Professor Rob G.H.H. Nelissen, Chairman of the Orthopaedics Department at Leiden University Medical Center, explains why clinical evidence is both an asset for patients and an ally for surgeons.
Curiosity is a major driver for innovation, with the aim to improve patient care. Total hip replacement was called ‘the operation of the [20th] century’.1 Some state no real innovation has happened in orthopaedics since then, blaming increased bureaucracy, while others are still curious about how to improve patient outcome.
Considering arthroplasty surgery, two of the major problems are mechanical loosening and the infection of implants. Both have an enormous impact on the patient’s quality of life and can even be life threatening if performed inadequately. Innovations in arthroplasty surgery are generally technological driven, from computer- and robot-assisted surgery to newer implants, although with less optimistic outcome for patients than intended.8, 13 The central issue for any new medical innovation should be a positive balance between the risks and the benefits for patients resulting from that innovation. Therefore, a rigorous phased introduction of innovation is needed. This is evident in some examples, including the percutaneous refixation of loosened implants with gene therapy2 and the induction heating of infected implants3, but not in all. This is despite the fact that innovative methods to ‘guarantee’ safety for patients receiving orthopaedic implants such as hips, knees, and shoulders etc. are readily available.12
Recently, innovation has come to focus on big data, such as real-world data from implant registries, to improve outcomes by benchmarking hospital performance.4 Healthcare evaluation research is low-hanging fruit’ which can have a huge effect on patient outcomes, and is also very cost-effective, thus lowering societal burden. Furthermore, results from such research can be easily implemented by regional or national groups of surgeons. In essence, it goes back to the idea of ‘no innovation without evaluation’ as developed by the IDEAL consortium,5 which stresses the aim of real innovation: improving patient care, which goes hand-in-hand with patient safety. Although this is always the intention, innovations may, however, also have an opposite, harmful effect on patients.
Using data from registries
Active and ageing populations are expected to have a tremendous impact on the number of hip and knee arthroplasties to be performed in the near future as many members of this population are likely to experience an orthopaedic problem. With regards to joint replacing implants, like hip, knee, and shoulder, some four million operations are performed on an annual basis.
Which medical device to use for which patient and, indeed, which medical device is requested in some countries is based on the personal preferences of surgeons and the availability of orthopaedic vendors. Evidence-based clinical practice seems to be an example of hyped-up terminology that has been around for decades but, in the end, value added healthcare to the patient, or an implant lasting a life time, should be the goal of an orthopaedic surgical intervention. Evidence should not only be based on a single centre study if real world data from (complete) regional or national arthroplasty registers are available. For the surgeon, this data can help to differentiate the best performing implants from those which are more mediocre. However, the data should be interpreted with care by orthopaedic surgeons who have a working knowledge of the methodology of data analysis (e.g. confounders, bias, risk adjustment, and case mix corrections).
Although data from joint implant registries are only available from some large registries like the NJR (UK, Wales, North Ireland, Isle of Man) , AOANJRR (Australia), LROI (Netherlands), and NARA (Scandinavian countries), to mention the largest four, several smaller regional registries are also present in Europe.11 In recent years, Germany has started a registry which now has 70% coverage, while the US registry is small and has a capture rate of 29%.
The value of implant registries has been shown by detecting the high revision rate of metal-on-metal (MoM) hip articulation implants, first detected in 2010, which is perhaps the most well-known worldwide disaster in orthopaedics.6,15 This was detected from a single national registry – the Australian Orthopaedic Association National Joint Replacement Registry. Soon thereafter, it was picked up by several other national registries worldwide, showing similar outcomes with this type of hip replacement. This information ultimately resulted in the withdrawal from the market of certain MoM total hip implants, but only after hundreds of thousands of patients had received them over the course of the previous several years.
An evidence based approach for the introduction of new implants as proposed for decades by several authors8, 10, 12, 13 and a classification on the performance of implants would have prevented such a disaster (as long as surgeons had adhered to the principles of evidence-based clinical practice).5
When it comes to a benchmark for implants, the Orthopaedic Data Evaluation Panel (ODEP) is used worldwide. Such a benchmarking system helps guide, not dictate, a surgeon’s choice for an implant with the most optimal outcome for their patients. Preferably, implants with the highest benchmark classification (i.e. 95% survival at 10 years) should be based on data from at least two national registers. Thus, registers can be used to guide orthopaedic surgeons in their choice of an implant for a specific patient, based on real-world data from a high validity registry.9, 17
Regulations
In May 2021 (with a transition phase of some years), the EU will implement the new medical device regulations (MDR) on medical implants and in vitro diagnostics with the aim of safeguarding patient safety by showing clinical evidence.7 The previous lack of adequate regulation by both the former EU Directive and FDA regulation is thus being repaired for the benefit of patient safety (and efficacy of the medical device).
In the past, this lack of evidence has led to the widespread use of potentially unsafe TKA and THA (e.g. metal on metal hip implants), with failure rates two to ten times the standard of national joint registries.6,9,13,15 Taking the above into consideration, the selection of any new implant including new surgical techniques should be clinically evaluated and any claims clinically proven. The latter is in accordance with the IDEAL consortium adagium: no surgical innovation without evaluation. The following stages for a safe and effective introduction of a new implant or surgical technique are: Idea, Development, Exploration, Assessment, Long-term follow-up (IDEAL).5, 17
A phased, evidence-based introduction of orthopaedic implants has been advocated for several decades now8, 10, 12, 13 and has indeed been picked-up, but slowly. The huge Asian market will profit from lower revision rates (i.e. 10% revision at five years, or 5% at five years) and this will have a huge impact on not only patients’ quality of life, but also on the associated social economic burden. This phased introduction of new implants has been pushed by some major adverse events, such as that concerning metal-on-metal hip implants, which had high revision rates and long-term adverse events.15
Modes of implant failure
A phased evidence-based introduction of new implants can identify three modes of implant failure:
- Expected, early detected failures;
- Expected, late detected failures; and
- Unexpected failures.
Expected, early detected failure modes are discovered in a pre-market setting (e.g. the fatigue of metal or liner wear). Expected, late detected failures are discovered in a post-market setting (e.g. the excessive early migration of the implant). Unexpected failure modes can be present in both the early pre-market and late post-market phase, depending on the type of failure mode (e.g. the excessive migration of the implant, or in terms of the biological response, such as the pseudotumours of metal-on-metal implants) and material breakdown (e.g. modular femoral neck fractures).
In general, the longer the pre-market phase lasts, the higher the likelihood of finding unexpected failures. Although evident failure modes will be detected in large patient groups after several years of implantation, the goal of any new implant should be to prevent adverse events before mass introduction in the market. Such an early detection modality of early, late, and unexpected failures can be achieved by evaluating the real-world data of daily practice from high quality regional or national implant registries. These registries should have a completeness of both primary and revision surgery of at least 90% and preferably over 95% to prevent selection bias.17 Even more, the presence of unexpected failures, which are usually rare (e.g. periprosthetic fractures), stress not only the importance of the high completeness of these data, but also the importance of collaboration between these national registries, as advocated by NARA (Nordic Arthroplasty Registers), NORE (Network Orthopaedic Registries of Europe, an EFORT committee11) and ISAR (International Society Arthroplasty Registries).
Despite the value of registries in a phased evidence-based introduction of new implants, the detection of failures will usually be present at mid-term or even later follow-up after exposure to tens of thousands of patients. An early detection of a possible long-term implant failure would not only protect thousands of patients from high loosening rates at 10 years, but would also help the industry in designing better implants (i.e. with less micromotion in the bone). Surrogate markers during the first post-operative year, which are predictive for long-term implant survival at 10 years, include implant micromotion measurements in 3D, such as RSA.12, 14, 18, 19, 20 This implant micromotion technique can bridge the gap between an evidence-based introduction of new implants and early high-quality outcomes. Furthermore, since measurements are accurate in up to 0.1mm and 0.1 dgr, only 50-60 patients are exposed to a new implant in a high-quality study comparing the new implant with the old. Implant micromotion measurements like RSA are validated surrogate markers for long-term THA and TKA outcome.12,14,18,19,20 The effect on society if RSA-tested TKA are used gives an estimated 22% to 35% reduction in revision for any reason compared to non-RSA-tested TKA in several national joint registries.12
Unexpected failures also require vigilance from surgeons not only interpreting data from national joint registries and micromotion studies, but also discussing and evaluating instrumentation, surgical techniques, and adverse events of the first cases with surgical users. While finding proof of superior effectiveness has become more challenging now than in the past, more surgeons have begun to adopt a more scientific strategy – based on clinical evidence – when selecting an implant. This imposes pressure on these first user surgeons to evaluate and analyse the results of the surgical intervention and patient outcomes in reference to the new product in a rigorous way. Such a system of surgeon-user panel evaluation (i.e. Beyond Compliance), where surgeons discuss their data and experiences with the new implant and instrumentation, improves outcome for patients but also product innovation.
A Toolbox Orthopaedic Implants
A phased evidence-based introduction of new implants that examines every possible mode of expected and unexpected failure will be a challenge. A Toolbox Orthopaedic Implants (TOI) could be used both for existing and new implants:
- Existing implants: an excellent implant has a mean 95% survival at 10 years based on data from at least two registries; and
- New implants: implant micromotion studies, Beyond Compliance, patient (reported) outcome measures.
A curious but critical appraisal of clinical evidence is a must, not only for patient safety, but also to develop innovative medical devices which show real improvements.6,13,16 This seems logical, since physicians have intended to improve patients’ quality of life for thousands of years, and yet sometimes the primum non nocere turns into a nocebo effect, which should be minimised for an optimal patient outcome. Innovation and evidence are not conflicting objectives, but no medical innovation should be made without clinical evidence in order to safeguard optimal outcomes for patients.
References
1 Learmonth ID. ‘The operation of the century: total hip replacement’. Lancet 2007; 370: 1508-19
2 Poorter JJ, Hoeben RC, Obermann TW, Huizinga TW, Nelissen RGHH. ‘Genetherapy for the treatment of hip prosthesis loosening: adverse events in a phase 1 clinical trial’. Hum. Gene Ther. 2008; 18;10: 1029-1038
3 Pijls BG, Sanders IMJG, Kuijper EJ, Nelissen RGHH. ‘Segmental induction heating of orthopaedic metal implants;’. Bone Joint Res. 2018 Dec 1; 7(11): 609-619. doi: 10.1302/2046-3758.711.BJR-2018-0080.R1. eCollection 2018 Nov
4 Schie van P, Steenbergen van L, Bodegom-Vos van L, Nelissen RGHH , Marang-van de Mheen PJ. ‘Between-Hospital Variation in Revision Rates After Total Hip and Knee Arthroplasty in the Netherlands: Directing Quality-Improvement Initiatives’. J Bone Joint Surg Am. 2020 Feb 19;102(4):315-324. doi: 10.2106/JBJS.19.00312
5 Barkun JS, Aronson JK, Feldman LS, et al, Vandenbroucke J. ‘Evaluation and stages of surgical innovations’. Lancet. 2009 Sep 26;374(9695):1089-96. doi: 10.1016/S0140-6736(09)61083-7
6 Ferguson RJ, Palmer AJ, Taylor A, Porter ML, Malchau H, Glyn-Jones S. ‘Hip replacement’. Lancet. 2018 Nov 3;392(10158):1662-1671. doi: 10.1016/S0140-6736(18)31777-X. Review
7 Fraser AG, Butchart EG, Szyman´ski P, Caiani EG, Crosby S, Kearney P, Van de Werf F. ‘The need for transparency of clinical evidence for medical devices in Europe’. Lancet. 2018 Aug 11;392(10146):521-530. doi: 10.1016/S0140-6736(18)31270-4. Epub 2018 Jul 17
8 Huiskes R. ‘Failed innovation in total hip replacement diagnosis and proposals for a cure’. Acta Orthop Scand 1993; 64 (6) 699-716
9 Keurentjes JC, Pijls BG, Van Tol FR, Mentink JF, Mes SD, Schoones JW, Fiocco M, Sedrakyan A, Nelissen RG. ‘Which implant should we use for primary total hip replacement? A systematic review and meta-analysis’. J Bone Joint Surg Am. 2014 Dec 17;96 Suppl 1:79-97. doi: 10.2106/JBJS.N.00397. Review
10 Malchau H. ‘On the importance of stepwise introduction of new hip implant technology’. Thesis. Göteborg University, Göteborg, Sweden; 1995
11 NORE. Network Orthopaedic Registries of Europe. www.EFORT.org/NORE
12 Nelissen RG, Pijls BG, Kärrholm J, Malchau H, Nieuwenhuijse MJ, Valstar ER. ‘RSA and registries: the quest for phased introduction of new implants’. J Bone Joint Surg Am. 2011 Dec 21;93 Suppl 3:62-5.
13 Nieuwenhuijse MJ, Nelissen RG, Schoones JW, Sedrakyan A. ‘Appraisal of evidence base for introduction of new implants in hip and knee replacement: a systematic review of five widely used device technologies’. BMJ. 2014 Sep 9;349:g5133. doi: 10.1136/bmj.g5133. Review
14 Pijls BG, Valstar ER, Nouta KA, Plevier JW, Fiocco M, Middeldorp S, Nelissen RG. ‘Early migration of tibial components is associated with late revision: a systematic review and meta-analysis of 21,000 knee arthroplasties’. Acta Orthop. 2012 Dec;83(6):614-24. doi: 10.3109/17453674.2012.747052. Epub 2012 Nov 9. Review
15 Pijls BG, Meessen JM, Schoones JW, Fiocco M, van der Heide HJ, Sedrakyan A, Nelissen RG. ‘Increased Mortality in Metal-on-Metal versus Non-Metal-on-Metal Primary Total Hip Arthroplasty at 10 Years and Longer Follow-Up: A Systematic Review and Meta-Analysis’. PLoS One. 2016 Jun 13;11(6):e0156051. doi: 10.1371/journal.pone.0156051. eCollection 2016. Review
16 Price AJ, Alvand A, Troelsen A, Katz JN, Hooper G, Gray A, Carr A, Beard D. ‘Knee replacement’. Lancet. 2018 Nov 3;392(10158):1672-1682. doi: 10.1016/S0140-6736(18)32344-4. Review
17 Sedrakyan A, Campbell B, Merino JG et al. ‘IDEAL-D: a rational framework for evaluating and regulating the use of medical devices’. BMJ 2016: 353: i2372
18 van der Voort P, Pijls BG, Nieuwenhuijse MJ, Jasper J, Fiocco M, Plevier JW, Middeldorp S, Valstar ER, Nelissen RG. ‘Early subsidence of shape-closed hip arthroplasty stems is associated with late revision. A systematic review and meta-analysis of 24 RSA studies and 56 survival studies’. Acta Orthop. 2015;86(5):575-85. doi: 10.3109/17453674.2015.1043832. Review
19 Hasan S, Marang-van de Mheen PJ, Kaptein BL, Nelissen RGHH, Pijls BG. ‘RSA-tested TKA Implants on Average Have Lower Mean 10-year Revision Rates Than Non-RSA-tested Designs’. Clin Orthop Relat Res. 2020 Jun;478(6):1232-1241. doi: 10.1097/CORR.0000000000001209
20 Hamersveld KT, Marang-van de Mheen PJ, Nelissen RGHH. ‘The effect of coronal alignment on tibial component migration following total knee arthroplasty: a cohort study with long-term radiostereometric analysis results’. J Bone Joint Surg Am. 2019 Jul 3;101(13):1203-1212. doi: 10.2106/JBJS.18.00691
Rob G.H.H. Nelissen, MD, PhD
Professor & Chairman, Department Orthopaedics, Rehabilitation, Physiotherapy
Leiden University Medical Center
+31 71 526 3606
r.g.h.h.nelissen@lumc.nl
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www.universiteitleiden.nl/en/staffmembers/rob-nelissen
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