Lumbar Artificial Disc Replacement (LADR)

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The Centers for Medicare and Medicaid Services (CMS) has determined that LADR is not reasonable and necessary for the Medicare population over sixty years of age. Therefore, Section 150.10 of the Medicare National Coverage Determination (NCD) Manual is amended to reflect the change from non-coverage for LADR with a specific implant to non-coverage for the LADR procedure 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-#00292R) 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 Subject: Coverage Decision Memorandum for Lumbar Artificial Disc Replacement (LADR) Date: August 14, 2007 I. Decision The Centers for Medicare and Medicaid Services (CMS) has determined that LADR is not reasonable and necessary for the Medicare population over sixty years of age. Therefore, Section 150.10 of the Medicare National Coverage Determination (NCD) Manual is amended to reflect the change from non-coverage for LADR with a specific implant to non-coverage for the LADR procedure 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 patients’ 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 stated “…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. Of the two lumbar artificial discs that are currently FDA approved, the 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 and the ProDisc®-L disc is the second generation of the device designed in the late 1980’s by Marnay. 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 ProDisc®-L and the Charite have similar modular designs but differ in the mechanical design mainly in how the metal endplates affix to the vertebral body and the fixation of the poly inlay. The ProDisc®-L disc has two metal endplates with ultimately fixation to the vertebral body through bony ingrowth and initial stabilization provided by a centrally located keel. The ultra-high molecular weight polyethylene inlay locks in place to the inferior endplate thereby producing a semi-constrained device. 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). In 2004 Anderson and Rouleau offered, “The current designs are diverse and, thus far, the effects of their individual characteristics on results are unknown.” The Food and Drug Administration summary noted “The ProDisc®-L total disc replacement has been commercially available in markets outside of the United States since 1990” (FDA Summary of Safety and Effectiveness Data for Expedited Premarket Approval (PMA) 2006). 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). III. History of Medicare Coverage On May 16, 2006, CMS issued a NCD (CMS NCD Manual Section 150.10) for LADR. The coverage decision was focused on the Charite™ lumbar artificial disc because it was the only lumbar artificial disc with FDA approval at that time. After completing the initial national coverage analysis, CMS made the following decision: LADR with the Charite™ lumbar artificial disc is not reasonable and necessary for the Medicare population over 60 years of age; therefore, LADR with the Charite™ lumbar artificial disc is non-covered for Medicare beneficiaries over 60 years of age. For Medicare beneficiaries 60 years of age and younger, there is no national coverage determination, leaving such determinations to continue to be made by the local contractors. Medicare coverage under the investigational device exemption (IDE) for other lumbar artificial discs in eligible clinical trials is not impacted. In the decision memorandum for LADR issued on May 16, 2006, CMS stated, “CMS is aware that there are several other disc technologies in FDA investigational device exemption clinical trials in the United States. As previously stated, CMS is evaluating LADR with a focus on the Charite lumbar artificial disc in this analysis, since this was the only disc implant that had FDA approval at this time. However, we anticipate that when other lumbar spinal disc implants receive 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 for each new disc implant.” 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 would be eligible for coverage under Part B, as physician services, under §1861(s)(1) and (2)(A) and under Part A, inpatient hospital services, under §1861(b). This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Date Action November 28, 2006 CMS initiates opening reconsideration of NCD for LADR. Initial 30-day public comment period begins. December 28, 2006 Initial 30-day public comment period closes. January 8, 2007 Meeting with Synthes May 25, 2007 Proposed Decision Memorandum posted and 30 day public comment period begins. June 24, 2007 Second public comment period closes. V. Food and Drug Administration (FDA) Status The FDA approved the PRODISC®-L Total Disc Replacement on August 14, 2006 (http://www.fda.gov/cdrh/pdf5/p050010a.pdf). The FDA approval letter stated, “This device is indicated for spinal arthroplasty in skeletally mature patients with degenerative disc disease (DDD) at one level from L3-S1. DDD is defined as discogenic back pain with degeneration of the disc confirmed by patient history and radiographic studies. These DDD patients should have no more than Grade 1 spondylolisthesis at the involved level. Patients receiving the PRODISC®-L Total Disc Replacement should have failed at least six months of conservative treatment prior to implantation of the PRODISC®-L Total Disc Replacement.”(FDA Approval Letter, August 14, 2006) 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 ProDisc 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 – Stauffer Coventry Classification 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. Some studies have reported range of motion as an outcome. Physiologic segmental mobility, as measured by range of motion, is viewed by some artificial disc proponents as an important design feature of the disc. This view is based on the premise that fusion surgery alters normal motion of the adjacent level disc, resulting in an increased likelihood of disease in those adjacent discs. Conversely, these proponents postulate that motion preservation by the artificial disc will prevent this. In our review of the literature, we were unable to find evidence that the theoretical mobility provided by the artificial disc directly correlates to a benefit in how the patient feels or functions, making the clinical significance of post treatment range of motion unclear. In addition, we are unable to identify any clinical evidence that supports the premise that segmental mobility prevents adjacent level disease. 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 ProDisc lumbar artificial disc will improve health outcomes in the Medicare population with low back pain due to degenerative disc disease? 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 March of 2007, the Medical Advisory Panel for the BCBS TEC reaffirmed the decision that artificial lumbar disc for DDD does not meet TEC criteria (BCBS TEC MAP March 2007 ). In June of 2007, BCBS TEC published an update of their TA titled Artificial Lumbar Disc Replacement. This update included the published evidence through May 2007 on the Charite and ProDisc artificial discs. In relation to the randomized, clinical trial for each of the discs, the author stated: “The effectiveness of fusion for chronic degenerative disc disease is not well established. There are few clinical trials and results are inconsistent. Neither of the studies discussed the effectiveness of fusion or justified the size of the noninferiority margin. The possible advantages of the artificial disc in terms of physical functioning should be measurable as a principal outcome.” The authors concluded: “Given what is known about fusion as a comparator treatment, both noninferiority trials may not provide evidence of efficacy. The specific noninferiority margins are not justified. The lower-than-expected success rates also raise additional questions regarding the validity of a noninferiority trial and the noninferiority margin selected. Viewed from the perspective of superiority trials, both trials are also suspect. The Charite trial showed little evidence of superiority, and the ProDisc analysis is problematic because of missing values and uncertain outcomes for all patients.” As in the original TA, the TEC concluded that artificial vertebral disc replacement met only one of five of the TEC criteria. The TEC determined “…the use of artificial lumbar discs for degenerative disc disease does not meet the TEC criteria.” (June 2007 Updated TEC Report) 3. Internal technology assessment The evidence summary and analysis in the original decision memorandum on LADR (available at http://www.cms.gov/mcd/viewdecisionmemo.asp?id=170 ) is incorporated into this document by reference. CMS performed an additional literature search utilizing PubMed for randomized (and nonrandomized) controlled trials (RCTs), cohort or case-control studies, case series studies and systemic reviews evaluating the use of ProDisc 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 ProDisc lumbar artificial disc came from the FDA PMA Application clinical trial and several case series reports. Evidence Summary Observational Studies A 2002 abstract by Thierry Marnay, ProDisc inventor, reported certain 7 – 11 year results with Prodisc (Marnay 2002). From 1990 to 1993, ninety-three prostheses were implanted in 64 patients from L2 to S1, of which thirty-nine had one level, twenty-one had 2 levels and four had 3 levels implanted. The age range of patients was not provided. Patients had failed conservative care for chronic back pain. It was stated, “The last follow up patients were at 8.6 years average of post surgery.” The time schedule for follow up evaluations was not provided. The VAS average preoperative score was 8.5 and then 3.0 at the final follow up (range of scores or point of time measurement not listed). At the long-term follow up, 65% of the patients reported that they were “entirely satisfied”, 28% “satisfied” and only 7% were “not satisfied”. The overall ODI score average was 8.3 (preoperative score, follow-up time not listed). During follow-up, five patients had fusion due to ongoing pain, one had a vascular complication and 2 had temporary sexual dysfunction. The author concluded “…that the Prodisc can remain mechanically stable and provide significant pain relief while maintaining motion in patients at 7 to 10 years follow-up.” It is not clear how many patients were lost to follow-up. In 2002 Mayer reported on the surgical technique for total lumbar disc replacement and included preliminary results for 34 patients (Mayer, Wiechert et al. 2002). Average age was 44 (range 25 to 65 years). The main indication was degenerative disc disease. Exclusions included spondylolisthesis, spinal stenosis, significant osteoarthritis of the facet joints, deformities, infection or tumor, unwillingness to comply with study requirements regarding follow-up visits and radiological controls, previous fusion attempts in the affected levels, pregnancy and incomplete workers’ compensation procedures. Twenty-six (76.5% of the original 34) patients had at least one visit for evaluation. Results revealed a mean operative time of 130.9 minutes (range 88 to 300minutes) and average blood loss was 117 ml per level (range 30 – 350 ml). The mean VAS preoperative score was 6.3 and was reduced at the 12 month visit to 3.4 (number of patients not given, standard deviation not given). The ODI ranged from 1 to 32 points before surgery (average 19.1, standard deviation 7.4 points). The average score at 12 months was 7.2 (“The change in postoperative score ranged from 27 points reduction to an increase of 12 points (standard deviation 9.6 points)”). There was no difference noted in results between one and two level implantation. Three complications related to the surgical procedure were reported. Tropiano reported a prospective analysis following 53 patients implanted by a single surgeon for a minimum of one year (range 1 to 2 years) (Tropiano, Huang et al. 2003). Patients had a mean age of 45 years (range 28 – 67 years) and included 18 men and 35 women. Diagnoses included degenerated disc and failed back surgery. Patients were excluded if they had facet degeneration, a history of abdominal or retroperitoneal surgery near planned surgical approach, osteoporosis or osteopenia, structural spinal deformities, or an absence of posterior elements due to previous surgery. Eleven patients had 2 discs implanted and two patients had three levels implanted. Mean operative time was 104 minutes (range 32 – 250 minutes), with a mean hospital stay of 9 days (range 4 – 31 days). Patients received low molecular weight heparin as prophylaxis for 21 days postoperatively. Patients began physiotherapy one month after surgery and also advanced to unrestricted activities as tolerated at that time. Clinical outcomes included back and leg pain as measured by the VAS (modified version); pain intensity measured on a 10 point scale from severe to none; ODI; quality of life measured as normal, slightly limited, hindered, or severely limited/impossible; return to work measured as normal, slightly limited, hindered, or severely limited/impossible; and patient satisfaction measured as entirely satisfied, satisfied or not satisfied. Results revealed 100% of patients were entirely satisfied or satisfied; 72% of patients resumed work and activities of daily living with 28% being slightly limited (though 7 of these patients on workers’ compensation said they could not work); patients improved significantly in VAS lumbar and radicular pain (to a mean score at 1.4 year follow-up of 1.3 +/- 1.78 for VAS lumbar and 1.9 +/- 2.59 VAS radicular); ODI improved from a preoperative mean score of 56 to a mean score of 14 at 1.4 years. Radiographic results revealed flexion-extension of 8 degrees for those implanted at L5-S1, and 10 degrees for those implanted at L4-L5. Clinical results of the single and multilevel replacements were equivalent. Complications occurred in 9% of patients and included vertebral body fracture, radicular pain, implant malposition, and retrograde ejaculation. Complications necessitated reoperation in three patients. The authors noted, “Randomized, prospective, long-term studies will be necessary to compare the effectiveness of arthrodesis with total disc replacement.” In 2005 Tropiano reported on clinical and radiographic results in 55 ProDisc patients (64 patients initially in the study), with a mean duration of follow-up of 8.7 years (range 7 to 11 years) (Tropiano, Huang et al. 2005). Patients had a minimum of 6 months nonoperative treatment prior to procedure. Exclusion included facet arthrosis, central or lateral recess stenosis, osteoporosis, sagittal or coronal plane deformity, and absence of posterior elements. Average patients age was 46 (range 25 to 65). A report of clinical results included, “Clinical results were evaluated by assessing preoperative and postoperative lumbar pain, radiculopathy, disability, and modified Stauffer-Coventry scores.” Stauffer–Coventry score (0-20 points) increased from an average of 7.04 pre-op to 16.1 post-op. Low back pain, lower limb pain, and impairment (all measured on 3 point scales) decreased at post-operative measurement. The authors stated, “Thirty-three of the fifty-five patients with sufficient follow-up had an excellent result, eight had a good result, and fourteen had a poor result.” Seven patients had both disc replacement and an adjacent fusion during the same operation. Five patients had approach related complications. The authors stated, “The Prodisc lumbar total disc replacement appears to be effective and safe for the treatment of symptomatic degenerative disc disease.” They also concluded, “Longer follow-up of this cohort of patients and randomized trials comparing disc replacement with arthrodesis are needed.” Bertagnoli reported on a case series of 118 patients age 18 to 60 with low back pain with or without radicular symptoms resulting from degenerative disc disease from L3 to S1, by a single surgeon using the ProDisc (Bertagnoli, Yue et al. 2005a). Patient’s pre-op assessment included plain radiographs, MRI and CT scans. Discography was used in selected circumstances. Exclusion criteria included patients with spinal stenosis, osteoporosis, prior fusion surgery, chronic infections, metal allergies, pregnancy, facet arthrosis, inadequate vertebral endplate size, more than one level of spondylosis, neuromuscular disease, workers’ compensation, spinal litigation, body mass index greater than 35, and any isthmic or degenerative spondylolisthesis greater than Grade 1. Patients had failed conservative treatment for a minimum of 9 months. The ODI, VAS, and measures of back pain and radicular pain (unclear if outcomes were validated) were chosen as outcomes. To assess changes over time, statistical methods used a longitudinal approach with general linear models (GLM) for continuous variables and generalized estimating equations (GEE) for patient satisfaction and back pain. Of the original 118 patients only 104 patients with complete data were analyzed. This interesting analysis showed that at 24 months, 91% had either occasional pain or no pain, with significant decreases in Oswestry disability scores that were sustained at 24 months (53% to 29%) and VAS change (7.6 to 3) was also sustained at 24 months. Medication usage revealed that 83% pre-operatively did not use narcotics and 90% post-op did not use narcotics. There were no device-related complications but several approach-related complications (3 hematomas and 1 retrograde ejaculation) that resolved, one complication of persistent leg pain that required posterior exploration and decompression, which revealed posterior subarticular stenosis. The authors concluded, “Single-level Prodisc lumbar total disc arthroplasty is a safe and efficacious treatment method for debilitating lumbar discogenic LBP.” They also stated, “Careful and appropriate patient selection is essential in ensuring optimal surgical outcomes.” In a 2005 case series Bertagnoli reported on patients with multilevel ProDisc implants (Bertagnoli, Yue et al. 2005b). This analysis included 25 patients (15 male, 10 female) with a minimum follow-up of 2 years, implanted by a single surgeon at a single site. Patients age 18 to 60 (median age 51) with disabling low back pain and minimal radicular pain with multiple lumbar spondylosis from L1 to S1 (confirmed by MRI and discogram/CT) were included in this study. Patients had failed 9 months of conservative treatment prior to implantation. Exclusion criteria were similar to other Bertagnoli reports, therefore did not include those with significant facet arthropathy, workers’ compensation, or spine litigation. Fifteen patients had 2 level implants and 10 patients had 3 level implants. VAS, ODI, leg and back pain percentages and radiographic data was collected at 3,6,12, and 24 months. The average operative time for a 2 level surgery was 135 minutes and for three levels was 184 minutes. Blood loss for a two level surgery averaged 275 ml and 350 ml for a three level surgery. Patients were discharged approximately 3.5 days post-op. For statistical analysis, repeated measures general linear models (GLM) were used for continuous variables and generalized estimating equations were used for dichotomous variables. Oswestry scores decreased from 65% to 21% at 24 months (p < 0.001) and VAS scores decreased from 8.3 to 2.1. Before surgery, all patients reported back pain. At the 24 month follow-up 92% of patients reported no or occasional back pain. Forty-eight percent of all patients had no or occasional leg pain pre-operatively, increasing to 100% at 24 months follow-up. The rate of patient satisfaction was 92% at 2 years. Post-op radiographs were obtained, with no correlation between clinical outcomes and pelvic incidence, tilt or sacral slope. Complications included a case of subsidence in a 36 year old male with no prior history of osteoporosis and a case of anterior extrusion of the polyethylene core in a patient who fell off a bicycle. There were no cases of vascular injury or neurologic injury. The authors concluded, “We think that these excellent results are a direct result not only due to the qualities of the implant, but moreover, of careful patient selection by an experienced low back surgeon.” In 2006 Bertagnoli reported on 20 patients, age 18 to 67 (median age 50, number of patients over 60 not reported), who were treated for symptomatic adjacent-segment degeneration after remote lumbar fusion (Bertagnoli, Yue et al. 2006a). Studies were performed by a surgeon at a single center. Pre-op studies included MRI, CT, and discography. Exclusion criteria were circumferential spinal stenosis, osteoporosis, chronic infections, metal allergies, pregnancy, facet joint arthrosis, inadequate vertebral endplate size, workers’ compensation, spinal litigation, body mass index greater than 35, and any isthmic or degenerative spondylolisthesis greater than Grade 1. Eighteen patients fulfilled all follow-up criteria to 24 months. VAS, ODI, presence of back and leg pain, and patient satisfaction scores were recorded. Statistical analysis used simple tests (t-tests for the continuous VAS and ODI scores, and nonparametric sign tests for the back and leg pain ordinal scores). Eight cases had undergone two-level fusion and two cases had undergone 3 level fusion. The remaining cases had undergone single-level fusion. Preoperatively, 75% had persistent back pain and 50% had persistent leg pain, whereas postoperatively 25% had persistent back pain and none had persistent leg pain. ODI and VAS both were improved from pre-op scores at 24 month follow-up (ODI 65.4 +/-1.5 to 29.9 +/- 1.6; VAS 7.7 +/- 0.3 to 3.4 +/- 0.4). Preoperatively, 23% of the patients worked part time and 13% worked full time; these rates increased to 38 and 27%, respectively. Thirty-five percent of the patients remained unemployed. Length and extent of pre-op disability was not described. Preoperatively, 69% never used narcotics and 31% regularly used narcotics and 63% regularly used tramadol; post-op, none used narcotics and 56% occasionally or regularly used tramadol. There were no device or approach related complications. The author concluded, “Analysis of early results indicated that ProDisc lumbar total disc arthroplasty is an efficacious treatment for symptomatic adjacent-segment lumbar discogenic low-back pain following remote fusion.” Also in 2006, Bertagnoli reported on a 104 patient case series for smokers versus nonsmokers, as smoking has been associated with poorer outcomes in spinal fusion surgery (Bertagnoli, Yue et al. 2006b). Patients 18 to 60 years of age were treated with single level disc arthroplasty (L4 to S1) by the primary author. Exclusion criteria included spinal stenosis, osteoporosis, prior fusion surgery, chronic infections, metal allergies, facet arthrosis, inadequate vertebral endplate size, more than one level of spondylosis, neuromuscular disease, pregnancy, workers’ compensation, spinal litigation, body mass index greater than 35, and/or any isthmic or degenerative spondylolisthesis greater than Grade 1. Outcomes examined were patient satisfaction, ODI, VAS, and assessments of neurologic, radiographic, and pain medication. A complete radiographic assessment was performed while discography was used only in certain circumstances. Patients were assessed preoperatively and then at 3,6,12, and 24 months. Differential change over time between smokers and nonsmokers was assessed with mixed effects models for continuous variables (ODI and VAS) and generalized estimating equations for patient satisfaction. Power analysis was done as well as a time-smoking interaction check. Only patients with complete data were analyzed. At 2 year follow-up, patient satisfaction was high (87% in nonsmokers, 94% in smokers). Implanted level disc motion ranged from 3 to 7 degrees. ODI average reduction was 10.69 (standard error of the mean of 1.06). Preoperative VAS decreased from 7.5 to 4.5 in smokers and from 7.5 to 3.8 in nonsmokers at the 2 years follow-up. The percentage of patients with leg pain in both groups decreased from about 50% preoperatively to 16% in smokers and 9% in nonsmokers. There was a decrease in medication usage in both smokers and nonsmokers, with preoperative narcotic use being 18% and 16% in smokers and nonsmokers respectively, to 5% and 4% (tramadol – an atypical opioid - use decreased from 27 to 25% in smokers, but increased from 26% to 30% in nonsmokers). The authors stated, “No correlation was determined to exist between clinical outcome and pelvic incidence, tilt, or sacral slope,” and, “Complications in this study were primarily limited to those associated with the operative approach and operative field.” The author further concluded, “The results of our study indicate that smokers do equally well compared with nonsmokers when ProDisc ADR is used in the treatment of debilitating lumbar spondylosis.” Additionally, Bertagnoli reported in 2006 on 22 patients treated by the primary author with ProDisc, median age of 63 years (range 61-71years) (Bertagnoli, Yue et al. 2006c). Exclusion criteria included spinal stenosis with neurogenic claudication, history of fusion, chronic infections, metal allergies, inadequate vertebral endplate size, pregnancy, workers’ compensation recipients, spinal litigation, body mass index greater than 35, and isthmic or degenerative spondylolisthesis greater than Grade 1, significant facet join arthrosis, and patients with T-scores on bone mineral density testing less than or equal to -2.5. There were 17 single-level, four two-level cases and one three-level case of lumbar artificial disc implantation. The primary research questions were whether there was a significant improvement in status from presurgery to 3 months postsurgery and whether there was enduring improvement from 3 months to 2 years postsurgery. Pre-op ODI mean was 27. Post-op ODI mean was 14 at 24 months. VAS pre-op mean score was 8 and the post-op mean score was 4 at 24 month follow-up. Patients in whom bone mineral density was decreased (no details) had concurrent prophylactic vertebroplasty. Of this population, only 15% used narcotics and 40% used tramadol before surgery, with 100% postoperatively not using narcotics after 24 months and 50% not using tramadol (but the reported post-op tramadol usage numbers didn’t add up appropriately). Clinical outcomes did not change significantly from the 3 to 24 month interval. Patient satisfaction was high. Overall complication rate in this older age group was higher (2 cases of foot drop, a case of loss of proprioception and vibration sensation necessitating cane assisted ambulation, two cases of subsidence where the T-scores were -2 and -1.76 for a total of 5/20 or 25%). It was stated, “Building on our early experience with two cases of subsidence, we now routinely perform open prophylactic vertebroplasty in which we use 5 to 10 ml of bone cement in the relevant vertebral bodies following implant placement but during the same operative session.” The authors did not comment on possible additional changes in biomechanics from vertebroplasty or recent reports in the literature, Trout and Kallmes 2006, of increased adjacent fractures in those who have had vertebroplasty. In 2006 Siepe reported on 92 patients with a minimum follow-up of 24 months (mean follow-up 34.2 months) (Siepe, Mayer et al. 2006). The objective of the study was to assess functional outcome after total lumbar disc replacement for varying indications, as the authors stated, “Presently, there is no evidence-based consensus on indications or contraindications for TDR.” The indications for the procedure included: DDD; DDD with soft disc herniation; osteochondrosis from a previous discectomy; and DDD with Modic changes. The average age of the patients was 42.3 years (range 21.9 – 66.1 years). Operations were performed at 1 (n= 77), 2 (n= 14), and 3 (n= 1) levels. Operating time averaged 115 minutes for one level and 190 minutes for 2 levels. Blood loss averaged 100 ML. VAS preoperative score averaged 7 +/-1.6, with an average 4.2 +/- 2.8 post-op reduction. ODI score averaged 40 +/- 15.6 preoperative and decreased 21 +/- 19 points post-op. Overall, 82.6% of patients were satisfied or highly satisfied. The authors concluded, “that age as a solitary factor does not pose a contraindication to disc replacement”, though better functional outcome was observed in younger patients (ages 30 – 40 years). The overall complication rate was 19.6%, requiring revision surgery at the index level in 8.7% of the patients and 2.2% at the non-index level. Complication rate was higher for 2 level replacements (35.7%) versus one level (14.3%). The overall rate for patients returning to their previous job or “some kind of modified professional activity” at their last visit was 68.1%. The authors concluded, “Because of significantly varying outcomes, indications for disc replacement must be defined precisely.” Chung reported on the 2-year clinical and radiographic outcomes of 36 patients by a single surgeon (Chung, Lee et al. 2006). The mean age was 43 years (range 25 to 58 years), with mean follow-up of 37 months. Both one level (25 patients) and two levels (11 patients) were treated. Medication usage preoperatively included nonsteroidal anti-inflammatory medications. Inclusion criteria included minimum disc height of 4mm, ODI of at least 40, and no more than 2 involved levels from L3 to S1. Exclusion criteria included scoliosis, spondylolysis, spondylolithesis, severe facet degeneration and BMD DEXA T score less than -2.5. Also, positive discography was required along with one or more of these findings: vacuum phenomenon, contained herniated nucleus pulposus, high-intensity zone signal, and decrease of intervertebral disc height. Results revealed mean ODI score improvement from 69.2 preoperatively to 34.8 at 6 weeks, 23.0 at 1 year, and 21.0 at 2 years (p < 0.001). Mean VAS low back pain scores improved from 7.5 preoperative to 3.7 at 6 weeks, 2.9 at 1 year and 3.0 at 2 years. Mean VAS leg pain scores improved from 4.7 preoperatively to 1.5 at 6 weeks, 1.1 at 1 year, and 1.2 at 2 years (p < 0.001). Range of motion at the index level increased from 9.7 degrees preoperatively to 12.7 degrees at 2 years. In an analysis examining factors associated with a successful clinical outcome (defined as > 75% improvement in ODI), single level versus two level and lower average segmental ROM at 2 years were associated with greater ODI improvement. Two patients had major vein injury which was repaired; three patients had increased leg pain postoperatively that resolved at 6 week follow-up. Schroven reported on a prospective nonrandomized study of 24 patients (Schroven and Dorofey 2006). Study inclusion included patients between 18 and 60 years of age, 6 months of conservative therapy, and diagnostic CT or MRI. Fourteen patients underwent TDR with ProDisc and 10 patients underwent anterior lumbar intervertebral fusion (ALIF). Follow-up was one year. Statistical analyses were not done due to the small size of the study. Baseline age, gender, spinal level, and ODI (38 out of 60) were comparable. For ProDisc, ODI was 15 at 6 months and 12 at 24 months. In the ALIF group, ODI was 25 at 6 months and 21 at 24 months. Complications in the ProDisc group included one case each of subsidence and facet arthritis. In the ALIF group, one patient had intra-operative hemorrhage. Hospitalization was 3.85 days in the ProDisc group versus 6.3 in the ALIF group. Mean blood loss was 100 ml in the ProDisc group versus 330 ml in the ALIF group. Mean operation time was 1 .5 hours in the ProDisc group versus 2.25 in the ALIF group. The author stated, “The small size of the groups and the limited follow-up period did not allow firm conclusions.” Preliminary ProDisc randomized trial reports A 2005 abstract by Delamarter reported on 180 patients in the ProDisc II clinical trial (127 patients underwent TDR and 53 patients had fusion) with follow-up of 2 to 3 years (Delamarter, Zigler et al. 2005). Patient inclusion and exclusion criteria were not reported in this abstract but can be accessed in the FDA summary of safety and effectiveness data. The author noted that with ProDisc TDR can be done at more than one level. He noted improvements in both the VAS and ODI scores were similar for TDR and fusion patients, but that the patient satisfaction was significantly better than the Charite disc (87% v. 73%). No dislocations or device related complications were reported. Delamarter also reported on “an interim comparative analysis and description of the first 78 randomized patients at 2 years from one site” (Delamarter, Bae et al. 2005). One or two levels of disc disease were included, with evaluation of plain radiographs, MRI, and occasionally discogram/CT scans. Inclusion criteria are listed as: degenerative disc disease in one or two adjacent levels between L3-S1, back and/or leg pain, failure of at least 6 months of conservative therapy, Oswestry score > 20/50 (> 40%), ability to comply with protocol and follow-up, ability to give informed consent, and radiographic evidence of disc degeneration. Exclusion criteria include: more than two levels of degenerative disc disease, endplate dimensions less than 34.5 mm medial-lateral or 27 mm anterior-posterior, known metal and/or polyethylene allergies, prior lumbar fusion surgery, clinically compromised vertebral bodies due to prior trauma, clinically significant degenerative facet disease, lytic spondylolisthesis and/or clinically significant stenosis, degenerative spondylolisthesis > grade 1, back or leg pain of unknown etiology, objective diagnosis of osteoporosis (DEXA scan), presence of metabolic bone disease, morbid obesity (Body Mass Index > 40), pregnancy or expected pregnancy within 3 years, active infection, medications that retard healing (eg. steroids), autoimmune diseases (eg. rheumatoid arthritis), systemic diseases (eg. AIDS, HIV, hepatitis), and active malignancy. Outcomes of ODI and VAS, range of motion, and demographics were analyzed statistically using mixed designs analysis of variance (ANOVA) with repeated measures for assessment interval and a grouping effect for treatment modality (SAS, GLM procedures). Student t-test and Chi squared were used for simple comparisons across treatments. For specific effects, post-hoc pair-wise statistical comparisons were made with Student t-tests or paired t-tests. Graphical comparisons were given for these interim results, with “From 6 months out to 2 years, the disc replacement patients continued to show more improvement than fusion patients, but the difference was not significant. At the longest follow-up, both groups were significantly improved form their preoperative estate.” Delmarter raised an important point in the discussion, that at the L5-S1 level is the least mobile in the lumbar spine, and that the difference in sagittal motion in the disc re