%/y for symptomatic ASD, the result here (approximately 0.8%) is only slightly greater than one-fourth of the value reported. However, the previously reported rate of 2.9% includes all symptomatic diseases, regardless of surgical or nonsurgical management. It should be noted that modern imaging techniques can demonstrate a higher incidence of disk degeneration in adjacent segments after ACDF despite 596 VOLUME 70 NUMBER 3 MARCH

4 INCIDENCE OF ASD AFTER ACDF FIGURE 1. Overall Kaplan-Meier analysis. A, at the end of the 10-year cohort, 94.4% of patients remained free from a secondary anterior cervical diskectomy and fusion (ACDF) operation. The average time from the first to the secondary ACDF operation was 23.3 months. B, among patients who received a secondary ACDF, 90.4% remained free from the third, and the mean time from the secondary to third was 19.7 months. NEUROSURGERY VOLUME 70 NUMBER 3 MARCH

5 WU ET AL FIGURE 2. Age- and sex-specific Kaplan-Meier analysis. A, at the end of the 10-year cohort, the percentage of patients free from a secondary anterior cervical diskectomy and fusion surgery was 94.8% in male and 94.1% in female patients. B, for the age groups. 60, 15 to 39, and 40 to 59 years, the percentage was 95.8%, 94.5%, and 93.7%, respectively. 598 VOLUME 70 NUMBER 3 MARCH

6 INCIDENCE OF ASD AFTER ACDF TABLE 3. Risk Analysis of a Second Anterior Cervical Diskectomy and Fusion Operation a Patients Who Received Only 1 ACDF (n = ), n (%) Patients Who Received a Second ACDF (n = 568), n (%) Adjusted Hazard Ratio (95% CI) P Demographic factors Male sex (58.2) 367 (64.6) 1.27 ( ).008 b Age, y (13.4) 92 (16.2) 1.45 ( ).009 b (55.5) 335 (59.0) 1.41 ( ).002 b $ (31.1) 141 (24.8)... Comorbidities Diabetes mellitus 1958 (10.4) 57 (10.0) 1.10 ( ).523 Hypertension 3008 (16.0) 87 (15.3) 1.17 ( ).213 Heart disease 1013 (5.4) 36 (6.3) 1.39 ( ).064 Cerebrovascular disease 570 (3.0) 22 (3.9) 1.40 ( ).134 Socioeconomic factors Insurance amount, New Taiwan dollars $ $ (15.0) 90 (15.8) 1.02 ( ) (37.4) 203 (35.7) 1.06 ( ) (26.6) 178 (31.3) 1.21 ( ).137 Fixed amount 3948 (21.0) 97 (17.1) Urbanization level 1 (Most urbanized) 5064 (26.9) 168 (29.6) 0.82 ( ) (31.8) 165 (29.0) 0.87 ( ) (16.5) 92 (16.2) 0.96 ( ) (15.6) 92 (16.2) 0.90 ( ) (Least urbanized) 1702 (9.0) 50 (8.8) a ACDF, anterior cervical diskectomy and fusion; CI, confidence interval. b Significant. FIGURE 3. Influences of age and sex on the incidence of adjacent segment disease (ASD). Predicted hazard ratio of ASD as a fitted Cox regression model of age at first anterior cervical diskectomy and fusion (ACDF) surgery for male (solid line) and female (solid dashed line) patients. Female patients $ 60 years of age at their first ACDF surgery were used as reference. symptoms. 15 Various clinical reports address the existence of ASD after ACDF, with either symptomatic clinical presentation or asymptomatic radiographic evidence at different occurrence rates. 5,16-18 The incidence reported in the present study included only those who actually received a secondary ACDF surgery, which is considered the most clinically relevant end point of ASD. Furthermore, the cultural preference in Asian countries to delay surgery until relatively late or at a clinically disabling status further lowers the rate of surgery, or at least prolongs the time of conservative treatment. This culture-related reluctance to undergo surgery has been reported for a few diseases Taking into the account the aforementioned causes, the incidence of reoperation after ACDF reported here, 7.6 per 1000 personyears, appears to be a very reasonable and practical estimation of clinically significant ASD necessitating reoperation. The present cohort contained all subaxial ACDF surgeries carried out in multiple centers in the entire country. The universal coverage of Taiwan s health insurance, supported by the government, provides unrestricted access to medical services from any healthcare provider for every patient. Therefore, any repeat surgery after the first ACDF within the follow-up period cannot escape the cohort, except for those carried out abroad. Thus, the uniquely comprehensive feature of the database enhances the accuracy and representation of the estimation of NEUROSURGERY VOLUME 70 NUMBER 3 MARCH

7 WU ET AL disease incidences. 14 Although it appears low compared with the value of Hilibrand et al, it can never overestimate the true number of reoperations for ASD after ACDF. The completeness of follow-up and well-executed Kaplan-Meier analysis are the merits of this report. This report demonstrates that younger patients have higher risks for secondary ACDF surgery, which also supports the observation of accelerated cervical disk degeneration on the adjacent segment after anterior fusion. 15 Of those who receive ACDF, 94.4% do not require a secondary operation at the end of a 10-year follow-up (Figure 1A). In other words, approximately 5.6% of patients who receive a first ACDF will eventually require a secondary additional surgery in the next 10 years, and of them, 9.6% will need a third one. The incidence of secondary ACDF is high enough to be statistically significant (P..05) to justify the development of new treatment strategies. Those who underwent ACDF and were, 60 years of age had an even higher risk of approximately 1.3 times (Table 3) that for patients. 60 years of age. One of the major rationales for applying currently available cervical artificial disks is to decrease or defer the occurrence of ASD. 3,10,22,23 Numerous devices have undergone clinical trials to prove their safety and efficacy compared with ACDF However, because of the relatively short follow-up period currently available in the literature, none of these trials has provided sufficient evidence of the efficacy of the avoidance of ASD by cervical arthroplasty. 12,13,24-26 Nevertheless, ACDF itself can predispose to future ACDF, which is proven in the present study. Whether cervical arthroplasty or other motion preservation strategies can solve the problem of ASD is beyond the scope of this study. Such an issue requires large-scale investigations, homogenously performed cervical arthrodesis, and long-term follow-up. There are limitations to this study. First, we used the assumption that the reoperation of ACDF is a consequence of ASD. Second, it is impossible to look into the details of each operative note to clarify the grafting material, instrumentation, and how many and which levels were fused in each ACDF operation in such a large database study. The NHIRD does not include detailed operative notes. Thus, the results reported here are a blend of calculations of all single-level and multilevel ACDF surgeries. The estimation is based on counting the events of multiple ACDF as for ASD, disregarding the number of vertebrae that underwent arthrodesis. However, there are only at most 6 disk levels in the subaxial cervical spine to fuse or at which ASD usually develops. Thus, more levels that fuse lead to a smaller number of levels for ASD to develop. Theoretically, more levels that fuse alter more biomechanical strength. The counterbalance of the 2 aforementioned factors can, to some extent, minimize the bias. Likewise, the ACDFs here were not divided into subgroups by graft materials, instrumentation, and causes of disk diseases. The variation of fusion rates should not alter the incidence of reoperation because, in most reports, the current ACDF technique yields fusion rates of around 95%. 18,27-30 However, the present report is the first to demonstrate the actual reoperation rate of ACDF in a cohort of patients. With the use of reoperations, the most clinically relevant end point of ASD, the estimation practically reflects the ASD of clinical significance. The study provides a different viewpoint for looking at the problem of ASD. The nationwide survey of the incidence of multiple ACDF in a span of more than a decade offers realistic statistics of the prevalence of ACDF reoperations, which can be helpful in understanding the natural history of cervical degenerative disk diseases. CONCLUSION In this large cohort, repeat ACDF surgery for ASD cumulated steadily for an annual incidence of approximately 0.8%. This is remarkably lower than the reported incidence of symptomatic ASD. At the end of the 10-year cohort, a considerable portion of patients (5.6%) underwent reoperation for ASD. Male and younger patients (, 60 years of age) were more likely to undergo reoperations. Disclosure The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. This study was based partly on data from the National Health Research Institutes database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes in Taiwan. The interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, the Department of Health, or the National Health Research Institutes. REFERENCES 1. Javedan SP, Dickman CA. 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J Neurosurg Spine. 2008;8(6): COMMENTS Overall, this article adds nicely to the literature on the incidence of adjacent segment degeneration (ASD) after anterior cervical diskectomy and fusion (ACDF). The use of a National Insurance Database, which captures the vast majority of a constrained population (the entire population of Taiwan in this instance), allows the authors to capture nearly all surgical procedures during the time period (excepting the small numbers that may have potentially left the country for surgery elsewhere). This large number, nearly patients with an index ACDF procedure, far exceeds the prior published reports, with a reported rate of reoperation 0.8%/y. However, this same database limits the quality of the interpretation by the authors. The authors correctly point out that they cannot analyze the details of the index surgery in terms of the number of levels treated, type of instrumentation used, or type of graft used. They also have not analyzed the indication for surgery: neck pain, radiculopathy, myelopathy, degenerative disease, infection, or trauma. Furthermore, although the authors can accurately state the incidence of a second operation during the 10-year period, they cannot delve into these data to ascertain whether this is at an adjacent level, a distal level, or even the same level (eg, for treatment of pseudoarthrosis). The authors limited their analysis of second operations to those that occurred. 3 months after the index surgery to reduce capturing reoperations at the same level, but this does not exclude this occurrence. 3 months out. Similarly, as the authors have pointed out, they cannot determine the incidence of symptomatic ASD, only the incidence of a second surgery in the subject population. It is very likely that the rate of symptomatic ASD is higher because not all patients with even symptomatic ASD will decide on a second surgery. Even with these drawbacks of analyzing this National Insurance Database, the 0.8% annual incidence of second ACDF surgery in a constrained population of patients undergoing index ACDF is an important addition to the literature. Neill M. Wright St. Louis, Missouri Although this study has significant limitations, which are highlighted by the authors, it has good computed incidence rates, which, together with use of Kaplan-Meier and Cox regression analysis for determining the risk of adjacent segment disease, make this a well-executed epidemiological study. Narendra Nathoo Ehud Mendel Columbus, Ohio This excellent work proves that the rate of adjacent segment degeneration is highly overestimated in the literature. Therefore, the benefit of dynamic restabilization of cervical motion segments has to be reconsidered with respect to its probable effect on adjacent segment degeneration. T.M. Markwalder Bern, Switzerland NEUROSURGERY VOLUME 70 NUMBER 3 MARCH