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Treatment protocol | Patients received three courses of SOX | PMC10468941 | ||
Neoadjuvant SOX chemotherapy | Patients were scheduled to receive three courses of NAC with oxaliplatin (130 mg/m | PMC10468941 | ||
Surgery | Since the current clinical trial was for older patients, the protocol surgery was only stipulated as “surgery for curative purposes.” Surgery was performed after confirming that the following two conditions were met. (1) A CT scan performed within 7–56 days from the date of the last S-1 administration to determine that surgery for curative purposes is feasible. (2) The patient must have a white blood cell count ≥ 3,000/mm | PMC10468941 | ||
Post-operative evaluation | ADVERSE EVENT, SURGICAL COMPLICATIONS, POSTOPERATIVE HEMORRHAGE, COMPLICATIONS | From the end of surgery to 30 days after surgery, the items that were evaluated included: (1) Initial discharge date after surgery; (2) Presence or absence of postoperative hemorrhage; (3) Presence or absence of re-operation; (4) Pathological findings; and (5) Postoperative early complications. The principal investigator’s or sub-investigator’ judgment related to the causal relationship with surgery was also recorded. Assessment of surgical complications was performed according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and Clavien–Dindo classification. | PMC10468941 | |
Statistical analysis | The primary endpoint of the trial was the dose intensity (DI) of the preoperative SOX | PMC10468941 | ||
Results | PMC10468941 | |||
Discussion | death, neutropenia, diarrhea, hyponatremia, dehydration, gastric cancer | NEUTROPENIA, ADVERSE EVENTS, DISEASE, HYPONATREMIA, DEHYDRATION, GASTRIC CANCER | This phase II study tested the safety and efficacy of SOXThe main research hypothesis of this study was that “NAC + radical gastrectomy for LAGC in older patients is as safe and effective as in the young.” The participants in this study were older than 70 years of age, were more likely to have comorbidities, and the incidence of adverse events during chemotherapy was expected to be higher than in younger patients. Therefore, we focused on safety evaluation, and set the DI of the preoperative SOXIn three trials of preoperative chemotherapy for stage III disease, the R0 resection rate was over 90% and the pRR was over 40% [All Grade or Grade 3–4 adverse events in preoperative chemotherapy in the older patients in this study were neutropenia and hyponatremia in 76.0/20.0% and 42.3/7.7%, respectively. We experienced one case of death due to severe diarrhea and dehydration. In KSCC1601 discussed above, which included patients aged 20 years and older, these adverse events were lower at 42.6/6.4% and 29.8/2.1%, respectively, suggesting that these adverse events may be more frequent and severe in older patients. We lost one patient due to diarrhea and dehydration. This may have been avoided if the patient had been hospitalized immediately after the onset of diarrhea. In the case of elderly patients, it is considered safe to hospitalize them when the first course of NAC-SOX therapy is introduced. Since the older patients have decreased organ function, careful observation should be continued even after outpatient follow-up, and hospitalization should be considered depending on the patient’s condition.There are various reports on the significance of chemotherapy in older patients with advanced or recurrent GC, although the issue remains controversial. This is because the older population is diverse, and patients cannot be stratified by age alone. A phase II study of S-1 monotherapy in patients aged 75 years or older reported favorable safety and efficacy [Another issue is the need for postoperative adjuvant chemotherapy after NAC. In the KSCC1801 study of older patients, postoperative adjuvant chemotherapy was not specified in the protocol due to safety concerns. However, 75% of the patients received postoperative adjuvant chemotherapy at the physician’s discretion. In Europe and the United States, perioperative chemotherapy is the standard treatment for locally advanced gastric cancer (NAC + surgery + postoperative chemotherapy). In East Asia, surgery plus postoperative adjuvant chemotherapy has been the standard treatment, and NAC’s additional effect has been verified. It remains unclear whether postoperative adjuvant chemotherapy can be omitted when NAC is administered, and whether there is a group of patients for whom it can be omitted. Subgroup analyses of clinical trials of postoperative adjuvant chemotherapy have not demonstrated an additional OS benefit in older patients [There were a few limitations to the study. First, the study was a single-arm, phase II clinical trial involving a small number of patients. Second, no comprehensive geriatric assessment or quality of life assessment was included in the study design. | PMC10468941 |
Conclusion | In this trial, the safety and efficacy of NAC-SOX | PMC10468941 | ||
Acknowledgements | We sincerely thank the participating patients and their families. We are indebted to the physicians and all other medical staff. We also thank Ms. Sakamoto and the staff at Clinical Research Support Center (CReS), Kyushu for their excellent data collection and management, secretarial assistance, and support. Editorial support in medical writing, assembling tables, creating high-resolution images based on authors’ detailed directions, collating author comments, copyediting, fact checking, and referencing, was provided by Editage, Cactus Communications. | PMC10468941 | ||
Funding | This research was funded by Yakult Honsha Co., Ltd. Head Office and was carried out by the CReS Kyushu. Due consideration was given so that the interests of the participants and the interests of the researchers do not conflict with each other (conflict of interest) by receiving funding from the company. The CReS Kyushu covered the expenses associated with this research and research cooperation expenses for the participating researchers, but the amounts paid were determined by various national regulations. | PMC10468941 | ||
Declarations | PMC10468941 | |||
Conflict of interest | Hiroshi Saeki (Department of General Surgical Science, Graduate School of Medicine, Gunma University), who is the Research Director of this study, is not in a state of conflict of interest with the Yakult Honsha Co., Ltd. Head Office. Y. Kakeji has received an honorarium from Taiho Pharmaceutical Co., Ltd. N. Izawa received research grants from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Sanofi K.K., Otsuka Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and honoraria from Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bristol-Myers Squibb Co., Chugai Pharmaceutical Co., Ltd., and Daiichi Sankyo Co., Ltd. E. Oki received honoraria from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Eli Lilly Japan K.K., Bristol-Myers Squibb Co., and Takeda Pharmaceutical Co., Ltd. M. Ota received honoraria from Bristol-Myers Squibb Co., Ono Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., and Daiichi Sankyo Co., Ltd. All remaining authors have declared no conflicts of interest. | PMC10468941 | ||
Human rights statement and informed consent | All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. This study was approved by the Clinical Research Network Fukuoka Certified Review Board (Certification No. CRB7180004). Informed consent to be included in the study, or the equivalent, was obtained from all patients. | PMC10468941 | ||
References | PMC10468941 | |||
Subject terms | trauma, traumatic | EVENTS, EVENT, RECRUITMENT | Intensive care unit (ICU) staff continue to face recurrent work-related traumatic events throughout the COVID-19 pandemic. Intrusive memories (IMs) of such traumatic events comprise sensory image-based memories. Harnessing research on preventing IMs with a novel behavioural intervention on the day of trauma, here we take critical next steps in developing this approach as a treatment for ICU staff who are already experiencing IMs days, weeks, or months post-trauma. To address the urgent need to develop novel mental health interventions, we used Bayesian statistical approaches to optimise a brief imagery-competing task intervention to reduce the number of IMs. We evaluated a digitised version of the intervention for remote, scalable delivery. We conducted a two-arm, parallel-group, randomised, adaptive Bayesian optimisation trial. Eligible participants worked clinically in a UK NHS ICU during the pandemic, experienced at least one work-related traumatic event, and at least three IMs in the week prior to recruitment. Participants were randomised to receive immediate or delayed (after 4 weeks) access to the intervention. Primary outcome was the number of IMs of trauma during week 4, controlling for baseline week. Analyses were conducted on an intention-to-treat basis as a between-group comparison. Prior to final analysis, sequential Bayesian analyses were conducted ( | PMC10131522 |
Introduction | traumatic, post-traumatic stress disorder, PTSD, deaths, primarily visual memories, trauma | EVENTS, EVENT, RECRUITMENT, VEHICLE ACCIDENT | Throughout the COVID-19 pandemic, frontline healthcare workers have been repeatedly exposed to potentially psychologically traumatic events, such as untimely and excess deaths of patients. After trauma, it is common to experience intrusive memories (IMs) of the event. These are emotional, sensory, and primarily visual memories (mental imagery) of the traumatic event that intrude repeatedly into mind, comprising a core clinical feature of post-traumatic stress disorder (PTSD) [The urgent need for scalable approaches to support the mental health of frontline healthcare workers, such as Intensive Care Unit (ICU) staff, was highlighted early in the pandemic [An imagery-competing task intervention approach (which includes computer gameplay) to prevent IMs was developed from insights from cognitive neuroscience and experimental research [A first proof-of-concept translation study from lab to clinic included patients in the emergency department (ED) within 6 h of a motor vehicle accident [While showing promise for the “prevention” of IMs soon after trauma [In the current trial, we sought to optimise and evaluate a brief digital imagery-competing task intervention [Given the rapid need for novel approaches during a pandemic, it was advantageous to evaluate the intervention, both swiftly and robustly. However, RCTs are notoriously lengthy, spanning several years before an intervention is optimised and evaluated. The COVID-19 pandemic has led to difficulties with participant recruitment and testing, underscoring the need to minimise sample sizes where possible [The sequential Bayesian design used here has previously been recommended for vaccine development [In sum, we aimed to optimise a brief digital imagery-competing task intervention to help reduce the number of IMs of work-related trauma being experienced by ICU staff. To this end, we used Bayesian statistical methodology to optimise trial design and guide decisions. Taken all together, our aim was that this intervention and the Bayesian methodology would help address the need for accelerated mental health treatment development for healthcare staff working during the COVID-19 pandemic. | PMC10131522 |
Material and methods | PMC10131522 | |||
Study design and participants | death, PTSD, DSM-5, traumatic | EVENT | We conducted a two-arm, parallel-group, randomised, adaptive Bayesian optimisation trial of a remotely delivered digital intervention. Ethical approval for the trial was granted by the Wales Research Ethics Committee (Wales REC 6, 21/WA/0173). The trial was registered prospectively at Clinical.Trials.gov (CTR: NCT04992390). The study protocol was added to a public depository (osf.io/2xn5m), and the trial had a data monitoring committee (DMC).The study was advertised via email and Twitter directly from the Intensive Care Society to its membership network, mailing list, and existing social media followers, supplemented by advertisements through Facebook. Advertisements contained a link to the study website: Eligible participants were adults aged 18 years or older, who worked in a clinical role in an NHS ICU or equivalent during the COVID-19 pandemic (e.g. as a member of ICU staff or deployed to work in the ICU during the pandemic), who had experienced at least one traumatic event related to their work (meeting criterion A of the DSM-5 criteria for PTSD: “exposure to actual or threatened death, serious injury, or sexual violence” by “directly experiencing the traumatic event(s)” or “witnessing, in person, the event(s) as it occurred to others”), had IMs of the traumatic event(s), and had experienced at least three IMs in the week prior to screening. Further, participants had internet access; were willing and able to be contacted by the research team during the study period; were able to read, write, and speak English; and were willing and able to provide informed consent and complete study procedures. Exclusion criteria were having fewer than three IMs during the baseline week after informed consent (i.e. the run-in week on Fig. | PMC10131522 |
Trial profile. | CONSORT diagram showing enrolment, allocation, and the analysis populations. | PMC10131522 | ||
Randomisation and masking | ® | Participants were randomly assigned (1:1) using a remote, secure web-based clinical research system (P1vital® ePRO) to either immediate intervention arm (immediate access to the brief digital imagery-competing task intervention plus symptom monitoring for 4 weeks) or delayed intervention arm (usual care for 4 weeks followed by access to the intervention plus symptom monitoring for 4 weeks).Randomisation occurred following the baseline week, and after baseline questionnaires (see protocol; osf.io/2xn5m). The allocation sequence was computer-generated consecutively using minimisation. Minimisation allocated the first participant to either arm, thereafter allocation was preferential to the arm with the fewest participants to minimise the difference in group sizes. The randomisation allocation percentage was originally set to 66% and altered to 85% after 61 participants were randomised (to ensure balance of groups after early stopping decision, see “Results”). Overall, 86 participants were randomly assigned to the delayed (Participants were blinded to group allocation. The statistician who conducted the interim analyses (VR), and researchers who contacted participants and facilitated the conduct of the task intervention were not blinded to group allocation. A researcher supported the technical use of the intervention in the first guided session in i-spero® and was aware that the participant completed a cognitive task. It is noted that all outcome data (including the primary outcome 4 weeks later) was self-reported by participants independently and directly into the online platform (P1vital® ePRO) removing the need for researcher input and reducing the risk of bias. That is, outcome assessments were masked to group allocation since they were self-reported by participants in the digital platform. Scoring of data was automatic in P1vital® ePRO, and thus independent from the researchers guiding the intervention session. | PMC10131522 | |
The intervention | ® | Straight after randomisation, participants in the immediate intervention arm gained access to the digital imagery-competing task intervention with symptom monitoring of IMs for 4 weeks. The intervention was delivered on a secure web platform (i-spero®) via smartphone, tablet, or computer. Participants had an initial researcher-guided session (~1 h, via Microsoft Teams) and thereafter used i-spero® in a self-directed manner (~25 min; with the option for support). The researcher-guided session consisted of step-by-step instructions, animated videos and multiple-choice questions. Participants were instructed to list their different IMs by typing a brief description. They selected one IM from their list, and very briefly brought the image to mind. After instructions on playing the computer game Tetris® using mental rotation, they played for 20 min. Finally, they were instructed on monitoring IMs in i-spero® and encouraged to use the intervention to target each memory on their list.The brief digital intervention on i-spero® and P1vital® ePRO are owned and manufactured by P1vital Products Ltd. Tetris® has been licensed for use within i-spero® from The Tetris Company. P1vital® ePRO, i-spero® and the brief digital intervention have been developed following a formal computerised system validation methodology which complies with Good Clinical Practice, FDA 21CFR Part 11 and ISO13485 Quality Management System. | PMC10131522 | |
Assessments | PMC10131522 | |||
Baseline | After informed consent, participants completed a daily IM diary online for 7 days (baseline week, day 0–6 i.e. run-in week on Fig. | PMC10131522 | ||
Primary outcome | trauma, PTSD, Clinician-Administered PTSD, traumatic | During week 4, participants in both arms were asked to again complete the daily IM diary for 7 days (i.e. from day 22 to 28, where day 1 is the guided session in immediate arm/equivalent timeframe in delayed arm) to record the number of IMs of traumatic event(s); The primary outcome measure was the total number of IMs recorded by participants in this daily IM diary in week 4.The outcome measure was derived from diaries used in clinical practice [The clinical meaning of a change in score may depend on the trauma population, as single-event trauma incurs fewer IMs than repeated trauma. For a PTSD diagnosis, the Clinician-Administered PTSD Scale for DSM–5 (CAPS-5) [ | PMC10131522 | |
Safety | ADVERSE EVENT | Adverse events were monitored through a standardised question (“have you experienced any untoward medical occurrences or other problems?”) at week 4 and week 8, as well as through any spontaneous reports from participants at any time point during the study. | PMC10131522 | |
Other outcomes | SECONDARY | The present article focuses solely on the sequential Bayesian analyses on the primary outcome measure. A standard analysis (using frequentist statistics) of the final study population including secondary outcome measures will be reported elsewhere [ | PMC10131522 | |
Statistical analysis | Informed by power estimates based on an effect size of The fundamental idea to a Bayesian approach is simple [All analyses were completed in R (version 4.1.2) on an intention-to-treat basis. We fitted a Bayesian model, where the primary outcome (intrusive memory count) was modelled using a Poisson linear mixed model. The baseline number of IMs, and treatment assignment were fitted as fixed effects with a random intercept effect for participant. As daily IM diary data used to calculate the primary outcome was collected sequentially over time (baseline or week 4), we used time series methods and an expectation-maximisation algorithm [ | PMC10131522 | ||
Boxplots for intrusive memory (IM) measures. | The midline of the boxplot is the median value, with the upper and lower limits of the box being the third and first quartile (75th and 25th percentile), and the whiskers covering 1.5 times the IQR. The dots depict outliers (each dot represents one participant that departed more than 1.5 times the IQR above the third quartile and below the first quartile). All outliers are included in this figure. In Bayesian hypothesis testing, a metric known as a Bayes Factor (BF) [In contrast to For this study, BFs were computed repeatedly during interim analyses, starting with 20 participants and approximately every 4–10 participants thereafter, up to a maximum of 150. Early stopping of the trial for either sufficient evidence of negative or positive effect was considered if the respective BFs exceeded a pre-defined threshold of 20 which would suggest strong evidence [We first calculated a BF for a negative effect of the intervention (i.e. whether participants in the immediate arm had a greater number of IMs at week 4 than the delayed arm). If this BF exceeded 20, we concluded that there was strong evidence for a negative effect of the intervention and the trial may need to be altered or stopped. We then calculated a BF for positive treatment effect (i.e. whether those in the immediate arm had fewer IMs at week 4 than the delayed arm, as opposed to having no difference). If this BF exceeded 20, we concluded that there was strong evidence for the effectiveness of the intervention and consideration could be given to stopping the trial early (Supplementary Information).Originally, we planned to explore potential “mechanistic” optimisations to improve the effectiveness of the intervention (e.g., time playing Tetris®). Given the rapid accumulation of evidence in favour of a positive treatment effect (see “Results”), we focused on practical “usability enhancements” to aid smooth digital delivery and user experience (Supplementary Information): this included repeating the intrusive memory visualisation step, adding a summary instruction video, and adding a graphical representation of daily IMs for the 4 weeks. An optimisation enhancement round was conducted on Feb 7, 2022, after 55 participants had been randomised. When testing for the effect of these enhancements, sample size analyses were first conducted to estimate the number of participants needed to test for a positive treatment effect, and to compare pre-and post-optimisation groups (Supplementary Figs. | PMC10131522 | ||
Results | Between Aug 16, 2021 and Apr 19, 2022, 125 participants were screened by the study team following pre-screening questionnaires (Fig. | PMC10131522 | ||
Baseline characteristics | SD | Trial participants had a mean age of 38.7 years (SD 9.9), were predominantly women ( | PMC10131522 | |
Treatment effects | Bayesian analyses of the primary outcome involved seven sequential analyses (after 20, 23, 29, 37, 41, 45, and 75 participants completed the primary outcome). From the first analysis (at | PMC10131522 | ||
Evidence progression. | SENSITIVITY | Sequential Bayesian analyses showed that the evidence (BFFor the final sample (For the round of “usability enhancement” optimisations (see “Method”) conducted on Feb 7, 2022, there was evidence for a positive treatment effect of the optimised intervention (BF = 7.31) based on analyses of 28 participants who entered the trial under the optimised intervention.Sensitivity analyses were completed for variation in Bayesian priors or model used, and to assess impact of outliers and missing data imputation (Supplementary Figs. | PMC10131522 | |
Safety | By using sequential analyses, we could early (at | PMC10131522 | ||
Discussion | traumas, trauma, affective or cognitive elements, traumatic | EVENTS, EVENT | Results showed strong evidence that ICU staff experiencing IMs after work-related traumatic events in the COVID-19 pandemic, had fewer IMs (median = 1 per week, IQR = 0–3) when they were given access to the brief digital imagery-competing task intervention, as opposed to usual care for 4 weeks (median = 10 per week, IQR = 6–16.5) (Fig. At trial entry, participants reported a very high number of work-related traumatic events during the pandemic (on average more than 35 traumas, Supplementary Table There remains an urgent need for scalable approaches to support the mental health of frontline healthcare workers. Given their high workload demands, we developed a brief and flexible digital imagery-competing task intervention approach to reduce IMs. After one initial session with research guidance, the intervention could thereafter be used independently and was repeatable to treat different IMs (e.g. intrusive image of a dying patients face; intrusive image of colleague on ambulance stretcher; etc) and new trauma. Compared to studies on the day of trauma [Adopting new statistical approaches for RCTs is an essential step in speeding up the development of new interventions, and associated moral and ethical decisions in the use of RCTs. By utilising advances in Bayesian trial methodology in the present study to optimise the brief digital imagery-competing task intervention, we substantially reduced the sample size and therefore the time and resources needed to run the trial (Fig. In general, the practical consequences of using more efficient adaptive Bayesian trial designs to develop therapeutic approaches are clear—they can provide information rapidly to support a go/no-go clinical development decision, thus helping treatment innovation by reducing the time required to progress to subsequently assess efficacy. Here, it helped us examine the effects of a new intervention approach. Methods advances are needed given the relatively slow progress of behavioural interventions since the 1960s [In retrospect, we could have conducted an even more efficient trial. As the evidence progression shows, there was sufficient evidence (BF > 20) when 29 participants had completed the trial to conclude that there were positive effects of the intervention. However, at that point to ensure the robustness of the results we conducted a more thorough sensitivity analyses. Simultaneously, we strived for equivalent allocation to the two arms (immediate and delayed), a balancing that ultimately delayed the conclusion of the study. Such sensitivity and balancing issues can be mitigated beforehand [The current study raises numerous questions for future research. For example, further analysis is important to identify whether the improvement is linked to intervention load. Interestingly, we think it is unlikely that there is a simple correlation between more sessions and improved outcomes—rather, when the intervention works optimally it is hypothesised that the participant would only need one session with the intervention per different intrusive memory. Thus, paradoxically we may expect that fewer sessions would be related to better outcomes, and a high number of sessions to be related to those who either have difficulties with using the intervention or who have a high number of different IMs on their list. Future work could also analyse individual differences in baseline number of IMs to determine how this impacts treatment response, as well as pre-existing mental health difficulties. Again, it may be the case that treatment response is not simply determined by the overall number of baseline IMs, but rather the number of different IMs on their list (i.e. distinct images/scenes from a traumatic event). It would be of interest to add a re-administration of the intrusive memory list post-intervention at the time of the primary outcome. This would allow a test of the hypothesis that use of the intervention is associated with a change in the sensory elements in the intrusive memory descriptions (hotspots) rather than say affective or cognitive elements, indicated by recent studies in both lab [As stated in the Introduction, the disruption of visuospatial processing while memory is being stored or updated should render the memory less likely to be triggered, i.e. from becoming intrusive [There is an urgent and unmet need to develop novel approaches to support the mental health of healthcare workers to continue to manage the emotionally traumatic nature of their clinical work [ | PMC10131522 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41380-023-02062-7. | PMC10131522 | ||
Acknowledgements | ® | The study was funded by the Wellcome Trust (223016/Z/21/Z). TJ is supported by a grant from UK Medical Research Council (MC_UU_00002/14). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. Tetris® has been licenced for use within i-spero® from The Tetris Company. The authors would like to thank the Intensive Care Society, in particular Dr Sandy Mather and Alex Day; Our Data Monitoring Committee members comprising Prof Andreas Reif (chair, Frankfurt am Main—Goethe University), Prof Steve Hollon (Vanderbilt University), Prof Ian Penton-Voak (Bristol University), and adjunct member Prof Michael B. Bonsall (University of Oxford); Trial Steering Committee including Prof Guy Goodwin, Pooyan Behbahani, and Rebecca Dias; Expert Advisors including Dr Nick Grey, Prof Sir Simon Wessely, and Prof Jonathon Bisson. Members of study team including Veronika Kubičková, Alfred Markham, Zunaid Islam and Marie Kanstrup for support; Our Data Management Team including Mark Dziedzic, Sameer Iqbal, and Nikita Shukan. | PMC10131522 | |
Author contributions | EAH | EAH and JK conceived the trial, gained funding, and contributed to the study design. CS and MBB provided expert input into the conception of the trial, and MBB and TJ into the study design. LI delivered the intervention, acquired the data, and with JK, JH and CS contributed to interpretation of the work. VR and MBB accessed and verified the underlying data. VR did the statistical analyses, and with MBB, EAH and PM contributed to the analysis of the work and interpretation of data. VR, PM, EAH and MBB wrote the first draft of the article. All authors contributed intellectual content, critically revised the article, and approved the submitted manuscript. | PMC10131522 | |
Funding | The study was funded by the Wellcome Trust (223016/Z/21/Z). The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. P1vital Products Ltd was the trial sponsor. Open access funding was provided by Uppsala University. | PMC10131522 | ||
Data availability | OSF | Anonymised databases with the individual participant data and the metadata for Bayesian analyses, along with a data dictionary are available on the Open Science Framework (OSF) (osf.io/m5cvj) for anyone who wishes to access the data for any purpose. The Study Protocol and Bayesian Statistical Analysis Plan are available on the OSF platform (osf.io/2xn5m). All data and supporting information mentioned above will be shared indefinitely and with no end date on the OSF platform. | PMC10131522 | |
Code availability | OSF | Analytical code files (R scripts) are available on the Open Science Framework (OSF) (osf.io/m5cvj) for anyone who wishes to access the code for any purpose. This will be shared indefinitely with no end date on the OSF platform. | PMC10131522 | |
Competing interests | EAH | The study was funded by the Wellcome Trust (223016/Z/21/Z). JK is shareholder and director of P1vital Products Ltd which is the study sponsor and manufacturer of i-spero®. VR and LI are employed by P1vital Products Ltd. MBB is an adjunct member of the DMC. CS salary is partly funded by National Institute for Health Research (NIHR133788) and Medical Research Council (MR/S035753/1 and MR/X005070/1). TJ is supported by a grant from UK Medical Research Council (MC_UU_00002/14). EAH salary is part funded by Wellcome Trust (223016/Z/21/Z) via consultancy to P1vital Products Ltd. EAH is on the Board of Trustees of the MQ Foundation. EAH also receives funding from the Swedish Research Council, Rannís The Icelandic Research Fund, OAK foundation, The Lupina Foundation and AFA Försäkring. EAH developed the intervention approach and training in using it (Anenome™). EAH receives book royalties from Guildford Press and Oxford University Press, and receives occasional honoraria for conference keynotes and clinical workshops. All other authors declare no competing interests. | PMC10131522 | |
References | PMC10131522 | |||
Purpose | hip arthroplasty, MP, THA | This study aimed to evaluate the efficacy and safety of combined methylprednisolone (MP) and tranexamic acid (TXA) in promoting accelerated rehabilitation following total hip arthroplasty (THA). We further investigated effective strategies for rapid rehabilitation post-THA. | PMC10548678 | |
Methods | nausea, MP, pain | INFLAMMATION | Conducted as a randomized controlled trial involving 80 patients, the study allocated subjects into two groups. The control group received saline and TXA, whereas the experimental group was administered with an additional dose of MP. Several clinical parameters, including markers of inflammation, pain, nausea, and coagulation factors, were meticulously assessed in both groups. | PMC10548678 |
Results | postoperative nausea and fatigue, blood glucose fluctuations, MP, pain | COMPLICATIONS | It was observed that the group receiving the MP + TXA treatment showcased significant reductions in postoperative levels of CRP and IL-6, as well as an alleviation in pain scores. Furthermore, this group demonstrated lower incidences of postoperative nausea and fatigue, facilitating enhanced hip joint mobility. Interestingly, this group did exhibit blood glucose fluctuations within the first 24 h postoperatively. However, there was no notable difference between the groups concerning transfusion rate, postoperative hospital stay duration, and coagulation profile, and no severe complications were reported. | PMC10548678 |
Conclusion | nausea, MP, fatigue, pain | PERIOPERATIVE COMPLICATION | The findings suggest that the combined administration of MP and TXA can appreciably enhance postoperative recovery, by reducing inflammatory markers, alleviating pain, reducing nausea and fatigue, and improving hip mobility, without leading to an increased risk of severe perioperative complications. This highlights the potential role of this combined therapy in facilitating improved postoperative patient experiences. | PMC10548678 |
Keywords | PMC10548678 | |||
Background | THA, terminal hip pathologies | Total Hip Arthroplasty (THA) constitutes a highly cost-effective therapeutic approach for terminal hip pathologies, as evidenced by a wide body of literature [ | PMC10548678 | |
Materials and methods | PMC10548678 | |||
Study design | thrombo-embolism, infections, hepatic and renal dysfunctions, cardio-pulmonary disorders, coagulation abnormalities, MP, THA | RHEUMATOID ARTHRITIS, TRANEXAMIC ACID ALLERGY, INFECTIONS, HEMATOLOGICAL DISORDERS, MALIGNANCIES | Our study adhered strictly to the protocols established by the Institutional Ethics Review Board of our institution and complied meticulously with the Guidelines on Standards for Reporting of Trials (CONSORT). We enrolled all patients undergoing initial Total Hip Arthroplasty (THA) in this study. However, we established exclusion criteria that included: methylprednisolone or tranexamic acid allergy, rheumatoid arthritis, existing infections, Body Mass Index (BMI) exceeding 30 kg/m2, one-stage bilateral hip replacement, revision surgery, coagulation abnormalities, hematological disorders, malignancies, severe cardio-pulmonary disorders, critical hepatic and renal dysfunctions, history of thrombo-embolism, preoperative hemoglobin less than 90 g/L, and usage of anticoagulation drugs within a week prior to surgery. The participants were randomly allocated to either the Tranexamic Acid (TXA) group or the Methylprednisolone plus Tranexamic Acid (MP + TXA) group as part of a single, single-blind, randomized controlled trial. Patient assignment was randomly ordered based on parity prior to surgery. We obtained written informed consent from each participant. | PMC10548678 |
Intervention | In the control group (TXA group, | PMC10548678 | ||
Perioperative management | thrombosis, nausea, pneumonia, hyperalgesia, Postoperative pain, PostOperative Nausea and Vomiting, pain, PONV | THROMBOSIS, PNEUMONIA, PULMONARY EMBOLISM, DEEP VEIN THROMBOSIS | All surgeries were conducted by senior orthopedic surgeons in a class-100 laminar flow operating theatre, employing either general or epidural anesthesia with a posterolateral surgical approach. The hip prostheses implanted were all uncemented and we did not place any drainage catheters.Postoperatively, the patients were transferred to the post-anesthetic recovery room, and the surgical site was padded routinely upon their return to the inpatient ward. We initiated intermittent orthopedic limb compression therapy until the patients commenced functional out-of-bed exercises. Guided by a rehabilitation therapist, all patients engaged in daily functional and walking exercises. Our strategy for managing pain and PostOperative Nausea and Vomiting (PONV) involved administering preoperative oral diclofenac sodium (100 mg tid) for hyperalgesia. Postoperative pain was evaluated using a 0–10 Visual Analogue Scale (VAS), with intramuscular tramadol (100 mg qd or bid) added when VAS exceeded 4. For severe pain (VAS > 6), intramuscular meperidine hydrochloride (100 mg qd) was given. Metoclopramide (10 mg intramuscularly) was employed as the first-line treatment for severe nausea (VAS > 4) or two or more episodes of PONV. All patients were prescribed subcutaneous naltrexone heparin calcium (0.3 mL, 2850 IU), with subsequent full doses given at 24-h intervals. Post-discharge, we administered rivaroxaban (10 mg orally qd) for 10 days to mitigate the risk of deep vein thrombosis of the lower extremities. Regular Doppler ultrasound and CT scans were used to detect thrombosis in the deep veins of the lower extremities and diagnose pneumonia or pulmonary embolism, respectively. | PMC10548678 |
Outcome measurements | blood loss, postoperative nausea and vomiting, fatigue, pain | BLOOD LOSS, COMPLICATIONS | Our primary outcome parameters included inflammatory marker (CRP and IL-6) levels at 24, 48, and 72 h post-surgery in both groups. We evaluated patients' pain levels using the VAS score, and we recorded both the quantity of pain and the amount of analgesics (tramadol and meperidine hydrochloride) used to assess the analgesic effect. We monitored postoperative blood glucose fluctuations, the incidence of postoperative nausea and vomiting, and the quantity of antiemetic medication (metoclopramide and ondansetron) used. Secondary outcomes encompassed fatigue scale (ICFS) and Range of Motion (ROM), total blood loss (calculated using the Gross formula), transfusion rates, postoperative length of stay (LOS), postoperative haemoglobin, Hematocrit (HCT) and coagulation values, and complications. | PMC10548678 |
Statistical analysis | For statistical analysis, we employed SPSS version 22.0. We reported continuous variables and mean standard deviations with a 95% confidence interval. We applied the Wilcoxon Mann–Whitney U test for numerical variables not normally distributed or anisotropic. We compared categorical variables using the Pearson χ2 test or Fisher's exact test. We considered p-values less than 0.05 to be statistically significant. | PMC10548678 | ||
Results | PMC10548678 | |||
Patient selection and baseline information | dysplasia, ONFH, MP, fatigue | OSTEONECROSIS OF THE FEMORAL HEAD, SECONDARY, DYSPLASIA, OSTEOARTHRITIS | Out of 89 consecutively screened patients, a final cohort of 80 was selected for participation in this study, following a six-month follow-up period and the application of exclusion criteria that removed 8 individuals. A further individual declined to participate. Of the remaining patients, 40 were allocated to the TXA group, while the remaining 40 were assigned to the MP + TXA group. Both primary and secondary outcomes were fully tracked over the follow-up period. Comparative baseline characteristics for both groups are provided in Table Baseline informationMP: Methylprednisolone; TXA: Tranexamic acid; n: number; CRP: C-reactive protein; IL-6: interleukin 6; Hb: Hemoglobin; Hct: Hematocrit; BMI: Body mass index; ICFS: Identity consequence fatigue scale; ASA: America anesthesia association; OA: Osteoarthritis; ONFH: Osteonecrosis of the femoral head; DDH: Development dysplasia hip; ROM: Range of motion; VAS: Visual analog scale; ASA: America anesthesia association; APTT: Activated partial thromboplastin time; y: Years; Pre-: PreoperativeCONSORT flow diagram. MP: Methylprednisolone; TXA: Tranexamic acid | PMC10548678 |
Inflammatory markers: CRP and IL-6 levels | MP | Postoperative levels of CRP and IL-6 showed an increase in comparison with preoperative levels in both treatment cohorts. Peak CRP levels were observed at 48 h postoperative; however, the MP + TXA group demonstrated lower levels at 24 h (Level of CRP in the two groups. MP:Methylprednisolone; TXA: Tranexamic acid Pre-, preoperative, post, postoperative. ****Level of IL-6 in the two groups. MP:Methylprednisolone; TXA: Tranexamic acid Pre-, preoperative, post, postoperative. **** | PMC10548678 | |
Pain evaluation and analgesic use | MP, pain | Postoperative VAS pain scores demonstrated a reduction in both treatment groups when compared to preoperative levels. At 24 h postoperatively, the MP + TXA group reported lower pain scores during both rest (Level of VAS scores at rest in the two groups. MP:Methylprednisolone; TXA: Tranexamic acid Pre-,preoperative; post, postoperative. ****Level of VAS scores at walking in the two groups. MP:Methylprednisolone; TXA: Tranexamic acid Pre-,preoperative; post, postoperative.****Consumption of analgesia and pain reliefMP: Methylprednisolone; TXA: Tranexamic acid; n: Number | PMC10548678 | |
Postoperative nausea, vomiting, and antiemetic use | PONV, postoperative nausea and vomiting, MP, Postoperative nausea and vomiting | DEEP VEIN THROMBOSIS, PULMONARY EMBOLISM, DVT | The incidence of postoperative nausea and vomiting (PONV) was significantly lower in the MP + TXA group compared to the TXA group (Secondary outcome indicators and complicationsPONV: Postoperative nausea and vomiting; ICFS: Identity-con-sequence-fatigue-scale; ROM: Range of motion; LOS: Length of hospital stay; Hb: Hemoglobin; Hct: Hematocrit; DVT: Deep vein thrombosis; PE: Pulmonary embolism; n: Number; APTT: Activated partial thromboplastin time; post: Postoperative | PMC10548678 |
Blood glucose variability | MP | BLOOD | There was no statistically significant difference in preoperative blood glucose profiles between the two groups (Level of Blood sugar fluctuations in the two groups. MP:Methylprednisolone; TXA: Tranexamic acid; Pre-, preoperative; post, postoperative.**** | PMC10548678 |
ICFS and ROM evaluation | Preoperatively, a comparison of the ICFS and ROM metrics between the two groups demonstrated no significant variation ( | PMC10548678 | ||
Blood loss, transfusion rates, and postoperative hemoglobin and hematocrit levels | blood loss | BLOOD LOSS | There were no significant differences observed between the two groups with regards to total blood loss ( | PMC10548678 |
Discussion | paresthesia, infections or gastrointestinal bleeds, postoperative nausea and vomiting, hyperglycemia, postoperative fatigue, PONV, MP, THA, trauma | HYPERGLYCEMIA, INFLAMMATION, PARESTHESIA, INTESTINAL OBSTRUCTION | In our research, we delved into the possibility of MP and TXA amalgamation to additionally lessen postoperative inflammatory reactions and stimulate swift recuperation. As far as we are aware, there is a lack of extensive research examining the effectiveness and safety of MP and TXA combined usage in patients undergoing total hip replacement procedures. The principal discoveries of our research indicate that the MP and TXA combination resulted in a significant decrease in postoperative CRP and IL-6 measurements, enhanced analgesic response, reduced the frequency of PONV and postoperative fatigue, expedited patients' rapid recovery, and did not heighten the risk of perioperative infections or gastrointestinal bleeds.Earlier investigations [Several factors contribute to postoperative nausea and vomiting (PONV), including surgical procedures, individual predisposition, the use of anesthesia and analgesic drugs, and importantly, the stimulation of inflammation. Recent studies suggest that the congregation of immune cells and inflammatory mediators, triggered by surgical trauma, may incite postoperative intestinal paresthesia or even lead to full-blown intestinal obstruction [However, the appropriate dose of MP in patients undergoing total hip arthroplasty (THA) remains contentious [Glucocorticoids administered preoperatively may induce hyperglycemia during the perioperative period [While the beneficial clinical efficacy of MP has been supported by numerous prior studies [ | PMC10548678 |
Author contributions | ZH was responsible for the design and writing of the article. Data retrieval, collection, and statistical analysis were undertaken by HD, CY, CZ, and WW. | PMC10548678 | ||
Funding | This project was sponsored by Hezhou Self-financed Project. | PMC10548678 | ||
Availability of data and materials | Data for this article were sourced from patients hospitalized at our institution for total hip arthroplasty. The data are both credible and reliable. | PMC10548678 | ||
Declarations | PMC10548678 | |||
Ethics approval and consent to participate | The paper was reviewed by the ethics committees of the affiliations of all five authors, who approved its content. All authors affirm their full compliance with ethical standards. The five authors of this article affirm that they fully comply with ethical standards. | PMC10548678 | ||
Informed Consent | Informed consent was required from the patients, and they signed to co-operate with the study. | PMC10548678 | ||
Competing interests | Neither this paper nor any of its authors have any conflicts of interest. | PMC10548678 | ||
References | PMC10548678 | |||
Key Points | PMC10474554 | |||
Question | Does patient-reported outcome measure (PROM)–based remote monitoring after hip and knee replacement surgery improve health outcomes compared with the standard of care? | PMC10474554 | ||
Findings | primary hip replacement, depression, fatigue | This multicenter randomized clinical trial included 3697 patients with primary hip replacement and 3110 with knee replacement across 9 German hospitals. The intervention group had a statistically significantly higher mean increase from baseline to 12 months after surgery in health-related quality of life score, fatigue score, and depression score compared with the control group. | PMC10474554 | |
Meaning | depression, fatigue | This randomized clinical trial found that postoperative PROM monitoring, including alerts for critical recovery, led to small improvements in several health dimensions (health-related quality of life and fatigue after hip and knee replacement and depression after hip replacement). | PMC10474554 | |
Importance | PROM, cancer | CANCER | Although remote patient-reported outcome measure (PROM) monitoring has shown promising results in cancer care, there is a lack of research on PROM monitoring in orthopedics. | PMC10474554 |
Objective | PROM | To determine whether PROM monitoring can improve health outcomes for patients with joint replacement compared with the standard of care. | PMC10474554 | |
Design, Setting, and Participants | A 2-group, patient-level randomized clinical trial (PROMoting Quality) across 9 German hospitals recruited patients aged 18 years or older with primary hip or knee replacement from October 1, 2019, to December 31, 2020, with follow-up until March 31, 2022. | PMC10474554 | ||
Interventions | PROM | Intervention and control groups received the standard of care and PROMs at hospital admission, discharge, and 12 months after surgery. In addition, the intervention group received PROMs at 1, 3, and 6 months after surgery. Based on prespecified PROM score thresholds, at these times, an automated alert signaled critical recovery paths to hospital study nurses. On notification, study nurses contacted patients and referred them to their physicians if necessary. | PMC10474554 | |
Main Outcomes and Measures | PROM, Knee Injury, Osteoarthritis, fatigue, depression, Disability | OSTEOARTHRITIS | The prespecified outcomes were the mean change in PROM scores (European Quality of Life 5-Dimension 5-Level version [EQ-5D-5L; range, −0.661 to 1.0, with higher values indicating higher levels of health-related quality of life (HRQOL)], European Quality of Life Visual Analogue Scale [EQ-VAS; range, 0-100, with higher values indicating higher levels of HRQOL], Hip Disability and Osteoarthritis Outcome Score–Physical Function Shortform [HOOS-PS; range, 0-100, with lower values indicating lower physical impairment] or Knee Injury and Osteoarthritis Outcome Score–Physical Function Shortform [KOOS-PS; range, 0-100, with lower values indicating lower physical impairment], Patient-Reported Outcomes Measurement Information System [PROMIS]–fatigue [range, 33.7-75.8, with lower values indicating lower levels of fatigue], and PROMIS-depression [range, 41-79.4, with lower values indicating lower levels of depression]) from baseline to 12 months after surgery. Analysis was on an intention-to-treat basis. | PMC10474554 |
Results | The study included 3697 patients with hip replacement (mean [SD] age, 65.8 [10.6] years; 2065 women [55.9%]) and 3110 patients with knee replacement (mean [SD] age, 66.0 [9.2] years; 1669 women [53.7%]). Exploratory analyses showed significantly better health outcomes in the intervention group on all PROMs except the EQ-5D-5L among patients with hip replacement, with a 2.10-point increase on the EQ-VAS in the intervention group compared with the control group (HOOS-PS, −1.86 points; PROMIS-fatigue, −0.69 points; PROMIS-depression, −0.57 points). Patients in the intervention group with knee replacement had a 1.24-point increase on the EQ-VAS, as well as significantly better scores on the KOOS-PS (−0.99 points) and PROMIS-fatigue (−0.84 points) compared with the control group. Mixed-effect models showed a significant difference in improvement on the EQ-VAS (hip replacement: effect estimate [EE], 1.66 [95% CI, 0.58-2.74]; knee replacement: EE, 1.71 [95% CI, 0.53-2.90]) and PROMIS-fatigue (hip replacement: EE, −0.65 [95% CI, −1.12 to −0.18]; knee replacement: EE, −0.71 [95% CI, −1.23 to −0.20]). The PROMIS-depression score was significantly reduced in the hip replacement group (EE, −0.60 [95% CI, −1.01 to −0.18]). | PMC10474554 | ||
Conclusions and Relevance | depression, fatigue | In this randomized clinical trial, the PROM-based monitoring intervention led to a small improvement in HRQOL and fatigue among patients with hip or knee replacement, as well as in depression among patients with hip replacement. | PMC10474554 | |
Trial registration | Deutsches Register Klinischer Studien ID: This randomized clinical trial evaluates whether patient-reported outcome measure monitoring can improve health outcomes for patients with joint replacement compared with the standard of care. | PMC10474554 | ||
Introduction | Patient-reported outcome measures (PROMs) are increasingly used for research and health technology assessment across indications and geographic regionsCritical recovery detection via PROMs has shown promising results in oncology, leading to higher survival rates, improved health-related quality of life (HRQOL), and reduced hospital visits.As quality variation persists and current outcome measures only partially reflect relevant outcomes after surgery, | PMC10474554 | ||
Methods | PMC10474554 | |||
Study Design | Knee Injury, Osteoarthritis | SECONDARY, OSTEOARTHRITIS | A 2-group, parallel patient-level randomized clinical trial, PROMoting Quality, was conducted across 9 German hospitals to assess a PROM-based monitoring intervention for patients with hip replacement or knee replacement. This study presents an a priori–specified analysis of the secondary outcomes. Patients were blinded to group assignment and group allocation sequence, which was digitally initiated at discharge (individual randomization) and concealed from patients, study nurses, and physicians. The study was conducted in line with the published study protocolPatients digitally received the German language versions of (1) the Hip Disability and Osteoarthritis Outcome Score–Physical Function Shortform (HOOS-PS) and Knee Injury and Osteoarthritis Outcome Score–Physical Function Shortform (KOOS-PS) to measure physical functioning, scored from 0 to 100, with lower values indicating lower physical impairmentAll PROMs are validated in German, and most PROMs are validated specifically for patients with hip replacement or knee replacement.The control group received PROMs before surgery (between admission to the hospital and surgery), at discharge, and 12 months after surgery, whereas the intervention group additionally received PROMs at 1, 3, and 6 months after surgery (step 1). Automated digital alerts signaled critical recovery paths to hospital study nurses at 1, 3, and 6 months after surgery via a digital notification in the study software of their work computer (step 2). | PMC10474554 |
Hospitals | The 9 participating hospitals included 1 university hospital, 1 nonteaching hospital, and 7 teaching hospitals. In Germany, the standard of care includes postsurgery rehabilitation in an inpatient or ambulatory care setting for 3 weeks. Five of the participating hospitals offer inpatient rehabilitation, but where patients receive rehabilitation depends on their health insurance. Both intervention and control group patients equally received the German preoperative and postoperative standard of care. Yearly case volumes per hospital in 2020 ranged from 348 to 2137 (mean, 1051) for hip replacement and from 284 to 1982 (mean, 952) for knee replacement. | PMC10474554 | ||
Patients | PROM, tumor | TUMOR | Study nurses and/or physicians aimed to include all eligible patients in the trial. Patients 18 years of age or older with prespecified surgery codes for hip replacement and knee replacement were included. Exclusion criteria were emergency and life-threatening cases, tumor prothesis, American Society of Anesthesiologists classifications 4 to 6, and patients without email access or without a relative supporting the PROM response. Randomization was triggered automatically at hospital discharge via the PROM-IT-software. A total of 6807 patients were included in the final analysis ( | PMC10474554 |
Outcomes | PROM | SECONDARY | Although the primary outcome of the PROMoting Quality trial was the cost-effectiveness of the intervention using a composite of all PROM scores, the primary outcomes of this secondary analysis are the trial’s secondary outcomes (ie, changes in individual PROM scores from baseline to 12 months after surgery). | PMC10474554 |
Statistical Analysis | PROM | Descriptive analyses were run per group and joint replacement type for the patient characteristics, PROM scores, and clinical characteristics. Analyses were separated per joint replacement type due to their different recovery durations and levels.As sensitivity analyses, the primary outcomes were assessed in a compliance-corrected sample | PMC10474554 | |
Results | PMC10474554 | |||
Patient Characteristics | Overall, 1854 patients with hip replacement (mean [SD] age, 65.9 [10.6] years; 1029 women [55.5%]) and 1564 patients with knee replacement (mean [SD] age, 66.1 [9.1] years; 839 women [53.6%]) were assigned to the intervention group, and 1843 patients with hip replacement (mean [SD] age, 65.7 [10.6] years; 1036 women [56.2%]) and 1546 patients with knee replacement (mean [SD] age, 65.9 [9.4] years; 830 women [53.7%]) were assigned to the control group ( | PMC10474554 | ||
Characteristics of the Study Population (Intention-to-Treat Population) | Knee Injury, Disability, Osteoarthritis, PROM | OSTEOARTHRITIS | Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); EQ-5D-5L, European Quality of Life 5-Dimension 5-Level version; EQ-VAS, European Quality of Life Visual Analogue Scale; HOOS-PS, Hip Disability and Osteoarthritis Outcome Score–Physical Function Shortform; KOOS-PS, Knee Injury and Osteoarthritis Outcome Score–Physical Function Shortform; PROM, patient-reported outcome measure; PROMIS, Patient-Reported Outcomes Measurement Information System.PROM scores have different score ranges: −0.661 to 1.0 for the EQ-5D-5L, 0 to 100 for the EQ-VAS, 0 to 100 for the HOOS-PS and KOOS-PS, 33.7 to 75.8 for the PROMIS-fatigue, and 41 to 79.4 for the PROMIS-depression. Higher values on the EQ-VAS and EQ-5D-5L indicate better health levels, whereas lower values on the HOOS-PS, KOOS-PS, PROMIS-fatigue, and PROMIS-depression indicate better health (less health impairment). Due to the low score range of the EQ-5D-5L, 3 digits after the decimal point are reported. | PMC10474554 |
Distriubtion of Raw Patient-Reported Outcome Measure (PROM) Scores for the Control and Intervention Groups | Knee Injury, Osteoarthritis | OSTEOARTHRITIS | Higher values on the European Quality of Life Visual Analogue Scale (EQ-VAS) indicate better health levels, whereas lower values in physical functioning (Hip Disability and Osteoarthritis Outcome Score–Physical Function Shortform or Knee Injury and Osteoarthritis Outcome Score–Physical Function Shortform [H/KOOS-PS]), Patient-Reported Outcomes Measurement Information System (PROMIS)–fatigue, and PROMIS-depression indicate better health (less health impairment). The box indicates the middle 50% of scores for the respective sample (the IQR). The line that divides the box into 2 parts indicates the median.The whiskers extend from each box to capture the range of the remaining data within ±1.5 times the IQR. Any score beyond that distance is considered an outlier and is indicated as a circle. | PMC10474554 |
Compliance in Answering the PROM Questionnaires | PROM | In the intervention group, response rates to the PROM questionnaires were at 85.3% (1582 of 1854), 87.8% (1627 of 1854), and 86.1% (1597 of 1854) at intervention time points at 1, 3, and 6 months after surgery, respectively, for patients with hip replacement and 85.1% (1331 of 1564), 85.3% (1334 of 1564), and 84.5% (1322 of 1564) at 1, 3, and 6 months after surgery, respectively, for patients with knee replacement. At 12 months after surgery, after the intervention timeframe, compliance was 84.0% (1558 of 1854) in the hip replacement intervention group, 84.9% (1565 of 1843) in the hip replacement control group, 82.4% (1288 of 1564) in the knee replacement intervention group and 82.7% (1279 of 1546) in the knee replacement control group. | PMC10474554 | |
Alerts Based on Critical PROM Scores and Reactions to Alerts | PROM | The percentage of alerts based on critical PROM scores as a share of the patients with hip replacement with available information on the critical values was 8.9% (157 of 1772) at 1 month, 25.6% (454 of 1773) at 3 months, and 24.8% (424 of 1709) at 6 months (eTable 6 in The proportion of treatment changes among patients who visited a physician in the quarter after the PROMs were asked was higher in the group of patients who were called vs those who were not called concerning some changes (eg, change in the aftercare physician at month 3 for patients with hip replacement: 9.8% [8 of 82] vs 2.5% [24 of 960]) but lower concerning other changes (eg, change in physiotherapy at month 3 for patients with hip replacement: 37.8% [31 of 82] vs 42.4% [407 of 960]) (eTable 7 in With the study protocol prescribing every patient with an alert to be called, a subanalysis of study nurses’ notes (eFigure 5 in | PMC10474554 | |
Main Analysis of the Primary Outcome: Mixed-Effect Models | After controlling for patient and treatment attributes in the mixed-effect models, the intervention showed significant effect estimates (EEs) for the changes in EQ-VAS score (EE, 1.66 [95% CI, 0.58-2.74]), PROMIS-fatigue score (EE, −0.65 [95% CI, −1.12 to −0.18]), and PROMIS-depression score (EE, −0.60 [95% CI, −1.01 to −0.18]) for patients with hip replacement (eTable 9 in The results of the mixed-effect models are visualized in | PMC10474554 | ||
Mixed-Effect Model Effect Estimates for the Intervention per Patient-Reported Outcome Measure (PROM) Score | The mixed-effect models used | PMC10474554 | ||
Discussion | PROM, fatigue | Overall, this randomized clinical trial demonstrated small, statistically significant health benefits in HRQOL and fatigue using the remote PROM monitoring intervention compared with the standard of care for patients with hip replacement and patients with knee replacement; for example, patients with hip replacement had a mean 2.10 between-group difference and 1.66 EE on the EQ-VAS, and a −0.69 between-group difference and −0.65 EE on the PROMIS-fatigue. The intention-to-treat analyses and compliance-corrected analyses confirm these results. In addition, among patients with hip replacement, a small but significant difference in the PROMIS-depression score was observed, with a −0.57 between-group difference and −0.60 EE.With regard to the clinical significance of the results, to our knowledge, there is currently no established standard for evaluating meaningful PROM score change differences between groups for all selected PROMs for patients with hip replacement or knee replacement. Considering current generic minimal important change (MIC) recommendations for PROMIS measures,Although the mean change in physical functioning (HOOS-PS and KOOS-PS) was significantly different between the intervention and control groups before adjustment, the significant difference disappeared after adjustment. This could reflect the change in this health dimension being driven by variables for which the randomization might not have completely accounted (eg, presurgery PROM scores). However, a significant difference was observed in the compliance-corrected population, with a difference of −1.85 and an EE of –0.89 for the HOOS-PS among the hip replacement group and a difference of −1.14 and an EE of –0.94 for the KOOS-PS among the knee replacement group, warranting further analysis into the relationship between compliance, alert reactions, and functional health outcomes.Due to the multistep nature of the intervention, it is unclear which aspect of the intervention caused the positive health changes. Whereas filling out the PROMs and, thus, patients reflecting more on their own health status might already have initiated change (step 1), change could have also been initiated by the reassuring idea that, if scores were critical, a health care professional would get in touch (step 2: alert to study nurses). The health changes might also have been triggered by calls or data transfers to patients by study nurses after the alerts (step 3), or by the actions based on the data transfer to physicians (step 4). Although around 70% of patients were informed about their critical values via a telephone call, around 20% received their values also or only per post or email (step 3). Given the low percentage of patients who were called and initiated PROM data transfers to physicians (hip replacement: 8.1%-21.1%; knee replacement: 7.9%-25.2%) (step 4), one could argue that earlier steps (monitoring, alerts, and calls) were more likely than the data transfer to physicians to drive the positive health changes. Considering the affected health dimensions, the results could point toward a “caring effect” through follow-up communication, rather than a “physical recovery effect” through in-person interventions. Virtual monitoring and telephone communication might have been especially relevant because the trial ran during the COVID-19 pandemic. Moreover, literature suggests that the completion of PROMs in itself can change the way in which patients think about their condition.Based on the presented information, some aspects should be considered when implementing the intervention into routine care. First, a high response rate of around 85% was achieved, in comparison with registry-based PROM collection, showing a mean response rate of 42% for digital PROMs without a reminder. | PMC10474554 | |
Strengths and Limitations | This study has some strengths. To our knowledge, it is the first randomized clinical trial evaluating the effect of PROM-based remote monitoring among patients receiving joint replacements. The randomized clinical trial design has several advantages, including randomization on the patient level, inclusion of multiple hospitals, and patient blinding, as well as the nonchangeability of group assignment via study nurses through the digital solution, and the large sample size. Moreover, the mixed-effects model accounts for several potential confounders. Because the intervention was not separated from routine care, the trial can give insights into the translation into routine practice.This study also has some limitations. The main limitation is the difficulty of isolating the intervention effect. We cannot determine which part of the intervention impacted the changes in health outcomes. Moreover, we cannot determine whether the differences were meaningful to patients or might have been partially explained through a learning effect. On the one hand, it would have been helpful to include earlier PROMs without alerts among the control group to evaluate whether a treatment effect before the 12-month mark could be observed. On the other hand, the control and intervention groups would have been more similar by both experiencing the monitoring step of the intervention. As in routine care, there might have been heterogeneity in the operationalization of the study design across hospitals. This possibility was addressed as much as possible via the study protocol, workshops, and regular check-ins with study nurses from all hospitals and controlling for the hospital in the mixed-effect model. Additionally, results might differ depending on the hospital implementing the intervention (eg, those with lower case volumes). | PMC10474554 |
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