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    DePuy Investigation into Ultima metal-on-metal hips

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    © All Rights Reserved
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    210 views58 pages

    DePuy Investigation Into Ultima Metal-On-Metal Hips

    Uploaded by

    Lisa Bartley
    DePuy Investigation into Ultima metal-on-metal hips

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    © All Rights Reserved
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    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. DEPUY037914800 PLT-00178-00001 Executive summary ens . anmeme 8 History son ses save cence sere Orthopaedic Subcommittee, Research Governance Committee 9 Summary of Meetings ss sssos sr seoneeene sn 10 Recommendations of the Orthopaedic Department July 2008, eel Gli Pole reer ree ee ee eee eee verre or 2A Results - — 24 Comments Conctusions References Appendices 2 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER, DEPUyo37914801 PLT-00178-00002 Executive Summary Introduction ‘The need for longer lasting join 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 fixation 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 (e.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 visible on plain sradually destroys the bone surrounding the implant overtime, “Xray and is described as showing “loosening” Since the 1990s the use of metal-on-mata bearings has been revisited with the advent of better design and improved control of manufacturing of the implants, The ‘Norfolk PCTs requested thatthe Orthopaedic Department at the NUH introduce the Birmingham MoM resurfacing in response to patient demand. However not all younger patients are suitable for @ 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 anew MoM beating linked to an established fernoral stem and cup design was trialled {following ethical and MHRA approval and after obtaining the relevant CE (Conformité Européene) marking was introduced and followed-up in a postmarket clinical follow-up study. Initial results were excellent with many patients reporting their hips es feeling “normal”, However overtime it became apparent that a number of patients were experiencing pain in the presence of normal pain Xrays, and a few of them were subsequently admitted as emergencies with either a fracture around the femoral stem, or ahip distocation. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DePUYOs7914802 PLT-00178-00003 ‘As some of the patients were part ofa research study this was reported (0 the Research Governance and Ethies Committees as a serious adverse event. The RGC asked for a subcommittee to investigate the problem, This began in March 2004 with the recommendation fo 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 implant’s use was discontinued, Methods All patients who had undergone the procedure, both NHS and private, were identified 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 1" August 2004, $45 patients underwent 652 hip arthroplasties, of these 434 hips (67%) were undertaken at the NNUH, the ret 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 (20%) were bilateral. A further 75 (13%) had a non-MoM THR on the contralateral side. The average age was 57 years with a range of 15 to 81 years Up to 31st 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 affected in 50, let in 32, and both hips in four, ‘The average BMI was 29.5 (range 21 t0 42.5), ‘The findings were 1, The failure rate has been 16% at 5 years (5% would be inline with current NICE ‘puidance, but 1% to 2% isthe norm at NNUH). 2. From the total cohort 100 hips have now been revised (up to "July 2008) 3. A-small number of revisions have been for ‘normal’ causes e infection, early dislocation ete 4, Extensive corrosion of the femoral stem wes found in almost all cases, PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914803, PLT-00178-00004 5, The metal ions released have killed the bone and soft tissues around the hip replacement resulting in: ‘Fluid collection often under high pressure causing pain , Tendon rupture causing hip dislocation Bone death resulting in fractures around the implant 6. There is no evidence tha the faifure has been due to poor surgical technique, in fact, the contrary isthe 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 B 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 tothe 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 idiosyncratic immune response which lowers the pH of the fluid bathing the prosthesis. Conclusions ‘The problems found with the Ultima TPS Metal-on-Metal hip replacement are ‘unusual and have not been found before. No cases have been reported to DePuy 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 forthe corrosion is unknown, therefore unforeseeable, but is being investigated, MRI scanning reveals the tissue changes in patients who have normal Xrays. Some patients without symptoms have these changes apparent on MAI scanning. These problems do nol appear to be related tothe Ultima metal-on- metal bearing itself Key recommendations PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY9S7914804 PLT-00178-00005 |. All patients should be recommended to undergo an MRE sean, 2. This should be undertaken annually for 3 years and then re-assessed about \whether to continue with further scans. 3. For patients who are asymptomatic but have positive MRI seans an ently revision procedure is recommended because: 1. The revision is easier to perform and can include cementing within ‘cement; this being similar physiologically toa primary THR b. 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 more compromised as more tissue is removed. ‘Particularly in men there is a small but increasing risk of periprosthetic fracture with time, 4. ‘Those patients who are asymaptomatic with an abnormal MRI sean, but not showing typical changes of MoM failure should have the sean repeated 6 months tater. 5. The patients will be recalled to dedicated clinics, see their clinician, receive the Patient Information Leaflet and discuss their personal management plan, 6. 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, DEPUY037914805 PLT-00178-00006 History Hip replacement was pioneered in Norwich by Ken MeKee inthe 1950s, 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 motal, This meta-on-metal (MoM) joint replacement had a high failure rate due to the design of the implant fixation surfaces and poor quality control over head and cup tolerances due to machining capability at that time. However many patents 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 ofa 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 bip arthroplasty. Ken MeKee introduced a polyethylene coup, this combination was known as the McKee-Arden, Modifications to the femoral ‘component lead to the McKee-Farra hip replacement, which was used throughout the world. In the 1980s and 1990s it became clear thatthe 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 sttceess of hip replacement in reducing the pain and disability experienced inthe tritc 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 ofall males and a third ofall female patients with rmetal-polyethylene hip replacements had required revision. In these circumstances there isa 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 number of companies have been re-visiting MoM bearings. Locally the Birmingham hip resurfacing prosthesis was introduced to the Norfolk & Norwich at the request ofthe Primary Care Truss in response to patient demand. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914806 PLT-00178-00007 ‘There has been along association of innovation and research between the Department of Trauma & Orthopaedics atthe Norfol:& Nonvich University Hospital Foundation Trast and DePuy Intervational Ltd, Leeds, UK (as Johnson & Johnson Orthopaedics Lid, prior fo 1998). Modem hip prostheses are modular with the replacement made up by the surgeon from a number of parts, thus allowing variations forthe 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 take part in a swidy 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 Ageney regulatory approval and was successflly completed resulting inthe implant obtaining the relevant CE (Conformité Buropéene) marking, Patients were then recruited as part of a post-market clinical follow-up study. ‘Tho prosthesis was used routinely from this time tll 2004, initially for ‘younger patients only. By the beginning of 2004 there had been 12 revisions, some ‘ith 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 ereated to look into the problem and try and find the cause of the fares. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914807 PLT-00178-00008 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 Jolin Nolan, Orthopaedic Surgeon NNUH Hugh Phillips (deceased) Orthopaedic Surgeon NNUH Clare Darrah, Research Manager, Insitute of Orthopaedics NUH ‘Andoni Toms, Radiologist NNUH ‘Tom Marshall, Radiologist NNUH John Cahir, Radiologist NNUH ‘Tim Barker, Histopathologist NNUHL Tan Clark, Professor of Biology UEA ‘Caren Peters, Research Immunologist 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 Brummit, Principal Bioengineer, DePuy Intemational PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER, DEPUY037914808 PLT-00178-00009 ‘Summary of Meetings of the Orthopaedic Subcommittee ‘March 2004 ‘The Subcommittee first met in 31% March 2004. At that meeting 20 patients were presented and their history, radiological and pathological findings discussed. OF these | had been revised and the other si likely to be revised. Three were straightforward revisions and did not eause concer, However seven patients had a sof 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 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 infection and reaction, The nature ofthe soft tissue reaction was discussed, includin metal ions, butno conclusion was able to be drawn. Te wos stressed thatthe mijorty of patients had excellent clinical and radiological results, beter than expected. It was also noted that th revision rate was ‘well within NICE guidelines, 1t was resolved that: +The company would Check the lot numbers of the revision patients to exclude ‘mamufactoring problem in a batch of implants. Check the finite element analysis fo exclude excessive medial oading € Report the problem to the Medicines and Healthcare products Regulatory Agency (MHRA). 4 Fund further analysis ofthe explants and soft tissue eCheck whether other users have had a similar problem, + Tho investigating team would: Send implants and soft tissue to Prof Gordon Blunn atthe Reyal Notional Orthopaedic Hospital for independent analysis. Pationt consent will need to be obtained b. _Infuture take blood samples, and keep soft tissue and explants on all sevision patents ©. Send the serum metal levels o Mike Clarkin New York State for opinion. 4. Gethistology reviewed by histopathologist in Adelaide. 10 PROTECTED DOCUNENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYa37914809, PLT-00178-00010 © 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 patents until the analyses have been performed and the problem identified August 2004 By August 200¢ it became clear that there was a significant problem at NUH. bbutnot elsewhere and that the numberof revisions was increasing, It was advised that no farther implantations should be performed. MHRA had been informed, December 2004 On the 2™ December 2004 the hypothesis was that there was an increase in torsional instability ofthe femoral stem lending to wear and severe stem corrosion within the coment mantle, The resultant metal ions then killed the adjacent bone and soft tissues, which may lead to femoral fracture, 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 i 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 nether the Exeter stem, which is ‘a almost identical prosthesis of stainless steel, nor the CPT prosthesis, whichis nother almost dential ster made from cobalt-chrome have not had this problem of carly 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 sereening process of 20 asymptomatic at-risk group patients who matched the charaeteristes of the abnormal patients using the new MRI metallic artefact reduction sequences, (MARS) pioneered at the NNUH radiology department, which it would fund, ‘+ The attisk group appeared to be large size males with thick femoral cortices, ‘with large stems and high offsets. u PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER, DEPUYO37914810 PLT-00178-00011 © The Company agreed to fund all MRI scans for symptomatic patients: anterior groin pain with difficulty straight-leg raising and pain on leaning forwards. or signs of loosening atthe calear on Xray. ‘© Itwas agreed to supply the data on heads, stem sizes and offsets of the whole cohort to the company, ‘+ That the Company contact Prof Gordon Blum for his thoughts, and to send all the explants to Dr Alison Davenport in Birmingham (independent corrosion expert) for an opinion. + The Company are performing mechanical fatigue tests on the stems to try to re-create the corrosion seen clinically inthe laboratory May 2008 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 MoM ehrome-cobalt, but not Cr.Co-HDP ot Ti-HDP systems, The synovium showed a marked three-layer response with exuberant fibrin production, plasma cells and large perivascular accumulations known as ALVAL (aseptic lymphocytic, vasculitis and associated lesions), This was in contrast to the macrophage response to HDP. The hypothesis was that Cr.Co particles were toxic to the synovium which ‘when damaged allowed an influx of the metal, This provoked a strong immunological reaction, The altered blood flow 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 idiosyncratic immune response to the metal particles, or due tothe implant? AA 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 PROTECTIVE ORDER. DEPUY037914811 PLT-00178-00012 ‘A presentation on the clinical and operative findings was given and showed these fitted in well with Dr Case's model, ‘The radiologists presented the 13 patients that had been reviewed by MRI of ‘hich six were from the DePuy-funded cohort, They described the evolution of their investigation. Their results also fited 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 jon levels than the Birmingham resurfacing hip hhad been reported in an independent clinical study. Other clinical studies on the same becring, but with a different femoral stem, out to the same follow-up had seen no similar problems, Examination of explants failed to show significant wear conforming the results of low wear in previous hip simulator studies, The corrosion noted was an exaggeration of atypical reaction. It was explained thatthe 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 inthe revised patients. Expert opinion from Dr Alison Davenport had suggested thatthe presence of an antibiotic in the cement could enhance corrosion, ‘The carbon content of the metal was also excluded as the source ofthe problem because this has been thoroughly investigated in hip simulator studies during product development, twas 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 heer Prof Blunn’s report before making final decision. + Accohort of asymptomatic patients with five control patients with the Exeter metal-on-plastic implant should undergo MRI to elucidate urther the findings on the scan. 1. was noted that there were no controls at the eurrent 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. + All treated patients would undergo yearly review PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914812 PLT-00178-00013 + Two patients identified with sensitivity to jewellery would be reviewed and further studies considered as cross-sensitivity between nickel and cobalt is known, + The company confirmed that there was indemnity for harm suffered by the patients enrolled in the initial clinical investigation in accordance ‘with ABHT guidance and would inform us of the details (subsequently provided), +The company agreed that the MRI findings could be reported to a radiology journal, and appreciated getting sight of t before ‘presentation for publication, + ‘The company were pleased that Dr Case felt that if there was an sbnormal immune response occurring in some cases then this could be treated by medical means. ‘March 2006 ‘A review of the investigations by DePuy showed thatthe finite element analysis had ‘been undertaken and did not show anything relevant, An interim report onthe fatigne testing (Exeter and TPS stems) was able to reproduce crevice corrosion but did not indicate any significant difference between stem typess. A final report was awaited Further testing was being developed by Leigh Brown of Huddersfield University. The DePuy MoM surface replacement (ASR) should undergo metallurgy testing to compare with this MoM bearing, Information had been supplied to MHRA which ‘vas 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 confismed that their discussions with surgeons had informed them about the specifi problems, but other centres had not reviewed patients in clinic, DePuy agreed to inform other TPS stem/PE cup users of the NUH experience. PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER, DEPUY037914813 PLT-00178-00014 ‘Regarding fulure funding of MRI for symplomalic patents; 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. Iwas suggested that clinical, radiological, and pathological scoring systems should be developed to corelate findings. 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 fluid. 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 comosion of approximately Imm. 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 UK), however relatively few hhad been used with cement (except in the USA). Tt was agreed that other tapered Polished stems were not showing any signs of problems. A patient with the TS stem ‘and a polyethylene cup had presented with large amounts of fluid around the hip on ‘MRI, but with mild symptoms who was going (o be rescanned patient in 3 months All other TPS and polyethylene cup patients were to be reviewed (approx 40 patients). Another patient ad 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 stem corrosion, but there was worry the amount of dead tissue and the possible toxicity effect of metal ions. A corrosion expert would investigate the eause of the problems since chromium 6 is known to be toxic and cause cell death. A discussion on how to investigate way this problem seemed unique to this region was undertaken with the suggestion that we needed to look in depth a the medical history, immunology. social history etc. June 2006 1s PROTECTED DOCUMENT, DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYos7a14814 PLT-00178-00015 A presenlalion of the histological findings showed 15 positive resulls and the rest had necrotic tissue. The principle findings were an acute lymphocytic vasculitis with varying levels of lymphoid tissue some in very large chumps with a vascular layer present in some, and an ulcerated synovial surface, This suggested a hypersensilivity- type immune reaction, Various histological findings were correlated withthe clinical and radiological findings, It was recommended that they should be a scoring system ofthe clinical findings and a scoring system of the radiological findings to correlate with the histological findings, DePuy reported that the analysis of the corroded femoral stems by Leigh Brown at Huddersfield 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 foreach patient ‘The MHRA 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 symptoms of pain although there had been one petiprosthetic fracture, Other sites needed to collet soft tissue samples, synovial fluid 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 eatly presentation of something that may oceur later in ‘other patients. The protocol for this work was to be done on this to include samples fom a control population ‘A paper on the MRI technique had undergone revision atthe request of the Journal, Some final information on histology was awaited Further work was proposed 1. Histology samples. All histology samples from the patients to be sent to Bristol All future revised patients should have synovial fuid aspirated to check for metal ions which could be analysed at Harwell 16 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER, DEPUYO37914815 PLT-00178-00016 '. Explants: photographs and explants to be sent to DePuy with intra- ‘operative photographs ‘© Asymptomatic controls for MRI: As many as possible need to be bilateral replacements, Protocol for lssue 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 waitten for analysis ofthese samples September 2006 ‘An update ofthe investigations was presented DePuy ‘+ Aninterim report from 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 significance of the offset design, and access to more data + DePuy had arranged a meeting with the MRHA 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 stratification inthe sampling and the question was ‘whether this stratification 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 significance of this was not certain at this stage. It was noted that hypoxia is known to destroy P fibres which maybe why patients maybe symptomless as well as having the changes. It was suggested that histological analysis looking for bypoxia 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, BMI W PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER, DEPUYO37914816, PLT-00178-00017 presentation with pain. dislocation, fracture or nerve palsy or positive Trendelenberg gait t was noted thatthe time to symptoms 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, toothpaste-like, or necrotic the volume of tissue and which soft tissues had been affected e.g. abductor tendons, extemal rotators, nd 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 infeetion present or possibly present or not present at that ‘operation. Intraoperative photographs would be useful + The asymptomatic MRI scans could now be undertaken, asthe protocol had passed Ethics and Research Governance Committee approval Its was important to have Metal-on-Metal patients with no symptoms and no loosening and Metal-on-Plastic patients with similar age characteristics and linked implant times + Itwas suggested that those surgeons at the Norfolk and Norwich University ‘Hospital who were using the DePuy ASR prosthesis (a MoM 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 distocation, 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 findings, and a further Birmingham hip had an MRI scan suggesting the same problem. Asymptomatic patients were being recruited for screening MRI. 18 PROTECTED DOCUNENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914817 PLT-00178-00018 DePuy were continuing to fund the Bristol investigations. They suggested that Professor Joshua Jacobs of Rush University, Chicago, a renowned corrosion expert should look at the data. Details ofthis proposal were requested. There was concem about the confidentiality of any data, ‘A detailed presentation had been given to the MHRA in November 2006 ‘where DePuy informed them that al surgeons implanting the Ultima TPS MoM ‘would be receiving a letter from DePuy suggesting 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 MoM bearing showed no difference in wear rates according to carbon content. After discussion it was suggested thet lowering the pH would cause corrosion, and therefore patients should have this mensured in vivo with a pH probe, It was suggested that destructive testing should be performed on some of the implants to look at wearin greater deta Bristol reported thot all their samples had been reviewed. There were 27 viable samples with 16 matched to Huddersfield wear scores. Immunochemistry had been performed on 14 samples of which 10 showed a weak correlation between inflammatory infiltrate and wear scores. Synovial fluid analysis was needed looking at cytokine profiling, metabolites and metal analyses for particle size and type, and protein-bound ions, In some patients there appeared to be a B cell-mediated response, ‘with an inverse correlation to time to revision, Further work with CD8 and CDS tests to check on T cell numbers would be undertaken. Discussion about whether Harwell ‘ora laboratory in Germany should be used for measuring metal levels occurred Future proposed projects were: ‘+ Polymorphisms looking at 60 symptomatic and 60 asymptomatic patients. ‘© Discuss with Prof Jonathan Powell from the Human Nutrition Unit in Cambridge about his possible input into the project ‘© Meet with the Oxford surgeons to discuss their group of resurfacing patients ‘with pseudotumour, PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPLYO37914818, PLT-00178-00019 Te 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 difficult inthe eurrent climate over autopsies Create a PhD studentship with the School of Biology UEA to look at the basic science of the problem, Prof Tim Burstein, a corrosion expert in Cambridge was to look at aster, The early findings would be presented at the British Hip Society meeting in March 2007. The radiology paper was with Skeletal Radiology. Mareh 2007 From the NNUH: DePuy ‘A meeting had occurred with Jonathan Powell in Cambridge. His laboratory has equipment for measuring metal ions. He suggested NMR of synovial fluid ‘The Action Arthritis PRD studentship was progressing. ‘The presentation atthe British Hip Society was well received. Two surgeons contacted the group to say that they had seen similar clinical symptoms in sunrevised patients Asyiptomadie patients had been found with MRI evidence of the problem. It vwas suggested that they should have further scans 6 months and at 1 year to ‘monitor progression A stainless stel stem had been revised with a loose component. There hal ‘been osteolysis but no soft tissue response. The stem would be examined for corrosion, Since there was NUH concer 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 a mixed picture, Some had perivascular lymphocytic infiltration 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-00178-00020 1 was important lo Took at the circulating metal ion blood levels as cel suicide ‘would lead to lower levels. Xrays need to be reviewed to look at pattems of arthritis before the primary hip replacement June 2007 DePuy TPS Corrosion Investigation at University of Leeds PROTECTED DOCUMENT. Prof Ann Neville presented a report of her preliminary findings, ‘The collection of explanted TPS stems received by DePuy had been visually inspected. ‘The assessment of the extent of damage by Leigh Brown al Huddersfield University seems in accordance with what was observed in this analysis ‘The extensively corroded TPS stem ref 06/526 explanted ftom Patient 1D 6685094 (DA) was sectioned following the approval for destructive testing sven atthe meeting held 30th March 2007. ‘The corrosion mechanism appears clear with litle 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/nead/linerishell) had been taken and indicated a possible mechanism ‘© Initiation of crevice corrosion on stem due to interface with the cement ‘mantle (polymer versus metal crevice) ‘©. Potential ofthe stem decreases (active direction) - confirmed by potential measurements (©. The driving force for galvanic corrosion is then inereased if the head and the shell are not corroding (>300mV) ©. Freting action will further move the potential inthe “active” direction Further testing programme to be discussed with DePuy PC questioned what valency the released Cr ions would have in this system citing a paper by Shuttleworth & Bundy in Biomaterials. JN indicated that he held a collection of explanted Exeter, Charnley and CPT stems which all showed evidence of corrosion, some to a similar extent to that 2 DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUY037914820, PLT-00178-00021 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, ‘+ Request for explanted TPS stems from centres using metal-on-polyethylene articulations to be made, Tt 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 confirmed to be stainless stool and not CoCr. ‘Synovial Fluid Analysis * Metal ion level testing was still to be arranged. * PC pointed out that it was imperative thatthe cytokine analysis was carried out from the materil obtained atthe first defrost. Polymorphism Study — Bristol University All agreed that the study was important + Funding from DePuy and an agreement with Bristol University was in place, + Bristol University need confirmation of ethical and research approval before DePuy's agreement can be signed by them. + N&N to submit ethics committe application for contro bloods to be taken Bristot Immunology Study ‘+ Caren Peters to prepare and circulate her manuscript in liew ofa final report before commencing her maternity leave MHRA Medical Device Alert ‘+ No new reports following release of DePuy’s “Dear Doctor” letter in February 2007. ‘+ MHRA had issued a Medical Device Alert on the TP/MOM combination on 14° June 2007, MHRA had taken 2 decision to issue a Medical Device Alert Within two weeks of having received DePuy’s “Dear Doctor” letter, but had 2 PROTECTED DOCUMENT. DOCUMENT SUBJECT TO PROTECTIVE ORDER. DEPUYO37914821 PLT-00178-00022 been unable (o implement il due to staf illness and resource issues. The MDA 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 notin the light of any new data, April 2008 ‘The group consolidated the findings of the project, The Radiology paper showing how {o.use MRI to define 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 T-lymphocytes that had not been reported before. ‘The clinical paper was almost complete with the conctusion that patients with the implant shonld 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 wns noted that the PRD studentship was funded, end that the details had been defined. It was to be advertised shortly with a start date at the end ofthe year. It was concluded thatthe research subcommittee should be disbanded as it had ‘completed the patient review and a management plan was now possible. It was resolved to give a report to the Research Governance Committee and also to the Onthopaedie Department at Clinical Governance. Further ongoing studies would continue as this was an important exercise. 23 PROTECTED DOCUMENT, DOCUMENT SUBJECT TO PROTECTIVE ORDER. DePUYo37914822 PLT-00178-00023 ‘Recommendations of the Orthopaedic Department July 2008 All patients should be recommended to undergo an MRI sca. 2. This should be undertaken for 3 years and then re-assessed about whether fo eontine swith father scans 3. Forpatients who are asymptomatic but have positive MRI scans an early revision procedure is recommended because: ‘+ The revisions easier and can include cementing within cement, this being similar physiologically toa primary THR ‘+The amount of tissue death increases with time, At revision as much dead tissue as possible should be excised, The results ofthe revision become increasingly compromised as more tissue is removed, + Inmen there i a small but increasing risk of perirosthetic fracture with time, 4. Those patients who are asymptomatic with an abnormal MRI sean, but nt showing typical changes of MoM failure should have the scan repeated 6 months later. 5, The treating clinicians need to inform the patents in person. 6 Wis reasonable on clinical grounds for the pationts fo wait until their nest annual

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