The Discover artificial disc replacement versus fusion in cervical radiculopathy—a randomized controlled outcome trial with 2-year follow-up

Accepted Manuscript The Discover Artificial Disc Replacement versus Fusion in Cervical Radiculopathy - A Randomized Controlled Outcome Trial with Two Years follow-up M. Skeppholm, L. Lindgren, T. Henriques, L. Vavruch, H. Löfgren, C. Olerud PII:

S1529-9430(15)00205-3

DOI:

10.1016/j.spinee.2015.02.039

Reference:

SPINEE 56222

To appear in:

The Spine Journal

Received Date: 22 June 2014 Revised Date:

6 February 2015

Accepted Date: 18 February 2015

Please cite this article as: Skeppholm M, Lindgren L, Henriques T, Vavruch L, Löfgren H, Olerud C, The Discover Artificial Disc Replacement versus Fusion in Cervical Radiculopathy - A Randomized Controlled Outcome Trial with Two Years follow-up, The Spine Journal (2015), doi: 10.1016/ j.spinee.2015.02.039. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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The Discover Artificial Disc Replacement versus Fusion in Cervical Radiculopathy - A Randomized Controlled Outcome Trial with Two Years follow-up.

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M. Skeppholm (1,2), L. Lindgren (1), T. Henriques (1), L. Vavruch (3), H. Löfgren (3), C. Olerud (4)

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1. Stockholm Spine Center, Löwenströmska Hospital, Upplands Väsby, Sweden. 2. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. 3. Neuro-Orthopaedic Center, Ryhov Hospital, Jönköping, Sweden. 4. Department of Orthopaedics, Uppsala University Hospital, Uppsala, Sweden.

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Acknowledgements: This study would not have been possible to conduct without the invaluable help of research nurse Eva Gulle. Eva, you have succeeded in collecting data and keeping track of both data files and surgeons. Thank you.

Contact: Martin Skeppholm, [email protected]

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Background Context Several previous studies comparing artificial disc replacement (ADR) and fusion have been conducted with cautiously positive results in favor of ADR. This study is not, in contrast to most previous studies, an investigational device exemption-study required by the Food and Drug Administration for approval to market the product in the U.S. This study was partially funded with unrestricted institutional research grants by the company marketing the artificial disc, used in this study. Purpose To compare outcomes between the concepts of an artificial disc to treatment with anterior cervical decompression and fusion (ACDF) and to register complications associated to the two treatments during a follow-up time of two years. Study Design/Setting Randomized controlled multicenter trial, including three spine centers in Sweden. Patient Sample Patients seeking care for cervical radiculopathy who fulfilled inclusion criteria. In total, 153 patients were included. Outcome Measures Self-assessment with NDI as primary outcome variable and EQ-5D and VAS as secondary outcome variables. Methods Patients were randomly allocated to either treatment with the Depuy Discover artificial disc or fusion with iliac crest bone graft and plating. Randomization was blinded to both patient and caregivers until time for implantation. Adverse events, complications, and revision surgery was registered as well as loss of follow-up. Results Data was available in 137 (91%) of the included and initially treated patients. Both groups improved significantly after surgery. NDI changed from 63.1 to 39.8 in an intention – to–treat analysis. No statistically significant difference between the ADR and the ACDF groups could be demonstrated with NDI values of 39.1 and 40.1 respectively. Nor in secondary outcome measures (EQ-5D and VAS) could any statistically significant differences be demonstrated between the groups. Nine patients in the ADR group and three in the fusion group underwent secondary surgery because of various reasons. Two patients in each group underwent secondary surgery because of adjacent segment pathology. Complication rates were not statistically significant between groups. Conclusion Artificial disc replacement did not result in better outcome compared to fusion measured with Neck Disability Index two years after surgery.

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Introduction

43 The gold standard surgical treatment for cervical radiculopathy is anterior cervical

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decompression and fusion (ACDF), which in a majority of patients leads to reduction of

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pain and increased quality of life. There is no high-level evidence that surgical treatment

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is better than non-surgical in the long term but it seems to give a more rapid

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improvement in the short term[1-4]. Concerns about how the decreased motion

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following ACDF is affecting the adjacent segments has given rise to the concept of

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motion-preserving implants with the aim of decreasing stress causing adjacent segment

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disease (ASD)[5, 6]. The number of different artificial disc replacement (ADR) devices

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has increased considerably during the past decade and all major manufacturers of spinal

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implants have at least one design on the market. Several previous studies comparing

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ADR and ACDF have been conducted with cautiously positive results in favor of ADR [7-

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12]. Common to most of these studies are that they were investigational device

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exemption (IDE)-studies required by the Food and Drug Administration (FDA) for

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approval to market the product in the U.S. Involvement of the company responsible for

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marketing and sales of the product is always associated with some risk for bias [13-16].

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This study was partially funded with unrestricted institutional grants from the company

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who markets the artificial disc used in the study. However, a written agreement between

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the company and the principal investigators was issued prior to study initiation. This

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was done to ensure that no interference from the company would occur. The company

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had no influence on study-design, follow-up or analysis of data, nor any access to data or

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information during the follow-up time. The only obligation towards the company was to

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use their artificial disc in the study. The aim of this study was to compare outcomes of

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the concepts of an artificial disc (Fig 1.) to those of ACDF with iliac crest bone graft and

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to register complications associated to the two treatments over a follow-up period of

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two years. The study was approved by the regional ethics committee in Stockholm

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(2006/1266-31/3) and registered at ISRCTN (reg. nr. 44347115).

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70 Patients and Methods

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The patients were recruited and treated between april 2007 and may 2010 at three

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different spine centers in Sweden: Stockholm Spine Center; Neuro-Orthopaedic Center,

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Ryhov Hospital, Jönköping; and Uppsala University Hospital. Patients referred to one of

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these departments who met inclusion criteria received both written and oral

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information about the study and inclusion was made after informed consent. Inclusion

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and exclusion criteria are listed in table 1. All patients were given the opportunity to

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discontinue their participation in the study at any time during the study period. 153

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patients, 73 men and 80 women, were included and allocated to either ADR or ACDF.

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Patient demographics at baseline are presented in table 2. Randomization was based on

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a computer-generated random list. The result of the random list was transferred to the

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allocation information, which was put into sealed envelopes and kept in a safe. At the

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time of inclusion, a consecutive envelope was taken out of the safe and was marked with

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the patients data. The envelope was not opened until time for insertion of the implant in

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the operating room. Thus, the surgeon was blinded for the result of the randomization

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during exposure of the operation field and the decompression of the nerve roots. Seven

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consultant spine surgeons, all with experience of both interventions, performed the

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surgery. Surgery was performed with a standard anterior approach aiming to

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decompress the affected nerve roots including removal of the posterior longitudinal

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ligament and also, if needed, the uncovertebral joints. Reconstruction in the ACDF group

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surgeon’s preference. A combination of bupivacaine (2.5 mg/ml) and adrenaline (5

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mg/ml) was given via a small catheter at the site for bone harvesting to decrease the

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pain for the first 1-2 postoperative days. Reconstruction in the ADR group was

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performed with the Discover™ artificial disc (DePuy Spine, Ryanham, MA, USA). The

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device is an unconstrained ball and socket construction consisting of three parts, two

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titanium endplates with a half spherical of polyethylene fixed into the caudal endplate.

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Primary stability is provided by six small spikes impacted into the vertebral endplates at

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implantation and secondary stability by bony ingrowth into a hydroxy apatite coating on

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both titanium endplates. The patients in the ADR group received low dose ketorolac for

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ten days postoperative with the purpose to reduce heterotopic bone formation.

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Otherwise, the postoperative regime was identical in both groups without any

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restrictions or neck collar.

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Outcome data were collected by self-reporting and validated questionnaires sent by mail

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to all patients. Neck Disability Index (NDI) was used as primary outcome variable and

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health related quality of life (HRQoL) was evaluated with EQ-5D. Furthermore, the

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patients had to report pain on a visual analogue scale, dysphagia with the Dysphagia

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Short Questionnaire[17], depression and anxiety with the Hospital Anxiety and

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Depression scale (HAD), and also answer questions about sick leave and analgesic

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consumption. Questionnaires were sent to the patients preoperatively, at 4 weeks, 3

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months, and at 1 and 2 years. If no reply was received after two reminders, it was

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considered that the patient was lost to follow-up. All patients had a return visit to the

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surgeon at three months and at one year; and those with continued problems after

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surgery also had the opportunity of additional visits to the surgeon for discussion and

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ACCEPTED MANUSCRIPT 5 clinical examination. 83 patients were randomized to ADR and 70 patients to ACDF. The

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skewness between the groups is explained by a list with more than 150 numbers to

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randomly allocate the patients, which resulted in this distribution. However, the groups

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were still randomly assembled and had the required sample size. Two patients were

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excluded from the study as the surgeon, during surgery but before randomization,

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decided that ADR would not be a satisfactory option as the required decompression

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resulted in too large losses of supporting bone structures. Nine patients (11%) in the

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ADR group and three (4%) in the ACDF group underwent secondary surgery within the

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first two years of follow-up. Two- year data was available for seven out of these patients

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in the ADR group and for all in the ACDF group. In the ADR group, five patients in total

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were lost to follow-up. In the ACDF group, two patients died of malignancy before the

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two-year follow-up and seven were lost to follow-up of other reasons. In total, 137

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patients (91%) of the initially included were followed up at two years. A flow chart,

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showing the distribution of patients between the groups with respect to number of

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reoperations and loss of follow-up, are shown in table 3.

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Radiographic assessment

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All referred patients had undergone a standard magnetic resonance investigation (MRI)

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of the cervical spine. If the MRI findings correlated to the clinical findings and the patient

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was included in the study, an additional plain x-ray including flexion and extension was

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conducted preoperatively. A computed tomography (CT) was obtained during the first

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postoperative days to evaluate the extent of decompression and implant position. At one

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year, a plain x-ray including flexion and extension was conducted. This x-ray was used at

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degree of motion within the implanted discs in the ADR group. At two year, a new CT

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was conducted as well as another plain x-ray with flexion and extension. A more

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structured evaluation of all radiographic data is ongoing, as well as follow-up with MRI

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five years after surgery, which will be reported separately.

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Statistics

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Sample size calculation for the study was performed with Neck Disability Index (NDI) as

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the primary outcome variable and a statistic superiority design. Standard deviation (SD)

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for NDI was set to 18 and the effect size to 10 units. The standard deviation value was

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chosen after calculations of outcomes in Neck Disability Index. Data was collected from

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the Swedish Spine Register and follow-up in patients who prior to this study underwent

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surgery for the same reason. The effect size of 10 has in previous studies been estimated

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to be the minimal detectable difference for this group of patients[18, 19]. With a

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significance level=0.05 and power of 80%, 51 patients in each group had to be included

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and with estimation for cross over between groups and non-compliance, the total

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number of patients planned for inclusion in the study was 150. Data in both groups were

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analyzed with descriptive statistics, and comparison between the groups was performed

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with independent t-test, Chi 2, Mann-Whitney U and Fischer exact test. Analysis of

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ordinal data within the groups was performed with Wilcoxon´s test and Friedman´s

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anova. For analysis of repeated measurements between the groups, Kruskall-Wallis

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anova was used. For some of the variables there were some occasional missing data,

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which were classified as missing completely at random. These data were replaced with a

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ACCEPTED MANUSCRIPT 7 logistic imputation model to reduce the risk of skewing the data. Patients without any

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data at the two-year follow-up were considered as patients lost to follow-up and were

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not analyzed. All patients with follow-up data at two years were included in an

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intention-to-treat (ITT) analysis and as a number of patients in both groups underwent

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secondary surgery, we also performed non-ITT-analysis. We did not choose the “as-

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treated” model, where patients are analyzed in the group they were assigned to or

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crossed over to, as follow-up times would have differed too much due to new surgery

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during follow-up. Instead, we choose the per-protocol (PP) model, in which patients who

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did not adhere to their assigned group were excluded from analysis. A p-value smaller

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than 0.05 was considered statistically significant. A Bonferroni correction was used for

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the level of significance in the subgroup analyses. The Statistica 12.0 package (StatSoft

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Inc., Tulsa, OK, USA) was used for all calculations.

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Results

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Both groups improved in the primary outcome variable between baseline to the two-

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year follow-up. Mean NDI values changed from 63.1(SD 15.3) to 39.8 (SD 19.4) in the

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ITT analysis and from 63.0 (SD 15.4) to 38.7 (SD 18.7) in the PP analysis. This change in

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NDI was statistically significant, p< 0.01, and likewise, the changes in secondary

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outcome variables in both ITT and PP analysis, p< 0.01. The results were stable between

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follow-ups at one- and two years regarding all outcome variables (fig. 2-5). When the

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two groups were compared, the mean values and medians in the primary and secondary

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outcome variables were similar in both groups at the two-year follow-up without any

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and is shown in tables 4 and 5. However, the ADR group had a lower mean EQ-5D-value

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at baseline and this was statistically significant in the ITT analysis, p=0.03, but not in the

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PP analysis, p=0.09. Operating time, blood loss and distribution of surgical levels are

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listed in table 6. The rates of secondary surgery was higher in the ADR group but not

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statistically significant, p=0.11. Complications and adverse events as defined were to

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some extent implant-associated with a higher proportion in the ACDF group, however,

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not statistically significant, p=0.16 (table 7). Partition of the groups into subgroups of 1-

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and 2-level treatment groups showed no statistical significant differences in the ACDF

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group. The same analysis in the ADR group showed lower mean NDI levels in the 2-level

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group compared to the 1-level group, 31.3 (SD 16.7) and 41.4 (SD 19.9) respectively.

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This difference could be clinically relevant but was not statistically significant after

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Bonferroni correction, p=0.07. The result is also reflected in EQ-5D with higher mean

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value in the 2-level group than in the 1-level group, 0.83 (SD 0.2) and 0.67 (SD 0.27)

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respectively. This difference was statistically significant, p=0.005, and was found both in

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the ITT and the PP analysis. It should also be pointed out that no statistical significance

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difference were seen between the 1 and 2-level groups regarding any of the outcome

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variables at baseline. The treatment groups were compared regarding sick leave and

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return-to-work status during follow-up and the result is presented in table 8. Both

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groups decreased their consumption of analgesics significantly after surgery but no

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significant difference between the groups could be seen at any time of follow-up. A

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comparison between smokers and non-smokers showed unfavorable outcome for the

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smokers in several outcome variables and was also reflected in the primary outcome

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variable NDI. Non-smokers improved from a baseline mean NDI of 61 (SD 15.3) to 37.3

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(SD 16.7) at the two-year follow-up while corresponding values for smokers were 67.6

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ACCEPTED MANUSCRIPT 9 (SD 15.3) and 45.8 (SD 24.1). The difference in NDI value between smokers and non-

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smokers at the two-year follow-up was statistically significant, p=0.03. The decisions for

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reoperation by respective surgeons in both groups were analyzed. Five patients in the

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ADR group underwent new surgery within the first year, mostly due to dissatisfaction

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with continued neck pain. All of these were 1-level ADR that were converted to fusions

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at index level. Contributing factors for the decision making of the surgeon´s decision-

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making were in three cases a non-optimal implant positioning and in two cases

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suspected implant instability or loosening. Two patients underwent a posterior

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unilateral foraminotomy; the indication for surgery in both cases was arm pain. Another

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two patients in the ADR group had new symptoms assessed as adjacent segment disease

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and were also converted to fusions at index level and adjacent level. Two patients in the

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ACDF group had secondary surgery with an additional fusion at adjacent level for the

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same reason and one patient was reoperated because of non-union. All patients who

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underwent secondary surgery were 1-level procedures, both in the ADR and the ACDF

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group.

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Discussion

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Both groups improved significantly after surgery and the interpretation of these data could be that surgery is very effective in a selected group of patients with cervical 237

radiculopathy. However, a weakness of this study, as with many other studies 238

comparing two surgical techniques, is that we do not have a non-surgical control group. 239 Furthermore, the knowledge about the natural history of cervical radiculopathy is very 240 limited. The results from several RCTs comparing ADR and ACDF have in recent years 241 been published and a majority of these are conducted as IDE studies and also with

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242 similar designs. Studies on the Discover disc have previously been published but none 243 of these were randomized controlled studies [20-22]. This study was not part of an IDE 244 study and has some differences in design compared to most of the previously conducted 245

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RCTs. First, we included both 1- and 2-level pathology since we believe that this better 246

reflects the mixture of surgery that is usually performed in this group of patients. 247

Secondly, allocation was blinded to both patient and caregiver until time for 248

reconstruction of the vertebral column. The reason for this was to minimize the

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surgeons’ bias in relation to the type of implant and also to prevent non-compliance to 250

allocation. Thirdly, iliac crest bone graft and anterior plating were used in the control

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group which probably was the reason for longer operating time within the group. 252

Previously published data indicate that autologous bone graft provides better conditions 253

for bony fusion and we wanted as far as possible to avoid non-union related 254

complications in the control group [23-26]. On the other hand, it can be argued that the 255 256

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use of iliac crest bone graft may result in donor site pain and a less favorable outcome in this group. Previously published studies concerning this indicate that donor site pain do 257

not affect quality of life in long term follow-ups [27-29], and even if donor site pain may 258 259

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be a problem in long term, it is very doubtful that this would be reflected in NDI. Another difference is that we used a superiority design in contrast to a majority of 260 261

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previous RCTs, which were performed, with non-inferiority designs. The objective with a non-inferiority design is to determine whether the experimental group has an equal or 262

unacceptable worse outcome than the control group. Non-inferiority trials are generally 263

more complex to interpret and can also have some serious pitfalls in their conclusions. 264 The design can be preferable when the effect size of the active control in comparison to 265 no treatment or placebo treatment is known. Critics of non-inferiority studies have 266 stated that this design may contribute to introduction of new treatments with equivalent

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267 or even inferior effect to existing standard treatment [30, 31]. However, this can 268 sometimes be justified if the new treatment has lower costs or fewer short- or long-term 269 complications. A few studies with longer follow-up time have shown higher rates of 270

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secondary surgery in the control group, mostly because of ASD [32-34]. However, other 271

studies contradict these results and there is still a lack of conclusive evidence for the 272

theory that ADR is protective against ASD [35-37]. Other possible side effects and 273

complications associated to either of the two treatments have been studied with some

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favor to ADR but the impact of these effects will probably not be enough in itself for 275

recommendation of the new treatment. In this study, a higher rate of reoperations was

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performed in the ADR group, which is also somewhat deviant compared to other studies. 277

The difference between the groups was not statistically significant but it should also be 278

pointed out, that the study was not powered for this analysis and a binary outcome as 279

reoperations or complications would require a much larger sample size. As an example, 280 281

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to find a statistically significant difference with the same level of significance and power (p < 0.05 and 80% respectively), 136 patients in each group would have been required 282

to find a statistically significant difference in complications and at least 220 in each 283 284

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group to find this difference in secondary surgeries. Even though an analysis of the outcome after secondary surgery is very uncertain, and also with varying times for 285 286

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follow-up, it seems that the five patients reoperated because of neck pain had a less favorable outcome with very small or no improvement compared to the others who 287

were re-operated due to other causes. This could indicate that this subgroup already at 288

baseline had several prognostic factors for a non-favorable outcome. A descriptive 289 analysis of the 12 (8%) patients who underwent secondary surgery revealed a group 290 with a poorer preoperative status. They reported lower HRQoL (mean EQ-5D 0.32, SD 291 0.33) and somewhat higher NDI (mean 67.1, SD 16.5) compared to the whole study

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292 population, but surprisingly enough somewhat lower VAS values. Moreover, 5 (42%) 293 were smokers, 6 (50%) were on full time sick leave because of their neck problem and 294 an additional 3 (22%) were on sick leave for reasons other than neck related disability. 295

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They also reported longer duration of symptoms before surgery, 9 (75%) with neck pain 296

and 6 (50%) with arm pain more than 2 years. A statistical analysis to compare this 297

group to the other in the study was not performed since sample size was too small but 298

when this group was removed from baseline data, there was not any statistically

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significant difference in HRQoL between the groups, p=0.09. The difference is probably 300

clinically relevant and since the levels in EQ-5D were equal in both treatment groups

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after surgery; the average improvement in HRQoL measured with EQ-5D was greater in 302

the ADR group than in the ACDF group. Patients with poor prognostic factors at baseline 303

were also present in the ACDF group, but these patients were, for some reason, not re304

operated to the same extent. One possible explanation is surgeon’s bias in the decision305

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making process; a combination of uncertainty about a new technology and a possibility 306

of performing further surgery might have contributed to the rate of reoperations, at 307

least among those patients predominantly with neck pain. We assume that a similar 308 309

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patient in the ACDF group was not offered secondary surgery due to neck pain if the radiographic analysis did not show a clear non-union or implant failure. A non-optimal 310 311

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implant positioning in the ADR group could also have been a factor for a poor outcome among these patients but in that case, higher values of improvement could have been 312

expected after secondary surgery. The results revealed when comparing 1 and 2-level 313

subgroups in the ADR group could be explained by a larger proportion of problems 314 originating from adjacent levels than the index level, initially judged as not being a 315 reason for surgery. 316

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317 Another interesting observation is the high proportion of smokers in this study 318 compared to the proportion of smokers in the Swedish population, 31% and 14% 319 (2010) respectively [38]. Smoking has been shown to be associated with markers for 320

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poorer socioeconomic status such as unemployment, low educational level and lower 321

income [39-41]. These data indicate that the individuals included this study are not a 322

representative part of the Swedish population and it also further confirms the theory of 323

smoking as a cause of degenerative changes in the cervical spine [42-44]. Smoking has

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previously also been shown to have a negative impact on outcome after spine surgery 325

[45]. Analysis of some of the data in this study also indicates that there are factors, other

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than those usually assessed to predict outcome, which might be of importance for a 327

successful result. Preoperative self-evaluation of physical impairment and psychosocial 328

factors might have a greater impact on the result after surgery than radiological findings 329

and surgical techniques with different implants [46, 47]. Such data are important as a 330 331

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basis for further studies on patient selection and optimization of results after selected surgery. Alternatives to surgery should always be considered and more studies 332

comparing surgery to non-surgical methods would be desirable to provide a better 333

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scientific basis for the treatments that health care providers offer this group of patients.

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Conclusion

343 No significant superiority in neck disability index or in secondary outcome variables

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could be seen in the disc replacement group compared to the ACDF group. Reoperation

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rates were higher among patients with disc replacement, not clearly associated,

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however, to implant-related events. A higher proportion of complications associated to

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surgery were detected in the ACDF group, mostly associated to bone-harvesting and

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postoperative dysphagia. The differences in secondary surgery and complications

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between the groups were not statistically significant. No differences in secondary

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surgery caused by adjacent segment disease could be seen between the two treatments

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after two years. Artificial disc replacement did not result in better outcome compared to

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fusion measured with Neck Disability Index two years after surgery.

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References

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1. Persson LC, Carlsson CA, Carlsson JY (1997) Long-lasting cervical radicular pain managed with surgery, physiotherapy, or a cervical collar. A prospective, randomized study. Spine 22:751-758 2. Peolsson A, Soderlund A, Engquist M, Lind B, Lofgren H, Vavruch L, Holtz A, WinstromChristersson A, Isaksson I, Oberg B (2013) Physical function outcome in cervical radiculopathy patients after physiotherapy alone compared with anterior surgery followed by physiotherapy: a prospective randomized study with a 2-year follow-up. Spine 38:300-307. doi: 10.1097/BRS.0b013e31826d2cbb 3. Fouyas IP, Statham PF, Sandercock PA (2002) Cochrane review on the role of surgery in cervical spondylotic radiculomyelopathy. Spine 27:736-747 4. Engquist M, Lofgren H, Oberg B, Holtz A, Peolsson A, Soderlund A, Vavruch L, Lind B (2013) Surgery versus nonsurgical treatment of cervical radiculopathy: a prospective, randomized study comparing surgery plus physiotherapy with physiotherapy alone with a 2-year follow-up. Spine 38:1715-1722. doi: 10.1097/BRS.0b013e31829ff095 5. Hilibrand AS, Carlson GD, Palumbo MA, Jones PK, Bohlman HH (1999) Radiculopathy and myelopathy at segments adjacent to the site of a previous anterior cervical arthrodesis. The Journal of bone and joint surgery American volume 81:519-528 6. Hilibrand AS, Robbins M (2004) Adjacent segment degeneration and adjacent segment disease: the consequences of spinal fusion? The spine journal : official journal of the North American Spine Society 4:190S-194S. doi: 10.1016/j.spinee.2004.07.007 7. Heller JG, Sasso RC, Papadopoulos SM, Anderson PA, Fessler RG, Hacker RJ, Coric D, Cauthen JC, Riew DK (2009) Comparison of BRYAN cervical disc arthroplasty with anterior cervical decompression and fusion: clinical and radiographic results of a randomized, controlled, clinical trial. Spine 34:101-107. doi: 10.1097/BRS.0b013e31818ee263 8. Mummaneni PV, Burkus JK, Haid RW, Traynelis VC, Zdeblick TA (2007) Clinical and radiographic analysis of cervical disc arthroplasty compared with allograft fusion: a randomized controlled clinical trial. Journal of neurosurgery Spine 6:198-209. doi: 10.3171/spi.2007.6.3.198 9. Murrey D, Janssen M, Delamarter R, Goldstein J, Zigler J, Tay B, Darden B (2009) 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. The spine journal : official journal of the North American Spine Society 9:275-286. doi: 10.1016/j.spinee.2008.05.006 10. Phillips FM, Lee JY, Geisler FH, Cappuccino A, Chaput CD, DeVine JG, Reah C, Gilder KM, Howell KM, McAfee PC (2013) A prospective, randomized, controlled clinical investigation comparing PCM cervical disc arthroplasty with anterior cervical discectomy and fusion. 2-year results from the US FDA IDE clinical trial. Spine 38:E907918. doi: 10.1097/BRS.0b013e318296232f 11. Sasso RC, Smucker JD, Hacker RJ, Heller JG (2007) Artificial disc versus fusion: a prospective, randomized study with 2-year follow-up on 99 patients. Spine 32:29332940; discussion 2941-2932. doi: 10.1097/BRS.0b013e31815d0034 12. Coric D, Nunley PD, Guyer RD, Musante D, Carmody CN, Gordon CR, Lauryssen C, Ohnmeiss DD, Boltes MO (2011) 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. Journal of neurosurgery Spine 15:348-358. doi: 10.3171/2011.5.SPINE10769

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13. Khan SN, Mermer MJ, Myers E, Sandhu HS (2008) The roles of funding source, clinical trial outcome, and quality of reporting in orthopedic surgery literature. Am J Orthop (Belle Mead NJ) 37:E205-212; discussion E212 14. Lexchin J (2012) Sponsorship bias in clinical research. The International journal of risk & safety in medicine 24:233-242. doi: 10.3233/JRS-2012-0574 15. McHenry L (2008) Biomedical research and corporate interests: a question of academic freedom. Mens sana monographs 6:146-156. doi: 10.4103/0973-1229.37086 16. Shah RV, Albert TJ, Bruegel-Sanchez V, Vaccaro AR, Hilibrand AS, Grauer JN (2005) Industry support and correlation to study outcome for papers published in Spine. Spine 30:1099-1104; discussion 1105 17. Skeppholm M, Ingebro C, Engstrom T, Olerud C (2012) The Dysphagia Short Questionnaire: an instrument for evaluation of dysphagia: a validation study with 12 months' follow-up after anterior cervical spine surgery. Spine 37:996-1002. doi: 10.1097/BRS.0b013e31823a7a5b 18. MacDermid JC, Walton DM, Avery S, Blanchard A, Etruw E, McAlpine C, Goldsmith CH (2009) Measurement properties of the neck disability index: a systematic review. The Journal of orthopaedic and sports physical therapy 39:400-417. doi: 10.2519/jospt.2009.2930 19. Cleland JA, Fritz JM, Whitman JM, Palmer JA (2006) The reliability and construct validity of the Neck Disability Index and patient specific functional scale in patients with cervical radiculopathy. Spine 31:598-602. doi: 10.1097/01.brs.0000201241.90914.22 20. Chen Y, Yuan W, Wu X, Chen H, Wang X, Yang L, He H, Liu Y, Tsai N, Peng Y, Gu S, Sun Q The effect of range of motion after single-level discover cervical artificial disk replacement. J Spinal Disord Tech 26:E158-162. doi: 10.1097/BSD.0b013e31828bc02f 00024720-201307000-00010 [pii] 21. Hou Y, Liu Y, Yuan W, Wang X, Chen H, Yang L, Zhang Y Cervical kinematics and radiological changes after Discover artificial disc replacement versus fusion. The spine journal : official journal of the North American Spine Society 14:867-877. doi: S15299430(13)01267-9 [pii] 10.1016/j.spinee.2013.07.432 22. Li J, Liang L, Ye XF, Qi M, Chen HJ, Yuan W Cervical arthroplasty with Discover prosthesis: clinical outcomes and analysis of factors that may influence postoperative range of motion. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 22:2303-2309. doi: 10.1007/s00586-013-2897-z 23. Epstein NE (2012) Iliac crest autograft versus alternative constructs for anterior cervical spine surgery: Pros, cons, and costs. Surgical neurology international 3:S143156. doi: 10.4103/2152-7806.98575 24. Lofgren H, Engquist M, Hoffmann P, Sigstedt B, Vavruch L (2010) Clinical and radiological evaluation of Trabecular Metal and the Smith-Robinson technique in anterior cervical fusion for degenerative disease: a prospective, randomized, controlled study with 2-year follow-up. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 19:464-473. doi: 10.1007/s00586-0091161-z 25. Vanek P, Bradac O, DeLacy P, Saur K, Belsan T, Benes V (2012) Comparison of 3 fusion techniques in the treatment of the degenerative cervical spine disease. Is standalone autograft really the "gold standard?": prospective study with 2-year follow-up. Spine 37:1645-1651. doi: 10.1097/BRS.0b013e31825413fe

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26. Jacobs W, Willems PC, Kruyt M, van Limbeek J, Anderson PG, Pavlov P, Bartels R, Oner C (2011) Systematic review of anterior interbody fusion techniques for single- and double-level cervical degenerative disc disease. Spine 36:E950-960. doi: 10.1097/BRS.0b013e31821cbba5 27. Baskin DS, Ryan P, Sonntag V, Westmark R, Widmayer MA (2003) A prospective, randomized, controlled cervical fusion study using recombinant human bone morphogenetic protein-2 with the CORNERSTONE-SR allograft ring and the ATLANTIS anterior cervical plate. Spine 28:1219-1224; discussion 1225. doi: 10.1097/01.BRS.0000065486.22141.CA 28. Lind BI, Zoega B, Rosen H (2007) Autograft versus interbody fusion cage without plate fixation in the cervical spine: a randomized clinical study using radiostereometry. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 16:1251-1256. doi: 10.1007/s00586-007-0337-7 29. Skeppholm M, Olerud C (2013) Pain from donor site after anterior cervical fusion with bone graft: a prospective randomized study with 12 months of follow-up. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 22:142-147. doi: 10.1007/s00586-012-2456-z 30. Fleming TR, Odem-Davis K, Rothmann MD, Li Shen Y (2011) Some essential considerations in the design and conduct of non-inferiority trials. Clin Trials 8:432-439. doi: 10.1177/1740774511410994 31. Schiller P, Burchardi N, Niestroj M, Kieser M (2012) Quality of reporting of clinical non-inferiority and equivalence randomised trials--update and extension. Trials 13:214. doi: 10.1186/1745-6215-13-214 32. Zigler JE, Delamarter R, Murrey D, Spivak J, Janssen M (2013) ProDisc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. Spine 38:203-209. doi: 10.1097/BRS.0b013e318278eb38 33. Mummaneni PV, Amin BY, Wu JC, Brodt ED, Dettori JR, Sasso RC (2012) Cervical artificial disc replacement versus fusion in the cervical spine: a systematic review comparing long-term follow-up results from two FDA trials. Evidence-based spine-care journal 3:59-66. doi: 10.1055/s-0031-1298610 34. Blumenthal SL, Ohnmeiss DD, Guyer RD, Zigler JE (2013) Reoperations in cervical total disc replacement compared with anterior cervical fusion: results compiled from multiple prospective food and drug administration investigational device exemption trials conducted at a single site. Spine 38:1177-1182. doi: 10.1097/BRS.0b013e31828ce774 35. Carrier CS, Bono CM, Lebl DR (2013) Evidence-based analysis of adjacent segment degeneration and disease after ACDF: a systematic review. The spine journal : official journal of the North American Spine Society 13:1370-1378. doi: 10.1016/j.spinee.2013.05.050 36. Nunley PD, Jawahar A, Cavanaugh DA, Gordon CR, Kerr EJ, 3rd, Utter PA (2013) Symptomatic adjacent segment disease after cervical total disc replacement: reexamining the clinical and radiological evidence with established criteria. The spine journal : official journal of the North American Spine Society 13:5-12. doi: 10.1016/j.spinee.2012.11.032 37. Verma K, Gandhi SD, Maltenfort M, Albert TJ, Hilibrand AS, Vaccaro AR, Radcliff KE (2013) Rate of adjacent segment disease in cervical disc arthroplasty versus single-level

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fusion: meta-analysis of prospective studies. Spine 38:2253-2257. doi: 10.1097/BRS.0000000000000052 38. Danielsson M, Gilljam H, Hemstrom O (2012) Tobacco habits and tobacco-related diseases: Health in Sweden: The National Public Health Report 2012. Chapter 10. Scandinavian journal of public health 40:197-210. doi: 10.1177/1403494812459607 39. Hiscock R, Bauld L, Amos A, Platt S (2012) Smoking and socioeconomic status in England: the rise of the never smoker and the disadvantaged smoker. J Public Health (Oxf) 34:390-396. doi: 10.1093/pubmed/fds012 40. Lindstrom M, Hanson BS, Ostergren PO, Berglund G (2000) Socioeconomic differences in smoking cessation: the role of social participation. Scandinavian journal of public health 28:200-208 41. Vogl M, Wenig CM, Leidl R, Pokhrel S (2012) Smoking and health-related quality of life in English general population: implications for economic evaluations. BMC public health 12:203. doi: 10.1186/1471-2458-12-203 42. Holm S, Nachemson A (1988) Nutrition of the intervertebral disc: acute effects of cigarette smoking. An experimental animal study. Upsala journal of medical sciences 93:91-99 43. An HS, Silveri CP, Simpson JM, File P, Simmons C, Simeone FA, Balderston RA (1994) Comparison of smoking habits between patients with surgically confirmed herniated lumbar and cervical disc disease and controls. Journal of spinal disorders 7:369-373 44. Nasto LA, Ngo K, Leme AS, Robinson AR, Dong Q, Roughley P, Usas A, Sowa GA, Pola E, Kang J, Niedernhofer LJ, Shapiro S, Vo NV (2013) Investigating the role of DNA damage in tobacco smoking-induced spine degeneration. The spine journal : official journal of the North American Spine Society. doi: 10.1016/j.spinee.2013.08.034 45. Sanden B, Forsth P, Michaelsson K (2011) Smokers show less improvement than nonsmokers two years after surgery for lumbar spinal stenosis: a study of 4555 patients from the Swedish spine register. Spine 36:1059-1064. doi: 10.1097/BRS.0b013e3181e92b36 46. Peolsson A, Peolsson M (2008) Predictive factors for long-term outcome of anterior cervical decompression and fusion: a multivariate data analysis. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 17:406-414. doi: 10.1007/s00586-007-0560-2 47. Wibault J, Oberg B, Dedering A, Lofgren H, Zsigmond P, Persson L, Peolsson A (2013) Individual factors associated with neck disability in patients with cervical radiculopathy scheduled for surgery: a study on physical impairments, psychosocial factors, and life style habits. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. doi: 10.1007/s00586-013-3066-0

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Exclusion criteria

Age 25-60 years

Previous cervical spine surgery

Symptoms of radiating arm pain with a duration of least 3 months.

More than 2 cervical levels requiring treatment

Correlating findings on MRI on 1 or 2 cervical levels.

Visible or severe arthrosis in facet joints evaluated preoperatively on plain x-rays and MRI

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Inclusion criteria

Eligible for both treatments.

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Ability to understand and read Swedish language.

Marked radiological signs or symptoms of myelopathy Drug abuse, dementia, or other reason to suspect poor adherence to follow-up

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Cervical malformation or marked cervical instability History of whiplash associated disorder (WAD) or severe cervical trauma

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Pregnancy

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Table 1. Inclusion and exclusion criteria.

Rheumatoid arthritis, known malignancy, active infection or other systemic disease Known allergy or hypersensitivity to any of the constituent materials of the implants or to NSAID´s.

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n=70

40/41 46.7 (6.7) 25 (31) 8 (10) 79 (18) 26

33/37 47.0 (6.9) 21 (31) 10 (14) 78 (14) 26

31 (38) 16 (20) 6 (7) 28 (35)

25 (36) 12 (17) 3 (4) 30 (43)

34 (42) 34 (42) 13 (16)

36 (51) 25 (36) 9 (13)

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ACDF

2 (3) 15 (21) 20 (29) 40 (57) 4 (6)

1 (1) 19 (27) 20 (29) 29 (42) 1 (1)

3 (4) 21 (26) 31 (38) 26 (32) 0 (0)

3 (4) 24 (34) 19 (27) 24 (34) 0 (0)

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Men/Females Age mean (SD) Smokers n (%) Unemployed n (%) Weight mean (SD) BMI mean Sick leave n (%) Full time Part time Other reason Not on sick leave Analgesic medication n(%) Regularly Irregularly No analgesics Neck pain duration n(%) <3 months 3-12 months 1-2 years >2 years No neck pain Arm pain duration n(%) <3 months 3-12 months 1-2 years >2 years No arm pain

ADR n=81

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HAD A mean (SD) 7 (4.2) 7 (4.1) HAD D mean (SD) 5 (3.5) 5 (3.7) Table 2. Demographics at baseline. “Other reason” for sick leave is defined as not being able to work as a result of other ill health than neck related. “Analgesic medication” includes all forms of medicaments to ease pain. HAD A is level of anxiety and HAD D level of depression.

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Flow Diagram

Assessed for eligibility n=287

Excluded n=134 Not meeting inclusion criteria n=119 Declined to participate n= 15

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Enrollment

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Randomized n=153

Allocation

Allocated to intervention ADR n=83 Received allocated intervention n=81 Did not receive allocated intervention n=2 (intervention not completed because of surgical technical problems)

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Allocated to intervention ACDF n=70 Received allocated intervention n=70 Did not receive allocated intervention n=0

Follow-Up

Lost to follow-up (without 2-year data n=5 )

Discontinued intervention n=3 (2 fusion at adjacent level, 1 reop pseudarthrosis)

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Discontinued intervention n=9 (5 extraction of implant and fusion at index level, 1 extraction of implant and fusion at index and adjacent level,1 reoperated due to ASD with ADR at adjacent level, 2 unilateral posterior foraminotomy)

Lost to follow-up (without 2-year data n=9)

Analysed (n=67 PP, n=76 ITT) Excluded from analysis (without 2-year data n=5)

Table 3. Flow diagram.

Analysed (n=58 PP, n=61 ITT )

Analysis

Excluded from analysis (without 2-year data n=9 )

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Baseline

VAS neck VAS arm

61-68

0.290.43*

52-63

51-63

Mean (SD) Median (range) 61.4 (14.2) 61.2 (092) 0.47 (0.30) 0.69 (0.24 -0.8)

95% C.I.

58.2 (23.1) 62.0 (0100) 56.9 (23.0) 62.0 (0100)

53-64

pvalue

58-65 0.25

0.40.54*

0.03

0.97

n=76 Mean (SD) Median (range) 39.1 (20.2) 35.0 (4 94) 0.70 (0.30) 0.79 (0.29 -1.0)

ACDF n=67

95% C.I.

51-62

0.73

Mean (SD) Median (range) 40.1 (18.5) 34.0 (10 - 90) 0.71 (0.26) 0.76 (0.17 -1.0)

27.4 (27.3) 18.0 (0 100) 20.7 (23.1) 14.0 (0 90)

95% C.I.

pvalue

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EQ5D

95% C.I

ADR

35-44

0.630.77

21-33

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NDI

n=81 Mean (SD) Median (range) 64.6 (16.2) 64.0 (26 -100) 0.36 (0.32) 0.25 (0.18 0.8) 57.6 (26.4) 62.0 (0 100) 57.1 (27.5) 60.0 (0 100)

Follow-up two years ACDF n=70

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ADR

16-26

28.6 (24.8) 21.0 (073) 20.3 (25.7) 9.0 (080)

36-45

0.77

0.650.77

0.92

23-35

0.68

14-26

0.26

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Table 4. ITT-analysis of all outcome variables presented with 95% confidence intervals. Shows change from baseline to follow-up at two years presented as means (SD) and medians (range).

*The EQ-5D scale is biphasic and is not normally distributed. This can explain why the

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confidence intervals are overlapping even though the p-value indicates a statistical significant difference with a p-level less than 0.05. The test of significance was done with the MannWhitney U and Kruskal-Wallis test for non-parametric data. The biphasic distribution is also reflected in the difference between mean and median values.

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Baseline

ADR

NDI

EQ5D

n=72 Mean (SD) Median (range) 64.1 (16.1) 64.0 (26 100) 0.37 (0.32) 0.28 (0.18 - 0.8)

95% C.I

6068

0.30.44

Follow-up two years ACDF n=67

Mean (SD) Median (range) 61.6 (14.3) 61.2 (092) 0.47 (0.30) 0.69 (0.24 -0.8)

95% C.I.

pvalue

5865

0.45

0.40.54

0.09

ADR n=67 Mean (SD) Median (range) 37.4 (19.3) 34.0 (4 94) 0.72 (0.29) 0.80 (0.29 -1.0)

95% C.I.

33-42

0.650.79

ACDF n=58 Mean (SD) Median (range) 40.7 (17.9) 34.0 (10 90) 0.71 (0.26) 0.76 (0.17 -1.0)

95% C.I.

pvalue

35-45

0.24

0.640.78

0.50

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VAS neck VAS arm

55.3 (25.9) 60.0 (0 100) 53.0 (26.4) 57.0 (0 100)

60.7 (20.1) 62.0 (0100) 57.4 (22.1) 61.0 (5100)

4961

4759

5666

0.35

5263

0.38

25.6 (26.6) 16.0 (0 100) 19.2 (21.8) 13.0 (0 84)

19-32

14-24

28.7 (25.0) 21.0 (073) 20.1 (25.7) 9.0 (080)

22-35

0.68

14-27

0.75

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Table 5. Per-protocol analysis of all outcome variables presented with 95% confidence intervals. Shows change from baseline to follow-up at two years presented as means (SD) and medians (range).

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ADR ACDF p-value Op time min (SD) 122 (43) 141 (38) 0.015 Blood loss ml (SD) 212 (159) 218 (178) 0.81 Levels 1/2 58/23 50/20 0.98 Table 6. Shows duration of surgery, peroperative blood loss and distribution of surgical levels in both groups.

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Complication Postop hematoma1 Infection donor site Horner´s syndrome Donor site pain2 Dysphagia3 Implant failure4 C7 palsy Wound infection Pseudarthrosis5 1

ADR 1 n/a 1 n/a 9 0 1 1 n/a

Leading to reoperation. VAS ≥4 at two-year follow-up. 3 DSQ ≥4 at two-year follow-up. 4 Material insufficience with breakage or loosening. 5 Leading to reoperation. 2

ACDF 0 3 0 5 12 0 0 0 1

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Dural tear Hoarsness6 N (%)

0 3 16 (20)

0 4 25 (36)

Four weeks

Three Months

One Year

Two Years

5 (6) 30 (37) 37 (46) 9 (11) 81

11 (14) 14 (17) 46 (57) 9 (11) 80

8 (10) 8 (10) 55 (71) 7 (9) 78

1 (1) 1 (1) 69 (91) 5 (6) 76

6 (9) 31 (44) 26 (37) 7 (10)

9 (14) 15 (23) 30 (45) 12 (18)

9 (14) 7 (11) 40 (62) 8 (13)

1 (2) 0 (0) 52 (85) 8 (13)

70

66

64

61

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ADR n (%) Full time sick leave Part time sick leave Working full time Other Total ACDF n (%) Full time sick leave Part time sick leave Working full time Other

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Table 7. Adverse events and complications as defined below, in both groups.

Total 6

First postoperative period.

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p-value 0.25 0.85 0.39 0.71 Table 8. Showing return to work status and sick leave in both groups between four weeks and two years after surgery (ITT-analysis).