Neck and upper extremity symptoms often arise from cervical disk degeneration. The primary treatment for this condition, after failure of nonoperative care, has been anterior cervical discectomy and fusion (ACDF). The results have generally been good, but there is a potential for pseudoarthrosis and acceleration of degeneration at the adjacent segments. Trying to address these problems, cervical total disk replacement (TDR) was introduced. Several prospective, randomized Food and Drug Administration (FDA)-regulated trials reporting 2-year outcomes have found cervical TDR to produce results similar or superior to ACDF for the treatment of single-level symptomatic degenerative disk disease.1–7 Subsequent studies found that these results were upheld during follow-up ranging from 4 to 7 years.8–11
In addition to the FDA-regulated studies in the United States, research has been conducted evaluating TDRs in Europe and Asia.12–17 These studies have reported good results achieved when using TDR. Zhang et al13 conducted a prospective, randomized study comparing TDR to ACDF with 24-month follow-up. Their findings of TDR producing results at least as good as those from ACDF were similar to those of the trials in the United States. Good results for cervical TDR were reported at 5-year follow-up from the SWISSspine registry.16 The government made participation in this registry mandatory for all TDRs implanted to determine the effectiveness and appropriate reimbursement for the procedure. It was found that TDR was safe and effective in reducing pain and pain medication consumption as well as improving quality of life.
The purpose of the current study was to compare clinical outcomes at 48-month follow-up of patients receiving cervical TDR with those receiving ACDF for single-level symptomatic disk degeneration.
MATERIALS AND METHODS
The study was a prospective, randomized, controlled clinical trial conducted at 23 centers across the United States. Patients were randomized in a 2:1 ratio with 164 patients being treated with the investigational device (Mobi-C Cervical Disc Prosthesis; LDR Medical, Troyes, France) and 81 were treated with ACDF. Details of the patients’ selection criteria, randomization, and surgical procedures have been described in detail elsewhere.7 The primary inclusion criteria were age 18–69 years, symptomatic degenerative disk disease with radiculopathy or myeloradiculopathy at 1 level from C3 to C7 that correlate with image findings, Neck Disability Index (NDI) scores of at least 30, no previous cervical fusion at any level or any prior surgery at the level to be operated, willing to stop use of nonsteroidal anti-inflammatory drugs for the period of 1 week before surgery to 3 months after surgery, and failure of at least 6 weeks of nonoperative care or having progressing neurological symptoms. Patients were excluded if any of the following were present: disk height of <3 mm, DEXA scan T-score of <−1.5, any metabolic bone disease, active malignancy or infection, body mass index of >40 kg/mg2, litigation related to spine injury, smoking >1 pack of cigarettes a day, marked cervical instability, or segmental angulation of >11 degrees at level to be treated or an adjacent segment.
The TDR device consists of 2 cobalt chromium endplates with a mobile ultrahigh–molecular weight polyethylene core between them. The endplates were titanium plasma sprayed and have a hydroxyapatite coating. The endplates have teeth for anchoring into the vertebral bodies. Patients randomized to the control group were treated with ACDF, with an anterior plate and corticocancellous allograft bone. Surgeons chose from the following plates to use: SLIM-LOC Anterior Cervical Plate System (Depuy Spine, Raynham, MA) or a Sofamor Danek ATLANTIS or ATLANTIS VISION Anterior Cervical Plate Systems (Medtronic, Memphis, TN). All surgeries were performed using a Smith-Robinson approach. The disk and osteophytes were removed and neural structures were decompressed as needed.
Study-related evaluations were performed before surgery and at 6 weeks and 3, 6, 12, 18, 24, 36, and 48 months postoperatively. The primary outcome measure was a composite success evaluation based on meeting each of the 3 criteria: (1) minimum 30-point improvement on the NDI if the baseline score was ≥60, or 50% improvement if the baseline was <60; (2) no device-related subsequent surgery (defined as removal, revision, supplemental fixation, or reoperation); and (3) no major complications defined as radiographic failure, neurological deterioration, or adverse events (AEs) classified as major complications by an independent Clinical Events Committee (CEC). A major complication related to radiographic failure at the TDR-treated level was defined as spontaneous fusion with radiographic evidence of bridging bone across the disk space and <2 degrees of angular motion on flexion/extension. In the ACDF, a major complication related to radiographic failure was pseudoarthrosis defined as at least 2 degrees of angular motion on flexion/extension, or radiolucencies at >50% of the graft vertebral body interface, or absence of bridging bone across the graft vertebral body interfaces.
Measured outcomes included the NDI, visual analog scales (VAS) separately assessing neck and arm pain, overall quality of life assessed by the SF-12, patient satisfaction, major complications, subsequent surgery rates, segmental range of motion (ROM), and adjacent-segment degeneration. Subsequent surgery was analyzed using 2 methods. First, the rate was calculated based on the safety definition that was used as part of the composite success rate and constituted a study failure. A second analysis was conducted which captured other reoperations at the index level that did not constitute a study failure and those not involving the index level.
Patient satisfaction was assessed using a questionnaire which asked patients to indicate whether they were very satisfied, somewhat satisfied, somewhat dissatisfied, or very dissatisfied with their treatment. Another satisfaction-related item asked patients whether they would definitely, probably, probably not, or definitely not recommend their respective treatment to a friend with the same symptoms.
All radiographic assessments were performed independently by Medical Metrics Inc. (Houston, TX). Measurements such as angles and disk space height were made using validated software. Parameters requiring interpretation, such as lucencies and bridging bone, were assessed by radiologists at MMI. Fusion was defined as bridging bone across the disk space, <2 degrees angular motion measured from flexion to extension, and <50% radiolucent lines at the graft vertebral endplate interfaces.
Radiographic analyses included evaluation of the adjacent segments and heterotopic ossification (HO). Adjacent-segment degeneration was determined radiographically based on the Kellgren-Lawrence scale.18,19 A patient with increased degeneration of at least 1 grade at the inferior or superior adjacent segment was considered to have adjacent-segment degeneration. HO was graded on a 0–4 scale adapted from the methods described by McAfee et al20 and Mehren et al21 (Table 1).
The TDR and ACDF treatment groups were well matched at baseline with respect to sex, age, body mass index, work status, NDI, VAS, and SF-12 scores.7 At baseline, the patient sample consisted of 164 patients in the investigational group and 81 patients in the control group. A summary of the 48-month follow-up status is provided in Table 2. The percentages of patients lost to follow-up were 15.8% in the investigational group and 21.0% in the control group.
This was designed as a noninferiority study with the composite success score being the primary outcome measure. The percentages of patients meeting the composite success criteria in the 2 treatment groups were compared using the Fisher exact analysis. The Fisher exact analyses were also used to compare secondary categorical data including subsequent surgery rates and adjacent-segment degeneration. The mean scores on secondary outcome measures including the NDI, VAS, and SF-12 were compared between groups using the 2-sample t tests. Patients who were lost to follow-up were not included in analyses, with the exception of reoperations and subsequent surgeries that occurred during available follow-up.
Composite Overall Success
At 48-month follow-up, the overall clinical success rates were similar in the 2 groups (TDR 69.5% vs. ACDF 58.7%), and TDR found to be statistically noninferior to fusion (Fig. 1).
The mean NDI scores improved significantly from baseline in both groups and these improvements were maintained throughout 48-month follow-up (Fig. 2). At 48 months, the NDI success component criterion was met in 80.5% of TDR patients and 78.2% of ACDF patients.
VAS Pain Scores
The mean VAS neck pain scores improved significantly from baseline in both treatment groups (Fig. 3A, P<0.0001) at all follow-up points through 48-month follow-up. VAS arm pain scores were derived from the more symptomatic arm at baseline, carried through 48 months. Both the TDR and ACDF groups showed significant improvement from baseline VAS arm pain scores (Fig. 3B, P<0.0001) throughout the 48-month follow-up.
Quality of Life (SF-12)
Both treatment groups showed statistically significant improvement in SF-12 PCS and MCS scores from baseline values at all postoperative timepoints (Figs. 4A, B, P<0.0001) throughout 48-month follow-up. At 48-month follow-up, there were no statistically significant differences in the mean PCS or MCS scores when comparing the 2 groups.
There was no statistically significant difference in the proportion of patients indicating that they were satisfied with the treatment received when comparing the 2 treatment groups. At 48-month follow-up, 88.6% of the TDR group and 83.6% of the ACDF group indicated that they were “very satisfied” with their treatment. In addition to satisfaction, patients were also asked whether they would recommend the treatment they received to a friend with the same symptoms and indications. At 48 months after surgery, the percentage of patients responding “definitely” was 87.8% in the TDR group and 81.8% in the ACDF group.
Between the time of treatment and 24 months postsurgery, 43 (24.0%) TDR patients and 23 (28.4%) of ACDF patients experienced an AE deemed definitely related or possibly related to the treatment device by the CEC. During this period, 6 (3.4%) TDR patients and 6 (7.4%) of ACDF patients experienced a serious AE related to the treatment device. From 24 to 48 months, device-related AE were experienced by 10 (5.6%) TDR patients and 2 (2.5%) ACDF patients. During the timeframe, 2 (1.1%) of TDR patients and 0 (0.0%) of ACDF patients experienced a serious AE that was deemed to be related or possibly related to the treatment device. All possibly and definitely related AEs were evaluated by the CEC to determine whether the event represented a major complication.
Overall major complications at 48 months occurred for 9.8% of TDR patients and 9.9% of ACDF patients. These complications included neurological deterioration (1.2% TDR, 2.5% ACDF), radiographic determination (4.9% TDR, 3.7% ACDF), and AEs deemed a major complication by the CEC (4.3% TDR, 3.7% ACDF).
Subsequent Surgical Intervention
Subsequent surgeries were defined as any surgical procedure at the treated level and classified as a removal, revision, supplemental fixation, or reoperation. At 48 months, the subsequent surgery rate was statistically significantly lower for TDR compared with the ACDF (TDR: 3.0% vs. ACDF: 9.9%, P<0.05). There were 5 subsequent surgeries in the TDR group, including 1 patient who underwent cervical laminectomy at the TDR level due to nerve impingement. In the other 4 cases, the TDR device was removed and replaced with ACDF. In 1 case, the TDR was oversized for the disk space. One patient developed HO with slight cord impingement in whom the TDR was replaced with ACDF and osteophyte removal. Another patient had ongoing symptoms and described being bothered by the feel of the device during flexion and extension and underwent TDR removal and fusion of this level and an adjacent segment. The remaining patient developed kyphosis attributed to malpositioning of the device with lack of fixation to the superior endplate.
Eight patients in the ACDF group underwent subsequent surgery. Five of these were for symptomatic pseudoarthrosis. In 1 additional patient undergoing ACDF at C4–C5, the plate’s screws placed into the C5 vertebral body were malpositioned infringing on the C5–C6 disk space, causing symptoms. The plate was removed and fusion was performed with a plate spanning from C4 to C6. One patient underwent posterior foraminotomy and fusion at the index level due to symptomatic cervical stenosis. In 2 patients, the anterior plate at the ACDF level was removed during surgery at adjacent segments.
Subsequent surgery rates were also calculated based on all subsequent procedures, not limited to those meeting the criteria used in the composite definition of success. There was 1 additional surgery in the TDR group. This patient underwent fusion to treat a herniated disk at the segment adjacent to the TDR level approximately 17 months after the index surgery. In the ACDF group, there were 2 additional surgeries. One was to evacuate a hematoma approximately 5 days after the index surgery. The other was performed approximately 20 months after the index fusion to treat symptoms arising from an adjacent segment. If these surgeries are included, the reoperation rates were 3.6% in the TDR group and 12.3% in the ACDF group (P<0.05).
In the TDR group, the mean ROM at the operated level was maintained with a baseline value of 8 degrees and a mean of 10 degrees at 48-month follow-up as measured from flexion/extension radiographic images (Fig. 5). At baseline, 78.1% of TDR patients had at least 4 degrees of motion in flexion/extension at the index level. At 48 months, 81.9% of these patients had at least 4 degrees of motion in flexion/extension. At 48 months, 94.4% of ACDF patients met the criteria for fusion.
Relevant HO was present in 23.8% of TDR patients (grade 3 noted in 15.9% and grade 4 in 7.9%). By 48 months postoperative, adjacent-segment degeneration occurred significantly more frequently in the ACDF group than in the TDR population (ACDF 60.7% vs. TDR 44.3%, P<0.05). The rates were greater with ACDF at both the inferior and superior adjacent segments (inferior segment: TDR: 30% vs. ACDF: 50%, P<0.025; superior segment: TDR: 34% vs. ACDF: 53%, P<0.025).
This prospective, randomized study found that the results of TDR being noninferior to ACDF at 2-year follow-up were maintained throughout 4-year follow-up, with TDR showing overall success superiority at some timepoints. These results are similar to those reported in other studies comparing TDR with ACDF with 4–7 years’ follow-up.8–11
At 48 months, the rate of subsequent surgery was significantly less in the TDR group than for ACDF. This finding concurs with other studies comparing reoperation rates with >2-year follow-up.22,23 In the current study, the primary reason for reoperation in the fusion group was symptomatic pseudoarthrosis (6.2%). This was the same as reported in another TDR IDE trial using ACDF with allograft and anterior plate as the control group with 5-year follow-up.23
A meta-analysis reported a rate of significant HO at 24 months postoperative to be approximately 17%.24 In the current study, grade 3 or 4 HO was noted in 23.8% of the TDR patients at 48 months, which is similar to or less than rates reported by others in studies with similar follow-up duration.25,26 In a study involving 1- and 2-level cervical TDR, at 4-year follow-up 63% of patients had grade 3 or 4 HO.26 Although this HO rate seems high, the authors found that it had no deleterious impact on a favorable clinical outcome. In the current study, 1 patient underwent reoperation for symptoms related to HO. Guerin et al27 investigated factors possibly related to the development of HO in a study of 71 patients with 12–36 months’ follow-up. They could not identify any such factors including age, sex, tobacco use, herniated disk type, TDR height, operative time, or estimated operative blood loss. The authors found that grade 3 and 4 HO were related to reduced ROM, it was not related to reduced clinical outcome.
This study found that adjacent-segment degeneration was significantly greater in the fusion group than in the TDR group at both the level superior and inferior to the operated level. Results of other studies on adjacent-segment degeneration comparing TDR with fusion are mixed.2,28–31 This variation may be due to multiple factors including the method used to evaluate the adjacent segments, length of follow-up, the particular device implanted, surgical technique, patient selection, demographic characteristics, or other factors. One study investigating adjacent-segment degeneration in TDR versus ACDF found no increased incidence with fusion at follow-up ranging from 24 to 48 months.32 Their study required that the patient received treatment for symptoms arising from the adjacent segment. This variation in defining adjacent-segment degeneration may help to explain results different from most other studies. These same authors found that the factors such as age, sex, smoking, and number of levels operated were not related to adjacent-segment degeneration. Of interest, they found that adjacent-segment degeneration was more likely to occur in patients who also had degeneration of their lumbar disks. The authors performed a subsequent study only on the TDR patients with a minimum follow-up of 4 years.33 They found not only was lumbar disk degeneration related to the development of adjacent-segment degeneration, but also osteopenia at the time of surgery. The authors estimated an annual incidence of patients receiving treatment for adjacent-level degeneration was 3.1%. Unfortunately, this extended study did not include a comparison with the fusion population.
In the current study, 0.6% of TDR patients underwent subsequent surgery to treat symptoms arising from the level adjacent to the index level (this procedure also included reoperation at the index level), which compares favorably to 3.7% in the ACDF group. Delamarter and Zigler23 also reported a lower reoperation rate at the adjacent segment at 5-year follow-up when comparing TDR with ACDF.
This study found significant improvements in both pain and function in both treatment groups. On average, TDR patients maintained their baseline ROM throughout the 24-month follow-up. Furthermore, TDR patients demonstrated significantly lower subsequent surgery and adjacent-segment degeneration rates compared with the ACDF control group. These results add support for the safety and efficacy of single-level TDR in appropriately selected patients.
The authors thank the other principal investigators for their contributions to the study: Charlie Gordon, MD, Texas Spine and Joint Hospital, Tyler, TX; Arnold Schwartz, MD, Orthopedic Spine Care of Long Island, Huntington Station, NY; Ali Araghi, MD, The Core Institute, Phoenix, AZ; David Tahernia, MD, Desert Orthopedic Center, Rancho Mirage, CA; Hazem Eltahawy, MD, University Neurologic Systems, Wayne State University, Detroit, MI; Reginald Tall, MD, Southeastern Clinical Research, Orlando, FL; Douglas Wong, MD, Panorama Orthopedics & Spine Center, Golden, CO; Gerald Schell, MD, St Mary’s of Saginaw, Field Neurosciences Institute, Saginaw, MI; Robert Jackson, MD, Saddleback Memorial Medical Center, Laguna Hills, CA; Michael Ramsey, MD, West Texas Spine, Odessa, TX; B. Christoph Meyer, MD, Houston Orthopedic Hospital, Bellaire, TX; Robert McLain, MD, Cleveland Clinic, Cleveland, OH; Jon Park, MD, Stanford Hospital and Clinics, Stanford, CA; Ed Simmons, MD, Simmons Orthopaedics and Spine Associates, Buffalo, NY; Mark Stern, MD, California Institute of Neurological Surgery, Escondido, CA; Phillip S. Yuan, MD, Memorial Orthopaedic Surgical Group, Long Beach, CA; and Guy O. Danielson III, MD, Texas Spine and Joint Hospital, Tyler, TX.
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