Anterior cervical discectomy and fusion (ACDF) has been the standard surgical procedure for cervical degenerative disc disease (DDD) associated with intractable radiculopathy or myelopathy since its inception in the 1950s.1,3,4,17,46 However, ACDF, which aims to eliminate segmental motion between the fused vertebrae, creates abnormal loads, increasing stress and intradiscal pressures on segments adjacent to the fusion.7,53 This altered biomechanics of the spine has been reported to increase the incidence of adjacent segment degeneration (ASD) and to cause recurrent radiculopathy in as many as 25% of patients.16,21,25,45
Cervical disc arthroplasty (CDA) has become a more commonly used surgical procedure in the treatment of cervical DDD. Several large Food and Drug Administration (FDA) investigational device exemption (IDE) clinical trials have established that CDA and ACDF are at least equally safe and effective in treating symptoms associated with single-level cervical DDD.13,18,20,22,36,37 However, many patients have multilevel disease, and multilevel CDA may be a desirable alternative to fusion because multilevel ACDF can cause even greater stresses to adjacent discs,30 thereby potentially hastening ASD. Furthermore, compared with single-level ACDF, multilevel ACDF yields higher rates of pseudarthrosis,48 complications, revisions, and reoperations.51 In contrast, CDA at 2 adjacent cervical levels has been found to provide near normal mobility at the 2 implanted levels without affecting the adjacent levels,19 so that each implanted segment in a multilevel CDA is considered biomechanically independent of the adjacent segments.42 An IDE study demonstrated that patient outcomes were superior and complications fewer with 2-level CDA than with 2-level ACDF.14 A recent meta-analysis reported that multilevel CDA is as safe and effective as single-level CDA for the treatment of cervical disc diseases.56
The purpose of this study, which is registered with the ClinicalTrials.gov database (http://clinicaltrials.gov; registration no. NCT00637156), is to report the 24-month results of an FDA-regulated IDE clinical trial that compared the safety and effectiveness of 2-level CDA using Prestige LP (Medtronic Inc.) with those of 2-level ACDF to treat cervical DDD at 2 contiguous levels.
Methods
Study Design
Patient enrollment required a diagnosis of DDD at 2 adjacent levels (from C-3 to C-7) involving intractable radiculopathy and/or myelopathy unresponsive to at least 6 weeks of nonoperative treatment. Inclusion and exclusion criteria are listed in Table 1. Patients were evaluated preoperatively, intraoperatively, and postoperatively at 1.5, 3, 6, 12, and 24 months. Data in this paper represent all available 24-month safety and effectiveness data as of April 15, 2015.
Inclusion and exclusion criteria
| Inclusion criteria |
| Cervical DDD at 2 adjacent levels from C-3 to C-7, requiring surgical treatment & involving intractable radiculopathy, myelopathy, or both |
| Herniated disc &/or osteophyte formation at each level to be treated, producing symptomatic nerve root &/or spinal cord compression, documented by patient history & radiographic studies |
| Unresponsive to nonop treatment for at least 6 wks, or progressive symptoms or signs of nerve root/spinal cord compression |
| No previous surgical intervention at the involved levels |
| At least 18 yrs old & skeletally mature |
| Preop NDI score ≥30 |
| Preop NRS neck pain score ≥8 |
| If female, non-pregnant, non-nursing, & agrees not to become pregnant |
| Willing to comply w/study plan & sign informed consent |
| Exclusion criteria |
| Cervical spinal condition other than symptomatic cervical DDD at the involved levels |
| Cervical instability relative to adjacent segments at either level, defined as sagittal plane translation >3.5 mm or sagittal plane angulation >20° |
| More than 2 cervical levels requiring surgical treatment |
| A fused level adjacent to the levels to be treated |
| Severe pathology of the facet joints of the involved vertebral bodies |
| Has previous surgical intervention at either or both of the involved levels or at adjacent levels |
| Previously diagnosed w/osteopenia or osteomalacia |
| If DEXA required, T score of −3.5 or lower, or T score of −2.5 or lower with vertebral crush fracture |
| Presence of spinal metastases |
| Overt or active infection |
| Insulin-dependent diabetes |
| Tobacco use |
| Chronic or acute renal failure or history of renal disease |
| Allergy or intolerance to stainless steel, titanium, or titanium alloy |
| Prisoner |
| Pregnant |
| Alcohol &/or drug abuse |
| Current or pending litigation regarding a spinal condition |
| Received drugs that can interfere w/bone metabolism w/in 2 wks prior to surgery |
DEXA = dual-energy x-ray absorptiometry.
Sample Size
Determination was based on the hypothesis of noninferiority in overall success of the investigational device compared with the control treatment. Expected success rates were assumed to be 72% and 70% in the investigational and control groups, respectively. With a noninferiority margin of 10%, an alpha level of 0.05, and a power of 80%, the required sample size was 177 patients for each group. With an adjustment of 15% for potential loss to follow-up, 210 ± 5 patients were needed per group. Given the 1:1 randomization, the enrollment goal for this trial was 420 ± 10 patients. Two hundred nine patients received the investigational device, and 188 patients received the control treatment.
The study was approved by independent institutional review boards at each investigational site. All patients who met inclusion requirements and agreed to participate signed an informed consent form. Patients at 30 participating sites were randomized into treatment groups at a 1:1 ratio stratified by site and by varying block sizes (2, 4, and 6). The randomization schedule was centrally generated by the sponsor's statistician using statistical software (SAS, SAS Institute Inc.). Patients and surgeons were blinded only through the screening and informed consent process.
Investigational Device
The Prestige LP is an unconstrained metal-on-metal device comprising 2 low-profile plates that interface through a ball-and-trough mechanism that allows for 4 independent degrees of freedom. The plates attach to the vertebral bodies through impaction of the dual serrated keels. The device comes in a variety of heights and depths to accommodate individual patient anatomy. The low-profile design of the Prestige LP, which avoids obstruction of adjacent levels, makes it well suited for multilevel implantation. Following an IDE clinical trial (NCT00667459), the Prestige LP artificial disc was approved by the FDA in 2014 to treat intractable radiculopathy or myelopathy at a single level of the cervical spine.
Control Device
The control group received a cortical ring allograft for each of the 2 levels and an Atlantis anterior cervical plate (Medtronic Inc.) as part of ACDF.
Surgical Procedure and Postoperative Care
The surgical procedures in both investigational and control groups were performed via a standard anterior approach. A thorough dissection was performed at both index levels. The anterior annulus, disc, and cartilaginous endplates were removed. Gentle distraction was performed, reestablishing the anatomical disc space height, using either intradiscal distraction or Caspar vertebral body distraction pins. The lateral margins of the disc space were exposed, extending superiorly off of the lateral margins of the inferior vertebral body. The posterior annulus and posterior longitudinal ligament were partially or totally removed based on pathology, and the central spinal canal was exposed and decompressed. The depth of the vertebral body was precisely measured with a caliper. In the investigational group, the endplates were preserved and prepared utilizing a dual keel-cutting device. The size of the Prestige LP implant was selected to approximate the depth and height of the interspace. Care was taken not to overdistract the interspace, and the implant was impacted into the disc space. In the control fusion group, the vertebral endplates were decorticated. An anterior plate was placed over the cortical ring allograft and secured to the adjacent vertebral bodies.
The postoperative care regimen could be modified at the treating physician's discretion to accommodate each patient's needs. The use of nonsteroidal antiinflammatory drugs was recommended to the investigational group for the first 2 postoperative weeks but not thereafter. Postoperative bracing was left to the discretion of the physician, but only a soft collar was recommended for the investigational group.
Clinical Outcome Assessments
Patients completed the following validated questionnaires: the Neck Disability Index (NDI),52 the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36),54 and the Numeric Rating Scale (NRS; from 0 to 20 representing intensity and frequency of pain) for neck and arm pain.32 Gait abnormality was also assessed and graded on a scale of 0–5 using Nurick's classification.38 Patients were evaluated preoperatively and postoperatively at 1.5, 3, 6, 12, 24 months.
Radiographic Assessment
Two independent radiologists from a core laboratory (Biomedical Systems) performed software-based measurements of digital radiographs. A third independent radiologist adjudicated divergent findings. For the investigational group, radiographic success was determined by the maintenance of motion at both treated levels, defined as 1) angulation > 4° but ≤ 20° of angular motion, and 2) no bridging bone forming a continuous bony connection with adjacent vertebral bodies. For the control group, radiographic success was determined by fusion at both treated levels, defined as 1) angulation ≤ 4°, 2) bridging bone as a continuous bony connection with the vertebral bodies above and below, and 3) no radiolucency covering more than 50% of either the superior or inferior surface of the graft.
Functional Spinal Unit Height Measurement
Functional spinal unit (FSU) height was used as a surrogate measure of subsidence given that disc height is difficult to measure after implantation of the study device. Postoperative anterior and posterior FSU height at both treated levels was compared with the same measurement obtained 6 weeks preoperatively. Subsidence was inferred if the FSU height, anterior or posterior, had decreased by at least 2 mm.
Heterotopic Ossification
In the investigational group, heterotopic ossification (HO) was assessed on radiographs and graded according to the classification by Mehren et al.:33 0 = no HO present, I = HO detectable in front of the vertebral body but not in the anatomical interdiscal space, II = HO growing in the disc space and possibly affecting the function of the prosthesis, III = bridging ossifications that still allow movement of the prosthesis, or IV = complete fusion of treated segment without movement in flexion or extension.
Safety Assessment
Neurological function was assessed by physician-conducted tests of motor, sensory, and reflex functions. Neurological success was achieved if the preoperative status was maintained or improved. An adverse event (AE) was defined as any adverse clinical sign, symptom, syndrome, or illness that occurred or worsened during the operative and postoperative periods but did not necessarily include the predictable postoperative reactions, such as chills or vomiting. Adverse event categorization followed the FDA suggestion for the single-level Prestige LP IDE trial,18 which was based, in part, on the study sponsor's internal AE process and in part on the Medical Dictionary for Regulatory Activities (MedDRA) coding system. This hybrid system places each of 20 classifications of AEs under a broad body system (for example, neurological, cardiac disorders), incident (for example, trauma, infection), or other (associated conditions or systems with small numerical incidence). The severity of each AE (Grades 1–4: mild, moderate, severe, or life threatening, respectively, according to WHO criteria) and the association with the implant or surgical procedure were assessed by 2 members of an independent Clinical Adjudication Committee (CAC). A third CAC member adjudicated in cases of disagreement. Secondary surgical interventions were classified as revision, removal, supplemental fixation, or reoperation.
Primary Trial End Point
The primary end point, as required by the FDA, was a composite measure of overall success. Overall success was achieved when all 4 of the following criteria were met: 1) NDI score improvement of ≥ 15 points over the preoperative score, 2) maintenance or improvement in neurological status compared with preoperatively, 3) no serious AE caused by the implant or by both the implant and surgical procedure, and 4) no additional surgery classified as supplemental fixation, revision, or nonelective implant removal.
Other Effectiveness Measurements
Foraminal encroachment was assessed using the foraminal compression test. Foraminal encroachment was deemed present when pain was provoked by applying downward pressure on a patient's head in the neutral position and rotating the head left and right. Patients were asked postoperatively to respond to 3 statements regarding satisfaction with their surgery: 1) I am satisfied with the results of my surgery; 2) I was helped as much as I thought I would be with my surgery; and 3) All things considered, I would have the surgery again for the same condition. The possible answers ranged from “definitely true” to “definitely false.” Patients were asked about the perceived effect of treatment. The 7 possible answers ranged from “completely recovered” to “vastly worsened.” Patient work status was recorded preoperatively and at all postoperative evaluations. Work status and time to return to work were compared between treatment groups.
Independent Data Review
As was done in the analysis of the 1-level Prestige LP IDE trial,18 the study sponsor delivered the entire database of raw data to independent biostatisticians at Vanderbilt University for analysis. This study reports the analyses and results of the independent team, which followed the FDA-approved methods from the original statistical plan and reached the same statistical conclusions as those in the study sponsor analysis. Statisticians for the sponsor used the SAS statistical software (SAS Institute Inc.) to generate the summary tables and WinBUGS (Cambridge Institute of Public Health) to conduct the Bayesian analysis. The independent statisticians at Vanderbilt used R software (R Foundation for Statistical Computing) for the summary tables and JAGS (Cambridge Institute of Public Health) to conduct the Bayesian analysis.
Statistical Analyses
The hypothesis in this trial was that the 24-month overall success rate of the investigational group would be statistically noninferior to that of the control group (with a noninferiority margin of 0.1). If noninferiority were established, we predetermined that superiority would be examined. Bayesian methods were used to compare outcomes between the treatment groups. In addition to the 24-month outcomes, 12-month outcomes were also incorporated into the Bayesian likelihood model, although the focus of the comparison was the 24-month outcomes. Noninformative priors were used.29 Noninferiority and superiority were established if the posterior probability was at least 95%. Analyses similar to those for the overall success rate were conducted for success in individual effectiveness end points: NDI, FSU height, NRS neck pain, NRS arm pain, Physical Component Summary (PCS), Mental Component Summary (MCS), neurological measure, and gait measure. Success for these individual end points was defined as follows: NDI improvement of at least 15 points; FSU height maintenance within 2 mm; and maintenance or improvement in neck pain, arm pain, SF-36 PCS, SF-36 MCS, neurological status, and gait status, respectively.
Secondary end points included safety measures (AEs and additional surgical procedures or interventions) and surgical and hospitalization information (operative time, blood loss, and number of hospital days). Bayesian methods were also used to examine the difference between the treatment groups for these end points. The null hypothesis (that there was no difference) was rejected if the 95% highest posterior density (HPD) included 0. Superiority was established if the posterior probability of a lower rate or mean in the investigational group than in the control group was at least 97.5%.
Descriptive statistics of demographics, baseline characteristics, and some postoperative measurements were presented using mean and standard deviation for continuous variables and frequencies for categorical variables. Statistical comparisons between groups were made using Fisher's t-test for continuous variables and Fisher's exact test for categorical variables. Preoperative to postoperative changes in NDI, NRS neck pain, NRS arm pain, and SF-36 PCS and MCS scores, as well as radiographic measurements of motion, were assessed using paired t-tests, and gait status and foraminal compression tests were assessed using exact McNemar's test. A p value < 0.05 was considered statistically significant.
To compare return-to-work status between the 2 treatment groups, a Cox proportional-hazards model was fitted with preoperative working status included as covariate.
The primary analysis data set consisted of all patients who received the study treatments. The outcomes of a small number of patients who required an additional procedure (removal, revision, or supplemental fixation) were classified as failures for overall success, and the patients' last observations prior to the additional procedure were carried forward for all subsequent evaluations of the other outcomes.
Results
All surgeries were performed in the period from June 2006 to November 2007. Patient participation is reported in Fig. 1 and patient accountability in Table 2. Data were available to assess overall success for 199 of 209 investigational patients and 160 of 188 control patients for follow-up rates of 95.2% and 85.1%, respectively.
Patient participation flow diagram.
Patient accountability
| Parameter | No. (%) | ||
|---|---|---|---|
| Investigational Group | Control Group | Total | |
| Time period | |||
| Preop | 209 (100) | 188 (100) | 397 (100) |
| Postop | |||
| 1.5 mos | 208/209 (99.5) | 185/188 (98.4) | 393/397 (99.0) |
| 3 mos | 205/209 (98.1) | 180/186* (96.8) | 385/395* (97.5) |
| 6 mos | 204/209 (97.6) | 176/186* (94.6) | 380/395* (96.2) |
| 12 mos | 203/209 (97.1) | 168/184* (91.3) | 371/393* (94.4) |
| 24 mos | 199/209 (95.2) | 164/180* (91.1) | 363/389* (93.3) |
| No. w/data for overall success | 199/209 (95.2) | 160/180* (88.9) | 359/389* (92.3) |
The denominator excludes patients who withdrew from the study or died.
Demographic and Preoperative Characteristics
Except for the fact that more investigational than control patients (69.9% vs 60.1%, p = 0.045) had worked prior to surgery, the 2 treatment groups were similar on all other demographic characteristics. Likewise, there were no significant preoperative differences between the 2 groups in the efficacy end points (NDI, SF-36 PCS and MCS, gait, and neurological function), medical condition, medical history, and medication usage (Table 3).
Demographic, preoperative, and surgical characteristics
| Variable | Investigational Group | Control Group | p Value |
|---|---|---|---|
| No. of patients | 209 | 188 | |
| Demographics | |||
| Age (yrs) | 47.1 ± 8.3 | 47.3 ± 7.7 | 0.844 |
| Body mass index (kg/m2) | 28.2 ± 5.6 | 28.6 ± 4.9 | 0.481 |
| Male | 92/209 (44) | 90/188 (47.9) | 0.480 |
| Race | 0.879 | ||
| White | 195/209 (93.3) | 172/188 (91.5) | |
| Black | 8/209 (3.8) | 8/188 (4.2) | |
| Asian | 1/209 (0.5) | 3/188 (1.6) | |
| Hispanic | 4/209 (1.9) | 4/188 (2.1) | |
| Other | 1/209 (0.5) | 1/188 (0.5) | |
| Marital status | 0.698 | ||
| Single | 25/209 (12) | 29/188 (15.4) | |
| Married | 146/209 (69.8) | 133/188 (70.7) | |
| Divorced | 32/209 (15.3) | 23/188 (12.2) | |
| Separated | 4/209 (1.9) | 2/188 (1.1) | |
| Widowed | 2/209 (1) | 1/188 (0.5) | |
| Education level | 0.652 | ||
| <High school | 21/209 (10) | 20/188 (10.6) | |
| High school | 63/209 (30.1) | 64/188 (34) | |
| >High school | 125/209 (59.8) | 104/188 (55.3) | |
| Workers' compensation | 26/209 (12.4) | 19/188 (10.1) | 0.527 |
| Unresolved spinal litigation case | 0/209 (0) | 1/188 (0.5) | 0.474 |
| Working preoperatively | 146/209 (69.9) | 113/188 (60.1) | 0.045 |
| Medical condition & medicine usage | |||
| Duration of symptoms | 0.340 | ||
| <6 wks | 5/209 (2.4) | 8/188 (4.2) | |
| 6 wks to 6 mos | 56/209 (26.8) | 58/188 (30.8) | |
| >6 mos | 148/209 (70.8) | 122/188 (64.9) | |
| Previous neck surgery | 0/209 (0) | 2/188 (1.1) | 0.224 |
| Medications | |||
| Nonnarcotic | 138/208 (66.3) | 133/185 (71.9) | 0.275 |
| Weak narcotic | 83/208 (39.9) | 78/186 (41.9) | 0.758 |
| Strong narcotic | 52/207 (25.1) | 44/188 (23.4) | 0.725 |
| Muscle relaxant | 75/208 (36.1) | 73/188 (38.8) | 0.604 |
| Abnormal status | |||
| Gait | 48/209 (23) | 56/188 (29.8) | 0.138 |
| Neurological motor | 112/209 (53.6) | 100/188 (53.2) | 1.000 |
| Neurological sensory | 124/209 (59.3) | 122/188 (64.9) | 0.257 |
| Neurological reflexes | 119/209 (56.9) | 113/188 (60.1) | 0.542 |
| Neurological overall | 167/209 (79.9) | 157/188 (83.5) | 0.367 |
| Preop clinical end points | |||
| NDI | 52.1 ± 13.4 | 53.2 ± 14.8 | 0.441 |
| SF-36 PCS | 31.8 ± 7.8 | 30.8 ± 7.4 | 0.189 |
| SF-36 MCS | 43.9 ± 11.8 | 43.8 ± 12.2 | 0.930 |
| NRS neck pain score | 16.2 ± 2.9 | 16.3 ± 2.6 | 0.720 |
| NRS arm pain score | 13.8 ± 5.6 | 14.4 ± 4.3 | 0.208 |
Values expressed as mean ± standard deviation or as number/number with data (percentage).
Surgical Data
All surgical procedures were performed via a standard extrapharyngeal approach. Blood loss and operative time were statistically different between the 2 treatment groups. Mean operative time was 2.1 ± 0.8 hours in the investigational group, compared with 1.7 ± 0.7 hours in the control group (posterior probability of superiority < 0.001). Blood loss was 67.2 ± 64.1 ml in the investigational group and 55.7 ± 46.3 ml in the control group (posterior probability of superiority = 0.019). Length of hospital stay was not different between the 2 groups (1.2 ± 0.5 and 1.3 ± 1.0 days). Proportions of inpatients were similar (75.6% investigational, 73.4% control). The operative levels were most frequently C5–6 and C6–7 (78% investigational, 75% control, for both levels).
Success Rates for Overall Success and Individual Effectiveness End Points
At 24 months after surgery, the observed rates of over all success were 81.4% and 69.4% for the investigational group and control group, respectively. The posterior mean for overall success in the investigational group exceeded that in the control group by 0.112 (95% HPD interval = 0.023 to 0.201) with a posterior probability of essentially 1 for noninferiority and 0.993 for superiority (Table 4), demonstrating the superiority of the investigational group for overall success. Noninferiority of the investigational group was demonstrated for all individual end points except for the SF-36 MCS, and superiority was demonstrated for NDI.
Comparison of success rates overall and for individual end points at 24 months
| Measure | Success Rates | Bayesian Analysis | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Investigational Group | Control Group | Probability of Noninferiority | Probability of Superiority | Posterior Mean & 95% HPD | |||||||||
| p1(investigational group) | p0(control group) | p0−p1 | |||||||||||
| Mean | Lower | Upper | Mean | Lower | Upper | Mean | Lower | Upper | |||||
| NDI | 87.9% (175/199) | 79.2% (126/159) | 1.000 | 0.986 | 0.871 | 0.822 | 0.913 | 0.784 | 0.720 | 0.844 | −0.086 | −0.165 | −0.009 |
| Neurological status | 91.4% (182/199) | 86.2% (137/159) | 1.000 | 0.925 | 0.902 | 0.858 | 0.939 | 0.853 | 0.796 | 0.902 | −0.049 | −0.117 | 0.017 |
| FSU | 93.5% (159/170) | 95.6% (132/138) | 0.998 | 0.275 | 0.923 | 0.879 | 0.957 | 0.940 | 0.896 | 0.972 | 0.016 | −0.039 | 0.071 |
| NRS neck pain | 98.0% (195/199) | 95.6% (152/159) | 1.000 | 0.848 | 0.969 | 0.941 | 0.988 | 0.948 | 0.910 | 0.976 | −0.021 | −0.064 | 0.019 |
| NRS arm pain | 88.9% (177/199) | 89.9% (143/159) | 0.997 | 0.390 | 0.880 | 0.833 | 0.920 | 0.889 | 0.837 | 0.932 | 0.009 | −0.057 | 0.074 |
| SF-36 PCS | 90.4% (178/197) | 87.8% (137/156) | 1.000 | 0.769 | 0.896 | 0.851 | 0.934 | 0.872 | 0.817 | 0.918 | −0.025 | −0.091 | 0.040 |
| SF-36 MCS | 69.0%(136/197) | 72.4% (113/156) | 0.945 | 0.308 | 0.687 | 0.622 | 0.749 | 0.712 | 0.640 | 0.779 | 0.024 | −0.070 | 0.118 |
| Gait success | 100% (199/199) | 98.7% (157/159) | 1.000 | 0.855 | 0.990 | 0.973 | 0.998 | 0.977 | 0.949 | 0.993 | −0.013 | −0.042 | 0.010 |
| Overall success | 81.4% (162/199) | 69.4%(111/160) | 1.000 | 0.993 | 0.803 | 0.746 | 0.855 | 0.691 | 0.620 | 0.758 | −0.112 | −0.201 | −0.023 |
Clinical Outcomes
Both the investigational and control groups exhibited significant preoperative to postoperative improvement in scores at all time points for NDI, NRS neck pain, NRS arm pain, SF-36 PCS, SF-36 MCS, gait status, and foraminal compression (Fig. 2). Improvement in NDI and NRS neck pain was greater at all time points for the investigational group. The NDI score improved from 52.1 ± 13.4 preoperatively to 15.0 ± 16.6 at the 24-month follow-up for the investigational group and from 53.2 ± 14.8 to 20.0 ± 20.5 for the control group. The neck pain score improved from 16.2 ± 2.9 to 4.3 ± 4.9 for the investigational group and from 16.3 ± 2.6 to 5.9 ± 5.5 in the control group.
Preoperative to postoperative improvement at all time points in investigational (INV) and control (CON) groups for NDI, NRS neck pain, NRS arm pain, SF-36 PCS, SF-36 MCS, gait status, and foraminal compression test.
Safety Outcomes
The maintenance or improvement of neurological status at 24 months was attained by 91.5% of investigational patients and 86.2% of controls. As previously mentioned, the rate of neurological success was noninferior in the investigational group (Table 4).
The proportion of patients experiencing any AE (Table 5) was 93.3% (195/209) in the investigational group and 92.0% (173/188) in the control group, which was not statistically different. The rate of patients who reported any serious (Grade 3 or 4) AE was significantly higher in the control group (90 [47.9%] of 188) than in the investigational group (72 [34.4%] of 209) with a posterior probability of superiority of 0.996 (Table 6). The rates of AEs associated with the implant or implant and surgical procedure were similar in the 2 groups: 15.8% (33/209) in the investigational group and 20.7% (39/188) in the control group. The rates of Grade 3 or 4 AEs associated with the implant or implant and surgical procedure were also similar in the 2 groups: 1.9% (4/209) in the investigational group and 5.8% (11/188) in the control group. The 2 groups also had similar rates regarding all specific types of AE (FDA hybrid AE categories) except for nonunion.
Time course of all AEs
| Event | Operatively | 1 Day–4 Wks Postop | 1.5 Mos Postop | 3 Mos Postop | 6 Mos Postop | 12 Mos Postop | 24 Mos Postop | Total | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of Events | No. of Patients | No. of Events | No. of Patients | No. of Events | No. of Patients | No. of Events | No. of Patients | No. of Events | No. of Patients | No. of Events | No. of Patients | No. of Events | No. of Patients | No. of Events | No. of Patients | |
| Investigational group | ||||||||||||||||
| Any AEs | 54 | 32 | 166 | 70 | 116 | 50 | 228 | 86 | 245 | 85 | 372 | 102 | 296 | 88 | 1477 | 195 (93.3) |
| Cancer | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) |
| Cardiac disorders | 2 | 1 | 2 | 2 | 3 | 3 | 1 | 1 | 8 | 2 | 8 | 8 | 4 | 4 | 28 | 18 (8.6) |
| Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) |
| Dysphagia/dysphonia | 1 | 1 | 5 | 5 | 2 | 2 | 1 | 1 | 0 | 0 | 4 | 4 | 1 | 1 | 14 | 14 (6.7) |
| Gastrointestinal | 5 | 3 | 13 | 8 | 0 | 0 | 12 | 7 | 16 | 7 | 38 | 21 | 17 | 9 | 101 | 43 (20.6) |
| HO | 0 | 0 | 1 | 1 | 0 | 0 | 3 | 3 | 3 | 3 | 9 | 8 | 11 | 9 | 27 | 22 (10.5) |
| Implant events | 4 | 4 | 2 | 1 | 1 | 1 | 0 | 0 | 3 | 2 | 0 | 0 | 5 | 5 | 15 | 13 (6.2) |
| Infection | 0 | 0 | 5 | 5 | 3 | 3 | 3 | 3 | 8 | 7 | 20 | 14 | 9 | 9 | 48 | 36(17.2) |
| Neck &/or arm pain | 13 | 6 | 38 | 17 | 36 | 25 | 59 | 37 | 44 | 30 | 52 | 32 | 52 | 32 | 294 | 127 (60.8) |
| Neurological | 7 | 6 | 23 | 16 | 21 | 14 | 45 | 26 | 37 | 26 | 33 | 21 | 33 | 19 | 199 | 89 (42.6) |
| Nonunion | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0) |
| Other | 8 | 6 | 27 | 24 | 13 | 10 | 20 | 14 | 34 | 24 | 52 | 33 | 41 | 28 | 195 | 97 (46.4) |
| Other pain | 4 | 4 | 26 | 22 | 23 | 16 | 45 | 33 | 44 | 30 | 68 | 44 | 49 | 32 | 259 | 125 (59.8) |
| Respiratory | 4 | 3 | 8 | 6 | 1 | 1 | 3 | 3 | 3 | 2 | 14 | 7 | 14 | 7 | 47 | 29 (13.9) |
| Spinal event | 2 | 2 | 3 | 2 | 7 | 5 | 20 | 10 | 32 | 18 | 45 | 28 | 40 | 19 | 149 | 74(35.4) |
| Trauma | 0 | 0 | 0 | 0 | 5 | 5 | 8 | 8 | 8 | 8 | 15 | 14 | 9 | 8 | 45 | 37(17.7) |
| Urogenital | 1 | 1 | 5 | 4 | 0 | 0 | 6 | 5 | 2 | 2 | 9 | 8 | 8 | 8 | 31 | 25 (12.0) |
| Vascular | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 3 | 3 | 1 | 1 | 6 | 5 (2.4) |
| Wound (noninfectious) | 2 | 2 | 8 | 7 | 1 | 1 | 1 | 1 | 3 | 2 | 2 | 2 | 2 | 2 | 19 | 15(7.2) |
| Control group | ||||||||||||||||
| Any AEs | 38 | 23 | 221 | 68 | 119 | 51 | 266 | 89 | 240 | 68 | 390 | 92 | 319 | 79 | 1593 | 173 (92.0) |
| Cancer | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 1 | 1 | 1 | 1 | 3 | 3(1.6) |
| Cardiac disorders | 3 | 2 | 0 | 0 | 0 | 0 | 1 | 1 | 3 | 2 | 8 | 8 | 3 | 3 | 18 | 16 (8.5) |
| Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 1 | 1 (0.5) |
| Dysphagia/dysphonia | 2 | 1 | 11 | 7 | 4 | 4 | 5 | 4 | 0 | 0 | 3 | 3 | 2 | 2 | 27 | 21(11.2) |
| Gastrointestinal | 2 | 2 | 16 | 7 | 3 | 3 | 7 | 3 | 6 | 5 | 28 | 13 | 17 | 11 | 79 | 38 (20.2) |
| HO | 0 | 0 | 2 | 2 | 2 | 2 | 5 | 4 | 5 | 4 | 3 | 3 | 7 | 7 | 24 | 21(11.2) |
| Implant events | 0 | 0 | 2 | 2 | 2 | 2 | 2 | 1 | 2 | 2 | 4 | 3 | 0 | 0 | 12 | 10 (5.3) |
| Infection | 1 | 1 | 7 | 7 | 3 | 3 | 7 | 6 | 3 | 3 | 11 | 9 | 9 | 8 | 41 | 32(17.0) |
| Neck &/or arm pain | 2 | 1 | 52 | 32 | 28 | 19 | 56 | 33 | 50 | 30 | 58 | 31 | 47 | 29 | 293 | 114 (60.6) |
| Neurological | 8 | 7 | 25 | 16 | 23 | 14 | 41 | 24 | 22 | 13 | 44 | 29 | 29 | 17 | 192 | 85 (45.2) |
| Nonunion | 0 | 0 | 1 | 1 | 1 | 1 | 7 | 7 | 6 | 6 | 2 | 2 | 1 | 1 | 18 | 18 (9.6) |
| Other | 6 | 6 | 24 | 17 | 9 | 6 | 27 | 12 | 22 | 15 | 71 | 35 | 57 | 29 | 216 | 87 (46.3) |
| Other pain | 6 | 6 | 36 | 22 | 21 | 19 | 40 | 30 | 57 | 32 | 74 | 40 | 61 | 37 | 295 | 113 (60.1) |
| Respiratory | 5 | 4 | 6 | 5 | 2 | 2 | 8 | 6 | 10 | 7 | 13 | 12 | 8 | 6 | 52 | 34(18.1) |
| Spinal event | 0 | 0 | 26 | 13 | 12 | 8 | 45 | 18 | 38 | 18 | 47 | 24 | 29 | 19 | 197 | 80 (42.6) |
| Trauma | 0 | 0 | 6 | 5 | 2 | 2 | 6 | 6 | 8 | 8 | 14 | 14 | 24 | 16 | 60 | 39 (20.7) |
| Urogenital | 1 | 1 | 4 | 4 | 5 | 2 | 3 | 2 | 4 | 2 | 5 | 3 | 14 | 7 | 36 | 19 (10.1) |
| Vascular | 0 | 0 | 1 | 1 | 1 | 1 | 2 | 2 | 0 | 0 | 1 | 1 | 9 | 3 | 14 | 8 (4.3) |
| Wound (noninfectious) | 2 | 2 | 2 | 2 | 0 | 0 | 4 | 3 | 4 | 2 | 2 | 1 | 1 | 1 | 15 | 11(5.9) |
Comparison of AE rates between investigational and control groups
| Variable | Event Rates (no. of patients [%]) | Posterior Mean & 95% HPD | Probability of Superiority | Null Hypothesis | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Investigational Group (209) | Control Group (188) | p1(investigational group) | p0(control group) | p0− p1 | |||||||||
| Mean | Lower | Upper | Mean | Lower | Upper | Mean | Lower | Upper | |||||
| AE related to implant/surgical procedure | 33(15.8) | 39 (20.7) | 0.161 | 0.112 | 0.211 | 0.211 | 0.156 | 0.271 | 0.049 | −0.026 | 0.126 | 0.899 | Accepted |
| Grade 3 or 4 AE related to implant or implant/surgical procedure | 4(1.9) | 11(5.8) | 0.024 | 0.006 | 0.045 | 0.063 | 0.031 | 0.098 | 0.040 | −0.000 | 0.081 | 0.979 | Accepted |
| Any Grade 3 or 4 AE | 72 (34.4) | 90(47.9) | 0.346 | 0.284 | 0.412 | 0.479 | 0.407 | 0.549 | 0.133 | 0.036 | 0.227 | 0.996 | Rejected |
| Patients w/any AE | 195 (93.3) | 173 (92.0) | 0.929 | 0.891 | 0.959 | 0.916 | 0.872 | 0.951 | −0.013 | −0.066 | 0.039 | 0.312 | Accepted |
| Cancer | 0 (0) | 3(1.6) | 0.005 | 0.000 | 0.017 | 0.021 | 0.006 | 0.046 | 0.016 | −0.003 | 0.042 | 0.953 | Accepted |
| Cardiac disorders | 18 (8.6) | 16 (8.5) | 0.090 | 0.056 | 0.132 | 0.090 | 0.053 | 0.134 | −0.001 | −0.056 | 0.056 | 0.491 | Accepted |
| Death | 0 (0) | 1 (0.5) | 0.005 | 0.000 | 0.018 | 0.011 | 0.001 | 0.029 | 0.006 | −0.010 | 0.026 | 0.775 | Accepted |
| Dysphagia/dysphonia | 14 (6.7) | 21(11.2) | 0.071 | 0.041 | 0.109 | 0.116 | 0.075 | 0.165 | 0.045 | −0.012 | 0.103 | 0.941 | Accepted |
| Gastrointestinal AE | 43 (20.6) | 38 (20.2) | 0.208 | 0.157 | 0.266 | 0.205 | 0.151 | 0.265 | −0.003 | −0.082 | 0.077 | 0.469 | Accepted |
| HO | 22 (10.5) | 21(11.2) | 0.109 | 0.071 | 0.154 | 0.116 | 0.075 | 0.165 | 0.007 | −0.054 | 0.069 | 0.583 | Accepted |
| Implant event | 13 (6.2) | 10 (5.3) | 0.066 | 0.037 | 0.103 | 0.058 | 0.03 | 0.095 | −0.008 | −0.056 | 0.039 | 0.361 | Accepted |
| Infection | 36(17.2) | 32(17.0) | 0.175 | 0.127 | 0.229 | 0.174 | 0.123 | 0.230 | −0.002 | −0.076 | 0.073 | 0.480 | Accepted |
| Neck &/or arm pain | 127 (60.8) | 114 (60.6) | 0.607 | 0.54 | 0.671 | 0.605 | 0.535 | 0.674 | −0.001 | −0.096 | 0.094 | 0.490 | Accepted |
| Neurological AE | 89 (42.6) | 85 (45.2) | 0.427 | 0.361 | 0.494 | 0.453 | 0.383 | 0.524 | 0.026 | −0.071 | 0.123 | 0.701 | Accepted |
| Nonunion | 0 (0) | 18 (9.6) | 0.005 | 0.000 | 0.017 | 0.100 | 0.061 | 0.146 | 0.095 | 0.056 | 0.142 | 1.000 | Rejected |
| Other AE | 97 (46.4) | 87 (46.3) | 0.464 | 0.397 | 0.532 | 0.463 | 0.393 | 0.534 | −0.001 | −0.099 | 0.096 | 0.490 | Accepted |
| Other pain | 125 (59.8) | 113 (60.1) | 0.597 | 0.53 | 0.662 | 0.600 | 0.530 | 0.669 | 0.003 | −0.093 | 0.099 | 0.525 | Accepted |
| Respiratory | 29 (13.9) | 34(18.1) | 0.142 | 0.099 | 0.192 | 0.184 | 0.132 | 0.242 | 0.042 | −0.030 | 0.115 | 0.872 | Accepted |
| Spinal event | 74(35.4) | 80 (42.6) | 0.355 | 0.293 | 0.421 | 0.426 | 0.357 | 0.497 | 0.071 | −0.024 | 0.166 | 0.928 | Accepted |
| Trauma | 37(17.7) | 39 (20.7) | 0.180 | 0.131 | 0.234 | 0.211 | 0.156 | 0.271 | 0.030 | −0.047 | 0.109 | 0.778 | Accepted |
| Urogenital AE | 25 (12.0) | 19 (10.1) | 0.123 | 0.083 | 0.171 | 0.105 | 0.066 | 0.152 | −0.018 | −0.080 | 0.044 | 0.281 | Accepted |
| Vascular AE | 5 (2.4) | 8 (4.2) | 0.028 | 0.011 | 0.055 | 0.047 | 0.022 | 0.082 | 0.019 | −0.017 | 0.058 | 0.846 | Accepted |
| Wound (noninfectious) | 15(7.2) | 11(5.8) | 0.076 | 0.044 | 0.115 | 0.063 | 0.033 | 0.101 | −0.013 | −0.063 | 0.037 | 0.304 | Accepted |
Grade 1 (mild), AE is noticeable but does not interfere with routine activity or require removal of the implant(s); Grade 2 (moderate), AE interferes with routine activity but responds to symptomatic therapy or rest and does not require removal of the implant(s); Grade 3 (severe), AE significantly limits the patient's ability to perform routine activities despite symptomatic therapy, may require hospitalization, and may require removal of the implant(s); Grade 4 (life-threatening), AE requires removal of the implant(s), or the patient is at immediate risk of death, even if the AE is not related to the implant(s).
Adverse events that required a second surgery at the index levels were considered revisions, removals, supplemental fixations, or reoperations. Revision was a procedure to adjust or in any way modify the original implant configuration. Removal was a procedure to remove one or more components of the original implant configuration without replacement with the same type of device. Supplemental fixation was a procedure to add spinal devices not approved as part of the protocol. Reoperation was a procedure that did not remove, modify, or add any component (for instance, decompression or removal of disc material and bone fragments). The observed rates of secondary surgeries at the index levels were 2.4% (5/209) for the investigational group and 8.0% (15/188) for the control group, (Table 7). The investigational group had a statistically lower rate of secondary surgeries than the control group, with a posterior probability of superiority of 0.994. There were no statistical differences between the 2 groups for any subcategory of secondary surgery. Five investigational patients (2.4%) and 6 control patients (3.2%) had secondary surgeries at adjacent levels.
Rates of secondary surgeries
| Surgery | Investigational Group (209 patients) | Control Group (188 patients) | Bayesian Analysis | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Posterior Mean & 95% HPD | Probability of Superiority | |||||||||||
| p1 (investigational group) | p0 (control group) | p0−p1 | ||||||||||
| Mean | Lower | Upper | Mean | Lower | Upper | Mean | Lower | Upper | ||||
| Any secondary surgery | 5 (2.4%) | 15 (8.0%) | 0.028 | 0.011 | 0.055 | 0.084 | 0.049 | 0.128 | 0.056 | 0.013 | 0.103 | 0.994 |
| Revision | 0 (0.0%) | 1 (0.5%) | 0.005 | 0 | 0.017 | 0.011 | 0.001 | 0.029 | 0.006 | −0.01 | 0.026 | 0.774 |
| Removal | 3 (1.4%) | 6 (3.2%) | 0.019 | 0.005 | 0.041 | 0.037 | 0.015 | 0.068 | 0.018 | 0.013 | 0.052 | 0.871 |
| Removal, elective | 0 (0.0%) | 2 (1.1%) | 0.005 | 0 | 0.017 | 0.016 | 0.003 | 0.038 | 0.011 | 0.007 | 0.034 | 0.895 |
| Supplemental fixation | 1 (0.5%) | 3 (1.6%) | 0.009 | 0.001 | 0.026 | 0.021 | 0.006 | 0.046 | 0.012 | 0.011 | 0.038 | 0.844 |
| Reoperation | 2 (1.0%) | 4 (2.1%) | 0.014 | 0.003 | 0.034 | 0.026 | 0.009 | 0.053 | 0.012 | 0.015 | 0.042 | 0.816 |
| Any secondary surgery at adjacent level | 5 (2.4%) | 6 (3.2%) | 0.028 | 0.008 | 0.051 | 0.037 | 0.013 | 0.064 | 0.008 | 0.027 | 0.044 | 0.684 |
Radiographic Outcomes
Functional spine unit height was radiographically evaluable in 308 patients and was maintained in 93.5% (159/170) of the investigational patients and 95.6% (132/138) of the control patients (Table 4). Radiographic success was achieved in 51.0% (100/196) of the investigational patients (as maintenance of motion with no evidence of bridging bone) and 82.1% (119/145) of the control patients (as fusion).
Motion at the index (for the investigational group) and adjacent levels was measured by comparing lateral flexion and extension radiographs (Fig. 3). Angular motion at the superior index level was 6.75° ± 4.16° and 6.92° ± 3.96° preoperatively and 24 months postoperatively, respectively. Angular motion at the inferior index level was 5.56° ± 3.89° and 6.85° ± 4.25° preoperatively and 24 months postoperatively, respectively. The change from the preoperative value was not significant for the superior index level but was significant (p = 0.001) for the inferior index level. Translatory motion at the superior index level was 1.48 ± 1.08 mm and 1.33 ± 0.78 mm preoperatively and 24 months postoperatively, respectively. Translatory motion at the inferior index level was 1.04 ± 0.74 mm and 1.16 ± 0.71 mm preoperatively and 24 months postoperatively, respectively. The change from the preoperative value was not significant for either the superior or inferior index levels.
Comparisons of angular and translation motion at baseline and 24 months in investigational (INV) and control (CON) groups.
For the adjacent level above the treated segments, mean preoperative angular motion was 9.89° ± 4.51° for the investigational group and 10.02° ± 4.41° for the control group. Postoperatively, mean angular motion at the level above the treated segments decreased significantly from baseline then gradually increased to 11.11° ± 4.76° for the investigational group and 11.16° ± 5.13° for the control group at 24 months (a significant increase from baseline for both groups). Mean preoperative angular motion at the adjacent level below the treated segments was consistently less than the angular motion at the level above the treated segments. Preoperative angular motion at the level below the treated segments was 5.02° ± 3.58° for the investigational group and 4.85° ± 3.32° for the control group. At 24 months after surgery, these values were 5.14° ± 3.66° (investigational) and 6.16° ± 3.88° (control), representing a significant increase for the control group.
Translatory motion followed a pattern similar to angular motion. Preoperative mean translatory motion at the adjacent level above the treated segments was 2.38 ± 1.35 mm for the investigational group and 2.42 ± 1.21 mm for the control group. It decreased significantly at 1.5 months (to 2.04 mm for the investigational group and 1.92 mm for the control group), then at 24 months it gradually increased to 2.66 ± 1.12 mm for the investigational group and 2.73 ± 1.16 mm for the control group, representing a significant increase from baseline for both groups. Preoperative mean translatory motion at the adjacent segment below the treated segments was 1.09 ± 0.64 mm for the investigational group and 1.04 ± 0.74 mm for the control group. At 24 months, these values were 1.25 ± 0.77 mm (investigational) and 1.46 ± 1.03 mm (control), representing a significant increase for the control group.
Heterotopic Ossification
At 24 months, the presence of any HO was identified in 27.8% (55/198) of the superior levels and 36.4% (72/198) of the inferior levels of investigational patients (Table 8). The presence and severity of HO gradually increased over the follow-up period. Severe HO (Grade III and IV) restricts motion of the segment and was evident in 3.5% of the patients at 6 months, 13.4% at 12 months, and 24.2% at 24 months. The incidence of HO did not impact clinical outcomes: the success rates were similar for patients with and without severe HO (Table 9).
Rates of HO in investigational patients at follow-up intervals
| FU Period & HO Grade | No. of Patients (%) | |
|---|---|---|
| Superior Level | Inferior Level | |
| 6 mos | ||
| 0 | 185/202 (91.6%) | 173/202 (85.6%) |
| I | 5/202 (2.5%) | 14/202 (6.9%) |
| II | 10/202 (5.0%) | 9/202 (4.4%) |
| III | 2/202 (1.0%) | 6/202 (3.0%) |
| IV | 0/202 (0.0%) | 0/202 (0.0%) |
| 12 mos | ||
| 0 | 164/202 (81.2%) | 151/202 (74.8%) |
| I | 9/202 (4.4%) | 11/202 (5.4%) |
| II | 15/202 (7.4%) | 18/202 (8.9%) |
| III | 14/202 (6.9%) | 21/202 (10.4%) |
| IV | 0/202 (0.0%) | 1/202 (0.5%) |
| 24 mos | ||
| 0 | 143/198 (72.2%) | 126/198 (63.6%) |
| I | 10/198 (5.1%) | 11/198 (5.6%) |
| II | 13/198 (6.6%) | 22/198 (11.1%) |
| III | 28/198 (14.1%) | 33/198 (16.7%) |
| IV | 4/198 (2.0%) | 6/198 (3.0%) |
Grade 0 = no HO present, Grade I = HO detectable in front of the vertebral body but not in the anatomic interdiscal space, Grade II = HO growing in the disc space and possibly affects function of the prosthesis, Grade III = bridging ossifications that still allow movement of the prosthesis, or Grade IV = complete fusion of the treated segment without movement in flexion/extension.
Success rates by severity of HO at 24 months
| Measure | Non-Severe HO (Grades 0, I, II) | Severe HO (Grades III, IV) | p Value |
|---|---|---|---|
| No. of patients | 150 | 48 | |
| NDI success | 131 (87.3%) | 44/48 (91.7%) | 0.605 |
| Neurological success | 140 (93.3%) | 42/48 (87.5%) | 0.225 |
| Second surgery failure | 3 | 0 | |
| Associated SAEs | 1 | 0 | |
| Overall success | 123 (82.0%) | 39/48 (81.3%) | 1.000 |
SAE = serious adverse event.
Patient Satisfaction and Perception of Treatment Effectiveness
We observed a higher proportion of success in the investigational group than in the control group regarding satisfaction with surgery. Success was defined as responses of “definitely true” or “mostly true” to statements about being satisfied with the results of surgery (94.5% investigational vs 89.3% control), being helped by the surgery (93.9% vs 85.5%), and a willingness to have the surgery again (93.4% vs 88.7%).
Perceived Effect of Treatment
Similar proportions of patients in the 2 treatment groups considered their treatment to be a success. At the 24-month follow-up, 97% of investigational and 93.7% of control patients answered that they were “completely recovered,” “much improved,” or “slightly improved.”
Return to Work
Preoperatively, 69.9% (146/209) of investigational patients and 60.1% (113/188) of control patients reported working. At 24 months, 72.9% (145/199) of investigational and 71.1% (113/159) of control patients reported working. The median return-to-work time after surgery was 49 days for investigational patients and 55 days for control patients. There was no significant difference between the 2 groups (p = 0.48 based on Cox proportional-hazards model adjusting for preoperative work status).
Discussion
At 24 months after surgery, overall success rates were 81.4% for the investigational group and 69.4% for the control group. Both the noninferiority and superiority of the investigational treatment were established, thereby demonstrating that arthroplasty with Prestige LP is at least as safe and effective as ACDF for treating DDD at 2 adjacent levels in the cervical spine. Besides overall success, greater improvement in disability and neck pain was attained by the CDA group than the ACDF group. Additionally, the CDA group underwent fewer secondary surgeries than the ACDF group. Although early artificial discs were prone to complications,41 currently available artificial discs are associated with better safety outcomes and fewer AEs and secondary surgeries than ACDF.15,31,35,50 The results of our study, in accordance with earlier studies, confirm the noninferiority and superiority of multilevel CDA outcomes compared with multilevel ACDF.9,14,24
Heterotopic ossification, with its increasing prevalence over time, is a well-known occurrence after CDA. Its prevalence after 2-level CDA has been found to be higher than,55 lower than,23 and similar to10,56 that after single-level CDA. The prevalence of severe HO (Grade III and IV) in the current study was similar to that reported in another 2-level CDA IDE trial,14 increasing from 3.5% at 6 months to 24.2% at 24 months. In our study, as in other studies,2,8,11,19,26–28,47 HO did not impact patient outcomes. Although the long-term impact of HO is not yet known,8,11,23,47 it is obviously counter to the goals of CDA, which are the maintenance of motion and the avoidance or reduction of ASD. Despite the HO, the CDA patients in this study underwent fewer adjacent segment surgeries (5 [2.4%] of 209) than the ACDF patients (6 [3.2%] of 188), even though this difference did not reach statistical significance. Other studies have also reported fewer adjacent segment operations after CDA than fusion, up to 7 years after surgery.6,15,36 Whether the expected ASD decrease will be an “unfulfilled promise”44 due to the progression of severe HO following CDA remains to be investigated.
The lack of blinding to treatment, a known source of bias, is a limitation of this study. It was not possible to blind the physicians because they had to perform the surgeries. To reduce physician bias, radiographic and safety assessments were conducted by independent reviewers. It was also not possible to blind the patients, who were alerted to their surgeries by processing insurance paperwork. It has been found that, in the absence of a double-blind approach, the investigational treatment is more likely to be judged favorably.12,34 Indeed, patients in this study reported greater improvement after CDA than ACDF. However, the decompression, which is similar in both control and treatment groups, is the part of each surgical procedure that is responsible for the reduction in pain and disability. Hence, one would expect patients in the 2 groups to report similar improvement.49 Studies comparing CDA with fusion15,20,22,36 have generally reported greater reductions in pain and disability following CDA with a variety of devices, but not consistently so.15,39,43,50 In the face of unexpected patient reports, one cannot rule out the influence of bias favoring the investigational treatment, but one should also expect such bias to wane once “reality sets in.” In that regard, some have noted that the patient-reported difference between CDA and ACDF has vanished over time,22 while, remarkably, other patients have continued to report superior improvement in the long term, even up to 7 years after cervical CDA compared with ACDF.5,6,14 Although one cannot rule out the existence of a bias favoring CDA in the short term, it seems improbable that bias would remain for so many years. In that respect, longer-term follow-up is underway to ascertain the longevity of the relative benefits of multilevel CDA over ACDF observed in this patient sample.
Another limitation of this study is the potential bias that may stem from conflicts of interest created by the financial relationship between the study sponsor and some investigators. However, several measures were taken to preclude the influence of conflicts of interest: all radiological assessments were made by independent reviewers, all AEs were evaluated by an independent committee, and all reported statistical analyses were performed by independent statisticians. The study sponsor provided the entire raw data set to a team of independent statisticians at Vanderbilt University. Using the statistical analysis plan in the study protocol approved by the FDA, the independent analysis team reached the same statistical conclusions as the study sponsor for all proposed comparisons.
Finally, it should be noted that this clinical trial included patients with intractable radiculopathy or myelopathy or both, at 2 adjacent levels. We report the results of the trial according to the FDA-approved statistical plan, which did not include analyses of pathology subgroups. These analyses and the implications regarding the appropriateness of treatment for the pathology subgroups will be addressed in a separate publication.
Conclusions
Overall, these findings indicate that CDA using Prestige LP is as effective and safe as ACDF for the treatment of cervical DDD at 2 contiguous levels. Hence, it is an alternative treatment for patients with symptoms at 2 adjacent levels of the cervical spine.
Disclosures
Drs. Gornet, Lanman, Burkus, Hodges, McConnell, and Dryer are currently or were previously consultants for Medtronic. Drs. Hui and Harrell received funding for statistical analysis from Medtronic. Dr. Copay has nothing to disclose.
Author Contributions
Conception and design: Gornet. Acquisition of data: Gornet, Lanman, Burkus, Hodges, McConnell, Dryer. Analysis and interpretation of data: Gornet, Copay, Nian, Harrell. Drafting the article: Gornet, Copay. Critically revising the article: Gornet, Lanman, Burkus, McConnell, Dryer, Copay. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Gornet. Statistical analysis: Nian, Harrell.
References
- 1↑
Bohlman HH, Emery SE, Goodfellow DB, Jones PK: Robinson anterior cervical discectomy and arthrodesis for cervical radiculopathy. Long-term follow-up of one hundred and twenty-two patients. J Bone Joint Surg Am 75:1298–1307, 1993
- 2↑
Brenke C, Scharf J, Schmieder K, Barth M: High prevalence of heterotopic ossification after cervical disc arthroplasty: outcome and intraoperative findings following explantation of 22 cervical disc prostheses. J Neurosurg Spine 17:141–146, 2012
- 3↑
Brodke DS, Zdeblick TA: Modified Smith-Robinson procedure for anterior cervical discectomy and fusion. Spine 17:10 Suppl S427–S430, 1992
- 4↑
Brown JA, Havel P, Ebraheim N, Greenblatt SH, Jackson WT: Cervical stabilization by plate and bone fusion. Spine (Phila Pa 1976) 13:236–240, 1988
- 5↑
Burkus JK, Haid RW, Traynelis VC, Mummaneni PV: Long-term clinical and radiographic outcomes of cervical disc replacement with the Prestige disc: results from a prospective randomized controlled clinical trial. J Neurosurg Spine 13:308–318, 2010
- 6↑
Burkus JK, Traynelis VC, Haid RW Jr, Mummaneni PV: Clinical and radiographic analysis of an artificial cervical disc: 7-year follow-up from the Prestige prospective randomized controlled clinical trial: Clinical article. J Neurosurg Spine 21:516–528, 2014
- 7↑
Chang UK, Kim DH, Lee MC, Willenberg R, Kim SH, Lim J: Changes in adjacent-level disc pressure and facet joint force after cervical arthroplasty compared with cervical discectomy and fusion. J Neurosurg Spine 7:33–39, 2007
- 8↑
Chen J, Wang X, Bai W, Shen X, Yuan W: Prevalence of heterotopic ossification after cervical total disc arthroplasty: a meta-analysis. Eur Spine J 21:674–680, 2012
- 9↑
Cheng L, Nie L, Zhang L, Hou Y: Fusion versus Bryan Cervical Disc in two-level cervical disc disease: a prospective, randomised study. Int Orthop 33:1347–1351, 2009
- 10↑
Cho HJ, Shin MH, Huh JW, Ryu KS, Park CK: Heterotopic ossification following cervical total disc replacement: iatrogenic or constitutional?. Korean J Spine 9:209–214, 2012
- 11↑
Cho YH, Kim KS, Kwon YM: Heterotopic ossification after cervical arthroplasty with ProDisc-C: time course radiographic follow-up over 3 years. Korean J Spine 10:19–24, 2013
- 12↑
Colditz GA, Miller JN, Mosteller F: How study design affects outcomes in comparisons of therapy. I: Medical. Stat Med 8:441–454, 1989
- 13↑
Coric D, Nunley PD, Guyer RD, Musante D, Carmody CN, Gordon CR, et al.: Prospective, randomized, multicenter study of cervical arthroplasty: 269 patients from the Kineflex|C artificial disc investigational device exemption study with a minimum 2-year follow-up: clinical article. J Neurosurg Spine 15:348–358, 2011
- 14↑
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 19:532–545, 2013
- 15↑
Delamarter RB, Murrey D, Janssen ME, Goldstein JA, Zigler J, Tay BK, et al.: Results at 24 months from the prospective, randomized, multicenter Investigational Device Exemption trial of ProDisc-C versus anterior cervical discectomy and fusion with 4-year follow-up and continued access patients. SAS J 4:122–128, 2010
- 16↑
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) 30:1165–1172, 2005
- 17↑
Fraser JF, Härtl R: Anterior approaches to fusion of the cervical spine: a metaanalysis of fusion rates. J Neurosurg Spine 6:298–303, 2007
- 18↑
Gornet MF, Burkus JK, Shaffrey ME, Argires PJ, Nian H, Harrell FE: Cervical disc arthroplasty with PRESTIGE LP disc versus anterior cervical discectomy and fusion: a prospective, multicenter investigational device exemption study. J Neurosurg Spine 23:558–573, 2015
- 19↑
Guérin P, Obeid I, Bourghli A, Meyrat R, Luc S, Gille O, et al.: Heterotopic ossification after cervical disc replacement: clinical significance and radiographic analysis. A prospective study. Acta Orthop Belg 78:80–86, 2012
- 20↑
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) 34:101–107, 2009
- 21↑
Hilibrand AS, Robbins M: Adjacent segment degeneration and adjacent segment disease: the consequences of spinal fusion?. Spine J 4:6 Suppl 190S–194S, 2004
- 22↑
Hisey MS, Bae HW, Davis R, Gaede S, Hoffman G, Kim K, et al.: Multi-center, prospective, randomized, controlled investigational device exemption clinical trial comparing Mobi-C Cervical Artificial Disc to anterior discectomy and fusion in the treatment of symptomatic degenerative disc disease in the cervical spine. Int J Spine Surg 8:7, 2014
- 23↑
Huppert J, Beaurain J, Steib JP, Bernard P, Dufour T, Hovorka I, et al.: Comparison between single- and multilevel patients: clinical and radiological outcomes 2 years after cervical disc replacement. Eur Spine J 20:1417–1426, 2011
- 24↑
Kepler CK, Brodt ED, Dettori JR, Albert TJ: Cervical artificial disc replacement versus fusion in the cervical spine: a systematic review comparing multilevel versus single-level surgery. Evid Based Spine Care J 3:S1 19–30, 2012
- 25↑
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 100:1 Suppl Spine 2–6, 2004
- 26
Lee JH, Jung TG, Kim HS, Jang JS, Lee SH: Analysis of the incidence and clinical effect of the heterotopic ossification in a single-level cervical artificial disc replacement. Spine J 10:676–682, 2010
- 27
Lee SE, Chung CK, Jahng TA: Early development and progression of heterotopic ossification in cervical total disc replacement. J Neurosurg Spine 16:31–36, 2012
- 28
Leung C, Casey AT, Goffin J, Kehr P, Liebig K, Lind B, et al.: Clinical significance of heterotopic ossification in cervical disc replacement: a prospective multicenter clinical trial. Neurosurgery 57:759–763, 2005
- 29↑
Lipscomb B, Ma G, Berry DA: Bayesian predictions of final outcomes: regulatory approval of a spinal implant. Clin Trials 2:325–349, 364–378, 2005
- 30↑
Lopez-Espina CG, Amirouche F, Havalad V: Multilevel cervical fusion and its effect on disc degeneration and osteophyte formation. Spine (Phila Pa 1976) 31:972–978, 2006
- 31↑
McAfee PC, Reah C, Gilder K, Eisermann L, Cunningham B: A meta-analysis of comparative outcomes following cervical arthroplasty or anterior cervical fusion: results from 4 prospective multicenter randomized clinical trials and up to 1226 patients. Spine (Phila Pa 1976) 37:943–952, 2012
- 32↑
McDowell I, Newell C: Measuring Health. A Guide to Rating Scales and Questionnaires New York, Oxford University Press, 1996
- 33↑
Mehren C, Suchomel P, Grochulla F, Barsa P, Sourkova P, Hradil J, et al.: Heterotopic ossification in total cervical artificial disc replacement. Spine (Phila Pa 1976) 31:2802–2806, 2006
- 34↑
Miller JN, Colditz GA, Mosteller F: How study design affects outcomes in comparisons of therapy. II: Surgical. Stat Med 8:455–466, 1989
- 35↑
Mummaneni PV, Amin BY, Wu JC, Brodt ED, Dettori JR, Sasso RC: Cervical artificial disc replacement versus fusion in the cervical spine: a systematic review comparing long-term follow-up results from two FDA trials. Evid Based Spine Care J 3:S1 59–66, 2012
- 36↑
Mummaneni PV, Burkus JK, Haid RW, Traynelis VC, Zdeblick TA: Clinical and radiographic analysis of cervical disc arthroplasty compared with allograft fusion: a randomized controlled clinical trial. J Neurosurg Spine 6:198–209, 2007
- 37↑
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 9:275–286, 2009
- 38↑
Nurick S: The pathogenesis of the spinal cord disorder associated with cervical spondylosis. Brain 95:87–100, 1972
- 39↑
Peng CW, Yue WM, Basit A, Guo CM, Tow BP, Chen JL, et al.: Intermediate results of the Prestige LP cervical disc replacement: clinical and radiological analysis with minimum two-year follow-up. Spine (Phila Pa 1976) 36:E105–E111, 2011
- 40
Phillips FM, Tzermiadianos MN, Voronov LI, Havey RM, Carandang G, Dooris A, et al.: Effect of two-level total disc replacement on cervical spine kinematics. Spine (Phila Pa 1976) 34:E794–E799, 2009
- 41↑
Pickett GE, Sekhon LH, Sears WR, Duggal N: Complications with cervical arthroplasty. J Neurosurg Spine 4:98–105, 2006
- 42↑
Pimenta L, McAfee PC, Cappuccino A, Cunningham BW, Diaz R, Coutinho E: Superiority of multilevel cervical arthroplasty outcomes versus single-level outcomes: 229 consecutive PCM prostheses. Spine (Phila Pa 1976) 32:1337–1344, 2007
- 43↑
Porchet F, Metcalf NH: Clinical outcomes with the Prestige II cervical disc: preliminary results from a prospective randomized clinical trial. Neurosurg Focus 17:3 E6, 2004
- 44↑
Riew KD, Schenk-Kisser JM, Skelly AC: Adjacent segment disease and C-ADR: promises fulfilled?. Evid Based Spine Care J 3:S1 39–46, 2012
- 45↑
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 3:417–423, 2005
- 46↑
Smith GW, Robinson RA: The treatment of certain cervical-spine disorders by anterior removal of the intervertebral disc and interbody fusion. J Bone Joint Surg Am 40-A:607–624, 1958
- 47↑
Suchomel P, Jurák L, Benes V III, 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 19:307–315, 2010
- 48↑
Swank ML, Lowery GL, Bhat AL, McDonough RF: Anterior cervical allograft arthrodesis and instrumentation: multilevel interbody grafting or strut graft reconstruction. Eur Spine J 6:138–143, 1997
- 49↑
Tharin S, Benzel EC: Cervical spine arthroplasty: fact or fiction: the absence of need for arthroplasty. Clin Neurosurg 59:82–90, 2012
- 50↑
Upadhyaya CD, Wu JC, Trost G, Haid RW, Traynelis VC, Tay B, et al.: Analysis of the three United States Food and Drug Administration investigational device exemption cervical arthroplasty trials. J Neurosurg Spine 16:216–228, 2012
- 51↑
Veeravagu A, Cole T, Jiang B, Ratliff JK: Revision rates and complication incidence in single- and multilevel anterior cervical discectomy and fusion procedures: an administrative database study. Spine J 14:1125–1131, 2014
- 52↑
Vernon H, Mior S: The Neck Disability Index: a study of reliability and validity. J Manipulative Physiol Ther 14:409–415, 1991
- 53↑
Wang CS, Chang JH, Chang TS, Chen HY, Cheng CW: Loading effects of anterior cervical spine fusion on adjacent segments. Kaohsiung J Med Sci 28:586–594, 2012
- 54↑
Ware JE, Kosinski M, Keller SK: SF-36 Physical and Mental Health Summary Scales: A User's Manual Boston, The Health Institute, 1994
- 55↑
Wu JC, Huang WC, Tsai HW, Ko CC, Fay LY, Tu TH, et al.: Differences between 1- and 2-level cervical arthroplasty: more heterotopic ossification in 2-level disc replacement: clinical article. J Neurosurg Spine 16:594–600, 2012
- 56↑
Zhao H, Cheng L, Hou Y, Liu Y, Liu B, Mundra JJ, et al.: Multilevel cervical disc arthroplasty (CDA) versus single-level CDA for the treatment of cervical disc diseases: a meta-analysis. Eur Spine J 24:101–112, 2015
