Cervical arthroplasty: a critical review of the literature

Accepted Manuscript Cervical Arthroplasty: A Critical Review of the Literature Matthew D. Alvin, MBA, MA E. Emily Abbott, MD Daniel Lubelski, BA Benjamin Kuhns, MS Amy S. Nowacki, PhD Michael P. Steinmetz, MD Edward C. Benzel, MD Thomas E. Mroz, MD PII:

S1529-9430(14)00355-6

DOI:

10.1016/j.spinee.2014.03.047

Reference:

SPINEE 55842

To appear in:

The Spine Journal

Received Date: 6 November 2013 Revised Date:

10 February 2014

Accepted Date: 26 March 2014

Please cite this article as: Alvin MD, Abbott EE, Lubelski D, Kuhns B, Nowacki AS, Steinmetz MP, Benzel EC, Mroz TE, Cervical Arthroplasty: A Critical Review of the Literature, The Spine Journal (2014), doi: 10.1016/j.spinee.2014.03.047. 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.

ACCEPTED MANUSCRIPT

Cervical Arthroplasty: A Critical Review of the Literature

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Matthew D. Alvin, MBA, MA1,2; E. Emily Abbott, MD1,3; Daniel Lubelski, BA1,4; Benjamin Kuhns, MS1,2; Amy S. Nowacki, PhD4,5; Michael P. Steinmetz, MD1,6; Edward C. Benzel, MD1,3,4; Thomas E. Mroz, MD1,3,4*

Cleveland Clinic Center for Spine Health, Cleveland Clinic, Cleveland, Ohio, USA

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Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

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Department of Neurological Surgery, Cleveland Clinic, Cleveland, Ohio, USA

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Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, USA

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Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA

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Department of Neurosciences, MetroHealth Medical Center, Cleveland, Ohio, USA

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Neurological Institute

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*Corresponding Author: Thomas E. Mroz, MD

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Cleveland Clinic Center for Spine Health Departments of Orthopaedic and Neurological Surgery The Cleveland Clinic

9500 Euclid Avenue, S-80 Cleveland, Ohio 44195 Tel: 216-445-9232 Fax: 216-363-2040 Email: [email protected]

ACCEPTED MANUSCRIPT

Acknowledgements The authors thank the Neurological Institute Knowledge Program for their help with outcomes data acquisition and Michael Truchon for his help with the formatting of Figure 1. Figures 1b-1e

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were obtained from the Food and Drug Administration (FDA) website and did not require permission per their guidelines. Figures 1a and 1f were obtained with permission from

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www.cxvascular.com and www.medlatest.com, respectively.

ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 1 1 2 3

Abstract

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an alternative to fusion. Proponents of arthroplasty assert it will maintain cervical motion and

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prevent or reduce adjacent segment degeneration. Accordingly, CDA, compared to fusion, would

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have the potential to improve clinical outcomes. Published studies have varying conclusions on

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whether CDA reduces complications and/or improves outcomes. As many of these previous

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studies have been funded by CDA manufacturers, we wanted to ascertain whether there was a

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greater likelihood for these studies to report positive results.

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Background context. Cervical disc arthroplasty (CDA) is a motion preserving procedure that is

Purpose. To critically assess the available literature on cervical arthroplasty with a focus on time

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of publication and conflict of interest.

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Study Design/Setting. Review of the literature.

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Methods. All clinical articles about CDA published in English through August 1st, 2013 were

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identified on Medline. Any paper that presented cervical disc arthroplasty clinical results was

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included. Study design, sample size, type of disc, length of follow-up, use of statistical analysis,

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quality of life (QOL) outcome scores, conflict of interest (COI), and complications were

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recorded. A meta-analysis was conducted stratifying studies by COI and publication date to

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identify differences in complication rates reported.

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Results. 74 studies were included that investigated 8 types of disc prosthesis; 22 met the criteria

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for a randomized controlled trial (RCT). All level Ib RCTs reported superior quality of life

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outcomes for CDA versus ACDF at 24 months. 50 of the 74 articles (68%) had a disclosure

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section, including all level Ib RCTs, which had significant COIs related to the respective studies.

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Those studies without a COI reported mean weighted average adjacent segment disease rates of

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6.3% with CDA and 6.2% with ACDF. In contrast, the reverse was reported by studies with a

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COI, for which the averages were 2.5% with CDA and 6.3% with ACDF. Those studies with a

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COI (n=31) had an overall weighted average heterotopic ossification rate of 22% while those

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studies with no COI (n=43) had a rate of 46%.

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Conclusions. Associated COIs did not influence QOL outcomes. COIs were more likely to be

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present in studies published after 2008, and those with a COI reported greater ASD rates for

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 2 1

ACDF than CDA. In addition, HO rates were much lower in studies with COI versus those

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without COI. Thus, COIs did not impact QOL outcomes, but were associated with lower

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complication rates.

4 Introduction

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A common surgical treatment for symptomatic cervical spondylosis (i.e., radiculopathy and/or

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myelopathy) is anterior cervical discectomy and fusion (ACDF). It has been shown to be safe

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and clinically efficacious. However, there exists considerable debate about degeneration and

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development of related disease at adjacent levels following fusion surgery.1-9 Specifically, it is

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unclear if such adjacent degeneration is a reflection of the natural history of spondylosis, or

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alternatively, if it is related to the adjacent fused segment. While some studies have shown an

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average 3% reoperation rate, others have shown rates exceeding 10% after 2 years to treat

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complications related to the index surgery.1

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Cervical disc arthroplasty (CDA) is an alternative to fusion after the index decompression

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procedure (i.e., discectomy). Interest in CDA has gained substantial momentum over the past

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decade.1-9 CDAs are designed to maintain cervical motion, and if segmental fusion is responsible

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for inducing adjacent level degeneration and disease, it could diminish the incidence or prevent

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the occurrence of this problem. Intuitively, maintaining near physiologic motion in the cervical

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spine, if possible, makes perfect sense. However, recent reports have shown a high incidence of

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heterotopic ossification (i.e., abnormal bone formation around or within the intervertebral disc

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space) and/or implant migration.1-9 There have been a multitude of published clinical trials

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investigating various artificial discs to date, with some studies showing better outcomes with

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CDA versus ACDF and others showing equivalent outcomes.1-9 Given the conflicting results,

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one must consider potential biases of the authors or conflicts of interest that may have led to

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under-reporting of complications or over-reporting of positive results. Bhandari et al.89 examined

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332 randomized trials in 13 leading surgical and medical journals and found significant positive

29

association between industry financial involvement and successful trial outcome. We suspect that

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some of the heterogeneity of conclusions may be due to the influences of having a conflict of

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interest (COI). The purpose of this study is to critically evaluate the literature on clinical and

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 3 1

quality of life (QOL) outcomes of CDA vs. ACDF with respect to both timeframe (published

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prior to or after 2008) and author COI.

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Methods

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A literature search was performed using the Medline database via the Pubmed search engine with

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the following search terms: ‘cervical arthroplasty,’ ‘cervical disc arthroplasty,’ ‘cervical disc

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replacement,’ and ‘disc replacement.’ Inclusion criteria was any papers that presented clinical

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results associated with the cervical disc replacement using a mechanical artificial disc.

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Biomechanical studies, radiographic studies, animal studies, and case reports were excluded as

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were articles dealing with nucleus replacement. All articles were reviewed and classified

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according to Level of Evidence (LOE) independently by two senior spine surgeons. The criteria

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put forth by Sackett et al.10 were used to analyze the data and stratify according to LOE. For the

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purposes of this study, only levels Ib, IIb, IIIb, and IV were relevant.10 The reported LOE may be

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different from the LOE derived using Sackett’s criteria and thus require downgrade. The reasons

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for downgrade included lack of adequate follow-up (<85% of original sample size), incomplete

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reporting of important outcome measures or percent of subjects available at follow-up, complete

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absence or incomplete reporting of statistical analysis of results, and/or inadequate sample size,

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which was defined in this study as n<50 patients undergoing CDA.

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All randomized controlled, retrospective, and prospective studies were presented for

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completeness. Studies were separated into early versus late studies in order to evaluate for

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differences. Anything published after 2008 were considered late studies. 2008 was chosen as the

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cutoff point for multiple reasons. First, the Prestige (Medtronic Sofamor Danek, Memphis, TN)

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and ProDisc (Synthes Spine, Paoli, PA) artificial discs were FDA-approved in 2007 while the

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others were approved in or after 2009. Second, a trend toward higher complication rates and

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conflicts of interest was observed for articles published during or after 2008, compared to earlier

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years. Finally, we used the concept of Scott’s Parabola to divide the articles at a point where

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“Encouraging Reports” were separated from “Widespread Enthusiasm,” corresponding to 2008

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as most likely that point.12 Scott’s Parabola describes a common theme in the medical profession

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of surgeries or medical therapies whereby early studies show great promise for the treatment at

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 4 the outset, the treatment becomes standard of care, and then falls into disuse as a result of

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subsequent negative outcome reports.12 All articles were then evaluated with regard to COI by

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review of their respective disclosure sections. Any remunerative or non-financial activity with

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the potential of creating bias in the author or author(s) of a published manuscript was considered

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a conflict of interest per the guidelines published online by the North American Spine Society

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(NASS).13 All included journals had a minimum of certain disclosure requirements, which were

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used to identify COIs. Though having a COI does not necessarily indicate investigator bias, COIs

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may add a potential source of bias that must be considered when interpreting the specific studies.

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Complications and/or adverse outcomes assessed included heterotopic ossification (HO),

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adjacent segment degeneration (ASDG), adjacent segment disease (ASDI) or other, such as

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dysphagia. ASDI, which is defined by symptom presentation clinically, was considered a distinct

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entity from ASDG, which is defined by radiographic presentation. Unless otherwise stated

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throughout this review, the studies analyzed surgery at a single level. In addition, all ACDF

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surgery was performed with allograft and plating.

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16 Statistical Analysis

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A meta-analysis was performed for the complication rates of ASDI and HO. Only studies that

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explicitly reported an ASDI rate for both the ACDF and CDA treatment arms were included in

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the ASDI analysis. The odds ratio for ASDI is presented with 95% confidence interval to assess

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the risk associated with ACDF compared to CDA. Only studies that explicitly reported an HO

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rate for the CDA treatment arm were included in the HO analysis. The complication rate for HO

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is presented with 95% confidence interval to assess the risk associated with CDA. The analyses

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were stratified based on COI status and publication timing (early vs. late). Some studies reported

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zero complications within one or both treatment arms, so a continuity correction was applied to

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each cell in that table when calculating the measure of association. Statistical heterogeneity

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across the various studies was tested with the use of Cochran's Q statistic. As a result of study

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heterogeneity, the primary data analysis was performed using a random-effects model

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(DerSimonian and Laird method94). Only study characteristics are provided for the complication

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rates of ASDG as this was infrequently reported. All stated p values are two-sided. R software

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version 2.14.0 for 64-bit Windows (The R Foundation for Statistical Computing, Vienna,

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Austria) was used for all statistical analysis.

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Results

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This review analyzed 22 RCTs, 40 prospective, and 12 retrospective studies (Tables 2-3); these

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studies can also be separated into 29 early studies, 45 late studies with 2008 chosen as the cutoff

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as discussed above. All articles were evaluated critically using well-established guidelines for

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level of evidence.10 53 of 74 (72%) studies were downgraded from their original study design for

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a variety of reasons. 19/31 (61%) with COI vs. 34/43 (79%) without COI (p=0.08) were

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downgraded, as well as 28/30 (93%) early studies vs. 25/44 (57%) late studies (p<0.01); this was

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most commonly due to lack of adequate follow-up, lack of or inadequate reporting of the type of

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outcome measures, and/or statistical analysis of results. This indicates substantial heterogeneity

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in study design, execution and/or reporting among the published trials on CDA, and detracts

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substantially from the strength of available evidence.

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16 Bryan Disc (Figure 1a)14-53

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All early and late studies showed statistically significantly pre- to postoperative improved QOL

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outcomes for Bryan CDA. Compared to early studies, late studies were more likely to have a

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COI, less likely to be downgraded in level of evidence, and more likely to report HO and ASD

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complication rates. The reported HO rates were lower in studies with COI relative to those

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without COI. There were no differences between studies with and without COI in terms of the

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percentage reporting significant differences in QOL outcomes.

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Prestige Cervical Disc (Figure 1b)54-61

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All early and late studies showed statistically significant pre- to postoperative improved QOL

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outcomes for Prestige CDA. Compared to early studies, late studies were less likely to be

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downgraded in level of evidence, more likely to report HO and ASD complication rates, and

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more likely to report significantly greater QOL improvements in in the CDA cohort.

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Porous Coated Motion (PCM) Artificial Cervical Disc (Figure 1c)62-65

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All studies reported a COI and all studies showed a statistically significant pre- to postoperative

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improvement within each group in clinical or QOL outcomes following PCM CDA.

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5 ProDisc-C (Figure 1d)66-76

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All early and late studies showed statistically significantly improved pre- to postoperative QOL

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outcomes for ProDisc-C CDA. Compared to early studies, late studies were less likely to be

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downgraded in level of evidence, more likely to report HO and ASD complication rates with

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lower HO rates in studies with a COI, and more likely to report significantly greater

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improvements in in the CDA cohort. However, there were no differences between the studies

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with and without a COI on whether the CDA cohort did or did not have significantly different

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QOL outcomes compared with the ACDF cohort.

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Mobi-C Disc (Figure 1e)77-84

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As of 8/29/2013, the Mobi-C disc received FDA approval as the first and only artificial disc for

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both single-level and multi-level CDA. Released reports by LDR Medical from their FDA IDE

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trial showed significant “success rate” of Mobi-C over ACDF for multi-level CDA (69.7%

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Mobi-C vs. 37.4% ACDF, p<0.01) and NDI improvement (78.2% Mobi-C vs. 61.8% ACDF).

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ASDI rates for inferior and superior levels (Mobi-C, ACDF) were (2.9%, 18.1%) and (13.1%,

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33.3%), respectively. However, the RCT has not yet been published.84

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Kineflex|C (Figure 1f)85

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Coric et al.85 (F/U 87% at 24 months) conducted an RCT and found statistically significant

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improvements in both cohorts for NDI and VAS scores, but did not provide any statistical

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comparison between cohorts. Overall “success rates,” defined as maintenance of improvement in

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neurologic status, 20% NDI score improvement, and no adverse events were higher in the

ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 7 1

Kineflex|C (KC) cohort (85%) than the ACDF cohort (71%). ASDI rates were 7.6% KC, 6.1%

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ACDF (no p-value) whereas ASDG rates were 9% KC, 24.8% ACDF (p<0.01).

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Discover86-88

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All three studies reported significantly improved NDI and VAS outcomes of the Discover cohort.

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Complication Rates (Tables 4 and 5)

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Nineteen studies reported complication rates for either ASDI or ASDG. Recording the rates as

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ASDI or ASDG was performed according to the specific designation in the study – “adjacent

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level disease” versus “adjacent segment degeneration.” The mean weighted averages (MWA) of

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ASDI and ASDG for CDA were 2.7% and 22.0%, respectively, varying by disc type and sample

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size. The MWAs of ASDI and ASDG for ACDF were 6.3% and 36.5%, respectively, which is

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about double that reported for CDA. Those studies without a COI (n=6) reported MWA ASDI

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and ASDG rates of 6.3% and 14.2% CDA, 6.2% and 0% ACDF, respectively. In contrast, the

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reverse was reported by studies with a COI (n=13), for which the ASDI and ASDG MWAs were

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2.5% and 24.3% CDA, 6.3% and 36.5% ACDF, respectively. In early studies (n=4), the MWA

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ASDI rates were 1.8% CDA (1.7% with COI, 4.6% without COI), 7.5% ACDF (8% with COI,

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0% without COI). The ASDG rates were 17.5% CDA, 34.6% ACDF. In late studies (n=15), the

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MWA ASDI rates were 3.1% CDA (2.1% with COI, 1.9% without COI), 5.6% ACDF (4.1%

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with COI, 12% without COI). The MWA ASDG rates were 23.0% CDA, 37.9% ACDF.

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Twenty-six studies reported complication rates for HO. HO rates varied from as low as 0% to as

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high as 94.1% with an overall weighted average of 30.3%. Those studies with a COI specifically

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reporting HO rates (n=11) had a MWA HO rate of 22% while those studies with no COI

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specifically reporting HO rates (n=15) had a MWA of 46%. Of the studies performed prior to

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2008 reporting HO rates (n=5), the MWA was 13.2%. Of the later studies reporting HO rates

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(n=21), the MWA was 34.4%.

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Statistical Analysis

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5). For ASDI, no significant study heterogeneity existed for COI and non-COI subgroups

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(p=0.17 and p=0.56, respectively), as well as for early and late subgroups (p=0.12 and p=0.48,

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respectively). Combined estimates showed that among studies with a COI, the odds of ASDI

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with ACDF were 2.54 times higher than ASDI with CDA. For those without a COI, the 95%

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confidence interval included 1 and, thus, there was insufficient evidence to conclude an

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association between ASDI and either surgery. Combined estimates also showed that among late

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studies, the odds of ASDI with ACDF were 1.72 times higher than with CDA. For early studies,

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the 95% confidence interval included 1 and, thus, there was insufficient evidence to conclude an association between ASDI and either surgery.

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For HO, significant study heterogeneity existed (p<0.0001) for both COI and non-COI

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subgroups, as well as early and late subgroups. Combined estimates showed that studies with a

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COI estimated the HO proportion as 11% whereas those without had an estimate of 42%.

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Combined estimates also showed that among early studies, the estimated HO proportion was 8%

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whereas late studies had an estimate of 30%.

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Cervical disc arthroplasty is an option for patients who have symptomatic disc disease that is

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refractory to non-operative care. As a new technology, CDA has undergone rigorous evaluation

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in a variety of studies that have been published over the last decade. There is an apparent

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discrepancy across studies in the reporting of heterotopic ossification, complications, and rates of

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ASDG and ASDI, and defining these differences is important for patient care. The purpose of

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this review was to review critically the clinical and radiographic outcomes associated with this

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novel technology.

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Early vs. Late Studies

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The statistical significance of more early studies being downgraded compared with late studies

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could be due to the initiation of more efficient follow-up methods. In addition, the greater

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emphasis of the late studies to be used for device FDA approval may have influenced the highly

ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 9 effective study designs and adequate follow-ups. Early studies (prior to 2008) were mainly level

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IIb evidence, prospective or retrospective in design, had short follow-up time or lower percent of

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follow-up, and had small patient sample sizes. Compared to the early studies, late studies (2008

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and after) were mainly level Ib evidence, RCT or prospective in design, had longer follow-up

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time and/or greater percent follow-up, and had larger patient sample sizes. In addition, COIs, as

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discussed below, were significantly more prevalent in late studies.

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COI

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Thirty-one of 74 studies (42%) included in this review were funded by industry. Thirty-one of 50

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studies (62%) with a disclosure section were funded by industry. Specifically, as shown in Table

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5, most studies received funding by the corporation who manufactured the disc being studied,

12

which raises questions about the validity of those results due to potential bias. To standardize our

13

analysis, COIs were defined per the NASS guidelines.13 The guidelines require disclosure of

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remuneration from or relationship with a company, receiving gifts from a company, holding an

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office in a company, or any interest, ownership, or employment in device or biologic

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distributorship.13 Prior to 2008, 3/15 studies (20%) reporting COIs were level Ib/IIb evidence.

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After 2008, 14/16 (87.5%) reporting COIs were level Ib/IIb evidence (p<0.01). This difference in

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number of studies with COIs likely is secondary to the development of multiple new artificial

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discs by companies interested in obtaining FDA. In a study evaluating COI in the scientific

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literature, Bhandari et al.89 examined 332 randomized trials in 13 leading surgical and medical

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journals in order to determine if an association existed between industry financial involvement

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and trial outcome(s). Industry funding was associated with a statistically significant supportive

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result (OR 1.9, 95% CI 1.3-3.5).89 After adjustment for study quality and sample size, the

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association remained significant (adjusted OR 1.8, 95% CI 1.1-3.0).89 The presence of corporate

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funding in the studies reviewed in the present study is noteworthy. Since the approval of the

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initial Bryan and Prestige discs, the market for CDA has grown rapidly to hundreds of millions

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of dollars.90 Currently, many cervical disc prostheses are in the process of applying for premarket

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approval within or outside the U.S., including: Cervicore (Stryker Spine, Allendale, NJ), M6-C

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(SpinalKinetics, Sunnyvale, CA), Baguera C (Signature Spine, Kingsgrove, NSW), Rotaio

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(Signus Spine, Chanhassen, MN), Cadisc-C (Ranier, Cambridge, UK), Secure-C (Globus

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Medical, Audubon, PA), Freedom (AxioMed, Newtown, PA), Discocerv (Scient’x/Alphatec,

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 10 1

Carlsbad, CA), and Altia TDI (Amedica, Salt Lake City, UT). Given this rapidly growing

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market, it is critical that potential biases are nullified and controlled in future studies.

3 COI and Quality of Life Outcomes

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Based on the peer-reviewed literature, there is some level Ib evidence available with two-year

6

follow-up that demonstrates superior clinical and QOL outcomes with the Bryan, Prestige, PCM,

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and ProDisc-C discs compared to single-level ACDF. The remainder, and the majority, of

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evidence on the Bryan, Prestige, PCM, and ProDisc-C discs all report improved clinical

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outcomes within both ACDF and CDA cohorts from preoperative to postoperative at the various

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times points reported up to 24 months; some studies maintained superiority of CDA over ACDF

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at 48-84 months. Prior to 2008, only 1/8 RCTs (12.5%) showed statistically significant greater

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QOL outcomes for CDA compared with ACDF; this study had a COI while 5 of the other 7

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RCTs that showed no significant differences had no COI reported. After 2008, 8/14 RCTs (57%)

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showed statistically significant greater QOL outcomes for CDA compared with ACDF. Seven of

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these 8 late RCTs (89%) also reported an industry-sponsored COI. Five of the other 6 late RCTs

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that did not show significant differences between cohorts reported an industry-sponsored COI as

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well. Thus, overall, the presence of a COI among late studies did not seem to significantly

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influence the QOL outcomes.

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COI, ASD, and HO

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The main driving force behind the development of CDA was the prevention or diminution of

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adjacent segment disease (ASDI) and degeneration (ASDG). Based on the studies analyzed in

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this review specifically reporting either ASDI or ASDG (n=19), there is inconclusive evidence to

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support the role of arthroplasty in significantly decreasing the incidence of ASDI or ASDG.

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While overall the MWA of ASDI/ASDG for CDA was half that for ACDF, thereby showing

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numerical support for the use of CDA over ACDF in reducing ASDI/G rates, significant

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differences existed when separating the studies by conflict of interest and year of publication.

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Those studies with a COI or published after 2008 were more likely to report greater ASD rates

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for ACDF cohorts than CDA cohorts with higher percentages reported for both cohorts in late

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studies compared to early studies. Interestingly, only 6 studies reported ASDG rates. Few studies

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actually defined “adjacent level disease” and some rates reported as ASDI rates may actually

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 11 have been ASDG rates. Despite this inconsistency in defining ASD/I/G, the meta-analysis

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undertaken showed a lack of significant heterogeneity among the studies analyzed and confirmed

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that ASDI was significantly higher for ACDF cohorts in studies with a COI or published after

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2008. It is important in future studies that ASD/I/G is defined appropriately as clinical versus

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radiological complications are different entities where the latter may not necessarily lead to

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clinical symptoms.

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HO rates reported by studies with COIs or performed after 2008 were, on average, more than

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double those reported by studies without COIs. This was confirmed by the meta-analysis.

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However, the meta-analysis also showed significant study heterogeneity (p<0.0001) among

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studies stratified by either COI or publication date. The variability in HO rates and heterogeneity

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identified in the meta-analysis may be due to patient sample differences or type of prosthesis

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used. Yi et al.91,92 analyzed the occurrence of HO in patients who underwent CDA and stratified

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the overall HO rate (40.6%) by disc type: Bryan disc (21%), Mobi-C disc (52.5%), and ProDisc-

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C disc (71.4%). In the present review, studies on Prestige discs reported the lowest HO rates

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(n=7 studies; 0%-3.2%), followed by Bryan discs (n=40 studies; 0%-17.8%), PCM discs (n=4

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studies; 0%-38%), ProDisc-C discs (2.9%-88%; n=11 studies), and finally Mobi-C discs (n=7

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studies; 62%-94.1%). This suggests potential superiority of certain disc types over others and

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warrants future comparative effectiveness studies among the choices of disc prosthesis.

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20 Summary

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Multiple reviews of the literature and meta-analyses of QOL outcomes have been performed in

23

the past few years on CDA versus ACDF.1-9 Most of these studies noted that while there are

24

significant differences in some patient reported outcomes favoring the usage of CDA over

25

ACDF, other clinical outcomes were either similar between the cohorts or failed to demonstrate

26

significant differences consistently in multiple follow-up intervals. None of the studies showed

27

that CDA resulted in inferior clinical outcomes relative to ACDF. Most reviews noted, at

28

minimum, equivalent safety and efficacy of CDA and ACDF. The findings of the present review

29

are supported by the findings of prior literature reviews on QOL outcomes, safety, and efficacy

30

of CDA compared to ACDF. This study also adds additional studies, not included in the prior

31

reviews, which highlight either the non-inferiority or superiority of CDA as an alternative to

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 12 1

ACDF. In addition, the present study confirms that the evidence is lacking to support CDA as a

2

strategy to significantly decrease the incidence of ASD in patients undergoing ACDF.

3 Compared to studies prior to 2008, those conducted after 2008 showed superior QOL outcomes

5

for CDA, had longer follow-up periods, had larger patient samples, had greater percentages of

6

complications reported, and had numerous COIs. The primary highlight of this review is that

7

there are financial COIs among authors for virtually all level Ib randomized control trials.

8

Relative to studies without COI, studies with COIs reported lower rates of ASD and HO for

9

CDA cohorts versus ACDF cohorts. This is a concerning association given that a main driving

10

point of this technology is to decrease the problems associated with adjacent level degeneration

11

and disease. As mentioned, level Ib evidence is used to establish standards for patient care.

12

While completing a RCT is a meritorious accomplishment, the association of pro-industry

13

outcomes with COI in studies included in this review makes it difficult to reconcile the data and

14

obscures the decision process for surgeons and patients. Clearly, this is not optimal, and accepted

15

standards among researchers, industry and peer-reviewed journals should be adopted to obviate

16

this situation in the future. Furthermore, there are different guidelines among journals for

17

qualifying COI. This adds yet another dimension of complexity for the reader. Only journals

18

with a minimum of certain disclosure requirements were included. The primary limitation of this

19

review is how differences among study classification systems for HO, ASDI, and ASDG may

20

impact the results presented here. Given a lack of exact definitions by each study, the

21

complication rates assessed may never be completely comparable. This is a limitation of most

22

systematic reviews of both prospective and retrospective studies.1-6

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Studies published after 2008 were more likely to have a COI, and those with a COI reported

27

greater ASDI/G complication rates for ACDF cohorts than CDA cohorts. In addition, HO rates

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were significantly lower in studies with COI versus those without COI. Studies with a conflict of

29

interest reported worse complication results for ACDF cohorts and better profiles (little to no

30

complications) for CDA cohorts. All studies reported improved statistically significant QOL

31

outcomes with their respective devices from preoperative to postoperative periods. Overall, the

ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 13 presence of a COI was not associated with the presence or absence of significant differences

2

between CDA and ACDF cohorts for QOL outcomes. Thus, COIs did not impact QOL

3

outcomes, but did significantly impact the complication rates of ASD and HO. In line with

4

Scott’s Parabola, CDA showed great promise with equivalent quality of life outcomes to ACDF

5

at an early stage, but now complication rates may put CDA on the downslope of the parabola. At

6

minimum, comparative studies between the various devices will be helpful in highlighting the

7

differences, if any, that exist in the clinical or radiographic outcomes or biomechanical function.

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Cost effectiveness studies between CDA and ACDF will also be of great benefit in determining

9

the optimal surgical option.

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References

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1. Yin S, Yu X, Zhou S, Yin Z, Qiu Y. Is Cervical Disc Arthroplasty Superior to Fusion for Treatment of Symptomatic Cervical Disc Disease? A Meta-Analysis. Clin Orthop Relat Res 2013;471:1904–1919. 2. Xing D, Ma X, Ma J, Wang J, Ma T, Chen Y. A meta-analysis of cervical arthroplasty compared to anterior cervical discectomy and fusion for single-level cervical disc disease. Journal of Clinical Neuroscience 2013;20:970-8. 3. Oh CH and Yoon SH. Past, Present, and Future of Cervical Arthroplasty. Keio J Med. 2013;62(2):47-52. 4. Yu Gao MM, Liu M, Li T, Huang F, Tang T, Xiang Z. A meta-analysis comparing the results of cervical disc arthroplasty with anterior cervical discectomy and fusion (ACDF) for the treatment of symptomatic cervical disc disease. J Bone Joint Surg Am. 2013;95:555-61. 5. Boselie TFM, Willems PC, van Mameren H, de Bie RA, Benzel EC, van Santbrink H. Arthroplasty versus fusion in single-level cervical degenerative disc disease: A Cochrane review. Spine 2013;38:E1096-1107. 6. Cepoiu-Martin M, Faris P, Lorenzetti D, Prefontaine E, Noseworthy T, Sutherland L. Artificial Cervical Disc Arthroplasty: A Systematic Review. Spine 2011;36:E1623-33. 7. Bartels R, Donk R, Verbeek ALM. No Justification for Cervical Disk Prostheses in Clinical Practice: A Meta-Analysis of Randomized Controlled Trials. Neurosurgery 2010; 66:1153-60. 8. 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) 2012;37:943-52. 9. Lu Y, Hecht AC, Cho S, Qureshi S. Cervical Disc Arthroplasty versus Anterior Cervical Discectomy and Fusion: A Systematic Review. Orthop Muscul Syst 2012 S2. 10. Sackett DL, Strauss SE, Richardson WS, et al. Evidence-Based Medicine: How to Practice and Teach EBM. Philadelphia, Pa: Churchill- Livingstone; 2000.

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11. Resnick DK, Choudhri TF, Dailey AT. Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine. Part I. Introduction and methodology. J Neurosurg Spine 2005;2:637-638. 12. Scott JW. Scott’s Parabola: The rise and fall of a surgical technique. Br Med J 2001;323:1477. 13. NASS Disclosure Policy. Revised March 2012. http://www.spine.org/Pages/PracticePolicy/EthicsProfConduct/NASSDisclosurePolicy 14. Sasso RC, Smucker, JD, Hacker RJ, Heller JG. Artificial disc versus fusion. A prospective, randomized study with 2-year follow-up on 99 patients. Spine 2007;26:2933-2940. 15. Sasso RC, Smucker, JD, Hacker RJ, Heller JG. Clinical outcomes of BRYAN cervical disc arthroplasty: A prospective, randomized, controlled, multicenter trial with 24-month follow-up. J Spinal Disord Tech 2007;20:481-491. 16. Hacker RJ. Cervical disc arthroplasty: a controlled randomized prospective study with intermediate follow-up results. J Neurosurg Spine 2005;3:424-428. 17. Coric D, Finger F, Boltes P. Prospective randomized controlled study of the Bryan Cervical Disc: Early clinical results from a single investigational site. J Neurosurg Spine 2006;4:31–35. 18. Pickett GE, Sekhon LH, Sears WR. Complications with cervical arthroplasty. J Neurosurg Spine 2006;4:98-105. 19. Pickett GE, Mitsis DK, Sekhon LH, Sears WR, Duggal N. Effects of a cervical disc prosthesis on segmental and cervical alignment. Neurosurg Focus 2004;17:E5. 20. Robertson JT, Papadopoulos SM, Traynelis VC. Assessment of adjacent segment disease in patients treated with cervical fusion or arthroplasty: a prospective 2-year study. J Neurosurg Spine 2005;3:417-423. 21. Lafuente J, Casey ATH, Petzold A, Brew S. The Bryan cervical disc prosthesis as an alternative to arthrodesis in the treatment of cervical spondylosis. J Bone and Joint Surg 2005:57; 508-512. 22. Sekhon L, Sears W, Duggal N. Cervical arthroplasty after previous surgery: results of treating 24 discs in 15 patients. J Neurosurg Spine 2005:3;335-341. 23. Duggal N, Pickett GE, Mitsis D, Keller JL. Early clinical and biomechanical results following cervical arthroplasty. Neurosurg Focus 2004;17:E9. 24. Anderson PA, Sasso RC, Rouleau JP, Carlson CS, Goffin J. l. The Bryan Cervical Disc: wear properties and early clinical results. Spine J 2004;4:303–9. 25. Goffin J, Van Calenbergh F, van Loon J, et al. Intermediate follow-up after treatment of degenerative disc disease with the Bryan cervical disc prosthesis: Single level and bilevel. Spine 2003;29:2673-2678. 26. Bryan VE. Cervical motion segment replacement. Eur Spine J 2002;11:S92-S97. 27. Yoon DH, Yi S, Shin HC et al. Clinical and radiological following cervical arthroplasty. Acta Neurochir (Wien) 2006;148:943-950. 28. Leung C, Casey A, Goffin J et al. Clinical significance of heterotopic ossification in cervical disc replacement: a prospective multicenter clinical trial. Neurosurgery 2005;57:759-763. 29. Sekhon L. Cervical arthroplasty in the management of spondylotic myelopathy. J Spinal Dis Techniques 2003;16:307-13.

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30. Shim CS, Lee S, Park H. Early clinical and radiologic outcomes of cervical arthroplasty with Bryan Cervical Disc Prosthesis. J Spinal Disord Tech 2006;19:465-470. 31. Coric D, Kim PK, Clemente JD, Boltes MO, Nussbaum M, James S. Prospective randomized study of cervical arthroplasty and anterior cervical discectomy and fusion with long-term follow-up: results in 74 patients from a single site. J Neurosurg Spine 2013;18:36-42. 32. Zhang X, Zhang X, Chen C, Zhang Y, Wang Z, et al. Randomized, controlled, multicenter, clinical trial comparing BRYAN cervical disc arthroplasty with anterior cervical decompression and fusion in China. Spine (Phila Pa 1976) 2012;37:433-438. 33. Cheng L, Nie L, Li M, Huo Y, Pan X. Superiority of the BRYAN(®) disc prosthesis for cervical myelopathy: a randomized study with 3-year follow-up. Clin Orthop Relat Res 2011;469:3408-14. 34. Sasso RC, Anderson PA, Riew KD, Heller JG. Results of cervical arthroplasty compared with anterior discectomy and fusion: four-year clinical outcomes in a prospective, randomized controlled trial. J Bone Joint Surg Am 2011;93:1684-1692. 35. Garrido BJ, Taha TA, Sasso RC. Clinical outcomes of Bryan cervical disc arthroplasty a prospective, randomized, controlled, single site trial with 48-month follow-up. J Spinal Disord Tech. 2010;23:367-71. 36. Heller JG, Sasso RC, Papadopoulos SM, et al. Comparison of BRYAN cervical disc arthroplasty with anterior cervical decompression and fusion: clinical and radiographic results of a randomized, controlled, clinical trial. Spine (Phila Pa 1976) 2009;34:101-7. 37. Yang S, Wu X, Hu Y, et al. Early and intermediate follow-up results after treatment of degenerative disc disease with the Bryan cervical disc prosthesis: single- and multiplelevel. Spine 2008;20:E371-7. 38. Quan GM, Vital JM, Hansen S, Pointillart V. Eight-year clinical and radiological followup of the Bryan cervical disc arthroplasty. Spine (Phila Pa 1976) 2011;36:639-46. 39. Ren X, Wang W, Chu T, Wang J, Li C, Jiang T. The intermediate clinical outcome and its limitations of Bryan cervical arthroplasty for treatment of cervical disc herniation. J Spinal Disord Tech 2011;24:221-9. 40. Coric D, Cassis J, Carew JD, Boltes MO. Prospective study of cervical arthroplasty in 98 patients involved in 1 of 3 separate investigational device exemption studies from a single investigational site with a minimum 2-year follow-up. Clinical article. J Neurosurg Spine 2010;13:715-21. 41. Goffin J, van Loon J, Van Calenbergh F, Lipscomb B. A clinical analysis of 4- and 6year follow-up results after cervical disc replacement surgery using the Bryan Cervical Disc Prosthesis. J Neurosurg Spine 2010;12:261-9. 42. Ryu KS, Park CK, Jun SC, Huh HY. Radiological changes of the operated and adjacent segments following cervical arthroplasty after a minimum 24-month follow-up: comparison between the Bryan and ProDisc-C devices. J Neurosurg Spine. 2010;13:299307. 43. Walraevans J, Demaerel P, Suetens P, et al. Longitudinal prospective long-term radiographic follow-up after treatment of single-level cervical disk disease with the Bryan Cervical Disc. Neurosurgery 2010;67:679-87. 44. Bhadra AK, Raman AS, Casey AT, Crawford RJ. Single-level cervical radiculopathy: clinical outcome and cost-effectiveness of four techniques of anterior cervical discectomy and fusion and disc arthroplasty. Eur Spine J. 2009;18:232-7.

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45. Yang YC, Nie L, Cheng L, Hou Y. Clinical and radiographic reports following cervical arthroplasty: a 24-month follow-up. Int Orthop. 2009;33:1037-42. 46. 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. 2009;33:1347-51. 47. Heidecke V, Burkert W, Brucke M, Rainov NG. Intervertebral disc replacement for cervical degenerative disease--clinical results and functional outcome at two years in patients implanted with the Bryan cervical disc prosthesis. Acta Neurochir (Wien). 2008;150:453-9. 48. Kim SW, Shin JH, Arbatin JJ, Park MS, Chung YK, McAfee PC. Effects of a cervical disc prosthesis on maintaining sagittal alignment of the functional spinal unit and overall sagittal balance of the cervical spine. Eur Spine J. 2008;17:20-9. 49. Wang Y, Cai B, Zhang XS, et al. Clinical outcomes of single level Bryan cervical disc arthroplasty: a prospective controlled study. Zhonghua Wai Ke Za Zhi. 2008;46:328-32. 50. Ding C, Hong Y, Liu H, Shi R, Hu T, Li T. Intermediate clinical outcome of Bryan Cervical Disc replacement for degenerative disk disease and its effect on adjacent segment disks. Orthopedics. 2012;35:e909-16. 51. Tu TH, Wu JC, Huang WC, et al. Heterotopic ossification after cervical total disc replacement: determination by CT and effects on clinical outcomes. J Neurosurg Spine. 2011;14:457-65. 52. 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. 2010;10:676-82. 53. Kim HK, Kim MH, Cho DS, Kim SH. Surgical outcome of cervical arthroplasty using bryan(r). J Korean Neurosurg Soc. 2009;46:532-7. 54. Wigfield CC, Gill SS, Nelson RJ, Metcalf NH, Robertson JT. The new Frenchay artificial cervical joint: results from a two-year pilot study. Spine (Phila Pa 1976) 2002;27:244652. 55. Porchet F, Newton H, Metcalf BS. Clinical outcomes with the Prestige II cervical disc: preliminary results from a prospective randomized clinical trial. Neurosurg Focus 2004;17:E6. 56. Mummaneni PV, Burkus JK, Haid RW, et al. Clinical and radiographic analysis of cervical disc arthroplasty compared with allograft fusion: a randomized controlled clinical trial. J Neurosurg Spine 2007;6:198-209. 57. Robertson JT, Metcalf NH. Long-term outcome after implantation of the Prestige I disc in an end-stage indication: 4-year results from a pilot study. Neurosurg Focus 2004;17:E10. 58. 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 2010;13:308318. 59. Riew KD, Buchowski JM, Sasso R, Zdeblick T, Metcalf NH, Anderson PA. Cervical disc arthroplasty compared with arthrodesis for the treatment of myelopathy. J Bone Joint Surg Am. 2008;90:2354-64. 60. Peng CW, Yue WM, Basit A, 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) 2011;36:E105-11.

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61. Riina J, Patel A, Dietz JW, Hoskins JS, Trammell TR, Schwartz DD. Comparison of single-level cervical fusion and a metal-on-metal cervical disc replacement device. Am J Orthop (Belle Mead NJ) 2008;37:E71-7. 62. Phillips FM, Lee JY, Geisler FH, et al. 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 (Phila Pa 1976) 2013;38:E907-18. 63. Pimenta L, McAfee, Cappuccino A, et al. Superiority of multilevel cervical arthroplasty outcomes versus single-level outcomes. 229 consecutive PCM prostheses. Spine 2007;32: 1337-1344. 64. Pimenta L, McAfee PC, Cappuccino A, Bellera FP, Link HD. Clinical experience with the new artificial cervical PCM (Cervitech) Disc. Spine J 2004;4:315S-321S. 65. McAfee PC. The indications for lumbar and cervical disc replacement. Spine J 2004;4:177S-181S. 66. Nabhan A, Ahlhelm F, Shariat K, et al. The ProDisc-C prosthesis: clinical and radiological experience 1 year after surgery. Spine 2007;32:1935-41. 67. Nabhan A, Ahlhelm F, Pitzen T. Disc replacement using Pro-Disc C versus fusion: a prospective randomised and controlled radiographic and clinical study. Eur Spine J. 2007;16:423-430. 68. Mehren C, Suchomel P, Grochulla F, et al. Heterotopic ossification in total cervical artificial disc replacement. Spine 2006;31:2802-2806. 69. Bertagnoli, Yue JJ, Pfeiffer F et al. Early results after ProDisc-C cervical disc replacement. J Neurosurg Spine 2005;2:403-410. 70. Bertagnoli R, Duggal N, Gwynedd EP, et al. Cervical total disc replacement, Part Two: Clinical results. Orthop Clin N Am 2005;36:355-362. 71. Murrey D, Janssen M, Delamarter R. Results of the prospective, randomized, controlled multicenter Food and Drug Administration investigational device exemption study of the ProDisc-C total disc replacement versus anterior discectomy and fusion for the treatment of 1-level symptomatic cervical disc disease. Spine J. 2009;9:275-86. 72. Kelly MP, Mok JM, Frisch RF, Tay BK. Adjacent segment motion after anterior cervical discectomy and fusion versus ProDisc-c cervical total disk arthroplasty: analysis from a randomized, controlled trial. Spine (Phila Pa 1976) 2011;36:1171-9. 73. Kesman T, Murrey D, Darden B. Single-center results at 7 years of prospective, randomized ProDisc-C total disc arthroplasty versus anterior cervical discectomy and fusion for treatment of one level symptomatic cervical disc disease. Evid Based Spine Care J. 2012;3:61-2. 74. Zigler JE, Delamarter R, Murrey D, Spivak J, Janssen M. ProDisc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. Spine (Phila Pa 1976) 2013;38:203-9. 75. Suchomel P, Jurak L, Benes V, et al. Clinical results and development of heterotopic ossification in total cervical disc replacement during a 4-year follow-up. Eur Spine J. 2010;19:307-15. 76. Peng CW, Quirno M, Bendo JA, Spivak JM, Goldstein JA. Effect of intervertebral disc height on postoperative motion and clinical outcomes after ProDisc-C cervical disc replacement. Spine J. 2009;9:551-5.

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77. Kim SH, Shin HC, Shin DA, Kim KN, Yoon do H. Early clinical experience with the mobi-C disc prosthesis. Yonsei Med J. 2007;48:457-64. 78. Park JH, Roh KH, Cho JY, Ra YS, Rhim SC, Noh SW. Comparative analysis of cervical arthroplasty using mobi-c(r) and anterior cervical discectomy and fusion using the solis(r) -cage. J Korean Neurosurg Soc. 2008;44:217-21. 79. Park JH, Rhim SC, Roh SW. Mid-term follow-up of clinical and radiologic outcomes in cervical total disk replacement (Mobi-C): incidence of heterotopic ossification and risk factors. J Spinal Disord Tech. 2013;26:141-5. 80. Guérin P, Obeid I, Bourghli A, et al. Heterotopic ossification after cervical disc replacement: clinical significance and radiographic analysis. A prospective study. Acta Orthop Belg. 2012;78:80-6. 81. Lee SE, Chung CK, Jahng TA. Early development and progression of heterotopic ossification in cervical total disc replacement. J Neurosurg Spine 2012;16:31-6. 82. Beaurain J, Bernard P, Dufour T, et al. Intermediate clinical and radiological results of cervical TDR (Mobi-C) with up to 2 years of follow-up. Eur Spine J. 2009;18:841-50. 83. Huppert J, Beaurain J, Steib JP, et al. Comparison between single- and multi-level patients: clinical and radiological outcomes 2 years after cervical disc replacement. Eur Spine J. 2011;20:1417-26. 84. Eisner, W. “FIRST AND ONLY TWO-LEVEL CERVICAL DISC APPROVED IN U.S.,” 8-29-2013 www.ryortho.com 85. Coric D, Nunley PD, Guyer RD, 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 2011;15:348-58. 86. Maldonado CV, Paz RD, Martin CB. Adjacent-level degeneration after cervical disc arthroplasty versus fusion. Eur Spine J. 2011;20:403-7. 87. Du J, Li M, Liu H, Meng H, He Q, Luo Z. Early follow-up outcomes after treatment of degenerative disc disease with the discover cervical disc prosthesis. Spine J. 2011;11:281-9. 88. 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. Eur Spine J. 2013 [Epub ahead of print] 89. Bhandari M, Busse JW, Jackowski D, et al. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ 2004;170:477-80. 90. The Spine Market Group, Medtech Insight, and the Advisory Board Online. Cervical Disc Arthroplasty: The Market. 2013. 91. Yi S, Shin DA, Kim KN. The predisposing factors for the heterotopic ossification after cervical artificial disc replacement. Spine J. 2013 [Epub ahead of print]. 92. Yi S, Kim KN, Yang MS. Difference in occurrence of heterotopic ossification according to prosthesis type in the cervical artificial disc replacement. Spine (Phila Pa 1976). 2010 Jul 15;35:1556-61. 93. Blum JA, Freeman K, Dart, RC, Cooper RJ. Requirements and Definitions in Conflict of Interest Policies of Medical Journals. JAMA 2009;302:2230-4. 94. DerSimonian, R. & Laird, N.M. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7:177-188.

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 19

Figure Legends

40

Figure 1. a = Bryan Disc; b = Prestige Disc; c = PCM Disc; d = ProDisc-C Disc; e = Mobi-C

41

Disc; f = Kineflex-C Disc

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ACCEPTED MANUSCRIPT Cervical Disc Arthroplasty: A Critical Review of the Literature 20 Figure 2. Forest Plot of ASDI by COI Status. N= sample size; ASDI = adjacent segment disease; CDA = cervical disc arthroplasty; CI = confidence interval; df = degrees of freedom; Q = Cochran's Q statistic for heterogeneity; RE = random effects

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Figure 3. Forest Plot of ASDI by Publication Date. N= sample size; ASDI = adjacent segment disease; CDA = cervical disc arthroplasty; CI = confidence interval; df = degrees of freedom; Q = Cochran's Q statistic for heterogeneity; RE = random effects Figure 4. Forest Plot of HO by COI Status. N= sample size; ASDI = adjacent segment disease; CDA = cervical disc arthroplasty; CI = confidence interval; df = degrees of freedom; Q = Cochran's Q statistic for heterogeneity; RE = random effects

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Figure 5. Forest Plot of HO by Publication Date. N= sample size; ASDI = adjacent segment disease; CDA = cervical disc arthroplasty; CI = confidence interval; df = degrees of freedom; Q = Cochran's Q statistic for heterogeneity; RE = random effects

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ACCEPTED MANUSCRIPT

Date of FDA Approval 5/12/2009

Prestige

Medtronic

7/16/2007

PCM

NuVasive

10/26/2012

ProDisc-C

Synthes Spine

12/17/2007

Mobi-C

LDR

8/7/2013

Kineflex Discover

SpinalMotion DePuy

N/A N/A

# studies 10 RCTs 22 PCs 8 RCs 4 RCTs 3 PCs 0 RCs 1 RCT 3 PCs 0 RCs 6 RCTs 4 PCs 1 RC 5 PCs 2 RCs 1 RCT 3 PCs

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Company Medtronic

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Disc Bryan

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Table 1. Summary of Disc Types

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RCT = Randomized control trial; PC = prospective cohort; RC = retrospective cohort

ACCEPTED MANUSCRIPT

Table 2. Summary of Bryan Literature VAS Neck Imp Imp Imp

VAS Arm Imp Imp Imp

Odom

Imp Imp Imp Imp Imp Imp Imp Imp

Imp Imp Imp Imp Imp Imp Imp

Imp Imp Imp Imp

Imp Imp*

Imp Imp Imp*

Imp Imp

Imp Imp Imp

Imp Imp Imp

SF36 PCS

SF36 MCS

Imp Imp Imp Imp Imp Imp Imp Imp

Imp Imp Imp Imp Imp Imp Imp Imp

Imp

Imp

Imp

Imp

Imp

Imp

Imp Imp

Imp Imp

Imp

Imp

Imp Imp Imp Imp Imp

Imp Imp Imp Imp

NP

NP

RI PT

NDI Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp

SC

Statistics Complete Complete Complete Complete Incomplete Complete Complete Complete NP NP Complete NP Complete Incomplete Complete Complete Complete Complete Complete NP Complete Complete Incomplete Incomplete Incomplete Incomplete Incomplete Complete Incomplete NP NP NP Incomplete Complete Incomplete NP Complete Incomplete Incomplete Complete

Imp

Imp Imp Imp

Imp* Imp Imp* Imp Imp Imp Imp* Imp

M AN U

F/U1 86% 48m 93% 24m 95% 24m 100% 36m 100% 48m 92% 24m 87% 24m 64% 24m 51% 24m 100% 12m NR Mean 35m 90% 24m 100% 48m Mean 27m 92% 48m Mean 31m Mean 30m 96.7% 24m 100% 24m Mean 24m 100% 24m 100% 12m NR 72% 24m 86% 12m 100% 12m 100% 24m 100% 24m 75% 24m 33% 24m 9% 24m 100% 24m Mean 26.7m Mean 14m Mean 29m 77% 3m NR 98% 12m NR

TE D

N 41 I, 33 C 60 I, 60 C 242 I, 221 C 41 I, 42 C 21 I, 26 C 242 I, 221 C 56 I, 59 C 56 I, 46 C 22 I, 24 C 17 I, 16 C 21 45 57 I, 41 C 98 36 89 15 I, 45 C 15 31 I, 34 C 54 47 59 19 74 105 I, 202 C 13 46 14 24 136 146 97 32 36 48 52 39 46 90 7

Imp Imp Imp

EP

Design RCT RCT RCT RCT RCT RCT RCT RCT RCT RCT PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC PC R R R R R R R R

AC C

Author (Yr, Ref) Coric 2012 Zhang 2012 Sasso 2011 Cheng 2011 Garrido 2010 Heller 2009 Sasso 2007 Sasso 2007 Hacker 2005 Coric 2006 Quan 2011 Ren 2011 Coric 2010 Goffin 2010 Ryu 2010 Walraevens 2010 Bhadra 2009 Yang 2009 Cheng 2008 Heidecke 2008 Kim 2008 Wang 2008 Yang 2008 Pickett 2006 Robertson 2005 Sekhon 2005 Lafuente 2005 Pickett 2004 Duggal 2004 Anderson 2004 Goffin 2003 Bryan 2002 Ding 2012 Tu 2011 Lee 2010 Kim 2009 Shim 2006 Yoon 2006 Leung 2005 Sekhon 2003

Imp

Imp Imp Imp

Imp* Imp Imp* Imp Imp Imp Imp* Imp

Imp Imp Imp Imp Imp

Imp Imp Imp Imp Imp

Imp Imp Imp

Imp Imp Imp* Imp Imp Imp

Imp Imp Imp* Imp Imp Imp

Imp

Imp

Imp

Imp Imp

Imp

Design LoE2 Ib Ib Ib Ib Ib Ib Ib Ib Ib Ib IIb IIb IIb IIb IIb IIb IIb IIb IIb IIIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb IIb

Sackett LoE IIb Ib Ib IIb IIb Ib Ib IIb IIb IIb IV IV IIb IIIb IV IIIb IV IV IIIb IV IIIb IIb IIIb IV IIIb IV IIIb IIIb IIIb IIIb IIIb IIIb IIIb IIIb IV IV IV IV IV IV

Downgrade3 5 N/A N/A 5 4,5 N/A N/A 1 1,2,4,5 2,4,5 1,3,5 3,4,5 N/A 4 1,3,5 2 3,5 3,5 5 4 1,3,5 N/A 4,5 1,2,3,4 1,2,4 4,5 4,5 5 2,4,5 1,4 1,2,4 1,2,4 5 5 1,2,3,4,5 3,4 1,5 1,4,5 2,4 3,5

AC C

EP

TE D

SC

M AN U

Key: 1 : % clinical follow-up 2 : Level of Evidence 3 : Reasons for downgrade: 1: Inadequate follow-up 2: Incomplete reporting of outcome measures 3: Incomplete / unclear reporting of percent follow-up 4: Partial or complete lack of statistical analysis of important outcomes measures 5: Inadequate sample size I: Investigational group (CDA) C: Control group (ACDF) Imp: Improved NP: not performed PC: Prospective cohort R: Retrospective *: Differentiation between VAS arm and neck scores not provided

RI PT

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ACCEPTED MANUSCRIPT

Table 3. Summary of Discover, Frenchay, Porous Coated Motion (PCM), Prestige, and ProDisc-C Literature N()

F/U1

Statistics

NDI

PC PC PC PC RCT PC PC PC PC R R R RCT PC PC PC RCT RCT RCT RCT PC PC PC RCT RCT RCT RCT RCT RCT PC PC PC PC R

Discover Discover Discover Frenchay KineflexC Mobi-C Mobi-C Mobi-C Mobi-C Mobi-C Mobi-C Mobi-C PCM PCM PCM PCM Prestige Prestige Prestige Prestige Prestige Prestige Prestige ProDisc-C ProDisc-C ProDisc-C ProDisc-C ProDisc-C ProDisc-C ProDisc-C ProDisc-C ProDisc-C ProDisc-C ProDisc-C

55 85 I, 105 C 25 15 136 I, 133 C 40 28 231 76 15 I, 18 C 32 I, 21 C 23 I 189 I, 153 C 140 53 23 276 I, 265 C 106 I, 93 C 276 I, 265 C 21 I, 28 C 40 I, 75 C 19 17 103 I, 106 C 22 I, 22 C 100 I, 99 C 103 I, 106 C 19 I, 21 C 13 I, 12 C 54 54 16 27 166

100% 24m 100% 36m Mean 15m 100% 24m 87% 24m Mean 24.3m 78.5% 24m 100% 24m 100% 24m Mean 28m Mean 20m Mean 6m 100% 24m NR NR 100% 3m 87% 24m 100% 24m 80% 24m 16% 24m Mean 24m 100% 24m 71% 48m 70% 60m 82% 84m 100% 24m 96.5% 24m 100% 12m 100% 6m 93% 48m 100% 12m 100% 12m 100% 12m Mean 24m

Complete Complete Complete NP Complete Complete Complete Complete Complete Incomplete Incomplete Complete Complete Incomplete NP NP Complete Complete Complete Incomplete Complete NP Incomplete Complete Complete Complete Complete Complete Complete Complete Incomplete Complete NP Complete

Imp Imp Imp Imp Imp Imp Imp Imp Imp

Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp*

VAS Arm Imp Imp Imp Imp Imp Imp Imp* Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp*

Imp Imp Imp Imp Imp Imp* Imp* Imp

Imp Imp Imp Imp Imp Imp Imp Imp

Imp Imp Imp Imp Imp* Imp Imp Imp

EP

TE D

M AN U

Imp

VAS Neck Imp

Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp Imp

Imp Imp Imp Imp Imp

Odom

SF36 PCS

RI PT

Disc

SC

Design

AC C

Author (Yr, Ref) Li 2013 Maldonado 2011 Du 2011 Wigfield 2002 Coric 2011 Guerin 2012 Lee 2012 Huppert 2011 Beaurain 2009 Park 2013 Park 2008 Kim 2007 Phillips 2013 Pimenta 2007 Pimenta 2004 McAfee 2004 Burkus 2010 Riew 2008 Mummaneni 2007 Porchet 2004 Peng 2011 Riina 2008 Robertson 2004 Zigler 2013 Kesman 2012 Kelly 2011 Murrey 2009 Nabhan 2007 Nabhan 2007 Suchomel 2010 Mehren 2006 Bertagnoli 2005 Bertagnoli 2005 Peng 2009

SF36 MCS

Imp

Imp

Imp

Imp

Imp

Imp Imp

Imp Imp

Imp*

Imp*

Imp Imp Imp Imp Imp

Imp Imp Imp Imp Imp

Imp Imp*

Imp Imp*

Imp

Imp

Imp

Imp Imp

Design LoE2 IIb IIb IIb IIb Ib IIb IIb IIb IIb IIb IIb IIb Ib IIb IIb IIb Ib Ib Ib Ib IIb IIb IIb Ib Ib Ib Ib Ib Ib IIb IIb IIb IIb IIb

Sackett LoE

Downgrade3

IIb IIb IIIb IV Ib IIIb IV IIb IIb IV IV IV Ib IV IV IV Ib Ib IIb IIb IV IV IV Ib IIb IIb Ib IIb IIb IIb IIb IIIb IIIb IV

N/A N/A 1,3,5 4,5 N/A 3,5 1,5 N/A N/A 3,4,5 3,4,5 1,3,5 N/A 1,3,4 1,3,4 1,4,5 N/A N/A 1 1,4,5 3,5 3,4,5 4,5 N/A 5 2 N/A 5 1,5 N/A N/A 5 4,5 3

AC C

EP

TE D

SC

M AN U

Key: 1 : % clinical follow-up 2 : Level of Evidence 3 : Reasons for downgrade: 1: Inadequate follow-up 2: Incomplete reporting of outcome measures 3: Incomplete / unclear reporting of percent follow-up 4: Partial or complete lack of statistical analysis of important outcomes measures 5: Inadequate sample size I: Investigational group (CDA) C: Control group (ACDF) Imp: Improved NP: not performed PC: Prospective cohort R: Retrospective NR: Not reported *: Differentiation between VAS arm and neck scores not provided

RI PT

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ACCEPTED MANUSCRIPT Table 4. Classification of Data, Conflict of Interest, Complications – No COI or Not reported AS Disease None None None None None None 4.6% I, 0% C None None None 9% I, 11% C None None None None None None None None None 19% None 5% I, 12% C None None None None None None None 5.4% I, 7% C None None None None None None None None None None None None

AS Degeneration None None None None None None None None None 7.2% I None None None None None None None None None 23% I 19% I None None None None None None None None None None None None None None None None 9.1% I None None None None None

Other 2.4% I, 16.7% C None None None None 17% 4.5% I, 4.2% C 7% None None None 3.5% I, 3.8% C None None None None None None None None None None 6.7% None None None 2.9% None None None 3.5% I, 6.8% C None None None None None None 10.5% None None None None None

RI PT

HO 2.4% 50% 27% 52.8% None None None None 17.8% 18% None None 27.7% 77.3% None 88% None None 57% None 47.6% 4.4% None 13% 6.7% None None 29% None None None None None None None None 94.1% 67% None None None None None

SC

COI None None None None None None None None None None None None None None None None None None None NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS NDS

M AN U

LOE IIb IIb IV IV IIIb IV IIb IIIb IV IIb IIIb IIb IIIb IV IV IIb IV IIb IIb IIb IV IV IIb IV IV IV IIb IV IIIb IIb IIb IIb IV IIIb IIIb IV IV IIb IV IV IV IIb IIIb

TE D

Disc Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Discover Discover Discover Mobi-C Mobi-C Prestige ProDisc-C ProDisc-C ProDisc-C ProDisc-C Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Bryan Mobi-C Mobi-C Mobi-C Mobi-C Prestige ProDisc-C ProDisc-C

EP

Year 2011 2011 2010 2010 2008 2006 2005 2005 2005 2013 2011 2011 2012 2012 2011 2010 2009 2007 2006 2012 2011 2011 2010 2009 2009 2009 2008 2008 2008 2008 2007 2006 2006 2004 2004 2003 2013 2009 2008 2007 2008 2007 2005

AC C

Author Cheng Tu Lee Ryu Yang Shim Hacker Lafuente Leung Li Du Maldonado Guerin Lee Peng Suchomel Peng Nabhan Mehren Ding Quan Ren Garrido Bhadra Yang Kim Cheng Heidecke Kim Wang Sasso Coric Yoon Duggal Pickett Sekhon Park Beaurain Park Kim Riina Nabhan Bertagnoli

Key: LOE: Level of Evidence COI: Conflict of Interest NDS: No Disclosure Section HO: Heterotopic Ossification ASD: Adjacent Segment Disease Other: Other notable complications I: Investigational group (CDA) C: Control group (ACDF) Re-op: Reoperation; Complication rates are reported in % with exact number in ()

Other Dysphagia N/A N/A N/A N/A Op. Failure Dysphonia Dysphonia N/A N/A N/A Osteophyte N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A Re-op. N/A N/A None Dysphagia N/A N/A N/A Re-op. N/A N/A N/A N/A N/A N/A Dysphagia N/A N/A N/A N/A N/A

ACCEPTED MANUSCRIPT Table 5. Classification of Data and Conflict of Interest – Specific COI Reported

Zhang

2012

Bryan

Sasso

2011

Bryan

Ib

Medtronic – Direct payments

None

Coric

2010

Bryan

IIb

Depuy/Spinal Motion – Consultant

5.6%

Goffin

2010

Bryan

IIIb

Medtronic – Funded

None

Walraevens Heller

2010 2009

Bryan Bryan

IIIb Ib

Medtronic – Funded Medtronic – Funded

34% None

Sasso Pickett Robertson

2007 2006 2005

Bryan Bryan Bryan

Ib IV IIIb

None 2.7% None

Sekhon Anderson Goffin Bryan Wigfield Coric

2005 2004 2003 2002 2002 2011

Bryan Bryan Bryan Bryan Frenchay KineflexC

IV IIIb IIIb IIIb IV Ib

Huppert Phillips

2011 2013

Mobi-C PCM

IIb Ib

Non-disclosed corporation – Funded Medtronic – Consultant Medtronic – Consultant, Medical Director of Cervical Division Medtronic – Consultant and Funded Medtronic – Funded Non-disclosed corporation – Funded Employee – Spinal Dynamics Corp. Non-disclosed corporation – Funded Spinal Motion, Inc. – Funded and statistical analysis Non-disclosed corporation – Funded NuVasive, Inc. – Funded

Pimenta McAfee

2007 2004

PCM PCM

IV IV

Pimenta Burkus

2004 2010

PCM Prestige

IV Ib

Riew

2008

Prestige

Ib

Mummaneni

2007

Prestige

Porchet Robertson Zigler

2004 2004 2013

Prestige Prestige ProDisc-C

Kesman

2012

Kelly Murrey

2009 2009

Bertagnoli

2005

12.5%

AS Disease 4.9% I 3% C 1.6% I 5% C 4.1% I 4.1% C 1.7% I 8.1% C 4.1% I 6.1% C None None

AS Degen None

None None 1.3% I 13.9% C None None None None None None

None None 17.5% I 34.6% C None None None None None 9.0% I 24.8% C None None

None None None None None None 62% 38%

Non-disclosed corporation – Funded Cervitech/Johnson & Johnson – Funded Cervitech – Funded and stock owner Medtronic – Funded

0.7% 1.9%

Medtronic – Funded

None

None 3.2%

None 39.1% I 49% C None None

None

None

None None

None 2.5% I 3.6% C None 5.4% None None 2.2% 2.0% None 13.3% 5% I 6.1% C 2.6% None 2.2% None

None 2.9% I 4.9% C None

None None

None

None 10.5% I 18% C 1.9% I 7.5% C 1.8% I 8.7% C None None 2.9% I 11.3% C None

None None None

Medtronic – Funded

None

IIb IV Ib

Medtronic – Employee Medtronic – Funded Synthes Spine – Funded

None None None

ProDisc-C

IIb

Synthes Spine – Funded

None

ProDisc-C ProDisc-C

IIb Ib

Synthes Spine – Funded Synthes Spine – Funded

None 2.9%

1.1% I 3.4% C None None 0% I 5.7% C 0% I 18% C None None

ProDisc-C

IIIb

Synthes Spine – Consultant/Lecturer

None

None

AC C

None

Re-operation 7.3% I 3% C 1.6% I 6.7% C 3.7% I 4.5% C 7.5% I 8.1% C 8.2%

None None

IIb

Key: LOE: Level of Evidence HO: Heterotopic Ossification ASD: Adjacent Segment Disease I: Investigational group (CDA) C: Control group (ACDF) Complication rates are reported in % with exact number in ()

None

RI PT

HO 17%

Ib

Conflict of Interest Medtronic – Consultant Spinal Motion – Stock Owner Chinese Medical Association

SC

LOE IIb

M AN U

Disc Bryan

TE D

Year 2012

EP

Author Coric

None

None None None None

None 1.9% I 8.5% C None

AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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AC C

EP

TE D

M AN U

SC

RI PT

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