Cervicaltotal disc replacement (cTDR) in properly indicated patients with single-level cervical disc pathology has been demonstrated to achieve satisfactory neural decompression and clinical outcomes equivalent to or better4,6,7,14–28,38than anterior cervical discectomy and fusion (ACDF) in 7 different prospective, randomized, controlled US FDA trials. Single-level long-term data have been published on the Bryan disc,34Pro-Disc-C,41and Prestige ST disc,8but this is the first report on the 5-year investigational device exemption (IDE) data for 2-level cervical arthroplasty.
Although both ACDF and cTDR satisfactorily treat clinically symptomatic cervical pathology, arthrodesis alters cervical mechanics1,2,11by placing increased stresses on adjacent segments, which may contribute to the development of symptomatic degeneration at those adjacent levels.6,14,15,18By preserving the motion of the operated segment, cTDR places comparatively less stresses on adjacent levels, which may serve to protect those levels.13,32,41Multilevel ACDF is biomechanically more demanding than single-level ACDF with concomitant greater stress distribution on adjacent levels.3,11,26Additionally, reoperation rates are generally higher in multilevel versus single-level ACDF.17Currently there is a paucity of Level I evidence evaluating the outcome of multilevel cTDR procedures.9,17,27
Mobi-C (LDR Medical) is a low-profile, mobile-bearing cTDR device composed of 2 cobalt-chromium alloy endplates and an ultra–high-molecular-weight polyethylene mobile core, resulting in a metal-on-polyethylene bearing surface. In April 2006, a large-scale, prospective, randomized, multicenter study was initiated at 24 sites comparing cTDR to ACDF in patients who had symptomatic cervical spondylosis at 2 contiguous levels. Davis et al. reported that at 2 years, the cTDR was associated with improved clinical success, greater reductions in Neck Disability Index (NDI) score, successful preservation of motion, and lower reoperation rate.12
The purpose of this study was to report the 5-year results of an IDE study of cTDR versus ACDF for the treatment of symptomatic 2-level contiguous cervical degenerative disc disease.
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Independent Review
We received the complete 5-year data set via electronic file transfer to analyze and draft this paper. This data set included all relevant baseline parameters as well as outcomes at each follow-up visit through 5 years. The worksheets were presented as .txt files generated via source code and output from the SAS database (SAS Institute) in accordance with the statistical analysis plan. No data were omitted or redacted by the sponsor. All study methodology was reviewed in conjunction with the study results. As the author team, we retained final authority for the content of the paper, including the discussion and conclusions. We were provided with the study protocol, data analysis plan, and all corresponding study data. We were given the opportunity to review the entire scope of data analysis conducted and were provided complete information and data relevant to the scope of this paper.
Study Design
The study design has been described previously in detail.12In brief, this was a prospective, randomized multicenter study at 24 clinical sites between April 2006 and March 2008 comparing the outcome of cTDR (Mobi-C) versus ACDF. The control group underwent ACDF with a corticocancellous allograft and an anterior cervical plate. Investigators were blinded up to time of the procedure because the investigator needed to be prepared to perform either the treatment or control surgery. Patients were unblinded after surgery because the postoperative protocol varied between the 2 treatments, and it was not possible to prevent patients from viewing their own radiographs. This study was registered with theclinicaltrials.govdatabase (registration no. NCT00389597).
Study Population
Patients had a diagnosis of radiculopathy or myeloradiculopathy at 2 contiguous levels from C-3 to C-7 that was unresponsive to nonoperative treatment for at least 6 weeks or demonstrated progressive symptoms necessitating immediate surgery (Table 1). Exclusion criteria included any prior cervical spine surgery (Table 1). The protocol specified a sample size of 196 cTDR subjects and 98 control subjects based on a projected 60% control success rate and 65% cTDR success rate, and 80% power for a 1-sided 0.05 significance level. Anticipated 10% loss-to-follow-up brought the total planned randomized sample size to 218 in the cTDR group and 109 in the ACDF control group. The study allowed for 1 nonrandomized training case per site. The nonrandomized patients were not included in the results of this paper.
Inclusion and exclusion criteria
| Inclusion criteria |
| Age 18–69 yrs |
| Symptomatic cervical degenerative disc disease in only 1 level between C-3 & C-7 w/: |
| Neck &/or arm pain; &/or |
| Decreased muscle strength; &/or |
| Abnormal sensation &/or abnormal reflexes. |
| Deficit confirmed by imaging (CT, MRI, or radiography). |
| NDI score ≥30 |
| Unresponsive to nonoperative, conservative treatment for at least 6 wks or presence of progressive symptoms or signs of nerve root/spinal cord compression despite continued nonoperative treatment. |
| No prior surgery at the operative level & no prior cervical fusion procedure at any level. |
| Physically & mentally able & willing to comply w/the protocol. |
| Signed informed consent. |
| Willingness to discontinue all use of NSAIDs from 1 wk before surgery until 3 mos after surgery. |
| Exclusion criteria |
| >1 vertebral level requiring treatment/immobile level between C-1 & C-7 from any cause. |
| Any prior spine surgery at operative level of any prior cervical fusion at any level. |
| Disc height <3 mm. |
| T-score less than −1.5 (osteoporosis evaluation). |
| Paget's disease, osteomalacia, or any other metabolic bone disease other than osteoporosis. |
| Active systemic infection of surgical site or history of or anticipated treatment for systemic infection including HIV/hepatitis C. |
| Active malignancy: a history of any invasive malignancy (except non-melanoma skin cancer), unless treated w/curative intent & there had been no clinical signs or symptoms of the malignancy >5 yrs. |
| Marked cervical instability on resting lateral or flexion-extension radiographs. |
| Known allergy to cobalt, chromium, molybdenum, or polyethylene. |
| Segmental angulation >11° at treatment or adjacent levels. |
| Rheumatoid arthritis, lupus, or other autoimmune disease. |
| Any diseases or conditions that would preclude accurate clinical evaluation. |
| Daily, high-dose oral &/or inhaled steroids or a history of chronic use of high-dose steroids. |
| BMI (kg/m2) >40. |
| Use of any other investigational drug or medical device w/in 30 days prior to surgery. |
| Pending personal litigation relating to spinal injury (workers' compensation not included). |
| Smoking >1 pack of cigarettes per day. |
| Reported to have mental illness or belonged to a vulnerable population. |
NSAID = nonsteroidal antiinflammatory drug.
Assuming that 2% of additional cases are lost per year, the power would be 99% for the overall success analysis.
Treatment Assignment
Three hundred thirty patients were randomized into the investigational device or the control group in a 2:1 ratio, resulting in 225 patients in the cTDR group and 105 in the ACDF group (Fig. 1).12A 2:1 randomization design has been suggested as a way to improve the cost-effectiveness of clinical trials when there is a notable difference in cost between treatments. An unbalanced randomization is also appropriate as a way to increase patient access to a new therapy, especially when the outcomes of the control therapy are well understood. The sample size required to test the 10% noninferiority hypothesis of the study treatment to the control was powered assuming 2:1 randomization. This randomization method met the Oxford Centre for Evidence-Based Medicine's criteria and the North American Spine Society's criteria for Level 1 evidence. Thus, the 2:1 randomization method improved the cost-effectiveness of the study and allowed a greater amount of data to be gathered on the investigational device, without sacrificing statistical power. Please see CONSORT Criteria for Methods Section (Appendix 1).
CONSORT flow chart. *Patients were screened as part of the 1- or 2-level arm. **Patients with any data available at the time point.
Follow-Up Routine
Patients were evaluated preoperatively and at 1.5, 3, 6, 12, 18, 24, 36, 48, and 60 months postoperatively. A total of 347 patients were randomized in the study, including 232 receiving cTDR and 115 receiving ACDF. Of these 347 patients, 225 in the cTDR group and 105 in the ACDF group received study surgery, with 17 patients withdrawing prior to surgery.12There were no patients who crossed over from one group to another during the study surgery. Therefore, the primary randomized analysis population included 225 cTDR patients and 105 ACDF patients. There were no statistically significant differences between treatment groups (Table 2) in terms of demographic factors or baseline outcome measures (Table 3). The cTDR and ACDF follow-up rates were 90.7% and 86.7%, respectively (p = 0.39), at 5 years. These follow-up rates include patients with any data available at the 5-year visit. The follow-up rates reported in the paper are based on the number of patients eligible for follow-up at 5 years and do not include patients who dropped out earlier in the study (e.g., due to death, device failures). Those patients who did not contribute to the 5-year follow-up are still considered active in the study and will continue to be followed going forward.
Patient demographics and baseline characteristics: primary analysis population
| Demographic Measure* | Randomized Mobi-C (n = 225) | Randomized ACDF (n = 105) | p Value (randomized groups) |
|---|---|---|---|
| Sex | 0.2375† | ||
| Male | 113 (50.2%) | 45 (42.9%) | |
| Female | 112 (49.8%) | 60 (57.1%) | |
| Age (yrs) | 0.3725‡ | ||
| Mean | 45.3 ± 8.10 | 46.2 ± 7.99 | |
| Range | 27–67 | 27–66 | |
| Ethnicity | >0.9999† | ||
| Hispanic or Latino | 14 (6.2%) | 7 (6.7%) | |
| Not Hispanic or Latino | 211 (93.8%) | 98 (93.3%) | |
| Race | >0.9999† | ||
| American Indian/Alaska Native | 3 (1.3%) | 1 (1.0%) | |
| Caucasian | 212 (94.2%) | 99例(94.3%) | |
| Asian | 4 (1.8%) | 0 | |
| Black | 5 (2.2%) | 4 (3.8%) | |
| Native Hawaiian/other Pacific islander | 0 | 0 | |
| Other | 1 (0.4%) | 1 (1.0%) | |
| Height, in | 0.4093‡ | ||
| Mean | 67.86 ± 3.604 | 67.51 ± 3.765 | |
| Range | 59.0–78.0 | 60.0–76.0 | |
| Weight, lbs | 0.7858‡ | ||
| Mean | 181.71 ± 36.117 | 182.86 ± 34.828 | |
| Range | 92.0–300.0 | 115.0–280.0 | |
| BMI, kg/m2 | 0.3586‡ | ||
| Mean | 27.625 ± 4.4697 | 28.102 ± 4.1953 | |
| Range | 16.83–39.54 | 19.66–39.78 | |
| History of nonop care (yes) | |||
| Pain medication§ | 208 (92.4%) | 100 (95.2%) | 0.7169† |
| Opioid use¶ | |||
| Opium alkaloid | 27 (12.0%) | 7 (6.7%) | 0.1741† |
| Semi-synthetic opioid derivative | 119 (52.9%) | 60 (57.1%) | 0.4794† |
| Synthetic opioid | 18 (8.0%) | 18 (17.1%) | 0.0215† |
| Physical therapy | 110 (48.9%) | 49 (46.7%) | 0.9290† |
| Collar | 27 (12.0%) | 15 (14.3%) | 0.6324† |
| Chiropractic | 61 (27.1%) | 23 (21.9%) | 0.5518† |
| Cervical traction | 45 (20.0%) | 21 (20.0%) | 0.6021† |
| Bed rest/immobilization | 110 (48.9%) | 49 (46.7%) | 0.6397† |
| Acupuncture | 18 (8.0%) | 6 (5.7%) | 0.4529† |
| Work status (being able to work) | 141 (62.7%) | 64 (61.0%) | >0.9999† |
| Driving status (being able to drive) | 210 (93.3%) | 102 (97.1%) | 0.4026† |
Data on amount and length of tobacco use were not captured.
Fisher exact test to compare frequencies between the treatments.
Unpaired t-test to compare across treatment groups.
Aggregate usage of medications determined to be pain medication presented for baseline comparison.
Opioid usage (aggregate) with specific categories is presented separately as a subset of pain medication. Injections were not categorically defined in the study protocol and as such are not presented here.
Preoperative evaluation of end points
| Variable | Randomized Mobi-C (n = 225) | Randomized ACDF (n = 105) | p Value (randomized groups) |
|---|---|---|---|
| NDI | 53.86 ± 15.576 | 55.35 ± 15.321 | 0.4150* |
| VAS neck pain | 71.24 ± 20.504 | 74.56 ± 18.937 | 0.1619* |
| VAS left arm pain | 48.32 ± 34.818 | 49.92±33.799 | 0.6948* |
| VAS right arm pain | 41.91 ± 35.265 | 45.64 ± 35.440 | 0.3726* |
| SF-12 PCS | 33.390 ± 6.7184 | 32.524 ± 7.6635 | 0.3051* |
| SF-12 MCS | 41.944 ± 11.3041 | 42.019 ± 11.9173 | 0.9564* |
| Normal neurological status† | |||
| Motor | 99 (44.0%) | 54 (51.4%) | 0.2363‡ |
| Sensory | |||
| Light touch | 110 (48.9%) | 56 (53.3%) | 0.4796‡ |
| Pinprick | 108 (48.0%) | 52 (49.5%) | 0.8140‡ |
| Reflexes | 80 (35.6%) | 41 (39.0%) | 0.5424‡ |
| Gait assessment§ | 215 (95.6%) | 98 (93.3%) | 0.5908‡ |
| Baseline ROM | |||
| Flexion-extension (°) | |||
| Superior level | 9.13 ± 4.849 | 9.33 ± 4.875 | 0.7355* |
| Inferior level | 7.44 ± 4.341 | 7.14 ± 3.860 | 0.5574* |
| Baseline ROM | |||
| Lateral bending (°) | |||
| Superior level | 5.76 ± 3.374 | 5.48 ± 3.041 | 0.4777* |
| Inferior level | 4.91 ± 3.265 | 4.77 ± 2.866 | 0.7227* |
Unpaired t-test to make comparison across treatments for all Mobi-C subjects compared to ACDF subjects.
Fisher exact test to compare frequencies between the treatments.
Normal defined as normal status for both left- and right-side assessments.
Gait was the only other neurological assessment performed, per the study protocol.
Outcome Measures
Outcome scores included NDI, visual analog scale (VAS) scores for neck pain and arm pain, patient satisfaction with treatment, patient recommendation for same treatment, quality of life (12-Item Short Form Health Survey [SF-12]), and dysphagia. Additional clinical parameters were also analyzed as outcome measures, including the neurological assessments of strength, reflex, and motor testing. Fusion status was assessed radiographically. Lack of fusion was defined as ≥ 2° of segmental movement on lateral flexion-extension radiographs, radiolucent lines at greater than 50% of the graft-vertebral interfaces, or lack of evidence of bridging trabecular bone. The study protocol did not specify the indications for reoperation in either treatment group. The decision to reoperate was determined solely by the treating surgeon and the patient's personal decision to proceed. A subsequent surgical intervention in either treatment group was strictly defined as a revision, removal, reoperation, or supplemental fixation at the index level.
Additionally, there was a composite definition for success similar to that used in other cervical arthroplasty device trials.12In this analysis the end point was defined with the approval of the FDA within the Mobi-C Post-Approval Studies) protocol. The previously published definition of overall success by Davis et al. has been altered within the Post-Approval Studies protocol to include only clinical end points.
Overall study success was defined as requiring all 5 of the following metrics: 1) NDI improvement of at least 15 points (out of 50) from baseline; 2) No subsequent surgical intervention at the index level or levels; 3) No potentially (possibly or probably) device-related adverse event; 4) Maintenance or improvement in all components of neurological status; and 5) No Mobi-C intraoperative changes in treatment.
As previously reported,12adverse events were defined and evaluated for relatedness in a blinded fashion to the treatment device when possible. In the tables, means are presented ± SD.
Results
Neck Disability Index
Patients in both groups showed significant improvement in NDI scores from baseline at all time points (Fig. 2andTable 4). The mean improvement in NDI (p = 0.0003) at 5 years was greater in the cTDR group (−37, SD 20) versus the ACDF group (−28, SD 18).
Mean NDI score by time point.Error barsrepresent standard deviations. Both groups improved significantly at each time point compared with baseline. *Unpaired t-test to compare change from baseline between groups, p < 0.05.
Mean NDI score by time point
| Time Point* | Mean | Standard Deviation | p Value† | ||
|---|---|---|---|---|---|
| TDR | ACDF | TDR | ACDF | ||
| Baseline | 53.9 | 55.4 | 15.58 | 15.32 | |
| Wk 6 | 25.7 | 34.3 | 17.69 | 18.05 | 0.0029 |
| Mo 3 | 19.3 | 28.8 | 17.54 | 21.64 | 0.0009 |
| Mo 6 | 17.9 | 25.1 | 17.38 | 19.53 | 0.0082 |
| Mo 12 | 17.6 | 25.5 | 18.52 | 21.37 | 0.0034 |
| Mo 18 | 18.4 | 25.7 | 18.24 | 21.2 | 0.0281 |
| Mo 24 | 16.5 | 24 | 16.91 | 19.34 | 0.0032 |
| Mo 36 | 16.5 | 26.9 | 17.82 | 21.41 | 0.0002 |
| Mo 48 | 17.2 | 25.5 | 18.76 | 21.25 | 0.0048 |
| Mo 60 | 16.8 | 26.4 | 17.43 | 20.37 | 0.0003 |
Both groups improved significantly at each time point compared to baseline.
Unpaired t-test to compare change from baseline between groups, p < 0.05.
Neck and Arm Pain
Patients in both groups showed marked improvement from baseline at all time points. There was more improvement in VAS neck pain and VAS arm pain in the cTDR group than the ACDF group, although the difference was not statistically significant (Tables 5and6).
Mean VAS neck pain score by time point
| Time Point* | Mean | Standard Deviation | p Value† | ||
|---|---|---|---|---|---|
| cTDR | ACDF | cTDR | ACDF | ||
| Baseline | 71.24 | 74.56 | 20.50 | 18.94 | |
| Wk 6 | 24.67 | 33.83 | 22.69 | 25.72 | 0.0822 |
| Mo 3 | 19.57 | 31.89 | 23.99 | 30.29 | 0.0101 |
| Mo 6 | 18.23 | 28.74 | 22.52 | 29.38 | 0.0303 |
| Mo 12 | 19.77 | 29.11 | 25.92 | 29.91 | 0.0682 |
| Mo 18 | 19.51 | 25.51 | 25.58 | 26.28 | 0.5366 |
| Mo 24 | 16.59 | 20.45 | 24.15 | 23.95 | 0.6869 |
| Mo 36 | 16.57 | 26.78 | 23.09 | 28.85 | 0.0517 |
| Mo 48 | 17.74 | 25.44 | 24.62 | 28.32 | 0.2729 |
| Mo 60 | 18.66 | 28.45 | 26.10 | 28.75 | 0.0743 |
Both groups improved significantly at each time point when compared to baseline.
Unpaired t-test to compare change from baseline between groups, p < 0.05.
Mean VAS arm pain score by time point
| Time Point* | Mean | Standard Deviation | p Value† | ||
|---|---|---|---|---|---|
| cTDR | ACDF | cTDR | ACDF | ||
| Baseline | 68.74 | 72.74 | 25.01 | 21.64 | |
| Wk 6 | 15.68 | 17.92 | 22.49 | 22.90 | 0.5387 |
| Mo 3 | 15.58 | 20.52 | 23.96 | 27.63 | 0.8052 |
| Mo 6 | 14.63 | 20.69 | 22.41 | 27.88 | 0.4163 |
| Mo 12 | 14.22 | 21.73 | 23.14 | 27.10 | 0.1419 |
| Mo 18 | 14.69 | 20.62 | 24.34 | 26.42 | 0.6282 |
| Mo 24 | 11.91 | 16.16 | 19.46 | 21.89 | 0.8663 |
| Mo 36 | 12.59 | 19.35 | 23.00 | 26.17 | 0.4016 |
| Mo 48 | 13.38 | 20.63 | 22.72 | 27.44 | 0.4868 |
| Mo 60 | 11.86 | 22.20 | 21.20 | 27.44 | 0.1487 |
The worst arm at baseline is followed. Both groups improved significantly at each time point when compared to baseline.
Unpaired t-test to compare change from baseline between groups, p < 0.05.
Patient Satisfaction
In both groups, the overall rates of patient satisfaction were high. However, there was significantly higher reported patient satisfaction in the cTDR group versus the ACDF group. At 5 years, 96.4% of cTDR patients and 89.5% of ACDF patients reported being either very satisfied or somewhat satisfied with their treatment (p = 0.04). At 5 years, 94.8% of patients in the cTDR group and 84.2% of patients in the ACDF group reported that they would definitely or probably recommend the surgery to a friend (p = 0.01).
Health-Related Quality of Life
There was significant improvement versus baseline in SF-12 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores in both groups. At 5 years (and at every time point), there was significantly more improvement in PCS scores in the cTDR patients (PCS Score 13) than ACDF patients (PCS Score 9; p = 0.0073) (Fig. 3andTable 7). There were no statistically significant differences in MCS scores between groups.
Mean SF-12 PCS score by time point.Error barsrepresent standard deviations. Both groups improved significantly at each time point compared with baseline. *Unpaired t-test to compare change from baseline between groups, p < 0.05.
Mean SF-12 PCS score by time point
| Timepoint* | Mean | Standard Deviation | p Value† | ||
|---|---|---|---|---|---|
| cTDR | ACDF | cTDR | ACDF | ||
| Baseline | 33.4 | 32.52 | 6.72 | 7.66 | |
| Mo 6 | 47.1 | 42.52 | 10.78 | 11.35 | 0.0061 |
| Mo 12 | 46.9 | 42.48 | 11.05 | 11.45 | 0.0090 |
| Mo 18 | 46.3 | 42.54 | 11.77 | 12.20 | 0.0483 |
| Mo 24 | 46.9 | 43.40 | 10.71 | 12.63 | 0.0333 |
| Mo 36 | 47.6 | 42.65 | 10.97 | 12.19 | 0.0060 |
| Mo 48 | 46.8 | 43.53 | 11.32 | 12.20 | 0.0459 |
| Mo 60 | 46.8 | 42.20 | 11.32 | 12.26 | 0.0073 |
Both groups improved significantly at each time point compared to baseline.
Unpaired t-test to compare change from baseline between groups, p < 0.05.
Subsequent Surgery
The rate of investigator-reported nonunion was 14% (15 patients) in ACDF. The fusion rate assessed by radiographic success was 90.5% (95/105) at 5 years. Of the 15 patients reported by investigators as nonunion, 9 of these patients progressed to symptomatic nonunion that required subsequent surgical interventions due to fusion failure. This corresponds to a symptomatic nonunion rate of 8.6%.
Overall, there were fewer secondary surgeries in the cTDR group than in the ACDF group (cTDR 7.1% [16/225] vs ACDF 21.0% [22/105]) (p = 0.0006). There were significantly fewer index-level secondary surgeries (p = 0.0003) that were classified as study failures in the cTDR group (4% [9/225]) than in the ACDF group (16.2% [17/105]). Comparing mean reoperation-free survivorship (Fig. 4), cTDR patients demonstrate a significantly lower probability for secondary surgical intervention through 5 years (p = 0.0002; log-rank test). The description of secondary surgery in both groups is provided inAppendix 2.
Kaplan-Meier survival functions for subsequent surgical interventions in ACDF and TDR patients. TDR patients demonstrate a significantly different survival function than ACDF patients for subsequent surgical intervention through 60 months (p = 0.0002, log-rank test).
There were significantly more index-level reoperations in the ACDF group (16.2%) than in the cTDR group (4.3%). There were also significantly more adjacent-level reoperations in the ACDF group (11.4%) than in the cTDR group (3.1%).
Overall Study Success
Using the FDA composite outcome measure for success, the overall success rates at 5 years were 61% and 31% for the cTDR and ACDF groups, respectively (p < 0.0001). The significantly higher overall success rate for the cTDR group meets superiority and noninferiority criteria. At each time point, there was a higher incidence rate of success in the cTDR group (Table 8). However, the differential in success rate between the 2 treatments increased following the 24-month follow-up interval. This is due to the decrease in the proportion of successful ACDF cases from 24 months of follow-up (42%) to 60 months of follow-up (31%) (Fig. 5).
Two-level overall success through 60 months
| Time Point | TDR | ACDF | Lower Bound* |
|---|---|---|---|
| Mo 6 | 140/219 (63.9%) | 44/97 (45.4%) | 0.0869 |
| Mo 12 | 134/215 (62.3%) | 43/95 (45.3%) | 0.0706 |
| Mo 18 | 126/213 (59.2%) | 42/92 (45.7%) | 0.0332 |
| Mo 24 | 145/221 (65.6%) | 42/99 (42.4%) | 0.1347 |
| Mo 36 | 137/202 (62.9%) | 31/87 (35.6%) | 0.1711 |
| Mo 48 | 125/203 (61.6%) | 29/89 (32.6%) | 0.1908 |
| Mo 60 | 124/204 (60.8%) | 29/93 (31.2%) | 0.1990 |
Lower bound > 0 confirms superiority of TDR.
Overall success through 60 months. Superiority of TDR over ACDF (p < 0.025).
Potentially Related Adverse Events
There was an increased percentage of all adverse events, treatment of emergent adverse events (i.e., those that occurred during the trial period, investigator-deemed adverse events, Clinical Event Committee–adjudicated adverse events, and related serious adverse events in the ACDF group at 5 years (Table 9). At the 5-year time point, the Clinical Event Committee determined that 10 patients in the cTDR group (4.4%) and 9 patients in the ACDF group (8.6%) had potentially device-related serious adverse events. There was no significant difference in the incidence of overall dysphagia and dysphonia complications in the cTDR group (16% of patients, 95% CI 11.4%–21.1%) than in the ACDF group (21% of patients, 95% CI 13.6%–30.0%). There were 4 cases of implant malposition (suboptimal or undesired location) in the cTDR group (1.7%).
Percentage of population with Clinical Event Committee–adjudicated adverse events by time point through 60 months
| Time Point | TDR (n = 225) | ACDF (n = 105) |
|---|---|---|
| Mo 6 | 1.3% | 1.0% |
| Mo 12 | 2.7% | 2.9% |
| Mo 18 | 3.1% | 6.7% |
| Mo 24 | 3.6% | 6.7% |
| Mo 36 | 4.0% | 6.7% |
| Mo 48 | 4.0% | 7.6% |
| Mo 60 | 4.4% | 8.6% |
Radiological Outcomes
cTDR patients maintained their baseline range of motion (ROM) in flexion/extension and lateral bending at both segments (Fig. 6). For cTDR patients, the mean ROM at the superior level was 10.1° ± 6.1° in flexion/extension (baseline 9.1° ± 4.8°). At the inferior level, the mean ROM was 8.4° ± 5.0° in flexion/extension (baseline 7.4° ± 4.3°). At 60 months, lateral bending in cTDR patients was 5.6° ± 3.6° in the superior level (baseline 5.8° ± 3.4°) and 5.1° ± 3.4° in the inferior level (baseline 4.9° ± 3.3°).
ROM in both flexion/extension (upper) and left/right lateral bending (lower) through 60 months (M).
Clinically relevant heterotopic ossification (Grade III or IV) was observed in 29.7% of cTDR patients with available radiographs at the 60-month time point. cTDR patients presented with clinically relevant heterotopic ossification in 20.0% of superior levels and 21.6% of inferior levels. Grade IV heterotopic ossification was evident in at least 1 level in 9.7% of cases.
通过与变性被定义为一个crease of 1 or more points of the Kellgren-Lawrence grading scale at 60 months in either segment when compared with baseline values. In patients who experienced degeneration at either level, cTDR patients had significantly less adjacent-segment degeneration than the ACDF group (50.7% for cTDR vs 90.5% for ACDF, p < 0.0001). The superior levels at 60 months indicated significantly less degeneration in cTDR patients (32.6%) than in ACDF patients (70.8%; p < 0.0001). Results for the inferior levels were similar (22.4% for the cTDR group vs 55.1% for the ACDF group; p < 0.0001).
Neurological Status
At 5 years, patients failing the neurological component of the FDA success criterion were 8.0% of cTDR patients (n = 18) and 5.7% of ACDF patients (n = 6); this difference was not significant. At 5 years, there were 18 instances of worsened muscle weakness (vs baseline) in the cTDR group and 12 instances of muscle weakness in the ACDF group.
Discussion
这是第一次报告的长期结果2-level cTDR from a US FDA IDE study. Two-level anterior cervical spine surgery, with cTDR or ACDF, is safe and effective in significantly improving patient outcome. Comparing cTDR and ACDF, disc replacement resulted in statistically significant greater improvement in general and disease-specific outcome measures compared with ACDF. Additionally, there was a lower incidence of index level and adjacent-level reoperation with cTDR.
Our results add to the growing body of literature that in the long term, cTDR results in improved clinical outcome versus ACDF in properly indicated patients who meet the inclusion and exclusion criteria described above.13,28–37,41There was a statistically significant greater improvement in the NDI, SF-12, and patient satisfaction in the cTDR grop than in the ACDF. Overall, a large percentage of patients reported that they were satisfied with their treatments (96.4% in the cTDR group, ACDF 89.5% in the ACDF group) or would undergo surgery again (94.8% in the cTDR group, 84.2% in the ACDF group). Other studies (using other implant systems) have also established more improvement in outcome and lower rates of reoperation with cTDR compared with ACDF for treatment of single-level pathology.10,13,32,41Not unexpectedly, the rate of major neurological adverse events and gait dysfunction was low in both study populations, confirming the safety of both procedures. In contrast to previous studies,21there was no significant increase in dysphagia associated with ACDF at any time point in this study using a validated dysphagia outcome measure.
The rate and etiology of reoperation following surgical fusion remains controversial. The present study lends credence to the belief that fusion predisposes patients to reoperation. In the cTDR population, there was a statistically significant lower rate of overall subsequent surgeries (7% in the cTDR group vs 21% in the ACDF group; p = 0.0006). The increased rate of subsequent surgery between the 2-year (11%) and 5-year (16%) end points in the ACDF population corresponded to changes in mean NDI score. The majority of the reoperations in both groups (9/16 cTDR patients vs 17/22 ACDF patients) involved the index level. The most common secondary surgery in the cTDR group at the index level was device removal. We surmise that in many cases the index-level device was removed to access or fixate adjacent-level pathology, not necessarily to correct pathology at the index level. Radiographic factors including motion may affect the outcome of the TDR. A full analysis of the radiographic predictors of secondary surgery, including clinical correlation, motion analysis, baseline degeneration, plate proximity to endplates, and degree of heterotopic ossification, is outside the scope of this clinically oriented paper.31The rate of investigator-reported nonunion in the ACDF population at any time point was 14% (15 patients). This rate of nonunion is comparable to the rates reported for 1-level ACDF with the ProDisc-C (13.1% at 5 years) and the Prestige disc (10.0% at 7 years).11,41The rate of secondary surgery for symptomatic pseudarthrosis (8.6%) is lower than historical estimates.39,40
Strengths of the study include the rigorous methodology involving prospective randomization with adequate statistical power. As a result of randomization, at baseline, the demographics and outcome scores were balanced between groups. Additionally, the 5-year follow-up rate was good in both groups, enabling adequate statistical power to test both noninferiority and superiority. Based on our analysis of follow-up, there is no evidence of any bias due to dropouts. The follow-up rates in our study for both Mobi-C and ACDF are comparable or higher than those reported in other long-term randomized control trials of cervical arthroplasty.8,24,41利用通用和疾病speci数组fic outcome measures and observing the effect (improved outcome in Mobi-C patients) in several different outcome measures (SF-12, NDI, satisfaction), we are more confident in our conclusion that 2-level cTDR was superior to ACDF than if the effect were only observed in a single instrument. Finally, in this case the data review was conducted using rigorous criteria in accord with FDA standards by independent investigators without any institutional or financial bias or prior involvement in the Mobi-C cTDR study.
Limitations of the study include the potential for affirmation bias on the part of the cTDR patients. Patients were not blinded to their treatment type since they may have had the opportunity to view their postoperative radiographs and they would have known about the presence or absence of a cervical collar for arthrodesis. It is possible that the improved outcome may be the result of affirmation bias. However, by 5 years we suspect that initial euphoria at inclusion into the treatment arm of a clinical trial may have subsided. Another limitation is the inherent subjectivity of the decision for reoperation.35在这项研究中,我们认为,再次手术的老鼠e represents an attempt to rescue deteriorating clinical outcomes, noting that the ACDF patient population experienced less NDI improvement, indicating a potential greater overall need for revision surgery. Each revision surgery was documented by the investigative site, including the related symptoms. A paper detailing the revision surgeries through 5 years is currently under review for publication. Early study definitions of success focused heavily on absence of neurological adverse events, since in the early days of cTDR there was some uncertainty among surgeons whether neurological adverse events would occur more frequently. Another limitation is that the racial distribution of the study population (94% Caucasian) does not reflect that of the United States as a whole. We are uncertain as to the reasons for this effect as the study was conducted at multiple centers. This finding may limit the generalizability of the results to non-Caucasian populations. All patients who were eligible for participation were offered the opportunity to participate in the trial. Other studies have also shown that minority participation in orthopedic trials is typically lower than would be expected based on census demographics.36Without further information, it is also difficult to determine if a new sensory deficit that is remote from the index surgical event represents a de novo peripheral nerve entrapment syndrome or a new cervical spine pathology. We would assume that clinically significant physical examination changes causing new radiculopathy or myelopathy would be reflected in the outcome measures and reoperations. Additionally, the study protocol called for allograft fusion in the control group, similar to that of other IDE studies on disc replacement.23–28我们假设,如果一个使用自体,reoperation rate might have been different; however, the use of an autograft has the potential for additional complications (such as donor site pain), and the decision not to use an autograft resulted in a well-matched control procedure to the cTDR group.
Conclusions
We found a higher rate of success based on improvement in outcome and a lower rate of reoperation, at index and adjacent levels, among patients who were treated with a Mobi-C cTDR at 2 levels versus an ACDF at 5 years. It is important to consider that these results apply to the study population of patients with radiculopathy or myelopathy, objective muscle weakness, at least moderate to severe neck and arm pain, and concordant pathology at 2 contiguous levels in whom at least 6 weeks of conservative treatment has failed. In patients meeting the above criteria who are otherwise appropriate surgical candidates, 2-level cTDR was safe and effective with a lower rate of related adverse events compared with ACDF.
Acknowledgments
We would like to acknowledge the contribution of the study investigators at each of the 24 clinical sites across the US.
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Disclosures
作者报告如下。雷德克利博士:联合国paid consultant for 4 Web Medical; board or committee member for ACSR; paid consultant for Altus Spine; paid consultant, research support, and unpaid consultant for DePuy, a Johnson & Johnson Company; intellectual property (IP) royalties, paid consultant, and research support from Globus Medical; unpaid consultant for LDR; paid consultant and research support from Medtronic; other financial or material support from NEXXT Spine; other financial or material support from NuVasive; paid consultant for Orthofix, Inc.; IP royalties and paid consultant for Orthopedic Sciences, Inc.; research support from Pacira pharmaceuticals; research support from Paradigm Spine; and other financial or material support from Stryker. Dr. Albert: board or committee member for AAOS; board or committee member for American Orthopaedic Association; stock or stock options from ASIP; IP royalties from Biomet; stock or stock options from Biometrix; stock or stock options from Breakaway Imaging; stock or stock options from Crosstree; IP royalties and paid consultant for DePuy, a Johnson & Johnson Company; paid consultant and stock or stock options from Facet-Link; stock or stock options from Gentis; stock or stock options from InViVo Therapeutics; stock or stock options from Invuity; publishing royalties, financial or material support from Jay Pee; editorial or governing boardJournal of Bone and Joint Surgery(American); stock or stock options in Paradigm Spine; stock or stock options in Pioneer; stock or stock options in PMIG; publishing royalties, financial or material support from Saunders/Mosby-Elsevier; board or committee member for Scoliosis Research Society; editorial or governing board forSpine;editorial or governing board forSpine Deformity Journal;在Spinicity股票或股票期权;出版royalties, financial or material support from Thieme; other financial or material support from United Healthcare; and stock or stock options in Vertech. Dr. Coric: royalties, stock ownership, and consultant for Spine Wave; stock ownership in DiscGenics and Spinal Motion; and consultant for Medtronic, Globus Medical, and United Healthcare; and speaking and/or teaching arrangements for Globus.
Author Contributions
Conception and design: all authors. Acquisition of data: Coric. Analysis and interpretation of data: all authors. Drafting the article: Radcliff, Albert. Critically revising the article: all authors. Reviewed submitted version of manuscript: Radcliff, Coric. Approved the final version of the manuscript on behalf of all authors: Radcliff. Study supervision: Coric.
Supplemental Information
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