Abstracts

INTRODUCTION

In cases of symptomatic radiculopathy and myelopathy caused by degenerative disc disease, anterior cervical discectomy and fusion (ACDF) surgery is a standard treatment.¹1. Brodke DS, Zdeblick TA. Modified Smith-Robinson procedure for anterior cervical discectomy and fusion. Spine (Phila Pa 1976). 1992;17(Suppl 10):S427-30.

2. Brown JA, Havel P, Ebraheim N, Greenblatt SH, Jackson WT. Cervical stabilization by plate and bone fusion. Spine (Phila Pa 1976). 1988;13(3):236-40.

3. Cummins BH, Robertson JT, Gill SS. Surgical experience with an implanted artificial cervical joint. J Neurosurg. 1998;88(6):943-8.

4. Fraser JF, Härtl R. Anterior approaches to fusion of the cervical spine: a metaanalysis of fusion rates. J Neurosurg Spine. 2007;6(4):298-303. ^{- 5}5. Zindrick M, Harris MB, Humphreys SC, O'Leary PT, Schneiderman G, Watters WC 3rd, et al. Cervical disc arthroplasty. J Am Acad Orthop Surg. 2010;18(10):631-7. However, ACDF has demonstrated prompting of hypermobility and heightened intradiscal pressures at adjacent levels due to the elimination of natural motion at treated segments.⁶6. DiAngelo DJ, Roberston JT, Metcalf NH, McVay BJ, Davis RC. Biomechanical testing of an artificial cervical joint and an anterior cervical plate. J Spinal Disord Tech. 2003;16(4):314-23.

7. Dmitriev AE, Cunningham BW, Hu N, Sell G, Vigna F, McAfee PC. Adjacent level intradiscal pressure and segmental kinematics following a cervical total disc arthroplasty: an in vitro human cadaveric model. Spine (Phila Pa 1976). 2005;30(10):1165-72.

8. Elsawaf A, Mastronardi L, Roperto R, Bozzao A, Caroli M, Ferrante L. Effect of cervical dynamics on adjacent segment degeneration after anterior cervical fusion with cages. Neurosurg Rev. 2009;32(2):215-24. ^{- 9}9. Matsunaga S, Kabayama S, Yamamoto T, Yone K, Sakou T, Nakanishi K. Strain on intervertebral discs after anterior cervical decompression and fusion. Spine (Phila Pa 1976). 1999;24(7):670-5. In ACDF patients, the altered stress and motion profiles are considered a primary cause for adjacent segment degeneration.¹⁰10. Hilibrand AS, Carlson GD, Palumbo MA, Jones PK, Bohlman HH. Radiculopathy and myelopathy at segments adjacent to the site of a previous anterior cervical arthrodesis. J Bone Joint Surg Am. 1999;81(4):519-28.

11. Kulkarni V, Rajshekhar V, Raghuram L. Accelerated spondylotic changes adjacent to the fused segment following central cervical corpectomy: magnetic resonance imaging study evidence. J Neurosurg. 2004 Jan;100(1 Suppl Spine):2-6. ^{- 12}12. Robertson JT, Papadopoulos SM, Traynelis VC. Assessment of adjacent-segment disease in patients treated with cervical fusion or arthroplasty: a prospective 2-year study. J Neurosurg Spine. 2005;3(6):417-23. Total disc replacement (TDR) maintains natural motion of treated segments and overall cervical spine biomechanics, thus TDR may avoid heightened adjacent segment degeneration and its symptoms while still providing necessary mechanical stability after neural decompression.¹³13. Hsu WK. The rationale for cervical disc arthroplasty. Tech Orthop. 2010;25:84-7 ^{, 14}14. Pracyk JB, Traynelis VC. Treatment of the painful motion segment: cervical arthroplasty. Spine (Phila Pa 1976). 2005;30(Suppl 16):S23-32. In comparing TDR and ACDF treatment at two contiguous levels, clinical data is minimally available. This prospectively controlled clinical study presents the largest known cohort of randomized patients treated at two contiguous levels with TDR in comparison to ACDF.

The Mobi-C^(r) Cervical Artificial Disc (LDR Medical; Troyes, France) is a semi-constrained, mobile bearing, bone sparing TDR evaluated in a prospective, randomized, controlled FDA investigational device exemptions (IDE) trial. (Figure 1) Previous two-year follow-up results¹⁵15. Davis RJ, Kim KD, Hisey MS, Hoffman GA, Bae HW, Gaede SE, et al. Cervical total disc replacement with the Mobi-C cervical artificial disc compared with anterior discectomy and fusion for treatment of 2-level symptomatic degenerative disc disease: a prospective, randomized, controlled multicenter clinical trial: clinical article. J Neurosurg Spine. 2013;19(5):532-45. have demonstrated specific clinical advantages of TDR as a safe and effective alternative to ACDF for indicated patients. Two-year results have also shown statistically improved pain and functional outcomes for two-level TDR.¹⁵15. Davis RJ, Kim KD, Hisey MS, Hoffman GA, Bae HW, Gaede SE, et al. Cervical total disc replacement with the Mobi-C cervical artificial disc compared with anterior discectomy and fusion for treatment of 2-level symptomatic degenerative disc disease: a prospective, randomized, controlled multicenter clinical trial: clinical article. J Neurosurg Spine. 2013;19(5):532-45. These clinical advantages are also supported by extensive Outside the United States (OUS) experience with TDR.¹⁶16. Huppert J, Beaurain J, Steib JP, Bernard P, Dufour T, Hovorka I, et al. Comparison between single-and multi-level patients: clinical and radiological outcomes 2 years after cervical disc replacement. Eur Spine J. 2011;20(9):1417-26. Here, we test the hypothesis that the enhanced clinical outcomes for two-level TDR at two years will be sustained through three years. Clinical Trial Registration no: NCT00389597 (ClinicalTrials.gov).

MATERIALS AND METHODS

Subjects and Study Design

A complete description of the study design and surgical technique was previously reported.¹⁵15. Davis RJ, Kim KD, Hisey MS, Hoffman GA, Bae HW, Gaede SE, et al. Cervical total disc replacement with the Mobi-C cervical artificial disc compared with anterior discectomy and fusion for treatment of 2-level symptomatic degenerative disc disease: a prospective, randomized, controlled multicenter clinical trial: clinical article. J Neurosurg Spine. 2013;19(5):532-45. As part of the FDA IDE randomized and controlled clinical trial, patient surgeries occurred between April 2006 and March 2008 at 24 clinical sites in the U.S. Requirements for the study included a diagnosis of DDD with radiculopathy or myeloradiculopathy at two contiguous levels from C3 to C7 that was unresponsive to non-operative treatment for at least six weeks or demonstrated progressive symptoms calling for immediate surgery. (Table 1) Prior cervical spine surgery was an exclusion criterion. (Table 2) Patients gave informed consent and were randomized in a 2:1 ratio (TDR: ACDF); 225 patients received treatment with a Mobi-C^(r) Cervical Artificial Disc and 105 patients received corticocancellous allograft and an anterior cervical plate using the standard ACDF technique. The Primary Analysis Population includes the TDR and ACDF randomized population for a total of 330 patients. In addition, 9 patients were used for training cases and treated with the TDR device. The Safety Population includes the 330 randomized patients and 9 TDR training patients for a total of 339 patients. While surgeons could not be blind to the treatment, patients were blinded until after surgery.

The treating surgeon possessed discretion over post-operative care and each patient went through a rehabilitation program intended to help the patient return to normal activity as soon as possible. Patients were evaluated pre-operatively and at 6 weeks, 3 months, 6 months, 12 months, 18 months, 24 months, and 36 months post-operatively. From one week before surgery to 3 months post-surgery, groups were asked to refrain from taking non-steroidal anti-inflammatory drugs (NSAIDs) with the exception of TDR patients diagnosed with heterotopic ossification (HO) after surgery.

Clinical Outcomes

Measures used to evaluate pain, function, patient satisfaction, and overall clinical success outcomes included: neck disability index (NDI), visual analogue scale (VAS) neck and arm pain, SF-12 Mental Component Score (MCS) and SF-12 Physical Component Score (PCS), subsequent surgical intervention, complications, neurologic function, return to work, radiographic success, patient satisfaction, range of motion (ROM), HO, and adjacent segment degeneration. All radiographic evaluations were conducted by independent radiologists and validated software through Medical Metrics, Inc. (MMI, Houston, TX).¹⁷17. Reitman CA, Hipp JA, Nguyen L, Esses SI. Changes in segmental intervertebral motion adjacent to cervical arthrodesis: a prospective study. Spine (Phila Pa 1976). 2004;29(11):E221-6. Adjacent segment degeneration was evaluated on the Kellgren-Lawrence scale of disc degeneration.¹⁸18. Croft P. An introduction to the Atlas of Standard Radiographs of Arthritis. Rheumatology (Oxford). 2005;44(Suppl 4):iv42. ^{, 19}19. Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957;16(4):494-502. All adverse effects (AEs) were measured and classified by the clinical events committee (CEC), composed of a neurosurgeon and two orthopedic surgeons. AEs were defined as any clinically adverse sign, symptom, syndrome, or illness that occurred or worsened during or after the initial surgery, regardless of cause.

Neurologic function was evaluated by the investigator through: reflex assessments at the treated levels, motor assessments, pin prick and light touch sensory function assessments. Neurologic success was defined as the absence of significant neurologic deterioration.

Patient satisfaction was determined by a questionnaire asking patients if they were very satisfied, somewhat satisfied, somewhat dissatisfied, or very dissatisfied with their treatment. In addition, patients were asked if they would definitely, probably, probably not or definitely not recommend the same treatment to a friend with the same symptoms and indications.

Subsequent surgical intervention was considered to be any secondary surgery of removal, revision, supplemental fixation or reoperation at an index level segment. Adjacent level subsequent surgeries not involving a treated level were recorded for further investigation but did not indicate a study failure. Radiographic success for the ACDF group was characterized as fusion of both treated levels; less than 2° of angular motion in flexion/extension and indication of bridging bone across the disc space and radiolucent lines at no more than 50% of the graft vertebral interfaces. Radiographic success for the TDR group was characterized as at least 2° angular motion in flexion/extension or no indication of bridging trabecular bone across the disc space. ROM was evaluated by lateral flexion/extension and AP right/left lateral bending radiographs at treated levels.

A composite endpoint was established with multiple conditions including: 1) ≥30 point improvement for patients with baseline

NDI ≥ 60 or 50% improvement for patients with baseline NDI <60; 2) no subsequent surgical intervention at either treated level; 3) AEs assessed by the CEC as major complications; 4) maintenance or improvement in neurologic function; 5) radiographic success. These outcome metrics determined overall success rates for both treatments. For this study, patient failure was considered as not meeting one or more of these five outcome metrics. The overall success component has been previously specified in greater detail.¹⁵15. Davis RJ, Kim KD, Hisey MS, Hoffman GA, Bae HW, Gaede SE, et al. Cervical total disc replacement with the Mobi-C cervical artificial disc compared with anterior discectomy and fusion for treatment of 2-level symptomatic degenerative disc disease: a prospective, randomized, controlled multicenter clinical trial: clinical article. J Neurosurg Spine. 2013;19(5):532-45.

Statistical Methods

A non-inferiority hypothesis was presented in this study to compare the overall success rates of the investigational and control procedures. An exact 95% one-sided confidence bound was used to determine non-inferiority. A post-hoc test assessed superiority in the event of non-inferiority. A 97.5% one-sided confidence bound was used to determine superiority if a 10% non-inferiority margin could be excluded.

Two-sided t-tests were used to assess statistical significance between groups for each continuous outcome measure at each time points. Fisher's exact tests were used to assess success or incident rates. Wilcoxon signed-rank tests were used to evaluate changes from baseline within treatment groups. Statistical significance was determined by a p-value less than 0.05.

RESULTS

Patient Accountability and Baseline Demographics

Three hundred thirty patients were enrolled and randomly assigned to either the TDR or ACDF group.Two hundred twenty five TDR patients and 105 ACDF patients underwent surgery. In addition, 9 patients underwent TDR surgeries as training cases; these patients received a TDR procedure but are not included in the randomized population. Only the randomized population comparisons are presented in the results. There were no significant statistical or clinical differences between baseline demographics of each group. (Table 3) The 36 month follow-up rate was 89.1% for the TDR group and 79.5% for the ACDF group.

NDI

Mean NDI scores were similar at baseline and both TDR and ACDF groups showed significant NDI improvement through 36 months (p<0.0001). In comparison to the ACDF group, the TDR group showed significantly greater NDI score improvement at each time point through 36 months. (Figure 2) The mean improvement in NDI score was 37.2 ± 20.7 for the TDR group and 26.9 ± 18.1 for the ACDF group at 36 months (p = 0.0002). NDI success rate was also significantly higher for TDR in comparison to ACDF at each time point (p<0.05). At 36 months, the TDR success rate was 80.2% while the ACDF success rate was 56.6% (p<0.0001).

VAS Neck and Arm Pain

VAS neck and arm pain scores were similar for TDR and ACDF groups at baseline and both groups showed significant improvement in both measures through 36 months (p<0.0001). At each post-operative time point, the TDR group had lower VAS neck pain scores. (Figure 3A) Notable statistical significant differences were demonstrated by the TDR group at 3 and 6 month time points. The mean improvement in VAS neck pain score from baseline at 36 months was 54.1 ± 28.9 for the TDR group and 46.5 ± 28.0 for the ACDF group. Mean VAS arm pain scores (Figure 3B) originate from the most symptomatic arm at baseline and continue through the 36 month time point. The mean improvement from baseline in VAS arm pain score was similar between groups with 57.0 ± 32.1 for TDR patients and 54.7 ± 29.7 for ACDF patients.

SF-12 MCS and PCS

Both the TDR and ACDF groups had similar and significant SF-12 MCS improvement from baseline through the 36 month follow-up period (p<0.0001). At 36 months, the mean SF-12 MCS score improvement from baseline was 9.3 ± 13.4 for the TDR group and 6.7 ± 14.0 for the ACDF group. (Figure 4A) Also, significant improvements in SF-12 PCS scores were shown in both groups through 36 months (p<0.0001) At each time point through the 36 month follow-up, the TDR group showed significantly greater improvement from baseline in SF-12 PCS scores in comparison to the ACDF group. (Figure 4B) At 36 months, the mean improvement from baseline SF-12 PCS scores was 14.1 ± 11.2 for the TDR group and 9.6 ± 12.0 for the ACDF group (p<0.05).

Neurologic Success

When evaluating neurologic deterioration, TDR and ACDF groups showed similar scores at baseline and there was no statistical significance at 36 months. At the 36 month follow-up point, 7.1% of TDR and 6.7% of ACDF patients experienced neurologic deterioration.

Return to work

For working patients (TDR = 139, ACDF = 60), time to return to work was calculated as the time from the date of surgery until the date the patient started working again. Average return to work time was 46 ± 101 days for TDR patients and 67 ± 113 days for ACDF patients. While this difference is not statistically significant, on average TDR patients return to work 21 days earlier.

Patient Satisfaction

The percentage of patients "very satisfied" or "somewhat satisfied" with their treatment was 94.4% of TDR patients and 93.3% of ACDF patients at 36 months (NS). At 36 months a statistically greater number of TDR patients (96.9%) compared to ACDF patients (88.0%) said they would "definitely recommend" or "probably recommend" the same treatment to a friend (p < 0.05).

Major Complications

AE's were major complications in 4.0% of TDR patients and 6.7% of ACDF patients at 36 months, as deemed by the CEC. No statistical significance was found for the difference between groups.

Subsequent Surgical Intervention

Post-operatively, symptomatic pseudarthrosis was the most common reason for subsequent surgery in the ACDF group as was seen in 8.6% of ACDF patients. TDR removal resulted from stenosis, device migration, poor endplate fixation, and persistent neck and/or shoulder pain. The cumulative rate of patients with subsequent surgeries at the index level was statistically lower in the TDR group at the 36 month follow-up point (p<0.0001). The subsequent surgery rate was 3.1% for the TDR group (7 patients, 9 surgeries) and 13.3% for the ACDF group (14 patients, 15 surgeries).

Radiographic Outcomes

ROM remained near baseline in flexion/extension (Figure 5A) and lateral bending (Figure 5B) at both segments for the TDR group. The mean ROM at the superior level was 10.1 ± 6.1º in flexion/extension (baseline: 9.1 ± 4.9º) and 5.3 ± 3.5º in lateral bending (baseline: 5.8 ± 3.4º) at 36 months for TDR patients. Also, the mean ROM at the inferior level was 8.2 ± 5.0º in flexion/extension (baseline: 7.4 ± 4.3º) and 5.5 ± 3.6º in right/left lateral bending (baseline: 4.9 ± 3.3) at 36 months for TDR patients.

At the 36 month time point, 12 TDR patients and 11 of ACDF patients failed the criteria for radiographic success. Clinically relevant HO (grades III and IV) was observed in 23.1% of TDR patients with radiographs available at the 36 month time point, with 8.7% of patients with the presence of grade IV HO at either level. TDR patients experienced clinically relevant HO in 15.4% of superior segments and 15.4% of inferior segments, totaling 15.4% (60/390) of treated levels.

In the ACDF cohort, 13.1% of patients with available radiographs failed to achieve fusion status at 36 months. ACDF patients experienced failed fusion in 9.5% of inferior levels and 3.6% of superior levels, totaling 6.5% of treated levels This does not include patients that had corrective surgery for failed fusion at earlier time points.

Adjacent segment degeneration was defined by the Kellgren-Lawrence grading scale as an increase of one or more points compared to the baseline values at either segment. No grade of degeneration or combination of grades led to statistically significant differences in adjacent segment degeneration between groups at baseline. The superior levels indicated a significant difference between 59.2% of ACDF and 26.7% of TDR patients showing degeneration at 36 months (p < 0.0001). Inferior level results were similar at 46.8% of ACDF and 15.2% of TDR patients showing degeneration (p < 0.0001).

One case of posterior migration was previously reported; no cases of migration or subsidence have been reported since the 24 month results.

Overall Success

Overall success incorporates the success rates of five individual components at this composite endpoint. Based on this predefined criteria, at the 36 month composite endpoint (Figure 6) 66.8% of the TDR group and 41.4% of the ACDF group achieved overall success (p<0.0001). TDR demonstrated better outcomes for all five individual components, however only NDI success and secondary surgery assessments showed statistically significant results. In the ACDF group, 43.4% of patients had failing NDI improvement in comparison to only 19.8% of TDR patients; NDI was the leading cause of ACDF group failure.

DISCUSSION

Here, we analyzed two-level TDR using two Mobi-C^(r) Cervical Artificial Discs for safety and efficacy comparisons to ACDF, the standard surgical treatment for degenerative disc disease. Three-year results are part of an ongoing randomized, controlled, clinical trial. Results presented were from the FDA, IDE trial and included the first level one evidence²⁰20. Phillips B, Ball, C., Sackett, D., Badenoch, D., Straus, S., Haynes, B., Dawes, M., Howick J.: Oxford Centre for Evidence-based Medicine - Levels of Evidence (March 2009). Available from: cebm.net/index.aspx?o=1025. (accessed 13 july 2013).
cebm.net/index.aspx?o=1025... of two-level TDR through 36 months. Regarding the predefined overall success rate, TDR treatment is statistically superior to that of ACDF. While both ACDF and TDR patients experienced significant improvement from baseline, at 36 months TDR demonstrated statistically better outcomes in NDI scores, SF-12 PCS scores, patient satisfaction, subsequent surgery rates, adjacent segment degeneration, and overall success.

The hypothesis that the previously reported two-year TDR results will continue through three years was confirmed through this two-level study. Statistical significance in NDI scores, SF-12 PCS scores, patient satisfaction, subsequent surgery rates, adjacent segment degeneration, and overall success was maintained from the 24 to 36 month follow-up points. Also, the two-level TDR results agree with those of one-level TDR IDE study results.²¹21. Garrido BJ, Taha TA, Sasso RC. Clinical outcomes of Bryan cervical disc arthroplasty a prospective, randomized, controlled, single site trial with 48-month follow-up. J Spinal Disord Tech. 2010;23(6):367-71. ^{, 22}22. Murrey D, Janssen M, Delamarter R, Goldstein J, Zigler J, Tay B, et al. Results of the prospective, randomized, controlled multicenter Food and Drug Administration investigational device exemption study of the ProDisc-C total disc replacement versus anterior discectomy and fusion for the treatment of 1-level symptomatic cervical disc disease. Spine J. 2009;9(4):275-86. In a 48 month study, Garrido et al.²¹21. Garrido BJ, Taha TA, Sasso RC. Clinical outcomes of Bryan cervical disc arthroplasty a prospective, randomized, controlled, single site trial with 48-month follow-up. J Spinal Disord Tech. 2010;23(6):367-71. reported similar or better outcomes for their single level TDR group with respect to NDI, neck pain, arm pain, and secondary surgery rates of the BRYAN Cervical Disc (Medtronic Sofamor Danek, Memphis, TN).

The composite overall success of TDR (66.8%) was statistically superior to ACDF (41.4%) at 36 months (p<0.0001). The overall success is mainly due to the statistical significance of NDI success and subsequent surgery components in favor of TDR. The statistically significant differences in NDI success between groups remained from 24 months to 36 months (p<0.0001). While the number of TDR patients requiring subsequent surgeries was maintained at 3.1%, the number of ACDF patients requiring subsequent surgeries increased from 11.4% at 24 months to 13.3% at 36 months.

HO is a primary concern for TDR. In the current study, we observed clinically relevant HO (grades III and IV) in 15.4% of segments and 23.1% of patients treated with TDR, which is similar to or less than other reports.²³23. Quan GM, Vital JM, Hansen S, Pointillart V. Eight-year clinical and radiological follow-up of the Bryan cervical disc arthroplasty. Spine (Phila Pa 1976). 2011;36(8):639-46

24. Suchomel P, Jurák L, Benes V 3rd, Brabec R, Bradác O, Elgawhary S. Clinical results and development of heterotopic ossification in total cervical disc replacement during a 4-year follow-up. Eur Spine J. 2010;19(2):307-15. ^{- 25}25. Zigler JE, Delamarter R, Murrey D, Spivak J, Janssen M. ProDisc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. Spine (Phila Pa 1976). 2013;38(3):203-9. HO was present in 14.4% of patients and 10.5% of segments as grade III and 8.7% of patients and 4.9% of segments as grade IV. A European study analyzing HO rates in Prodisc-C (Synthes Spine Company, L.P., West Chester, PA) patients at 4 years reported an overall 63% incidence of clinically relevant grade III (45%) and grade IV (18%) HO.²⁴24. Suchomel P, Jurák L, Benes V 3rd, Brabec R, Bradác O, Elgawhary S. Clinical results and development of heterotopic ossification in total cervical disc replacement during a 4-year follow-up. Eur Spine J. 2010;19(2):307-15. Another study analyzing 21 BRYAN Cervical Disc patients at an 8 year follow-up reported an overall 76.2% incidence of grade III (42.9%) and IV (33.3%) HO.²³23. Quan GM, Vital JM, Hansen S, Pointillart V. Eight-year clinical and radiological follow-up of the Bryan cervical disc arthroplasty. Spine (Phila Pa 1976). 2011;36(8):639-46 The 5-year results of ProDisc-C in the U.S. showed 6 of the 103 patients with grade IV HO present at the index level, however grade III HO was not reported leaving analysis of clinically relevant HO inconclusive in this study.²⁵25. Zigler JE, Delamarter R, Murrey D, Spivak J, Janssen M. ProDisc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. Spine (Phila Pa 1976). 2013;38(3):203-9. One major difference between the current study and the others mentioned is the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been correlated with a decrease in HO formation. In this study, patients were asked to refrain from NSAID usage before and after surgery. Therefore, since other device trials did not restrict NSAID usage, this difference should be noted in comparisons of the current study and others mentioned. The limited HO rate data available after four or more years also leads to difficult comparisons between TDR devices. Despite these data limitations, concern remains regarding HO in TDR procedures; long-term investigations are needed to analyze the clinical instances and effects of HO.

Another major concern in degenerative disc disease surgery is the possibility of adjacent segment degeneration. Mechanisms leading to the high rates of adjacent segment deterioration in ACDF patients are not clear. While TDR may not eradicate adjacent segment degeneration, radiographic degeneration is reduced with TDR devices. It has been suggested that the preserved biomechanics at the index and adjacent levels maintain the adjacent segments in TDR. However, continued long-term follow-up of TDR patients should further define the mechanism by which radiographic degeneration is correlated to TDR.

Due to recent approval, there is no two-level TDR and ACDF direct comparison data available for treatment of DDD. However, long term data is available for one-level TDR and has proven that this treatment is at least as effective as one-level ACDF in relieving neurologic pain and motor impairment caused by DDD.²⁶26. Heller JG, Sasso RC, Papadopoulos SM, Anderson PA, Fessler RG, Hacker RJ, et al. Comparison of BRYAN cervical disc arthroplasty with anterior cervical decompression and fusion: clinical and radiographic results of a randomized, controlled, clinical trial. Spine (Phila Pa 1976). 2009;34(2):101-7. ^{, 22}22. Murrey D, Janssen M, Delamarter R, Goldstein J, Zigler J, Tay B, et al. Results of the prospective, randomized, controlled multicenter Food and Drug Administration investigational device exemption study of the ProDisc-C total disc replacement versus anterior discectomy and fusion for the treatment of 1-level symptomatic cervical disc disease. Spine J. 2009;9(4):275-86. Data up to five years post-surgery show TDR providing safe and effective surgical outcomes.²⁵25. Zigler JE, Delamarter R, Murrey D, Spivak J, Janssen M. ProDisc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. Spine (Phila Pa 1976). 2013;38(3):203-9. In a recent study, TDR is demonstrated superior to ACDF for one-level treatment.²⁷27. Food and Drug A. Summary of Safety and Effectiveness Data: SECURE-C Cervical Disc. Available from: http://www.accessdata.fda.gov/cdrh_docs/pdf10/p100003b.pdf
http://www.accessdata.fda.gov/cdrh_docs/... Evidence continues to indicate that at multiple levels, ACDF efficacy decreases and treatment may cause higher stress and hypermobility at adjacent segments.²⁸28. Lopez-Espina CG, Amirouche F, Havalad V. Multilevel cervical fusion and its effect on disc degeneration and osteophyte formation. Spine (Phila Pa 1976). 2006;31(9):972-8. ^{, 29}29. Wigfield C, Gill S, Nelson R, Langdon I, Metcalf N, Robertson J. Influence of an artificial cervical joint compared with fusion on adjacent-level motion in the treatment of degenerative cervical disc disease. J Neurosurg. 2002;96(Suppl 1):17-21. It is possible that these observed ACDF effects are primary contributing factors for the increase in rate of adjacent segment degeneration in treated patients. The excess motion and stress at adjacent levels in ACDF patients are avoided in two-level TDR which preserves cervical mobility at treated levels.¹⁵15. Davis RJ, Kim KD, Hisey MS, Hoffman GA, Bae HW, Gaede SE, et al. Cervical total disc replacement with the Mobi-C cervical artificial disc compared with anterior discectomy and fusion for treatment of 2-level symptomatic degenerative disc disease: a prospective, randomized, controlled multicenter clinical trial: clinical article. J Neurosurg Spine. 2013;19(5):532-45.

CONCLUSIONS

This IDE study through 36 months provides data to demonstrate clinically relevant benefits of TDR over ACDF. Improved clinical outcomes of TDR include pain and function outcomes and superiority in overall primary endpoint success. Occurrences of adjacent segment degeneration and subsequent surgeries were also reduced with TDR. Authors expect both future studies and long-term follow-up of this patient cohort to further establish the superiority of two-level TDR as a surgical option for symptomatic degenerative disc disease.

Disclosure

Dr. Davis has served as a consultant for LDR, has received clinical or research support for this study from LDR, and has received support for statistical analysis and for study/writing or editorial assistance on this paper from LDR. Dr. Bae is a patent holder for LDR Spine, has invested in a private fund that holds equity in LDR Spine among other medical companies, has received research support from LDR Spine, and receives royalties for products from NuVasive, Stryker, and Zimmer Spine. Dr. Hisey serves as a consultant for LDR Spine, Zimmer Spine, DePuy/Synthes Spine, and Baxano Surgical, and is a patent holder for LDR Spine and Zimmer Spine. Dr. Kim is a patent holder for LDR, and is a consultant for LDR, Globus, and Stryker. Dr. Nunley has direct stock ownership in Amedica, Paradigm Spine, and Spineology; has received support of non-study-related clinical or research effort from the Cervical Spine Research Society, K2M, Biomet Spine, Axiomed, Medtronic, Nutech, NuVasive, Spinal Motion, and Vertiflex; is a patent holder for K2M and LDR Spine (specifically for the ROI-A Anterior lumbar interbody fusion cage); is a consultant for Nutech; and has received royalties, performed speaking and teaching arrangements, and served on the scientific advisory board of Osprey Biomedical and K2M. Dr. Hoffman has direct stock ownership in, and serves as a consultant to, LDR and Nanovis. Dr. Gaede has received clinical or research support for this study from LDR.

Author contributions to the study and manuscript preparation include the following. Acquisition of data: all authors. Analysis and interpretation of data: Davis. Drafting the article: Davis. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Davis.

LDR contributed to the design and conduct of the study and also provided assistance with analysis of data and manuscript review. The authors would like to thank the other principal investigators for their contributions to the study: Charley Gordon, MD., Precision Spine Care, Tyler, Texas; Daniel Peterson, M.D., Austin Brain and Spine, Austin, Texas; Ralph Rashbaum, M.D., Texas Back Institute, Plano, Texas; Arnold Schwartz, M.D., Orthopedic Spine Care of Long Island, Huntington Station, New York; Ali Araghi, M.D., The Core Institute, Phoenix, Arizona; David Tahernia, M.D., Desert Orthopedic Center, Rancho Mirage, California; Hazem Eltahawy, M.D., University Neurologic Systems, Wayne State University, Detroit, Michigan; Reginald Tall, M.D., Southeastern Clinical Research, Orlando, Florida; Douglas Wong, M.D., Panorama Orthopedics & Spine Center, Golden, Colorado; Gerald Schell, M.D., St. Mary's of Saginaw, Field Neurosciences Institute, Saginaw, Michigan; Robert Jackson, MD.,Orange County Neurosurgical Associcaites, Laguna Hills, California; Michael Ramsey, M.D., West Texas Spine, Odessa, Texas; B. Christoph Meyer, M.D., Houston Orthopedic Hospital, Bellaire, Texas; Robert McLain, M.D., Cleveland Clinic, Cleveland, Ohio; Jon Park, M.D., Stanford Hospital and Clinics, Stanford, California; Ed Simmons, M.D., Simmons Orthopaedics and Spine Associates, Buffalo, New York; Mark Stern, M.D., California Institute of Neurological Surgery, Escondido, California; Guy O. Danielson, MD., Precision Spine Care, Tyler, Texas; and Phillip S. Yuan, M.D., Memorial Orthopaedic Surgical Group, Long Beach, California. The principal author would also like to thank Kelly Frank, M.S., of LDR Spine, Austin, Texas, for her assistance with data analysis and manuscript review.

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