An Investigation into the Performance of the Ultima TPS Metal- on-Metal Hip Replacement July 2008 Orthopaedic Subcommittee, East Norfolk and Waveney Research Consortium Research Governance Committee PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. EXHIBIT Gami- 075 EXHIBIT 8 WIT: DATE: 0. CAMPBELL, RPH cca DEPUY037914800 PLT-OO178-00001 Executive summary History Orthopaedic Subcommittee, Research Govemance Committee .. . Summary of Meetings Recommendations of the Orthopaedic Department July 2008 The Patients Results Comments Conclusions References Appendices PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914801 PLT-OO178-00002 Executive Summary Introduction The need for longer lasting joint replacements has increased because of the success of established implants and the request for the procedure by younger, more active patients. At the Norfolk Norwich University Hospital there has been a long- standing interest in total hip replacement starting in the 1950?s with Ken McKee= one of the pioneers of the operation. His early design had a metal-on-metal bearing. This was found to have an early high failure rate because the design of the ?xation surfaces and quality control over machining of components was not good enough. However some of his patients had successful implants lasting over 40 years. The established hip replacements g. the Charnley, and the Exeter) use a metal on plastic bearing with a metal femoral stem with a high-density polyethylene cup. This combination is very successful, but its long-term survival is compromised by wear of the cup. The resulting wear debris sets up a biological reaction which gradually destroys the bone surrounding the implant over time. This is visible on plain Xray and is described as showing ?loosening?. Since the 19905 the use of metal-on-metal bearings has been revisited with the advent of better design and improved control of manufacturing of the implants. The Norfolk PCTs requested that the Orthopaedic Department at the NNUH introduce the Birmingham resurfacing in response to patient demand. However not all younger patients are suitable for a resurfacing hip, therefore there was a need for a MOM total hip replacement. There has been a long-standing association between the Orthopaedic Department at the NNUH and DePuy International (as Johnson Johnson Orthopaedics prior to 1998) looking at innovation in joint prostheses. In 1997 a new bearing linked to an established femoral stem and cup design was trialled following ethical and approval and after obtaining the relevant CE (Conformit? Europ?ene) marking was introduced and followed-up in a postmarket clinical follow?up study. Initial results were excellent with many patients reporting their hips as feeling ?normal?. However over time it became apparent that a number of patients were experiencing pain in the presence of normal plain Xrays, and a few of them were subsequently admitted as emergencies with either a fracture around the femoral stem= or a hip dislocation. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914802 PLT-OO178-00003 As some of the patients were part of a research study this was reported to the Research Governance and Ethics Committees as a serious adverse event. The RGC asked for a subcommittee to investigate the problem. This began in March 2004 with the recommendation to only use the implant in patients who were expecting it= and patients undergoing bilateral replacement. By August 2004 it was clear the problem was greater than originally thought and so the iinplant?s use was discontinued. Methods All patients who had undergone the procedure. both NHS and private, were identi?ed from existing databases and from surgeons records. Following Ethics Committee approval, all patients undergoing revision procedures had blood, soft tissue and bone samples taken, and the explants collected. A large number of studies were undertaken looking at the radiology, histology and immunology. Results From 4th February 1997 to 1St August 2004, 545 patients underwent 652 hip arthroplasties, of these 434 hips were undertaken at the NNUH, the rest at the Spire Hospital Norwich. Three hundred and two were men and 243 were female. The right was implanted in 349 and left in 303. One hundred and seven were bilateral. A further 75 had a non-MOM on the contralateral side. The average age was 57 years with a range of 15 to 81 years. Up to 3131; January 2008, 82 patients with 90 hips were revised. Of these 44 were male and 38 female. The average age was 51 years (range 15 to 75). The right hip was a?ected in 50, left in 32, and both hips in four. The average BMI was 29.5 (range 21 to 42.5). The ?ndings were: I. The failure rate has been 16% at 5 years would be in line with current NICE guidance: but 1% to 2 isthe norm at NNUH). 2. From the total cohort 100 hips have now been revised (up to lululy 2008). 3. A small number of revisions have been for ?normal? causes e. g. infection, early dislocation etc. 4. Extensive corrosion of the femoral stem was found in almost all cases. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914803 PLT-OO178-00004 The metal ions released have killed the bone and soft tissues around the hip replacement resulting in: a. Fluid collection often under high pressure causing pain b. Tendon rupture causing hip dislocation 0. Bone death resulting in fractures around the implant 6. There is no evidence that the failure has been due to poor surgical technique, in fact, the contrary is the case with the immediate post-operative Xrays showing proper implant positioning of both stem and cup and a very good cementing technique. Excellent or good Barrack cementation grades of A and were consistently observed. 7. Patients who do not have the problem of metallosis typically have very good functional outcomes. The cause of the stem corrosion is currently uncertain. Two possible explanations are being investigated, although there may be other unknown explanations: 1. The implant has formed a galvanic cell, due to the titanium shell and particular design and fixation mechanism of the tapered polished cobalt'chrome femoral stem. 2. A local Norfolk genetic polymorphism has led to an immune response which lowers the pH of the ?uid bathing the prosthesis. Conclusions The problems formd with the Ultima TPS Metal-on-Metal hip replacement are unusual and have not been found before. No cases have been reported to DePuv or MHRA outside the NNUH cohort. A failing conventional prosthesis presenting with pain is normally evident on plain Xray. In this cohort, Xrays appear normal, but excessive corrosion of the femoral stem has led to a massive metal ionosis and death of nearby tissues. The reason for the corrosion is unknown, therefore unforeseeable= but is being investigated. MRI scanning reveals the tissue changes in patients who have normal Xrays. Some patients without have these changes apparent on MRI scanning. These problems do not appear to be related to the Ultima metal?on- metal bearing itself. Key recommendations PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914804 PLT-OO178-00005 r0 VI 6. All patients should be recommended to undergo an MRI scan. This should be undertaken annually for 3 years and then re-assessed about whether to continue with further scans. For patients who are but have positive MRI scans an early revision procedure is recommended because: a. The revision is easier to perform and can include cementing within cement; this being similar physiologically to a primary THR b. The amount of tissue death increases with time. At revision as much dead tissue as possible should be escised. The results of the revision become more compromised as more tissue is removed. 0. Particularly in men there is a small but increasing risk of periprosthetic fracture with time. Those patients who are with an abnormal MRI scan, but not showing typical changes of failure should have the scan repeated 6 months later. The patients will be recalled to dedicated clinics, see their clinician, receive the Patient Information Lea?et and discuss their personal management plan. Those patients who currently do not attend regular follow-up (DNAs) should be actively encouraged to do so. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914805 PLT-OO178-00006 History Hip replacement was pioneered in Norwich by Ken McKee in the 19503. The head of the femur was replaced by a metal head with a neck and stem attached with the stem placed down the femoral canal. The acetabulum was replaced with a cup, also made of metal. This metal-on?metal (MOM) joint replacement had a high failure rate due to the design of the implant ?xation surfaces and poor quality control over head and cup tolerances clue to machining capability at that time. However many patients did not experience an early failure and some have successful McKee hips that have lasted over 40 years. To overcome the early failure rate, Sir John Charnley introduced the concept of a low friction arthroplasty using a high density polyethylene cup. Successful outcomes with this meant that the metal-polyethylene cup combination became the gold standard for hip arthroplasty. Ken McKee introduced a polyethylene cup, this combination was known as the McKee-Arden. Modi?cations to the femoral component lead to the McKee-Farrar hip replacement} which was used throughout the world. In the 19805 and 19905 it became clear that the metal-polyethylene bearing led to wear, with the polyethylene wear debris setting up a biological response causing bone lysis and loosening of the prosthesis. This problem becomes increasingly common after 10 years implantation, with very few prostheses lasting longer than 20 years. In general this is well past the life expectancy of the patient. However the success of hip replacement in reducing the pain and disability experienced in the arthritic hip has led to an increasingly younger patient population demanding the operation. However for these younger patients, 2007 Swedish hip registry data showed that by 14 years, a quarter of all males and a third of all female patients with metal-polyethylene hip replacements had required revision. In these circumstances there is a strong reason to find a bearing surface that will exceed the life expectancy of these younger and active patients. Since Ken McKee?s time, the manufacture of implants has improved dramatically with better designs and the use of computer numerical control (CNC) machining and a Inunber of companies have been re-visiting MOM bearings. Locally the Birmingham hip resurfacing prosthesis was introduced to the Norfolk Norwich at the request of the Primary Care Trusts in response to patient demand. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914806 PLT-OO178-00007 There has been a long association of innovation and research between the Department of Trauma 85 Orthopaedics at the Norfolk Norwich University Hospital Foundation Trust and DePuy International Ltd: Leeds, UK (as Johnson Johnson Orthopaedics Ltd, prior to 1998). Modern hip prostheses are modular with the replacement made up by the surgeon from a number of parts, thus allowing variations for the patient?s anatomy. Around 1995 it was proposed to trial a MOM implant using established designs of hip components except that anew metal ?liner?, the bearing surface of the acetabular component, needed trialling as there was a novel taper connection between it and the acetabular shell. Along with two other UK sites, the NNUH therefore agreed to talce part in a study looking at 50 patients with a 6-month follow-up ('20 were recruited at NNUH). This study was undertaken in 1997 with prior ethics committee and Medical Devices Agency regulatory approval and was successfully completed resulting in the implant obtaining the relevant CE (Conformit? Europ?ene) marking. Patients were then recruited as part of a post-market clinical follow-up study. The prosthesis was used routinely from this time till 2004, initially for younger patients only. By the beginning of 2004 there had been 12 revisions, some with periprosthetic fractures and some presenting an unusual pathology. Since the initial cohort. was part of a research study, this was reported to the Research Governance Committee of the Norfolk Norwich Consortium. At their request an Orthopaedic Subcommittee was then created to look into the problem and try and ?nd the cause of the failures. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914807 PLT-OO178-00008 Orthopaedic Subcommittee, Research Governance Committee The Subcommittee was set up to investigate the problem. It included representatives from the Orthopaedic Department of the NNUH, along with radiologists and a histopathologist, DePuy International Clinical Research and Hip Research Development Departments, the School of Biology at the University of East Anglia, and immunologists from Bristol University. Simon Donell (Chairman) Keith Tucker, Orthopaedic Surgeon NNUH John Nolan, Orthopaedic Surgeon NNUH Hugh Phillips (deceased) Orthopaedic Surgeon NNUH Clare Darrah, Research Manager, Institute of Orthopaedics NNUH Andoni Toms, Radiologist NN Torn Marshall, Radiologist NNUH John Cahir, Radiologist NNUH Tim Barker, l-listopathologist NN UH Ian Clark, Professor of Biology UEA Caren Peters, Research Immunolo gist Bristol University Patrick Case, Immunologist Bristol University Mick Borroff, Director of Clinical Research Reimbursement, DePuy International Richard Farrar, Director of Hip Development, DePuy International Graham Isaac, Distinguished Research Fellow, DePuy International Ken Brummitt, Principal Bioengineer, DePuy International PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914808 PLT-OO178-00009 Summary of Meetings of the Orthopaedic Subcommittee March 2004 The Subcommittee ?rst met in 31St March 2004. At that meeting 20 patients were presented and their history= radiological and pathOIOgical ?ndings discussed. Of these 14 had been revised and the other six likely to be revised. Three were straightforward revisions and did not cause concern. However seven patients had a soft tissue reaction ?like toothpaste? without bony lysis which seemed to be an undescribed mode of failure for hip prostheses. It was noted that these patients tended to be overweight, with a history of injury, most presenting with groin pain but having no radiological evidence of loosening. Three had presented with a periprosthetic fracture and two after dislocation One patient was noted to have an eosinophilia in the soft tissue reaction. The nature of the soft tissue reaction was discussed, including infection and metal ions, but no conclusion was able to be drawn. It was stressed that the majority of patients had excellent clinical and radiological results; better than expected. It was also noted that the revision rate was well within ICE guidelines, it was resolved that: - The company would: it Check the lot numbers of the revision patients to exclude a manufacturing problem in a batch of implants. b. Check the ?nite element analysis to exclude excessive medial loading c. Report the problem to the Medicines and Healthcare products Regulatory Agency (MI-IRA). d. Fund further analysis of the explants and soft tissue. 6. Check whether other users have had a similar problem. - The investigating team would: a. Send implants and soft tissue to Prof Gordon Blunn at the Royal National Orthopaedic Hospital for independent analysis. Patient consent will need to be obtained. b. In future take blood samples, and keep soft tissue and explants on all revision patients. 0. Send the serum metal levels to Mike Clark in New York State for opinion. d. Get histology reviewed by histopatholo gist in Adelaide. 10 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914809 PLT-OO178-00010 6. Continue using the implant for patients undergoing a second side operation and those already expecting it, and not to use the implant routinely for other patients until the analyses have been performed and the problem identi?ed. August 2004 By August 2004 it became clear that there was a signi?cant problem at NNUH but not elsewhere and that the number of revisions was increasing. It was advised that no further implantations should be performed. had been informed. December 2004 On the 2mi December 2004 the hypothesis was that there was an increase in torsional instability of the femoral stem leading to wear and severe stem corrosion within the cement mantle. The resultant metal ions then killed the adjacent bone and soft tissues, which may lead to femoral ?'acture. It was noted that one patient with bilateral implants only had one hip affected. The corrosion was much quicker than is normally expected. The cobalt-chrome has a passivation layer which is affected by bone cement which after initial fretting self-passivates. Many hip prostheses show signs of mild corrosion with time at revision. Occasionally, severe corrosion has been observed with cemented Exeter stems. Given that neither the Exeter stem. which is an almost identical prosthesis of stainless steel, nor the CPT prosthesis, which is another almost identical stem made from cobalt-chrome have not had this problem of early, extensive corrosion or abnormal soft tissue reactions, it was not clear why the Ultima TPS cobalt-chrome stem was having a corrosion problem. The increased torsional instability might have been due to the higher offset implants. At this stage the following was concluded: - The Company proposed that there should be an MRI screening process of 20 at-risk group patients who matched the characteristics of the abnormal patients using the new MRI metallic artefact reduction sequences (MARS) pioneered at the NNUH radiology department, which it would ?md. - The at?risk group appeared to be large size males with thick femoral cortices, with large stems and high offsets. ll PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914810 PLT-OO178-00011 The Company agreed to fund all MRI scans for patients: anterior groin pain with dif?culty straight-leg raising and pain on leaning forwards. Or signs of loosening at the calcar on Xray. . It was agreed to supply the data on heads, stem sizes and offsets of the whole cohort to the company. 0 That the Company contact Prof Gordon Blunn for his thoughts, and to send all the explants to Dr Alison Davenport in Birmingham (independent corrosion expert) for an opinion. 0 The Company are performing mechanical fatigue tests on the stems to try to re-create the corrosion seen clinically in the laboratory. May 2005 Review of problem: Patrick Case gave a presentation on his work in this area and outlined what he thought the problem is. In summary there was an immunological response to metal particles that is found in chrome-cobalt, but not or systems. The synovium showed a marked three-layer response with exuberant ?brin production, plasma cells and large perivascular accumulations known as ALVAL (aseptic vasculitis and associated lesions). This was in contrast to the macmphage response to HDP. The hypothesis was that Cr. Co particles were toxic to the syriovim'n which when damaged allowed an in?ux of the metal. This provoked a strong immtmological reaction. The altered blood ?ow decreased the oxygen tension in the tissues and this caused pain (early). The alteration of the haemodynamics led to oedema (clinically presenting as an effusion and swelling). This may cause the hip to dislocate. The continuing process led to bone pathology with osteocyte death, osteolysis and lucent lines. The question raised was the problem due to the patient and an immune response to the metal particles. or due to the implant? A study was proposed looking at fresh blood and tissue samples to identify the exact type of immune response present. This would require a research assistant and some material costs of around ?29 000, taking about a year to complete. 12 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO ORDER. DEPUY037914511 PLT-OO178-00012 A presentation on the clinical and operative ?ndings was given and showed these ?tted in well with Dr Case?s model. The radiologists presented the 13 patients that had been reviewed by MRI of which six were from the DePuy?funded cohort. They described the evolution of their investigation. Their results also ?tted in well with Dr Case?s model. The DePuy team reported that in the company?s view, the bearing itself was not the problem. Lower blood metal ion levels than the Birmingham resurfacing hip had been reported in an independent clinical study. Other clinical studies on the same hearing, but with a different femoral stem= out to the same follow-up had seen no similar problems. Examination of explants failed to Show signi?cant wear conforming the results of low wear in previous hip simulator studies. The corrosion noted was an exaggeration of a typical reaction. It was explained that the good cement fixation may have created a corrosion cell in the crevice between the implant and the cement. Perversely this is usually prevented by a vent through a cement crack. It was pointed out no cracks in the cement had been noted in the revised patients. Expert opinion from Dr Alison Davenport had suggested that the presence of an antibiotic in the cement could enhance corrosion. The carbon content of the metal was also excluded as the source of the problem because this has been thoroughly investigated in hip simulator studies during product development. It was concluded that: - DePuy would consider Dr Case?s request for funds (subsequently agreed). His proposal would need a formal application to COREC. The company would like to hear Prof Blunn?s report before making a ?nal decision. 0 A cohort of patients with ?ve control patients with the Exeter metal-on-plastic implant should undergo MRI to elucidate further the ?ndings on the scan. It was noted that there were no controls at the current time. A formal proposal would be required and the company would consider funding it (subsequently agreed). - Those patients with a positive MRI would undergo closer review or revision arranged. a All treated patients would undergo yearly review 13 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914812 PLT-OO178-00013 0 Two patients identi?ed with sensitivity to jewellery would be reviewed and further studies considered as cross-sensitivity between nickel and cobalt is known. 0 The company con?rmed that there was indemnity for harm suffered by the patients enrolled in the initial clinical investigation in accordance with ABHI guidance and would inform us of the details (subsequently provided). - The company agreed that the MRI ?ndings could be reported to a radiology journal: and appreciated getting sight of it before presentation for publication . The company were pleased that Dr Case felt that if there was an abnormal immune response occurring in so me cases then this could be treated by medical means. March 2006 A review of the investigations by DePuy showed that the ?nite element analysis had been undertaken and did not show anything relevant. An interim report on the fatigue testing (Exeter and TPS stems) was able to reproduce crevice corrosion but did not indicate any signi?cant difference between stem typess. A ?nal report was awaited . Further testing was being developed by Leigh Brown of Hudders?eld University. The DePuy surface replacement (ASR) should undergo metallurgy testing to comp are with this MGM bearing. Information had been supplied to MHRA which was undertaking a major review on the safety of the device in conjunction with DePuy. The MHRA was not aware of any corrosion issues to date with other MOM implants. Other Ultima TPS users and MOM articulation users had been contacted by DePuy. Some 6,000 stems had been sold. Only the NNUH had reported any problems. It was questioned whether other users had reviewed their patients and been told about the specific problems. DePuy con?rmed that their discussions with surgeons had informed them about the speci?c problems, but other centres had not reviewed patients in clinic. DePuy agreed to inform other TPS stem/PE cup users of the NNUH experience. 14 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914813 PLT-OO178-00014 Regarding future funding of MRI for patients; DePuy agreed to continue the funding for MRI scans. They needed to be informed when the agreed limits were nearly reached as they would then arrange more funding for research purposes. It was suggested that clinical. radiological, and pathological scoring systems should be developed to correlate ?ndings. Patrick Case introduced a new tissue sampling technique with special test kits and arranged with School of Biology at UEA to supervise sample preparation. Dissection should be at right angles to the skin, and orientation needed to be labelled. There was the possibility of looking at cellular metabolism in synovial ?uid. Samples would need to be transferred. with patients consent, to Bristol as quickly as possible. An update on further treated patients was undertaken. A stem was shown with corrosion of approximately 1mm. There was a discussion about the metal composition of the stems and it was suggested that maybe this should be looked into. There was a concern that there might be an inadvertent mismatch of head and liner metals which needed to be investigated. Comparator stems such as the CPT were available in cobalt-chrome (until 2002 this was stainless steel in the however relatively few had been used with cement (except in the USA). It was agreed that other tapered polished stems were not showing any signs of problems. A patient with the TPS stem and a polyethylene cup had presented with large amounts of ?uid around the hip on MRI, but with mild who was going to be rescanned patient in 3 months. All other TPS and polyethylene cup patients were to be reviewed (approx 40 patients). Another patient had had the stem revised where there was no evidence of corrosion after 3 years but there was evidence of soft tissue death Two other patients had shown evidence of dead soft tissue without stern corrosiona but there was wony the amount of dead tissue and the possible toxicity effect of metal ions. A corrosion expert would investigate the cause of the problems since chromium 6 is known to be toxic and cause cell death. A discussion on how to investigate why this problem seemed unique to this region was undertaken with the suggestion that we needed to look in depth at the medical history= social history etc. June 2006 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914814 PLT-OO178-00015 A presentation of the histological ?ndings showed 15 positive results and the rest had necrotic tissue. The principle ?ndings were an acute vasculitis with varying levels of tissue some in very large clumps with a vascular layer present in some, and an ulcerated surface. This suggested a hypersensitivity- type immune reaction Various histological findings were correlated with the clinical and radiological ?ndings. it was recommended that they should be a scoring system of the clinical findings and a scoring system of the radiological findings to correlate with the histological ?ndings. DePuy reported that the analysis of the corroded femoral stems by Leigh Brown at Hudders?eld University showed that there was one patient with no corrosion and then a range from slight to moderate to severe. There was a question about whether an antibiotic in the cement was causing the local pH to drop and therefore allow dissolution of the metal ions into the surrounding soft tissues. It was resolved to investigate which antibiotics have been used in which cement for each patient. The MIRA were awaiting the corrosion analysis but otherwise were fully informed: Professor David Williams in Liverpool was going to review the explants and all that we had should be sent. Prof Blunn had been chased but had been unresponsive. Review of the other sites showed that no patients had of pain although there had been one petiprosthetic fracture. Other sites need ed to collect soft tissue samples, synovial ?uid and explants from any patient who has a revision. There was a discussion around genetic polymorphisms and whether the local Norfolk population had an unusual polymorphisms. It was felt that might be a polymorphism causing an early presentation of something that may occur later in other patients. The protocol for this work was to be done on this to include samples from a control population. A paper on the MRI technique had undergone revision at the request of the Journal. Some final information on histology was awaited. Further worlr was proposed: a. Histology samples. All histology samples from the patients to be sent to Bristol. All future revised patients should have synovial ?uid aspirated to check for metal ions which could be analysed at Harwell 16 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914815 PLT-OO178-00016 b. Explants: photographs and explants to be sent to DePuy with intra- operative photographs. c. controls for MRI: As many as possible need to be bilateral replacements. Protocol for tissue samples from control with S- ROM Metal-on?Metal hips and 10 patients with Metal-on-Polyethylene revisions. Any patient undergoing a revision in these categories would have tissues taken under the current tissue back consent and a protocol would be written for analysis of these samples. September 2006 An update of the investigations was presented: DePuy - An interim report ?'om Professor David Williams at Liverpool suggested that no single factor was responsible for changing a stable state into an unstable state. He was not convinced that the problem was the cement. He felt that he needed to understand the histological and pathological evidence, corrosion score= the signi?cance of the off set design, and access to more data. - DePuy had arranged a meeting with the MRI-IA to discuss the problem with this cohort. Bristol - The histology on 26 specimens had been completed of which 19 had viable data. There appeared to be strati?cation in the sampling and the question was whether this strati?cation was associated with, for instance, the amount of corrosion on the prosthesis. Collaboration with Scotland on immunological synapsing suggested and agreed. It was noted that preliminary data on the metal counts in synovial fluid showed some high chromium levels as well as other metal amounts and the signi?cance of this was not certain at this stage. It was noted that hypoxia is known to destroy ?bres which maybe why patients maybe as well as having the changes. It was suggested that histological analysis looking for hypoxia would be another way forward. NNUH - The radiological score was presented and agreed. For the clinical scoring, it was noted that a number of factors needed to be considered; age gender, 17 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914816 PLT-OO178-00017 presentation with pain dislocation. fracture or nerve palsy or positive Trend elenberg gait. It was noted that the time to or time to dislocation was important to note and also to record the Oxford hip scores. From the point of view of the operation there was the subjective view of the abnormal tissue there if a velvety= to othp aste-like, or necrotic the volume of tissue and which soft tissues had been affected eg. abductor tendons, external rotators= and necrotic bone as well as the area of any baldness and the percentage detachment of tendon around the upper femur. All of this should be graded into none, mild, moderate or severe. It was also felt important to record whether the acetabular socket was normal or not, and whether there was thought to be infection present or possibly present or not present at that operation lntraoperative photographs would be useful. 0 The MRI scans could now be undertaken, as the protocol had passed Ethics and Research Governance Committee approval. Its was important to have Metal-on-Metal patients with no and no loosening and Metal-on?Plastic patients with similar age characteristics and linked implant times a It was suggested that those surgeons at the Norfolk and Norwich University Hospital who were using the DePuy ASR prosthesis (a prosthesis without a femoral stem (surface replacement) should be informed that if any underwent revision then samples would be required as this would be a group where the same CoCr metals were involved but no stem. January 2007 A further 13 patients had been revised including one with a sciatic nerve palsy. Two patients had presented with recurrent dislocation. One revised patient had recurrent dislocation that improved over 9 months. Apart from the Ultima TPS MOM patients, one Birmingham hip had been revised with apparently similar ?ndings, and a further Birmingham hip had an MRI scan suggesting the same problem. patients were being recruited for screening MRI. 18 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYD37914817 PLT-OO178-00018 DePuy were continuing to fund the Bristol investigations. The)! suggested that Professor Joshua Jacobs of Rush University, Chicago, a renowned corrosion expert should look at the data Details of this proposal were requested. There was concern about the con?dentiality of any data. A detailed presentation had been given to the MHRA in November 2006 where DePuy informed them that all surgeons implanting the Ultima TPS MOM would be receiving a letter from DePuy suggestng how the clinical problem presents and how to get the patient scanned. A copy of the presentation to MHRA was provided . Results of pre-clinical testing of the Ultima bearing showed no difference in wear rates according to carbon content. After discussion it was suggested that lowering the pH would cause corrosion= and therefore patients should have this measured in vivo with a pH probe. It was suggested that destructive testing should be performed on some of the implants to look at wear in greater detail. Bristol reported that all their samples had been reviewed. There were 27 viable samples with 16 matched to Hudd ers?eld wear scores. Immrmochemistry had been performed on 14 samples of which 10 showed a weak correlation between in?ammatory in?ltrate and wear scores. Synovial ?uid analysis was needed looking at cytokine pro?ling, metabolites and metal analyses for particle size and type, and protein-bound ions. In some patients there appeared to be aB cell-mediated response, with an inverse correlation to time to revision. Further work with CD8 and CD4 tests to check on cell numbers would be undertaken Discussion about whether Harwell or a laboratory in Germany should be used for measuring metal levels occurred. Future preposed projects were: - Polymorphisms looking at 60 and 60 patients. 0 Discuss with Prof Jonathan Powell from the Human Nutrition Unit in Cambridge about his possible input into the project 0 Meet with the Oxford surgeons to discuss their group of resurfacing patients with pseudotumour. l9 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. PLT-OO178-00019 It would be useful to perform autopsies on any patient with a MOM implant to assess dissemination of metal ions. although it was recognised that this might be dif?cult in the current climate over autopsies. 0 Create a Studentship with the School of Biology UEA to look at the basic science of the problem. 0 Prof Tim Burstein, a corrosion expert in Cambridge was to look at a stem. The early ?ndings would be presented at the British Hip Society meeting in March 2007. The radiology paper was with Skeletal Radiology. March 2007 From the NNUH: - A meeting had occurred with Jonathan Powell in Cambridge. His laboratory has equipment for measuring metal ions. He suggested MR of synovial ?uid. 0 The Action Arthritis studentship was progressing. - The presentation at the British Hip Society was well received. Two surgeons contacted the group to say that they had seen similar clinical in unrevised patients. - patients had been found with MRI evidence of the problem. It was suggested that they should have further scans 6 months and at 1 year to monitor progression. 0 A stainless steel stem had been revised with a loose component. There had been osteolysis but no soft tissue response. The stem would be examined for corrosion. DePuy - Since there was NNUH concern in using Dr Joshua Jacobs as a corrosion expert it was proposed that Profs John Fisher and/'or Ann Neville in Leeds should look at the tribology and corrosion for an opinion. Bristol . The control specimens showed amixed picture. Some had perivascular in?ltration similar to the revision specimens and consistent with rheumatoid arthritis. It was suggested that the revised patients had undergone cell suicide (apoptosis) rather than necrosis in response to the high metal load. 20 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914819 PLT-OO178-00020 It was important to look at the circulating metal ion blood levels as cell suicide would lead to lower levels. Xrays need to be reviewed to look at patients of arthritis before the primary hip replacement June 2007 DePuy TPS Corrosion investigation at. University of Leeds Prof Ann Neville presented a report of her preliminary ?ndings. The collection of explanted TPS stems received by DePuy had been visually inspected. The assessment of the extent of damage by Leigh Brown at Hudders?eld University seems in accordance with what was observed in this analysis. The extensively corroded TPS stern ref 06/526 explanted from Patient ID 685094 (DA) was sectioned following the approval for destructive testing given at the meeting held 30th March 2007. The corrosion mechanism appears clear with little sign of any mechanical damage and hence appears to be purely crevice corrosion a form of electrochemical damage. Potential measurements on the individual implant components (stem/headfliner/shell) had been taken and indicated a possible mechanism: 0 Initiation of crevice corrosion on stem due to interface with the cement mantle (polymer versus metal crevice) 0 Potential of the stem decreases (active direction) - con?rmed by potential measurements 0 The driving force for galvanic corrosion is then increased if the head and the shell are not corroding (>300rnV) Fretting action will further move the potential in the ?active" direction Further testing programme to be discussed with uy PC questioned what valency the released Cr ions would have in this system citing a paper by Shuttleworth Bondy in Biomateiials. IN indicated that he held a collection of explanted Exeter. Chamley and CPT stems which all showed evidence of corrosion, some to a similar extent to that 21 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914820 PLT-OO178-00021 seen in the worst TPS stems. AN requested some samples of Simplex bone cement for testing. These will all be forwarded to AN for evaluation. 0 Request for explanted TPS stems from centres using metal-on?polyethylene articulations to be made. It was noted that the MRI reports from the three patients with TPS and metal-on-polyethylene bearings from Mr Gregori were all negative. . A patient with a stainless steel Elite Plus stem and MOM Cup had been revised. The component was loose with osteolysis, but no soft tissue response. After examination by DePuy; the femoral head was con?rmed to be stainless steel and not CoCr. Synovial Fluid Analysis - Metal ion level testing was still to be arranged. a PC pointed out that it was imperative that the cytokine analysis was carried out from the material obtained at the ?rst defrost. Polymorphism Study Bristol University - All agreed that the study was important. . Funding from DePuy and an agreement with Bristol University was in place. 0 Bristol University need con?rmation of ethical and research approval before DePuy?s agreement can be signed by them. - to submit ethics committee application for control bloods to be taken Bristol Immunology Study - Caren Peters to prepare and circulate her manuscript in lieu of a ?nal report before commencing her maternity leave MHRA Medical Device Alert 0 No new reports following release of DePuy?s ?Dear Doctor? letter in February 2007. MHRA had issued a Medical Device Alert on the combination on 14?11 June 2007. MHRA had taken a decision to issue a Medical Device Alert within two weeks of having received DePuy?s ?Dear Doctor? letter, but had 22 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914821 PLT-OO178-00022 been unable to implement it due to staff illness and resource issues. The MBA notice was being issued on a precautionary basis, in case a surgeon was referred a case involving a TPS stem with an Ultima MOM Cup. and not in the light of any new data. April 2003 The group consolidated the ?ndings of the project. The Radiology paper showing how to use MRI to de?ne the problem was published. The Immunology paper was submitted which showed that the response to the high metal ions was to stimulate the immune system with an increase in that had not been reported before. The clinical paper was almost complete with the conclusion that patients with the implant should undergo an MRI scan. Patrick Case gave a presentation on how abnormal immunology could drive the corrosion through lowering the pH around the stem. The importance of the polymorphism study was emphasised. It was noted that the studentship was funded, and that the details had been de?ned. It was to be advertised shortly with a start date at the end of the year. It was concluded that the research subcommittee should be disbanded as it had completed the patient review and a management plan was no possible. It was resolved to give a report to the Research Governance Committee and also to the Orthopaedic Department at Clinical Governance. Further ongoing studies would continue as this was an important exercise. 23 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914822 PLT-OO178-00023 Recommendations of the Orthopaedic Department July 2008 1. All patients should be recommended to undergo an MRI scan. 2. This should be undertaken for 3 years and then re-assessed about whether to continue with further scans. 3. For patients who are but have positive MRI scans an early revision procedure is recommended because: - The revision is easier and can include cementing within cement this being similar physiologically to a primary THR - The amount of tissue death increases with time. At revision as much dead tissue as possible should be excised, The results of the revision become increasingly compromised as more tissue is removed. 0 In men there is a small but increasing risk of periprosthetic fracture with time. 4. Those patients who are with an abnormal MRI scan, but not showing typical changes of MOM failure should have the scan repeated 6 months later. 5. The treating clinicians need to inform the patients in person. 6. It is reasonable on clinical grounds for the patients to wait until their next annual clinic appointment. The dedicated clinics occur every 3 months. However it would be appropriate to make resources available to increase these to at least every month till all patients are informed. 7. There has been long-standing concern that high metal ion levels and the immune response to them may lead to an increase risk of It was felt that a full blood count should be taken at each clinic visit as a sensible precaution. 8. Those patients who currently do not attend regular follow-up (DNAs) should be actively encouraged to do so. 9. Resources need to be made available for the patients to undertake the appropriate MRI scan in a timely manner. 10. A Patient Information Lea?et will be produced urgently. involving patients in its design and contents ll. It was noted that the numbers of revisions needed may be too great for the original treating clinicians. Ifnecessary the other hip surgeons are prepared to help out to get the work done in a timely manner. 12. There was a strong sense that the failure of this implant has been unforseeable and that the patients had undergone expert treatment. All the professionals involved had acted appropriately. The Department as a whole will support the management of these patients to produce the best outcomes for them. 24 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914823 PLT-OO178-00024 The Patients Total cohort From 4th February 1997 to I?t August 2004. 545 patients underwent 652 hip arthroplasties, of these 434 hips were undertaken at the NNUH the rest at the Spire Hospital Norwich. Three hundred and two were men and 243 were female. The right was implanted in 349 and left in 303. One himdred and seven were bilateral. A further 75 had a non?MOM on the contralateral side. The average age was 57 years with a range of 15 to 81 years. Revision cohort Up to 3lst January 2008 82 patients with 90 hips were revised. Of these 44 were male and 38 female. The average age was 51 years (range 15 to 75). The right hip was a?ected in 50= left in 32, and both hips in four. The average BMI was 29.5 (range 21 to 42.5). Results (from paper submitted to the Journal of Bone Joint Surgery [AmericanD Table 1 shows the number of hips done by year and the number revised in each year. Table 1. Revisions and revision rate by year. Year Revision Cases RIP failure 1997 l4 3 14 1998 0 0 0 1999 3 49 6 2000 20 91 0 22 2001 4 07 0 3 2002 23 152 0 15 2003 24 15 8 15 2004 7 69 0 10 Totals 93 651 5 14 Clinical presentation Typically the patients were delighted with the result. of the arthroplasty. However, if 25 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914824 PLT-OO178-00025 there was a problem, they would describe it as ?not quite right", usually at least 2 years after implantation. They then deteriorated with the predominant complaint being pain typically felt in the groin and thigh. The reasons for revision are shown in Table 2, noting that 39% had normal radiographs and no pain, and 70% had soundly ?xed implants. The implant fracture was through the neck of the femoral stem in a patient with a BMI of 42.5. Two patients had palpable masses which turned out to be ?uid collections. and one had a sinus that was culture negative, but positive cultures were found in the peri-implant soft tissues at revision operation. One patient developed late sciatic nerve palsy as a result of the soft tissue reaction involving the nerve directly. The palsy did not improve after revision surgery. Table 2. The reason for revision correlated with plain radio graphic ?ndings Cause Normal Loosening Total Pain 35 9 44 Periprosthetic fracture 13 3 16 Dislocation Early 3 0 3 Late 12 4 16 Infection 6 3 9 Implant fracture 1 0 At operation the ?ndings were an opaque ?uid collection that could be under great pressure, and soft tissue necrosis, that at its extreme could be associated with avulsed gluteal tendons. The denuded upper femur was associated with sruface avascularity. The prosthesis was typically very well ?xed with an intact cement mantle, except when there was a periprosthetic fracture. The femoral stem was 26 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914825 PLT-OO178-00026 corroded where it was in contact with the cement in all cases and the extent. and depth of corrosion was often severe. Infection Six patients had culture positive infections at revision; three with Staphylococcus aureus (two being methicillin?resistant)= one with Streptococcus Group G, one with Enterococcas, and one with Coliform species. Eight patients had histological ?ndings consistent with infection of which one was the proven Enterococcus infection and three had been treated for prosthetic infection prior to revision. None of the suspicious cases has gone on to another revision. Therefore nine patients had infected implants giving an overall infection rate for the whole cohort of and 10% for the revision cohort. Implant survival and revision rares- Figure 1 shows the Kaplan-Meier survivorship for the whole cohort. It can be seen that the 5 year failure rate is around 16%. 27 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914826 PLT-OO178-00027 TPS Metal on Metal Survival Percent survival so 160 15:: Months Perz'prosrherfc?'acrures Sixteen patients sustained a periprosthetic fracture; three were Vancouver AG where one was noted intra-operatively, but not on plain ?lm. One was Vancouver AL, also found ultra-operatively, the rest were Vancouver Bl, the typical pattern being medial wall (Figure 8) involving the lesser trochanter: and usually comminuted. All but two patients were male. This is signi?cantly different from the total cohort test 0.001). One of the female periprosthetic fractures was a transverse fracture at the stem tip, pre-fracture radiographs showing lateral cortical thickening suggesting a stress reaction, Periprosthetic fractures were therefore ovenvhelmingly in men. In two it followed a fall from a height and the rest were lox-v-velocity. Other complied/tom ofrhe mam cohort Details of complications not requiring revision surgery were available for 574 hips These were 15 venous thromboembolism but no pulmonary emboli, and 28 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914827 PLT-OO178-00028 nine had a persistent wound leakage. Four patients were found to have ?squeaking? or ?dunking". There was one iliotibial band defect. Renal?mc?on Of the 82 revision patients full results were available on 67; the 52 NHS patients and 15 private patients who underwent their revision operation at the public hospital. The other patients did not have their initial pre?primary operation blood tests available. Of the 67. 12 had abnormal blood results prior to the primary procedure which subsequently returned to normal. Another seven patients had abnormal results prior to their revision procedure, which subsequently returned to normal post- operatively. Four patients had persistent abnormal results, of which one had chronic renal failure. Radiological results Of the 90 revised hips immediate primary arthroplasty post-operative radiographs were found for 83. The Barrack grade was and none were found to be grade C. Acetabular inclination measured between 27? and 60?, (n 82, mean 46? with 49 between 40? and 50'. The acetabular cup height (n 82) ranged between -15 to 22 mm (mean +3 mm 7.1 mm). The lateral offset varied from -30 to +28 (n mean 2.8 mm 10.7 mm). The leg length discrepancy (n =81) varied from ~25 mm to +18 mm (mean 0.4 mm SDrk8.7 mm). On the AP radiograph. stern position varied between 3? valgus to 8? varus. (11:83. mean varus 2? Forty??ve hip althroplasties in 43 patients were examined with MR imaging prior to revision surgery. These included 25 right and 20 left in 29 women and 29 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914828 PLT-OO178-00029 14 men. The median age of the patients examined with MRI was 62 years (range 38 to 84 years). The median time from the primary operation to the MR examination was 40 months (range 11 to 85 months) and the median time to revision from the MRI was 5.6 months (range 0.1 to 30.3 months). Forty-one of the 45 MR examinations demonstrated a ?uid-?lled periprosthetic cavity. The cavity was lined by a thick (up to 1 cm) ragged wall and was contiguous with the neck of the femoral prosthesis. The cavity was most commonly positioned superolateral to the femoral neck extending into the gluteal compartment and deep to the fascia lata overlying the greater trochanter (n 40). In one patient the cavity was positioned antero?inferiorly replacing the proximal vastus intermedius. In ?ve patients with a periprosthetic cavity this was demonstrated to extend through the fascia late into the subcutaneous fat (13 In four patients the primary cavity extended into the quadriceps compartment. Other ?uid containing periprosthetic ?uid ?lled structures were a seroma a psoas bursa, and a sinus tract. Of the 45 revised hips imaged with MRI, atrophy of the gluteus medias (n 22, gluteus minimus (n 20, 44%) and at least one of the short external rotators (n 21= 47%) was a common ?nding. Avulsion of the tendons of these muscles was demonstrated as follows: gluteus medius (n 11, gluteus minimus (n 12, 27%) and at least one of? the short external rotators (n 5, 1 Bone marrow edema in the proximal femur was demonstrated in the greater trochanter in 22 the lesser trochanter in 21 the anterior inter- trochanteric region in and posteriorly in 5 patients. Fractures. of the medial calcar (n l) and the greater trochanter (n were demonstrated in two patients. 30 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914829 PLT-OO178-00030 Histological results The histological appearances of excised periprosthetic tissues was characteristic and entirely unlike metal-on-polyethylene reactions. Seventy?six Specimens were available for analysis of which 62 showed the typical necrotic reaction. The non-typical samples were early in the series where the specimens were small and/or super?cial. Of the 76, eight showed additional active in?ammatory changes that were suspicious of infection; ?ve in otherr-vise typical MOM cases: and three in non-typical cases. Of the 62 ?typical? MOM cases, 57 had an inner surface layer of acellular eosinOphilic amorphous ?brinoid material. Twenty four contained necrotic tissue only (Figure 10 A), within which original structures such as blood vessels and adipose tissue could be identi?ed, either on staining or, more readily, with the use of an EPS stain. The remaining 38 contained similar necrotic tissue and, in addition, peripheral viable tissue. This was ?brotic, and in 35 of these 38 there ivvas a perivascular and diffuse in?ltrate of variable density (Figure 10 B). I-Iistiocyles were also present and in 19 there was an ill-defined granulomatous reaction at the necrotic/viable tissue interface. Four had an appreciable eosinophil component. Plasma cells were sparse and neutrophils were not a feature except in those cases with possible infection. Seven had visible metal particles in the necrotic tissue while 16 had microsc0pic metal particles either free or in macrophages in the fibrinous surface layer. In three probable metal particles were present in peripherally-situated macrophages. 31 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914830 PLT-001 78-00031 One of the revised patients (to a metal on polyethylene implant) went on to a further revision for recurrent dislocation. Histological analysis showed that there was still an ongoing reaction to metallosis typical of this cohort. despite removal of the MOM implant. Comments This study has shown an unusual presentation of failure of a novel MOM hip arthroplasty where the predominant feature was pain, with normal plain radio graphs, i.e. the implant was soundly ?xed at both the femoral and acetabular bone interface. Most reports of MOM failure describe aseptic loosening with histological evidence of hypersensitivity. The reason for the failure was excessive corrosion from the cobalt-chromium femoral stem causing a metal ionosis; only 39% of the histological specimens showed obvious metal fragments. The bearing surfaces were pristine with the corrosion confined to where the femoral stem was is direct contact with acrylic cement. The corrosion led to a massive metal ionosis which caused necrosis in the periprosthetic tissues. Massive fluid collections under pressure appeared to be the cause of the pain experienced by the patients, as the pain was temporarily relieved on aspiration of the ?uid. The hi gh rate of late dislocations was due to the amision of the gluteal and short external rotator tendons. No obvious abnormality was present on the plain radiographs (although careful review can suggest soft tissue changes consistent with a large ?uid collection) as there was no reaction at the bone?cement interface and no calcium loss was evident in the dead bone. However the osteonecrosis did lead to periprosthetic fractures as one of the failure mechanisms. Jacobs et al in a multicentre study reported a comparative cohort study with the identical acetabular shell, metal? on-metal bearing but with the cementless S-ROM femoral stem (Johnson Johnson; 32 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914831 PLT-OO178-00032 Raynhann MA) with a cobalt-chrome 28 mm head. The stem was titanium alloy. The other cohort used a ZTT II acetabular cup (Johnson 85 Johnson; Raynham, MA) with a polyethylene liner and also the femoral stem. At 3 to 6-year follow?up one MOM out of 95 had loosened at 4 years, with one dislocation and 12 with trochanteric bursitis. Out of 76 of the polyethylene group none had loosened nor dislocated, and three had trochanteric bursitis. These results are very satisfactory and notably different from our own. Clearly the level of metal ion production in the soft tissues was acceptable with a titanium alloy femoral stem. Massive metallosis has been reported in a ceramic on cobalt-chrome bearing with a hydroxyapatite coated titanium femoral stem. This presented with pain and an_ expanding proximal thigh mass. Computed tomography of the hip showed a 14 cm mass involving the acetabulurn, gluteus medius and maximus and extending into the thigh. Histology was reported as necrosis with massive metallosis. A further two cases with groin and normal plain radiographs have also recently been reported. On histology they found ?diffuse or sometimes nodular dense in?ltration, mostly around small venous blood vessels with only rare plasma cells, in between many macrophages with phagocytosed metal particles.? In our cohort the soft tissue response has led to characteristic changes on metal-suppression MRI sequences and on histology. The demonstrates ?uid collections of variable size with an irregular wall, most commonly extending into the gluteal compartment, with muscle atrophy of gluteus medius and minimus being common Muscle edema is noted, along with bone marrow edema. Histology demonstrated extensive tissue necrosis and a dense perivascular in?ltrate. A network of ?brin surrounds ?ghosts? of dead cellular material, with proliferation surrounding blood. vessels in the pseudocapsule of the hip joint. These are similar ?ndings to those of Davies et a1. 33 PROTECTED DOCUMENT. DOCUMENT SUBJECT To PROTECTIVE ORDER. DEPUY037914832 PLT-OO178-00033 It seems that this response is directly due to the massive ionic load. It should be noted that the same effect may be occurring in hip resurfacing arthroplasty. High metal loss could be due to poor surgical technique: however the cementation was satisfactory in the majority of failed implants. Abnormal cup inclination has been a proposed cause. and in this cohort an ideal position was present on 60%= and three were unacceptable. Without knowing the cup position for the whole cohort, it is not possible to say if this correlated with failure. but it is unlikely. Brodner et al showed no correlation between cup inclination and serum cobalt levels, nor was chronic renal failure associated with a poor outcome. Although they noted that their study was underpowered. Metal-on?metal bearings are known to shed metal ions over a very long time period. Patients with well fixed Ring MOM prostheses showed five times the reference serum levels of cobalt and three times for chromium. However a long-term study of an original McKee metal-on?metal bearing did not show necrosis in bone or soft tissue in an patient. Nor were cobalt or chrome ions found in the soft tissues. This would indicate that where the tribology was fortuitousl)-' correct with appropriate sphericity. clearance and surface roughness of the bearings then excessive metallosis can be avoided. The problem in this cohort may he one of galvanic corrosion caused by the combination of the titanium shell and the cobalt-chromium alloy stem. A titanium stem with a cobalt-cluome alloy bearing has been shown to lead to corrosion and failure. Scratching of the titanium smface worsens this effect. This leads to a capacitive impedance of nearly zero, favouring an electrochemical dissolution process at the implant surface. Wolner et a1 noted in the laboratory that the passivation. repassivation and corrosion of a metal-on-metai slide in combination with a partly 34 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914833 PLT-OO178-00034 damaged titanium alloy surface is quite complex. Between the CoCrMo alloy used and the Ti material, a potential can be established, the value of which depends on the electrolyte composition and the temperature that results in a dissolution process of components of the Ti?Al?Nb alloy. However, a cathodic partial reaction at cathodic active areas in the CoCrMo alloy can cause anodic dissolution reactions on anodic active parts at the tribologically treated metal-on?metal slide. This results in enhanced cobalt and chromium ion concentrations in solution. It has been suggested that the better the cement ?xation of the stem, the worse the corrosion, as the material is ?held" in small pockets around the stem which reduces the natural circulation of ?uid that can occur during cyclical loading when the femoral stem moves within the cement mantle. It was notable that the corrosion was con?ned to the stern surface contained within the cement mantle. However other units that have used this implant combination (a total of around 400 hip replacements), or the same acetabular cup and head with a different design of cobalt-chromiiun stern have not recorded this problem in any of them. Further work is underway to attempt to replicate these unusual corrosion results in vitro through appropriate laboratory studies. Such work should assist in furthering our understanding of the factors leading to such effects when implant systems are used within the human body in conditions of dynamic loading. We are also uncertain of the signi?cance of the hi gh-carbon cobalt-chro me alloy insert articulating with the low- carbon cobalt-chrome alloy head. An immune response may be another explanation. The mechanism of the immune reaction seen in these cases is unknown but it does fall within a stereotype that has been reported for hip replacements. It has been suggested for some time that a subtype of orthopaedic patients may exist that is PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914834 PLT-OO178-00035 particularly prone to mounting an immune reaction against the metals in the implant. This may be similar to contact sensitivity in the skin that is seen in some patients a?er exposure to the same metals. This hypothesis is currently being further investigated through the study of genetic polymorphisms in these patients. We would hypothesise that a combination of patient and metal ion, metal protein complex or metal nanoparticle induces this unusual response. This process causes an alteration of blood flow and also oedema in the soft tissues and bone surrounding the implant. This then leads to anoxia and a lowered pH which in turn may further increase the corrosion of the implant; previous studies of loosened implants have shown a signi?cant reduction in pH._It is possible therefore to envisage a feed- forward mechanism of implant failure in these hips that is analogous to the feed-fonvard mechanism of aseptic loosening that is seen in metal-on-polyethylene hips as a result of particle disease. Conclusion The investigation has shovm a high revision rate (16% at 5 years) of the Ultima TPS total hip arthroplasty using an uncemented Metal-on?Metal Acetabular Cup and cemented cobalt-chromium tapered polished stem. The failure was due to necrosis of pen-implant bone and soft tissues from massive metallosis the cause of which is uncertain. Two explanations are being explored. The ?rst is that galvanic corrosion has been generated by combining a titanium shell with the rest of the construct of cobalt?chrome. However no other unit which has used this implant combination has reported the same problem. Therefore a second possibility is that there the local population has a genetic polymorphism to explain the immune response which has led to corrosion of the stem by; for instance, lowering the pH of the synovial ?uid. 36 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914835 PLT-OO178-00036 Patients with failure of this MOM hip arthroplasty generally have at least 2 years of excellent pain-free function. After this they start complaining that it is not quite right, and maybe diagnosed with a no chanteric bursitis. They typically develop groin or thigh pain with activity, and their plain radio graphs are usually normal. A few may present with a pseudotumour of the thigh. Patients with these should undergo an MRI scan which should con?rm the problem. If not then revised they may present later with a periprosthetic femoral fracture; this complication occurring predominantly in men. A few patients maybe completely and present with a spontaneous periprosthetio fracture. Regular MRI follow-up should be considered for all patients treated with this MOM hip arthroplasty. 37 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914836 PLT-OO178-00037 References McKee GK Watson-Farrar .T. Raplacement of arthritic hips by the McKee-Fairer prosthesis, Bone JointSurg [Br] 1966: 48-B: 245?259. August AC. Aldam CH, Pynsent PB. The McKee-Farrar hip arthroplasty: a long-term study. Bone Joint Surg B1'l986; 68-B: 520-527. Chamlcy .T. The long term results of low-friction arthroplasty of the hip perform ed as primary intervention. Bone Joint Surg Br 28. Char-ole)" J. Low friction arthroplasty of the hip. Berlin: Springer Verlag; l979. p. 3 Schmalzried TP. 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Khan M.'l'akahaslu Kuiper .IH, Sieniawska CE, 'l?akagiK, Richardson Current in Vivo Wear of Metal-eri-Mcml Bearings Assessed by Exercise-Related Rise in Plasma CohaltLevel Orthopaedic Res 2006?. 24: 2029?2035. Gan-'ki'odger DJ. Topical Review Metal sensitivities and orthopaedic implants revisited: the potential for metal allergy with the new metal-on-metal joint prostheses. Br Dcnnatology 2003; [48: 1089? 1093. DaVies AP, HG, Campbell PA, Learmonth ID, Case CP. An Unusual Pen?vascular In?ltration in Tissues Around Contemporary Metal-on~Meta1 Joint Replacements. Bone Joint Surg Am. 2005?. 81A: 18-27. Hart Al, Hester T, Sinclair K, Powell Jj, Goodship AB, Pele L, Fersht NL, Skinner J. The association between metal ions from hip resurfacing and reduced T-cell counts. Bone Joint Surg Br 2006; SB-B: 449-454. Park Y-S, Moon Y-W, Lira S-J, Yang .T-M, Ahn G, Choi Y-L. Early Osteolysis Following Second- eneration Metal-on-Metal Hip Replacement. Bone Joint .S?urg Am 2005; 87-A: 15 5-1521 . Willert H-G, Buchhom GH, Fayyazi A. Flury R, Windler M, Kester G, Lohmann CH. Metal?on-Metal Bearings and Hypersensitivity in Patients with Arti?cial Hip Joints: A Clinical And Histomorphologica] Study Bone Joint SurgAm 2005:. 874.: 28-36. Korovessis P, Petsinis Repanti M, RepantisT. Metallosis After Contemporary Metal?on-Metal Total Hip Arthroplasty? Five To Nine-Year Follow-Up. JBone JointS rug/1m 2006; 88-A: 1 183-1 191. Milosev Y, Trebse R, Kovac S, Cor A, Pisot V. Survivorship and Retrieval Analysis of Sikornet Metal-on?Metal Total Hip Replacements at a Mean of Seven Years. Bone Joint Sui-gel": 2006'. I 1 73-1 182. Toms AP, Marshall TI, Cahir J, Dal-rah C, Nolan J, Donell ST, Barker T, Tucker .TK. MRI of early metal?on-melal total hip arthroplasty: a retrospective review of radiological ?ndings in 20 hips. ClinicalRadfolagy 2008; 63: 49-58. Brodner W, Bitzan P, Meisinger V, Kaider A, Gottsauner-Wolf F. Kotz R. Serum cobalt levels after metal-on-rnetal total hip arthroplasty. JBone Joint Surg [4711] 2003; 85-A: 2163-2173. Johnston RC, Fitzgerald RHI, Harris WH, Poss R, Mueller Sledge CE. Clinical and radiographic evaluation of total hip replacement. A standard system of terminology for reporting results. Bone Joint Sm?gx'lm Duncan CP, Masri BA. Fractures of the femur after hip replacement. Instr Course Last 1995; 44: 293- 304. Jacob; M, Gorab R, David Mattingly D, Lorence Trick L, Southivor?i C. Tln'ee- to Six-Year Results With the Ultimo Metal-on-Metal Hip Articulation for Primary Total Hip ArthIOplasty. Arthroplasty 2004; 19 Suppl. 2: 48-53. Valenti .TR, Del R10 1, Amillo S. Case 1?eport. Catastrophic Wear in a Metal?On?Ceramic Total HipArthIOplasty. Arihroplasn: (available on-line) Gather FW, Book A, Trattrlig S, Lintner F, P. Case Report. Cystic Lesion of the Groin due to Metallosis: A Rare Long-Term Complication of Metal-on?Metal Total Hip Artln'0plasty. Arthroplasn- 200?: 22. 923027. Boardman DR, Middleton FR, Kavanagh TG. Case Report. A benign psoas mass following metal-on- metal resurfacing of the hip. .7 Bone Joint ,S'urgfir 2006'. 88-13: 402-404. 39 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914838 PLT-00178-00039 Sauv? P, Mountney .T, Khan T, De Beer Jr Higgins B, Grover M. Metal ion levels after metal-on-metal Ring,T total hip replacement. A 30-year follow-up study. Bone JointSm?g Br 2007'. 89-B: 586-90. Clarke Ml", Darrel] (J, Stewart lngham Fisher .1, Nolan Long-'l'eim Clinical, Radiological and [-listnpathologica] Follow-Up of Well-Fixed McKee-Farrar Metal-On?Metal Total Hip ArthJ?Oplas-ty. Arthroplasty 2005; 20: 542?546. Boliler M, Kanz F, Schwarz B, Steffan 1. Walter A, Plank H. Knahr K. Adverse tissue reactions to wear particles from CcHilloy articulations, increased by alumina-blasting particle contamination from cementless Ti-ba sed total hip implants: a report of seven revisions with early failure. Bone Joint Surg Br 2002'. 84-3: 128-136. Wolncr C, Nauer GE, Putz V, Tschegg 3. Possible reasons for the unexpected bad biocompatibility of metal-on-metal hip implants. rl-i?ateri?als Science and Engineering 2006; 26: 34 40. Tipper 11., irkins P1- Ingham E. Fisher 1: Stone MH, Farrar R. Quantitative analysis of the wear and wear de tiris from low and high carbon content cobalt chrome alloys used in metal on metal total hip replacements. Materials Science 1999'. 10: 353-362.. Konttinen YT. Takagi M, Mandelin J. Lassus J. 58.10 J, Aincln M, Li Virtaum I, Liljestrorn M, Sakai H, Kobayashi Y, Sorsa T. Lappalainen R, Demuldcr A, Santavirta S. Acid attack and cathepsin in bone resorption around total hip replacement prosthesis. Bane Miner Res 2001; 16(10): 1780-6. 40 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. PLT-00178-00040 APPENDICES Appendix 1. Recommended Care Pathway Clinic appointment arranged Patient attends clinic: 1. Consultation with clinician 2. Patient Information Lea?et 3. MRI scan arranged 4. FBC scan reported Normal Typical Abnormal Normal 7379mm! Abnormal MOM MOM change?3' changes Arrange Rep eat Repeat revision THR MRI scan MRI scan annually in 6 months 1 i Treat as normal TI-IR (exclude Recommend infection). revision THR If not revised repeat MRI annually PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. 41 DEPUY037914840 PLT-OO178-00041 Appendix 2. Peer-reviewed papers Toms AP, Marshall TJ, Cahir J, De rrah C, Nolan J, Donell ST, Barker Tucker JK. MRI of early melal-on?melal total hip arthroplasty: a retrospective review of radiological ?ndings in 20 hips. Clinical Radiology 2008 63: 49-58. Peters C, Case P. neogenesis An alternative explanation for the pathology seen in pal-prosthetic tissue from metal- on- metal total hip replacements Bone Joint Surg [Br] (submitted May 2008) Donell ST, Darrah C, Nolan J, Tucker JK et al. Metal-on?metal hip arthroplasty early failure in the presence of normal plain radiographs. Bone Joint Surg [Am] (submitted July 2008) 42 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYU37914841 PLT-OO178-00042 Appendix 3. The Ultima TPS MOM Implant The Implant (Stem): . Ultima (her) Collarless Tapered Polished Stern Wrought Cobalt Chromium Alloy (to ISO 5832?12) ?Super Finished? 28mm Head (0.01 microns max) ASTM F1537 low carbon CoCrMo spericity 5 microns Centraliser Standard and hi gh-of?fset ranges Ultima 0&er Porous coated alloy shell - S-ROM - Neutral and 10 degree Taper-locked liner (super ?nished wrought high carbon CoCrMo to ASTM F1 5 3 7) Diametral clearance 60i20 microns 43 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914842 PLT-OO178-00043 Appendix 4. Investigations undertaken by the Subcommittee Clinical Case note review Radiological Plain Xi'av Post-operative alignment Barrack cementation grade Periprosthetic fracture grade MRI scan Metal aerifact suppression (MARS) protocol Comparison of MOM patients with MOP Laboratory Specimen analysis Blood and urine Renal function Metal levels Report from Mike Clarke (19 09 05): Of the 25 patients Ihave at least one result on, at least 14 have elevated pre-operative chromium levels and 7 have elevated preoperative cobalt levels. This gives me some cause for concern. In other studies, the ICP-MS based mean Cr levels in unoperated patients has been about 0.2 ng/rnl. Here it is 0.9ng/ml. The standard deviation is also higher. Whether there is something in the water up there I don?t know, but something about the data seems odd. Overall= there is no de?nitive trend over several years either. This in itself is not a major issue, the lack of consistency within a single patient is somewhat troublesome. I believe we have missed something: contamination at sampling, error in measurement, or some unusual occupational exposure issues. In any case, it makes sensible determination of the results a dangerous task. Joint ?uid Histological Haemotoxilin and Eosin staining 44 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914843 PLT-OO178-00044 EPS Staining Immunological T-cell stains Biomecham'cal Corrosiou Bearing wear Batch number review The Company reviewed the product batch numbers and raw material batch numbers and found no pattern. Lot numbers are distributed from both New Milton and Leeds controlled production sites. The same lot numbers appear in ?normal? and ?unusual? revisions and unrevised cases. There had been no change in materials, or production methods. The production site had changed in 1999 from the New Milton to the Leeds site without any changes in manufacture, other than the move to altemative well?validated cleaning and sterilisation processes as used on Charnley stems etc. Similar prostheses had not had similar problems reported. Materials review The Ultima TPS stenL 28mm head and metal acetabular cup liners are all manufactured from cobalt chromium molybdenum alloy. The Ultima TPS stem is made from wrought cobalt chromium molybdenum alloy to ISO 5832 Implants for surgery - Metallic materials - Part 12: Wrought cobalt-chromium? molybdenum alloy. The femoral head and cup liner meet the same ASTM F1537 Standard Speci?cation for Wrought Cobalt-280hromium? 6Molybdenum Alloys for Surgical Implants. The head is low-carbon cobalt chrome (Le. carbon content controlled to the lower end of the speci?ed range) and the liner is a high-carbon cobalt chrome (Le. carbon content controlled to the upper end of the speci?ed range), PROTECTED DOCUMENT- DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914844 PLT-OO178-00045 These different bearing materials were extensively researched (R arrar with Prof Dowson, Leeds University) during the product development. The bearing cl earance: surface roughness= sphericity and alloy composition/type were all investigated in hip simulator wear testing. The testing showed that the carbon content of bearing surfaces did not affect wear properties in vitro. Complaint History Review Up to November 2006, 9 complaints regarding the Ultima MOM Cup (excluding any from NNUH) had been received 0 5 revised for osteotvsis with S-ROM stems? (see Parks et al paper) - 1 liner revised for dislocation at day 2 surgeon technical error 1 revised for late infection - scratched head - 1 pain and late dislocation no metallosis noted 1 late dislocation - ??metallosis, stem not available for analysis Literature review A literature search was undertaken to identify papers reporting health outcomes of hip replacement involving either the Ultima TPS stem or Ultima MOM articulation. 46 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914845 PLT-OO178-00046 1. Wilkinson SJ, Downing M, Ashcroft GP, Gibson PH, Hukins DWL and Reid DM. Bone density changes for 4 total hip prostheses: early DXA results from a randomised trial. Rhetunatolog 2001 40 Suppl: 94 Periprosthetic bone loss at 6 month and 12 months follow-up is more obvious with Chamley and Ultima Straight Stern prostheses, while the Exeter and Ultima TPS stems demonstrate very little overall bone density change. An analysis of individual Gruen zones may show the sites at which remodelling is occurring. 2. Downing MIL Ashcroft GP, Gibson PH, Reid= DM and Hukins DWL. Comparative RSA migration patterns of 4 hip prosthesis: early results of a randomised trial. Rheumatology 2001 40 Supp I: 103 The average observed migration pattern of the TPS was statistically equivalent to the Exeter design. Both types subside rapidly to 6 months, showing signs of retardation by 12 months. In contrast the Charnley and Straight Stem exhibited signi?cantly less total subsidence at both intervals. 3. Downing MR, Ashcroft P, Lawrie D, Hutchison I, Knight D, Ledmgham and Gibson P. JBJS 2004; 86-B Suppl: 71 The average observed migration pattern of the Ulti ma TPS stem was statistically equivalent to the Exeter design in terms of distal migration using RSA at 2 years. 4. Clarke MT, Lee PT, Arora A and Villar RN Levels of metal ions after small- and large- diameter metal-on-rnetal hip arthroplasty. JBJS Serum cobalt and chromium metal ion concentrations for Birmingham Hip Resurfacing components were signi?cantly greater than 28mm Ultima MOM 47 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914846 PLT-OO178-00047 THA implanted with Ultima Straight stems at a median of 16 months follow- up in a matched pair comparison. Jacobs M. Gorab Mattingly D, Trick and Southworth C. Three- to Six-Year Results With the Ultima Metal-on-Metal Hip Articulation for Primary Total Hip Arthroplasty. Arthroplasty 2004; 19 Suppl 2: 48-52 One hundred seventy-one primary total hip arthroplasties were evaluated in a U1 prospective, randomised study. Ninety-?ve involved an Ultima metal?backed cup with an all-metal liner and 76 involved an S-ROM metal-backed polyethylene cup that was used as the control. All were implanted with an S- ROM cementless titanium alloy femoral component with a 28 mm head. The mean follow-up period was 3.7 years (range, 3.0 The average postoperative Harris hip score was 95.4 (range. 65~100) for the metal-om metal group and 96.1 (range: 65?100) for the metal-on-polyethylene group. Radiographic results were not statistically di?erent between the 2 groups. Early results show the metal-on-metal articulation has been successful to date and justify continued clinical use. 6. Shetty NR, Hamer Kerry RM, Stookley I and Wilkinson JM Exeter versus Ultima TPS femoral stem: a randomised early outcomes study. IBIS 2005; 88-B Supp II: 248. The Exeter (Howrnedica Ltd) and Ultima-TPS (DePuy Ltd) implants are both collarless, polished= double-tapered, cemented femoral implants. The Easter is manufactured in stainless steel and has an excellent long-term survivorship. The Ultima TPS is manufactured in cobalt?chrome and has been recently introduced. The aim of this study was to compare the early performance of these implants in a 2-year randomised clinical trial. Patients with uncomplicated primary or secondary osteoarthritis of the hip undergoing unilateral cemented THA were recruited between June 2000 and September 2002. Bone mineral density, stem migration and Oxford Hip score data suggest that the early performance of the two implants studied is similar. However, long-term survivorship data is required to con?rm their equivalency. 48 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914847 PLT-OO178-00048 7. Park Y-S, Moon Y-W, Lim S-l, Yang J-M, Ahn and Choi Y-L. Early osteolysis following second-generation metal-on-metal hip replacement. IBIS 2005; 87-A: 1515-1521 Park reported on a cohort of 169 Ultima MOM Cup with titanium alloy SROM cementless stems in a Korean population at aminimum 2 yr follow-up. Mean age was 56.7 (range 41-68) years. 2 had been revised: 1 for late dislocation and 1 for proximal femoral osteolysis in the greater trochanter. No metallosis or in?ammation was seen at revision. had proximal femoral osteolysis, suggesting a different failure mode. A total of ?ve revisions have been reported to DePuy - none involve abnormal soft tissue reactions. No papers report any similar ?nding to those from the NNUH cohort. Conclusion; Studies on cemented Ultima TPS stems show equivalent performance to the Exeter stem when used with polyethylene acetabular cups. Studies on the Ultima MOM articulation show generally good results. The ?ndings of Jacobs and Park with Ultima MOM articulations on SROM cementless stems are different. Jacobs? was arandomised controlled trial conducted under FDA IDE regulations and the excellent results were reported at 3-6 years. Park?s series was at shorter 2-year follow-up in a Korean population with some osteolysis ?ndings. Finite element analysis FEA testing was carried out as part of the product development to examine the potential loading of the proximal femur by the TPS stern design compared to the Eseter stem. This work was reviewed again and its conclusion that the loading was acceptable was supported. Clinical Users Review - Implant Combinations Reviewed Ultima TPS stern implanted with: Ultima MOM Cup MOM head) 49 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914848 PLT-OO178-00049 - Ultima Cemented PE Cup standard head) PE 0 Duraloc Cementless PE Cup standard head) Ultima MOM Cup implanted with: Ultima TPS Cemented Stem MOM head) CoCr Ultima Cemented Straight Stem MOM head) CoCr - G2 Cemented Stem head) CoCr Cementless Stem MOM head) Interviews were conducted with surgeoris having known cohorts of hip replacements using Ultima MOM articulations. A cohort Of 30 Ultima TPS MOM and 5 SROM Ultirna MOM had one TPS revision for deep infection and one TPS following a periprosthetic fracture out to 5 years. Another cohort of 46 Ultima TPS MOM articulations had no revisions, two patients had negative MRI scans. A cohort of 180 MOM cups implanted with stems in four centres had found only one revision for traumatic cup loosening out to 5.7 years. A prospective consecutive cohort of 81 Ultima MOM cups implanted with cobalt-chrome Ultima Straight Stems with a minimum follow- up of 5 years have no revisions. A cohort of 464 TPS stems implanted with PE cups with a minimum 3 year follow-up reported four stem revisions (one aseptic loosening, one dislocation, two infection and one for cup failure). NO similar abnormal soft tissue problems to NNUH were reported in studies or as product complaints. Corrosion analysis Ann Neville, Professor ofTribology and Surface Engineering and John Fisher, Professor of Mechanical Engineering, Leeds University. Examination Of the recovered prostheses has shown clear corrosion attack on the stem with little evidence of directional attack: which would be common in fretting failures. The hypothesis is therefore that this corrosion is a multi- stage process comprising the following steps: PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914849 PLT-OO178-00050 I Initiation of crevice corrosion at the stem/cement interface. This involves little or no effect of tribological processes at this stage and is initiated by pure electrochemical processes. 0 The difference in potential which then results because of the different materials in the cup, femoral head and shell then drives a galvanic corrosion mechanism which could be accelerated by tribological processes at the stem/cement interface. This hypothesis is supported by preliminary potential measurements made on failed and polished surfaces of the Ultima TPS components. Further work is cit?going. Mechanical fatigue ISO standard fatigue testing was carried out with TPS and Exeter stems potted in PMMA cement. Corrosion was observed with both stems. There were some observed differences in the degree of corrosion between the bone cement types used at NNUH, suggesting that the antibiotic could have a role in the extent of corrosion: Simplex P/plain Palaces R/gentamicin Simplex colistin Source of metal debris Corrosion can be demonstrated in many stem types and materials at retrieval 0 In a sample of 20 TPS retrieved stems, only 3 demonstrated low amounts of surface damage . Metal loss estimations 0.5 5.6 mm3 from the bearing 0.01?10 mm3 from the stem corrosion The evaluation into the source of the metallosis being either the corroded TPS stems or the MOM bearing concluded that this is not a MOM bearing problem. 0 Lee Villar (JBJS 2003 85B: 913-917) data on blood ions from Ultima vs. BHS: lower for Ultima MOM group. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914850 PLT-OO178-00051 - US peer reviewed RCT data out to 6 years of Ultima MOM articulation with S-ROM cementless stems (Jacobs et al. JOA: 2004; 19 Suppl 2: 43.52). 0 Dick cohort out to 9 years with S-ROM and cemented cobalt chrome G2 stems. - Villar cohort out to min-5 years with cemented cobalt chrome Ultima Straight Stem with no revisions. The majority of explanted Ultima TPS stems from NNUH examined show signi?cant levels of corrosion. . Retrieval Uitima MOM heads/liners still within or close to their manufacturing tolerances. - Recent test data on ASE/Pinnacle etc at Leeds do es not indicate invalidity of original; hip simulator testing done in 1996. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. I DEPUY037914851 PLT-OO178-00052 Appendix 5. MHRA Device Alert and DePuy ?Dear Doctor? letter Safeguarding public health MEDICAL DEVICE ALERT Issued: 14 June 2007 at 12:00 Ref: MDN20071054 Immediate action ?i Action I Update Information request Device: Total hip re placement: DePuy Ultimo TPS femoral stem used in Wage 2 combination with Uitima metal-on-metai articulation. Pro bi em: . Unexplained groin pain. a The need for early revision due to pa'iprostheiio soft tissue necrosis. Action by: Orthopaedic surgeons. Action: Refer patients with this implant combination who present with uneXpiained groin pain for scan. This is in line with the parameters recommended by DePuy (see recommendations for patient management under'Actlon? in the appendix). Patients with abnormal signs should be considered for an earty revision. Page 2 Report revisions of metai?on-metai articulations where corrosion andlor periprosthetic soft tissue reaction are observed to the implant manufacturer and the MHRA. Distributed to: NHS trusts in England Chief Executives' Healthcare Commission (CHM) Headquarters Primary care trusts in England Chief Executives *via CE Bulletin bPaga 2 Contacts: Details of manufacturer contacts and MHRA contacts fortechniwl and clinical aspects. Change of address or removal from address list for Heaiihcare Commission. Appendix: bFage4-B Letter from Deng. bPago 2-3 If Action deadlines for the Safety Alon Broadcast System Daadline {notion underway): 17 July 2007 I Deadline [action complete}: 1? August 2007 This notice is also on our website: Madam: ond Hodthcaro oroauots Regulatory Agency Pogo 1 or 6 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914852 PLT-OO178-00053 Issued: 14 June 2007 at 12:00 Ref: MDAIZOOTI054 Device: DePuy Ultin-a TPS femoral stem used ln combination with Ultima metal?on?meial articulation. These components were only sold in combination in the UK. France and Italy. Pro blem: The Ultima TPS femoral stem and Ultin?e metalon-rnetal articulation (femoral head plus metal acetabular cup) is a total hip replacement system that has been on the market in the UK since 1997. The Ultima TPS femoral stem is still available but the Ultimo meial?on-metal femoral head and acetabular cup were discontinued in 2005. Up to April 2007. one UK study has reported 43 revisions (from a cohort of 637 hips) associated with extensive periprosthetlc soft tissue necrosis. Some also involved late dislocation or periprosthetic fracture. The revisions were required one to seven years alter implantation. There have been no other con?rmed reports. When these storm were explanted. extensive corrosion was observed on the surface of many of them within the area of the cement mantle. This level at corrosion of cemented polished cobalt chromium molybdenum stems has not previously been reported in the orthopaedic literature and the explanation for it is unclear. DePuy has already communicated this lntormetlonto UK hospitals that implanted these devices. A copy of their letter, including recommendations for imaging and patient management. is in the appendix. Distribution: Please bring this notice to the attention of all who need to know or be aware of it. This may include distribution by: Trusts to: Healihcare Commission (OHM) to: SABS liaison of?cers for onward disIn?bution to all relevant statt Includng: Headquarters for onward cisln?bulion lo: - Directors of radiology . Hospitals in the hdcpendanl sector I Medical mentors - tndapendonttreahnent centres MR superintendent radographers - Onhopaedlc surgeons . Risk managers Primary care trusts to: SABS liaison moors to: onward olstnoullon to all relevant - Directors at Dubtlc health Contacts: Enquiries to the manufacturer should be addressed to: Mr Paul Amott DePuy international Number One White Rose Of?ce Park Millshaw Park Lane Leeds L511 DEA Tel: 0113 387 7500 Fax: 0113 387 7890 E-mail: Medicines and products Regulatory Agency Page 2 d6 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914853 PLT-OO178-00054 Issued: 14 June 2007 at 12:00 Ref: MDAI20071054 Contacts (continued): Enquiries to the MHRA should quote reference number 200710021001108?li014 and be addressed to: Technical aspects: Clinical aspects: Dr Elsie Danien or Miss Celina Cundy Dr Susanne Ludgate Medicines a. products Regulatory Agency Medicines a. Heailhco re products Regulatory Agency Market Towers Market Towers 1 Nine Elms Lane 1 Nine Elms Lane London SW8 5N0 London SW8 5N0 Tel: 020 7034 3276i 3305 Tel: 020 7084 3123 Fax: 020 7084 3106 Fax: 020 7084 3111 E-mail: elsie.damien@rrhra.gsi.gov.uk E?rnail: celina .cundy@mhra .gsi.gov.uk Change of address or removal from address list for Healthcare Commission: Commission Finsbury Tower 103-105 Bunhiil Row London EC1Y 8TG Tel: 020 7448 0842 Email: How to report adverse incidents incidents relating to medical devices mist be reported tothe Medicines and Heaithcare products Regulatory Aganoy as soon as possible. Further infonnation about reporting incidents; on-line incident reporting facilities; and domloadabie report forms are available from MHRA's website Alternatively: further information and printed incident report forms are available from MHRA Adverse inoidenl Centre Medicines and Healthcare products Regulatory Agency Market Towers, 1 Nine Elms Lane. London SWB 5ND Telephone 020 7084 3080 or Fax 020 7034 31. or email: (An answerphone service operates outside normal office hours) Medical Device Alerts are available in full text on the MHRA website: Further information about SABS can be found at gov MHRA is an executive agency of the Department of Health 6) Crown Copyright 2007 Addressees may take copies for distribution within ti'reircwn organisations Medicines Ind Heallncaro products Regulatory Agency Page 3 01 6 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. U1 U1 DEPUY037914854 PLT-OO178-00055 Appendix to MDA120071054 DePuy. .Mr?rmw-wn DePuy inlemilional Lid Number One Willa Rose Of?ce Panic Milshaw Pail Lane To all surgeons implanting TPS femoral Enqand stem with the Metal-on-Metal articulation T941 ?44 ?131357 7500 Fax: .44 In) so? 7590 February 2007 Dear Dr Ra: TF8 femoral stem and Metal-omMeial articulation Our records indiwte that you or one 0! your colleagues has boon a pontoon: orim above prosthetic combination oi implants and I would ?torsion like to draw your attention to the possible other? performance of this portbuiu combination and action to be taken. Revision Experience UeF'uy is currently aware at a cohort of 637 hips at one centre when-3 80 revisions at 2 - 9 years follow-up have been required for the Uliirna? TPS femoral stem and Uitima? Metal-on-Metal articulation. 21 of these are considered to be 'normal? revisions (6.9. for infection. trauma elm). However. 39 revisions have been associated with extensive peripronlhokson tissue morals. somolimoosevero. This represents a talura rate of 3.3% tor the roviaiona exhibiting no reaction and 6.1% for the revisions with a necrotic reaction. Some dtheso cases with reactions have been associated with late dislocation or pen-prosthetic fradure. A1 retrieval, enemive con'osion has been found on the surface of many oi the polished stems. within the cement mantle. This level of corrosion has not been reported in the orthopaedic literature before with cobalt chromium molybdenum cemented stems? Presentation Patients have presented with the following: - Groin pain I Pain with activity and with flexlon . Pain development irorn intermittent to Constant - Efiuelon on MRI . Time to presentation 6 months several years - Largely normal monographs (position. migration. cementa?on. osteoiysis) Normal in?ammatory markers Action if you have any patients prosmting with groin pain and no obvious oxphnaiion. we recommend that the patient: be refened for an scan of the pert-prosthetic soft tissue using Metallic Ariefacl Reduction Sequences (MARS), The MRI should be Rng'rbrodmu: summarize Land! Let nor, Styled R-gimmi in. 3mm Medicine! and Healthcere products Regdalory?gency Page ii are PROTECTED DOCUMENT- DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914855 PLT-00178-00056 Appendix to with spin achn (no spectral lat and lnvarsinn sequences using the maximal bandwidth and malr'at size that time will allow. mam wit be toast the lraquancy unending direction and the Windham use of phase Ind {aqua-Icy orionmlinn wit optimis- the at the porivptaalhelic soft assoc. Nearly all swiptormtic patients Mveal least one of a number at inch?ng pan-Milli: inflammatory masses. bone marrow oedema. muscle oedema. and mulch atrophy and avutsion. Patients with abnormal signs ?would be considered for on early mvision. since tissue necrosis may progress rapidly. BACKGROUND AND INVESTIGATION The total hip mpiaoamont system was introduced in the UK by Johnson a. Johnwn onhopnedlca in 1937. Implantable onmpanmls in the system incleed the mdulnr lanyard minimal maul-d [amoral stem and the Metal art-Mm The atom 13 I tenured pointed slam made from wrought cobalt molybdenum: alloy. it has been widely hnplanied in the UK. mainly With the umm.? sum-d Cut: and Dunks. cementum Cup to aim a aluminum? excellent Matal-nn-Melal Articulation Tho ULTlliiA" MOM 01p was a mminml coated titanium alloy cam otter she! with a tape: located cobalt chromium molybdenum Bnor designed to articulate with a spoofs Wniahad 28mm admit chromium molybdenum lunoral head. The implant has been discunt?nud tor martial reasons. having been replaced by the Pinnacle? aoetabular cup system. This 28mm MOM heating was designed after extensive hip simulator testing that investigated diametral clearance. surface roughness, sphericity and metal composition. The wear properties of the 23mm MOM bearing in?w?vo were Investigated in an indapandant study by Clarke 9! at?. Serum whall and chromium metal ion Wits tor Hip Ream-lacing components were signi?cantly greator than 23mm at a median at 16 months toltowup in a mum pair comparison. Investigation An extensive Investigation has taliad to establish categorically why the TPS tapered polished shim oama?mas mrmdas in this manner. Cobalt chromium molybdenum alloy is naturally considered to be highly corrosion resistant lit-WW). Users of both femoral and acetabutar implants at other centres have been wntacted. but to dale. no others have observed this problem. clinical performance of the lmm.mummni thnW?kmdh-?a-r-r? . '1:th Hi! ?drumming In! malno- dancinrr?al?mrulnl humustr. ?mam.- El?n". Medicines and products RegulatoryAgency Page 5 of 8 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914856 PLT-OO178-00057 Appendix to MDAIZOOTIO54 TPS stem with marathon-polyethylene articulations is completely normal. Full details at this problem have been shared with MHRA (Devices). Following Iha tnmligatlans and IBHGVEIIB analyst DaPuy believes that the necrosis observed at "vision I: caused by patient: routing to much higher levels of metallic ions than acorn-int in a momma-metal articulation. dariwd prircipally from the canodad surfaces at the stern combined will that gar-termed from normal wear of the MOM bsalinn. Enqulrloo Enquiries Ih? matter should bu ducted lo International Vlguanca Manager In mdancawkh cur post markelh'vg nmmiilanoa activities, DaPuy will continua to manila: tho porfonmnca of those drains and laka any actian new to ensure getienl stately. Yours sincerely liltEL Allan Ritchie MBA. VioeJPresident Research Development Medicines and Healthcar: products RegLIaloryAgency Pug! 6 d6 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914857 PLT-00178-00058