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What can we learn from experience? Impact of healthcare provider effects in the total or partial knee arthroplasty trial (TOPKAT)

Is over recruitment to a single site problematic for surgical trials?

Can we recruit to expertise trials? Experience from the total or partial knee arthroplasty trial (TOPKAT)

Efficacy of Liposomal Bupivacaine and Bupivacaine Hydrochloride vs Bupivacaine Hydrochloride Alone as a Periarticular Anesthetic for Patients Undergoing Knee Replacement: A Randomized Clinical Trial.

IMPORTANCE: More than half of patients who undergo knee replacement surgery report substantial acute postoperative pain. OBJECTIVE: To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, patient-blinded, pragmatic, randomized clinical superiority trial involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29, 2018, and February 29, 2020, and followed up for 1 year after surgery. Follow-up was completed March 1, 2021. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis. INTERVENTIONS: Two hundred sixty-six milligrams of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery. MAIN OUTCOME AND MEASURES: The coprimary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain visual analog scale (VAS) score area under the curve (AUC) from 6 to 72 hours. Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year. Adverse events and serious adverse events up to 12 months after randomization were also assessed. RESULTS: Among the 533 participants included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8%) and 246 were men (46.2%). Baseline characteristics were balanced between study groups. There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted mean difference, 0.54 [97.5% CI, -2.05 to 3.13]; P = .64) or the pain VAS score AUC at 6 to 72 hours (-21.5 [97.5% CI, -46.8 to 3.8]; P = .06). Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery (adjusted difference -0.54 [97.5% CI, -1.07 to -0.02]; P = .02). No difference in cumulative opioid consumption and functional outcomes was detected. Liposomal bupivacaine was not cost-effective compared with the control treatment. No difference in adverse or serious adverse events was found between the liposomal bupivacaine and control groups. CONCLUSIONS AND RELEVANCE: This study found no difference in postoperative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery. TRIAL REGISTRATION: isrctn.com Identifier: ISRCTN54191675.

The pharmacological profile of a novel highly potent bisphosphonate, OX14 (1-fluoro-2-(imidazo-[1,2 alpha]pyridin-3-yl)ethyl-bisphosphonate), with reduced bone affinity, which is as effective as zoledronate in the treatment of myeloma bone disease in JJN3-NOD/SCID-[gamma] mice

Barriers and enablers to the effective implementation of robotic assisted surgery.

BACKGROUND: Implementation of Robotic Assisted Surgery (RAS) is complex as it requires adjustments to associated physical infrastructure, but also changes to processes and behaviours. With the global objective of optimising and improving RAS implementation, this study aimed to: 1) Explore the barriers and enablers to RAS service adoption, incorporating an assessment of behavioural influences; 2) Provide an optimised plan for effective RAS implementation, with the incorporation of theory-informed implementation strategies that have been adapted to address the barriers/enablers that affect RAS service adoption. METHODS: Semi-structured interviews were conducted with RAS personnel and stakeholders, including: surgeons, theatre staff, managers, industry representatives, and policy-makers/commissioners. The Theoretical Domains Framework (TDF) and the Consolidated Framework for Implementation Research (CFIR) was used to identify barriers and enablers that represent individual behaviours, capabilities, attitudes, beliefs, and external organisational factors that influence the implementation of RAS. RESULTS: Findings suggest that implementation planning has three separate phases-pre-, early, and late implementation. For pre-implementation, barriers and enablers identified included the cost of RAS equipment and issues of economic viability, weak outcome evidence for RAS, a preponderance of an eminence driven model, the clinician/manager relationship, and views around the uptake and expansion of RAS in the future. Early implementation findings revealed role changes for theatre personnel and an enhanced team approach, reliance on industry for training provision, and changes in skill sets and attentional processes. Late implementation factors included equipment maintenance costs, technological limitations, changes to cognition during RAS routine use, and benefits to institutions/healthcare professionals (such as ergonomic improvement). CONCLUSION: Together, findings suggest the factors that affect RAS implementation are multi-faceted and change across the life-cycle of intervention adoption. Theory-informed strategies are suggested which can optimise implementation of RAS. Optimisation strategies need planning from the outset.

Current issues and future considerations for the wider implementation of robotic-assisted surgery: a qualitative study.

OBJECTIVES: The effective implementation of a fast-changing healthcare delivery innovation, such as robotic-assisted surgery (RAS), into a healthcare system, can be affected (both positively and negatively) by external contextual factors. As part of a wider project investigating ways to optimise the implementation of RAS, this qualitative study aimed to uncover current issues of RAS and predictions about the future of robotic surgery. We refer to 'current issues' as the topical and salient challenges and opportunities related to the introduction of RAS in the UK healthcare system, from the perspectives of key stakeholders involved in the delivery and implementation of RAS. DESIGN: Semi-structured interviews and focus groups were conducted. A thematic analysis was conducted to summarise salient issues that were articulated by the participants. SETTING AND PARTICIPANTS: The interview sample (n=35) comprised surgeons, wider theatre staff and other relevant personnel involved in the introduction and delivery of RAS services across the UK, including service managers and policymakers/commissioners. Two focus groups were also conducted with surgical trainees (n=7) and members of the public (n=8), respectively. RESULTS: The results revealed a largely positive attitude towards the introduction of RAS technology and an expectation of continued rapid expansion. Areas perceived to be particularly pertinent and requiring ongoing attention were also highlighted, including the need to achieve improved quality control, expertise quantification and training issues and the need to educate the public. Issues of centralisation, service organisation and equity of access were also emphasised. CONCLUSIONS: Our study has highlighted a range of issues perceived to be particularly pertinent to the current and future provision of RAS which should be addressed. The areas outlined can enable healthcare managers and surgeons to plan for the adoption and/or expansion of RAS services.

Efficacy of liposomal bupivacaine and bupivacaine hydrochloride vs bupivacaine hydrochloride alone as a periarticular anesthetic for patients undergoing knee replacement

Importance: More than half of patients who undergo knee replacement surgery report substantial acute postoperative pain. Objective: To evaluate the efficacy and cost-effectiveness of periarticular liposomal bupivacaine for recovery and pain management after knee replacement. Design, Setting, and Participants: This multicenter, patient-blinded, pragmatic, randomized clinical superiority trial involved 533 participants at 11 institutions within the National Health Service in England. Adults undergoing primary unilateral knee replacement for symptomatic end-stage osteoarthritis were enrolled between March 29, 2018, and February 29, 2020, and followed up for 1 year after surgery. Follow-up was completed March 1, 2021. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis. Interventions: Two hundred sixty-six milligrams of liposomal bupivacaine admixed with 100 mg of bupivacaine hydrochloride compared with 100 mg of bupivacaine hydrochloride alone (control) administered by periarticular injection at the time of surgery. Main Outcome and Measures: The coprimary outcomes were Quality of Recovery 40 (QoR-40) score at 72 hours and pain visual analog scale (VAS) score area under the curve (AUC) from 6 to 72 hours. Secondary outcomes included QoR-40 and mean pain VAS at days 0 (evening of surgery), 1, 2, and 3; cumulative opioid consumption for 72 hours; functional outcomes and quality of life at 6 weeks, 6 months, and 1 year; and cost-effectiveness for 1 year. Adverse events and serious adverse events up to 12 months after randomization were also assessed. Results: Among the 533 participants included in the analysis, the mean (SD) age was 69.0 (9.7) years; 287 patients were women (53.8%) and 246 were men (46.2%). Baseline characteristics were balanced between study groups. There was no difference between the liposomal bupivacaine and control groups in QoR-40 score at 72 hours (adjusted mean difference, 0.54 [97.5% CI, −2.05 to 3.13]; P = .64) or the pain VAS score AUC at 6 to 72 hours (−21.5 [97.5% CI, −46.8 to 3.8]; P = .06). Analyses of pain VAS and QoR-40 scores demonstrated only 1 statistically significant difference, with the liposomal bupivacaine arm having lower pain scores the evening of surgery (adjusted difference −0.54 [97.5% CI, −1.07 to −0.02]; P = .02). No difference in cumulative opioid consumption and functional outcomes was detected. Liposomal bupivacaine was not cost-effective compared with the control treatment. No difference in adverse or serious adverse events was found between the liposomal bupivacaine and control groups. Conclusions and Relevance: This study found no difference in postoperative recovery or pain associated with the use of periarticular liposomal bupivacaine compared with bupivacaine hydrochloride alone in patients who underwent knee replacement surgery.

Impact of timing of follow-up upon outcome in the TOPKAT trial

RIFINs displayed on malaria-infected erythrocytes bind KIR2DL1 and KIR2DS1.

Natural killer (NK) cells use inhibitory and activating immune receptors to differentiate between human cells and pathogens. Signalling by these receptors determines whether an NK cell becomes activated and destroys a target cell. In some cases, such as killer immunoglobulin-like receptors, immune receptors are found in pairs, with inhibitory and activating receptors containing nearly identical extracellular ligand-binding domains coupled to different intracellular signalling domains1. Previous studies showed that repetitive interspersed family (RIFIN) proteins, displayed on the surfaces of Plasmodium falciparum-infected erythrocytes, can bind to inhibitory immune receptors and dampen NK cell activation2,3, reducing parasite killing. However, no pathogen-derived ligand has been identified for any human activating receptor. Here we identified a clade of RIFINs that bind to inhibitory immune receptor KIR2DL1 more strongly than KIR2DL1 binds to the human ligand (MHC class I). This interaction mediates inhibitory signalling and suppresses the activation of KIR2DL1-expressing NK cells. We show that KIR2DL1-binding RIFINs are abundant in field-isolated strains from both Africa and Asia and reveal how the two RIFINs bind to KIR2DL1. The RIFIN binding surface of KIR2DL1 is conserved in the cognate activating immune receptor KIR2DS1. We find that KIR2DL1-binding RIFINs can also bind to KIR2DS1, resulting in the activation of KIR2DS1-expressing NK cells. This study demonstrates that activating killer immunoglobulin-like receptors can recruit NK cells to target a pathogen and reveals a potential role for activating immune receptors in controlling malaria infection.

Group sequential designs in pragmatic trials: feasibility and assessment of utility using data from a number of recent surgical RCTs.

BACKGROUND: Assessing the long term effects of many surgical interventions tested in pragmatic RCTs may require extended periods of participant follow-up to assess effectiveness and use patient-reported outcomes that require large sample sizes. Consequently the RCTs are often perceived as being expensive and time-consuming, particularly if the results show the test intervention is not effective. Adaptive, and particularly group sequential, designs have great potential to improve the efficiency and cost of testing new and existing surgical interventions. As a means to assess the potential utility of group sequential designs, we re-analyse data from a number of recent high-profile RCTs and assess whether using such a design would have caused the trial to stop early. METHODS: Many pragmatic RCTs monitor participants at a number of occasions (e.g. at 6, 12 and 24 months after surgery) during follow-up as a means to assess recovery and also to keep participants engaged with the trial process. Conventionally one of the outcomes is selected as the primary (final) outcome, for clinical reasons, with others designated as either early or late outcomes. In such settings, novel group sequential designs that use data from not only the final outcome but also from early outcomes at interim analyses can be used to inform stopping decisions. We describe data from seven recent surgical RCTs (WAT, DRAFFT, WOLLF, FASHION, CSAW, FIXDT, TOPKAT), and outline possible group sequential designs that could plausibly have been proposed at the design stage. We then simulate how these group sequential designs could have proceeded, by using the observed data and dates to replicate how information could have accumulated and decisions been made for each RCT. RESULTS: The results of the simulated group sequential designs showed that for two of the RCTs it was highly likely that they would have stopped for futility at interim analyses, potentially saving considerable time (15 and 23 months) and costs and avoiding patients being exposed to interventions that were either ineffective or no better than standard care. We discuss the characteristics of RCTs that are important in order to use the methodology we describe, particularly the value of early outcomes and the window of opportunity when early stopping decisions can be made and how it is related to the length of recruitment period and follow-up. CONCLUSIONS: The results for five of the RCTs tested showed that group sequential designs using early outcome data would have been feasible and likely to provide designs that were at least as efficient, and possibly more efficient, than the original fixed sample size designs. In general, the amount of information provided by the early outcomes was surprisingly large, due to the strength of correlations with the primary outcome. This suggests that the methods described here are likely to provide benefits more generally across the range of surgical trials and more widely in other application areas where trial designs, outcomes and follow-up patterns are structured and behave similarly.

ACL Surgery Necessity in Non-Acute Patients (ACL SNNAP): a statistical analysis plan for a randomised controlled trial.

BACKGROUND: Rupture of the anterior cruciate ligament (ACL) is a common injury, primarily affecting young, active individuals. Despite surgical intervention being the more common treatment for patients suffering ACL ruptures, current management is based on limited and generally low-quality evidence. We describe a statistical analysis plan (SAP) for the ACL SNNAP randomised controlled trial, which aims to investigate the necessity of surgical management in patients with ACL injuries. METHODS/DESIGN: ACL SNNAP is a pragmatic, multi-centre, superiority, parallel-group randomised controlled trial in participants with a symptomatic non-acute ACL deficient knee. Participants are allocated in a 1:1 ratio to either non-surgical management (rehabilitation) or surgical management (reconstruction) with the aim of assessing the efficacy and cost-effectiveness. The primary outcome of the study is the Knee Injury and Osteoarthritis Outcome Score (KOOS4) at 18 months post-randomisation. The KOOS4 score at 18 months will be evaluated using a linear regression model adjusting for recruitment centre and baseline KOOS4 scores, allowing for intra-centre correlation. A secondary analysis of the primary outcome will be carried out using an area under the curve (AUC) approach using treatment estimates obtained from a mixed model using baseline, 6 months, 12 months, and 18 months post-randomisation outcome data. Secondary outcomes will be measured at 18 months and will include return to activity/level of sport participation, intervention-related complications, the EQ-5D-5L questionnaire, all 5 individual subscales of the KOOS questionnaire, the ACL-QOL score, expectations of return to activity and cost-effectiveness of the interventions. Missing primary outcome data will be investigated through a sensitivity analysis. Full details of the planned methods for the statistical analysis of clinical outcomes are presented in this paper. The study protocol for the ACL SNNAP trial has been published previously. DISCUSSION: The methods of analysis for the ACL SNNAP trial have been described here to minimise the risk of data-driven results and reporting bias. Any deviations from the analysis methods described in this paper will be described in full and justified in the publications of the trial results. TRIAL REGISTRATION: ISRCTN ISRCTN10110685 . Registered on 16 November 2016.

Rehabilitation versus surgical reconstruction for non-acute anterior cruciate ligament injury (ACL SNNAP): a pragmatic randomised controlled trial.

BACKGROUND: Anterior cruciate ligament (ACL) rupture is a common debilitating injury that can cause instability of the knee. We aimed to investigate the best management strategy between reconstructive surgery and non-surgical treatment for patients with a non-acute ACL injury and persistent symptoms of instability. METHODS: We did a pragmatic, multicentre, superiority, randomised controlled trial in 29 secondary care National Health Service orthopaedic units in the UK. Patients with symptomatic knee problems (instability) consistent with an ACL injury were eligible. We excluded patients with meniscal pathology with characteristics that indicate immediate surgery. Patients were randomly assigned (1:1) by computer to either surgery (reconstruction) or rehabilitation (physiotherapy but with subsequent reconstruction permitted if instability persisted after treatment), stratified by site and baseline Knee Injury and Osteoarthritis Outcome Score-4 domain version (KOOS4). This management design represented normal practice. The primary outcome was KOOS4 at 18 months after randomisation. The principal analyses were intention-to-treat based, with KOOS4 results analysed using linear regression. This trial is registered with ISRCTN, ISRCTN10110685, and ClinicalTrials.gov, NCT02980367. FINDINGS: Between Feb 1, 2017, and April 12, 2020, we recruited 316 patients. 156 (49%) participants were randomly assigned to the surgical reconstruction group and 160 (51%) to the rehabilitation group. Mean KOOS4 at 18 months was 73·0 (SD 18·3) in the surgical group and 64·6 (21·6) in the rehabilitation group. The adjusted mean difference was 7·9 (95% CI 2·5-13·2; p=0·0053) in favour of surgical management. 65 (41%) of 160 patients allocated to rehabilitation underwent subsequent surgery according to protocol within 18 months. 43 (28%) of 156 patients allocated to surgery did not receive their allocated treatment. We found no differences between groups in the proportion of intervention-related complications. INTERPRETATION: Surgical reconstruction as a management strategy for patients with non-acute ACL injury with persistent symptoms of instability was clinically superior and more cost-effective in comparison with rehabilitation management. FUNDING: The UK National Institute for Health Research Health Technology Assessment Programme.

Assessing a 12-month course of oral alendronate for adults with avascular necrosis of the hip: MANTIS RCT with internal pilot.

BACKGROUND: People with avascular necrosis of the hip have very limited treatment options currently available to stop the progression of this disease; this often results in the need for a hip replacement. There is some weak evidence that a class of drugs called bisphosphonates may delay the course of the disease, and this trial was commissioned and set up to provide robust evidence regarding the use of bisphosphonates in adults aged ≥ 18 years with this condition. OBJECTIVES: The aim of the Managing Avascular Necrosis Treatments: an Interventional Study ( MANTIS ) trial was to evaluate the clinical effectiveness and cost-effectiveness of a 12-month course of alendronate in the treatment of avascular necrosis. DESIGN: This was a 66-month, definitive, multisite, two-arm, parallel-group, placebo-controlled, double-blind, randomised controlled trial, with an internal pilot phase. SETTING: Eight secondary care NHS hospitals across the UK. PARTICIPANTS: Planned trial size - 280 adult patients with avascular necrosis. INTERVENTION: Participants in the intervention group received 70 mg of alendronate (an oral bisphosphonate) weekly for 12 months. MAIN OUTCOMES: The main outcomes were Oxford Hip Score at 12 months (short-term outcome) and the time to decision that a hip replacement is required at 36 months (long-term outcome). RESULTS: Twenty-one patients were recruited and randomised to receive either the intervention drug, alendronate, or a placebo-matched tablet. LIMITATIONS: This trial was principally limited by low disease prevalence. Other limitations included the late disease stage at which participants were identified and the rapid progression of the disease. FUTURE WORK: This trial was limited by a low recruitment rate. Avascular necrosis of the hip should be treated as a rare disease. Future trials would need to recruit many more sites and recruit over a longer time period, and, for this reason, a registry may provide a more effective means of collecting data pertaining to this disease. CONCLUSIONS: The MANTIS trial was terminated at the end of the pilot phase, because it did not meet its go/no-go criteria. The main issue was a poor recruitment rate, owing to a lower than expected disease prevalence and difficulties in identifying the condition at a sufficiently early stage. Those patients who were identified and screened either were too advanced in their disease progression or were already taking medication. We would not recommend that a short-term interventional study is conducted on this condition until its prevalence, geographic foci and natural history and better understood. The difficulty of acquiring this understanding is likely to be a barrier in most health-care markets. One means of developing this understanding would be the introduction of a database/registry for patients suffering from avascular necrosis of the hip. TRIAL REGISTRATION: The trial is registered as ISRCTN14015902. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 43. See the NIHR Journals Library website for further project information.

The feasibility of a randomised control trial to assess physiotherapy against surgery for recurrent patellar instability.

BACKGROUND: Patellar instability is a relatively common condition that leads to disability and restriction of activities. People with recurrent instability may be given the option of physiotherapy or surgery though this is largely driven by clinician preference rather than by a strong evidence base. We sought to determine the feasibility of conducting a definitive trial comparing physiotherapy with surgical treatment for people with recurrent patellar instability. METHODS: This was a pragmatic, open-label, two-arm feasibility randomised control trial (RCT) with an embedded interview component recruiting across three NHS sites comparing surgical treatment to a package of best conservative care; 'Personalised Knee Therapy' (PKT). The primary feasibility outcome was the recruitment rate per centre (expected rate 1 to 1.5 participants recruited each month). Secondary outcomes included the rate of follow-up (over 80% expected at 12 months) and a series of participant-reported outcomes taken at 3, 6 and 12 months following randomisation, including the Norwich Patellar Instability Score (NPIS), the Kujala Patellofemoral Disorder Score (KPDS), EuroQol-5D-5L, self-reported global assessment of change, satisfaction at each time point and resources use. RESULTS: We recruited 19 participants. Of these, 18 participants (95%) were followed-up at 12 months and 1 (5%) withdrew. One centre recruited at just over one case per month, one centre was unable to recruit, and one centre recruited at over one case per month after a change in participant screening approach. Ten participants were allocated into the PKT arm, with nine to the surgical arm. Mean Norwich Patellar Instability Score improved from 40.6 (standard deviation 22.1) to 28.2 (SD 25.4) from baseline to 12 months. CONCLUSION: This feasibility trial identified a number of challenges and required a series of changes to ensure adequate recruitment and follow-up. These changes helped achieve a sufficient recruitment and follow-up rate. The revised trial design is feasible to be conducted as a definitive trial to answer this important clinical question for people with chronic patellar instability. TRIAL REGISTRATION: The trial was prospectively registered on the International Standard Randomised Controlled Trial Number registry on the 22/12/2016 (reference number: ISRCTN14950321). http://www.isrctn.com/ISRCTN14950321.

Tendon cells isolated from patients with persistent shoulder tendinopathy show dysregulated resolution responses

Benefits and harms of placebo in surgical randomised clinical trials: a systematic review

Objective: To investigate whether placebo controls should be used in the evaluation of surgical interventions. Design: Systematic review. Data sources: We searched Medline, Embase, and the Cochrane Controlled Trials Register from their inception to November 2013. Study selection: Randomised clinical trials comparing any surgical intervention with placebo. Surgery was defined as any procedure that both changes the anatomy and requires a skin incision or use of endoscopic techniques. Data extraction: Three reviewers (KW, BJFD, IR) independently identified the relevant trials and extracted data on study details, outcomes, and harms from included studies. Results: In 39 out of 53 (74%) trials there was improvement in the placebo arm and in 27 (51%) trials the effect of placebo did not differ from that of surgery. In 26 (49%) trials, surgery was superior to placebo but the magnitude of the effect of the surgical intervention over that of the placebo was generally small. Serious adverse events were reported in the placebo arm in 18 trials (34%) and in the surgical arm in 22 trials (41.5%); in four trials authors did not specify in which arm the events occurred. However, in many studies adverse events were unrelated to the intervention or associated with the severity of the condition. The existing placebo controlled trials investigated only less invasive procedures that did not involve laparotomy, thoracotomy, craniotomy, or extensive tissue dissection. Conclusions: Placebo controlled trial is a powerful, feasible way of showing the efficacy of surgical procedures. The risks of adverse effects associated with the placebo are small. In half of the studies, the results provide evidence against continued use of the investigated surgical procedures. Without well designed placebo controlled trials of surgery, ineffective treatment may continue unchallenged.

The use of placebo in randomised surgical clinical trials

Minimal important change or difference for the oxford hip and knee scores following joint replacement surgery

What influences surgeons’ experience of surgical research?