Title: Risk-benefit and costs of unicompartmental (compared to total) knee replacement for patients with multiple co-morbidities: a non-randomised study, and different novel approaches to minimise confounding.
Funder: Department of Health and Social Care

Abstract: RATIONALE Although an NIHR-funded RCT (TOPKAT) is ongoing to compare unicompartemental (UKR) and total knee replacement (TKR), limited follow-up and restrictive eligibility criteria will limit the usefulness of its findings for patients with multiple co-morbidities as well as for studying complications and long-term outcomes. AIMS 1.To validate methods to minimise confounding: we will replicate TOPKAT by analysing the association between UKR (compared to TKR) and patient reported outcomes (PROMs) amongst participants in the National Joint Registry (NJR) eligible for TOPKAT (ASA grade <3). Different statistical analyses will be conducted separately, and those able to replicate the 1-year findings from TOPKAT will be deemed valid (for Aim 2); 2.To study the benefits (PROMs), risks (revision, complications, and mortality), hospital costs and cost-effectiveness of UKR (compared to TKR) amongst NJR participants not eligible for TOPKAT (ASA 3+). METHODS -Design: cohort study -Setting: We will use routinely-collected data from the NJR linked to hospital records (HES) and PROMs Database. -Participants: Two cohorts: 1. NJR participants undergoing UKR/TKR with ASA 1 or 2, eligible for TOPKAT (comparison cohort); and 2. participants in the NJR undergoing UKR/TKR with ASA 3+ (multi-morbidity cohort). -Health technology being assessed: UKR versus TKR. -Outcomes: 1.Primary: six-month post-operative Oxford Knee Score (PROMs); 2.Secondary: one and 5-year risks (revision, infection, cardiovascular disease, and venous thromboembolism), mortality, health-related quality of life (EQ-5D), and NHS hospital costs. -Power (primary outcome): Based on published data(1), at least 720 UKR and 8,400 TKR recipients in the smaller (multimorbidity) cohort will have linked PROMs. With an expected standard deviation of 8, power will be 90% to detect a minimally clinically important difference of 2+ points in Oxford Knee Score(2). -Statistics: linear regression will be used to study PROMs. Survival models will be fitted to study time-to-event (complications/mortality) according to UKR/TKR. In the first stage, different methods will be tested to evaluate the association between KR type and both primary and secondary outcomes in the comparison cohort: 1.Propensity score (PS) methods; 2.High-dimensional PS; AND 3.Instrumental variable analyses (instrument/s to be confirmed once assumptions are tested) In a second stage, those methods able to obtain results equivalent to the 1-year findings from TOPKAT will be applied to the analysis of the association between UKR (compared to TKR) and all study outcomes (benefits, risks, and cost-effectiveness) in the multi-morbidity cohort. TIME TABLE: Months 1-6: Approval of the research proposal, data extraction, and linkage. Months 7-10: Data management. Months11-14: Data analyses for Aim 1. Month 15: Reporting on results of Aim 1 (go-no go milestone). The study will not progress if none of the proposed methods obtains results comparable to TOPKAT. Months 16-19: Data analyses for Aim 2. Months 20-22: Internal discussion and –if needed- additional analysis. Months 23-25: Reporting and dissemination of research findings, and closure. EXPERTISE: Multidisciplinary team including academic general practitioners, orthopaedic surgeons, and experts in orthopaedics, rheumatology, epidemiology, statistics, clinical trials, health economics, and analysis of routinely-collected data, as well as patient representative

Lay abstract: This study will compare the risks, benefits, and costs of partial compared to total knee replacement and, at the same time, it will evaluate different study methodologies. In TOPKAT study (Total or Partial Knee Arthroplasty Trial), patients with knee damage were randomly given either partial or total knee surgery. In such studies, random allocation to different treatments provides similar patient groups that can be compared to provide evidence on the treatment effects. Even though TOPKAT will give information on both procedures, randomised studies (and particularly surgical ones) have difficulties as they: 1. are very costly and ethically challenging. 2. do not provide information on rare events and long-term effects, like complications or mortality. 3. do not include patients with a complex medical history. 4. might not be representative of real life as they are conducted within a controlled research environment. There are however increasing opportunities for efficient studies using de-identified electronic medical records from actual practice, potentially including all NHS (National Health Service) patients. The disadvantage of using such data is that patients receive different interventions based on clinical guidance and experience. As a consequence, treatment groups are different in nature. Hence, direct comparison of outcomes between the groups is difficult unless these differences are accounted for. Novel research methods to analyse routinely-collected data have been used for comparing drug and vaccine effects in large populations and might prove useful for the comparison of different surgical procedures. We will use routinely-collected data from hospital de-identified electronic medical records linked to two other sources: 1.the National Joint Registry, which contains information on anyone undergoing joint replacement surgery in England or Wales; and 2.the national patient reported outcomes (PROMS) database, which collects data on disease-specific outcomes and health-related quality of life before and after knee/hip replacement in the English NHS. With these data we will aim to: 1. Test the validity of the proposed methods to replicate the results from the ‘gold standard’ TOPKAT study. 2. Use those ‘valid’ methods to assess the benefits, risks, hospital costs, and cost-effectiveness of partial compared to total knee replacement amongst patients with multiple conditions (i.e. those not eligible for studies like TOPKAT). To ensure patient and public perspective is present in the study, there will be a PPI (Patient and Public Involvement) representative evaluating the progress of the study and a PPI group that will discuss the methodology used as an alternative to the “traditional” randomised surgical trials. The findings of this study will: • Benefit patients and the NHS by providing information on the risks, benefits, costs, and cost-effectiveness of partial and total knee replacement for patients with multiple conditions. • Inform on the usefulness of cheaper and faster research studies using routinely-collected data for the assessment of surgical alternatives. The results will be published in the NIHR Journal, presented at conferences, reported as papers, and explained in leaflets and meetings with patients.

Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;6.4 SURGERY
Health categories: MUSCULOSKELETAL