Current Randomized Controlled Trials Research Articles

Vitamin D Supplementation for Patients with Dysmenorrhoea: A Meta-Analysis with Trial Sequential Analysis of Randomised Controlled Trials.

Vitamin D reduces prostaglandin levels and inflammation, making it a promising treatment option for dysmenorrhoea. However, its effects on pain intensity in different types of dysmenorrhoea remain unclear. We examined whether vitamin D supplementation decreases pain intensity in patients with dysmenorrhoea. The Cochrane Library, Embase, Google Scholar, Medline, and Scopus databases were searched from inception to 30 December 2023. Randomised controlled trials (RCTs) evaluating vitamin D supplementation effects on such patients were included. The primary and secondary outcomes were measured by the changes in pain intensity and rescue analgesic use, respectively. Pooled mean differences and rate ratios were calculated using a random-effect model; trial sequential analysis (TSA) was also performed. Overall, 11 studies involving 687 participants were included. Vitamin D supplementation significantly decreased pain intensity in patients with dysmenorrhoea compared with controls (pooled mean difference, -1.64; 95% confidence interval, -2.27 to -1.00; p < 0.001; CoE, moderate; I2 statistic, 79.43%) and indicated substantial heterogeneity among the included studies. TSA revealed that the current RCTs provide sufficient information. In subgroup analyses, vitamin D supplement reduced primary dysmenorrhoea pain but not secondary dysmenorrhoea pain. In conclusion, although substantial heterogeneity persists, vitamin D supplementation decreased pain intensity in patients with dysmenorrhea, especially in those with primary dysmenorrhoea.

Prucalopride and Bowel Function Post Gastrointestinal Surgery: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Prolonged postoperative ileus (PPOI) contributes to morbidity and prolonged hospitalization. Prucalopride, a selective 5-hydroxytryptamine receptor agonist, may enhance bowel motility. This review assesses whether the perioperative use of prucalopride compared to placebo is associated with accelerated return of bowel function post gastrointestinal (GI) surgery. OVID, CENTRAL, and EMBASE were searched as of January 2024 to identify randomized controlled trials (RCTs) comparing prucalopride and placebo for prevention of PPOI in adult patients undergoing GI surgery. The primary outcomes were time to stool, time to flatus, and time to oral tolerance. The secondary outcomes were incidence of PPOI, length of stay (LOS), postoperative complications, adverse events, and overall costs. The Cochrane risk of bias tool for randomized trials and the Grading of Recommendations, Assessment, Development, and Evaluations framework were used. An inverse variance random effects model was used. From 174 citations, 3 RCTs with 139 patients in each treatment group were included. Patients underwent a variety of GI surgeries. Patients treated with prucalopride had a decreased time to stool (mean difference 36.82 hours, 95% CI 59.4 to 14.24 hours lower, I2 = 62%, low certainty evidence). Other outcomes were not statistically significantly different (very low certainty evidence). Postoperative complications and adverse events could not be meta-analyzed due to heterogeneity; yet individual studies suggested no significant differences (very low certainty evidence). Current RCT evidence suggests that prucalopride may enhance postoperative return of bowel function. Larger RCTs assessing patient important outcomes and associated costs are needed before routine use of this agent.

Prophylactic Radiotherapy Of MInimally Symptomatic Spinal Disease (PROMISSeD): study protocol for a randomized controlled trial

BackgroundEarly palliative/pre-emptive intervention improves clinical outcomes and quality of life for patients with metastatic cancer. A previous signal-seeking randomized controlled trial (RCT) demonstrated that early upfront radiotherapy to asymptomatic or minimally symptomatic high-risk osseous metastases led to reduction in skeletal-related events (SREs), a benefit driven primarily by subgroup of high-risk spine metastasis. The current RCT aims to determine whether early palliative/pre-emptive radiotherapy in patients with high-risk, asymptomatic or minimally symptomatic spine metastases will lead to fewer SREs within 1 year.MethodsThis is a single-center, parallel-arm, in-progress RCT in adults (≥ 18 years) with ECOG performance status 0–2 and asymptomatic or minimally symptomatic (not requiring opioids) high-risk spine metastases from histologically confirmed solid tumor malignancies with > 5 sites of metastatic disease on cross-sectional imaging. High-risk spine metastases are defined by the following: (a) bulkiest disease sites ≥ 2 cm; (b) junctional disease (occiput to C2, C7-T1, T12-L2, L5-S1); (c) posterior element involvement; or (d) vertebral body compression deformity > 50%. Patients are randomized 1:1 to receive either standard-of-care systemic therapy (arm 1) or upfront, early radiotherapy to ≤ 5 high-risk spine lesions plus standard-of-care systemic therapy (arm 2), in the form of 20–30 Gy of radiation in 2–10 fractions. The primary endpoint is SRE, a composite outcome including spinal fracture, spinal cord compression, need for palliative radiotherapy, interventional procedures, or spinal surgery. Secondary endpoints include (1) surrogates of health care cost, including the number and duration of SRE-related hospitalizations; (2) overall survival; (3) pain-free survival; and (4) quality of life. Study instruments will be captured pre-treatment, at baseline, during treatment, and at 1, 3, 6, 12, and 24 months post-treatment. The trial aims to accrue 74 patients over 2 years to achieve > 80% power in detecting difference using two-sample proportion test with alpha < 0.05.DiscussionThe results of this RCT will demonstrate the value, if any, of early radiotherapy for high-risk spine metastases. The trial has received IRB approval, funding, and prospective registration (NCT05534321) and has been open to accrual since August 19, 2022. If positive, the trial will expand the scope and utility of spine radiotherapy.Trial registrationClinicalTrials.Gov NCT05534321. Registered September 9, 2022.Trial statusVersion 2.0 of the protocol (2021-KOT-002), revised last on September 2, 2022, was approved by the WCG institutional review board (Study Number 1337188, IRB tracking number 20223735). The trial was first posted on ClinicalTrials.Gov on September 9, 2022 (NCT05534321). Patient enrollment commenced on August 19, 2022, and is expected to be completed in 2 years, likely by August 2024.

Estimation of treatment effects in early-phase randomized clinical trials involving external control data

ABSTRACT There are good reasons to perform a randomized controlled trial (RCT) even in early phases of clinical development. However, the low sample sizes in those settings lead to high variability of the treatment effect estimate. The variability could be reduced by adding external control data if available. For the common setting of suitable subject-level control group data only available from one external (clinical trial or real-world) data source, we evaluate different analysis options for estimating the treatment effect via hazard ratios. The impact of the external control data is usually guided by the level of similarity with the current RCT data. Such level of similarity can be determined via outcome and/or baseline covariate data comparisons. We provide an overview over existing methods, propose a novel option for a combined assessment of outcome and baseline data, and compare a selected set of approaches in a simulation study under varying assumptions regarding observable and unobservable confounder distributions using a time-to-event model. Our various simulation scenarios also reflect the differences between external clinical trial and real-world data. Data combinations via simple outcome-based borrowing or simple propensity score weighting with baseline covariate data are not recommended. Analysis options which conflate outcome and baseline covariate data perform best in our simulation study.

MIRACLE2 Score Compared With Downtime and Current Selection Criterion for Invasive Cardiovascular Therapies After OHCA

BackgroundThe MIRACLE2 score is the only risk score that does not incorporate and can be used for selection of therapies after out-of-hospital cardiac arrest (OHCA). ObjectivesThis study sought to compare the discrimination performance of the MIRACLE2 score, downtime, and current randomized controlled trial (RCT) recruitment criteria in predicting poor neurologic outcome after out-of-hospital cardiac arrest (OHCA). MethodsWe used the EUCAR (European Cardiac Arrest Registry), a retrospective cohort from 6 centers (May 2012-September 2022). The primary outcome was poor neurologic outcome on hospital discharge (cerebral performance category 3-5). ResultsA total of 1,259 patients (total downtime = 25 minutes; IQR: 15-36 minutes) were included in the study. Poor outcome occurred in 41.8% with downtime <30 minutes and in 79.3% for those with downtime >30 minutes. In a multivariable logistic regression analysis, MIRACLE2 had a stronger association with outcome (OR: 2.23; 95% CI: 1.98-2.51; P < 0.0001) than zero flow (OR: 1.07; 95% CI: 1.01-1.13; P = 0.013), low flow (OR: 1.04; 95% CI: 0.99-1.09; P = 0.054), and total downtime (OR: 0.99; 95% CI: 0.95-1.03; P = 0.52). MIRACLE2 had substantially superior discrimination for the primary endpoint (AUC: 0.877; 95% CI: 0.854-0.897) than zero flow (AUC: 0.610; 95% CI: 0.577-0.642), low flow (AUC: 0.725; 95% CI: 0.695-0.754), and total downtime (AUC: 0.732; 95% CI: 0.701-0.760). For those modeled for exclusion from study recruitment, the positive predictive value of MIRACLE2 ≥5 for poor outcome was significantly higher (0.92) than the CULPRIT-SHOCK (Culprit lesion only PCI Versus Multivessel PCI in Cardiogenic Shock) (0.80), EUROSHOCK (Testing the value of Novel Strategy and Its Cost Efficacy In Order to Improve the Poor Outcomes in Cardiogenic Shock) (0.74) and ECLS-SHOCK (Extra-corporeal life support in Cardiogenic shock) criteria (0.81) (P < 0.001). ConclusionsThe MIRACLE2 score has superior prediction of outcome after OHCA than downtime and higher discrimination of poor outcome than the current RCT recruitment criteria. The potential for the MIRACLE2 score to improve the selection of OHCA patients should be evaluated formally in future RCTs.

Exclusion of pregnant and lactating persons from breast cancer clinical trials: a review of active trials registered on ClinicalTrials.gov.

Treatment of pregnancy-associated breast cancer is complex, as providers try to balance risks to the pregnant person and the developing fetus. Given increased case fatality and increasing incidence, there is a pressing need understand the efficacy and safety of different treatment regimens in this population; however, pregnant and lactating people have traditionally been excluded from participating in randomized controlled trials (RCTs). Given recent efforts to expand the inclusion criteria for oncology RCTs, this study aimed to review the inclusion/exclusion criteria of current breast cancer RCTs to assess what proportion of trials permitted enrollment of pregnant and lactating persons. We conducted a comprehensive search of ClinicalTrials.gov in January 2022 to identify interventional studies of breast cancer in adults that were actively recruiting. The primary outcomes were the exclusion of pregnant and lactating people. The search identified 1706 studies, of which 1451 met eligibility criteria. Overall, 69.4% and 54.8% of studies excluded pregnant and lactating people, respectively. The exclusion of pregnant and lactating persons differed by study characteristics but extended across all trial designs, locations, phases and interventions. Exclusion of pregnant and lactating persons was most common in trials where the intervention was biological (86.3%), drug (83.5%) or radiation (81.5%). The exclusion of pregnant and lactating people from clinical trials contributes to evidence gaps in how to treat this population. A paradigm shift is needed that focuses on how research can be used to protect pregnant people from future harms, instead of protecting pregnant people from research-related risks.

Outcomes of Transarterial Embolisation (TAE) vs. Transarterial Chemoembolisation (TACE) for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Although hepatocellular carcinoma is increasingly common, debate exists surrounding the management of patients with unresectable disease comparing transarterial embolisation (TAE) or transarterial chemoembolisation (TACE). This study aimed to compare the outcomes of patients receiving TAE and TACE. A systematic review was performed using PubMed, Medline, Embase, and Cochrane databases to identify randomised controlled trials (RCTs) until August 2021. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and adverse events. Five studies with 609 patients were included in the analysis. There was no statistically significant difference in the OS (p = 0.36) and PFS (p = 0.81). There was no difference in OS among patients treated with a single TACE/TAE versus repeat treatments. Post-procedural adverse effects were higher in the TACE group but were not statistically significant. TACE has comparable long-term survival and complications profile to TAE for patients with HCC. However, the low-to-moderate quality of current RCTs warrants high-quality RCTs are necessary to provide enough evidence to give a definitive answer and inform treatment plans for the future.

Effects of an eating club for people with a psychotic disorder on personal recovery: Results of a randomized controlled trial

Background and objectivesMany people with a psychotic disorder are coping with severe psychosocial limitations related to their illness. The current randomized controlled trial (RCT) investigates the effects of an eating club intervention (HospitalitY (HY)) aimed to improve personal and societal recovery. MethodsIn 15 biweekly sessions participants received individual home-based skill training and guided peer support sessions in groups of three participants from a trained nurse. A multi-center RCT was conducted (intended sample size: n = 84; n = 7 per block) in patients with a diagnosis of schizophrenia spectrum receiving community treatment. HospitalitY was compared to a Waiting List Control (WLC) condition at three time points (baseline, end-of-treatment (8 months) and follow-up (12 months)) using personal recovery as primary outcome and loneliness, social support, self-stigma, self-esteem, social skills, (social) functioning, independency competence, and psychopathology as secondary outcomes. Outcomes were evaluated with a mixed modeling statistical procedure. ResultsThe HY-intervention had no significant effects on personal recovery or secondary outcomes. More attendance was associated with higher scores on social functioning. LimitationsWith N = 43 participants included, power was insufficient. Seven HY-groups were started, from which three discontinued before the sixth meeting, one HY group stopped due the start of the COVID-19 pandemic. ConclusionsDespite a promising pilot study on feasibility, the current RCT did not show any effects of the HY intervention. A mixed qualitative-quantitative research methods might be more appropriate for researching the HospitalitY-intervention to investigate what social and cognitive processes are at play in this peer guided social intervention.

Antibiotics in the non-surgical treatment of peri-implantitis.

Four electronic databases (MEDLINE via Pubmed; EMBASE via Ovid; EBSCO Dentistry and Oral Science Source), in addition to six related journals (Clinical Implant Dentistry and Related Research; Clinical Oral Implants Research; International Journal of Oral and Maxillofacial Implants; International Journal of Oral Implantology; Journal of Clinical Periodontology; Journal of Periodontology), were searched for publications until 2022. Randomised controlled trials (RCTs), evaluating the effectiveness of local or systemic antibiotics as an adjunct in the non-surgical treatment (NST) for peri-implantitis (PI), were assessed. The eligibility criteria included RCTs with a parallel group, split-mouth design and appropriate NST interventions over a three to twelve month period. Data were extracted from RCTs to capture a multitude of primary outcomes, including: implant success rate, radiographic marginal bone loss rate, periodontal health changes and PI resolution. Risk of bias assessments were made using the Cochrane Collaboration's tool, by two authors independently and in duplicate. RCTs with similar observation periods and interventions were included in the meta-analyses. Random-effects meta-analyses of mean differences or relative risks with 95% confidence intervals were calculated, in additional to data heterogeneity calibration through I2 statistics. Following the screening of 270 papers, six RCTs were included, which resulted in the evaluation of 391 patients (375 implants). Adjunctive local antibiotic therapy at disease sites showed statistically significant periodontal outcomes; improvements in success rate (risk ratio = 9.89; 95% CI 2.39-40.84), probing pocket depth (mean difference (MD) = 0.6 mm; 95% CI 0.42-0.78) and bleeding on probing (MD = 0.15%; 95% CI 0.10-0.19). Conversely, adjunctive systemic antibiotics improved probing pocket depths (MD = 1.15 mm; 95% CI 0.31-1.99) and probing attachment levels only (MD = 1.10 mm; 95% CI 0.13-2.08). Across the six included RCTs, the bone loss rate and PI resolution rate determined no significant differences between the groups; mirrored in the single studies and in the meta-analysis. Disease resolution ranged from 2 to 65%. Two of the studies were found to be at low risk of bias and four presented with some concerns. Adjunctive antibiotics aid NST. However, the heterogeneity of study methods and low quality of current RCTs evidenced, deem their role in NSTs of PI as inconclusive.

Unit information prior for incorporating real-world evidence into randomized controlled trials.

Randomized controlled trials (RCTs) have been widely recognized as the gold standard to infer the treatment effect in clinical research. Recently, there has been growing interest in enhancing and complementing the result in an RCT by integrating real-world evidence from observational studies. The unit information prior (UIP) is a newly proposed technique that can effectively borrow information from multiple historical datasets. We extend this generic approach to synthesize the non-randomized evidence into a current RCT. Not only does the UIP only require summary statistics published from observational studies for ease of implementation, but it also has clear interpretations and can alleviate the potential bias in the real-world evidence via weighting schemes. Extensive numerical experiments show that the UIP can improve the statistical efficiency in estimating the treatment effect for various types of outcome variables. The practical potential of our UIP approach is further illustrated with a real trial of hydroxychloroquine for treating COVID-19 patients.

LESSONS FROM THE IMPLEMENTATION OF THE TRANSITIONAL CARE MODEL DURING THE COVID-19 PANDEMIC

Abstract Multiple randomized controlled trials (RCTs) evaluating the Transitional Care Model (TCM)- an advanced practice registered nurse-led (APRN), team-based, care management strategy- have shown improved outcomes for older adults transitioning from hospital to home. In the current RCT, enrollment of older adults hospitalized with heart failure, chronic obstructive pulmonary disease, or pneumonia began in February 2020, just as the COVID-19 pandemic developed across the U.S. The COVID-19 pandemic dramatically impacted healthcare delivery across diverse local contexts. This parallel convergent mixed methods study aimed to explore the implementation of the TCM intervention as intended during Year 2 of the RCT (February 2021 to January 2022). This mixed-methods analysis presents the challenges and strategies to a key TCM component, “hospital-to-home,” which focuses on delivering in-person visits to patients, as identified through a qualitative descriptive analysis of 63 clinical team and leadership meetings combined with implementation fidelity data collected simultaneously on 188 TCM participants. In Year 2 of the trial, COVID-19-specific challenges continued, including COVID-19 exposure, policy changes, patients declining services, and limited safety equipment. Some challenges to the hospital-to-home TCM component occurred regardless of COVID-19, including patient (e.g., lack of engagement), nurse provider (e.g., TCM learning curve), and system (e.g., reduced primary care access) barriers. Collectively, these challenges resulted in lower fidelity to APRNs visit patterns during TCM delivery. Strategies to address these challenges were identified. The findings provide critical insight into how to target quality improvement strategies to improve the delivery of services, such as the TCM, from hospital to home settings.

Associations between therapist factors and treatment efficacy in randomized controlled trials of trauma-focused cognitive behavioral therapy for children and youth: A systematic review and meta-analysis.

Previous research suggests that the effect of therapist factors on patient outcomes is significant. Yet, to date, no reviews have explored the potential effects of therapist characteristics on treatment outcomes for children and youth with posttraumatic stress disorder (PTSD). This systematic review and meta-analysis aimed to summarize the professional characteristics of trial therapists delivering trauma-focused cognitive behavioral interventions (TF-CBT) for child PTSD in clinical trials and understand the association between treatment efficacy and therapist factors. Systematic searches for randomized controlled trials (RCTs) published through November 3, 2020, were conducted; 40 RCTs were included in the full review. PTSD treatment outcome data were extracted from each publication along with any available data regarding trial therapists. Subgroup analyses were conducted to compare the outcomes of interventions conducted by different types of therapists. All therapist groups yielded significant effects for TF-CBT relative to active and passive control conditions, with the largest effect size, Hedges' g = -1.11, for RCTs that used clinical psychologists and psychiatrists. A significant moderating effect was found when comparing the treatment outcomes of clinical psychologists and psychiatrists versus other professionals, p = .044; however, this effect was no longer apparent when only studies with an active control arm were included. Further moderator analyses demonstrated no significant differences regarding therapists' educational and professional backgrounds and PTSD treatment outcomes. The current RCT evidence for TF-CBT for children and youth with PTSD does not suggest that therapist educational or professional background influences treatment efficacy. Limitations and implications for future research are discussed.

A24 GENERALIZABILITY OF CROHN’S DISEASE RANDOMIZED CONTROLLED TRIALS COMPARED TO CLINICAL PRACTICE

BackgroundThere are no curative medical therapies for Crohn’s disease (CD). However, multiple novel treatment options are currently being evaluated in randomized controlled trials (RCTs). Historically, CD populations enrolled in RCTs have not reflected the heterogeneity of patients observed in clinical practice due to strict inclusion/exclusion criteria and protocolized trial procedures do not reflect day-to-day care. These factors have raised concerns that results from pivotal RCTs required for drug approval are poorly generalizable.AimsTo assess the generalizability of CD RCTs, we evaluated the proportion of CD patients initiating ustekinumab or vedolizumab in clinical care who would have been eligible for enrolment in the corresponding phase 3 registrational induction trial, and the factors impacting trial eligibility.MethodsThis is a retrospective cohort study using data from two ambulatory IBD clinics in Calgary, AB. Our study population included consecutive adult (>=18 years) patients with a confirmed diagnosis of CD, newly initiated on ustekinumab or vedolizumab between January 1, 2018 and January 1, 2020. We then applied the inclusion/exclusion criteria from the phase 3 GEMINI II/III and UNITI I/II induction trials to determine the proportion of patients who would have been trial-eligible. We then tabulated the indications for trial exclusion to determine the characteristics of patients who would not have been reflected in the trial population.ResultsA total of 50 patients were included. The median age was 42.5 years. Most patients non-stricturing non-penetrating disease (44%, 22/50) and ileocolonic disease distribution (48%, 24/50). A total of 66% (33/50) would have been eligible for inclusion in GEMINI II/III and (30/50) 60% would be eligible for inclusion in UNITI I/II. The most common reasons for trial exclusion included extensive surgery (total colectomy/subtotal colectomy) with short bowel or ileostomy (n=12), surgery within 6 months of enrolment (n=3), multiple previous resections (n=2). Four patients were excluded based on intra-abdominal abscess. A total of 13 patients (26%) were temporarily ineligible due to recent biologic switch and would have required an 8-week washout prior to trial enrolment. Only two patients were excluded based on age (>80 years).ConclusionsAlthough most patients on ustekinumab or vedolizumab would have been eligible for the respective pivotal trials, patients who have complications of disease, extensive surgery, or altered anatomy are not reflected in current RCTs.Funding AgenciesNone

P643 Generalizability of Crohn’s disease randomized controlled trials compared to clinical practice

Abstract Background There are no curative medical therapies for Crohn’s disease (CD). However, multiple novel treatment options are currently being evaluated in randomized controlled trials (RCTs). Historically, CD populations enrolled in RCTs have not reflected the heterogeneity of patients observed in clinical practice due to strict inclusion/exclusion criteria and protocolized trial procedures do not reflect day-to-day care. These factors have raised concerns that results from pivotal RCTs required for drug approval are poorly generalizable. The aim of this study is to assess the generalizability of CD RCTs. We evaluated the proportion of CD patients initiating ustekinumab or vedolizumab in clinical care who would have been eligible for enrolment in the corresponding phase 3 registrational induction trial, and the factors impacting trial eligibility. Methods This is a retrospective cohort study using data from two ambulatory IBD clinics in Calgary, AB. Our study population included consecutive adult (&amp;gt;=18 years) patients with a confirmed diagnosis of CD, newly initiated on ustekinumab or vedolizumab between January 1, 2018 and January 1, 2020. We then applied the inclusion/exclusion criteria from the phase 3 GEMINI II/III and UNITI I/II induction trials to determine the proportion of patients who would have been trial-eligible. We then tabulated the indications for trial exclusion to determine the characteristics of patients who would not have been reflected in the trial population. Results A total of 50 patients were included. The results are outlined in Table 1. The median age was 42.5 years. Most patients had non-stricturing non-penetrating disease (44%, 22/50) and ileocolonic disease distribution (48%, 24/50). A total of 66% (33/50) would have been eligible for inclusion in GEMINI II/III and (30/50) 60% would be eligible for inclusion in UNITI I/II. The most common reasons for trial exclusion included extensive surgery (total colectomy/subtotal colectomy) with short bowel or ileostomy (n=12) and surgery within 6 months of enrolment (n=3), multiple previous resections (n=2). Four patients were excluded based on intra-abdominal abscess. A total of 13 patients (26%) were temporarily ineligible due to recent biologic switch and would have required an 8-week washout prior to trial enrolment. Only two patients were excluded based on age (&amp;gt;80 years). Conclusion Although most patients on ustekinumab or vedolizumab would have been eligible for the respective pivotal trials, patients who have complications of disease, extensive surgery, or altered anatomy are not reflected in current RCTs.

Clinical research in homeopathy: asking the right questions

Identifying the ‘right’ clinical research questions in homeopathic medicine requires that the targets for that research are clearly and optimally defined. The definition of such targets depends, in turn, on a full and clear understanding of the current research evidence base. Moreover, it is crucial to retain a scientifically objective and consistent approach that is not distracted by extremes of opinion on either side of the debate about the research evidence in homeopathy.&#x0D; &#x0D; The main focus logically must be on randomised controlled trials (RCTs) because, despite reservations about their application to homeopathy research in the past, they are the only available way to prove cause and effect of an intervention. Many commentators, however, have failed to distinguish between the findings of placebo- and other-than-placebo (OTP)- controlled trials, while the individualised style of the normal homeopathic intervention and the main effects anticipated from that intervention have not always been properly reflected. Thus, the interpretation of findings in terms of ‘efficacy’ or ‘effectiveness’ of the intervention is often unclear.&#x0D; &#x0D; Our method of ‘vote counting’ the results of RCTs in homeopathy has enabled a clear categorisation of the research evidence, together with an opportunity to reflect condition-specific findings. That approach is not without flaws, however, and a more appropriate and sophisticated systematic review (SR) of the RCT evidence would be additionally helpful. Previous SRs of RCTs in homeopathy have typically failed to provide clear conclusions about the effectiveness of homeopathy as a system of medicine or about the efficacy of particular medicines. This is largely the result of a failure to distinguish: individualised from non-individualised homeopathy; treatment from prophylaxis; and internal validity (risk of bias) from model validity (‘state of the art’ practice and relevant outcome measures). And SRs have paid little attention to the potency of the homeopathic medicines used, to reviewing OTP-controlled RCTs, or to distinguishing between research published in the peer-reviewed and the non-peer-reviewed literature.&#x0D; &#x0D; A clearer and more complete awareness of the current RCT evidence will emerge from the above SR programme, which is now in progress. Importantly, the attributes of homeopathy and study design that it addresses can be fully reflected in answering the key questions that are then applied to new RCTs in homeopathy.

To Cement or Not to Cement: Have We Answered the Question?: Commentary on an article by Hasan R. Mohammad, MBChB, MRes(Dist), MRCS (Eng), DPhil(Oxon), et al.: "A Matched Comparison of the Long-Term Outcomes of Cemented and Cementless Total Knee Replacements, Based on Data from National Databases. An Analysis from the National Joint Registry of England, Wales, Northern Ireland and the

Commentary The debate regarding the optimal method of fixation in total knee arthroplasty (TKA) has continued for almost 40 years, beginning with case series and culminating recently with intermediate-term results from randomized controlled trials (RCTs). The ongoing interest in this debate is justified: TKA patients are getting younger, making implant longevity a priority; post-TKA dissatisfaction remains prevalent, leading to the question of whether implant fixation contributes to pain; and infection is still the most common reason for revision, prompting the desire to simplify surgery and reduce operative time. The popularity of cementless TKA has very recently increased, as reflected in the 2020 annual reports of the Australian Orthopaedic Association National Joint Replacement Registry and the American Joint Replacement Registry. Yet, to date, there have been few long-term (>10-year) large-scale studies that have investigated the clinical outcomes of cemented versus cementless TKA, while accounting for pertinent variables such as age, body mass index, and bone quality. Mohammad and colleagues have challenged this gap in the literature by conducting a rigorous propensity-score-matched cohort analysis of 22,477 patients treated with cementless TKA and 22,477 patients treated with cemented TKA from 2004 to 2018 with Great Britain’s National Joint Registry (NJR). This is the largest long-term matched analysis of TKA outcomes according to fixation type. Their results can be interpreted differently, depending on where your personal loyalties lie. Cement advocates will point out the lower overall implant survival rate, higher rate of reoperation (but not of component revision), and higher rate of revision for pain associated with cementless TKA. Cement cynics will stress the lower infection rate, lower overall reoperation rate, and lower aseptic loosening rate in patients <65 years of age associated with cementless TKA. Regardless of these differences, the study found that both fixation techniques exhibited a survival probability of >95%. Furthermore, historical concerns associated with cementless fixation, including early loosening and periprosthetic fractures, were not observed, nor were older designs associated with higher failure rates. Are the above results enough to encourage the masses to abandon cement in primary TKA? In isolation, probably not. However, the mounting evidence creates a compelling argument. Over the last 10 years, 6 separate RCTs comparing fixation techniques have found little difference in revision rates or survival1-6, at least in the short term. Does the internal consistency of each of these trials apply to your clinical practice? Not universally, but for a young patient who presents with good bone quality, mild/moderate deformity, and no predictors of poor postoperative pain coping, what strong argument exists against attempting cementless TKA? One may be able to point to the observation that cementless components tend to migrate more in the first 3 months to 2 years, but cemented components do so as well, sometimes even to a greater extent7. It is true that several important questions remain: what happens to the current RCT data at intermediate and long-term milestones? Are implant revisions easier with one type of fixation versus the other? Does fixation survival differ in mechanically versus kinematically aligned TKA? Is there an optimal porous surface coverage and keel/stem length that stands above other designs? Evidently, it will take more high-quality studies to answer all of these questions, but that should not necessarily stop surgeons from being selective in their clinical decisions. For now, it is clear that cement is certainly here to stay in primary TKA, especially in older, osteoporotic patients. However, we appear to be headed to what has already happened in hip arthroplasty—a recognition that a one-method-fits-all approach does not work for every patient. I congratulate the authors in helping us get one step closer to this reality.

Silicone gel sheeting for treating hypertrophic scars.

Silicone gel sheeting for treating hypertrophic scars.

Eligibility for mechanical circulatory support devices based on current and past randomised cardiogenic shock trials.

Mechanical circulatory support devices (MCS) are potentially effective treatments for cardiogenic shock (CS) and are thus evaluated in several randomised controlled trials (RCTs). However, it is not clear how enrolment criteria of these RCTs apply to a real-world CS population. This study aimed to shed light on eligibility to these trials. Pragmatic enrolment criteria for the IABP-SHOCK II, the DanGer-SHOCK, the ECLS-SHOCK and the EURO-SHOCK trials were retrospectively applied to 1305 CS patients admitted to a tertiary care hospital between 2009 and 2019. Based on this, major enrolment criteria were identified and outcome between eligible and ineligible patients was assessed. In this study, 415 (31.8%) patients were eligible for any study. Lowest eligibility was observed for DanGer-SHOCK (11.9%) and the highest for IABP-SHOCK II (26.9%). Over all trials, inclusion criteria were more restrictive than exclusion criteria and absence of CS caused by acute myocardial infarction (AMI) was the primary reason for non-eligibility. However, even in CS caused by AMI, enrolment criteria were only met in 65.4% of patients. Importantly, 30-day mortality was high across all patients/trials, irrespective of eligibility or non-eligibility. The present study highlights that current and past RCTs only reflect about a third of the overall CS population. While enrolment criteria are a necessary aspect of RCTs, their application limits generalisability of the trials' findings. More trials on CS sub-populations not represented by current or past trials, e.g. CS not caused by AMI, are needed, especially as mortality is high irrespective of eligibility status.

Does exercise prevent major non-communicable diseases and premature mortality? A critical review based on results from randomized controlled trials.

Observational studies show that physical activity is strongly associated with a reduced risk of premature mortality and major non-communicable diseases. We reviewed to which extent these associations have been confirmed in randomized controlled trials (RCTs) for the outcomes of mortality, cardiovascular disease (CVD), type 2 diabetes (T2D), and fracture. The results show that exercise does not reduce all-cause mortality and incident CVD in older adults or in people with chronic conditions, based on RCTs comprising ∼50,000 participants. The results also indicate a lack of effect on cardiovascular mortality in people with chronic conditions, based on RCTs comprising ∼11,000 participants. Furthermore, there is inconsistent evidence regarding the effect of exercise on fractures in older adults, based on RCTs comprising ∼40,000 participants. Finally, based on RCTs comprising ∼17,000 participants, exercise reduces T2D incidence in people with prediabetes when combined with dietary modification, although evidence for the individual effect of exercise is lacking. Identified shortcomings of the current evidence include risks of publication bias, lack of high-quality studies in certain high-risk populations, and inconstant evidence with respect to some outcomes. Thus, additional large trials would be of value, especially with fracture as the primary outcome. In conclusion, according to current RCT evidence, exercise can prevent T2D assuming it is combined with dietary intervention. However, the current evidence shows that exercise does not prevent premature mortality or CVD, with inconsistent evidence for fractures.

Efficacy and safety of cerebral embolic protection systems during transcatheter aortic valve replacement: a review of current clinical findings

ABSTRACT Introduction Cerebrovascular events are one of the most serious consequences after transcatheter aortic valve replacement (TAVR). More than half of the cerebrovascular events following TAVR are due to procedure-related emboli. Embolic protection devices (EPDs) have the potential to decrease cerebrovascular events during TAVR procedure. However, randomized controlled trials (RCTs) have not conclusively determined if EPDs are effective, likely because of small number of patients enrolled. However, meta-analyses and propensity-matched analyses from large registries have shown efficacy and suggest the importance of EPDs in prevention of stroke during TAVR and perhaps other structural heart procedures. Areas covered This review will focus on clinical and histopathologic studies examining the efficacy, safety, and histopathologic device capture findings in the presence and absence of EPDs during TAVR procedures. Expert opinion Clinical studies have not conclusively determined the efficacy of EPDs. Current ongoing large-scale RCT (PROTECTED TAVR [NCT04149535]) has the potential to prove their efficacy. Histopathological evaluation of debris captured by EPDs contributes to our understanding of the mechanisms of TAVR procedure-related embolic events and suggests the importance of preventing cerebral embolization of debris released during this and other structural heart procedures.