Lumbar Artificial Disc Replacement

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The Centers for Medicare and Medicaid Services (CMS) has found that lumbar artificial disc replacement (LADR) with the Charite lumbar artificial disc is not reasonable and necessary for the Medicare population over sixty years of age. Therefore, we are issuing a national noncoverage determination for LADR with the Charite lumbar artificial disc for the Medicare population over sixty years of age. For Medicare beneficiaries sixty years of age and under, there is no national coverage determination, leaving such determinations to be made on a local basis.

Decision Memo: To: Administrative File: (CAG-#00292N) Lumbar Artificial Disc Replacement From: Steve Phurrough, MD, MPA Director Coverage and Analysis Group Marcel E. Salive, MD, MPH Director Division of Medical and Surgical Services Deirdre O’Connor Lead Health Policy Analyst, Division of Medical and Surgical Services Jyme Schafer, MD, MPH Lead Medical Officer, Division of Medical and Surgical Services Shamiram Feinglass, MD, MPH Medical Officer, Division of Items and Devices Subject: Coverage Decision Memorandum for Lumbar Artificial Disc Replacement Date: May 16, 2006 I. Decision The Centers for Medicare and Medicaid Services (CMS) has found that lumbar artificial disc replacement (LADR) with the Charite lumbar artificial disc is not reasonable and necessary for the Medicare population over sixty years of age. Therefore, we are issuing a national noncoverage determination for LADR with the Charite lumbar artificial disc for the Medicare population over sixty years of age. For Medicare beneficiaries sixty years of age and under, there is no national coverage determination, leaving such determinations to be made on a local basis. II. Background Millions of Americans suffer from pain-related problems (Salovey, Seiber et al. 1992). Low back pain is a common condition, with sixty to eighty percent of U.S. adults afflicted at some time during their life (U.S. Preventive Services Task Force 1996). Low back pain can be defined as symptoms of pain, muscle tension, or stiffness localized below the costal margin and above the inferior gluteal folds, with or without leg pain (Manek, MacGregor 2005). Low back pain can be thought of as being either nonspecific or specific. In specific types of low back pain, the symptoms are caused by pathological conditions such as spinal fractures, cancer, or infection and can be identified and treated appropriately (Manek, MacGregor 2005). Approximately 90% of low back pain is of the nonspecific type (Manek, MacGregor 2005). In nonspecific low back pain, most patient’s symptoms resolve satisfactorily within a relatively short time span. In the 5 – 10% of patients whose pain does not satisfactorily resolve, the symptoms can be disabling. Some psychosocial risk factors for the progression to chronicity have been identified (Manek, MacGregor 2005). In general, the social and economic impact of chronic pain is enormous (Salovey, Seiber et al. 1992). Discovering the cause for nonspecific low back symptoms remains challenging. Haldeman states “…we do not know the origin of low back pain in the majority of cases…” and attributes this conundrum to the unique anatomic complexity of the spine (Haldeman 1999). Neurophysiologic mechanisms of pain sensation are poorly understood, adding to the difficulty in localizing the pain source (Haldeman 1999). Frequently, persistent low back pain is attributed to a damaged intervertebral disc, which bears some of the highest loads in the human body and is almost avascular (Huang, Sandhu 2004). Disc damage, or degeneration, can occur as an ongoing process where ultimately the disc’s reparative capacity is overwhelmed, leading to continued changes. Huang and Sandhu stated, “it is not surprising that DDD [degenerative disc disease] is a common phenomenon in middle age and a universal condition in old age.” While from a simple mechanical aspect it could be hypothesized that DDD is a cause for pain, disc degeneration is also observed in individuals without pain (Boden, David et al. 1990). Initial treatment of pain believed to be caused from degenerative disc disease is conservative care. Conservative care can include physical therapy, manipulation, massage, pain medications, and exercise. The majority of patients will have acceptable results with a non-surgical approach. When patients fail conservative care, surgery becomes an option. Until recently in the United States, surgical options available for degenerative disc disease have ranged from discectomies (open or microsurgical) to percutaneous nucleotomies, chemical and thermal nucleolysis and/or spinal fusion (Gibson, Wassell 2005). Spinal fusion has been the predominant surgical treatment for degenerative disc disease (DDD) that does not respond to other treatments. Fusion proposes to relieve pain by eliminating motion in the area of the disc space and/or by disc mechanical load reduction. Nevertheless, the indications for lumbar spinal fusion are variable and not clearly defined (Krismer 2002). These different opinions concerning the indications for back surgery are reflected in the significant regional variation of rates of surgery, surgical techniques used, technical success and rate of fusion (Gibson, Wassell 2005). Satisfactory clinical outcomes can range from 16 to 95% (Gibson, Wassell 2005). Short term relief of pain may perhaps occur with the various types of fusion procedures, but long-term results remain controversial (Bertagnoli, Kumar 2002). Suspected problems include accelerated degeneration of the adjacent lumbar segments, pseudoarthrosis, spinal stenosis and persistent or recurrent low-back pain. In an attempt to overcome these potential long-term problems, the idea of a total artificial disc replacement as a treatment for pain believed secondary to degenerative disc disease has been proposed as an alternative to spinal fusion. As possible added benefits, it has been postulated that total disc replacement may have a protective role on the facet joints, and restore lumbar segment motion (Bertagnoli, Kumar 2002). The artificial disc concept is not new. In the late 1960’s, Fernstrom explored the possibility of replacing the intervertebral disc with an artificial disc. Much research and development work has been done since then. The current Charite disc is the third modification of a device first developed in 1982 by Buttener-Janz and Schellnack at the Charite Clinic in the former East Germany. There are other artificial discs in use in other countries and additional disc implants under development. Intervertebral disc replacement design has been problematic due to the three-column structure of the spine, and the three separate joints at each level. The disc is not a true joint, and functions in both mobility and damping, with the center of rotation moving constantly along three axes (Gunzburg, Mayer et al. 2002). Huang and Sandhu suggest the ideal disc replacement would perform the functions of the replaced native disc, which include preservation of physiologic range of motion, transmission of compressive loads across the disc space, protection of the posterior elements (facets) from abnormal loads, and then to function for many years. In general, the current replacement discs that are either approved or under FDA approved trials in the US have metal endplates that affix to the vertebral bony endplates with some mechanism between these two plates that allows for motion in various planes. The Charite disc has an ultra high molecular weight polyethylene insert that sits between the two metal endplates. The metal endplates have external spikes for engagement of the device into the vertebral bony endplates. Components come in various sizes for a close fit to the patient’s anatomy. The motion of this disc is thought to be minimally constrained in flexion, extension, lateral bending, and axial rotation. It is constrained in compression. The other disc implants in development in the United States are somewhat similar but can vary in material (metal on polymer or metal on metal), motion design, and method of fixation to vertebral endplate (Santos, Polly et al. 2004). Anderson and Rouleau offered, “The current designs are diverse and, thus far, the effects of their individual characteristics on results are unknown.” As of 2004, more than 7,000 patients worldwide had been implanted with the Charite disc (FDA In-depth Statistical Review for Expedited Premarket Approval (PMA) 2004). The surgical procedure for disc replacement involves an anterior approach for exposure of the spine. With this approach, complications of vessel injury can occur and have the potential to be life threatening (Santos, Polly et al. 2004). On revision surgery, Santos, et al., stated, “Revision surgery for a failed disc arthroplasty is life threatening. Dealing with the scarring around the great vessels is the main challenge. Indeed, the location of vital vascular structures may make it altogether impossible to perform such anterior abdominal exposures.” Other postoperative difficulties such as infection, persistent pain, instability, and osteolysis can occur (Santos, Polly et al. 2004). The Charite lumbar artificial disc is referred to in numerous ways (SB Charite, Charite SB and sometimes with the number I, II or III) in the many articles reviewed for this analysis. The designation of the number I, II, III denotes the Charite design that was being used at the time. The Charite disc has gone through changes in the design over the years and the numbers designate the design model. The Charite PMA trial used the most current design, the SB Charite III. For the purposes of this document, the term Charite will be used to refer to the implant. If a particular article identifies the design number (I, II, or III), that will be indicated. III. History of Medicare Coverage Medicare does not currently have a national coverage determination (NCD) on lumbar artificial disc replacement. Coverage for the procedure is overseen by local Medicare contractors. Medicare also does not have a NCD for other spinal surgeries for degenerative disc disease. Decisions concerning coverage for those procedures are made at a local level. Current Request On August 16, 2005, CMS accepted a request from Richard A. Deyo, M.D., for an NCD on the CHARITE-Lumbar Artificial Disc Replacement for non-coverage. Dr. Deyo had a concern that, “the Charite disc is a new technology whose real place in spine therapy remains to be determined,” and that important scientific evidence generalizing safety and effectiveness is not available. CMS is evaluating lumbar artificial disc replacement with a particular focus on the Charite lumbar artificial disc in this analysis, since this was the only disc implant that had FDA approval at the time this national coverage analysis (NCA) was completed. However, we anticipate that when another lumbar spinal disc implant receives approval from the FDA that CMS will, by external request or internal direction, open this NCD for reconsideration with a thorough review of the evidence. Benefit Category Medicare is a defined benefit program. An item or service must fall within a benefit category as a prerequisite to Medicare coverage. §1812 (Scope of Part A); §1832 (Scope of Part B); §1861(s) (Definitions of Medical and Other Health Services). LADR with the Charite lumbar artificial disc would be eligible for coverage under Part B, as physicians services, under §1861(s)(1) and (2)(A) and under Part A, inpatient hospital services, under §1861(b). IV. Timeline of Recent Activities Date Action August 5, 2005 Dr. Richard A. Deyo submitted a letter formally requesting an NCD on the CHARITE-Lumbar Artificial Disc Replacement for non-coverage. August 16, 2005 CMS opened the NCD process pursuant to Dr. Deyo’s request. A tracking sheet was posted on the web site and the initial 30 day public comment period commenced. September 12, 2005 Meeting with DePuy Spine. September 16, 2005 The initial 30 day public comment period ended. March 6, 2006 Meeting with J&J, DePuy Spine. V. Food and Drug Administration (FDA) Status The FDA approved the CHARITE™ Artificial Disc in October of 2004 (http://www.fda.gov/cdrh/pdf4/p040006.html) . The CHARITE™ Artificial Disc is indicated for spinal arthroplasty in patients who are skeletally mature, have degenerative disc disease at one level in the lumbar spine from L4 to S1, have no more than 3 mm of spondylolisthesis at the involved level, and have had no relief from pain after at least six months of non-surgical treatment. It is an artificial intervertebral disc made from metal and plastic that is used during a spinal arthroplasty to replace a diseased or damaged intervertebral disc and also treat pain associated with degenerative disc disease. VI. General Methodological Principles When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that the agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. In general, features of clinical studies that improve quality and decrease bias include the selection of a clinically relevant cohort, the consistent use of a single good reference standard, and the blinding of readers of the index test, and reference test results. Public comment sometimes cites the published clinical evidence and gives CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. CMS uses the initial public comments to inform its proposed decision. CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum. VII. Evidence A. Introduction A summary of the evidence used to arrive at the determination is provided. This summary represents the evidence relating to the treatment of pain from degenerative disc disease with LADR with the Charite lumbar artificial disc and includes a clinical trial, case series reports, and technical reviews. The evidence CMS examines has as its focus health outcomes, or, the benefits and harms of a particular treatment. Outcomes that are usually heavily weighted by CMS - morbidity and mortality - are difficult to examine in the context of treatment for chronic low back pain which is a symptom, not a disease. In chronic low back pain, sustained improvement in pain perception and a reduction in the pain-related functional restriction are generally the focus of study outcomes. Measuring a reliable improvement in chronic pain is problematic as pain is subjective and is particularly responsive to the placebo effect; therefore, clinical trials with appropriate controls utilizing independently assessed validated instruments are most heavily weighted. The measurement of treatment effect for low back pain has shifted from physician-based assessment (with outcomes of excellent, good, fair, and poor) to a patient-based self-report of pain and disability (Hagg, Fritzell et al. 2003). Treatment effect in chronic low back pain is measured with patient-based, multi-item instruments. Two instruments validated for measurement of back pain are commonly used in the assessment of low back pain from degenerative disc disease (Hagg, Fritzell et al. 2003). The Oswestry Disability Index (ODI) is a condition-specific outcome measure used in the management of spinal disorders. The measure is an indication of the extent to which a person’s functional level is restricted by pain. The other commonly used measure in chronic back pain treatment effect is the visual analogue scale (VAS), which is a method to assess pain intensity. With the use of these instruments for measurement, a consideration must be given to the clinical meaning of a change in the score (or, for a change in instrument score to be clinically meaningful the patient should experience a change in how he feels or functions). Other considerations include the error of measurement of the instrument used and the clinical importance of a statistically significant score change. In a 2003 study by Hagg of 289 patients treated surgically or non-surgically in a randomized controlled trial, the standard error of measurement of the ODI was 4 units, with a 95% tolerance interval of 10, and the minimum difference that appeared clinically important was 10 units (Hagg, Fritzell et al. 2003). The minimal clinically important difference of VAS back pain was 18 – 19 units with a 95% tolerance interval of 15. It was interesting to note that in this study, improvement after treatment tended to occur to a greater extent in sleep disturbance, ability to do usual things and psychological irritability, but to a lesser extent in the ability to sit, stand and lift. Some investigators have used the Stauffer Coventry classification, or some modification thereof to measure results. The criteria for clinical results for the Stauffer and Coventry classification are provided in Table 1 (Sott, Harrison 2000). Table 1 Pain relief (%) Return to work Physical restriction Use of analgesics Good 76 – 100 Yes No or slight No Fair 26 – 75 Yes, with limitations Yes, limited activities Frequent (mild) Poor < 25 No, disabled Yes, greatly limited Regular (strong) Additionally, other quality of life measures are sometimes used. The SF-36 Health Survey, a 36 question form that measures general health status, can be used. Of the 8 health profiles that are included in this survey, only one or two components may be reported, such as the physical functioning composite score or the mental health composite score. Physiologic segmental mobility is viewed as an important design feature of the artificial disc. Some studies have reported range of motion as an outcome. With fusion, there is reduced motion at the fused segment. The FDA has defined fusion as < 5 degrees of angular motion (FDA guidance document 2000). The theoretical mobility provided by the artificial disc has yet to directly correlate to a proven benefit in how the patient feels or functions, making the clinical significance of post treatment range of motion unclear. Therefore, CMS does not consider post treatment range of motion an important clinical outcome of interest in this memorandum. Well designed clinical trials can provide the strongest evidence for treatment effect. Clinical trials can be designed to show superiority, a priori, where the superior clinical performance of the investigational agent as compared to the control agent is anticipated. When the investigational agent is believed to have comparable efficacy to the control, but has other advantages, for example fewer adverse events or less cost, a noninferiority trial is an option. In a noninferiority trial, the aim is to demonstrate that the investigational agent is not worse than the control by a certain pre-specified margin, referred to as the delta. In the statistical approach for noninferiority analysis, the delta is compared with the one-sided 95% confidence interval for the difference between the success rate point estimates of the investigational agent and control. If the lower bound of this one-sided confidence interval is less than the delta, then the statistical definition of noninferiority is met. B. Discussion of evidence 1. Question: The development of an assessment in support of Medicare coverage decisions is based on the same general question for almost all requests: "Is the evidence sufficient to conclude that the application of the item or service under study will improve health outcomes for Medicare patients?" For this NCD, the question of interest is: Is the evidence sufficient to conclude that LADR with the Charite lumbar artificial disc will have health benefits for low back pain due to degenerative disc disease in the Medicare population? 2. External technology assessment CMS did not commission an external technology assessment (TA); however, an external TA was identified on the topic of Artificial Vertebral Disc Replacement. In April of 2005, the Blue Cross Blue Shield Technology Evaluation Center (TEC) published a TA titled, Artificial Vertebral Disc Replacement. Artificial Vertebral Disc Replacement met only one of five of the TEC criteria. The TEC determined “…the use of artificial vertebral discs for degenerative disc disease does not meet the TEC criteria.” The following criteria were not met: 1) The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes; 2) The technology must improve the net health outcome; 3) The technology must be as beneficial as any established alternatives; and, 4) The improvement must be attainable outside the investigational setting. In summary the TEC report stated the following. “…the evidence supporting the effectiveness of the Charite artificial disc is limited. Case series provides little evidence of efficacy, particularly in the case of back pain due to degenerative disc disease, where outcomes can be influenced by patient selection, placebo effects, or natural history.” It was further stated: “The only randomized, controlled trial has several methodologic issues that make it difficult to interpret results.” “…A noninferiority trial design implies that there is a trade-off between efficacy outcomes and some other advantage of a new technology, for example, morbidity or invasiveness, such that a less-stringent threshold for efficacy is acceptable. However, at this time, no such advantage has been demonstrated for the Charite artificial disc.” Another concern identified was “…that the lack of a prespecified analysis plan, unexplained closure of the database before all patients reached completion, and lack of intent-to-treat analysis may cast some doubt on the analysis.” The TEC conclusion was, “Given the broader clinical context, and the concerns with the sole randomized, controlled trial, the evidence is not sufficient to conclude that the use of artificial vertebral disc improves health outcomes.” They further concluded that “The evidence is insufficient to determine whether the use of artificial vertebral discs improves net health outcome or whether they are as beneficial as any established alternative.”; and expressed concern “Whether the use of artificial vertebral discs improves health outcomes has not been established in the investigational settings.” 3. Internal technology assessment CMS performed an extensive literature search utilizing PubMed for new randomized controlled trials (RCTs) and systemic reviews evaluating the use of lumbar artificial disc replacements for the treatment of degenerative disc disease. The literature search was limited to the English language and specific to the human population, but included studies conducted in all countries, including the United States (see evidence tables in Appendix B). Public access information from the FDA website was also used. Evidence for the Charite lumbar artificial disc came from the FDA PMA Application clinical trial, several case series reports, a systematic review, and adverse events reported to the FDA’s Manufacturer and User Facility Device Experience (MAUDE) database . Evidence Summary Charite Clinical Trial In 2005, Blumenthal and McAfee (in two articles) published results of the clinical trial of the Charite III disc compared to the Bagby and Kuslich (BAK) interbody fusion device that led to FDA approval in October, 2004 (Blumenthal, McAfee et al. 2005; McAfee, Cunningham et al. 2005). The investigators’ purpose was to compare the safety and effectiveness of LADR, using the Charite disc, with anterior interbody fusion, for the treatment of single-level degenerative disc disease from L4-S1, unresponsive to nonoperative treatment for at least 6 months prior to enrollment. The trial enrolled 375 patients at 14 centers across the United States. The inclusion criteria included: 1) age 18 to 60 years; 2) symptomatic DDD confirmed by discography; 3) single-level DDD at L4-L5 or L5-S1; 4) Oswestry score ≥ 30; 5) VAS score ≥ 40 (of 100); 6) failed ≥ 6 mos of appropriate non-operative care; 7) back and/or leg pain with no nerve root compression; 8) able to tolerate anterior approach; 9) able and willing to comply with follow-up schedule; 10) willing to give written informed consent. Exclusion Criteria included the following: Previous thoracic or lumbar fusion, Current or prior fracture at L4, L5, or S1, Symptomatic multilevel degeneration, Noncontained herniated nucleus pulposus, Spondylosis, Spondylolisthesis > 3 mm, Scoliosis > 11°, Mid-sagittal stenosis < 8 mm, Positive straight leg raise, Spinal tumor, Osteoporosis, osteopenia, or metabolic bone disease, Infection, Facet joint arthrosis, Psychosocial disorder, Morbid obesity, Metal allergy, Use of a bone growth stimulator, Participation in another study, Arachnoiditis, Chronic steroid use, Autoimmune disorder, Pregnancy, or Other spinal surgery at affected level (except discectomy, laminotomy/ectomy, without accompanying facetotomy or nucleolysis at the same level to be treated). Up to five patients at each location (71 total patients) received disc replacement before randomization, which was provided for in the protocol as the opportunity to “insure technical competence with the treatment procedure.” Patients were randomized in a 2:1 ratio (treatment: control), stratified by site in blocks of six. Allocation concealment was done with sequentially numbered envelopes that were opened before surgery, so investigators, staff, and patients were blinded up until this point. Of the randomized patients, 205 patients received the Charite disc replacement and 99 received the BAK cage fusion 1 . Control and treatment groups did not differ statistically on gender, age, race, height, previous spinal surgery, and preoperative work status, but did vary on weight (treatment mean 77.5 kg [SD 15.67], control mean 81.7 kg [SD 16.46], p = 0.0349), with body mass index being borderline significant (26 [SD 4.23], control 27 [SD 4.76], p = 0.0557). The control group received anterior fusion with BAK threaded fusion cages packed with iliac crest autograft. The statistical hypothesis was one of noninferiority, or equivalence, to BAK fusion, where equivalence was defined such that the success rate of Charite was no worse than that of BAK by a pre-specified delta of 15% in the investigator’s protocol. Data were collected at regular intervals up to 24 months post procedure through the trial end and included the ODI, VAS, SF-36 scores, and radiographic information. In a publicly accessible FDA document, concomitant disease of the participants is mentioned as is their activity level before back injury and pre-operatively, as listed in Table 2 (FDA In-depth Statistical Review for Expedited PMA 2004). Though the distribution of normal activity level before back injury did not differ at baseline between treatment and control, there were significantly more active patients in the Charite group than in the BAK group just before surgery (p = 0.02). Significance testing comparing treatment and control concomitant disease at baseline was not reported. The reviewer noted, “There were some covariate imbalances between the two groups (e.g., age, BMI and pre-operative activity level, etc…) indicating that patients in the BAK group could have been worse to start.” Table 2 Baseline evaluation Charite n= 182 BAK n= 85 p-value * Normal Activity level Before back injury Active Moderate Light Minimal 167 (92%) 13 (7%) 1 (1%) 1 (1%) 73(86%) 10 (12%) 2 (2%) 0 0.23 Pre-operative Activity Active Moderate Light Minimal 9 (5%) 25 (14%) 48 (26%) 100 (55%) 0 5 (6%) 23 (27%) 57 (67%) 0.02 Concomitant Disease (> 3%) Hypertension Asthma Hepatitis Osteoarthritis Anemia Peptic Ulcer Cancer Other 15 (8%) 11 (6%) 5 (3%) 7 (4%) 6 (3%) 6 (3%) 2 (1%) 80 (44%) 12 (14%) 6 (7%) 7 (7%) 3 (4%) 4 (5%) 3 (4%) 3 (4%) 33 (39%) * Fisher’s exact test for categorical variables and t-test for continuous variables Clinical success was judged in terms of a composite outcome that required these four criteria to be met: 1. Improvement in the ODI of at least 25% at 24 months as compared to baseline, 2. No device failures requiring revision, reoperation or removal, 3. Absence of major complications, defined as major blood vessel injury, neurologic damage, or nerve root injury, and 4. Maintenance or improvement in neurological status at 24 months, with no new permanent neurological deficits compared to baseline. Patient accountability from the Blumenthal article and the FDA summary of safety and effectiveness data is reported in Table 3 (FDA Summary of Safety and Effectiveness Data 2004). Table 3 12 months 24 months Patients Charite Control Charite Control Randomized Deaths Failures Withdrawn Expected Missed Actual 205 1 7 5 192 8 184 99 0 4 9 86 5 81 205 1 12 16 176 15 161 99 0 8 17 74 8 66 Note: failures include device removals, revisions, and supplemental fixations. Expected = randomized patients – deaths – failures – withdrawn. Missed are those patients who were “out of the window” of the protocol. No statistical analysis plan was in the original protocol documents (FDA in-depth statistical review for expedited PMA 2004). The 71 patients that were regarded as training patients were not included in this analysis. Using the composite measure for clinical success, the artificial disc had an overall success rate reported as 57% and the BAK cage had a success rate of 46%, with the noninferior p value listed as 0.0001. Numerators and denominators were not given for these numbers, but this appears to be a strict intention to treat analysis. The FDA requested that the data also be analyzed and reported using: 1) an improvement in the ODI ≥ 15 points at 24 months compared to the score at baseline; and 2) a noninferiority margin of 10%. The FDA concluded that “The two-sided confidence interval indicates that the overall success rate for the Charite Artificial Disc is not worse than the control rate by more than 10%, regardless of which set of study success criteria is used” (FDA Summary of Safety and Effectiveness Data 2004). Though, for the previous analysis the table says “Comparison of Success Rates for Efficacy at 24 months”, the number of subjects (completers) was 184 for Charite and 81 for the control, which corresponds to the 12 month completers. Blumenthal, et al., stated, “Sensitivity analysis were performed to evaluate the potential impact of incomplete subjects (e.g., lost to follow-up).” There was no difference between the two groups as far as operative time (111 minutes in the investigational group and 115.3 minutes in the control group, p = 0.562), blood loss (207 cc in the investigational group and 224 cc in the control group, p = 0.6012), or level of implantation. Mean duration of hospitalization did differ; however, discharge criteria were not standardized (investigational 3.7 days [SD 1.8], control 4.2 days [SD 1.99]; p = 0.004). In both investigational and control arms the VAS and ODI scores improved at all follow-up times compared to baseline (p < 0.001 for all times). Changes were more rapid in the Charite group, and the difference between the two groups was statistically significant until the 24 month follow-up for both groups. No conclusions can be made in respect to time to improvement as the study was designed to demonstrate noninferiority at the 24 month time frame only. At 24 months, the mean decrease in ODI in the investigational group (from 51 to 26) as compared to the control group (52 to 33) did not differ significantly (p = 0.267); similarly, VAS decrease in the investigational group (from 7.2 to 3.1) as compared to the control group (7.2 to 3.7) did not differ significantly (p = 0.1074). For the component SF-36 scores, 99 (73%) Charite patients and 41 (66%) BAK patients had a 15% or greater improvement in the Physical Composite Score (PCS) at 24 months, and 68 (50%) Charite patients and 34 (55%) BAK patients had a 15% improvement for the Mental Composite Score (MCS). These were not statistically different with a p = 0.345 and 0.4959, respectively (FDA PMA Memorandum Clinical Review 2004). The adverse events from the FDA clinical review are listed in Table 4 (FDA PMA Memorandum Clinical Review 2004). Device failure appeared to be incorporated into the composite clinical success score, but the category in the composite score for major complications was narrower than the adverse events listed in Table 4 (Blue Cross Blue Shield 2005). Device-related adverse events do not appear to be incorporated into the composite score (Blue Cross Blue Shield 2005). From Table 4, Charite had a higher percentage of patients with severe or life threatening events and device related adverse events; p values were not given. Table 4* Adverse Events Charite disc BAK cage Patients with severe or life threatening events 15% (30/205) 9% (9/99) Device-related adverse events 7.3% (15/205) 4% (4/99) Device failures 4.9% (10/205) 8.1% (8/99) *FDA PMA memorandum Clinical Review 2004 At 24 months, many patients who met the criteria of clinical success were using narcotics to control pain. In the patients deemed a success at 24 months, the rate of narcotic usage in the investigational group was 64% (73 of 114) and 80.4% (37 of 46) in the control group. Narcotic usage was not defined and was not given for patients who did not meet the success criteria at the 24 month follow-up. Follow-up radiographs were obtained, scanned, digitalized, and analyzed by a software program (McAfee, Cunningham et al. 2005). At 24 months, range of motion (ROM) as measured on lateral flexion/extension films was 113.6% of preoperative measure (a 13.6% increase from baseline) in the investigational group and decreased in the control group, as would be expected for fusion. No statistically significant association was found between ROM and success/failure at 24 months for those who had data available to the FDA reviewer (FDA Summary of Safety and Effectiveness Data 2004). Fusion rate was judged to be 91.9%. At 24 months, 82.9% of both the Charite artificial disc training and randomized subjects were graded as having ideal placement, 10.7% as suboptimal placement, and 6.2% as poor placement. The authors stated that ODI scores at 24 months correlated with the degree of technical accuracy (p < 0.05), as did VAS scores (p = 0.016). The disc was more effective in restoring height of the collapsed disc space as compared to fusion (p < 0.05), and had less subsidence (p < 0.05). The authors stated that, “Long-term radiographic follow-up is necessary to determine if TDR [total disc replacement] can prevent adjacent segment breakdown.” Neurologic status included the following information: reflexes at the knee and ankle; motor function; sensitivity to light touch; strength of lower extremities; and straight leg raise. Neurologic status was reported as equivalent between the investigational group and control group at 6, 12 and 24 months (Geisler, Blumenthal et al. 2004). There was no significant difference between the proportion of patients with neurological adverse events comparing investigational group (16.6%) to control group (17.2%). Limited information was provided in the FDA’s summary of safety and effectiveness data for the initial training group of 71 patients (FDA Summary of Safety and Effectiveness Data 2004). There were higher early (within the first 2 days of surgery) adverse events in this group (33 patients, or 46.5%) than in the randomized group (58 patients, 28.3%). The rates at all other time periods were similar between the two groups. There were more device-related adverse events in the training cases (8 events, 11.3%) than in the randomized group (16 events, 7.8%). Case Series In 1994, Griffith published a retrospective review of 93 patients (3 surgeons’ experience) with 139 Charite III implants, referred to as “Model III” (Griffith, Shelokov et al. 1994). A single prosthesis was implanted in 53%, two prostheses in 45%, and 2% received three prostheses. One surgeon provided additional data on 58 earlier design prostheses (Models I and II) that were implanted in 49 patients. The authors analyzed data mainly from those patients implanted with the Model III disc, unless it was noted otherwise. Including all data, average age was 43.0 +/- 7.3 years (range: 25 to 59). For the primary study group, the diagnosis was DDD (65.2%), postnucleotomy syndrome (15.0%), internal disc derangement (10.9%), failed fusion (3.3%), instability (1.2%), and herniated nucleus pulposus (1.2%). Forty-one percent had prior back surgery. Average follow-up was 11.9 +/- 8.3 (n= 90) months (range of 1 to 37 months). Three percent of patients who were implanted with Model III were not followed up or were lost to follow up. If patients had more than one follow-up, the last follow-up visit was used for the analyses. Pain experience was measured using a 10 point analog pain scale for right and left leg pain and back pain. There was improvement in the intensity of pain in all three areas (p < 0.001), with a total of 71 patients (one surgeon did not report analog pain scores) included in this analysis. Patients’ pain was also judged by qualitative change in pain intensity for these three areas as increased, decreased, or unchanged. Here, also, most patients had an improvement (p < 0.01). Neurologic weakness (by physical exam) was present in 21 patients (23%) before the surgery. At the follow-up, 17 of 21 patients no longer presented with neurologic weakness. Similarly, there was a 50% reduction in the number of patients with a positive straight leg raising (SLR) test on follow-up exam (left leg positive SLR: 69% preoperative to 35.5% on follow-up; right leg positive SLR: 63% preoperative to 38.7% on follow-up). A comparison of the patients’ ability to walk preoperatively and at the most recent follow-up (n= 71, data was unavailable from one surgeon) showed that 39% improved their self-reported walking distance, 2% decreased their walking distance, and 58% remained the same. Subjective, clinical estimates of lumbar flexion and extension showed an increase in both flexion and extension (p < 0.01), though the authors noted that the data should be viewed with caution since they were obtained retrospectively and “were not independently assessed with a validated technique.” No statistical difference in work status at follow-up could be detected, though work status results differed between the individual surgeons (p value not given). The authors stated, “Inappropriate choice of prosthetic size resulting in implant migration/subsidence or dislocation occurred in 6.5% of the patients in which Model III was used; the incidence of these complications as a function of the number of prostheses implanted was 4.3%.” The reported complications that were related to the procedure, but not necessarily to the device’s function, included: phlebitis/leg thrombosis (2), injured vein (6), wound bleeding/dehiscence (2), superficial wound infection (1), muscle atrophy (1), urinary tract infection (4), incontinence (3), constipation/defecation difficulty (4), nausea (1), skin paresthesia (1), hematoma (11), hypotension by blood loss (1), retroejaculation (1), and sympathetic sign in left leg (1). Complications considered by the authors as equivocal included: allergy (1), instability “feeling” (2), new paresthesia (1), unspecified neurologic (2), abdominal, leg, thigh, or lumbar pain (10). The Charite III had 3 re-operations out of 93 patients (3%). The re-operation rate for I and II due to complications of implantation was reported to be 5 of 49 patients (10%). In 1996, Cinotti retrospectively analyzed the follow-up of 46 patients who had the Charite III disc implanted (Cinotti, David et al. 1996). Preoperative diagnosis included disc degeneration in 22 patients and failed disc excision surgery in 24 patients. Thirty-six patients had a single level prosthesis and 10 patients had 2 levels implanted. Post- surgery follow-up ranged from 2 to 5 years, with an average of 3.2 years. The patients had been operated on by one surgeon. Surgery contraindications were degenerative changes of the facet joints identified by CT or MRI, disc degeneration adjacent to a fused area and spondylolisthesis. After surgery, 18 patients wore a corset for 3 months, and 28 patients began exercising within 1 week after surgery (no details). Patients were evaluated by one of the authors who did not participate in the disc replacements. Patients’ overall satisfaction, as well as pain sensation, need for analgesics, and the ability to resume work or activities of daily living was reported. Guidelines previously reported by the authors (not detailed in this paper) were used to rate clinical results as excellent, good, fair, or poor. Clinical outcome was rated as excellent in 11 patients (24%), good in eighteen (39%), fair in fourteen (30%), and poor in three (7%). Patients’ satisfaction was reported as a great benefit by 14 patients (30%), a great but not complete benefit by 17 patients (37%), a mild improvement by 12 patients (26%), and no improvement or worsening by three (7%). Analgesic drugs were taken occasionally by four patients (9%) and continuously by twelve (26%). Resumption of work or daily life activities occurred at the same level in 31 cases (67%) and at a lower level in nine (20%). Four patients, (9%), stated they could not work because of severe back pain and 2 were unemployed. Clinical results were rated as satisfactory in 69% of patients (25 of 36) who had single level disc replacement and 40% (4 of 10) in those who had 2 level disc replacement. Eight of 17 patients who had unsatisfactory results had a subsequent fusion. Seven of the eight underwent posterolateral fusion with the disc implant left in place, with only three of these patients having satisfactory results at follow-up. The authors stated, “In the present series, the proportion of satisfactory results (63%) was lower compared with the figures reported for arthrodesis (65 – 90%).” They attributed part of this to the learning curve of the surgery, and that the surgical indications and treatment of patients after surgery changed over time with the surgeon’s increasing experience. Two level surgery was discontinued. They further concluded, “The main cause of poor outcomes appear to be an inappropriate selection of patients undergoing disc replacement…”. The authors commented on important issues related to the surgical approach; because “the placement of the prosthesis into the disc space needs a larger exposure of the anterior annulus compared with anterior interbody fusion”, there is a “greater risk of damaging the big vessels and the sympathetic chain”, with mobilization of big vessels carrying a greater risk of complications in elderly patients. The authors reported a complication rate in patients undergoing disc arthroplasty of 19%, with a comparable rate in those who had anterior fusion of 15%. Other complications are also noted. One patient (2%) had an anterior dislocation of the implant, and 9% had subsidence of the prosthesis into the vertebral bodies, attributed to undersizing of the prosthesis. Interestingly, in patients with a malpositioned prosthesis, there often was noted ossification of the intervertebral space. They noted that, “in case of failure of the prosthesis, there is an intrinsic tendency for the motion segment to undergo fusion.” There was an average vertebral motion of 9 degrees in the sagittal plane at the operated level, while the authors suggested that the prosthesis should have provided a range of motion of 12- 14 degrees in flexion-extension. It was unclear what this meant clinically. Longer term follow-up was recommended to monitor for prosthesis failure, wear of the materials, and loosening of the implant. In 1997, Lemaire reported on a series of 105 Charite patients with average follow-up of 51 months (Lemaire, Skalli et al. 1997). The average age of the patients was 39.2 years (range 24 – 50 years). Fifty patients (48%) had undergone at least one operation. Clinical results were measured using a modified Stauffer-Coventry rating scale which scored low back pain occurrence, radicular pain occurrence, neurologic deficit, medication use, participation in daily living activities, work status preop and post op, and psychiatric status. Results (Table 5) were measured as relative gain (the authors stated, relative gain “ = absolute gain/maximal gain minus preoperative score”, where the assumption is that this is the same formula as in the 2005 Lemaire article, where relative gain is defined as post-operative score - preoperative score/maximum possible score – preoperative score). Table 5. Relative Gain Result Percentage of Patients > 70% Good 79 60% – 70% Fair or Satisfactory 5.8 < 60% Poor 15.2 The authors attributed bad results to incorrect indications (osteoporosis, posterior osteoarthritis, overlying thoracolumbar kyphosis), secondary progression of a posterior facet joint syndrome, or non-return to work. Eighty-seven percent of patients returned to work. Sixty percent had the same work activity, 27 % had reduced activity, and 13% did not return to work. Ten percent returned to “intense sports activities.” Complications occurred in 11 patients (10%): 5 vascular problems (2 phlebitis, 2 pulmonary embolism, 1 acute leg ischemia); 2 temporary neurologic deficits (1 total regressive sexual disorder at 1 year, 1 paralysis at L5 with recovery after revision and fusion); and 4 cases of bone related complications (1 L5 endplate facture requiring revision with arthrodesis, 1 L5 endplate subsidence of osteoporotic origin, 2 periprosthetic ossifications). Only 3 of these complications were attributed to technique. The results were also analyzed anatomically, biomechanically, and kinematically from X-rays. The average L4-L5 mobility was 9.7 degrees flexion, 3 degrees extension, and 4 degrees lateral bending. At L5-S1 level, these values were 6 degrees, 3 degrees, and 3 degrees, respectively. Interestingly, there was a correlation between posterior joint pain and anterior positioning greater than or equal to 4mm. These authors concluded, “In fact, the proper indication for surgery is crucial for good results.” A 1999 study by Zeegers in the Netherlands reported on 2 year results for 50 prospectively studied patients that he had operated on (Zeegers, Bohnen et al. 1999). There was a 13% rate of permanent side-effects and/or complications, with 4% related to poor implantation technique. Seventy-five prosthesis were placed in 50 patients: 29 patients had one level insertion, 18 had two level insertion, and 3 patients had three prostheses inserted. Four patients were lost to follow-up (unclear how these patients were regarded). The mean age at the operation was 43 years (24 – 59 years). Mean duration of low back complaints was 10 years (range 1 – 35 years). Fifty-four percent had undergone previous surgery. Patients under 45 years of age were associated with a statistically significant better outcome (< 0.05). Seventy percent of the patients had a positive clinical result defined as a good or fair result from the Stauffer and Coventry criteria. Sixty-five percent (30/46) showed improvement of low back pain. Eighty-one percent returned to some work and 43% returned to their original work. Only fifteen out of 34 patients were able to decrease their analgesic intake. Twelve patients (24%) out of the fifty initial patients needed re-operation which involved 24 procedures (re-operation at the segment with a prosthesis: 6; re-operation at other levels: 11; re-operation related to complications: 7). Side-effects or complications at, or after, the first implantation operation were reported 52 times by 30 patients, with permanent sequela and complications seen in 13%. These included dysaesthesia of legs (3 permanent), painful/numb scar or hematoma (17 temporary), abdominal problems (3 temporary), new or progression of old pain (5 temporary), sympathectomy effect (4 permanent), aortic lesion at removal of prosthesis (temporary), general complication of urinary tract infection, impotence, deep venous thrombosis (5 temporary), malposition of prosthesis (one temporary and one permanent). Fourteen percent of all levels with a prosthesis showed a decrease in height 2 years after surgery. There was no significant migration (> 2mm). The range of motion of the prosthesis between flexion and extension averaged 9 degrees 2 years postoperatively, which equaled the preoperative ROM. The authors provided these comments, “A critical review of our good and poor clinical results makes clear how difficult it is to find the real origin of low back pain,” and, “Several indications and contra-indications for ADR [artificial disc replacement] have been previously reported, but are not unanimously accepted.” A small case series study by Sott and Harrison in the UK attempted to study patients over 45 years of age (Sott, Harrison 2000). They mentioned that an upper age limit of 45 years was proposed by the manufacturers and several authors, “as increasing age may lead to weakening of the bone structure supporting the prosthesis.” Fifteen prostheses were implanted into 14 patients aged 31 to 61 years (mean age 48 years). Nine prostheses were implanted at level L4/L5, four at L3/L4 and two at L5/S1. None of the patients were able to carry out their usual professional, domestic or leisure activities without pain preoperatively. The patients were followed for an average of 48 months (18 to 68 months). Four patients were followed up by phone. Criteria for clinical results were according to th