Randomized Controlled Trials Findings Research Articles

Estimating the effects of cancer screening in clinical practice settings: The role of selective uptake and suboptimal adherence along the cancer screening continuum.

Randomized controlled trials (RCTs) are the gold standard in determining efficacy of cancer screening tests. Yet, systematic differences between RCT and the general populations eligible for screening raise concerns about the generalizability and relevance of RCT findings to guide the development and dissemination of cancer screening programs. Observational studies from clinical practice settings have documented selective uptake in screening - i.e., variation across subgroups regarding who is screened and not screened - as well as suboptimal adherence to screening recommendations, including follow-up of positive findings with subsequent imaging studies and diagnostic invasive procedures. When the effectiveness of a screening intervention varies across subgroups, and there is selective uptake and suboptimal adherence to screening in clinical practice relative to that in the RCT, the effects of screening reported in RCTs are not expected to generalize to clinical practice settings. Understanding the impacts of selective uptake and suboptimal adherence on estimates of the effectiveness of cancer screening in clinical practice will generate evidence that can be used to inform future screening recommendations and enhance shared decision-making tools.

Research protocol for an observational health data analysis to assess the applicability of randomized controlled trials focusing on newly diagnosed metastatic prostate cancer using real-world data: PIONEER IMI’s “big data for better outcomes” program

Background: Metastatic prostate cancer (PCa) constitutes ~5% of all new PCa diagnoses in Western countries. For most cases, primary consideration should be given to systemic therapies as the first-line approach based on evidence from randomized controlled trials (RCTs). Despite the importance of RCTs as the pinnacle of evidence in modern medicine, concerns have been raised about their applicability to real-life scenarios. These trials often feature participants who are younger with better performance statuses and prognoses compared to their real-world counterparts. The PIONEER project falls under the Innovative Medicine Initiative’s (IMI) “Big Data for Better Outcomes” initiative, aimed at revolutionizing PCa care in Europe. The central focus lies in improving cancer-related outcomes, enhancing health system efficiency, and elevating the quality of health and social care. This study endeavours to evaluate the generalizability of RCT findings concerning newly diagnosed metastatic PCa. Methods: A systematic review of the literature will be conducted to compile patient characteristics from RCTs addressing this subject within the past decade. To create a real-world benchmark, patients with recently diagnosed metastatic PCa from a network of population-based databases will serve as a comparison group. The objective is to assess the applicability of RCT results in two ways. First, a comparison will be made between the characteristics of patients with newly diagnosed metastatic PCa enroled in RCTs and those with the same condition included in our databases which might represent the real-world setting. Second, an evaluation will be undertaken to determine the proportion of real-world patients with newly diagnosed metastatic PCa who meet the criteria for RCT enrolment. This study will rely on extensive observational data, primarily sourced from population-based registries, electronic health records, and insurance claims data. The study cohort is established upon routinely gathered healthcare data, meticulously mapped to the Observational Medical Outcomes Partnership Common Data Model.

Clinical and physiological advances in sedentary behavior research.

Sedentary behavior, defined as sitting with low energy expenditure, has emerged as a modifiable risk factor that affects our physiology and health. Evidence for the detrimental effects of sedentary behavior/physical inactivity on health, however, stems largely from epidemiological studies, which cannot address causalities. Acute and short-term sedentary behavior reduction interventions have been performed; however, in these studies, sitting has often been replaced by formal physical activity options, such as exercise, and long-term studies in subjects with cardiometabolic risk factors are still relatively few. We have recently conducted a long-term randomized controlled trial (RCT) to reduce daily sitting, without formal exercise, in metabolic syndrome patients, and this mini-review presents these studies with physiological aspects. The findings indicate that sedentary behavior reduction can prevent the increase in levels of many cardiometabolic risk factors after 3 months, but more intense physical activity rather than only reducing daily sitting time may be needed to further reduce the risk factor levels. At 6-month time point reduced sitting reduced fasting insulin, while successfully reducing sitting and body fat had beneficial effects also on whole-body insulin sensitivity, but other effects were relatively minor. Reduced sitting did not improve maximal aerobic fitness after 6 months, but an increase in daily steps was positively associated with an increase in fitness. However, the more the participants replaced sitting with standing, the more their maximal aerobic fitness was reduced. Overall, although the analysis of the collected data is still ongoing, our RCT findings suggest that the physiological and health effects of reduced sitting are relatively minor and that physical activities such as taking more daily walking steps are needed, which would be more beneficial and time-efficient for improving human health.

The Fragility of Statistical Findings in the Femoral Neck Fracture Literature: A Systematic Review of Randomized Controlled Trials.

Randomized controlled trials (RCTs) in the femoral neck fracture literature frequently report P -values for outcomes, which have substantial implications in guiding surgical management. This study used the fragility index (FI), reverse fragility index (rFI), and fragility quotient (FQ) to assess the statistical stability of outcomes reported in RCTs evaluating the management and treatment of femoral neck fractures. PubMed, Embase, and MEDLINE were queried for RCTs (January 1, 2010 to February 28, 2023). RCTs that evaluated surgical management or treatment of femoral neck fractures were included. RCTs with 2 treatment arms reporting categorical dichotomous outcomes were included. Non-RCT studies, RCTs with greater than 2 treatment arms, and RCTs without a femoral neck fracture cohort were excluded. The FI and rFI were calculated as the number of outcome event reversals required to alter statistical significance for significant ( P < 0.05) and nonsignificant ( P ≥ 0.05) outcomes, respectively. The FQ was calculated by dividing the FI by the sample size for the study. Nine hundred eighty-five articles were screened, with 71 studies included for analysis. The median FI across a total of 197 outcomes was 4 [interquartile range (IQR) 2-5] with an associated FQ of 0.033 (IQR 0.017-0.060). Forty-seven outcomes were statistically significant with a median FI of 2 (IQR 1-4) and associated FQ of 0.02 (IQR 0.014-0.043). One hundred fifty outcomes were statistically nonsignificant with a median rFI of 4 (IQR 3-5) and associated FQ of 0.037 (IQR 0.019-0.065). Statistical findings in femoral neck fracture RCTs are fragile, with reversal of a median 4 outcomes altering significance of study findings. The authors thus recommend standardized reporting of P -values with FI and FQ metrics to aid in interpreting the robustness of outcomes in femoral neck fracture RCTs. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Statistical Fragility of Marrow Stimulation for Cartilage Defects of the Knee: A Systematic Review of Randomized Controlled Trials.

Marrow stimulation is used to address knee cartilage defects. In this study, we used the fragility index (FI), reverse fragility index (rFI), and fragility quotient (FQ) to evaluate statistical fragility of outcomes reported in randomized controlled trials (RCTs) evaluating marrow stimulation. PubMed, Embase, and MEDLINE were queried for recent RCTs (January 1, 2010-September 5, 2023) assessing marrow stimulation for cartilage defects of the knee. The FI and rFI were calculated as the number of outcome event reversals required to alter statistical significance for significant and nonsignificant outcomes, respectively. The FQ was determined by dividing the FI by the study sample size. Across 155 total outcomes from 21 RCTs, the median FI was 3 (interquartile range [IQR], 2-5), with an associated median FQ of 0.067 (IQR, 0.033-0.010). Thirty-two outcomes were statistically significant, with a median FI of 2 (IQR, 1-3.25) and FQ of 0.050 (IQR, 0.025-0.069). Ten of the 32 (31.3%) outcomes reported as statistically significant had an FI of 1. In total, 123 outcomes were nonsignificant, with a median rFI of 3 (IQR, 2-5). Studies assessing stem cell augments were the most fragile, with a median FI of 2. In 55.5% of outcomes, the number of patients lost to follow-up was greater than or equal to the FI. Statistical findings in RCTs evaluating marrow stimulation for cartilage defects of the knee are statistically fragile. We recommend combined reporting of P-values with FI and FQ metrics to aid in the interpretation of clinical findings in comparative trials assessing cartilage restoration.

Evaluating Physician-AI Interaction for Multiple Myeloma Management: Paving the Path Towards Precision Oncology

Introduction The gap between clinical trials and real-world care continues to grow in the field of multiple myeloma (MM). Randomized controlled trials (RCTs) cannot account for every patient scenario. Modern clinical decision support systems (CDSSs) that leverage machine learning (ML) models offer an alternate path to precision oncology. However, little work has been done to understand how clinicians reconcile RCT with ML data, particularly when results are discordant. Aim We designed a CDSS that displays simulated survival and adverse event data from an RCT and ML model and conducted a survey study to evaluate how clinicians incorporate the available data to make treatment decisions for 12 patients with MM. Methods Participants were presented with varying combinations of RCT and ML results in increasing “tiers” of information for 12 patients (A-L) with MM (Table 1). In tier 1, participants were provided RCT data only. In tier 2, participants were given outcomes of an ML model and in tier 3, they were provided with information about how the model was trained and validated. At each tier, participants were asked to select a treatment (“red pill” or “blue pill”), rate their confidence in treatment on a Likert scale from 1-10, and when ML data was available, rate their perceived reliability of the model on a Likert scale from 1-10. Participants were recruited from internal medicine and hematology/oncology departments via email between January and April 2023, and were offered a $50 Amazon gift card as incentive. We used descriptive statistics to analyze respondent characteristics. For each scenario, we ran two-sample paired t-tests to compare the change in confidence and reliability between tier 2 and tier 1 (ML versus RCT data) and tier 3 versus tier 2 (ML data with information about training and validation versus without). We utilized a Bonferroni correction to adjust the alpha level for significance. We also ran McNemar's tests with a Bonferroni correction to assess the difference in proportions of blue pill selection at different tiers to characterize the extent of treatment switching. Results A total of 284 physicians were invited to participate in the study and 32 participated, for a response rate of 11.3%. Half were internal medicine residents and half were hematology/oncology fellows and attendings. A majority were male (72.0%), white (69.0%) and all were less than 40 years of age. For scenarios A-D, the patient met inclusion criteria for the RCT and was well represented in training data for the ML model. Confidence was highest for scenario A where survival results between the RCT and ML model were concordant (Figure 1). Across scenarios B, C, and D, confidence dropped after seeing the ML results (B: p=0.05, C: p=0.05, D: p=0.36) but increased after participants learned the ML model was trained on patients like theirs (B: p=.002, C: p=0.17, D: p=0.06). In scenarios C and D, a majority of participants switched treatment after learning the ML model showed no benefit with the red pill (C: p=5.1x10 -4, D: p=1.5x10 -5). In scenarios E-H, the patient did not meet inclusion criteria for the RCT but was well represented in the training data for the ML model. When the ML model showed worse adverse events (F) or no benefit with the red pill (G, H) the majority of participants switched treatment choice (F: p=0.27, G: p=0.002, H: p=1.9x10 -4). There was an increase in confidence when participants learned the ML model had been trained on representative patients (E: p=0.008, F: p=0.01, G: p=0.18, H: p=2.0x10 -3). In scenarios I-L, the patient did not meet inclusion criteria for the RCT and was not well represented in the training data for the ML model. There was a decrease in confidence when participants learned this in tier 3 (I: p=0.18, J: p=3.0x10 -4, K: p=0.05, L: p=0.009). However, the majority of participants still switched to the blue pill when the ML model showed no benefit with the red pill (K: p=1.9x10 -4). Conclusions Confidence in treatment was highest when RCT and ML findings were concordant. Participants chose treatments based on ML model estimates even before assessing how the ML model was trained or validated. Participants preferred the treatment that demonstrated a survival benefit, regardless of whether it was supported by RCT data or an ML model.

Abstract 073: Thrombectomy Alone Versus Bridging Intravenous Alteplase in A US Population: Regression Discontinuity Analysis

Introduction Recent randomized controlled trials (RCT) failed to demonstrate the non‐inferiority of skipping IV tPA in patients with planned endovascular therapy (EVT). None of these studies included patients from the US due to regulatory challenges. Given that practice patterns vary relative to Asia, Australia, and Europe, we sought to address this topic using a validated alternative to RCTs, regression discontinuity (RD). Methods From the prospectively collected SVIN Registry encompassing all consecutive patients treated with EVT from 12 centers across the US, we identified patients from 12/2010 – 12/2021. RD design achieves quasi‐randomization and can determine causal effects by analyzing subjects on immediately adjacent sides of a cutoff. Here, we take advantage of the sharp drop in the likelihood of IV tPA treatment at the 4.5‐hour mark from the patients’ last known well time. Subjects immediately on either side of the cutoff have markedly different probabilities of receiving the treatment while sharing similar characteristics in other relevant aspects. Patients were excluded if they underwent EVT after inter‐hospital transfer, were inpatient at the time of acute ischemic stroke (AIS), received IV tPA outside the 4.5‐hour window, or were treated with EVT after the 10‐hour window, as these patients would not contribute to the RD analysis. The primary outcome was a good functional outcome defined as 90‐day mRS 0‐2 and was analyzed using validated RD analysis methods with local linear regressions and triangular kernel weights. Secondary endpoints included rates of symptomatic intracranial hemorrhage and substantial reperfusion. Results Among 961 patients who met inclusion criteria, all 12 EVT centers within the SVIN Registry were represented. The median age was 70 [IQR 58‐79], 48% were female, NIHSS was 17, and the most common occlusion location was M1 MCA (45%). There were no substantial differences in presentation characteristics between patients treated with IV tPA and without. We observed a significant fall (30%) in the probability of tPA around the cutoff time of 235 minutes from the last known well to hospital arrival (allowing 35 minutes for in‐hospital evaluation from the 4.5‐hour cutoff), while there were no significant differences in other relevant features including age, NIHSS, ASPECTS, and final reperfusion grade at the cutoff, validating the underlying RD assumptions (Figure A). In RD analysis, we observed no association between IV tPA treatment and functional independence at 90‐days in patients undergoing EVT (risk difference ‐0.29 (95% CI [‐2.75 to 2.15]) (Figure B), nor in the secondary outcomes of excellent outcomes (mRS 0‐1) at 90 days, mortality, symptomatic ICH or first pass reperfusion. Conclusion Here, we perform what we believe to be the strongest study to date examining the benefit of IV tPA in patients undergoing EVT for LVO AIS in a US‐based cohort, and we find no evidence of association with 90‐day functional independence, consistent with findings of RCTs performed outside the US.

The Hans Kai trial: study protocol of a mixed methods randomized controlled trial evaluating a peer-led health promotion program for adults with or without noncommunicable diseases

BackgroundA significant proportion of Canadian adults is impacted by chronic noncommunicable diseases. These conditions may be improved by peer-led health promotion interventions that target modifiable risk factors; however, to date, there is mixed evidence on the effectiveness of these interventions. Unlike other health promotion programs, Hans Kai is grounded in a holistic model of health that simultaneously addresses multiple determinants of health at different levels of human ecology. In Hans Kai, a set of informational sessions that are delivered in a group setting by healthcare professionals are followed by regular peer-led group meetings in a self-governed support group setting that is designed to promote implementation of newly learned health competences. The Hans Kai trial described here aims to evaluate the efficacy of the Hans Kai program in promoting the health and wellbeing of its participants and investigate the experiences of the Hans Kai participants and facilitators.MethodsThis research will involve a mixed methods trial combining an experimental component with a qualitative component. The experimental component will involve a 6-month 2-group parallel superiority randomized controlled trial (RCT) in which 105 participants will be randomly assigned to two conditions, an intervention group (n = 70) that will participate in the Hans Kai program and a control group (n = 35) that will have access to standard care using a computer-generated random sequence; blinding will not occur. The RCT will test the impact of the program on several health outcomes and will be followed by a 12–18-month observational follow-up study that will provide data on the long-term durability of the 6-month RCT health outcomes. The qualitative component will investigate the experiences of program participants (n = 30) and facilitators (n = 15) to identify the main strengths and limitations of Hans Kai, uncover potential implementation issues, and elucidate the mechanisms through which the program works. The population of interest will include adults aged 18 + with or without chronic health conditions who self-report an interest in taking control of their own health and improving their lifestyle. In the RCT, all outcomes of interest will be measured using a multi-method approach, involving self-report questionnaires and objective indicators, and within-subject mean changes in outcomes over time between the two groups will be compared to address the RCT aims. Similarly, in the qualitative component, a multi-method approach, involving in-depth individual interviews, photovoice, and online surveys, will be used to reach a deeper and more nuanced understanding of the program strengths, how the program works, and for which people it is more effective. Adaptable components of the program will also be investigated and modified according to the feedback provided by the RCT participants. In the mixed methods integration of evidence, the qualitative findings will be used to explain the quantitative RCT results.DiscussionThe RCT findings will help support the further development and use of Hans Kai as well as other peer-led health promotion interventions.Trial registrationUnited Stated Clinical Trial Registry ClinicalTrials.gov (registration# NCT03949725; Protocol version 2, June 22nd, 2022).

Adequate effectiveness of ribociclib plus letrozole or fulvestrant in patients with advanced or metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer treated in routine Bulgarian clinical practice

Randomized controlled trials (RCTs) are typically conducted in highly selected patient populations to ideally demonstrate unconfounded clinical efficacy of a drug. In the real world, there may be confounding factors, such as comorbidities or less frequent monitoring. It has therefore become standard practice in many countries to validate findings from RCTs against available real-world datasets. The present analysis investigated a real-world evidence (RWE) cohort of Bulgarian patients treated with ribociclib in combination with letrozole or fulvestrant and compared the clinical benefit rate (CBR, defined as complete remission [CR] or partial remission [PR] or stable disease [SD]) and progression-free survival (PFS) and overall survival (OS) with pivotal RCTs. Data from 812 patients treated between 2018 and 2022 were used. The number of patients at risk was statistically robust to compare PFS and OS during the earlier periods of the real-world data analysis with the corresponding RCTs. Baseline characteristics (age, hormone receptor status, status of newly diagnosed vs. existing, previous treatments, performance status and tumor stage) were largely comparable between the RWE cohort and the RCTs. The RWE cohorts corroborated RCT findings of a CBR benefit of the ribociclib plus letrozole or fulvestrant combination compared to letrozole or fulvestrant alone. In the periods of adequate statistical robustness, PFS and OS were comparable within 95% confidence intervals (CIs) with RCT findings. This analysis found that patients with comparable characteristics use ribociclib in the real-world similarly to what has been investigated in the RCTs. Real-world effectiveness and outcomes of ribociclib combination therapy were comparable with observations from RCTs.

The Fragility of Statistical Significance in Sham Orthopaedic Surgery: A Systematic Review of Randomized Controlled Trials.

The purpose of this study was to determine the stability of statistical findings among sham surgery randomized controlled trials (RCTs) in orthopaedic surgery using fragility analysis. PubMed systematic review was conducted to include studies reporting dichotomous outcomes pertaining to sham surgery. The final review included eight RCTs involving only partial meniscectomies and vertebroplasties from 2009 to 2020. With a fixed sample size with dichotomous outcome measures (events versus non-events), the Total Fragility Index (TFI), which is composed of the fragility index (FI) and reverse fragility index (RFI), was calculated by altering the ratio of events to non-events in an iterative fashion until results were reversed from significant to nonsignificant findings (FI) or vice versa (RFI). The TFI, FI, and RFI were divided by their sample sizes to obtain the respective total fragility quotient, fragility quotient (FQ), and reverse fragility quotient. Median fragility indices and quotients were reported for all studies. The eight RCTs included 50 dichotomous outcomes involving either partial meniscectomies or vertebroplasties, with a median TFI and total fragility quotient of 5 [interquartile range (IQR) 4 to 6] and 0.035 (IQR 0.028 to 0.048), respectively, indicating that a median of five total patients or 3.5 per 100 patients would need to experience a different outcome to reverse significant or insignificant findings for each of the eight trials. Among the 8 statistically significant ( P < 0.05) outcome events (16%), the respective FI and FQ were 2 (IQR 1 to 5) and 0.018 (IQR 0.010 to 0.044). Among the 42 statistically insignificant outcome events (84%), the respective RFI and reverse fragility quotient were 5 (IQR 4 to 6) and 0.04 (IQR 0.034 to 0.048). The median number of patients lost to follow-up was 1.5 (IQR 0.5 to 2). The unstable findings in partial meniscectomy and vertebroplasty sham surgical RCTs undermine their study conclusions and recommendations. We recommend using fragility analysis in future sham surgical RCTs to contextualize statistical findings. Level IV; Systematic Review.

Lowering the statistical significance threshold of randomized controlled trials in three major general anesthesiology journals.

The primary objective of our study was to determine how lowering a P value threshold from 0.05 to 0.005 would affect the statistical significance of previously published randomized controlled trials (RCTs) in major anesthesiology journals. We searched the PubMed database for studies electronically published in 2020 within three major general anesthesiology journals as indexed by both Google Metrics and Scimago Journal & Country Rank. Studies included were RCTs published in 2020 in Anesthesiology, Anesthesia & Analgesia, and the British Journal of Anaesthesia; had a primary endpoint, and used a P value threshold to determine the effect of the intervention. We performed screening and data extraction in a masked duplicate fashion. Ninety-one RCTs met inclusion criteria. The most frequently studied type of intervention was drugs (44/91, 48%). From the 91 trials, 99 primary endpoints, and thus P values, were obtained. Fifty-eight (59%) endpoints had a P value < 0.05 and 41 (41%) had a P value ≥ 0.05. Of the 58 primary endpoints previously considered statistically significant, 21 (36%) P values would maintain statistical significance at P < 0.005, and 37 (64%) would be reclassified as "suggestive." Lowering a P value threshold of 0.05 to 0.005 would have altered one third of significance interpretations of RCTs in the surveyed anesthesiology literature. Thus, it is important for readers to consider post hoc probabilities when evaluating clinical trial results. Although the present study focused on the anesthesiology literature, we suggest that our results warrant further research within other fields of medicine to help avoid clinical misinterpretation of RCT findings and improve quality of care.

Implementation of an mHealth intervention to increase adherence to triage among HPV positive women with HPV—self-collection (ATICA study): post-implementation evaluation from the women's perspective

BackgroundLow adherence to triage after positive screening is a widespread problem for cervical cancer screening programs in Low- and Middle-income Countries. Adherence to cytology-based triage can be challenging, especially among women with self-collected tests. SMS-based interventions are accepted by women and can increase screening uptake. The ATICA study was an effectiveness-implementation hybrid type I trial, combining a cluster randomized controlled trial (RCT) with a mixed-methods implementation evaluation involving quantitative and qualitative methods. Although the RCT provided evidence regarding the effectiveness of the SMS-based intervention, less is known about its acceptability, relevance, and usefulness from the women´s perspective.MethodsWe carried out a cross-sectional study based on a structured questionnaire among HPV-positive women who were enrolled in ATICA's intervention group. We measured acceptability, appropriateness, and message content comprehension. Also, we evaluated if the SMS message was considered a cue to encourage women to pick up their HPV test results and promote the triage.ResultsWe interviewed 370 HPV-positive women. Acceptability of SMS messages among women who had received at least one message was high (97%). We found high levels of agreement in all appropriateness dimensions. More than 77% of women showed high comprehension of the content. Among women who received at least one SMS message, 76% went to the health center to pick up their results. Among those who got their results, 90% reported that the SMS message had influenced them to go. We found no significant differences in acceptability, appropriateness or message comprehension between women who adhered to triage and those who did not adhere after receiving the SMS messages.ConclusionThe intervention was highly acceptable, and women reported SMS was an appropriate channel to be informed about HPV test results availability. SMS was also a useful cue to go to the health center to pick up results. The implementation did not encounter barriers associated with the SMS message itself, suggesting the existence of other obstacles to triage adherence. Our results support the RCT findings that scaling up SMS is a highly acceptable intervention to promote cervical screening triage adherence.

Postmarket Surveillance for Effective Regulation of Digital Mental Health Treatments.

Postmarket Surveillance for Effective Regulation of Digital Mental Health Treatments.

THE HIPHOP STUDY: A FEASIBILITY STUDY FOR A RANDOMIZED CONTROLLED TRIAL OF HYBRID VERSUS CEMENTED TOTAL HIP ARTHROPLASTY

Studies have shown that 10–30% patients do not achieve optimal function outcomes after total hip replacement (THR). High quality randomised controlled trials (RCTs) evaluating the clinical and cost-effectiveness of techniques to improve functional outcomes after THR are lacking. We performed this study to evaluate the feasibility of a RCT comparing patient-reported functional outcomes after hybrid or fully cemented THR (ISRCTN11097021).Patients were recruited from two centres and randomised to receive either a fully cemented or hybrid THR. Data collection included Patient Reported Outcome Measures (PROMs), non-serious adverse events of special interest (AESI), serious adverse device effects (SADE) and NHS resource use. Qualitative interviews were undertaken to understand a) patient experiences of study processes and their reasons for taking part or not, and b) to understand surgeons’ perceptions of the study, factors affecting willingness to participate, and barriers to implementation of the future RCT findings.The target of 40 patients were successfully recruited for the feasibility RCT; the ratio of successful recruitment to eligible patients was 0.61 across both sites. Treatment crossovers occurred in four patients, all related to bone quality. Four patients were withdrawn due to not undergoing surgery within the study window because of the pandemic. Follow-up was 100% and PROMs were completed by all patients at all time points. The feasibility of conducting a within-trial cost-utility analysis was demonstrated. Interviews were conducted with 27 patients and 16 surgeons. Patients and surgeons generally found the study procedures acceptable and workable. Some declined participation because they did not want treatment allocated at random, or because blinding was off-putting. Surgeons’ perceptions of equipoise varied, and implementation of findings from the future RCT would need to recognise the ‘craft’ nature of surgery and the issue of training.We conclude that a full RCT with economic analysis will be both feasible and practicable, although mechanisms to safely implement potential changes to practice because of RCT findings may need consideration by the wider arthroplasty community.

What Four Decades of Meta-Analysis Have Taught Us About Youth Psychotherapy and the Science of Research Synthesis.

Intervention scientists have published more than 600 randomized controlled trials (RCTs) of youth psychotherapies. Four decades of meta-analyses have been used to synthesize the RCT findings and identify scientifically and clinically significant patterns. These meta-analyses have limitations, noted herein, but they have advanced our understanding of youth psychotherapy, revealing (a) mental health problems for which our interventions are more and less successful (e.g., anxiety and depression, respectively); (b) the benefits of single-session interventions, interventions delivered remotely, and interventions tested in low- and middle-income countries; (c) the association of societal sexism and racism with reduced treatment benefit in majority-girl and majority-Black groups; and, importantly, (d) the finding that average youth treatment benefit has not increased across five decades of research, suggesting that new strategies may be needed. Opportunities for the future include boosting relevance to policy and practice and using meta-analysis to identify mechanisms of change and guide personalization of treatment. Expected final online publication date for the Annual Review of Clinical Psychology, Volume 19 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Individual participant data sharing intentions and practices during the coronavirus disease-2019 pandemic: A rapid review

Abstract The coronavirus disease-2019 (COVID-19) pandemic has led to the irrational use of drugs in the absence of clinical management guidelines. Access to individual participant data (IPD) from clinical trials aids the evidence synthesis approaches. We undertook a rapid review to infer IPD sharing intentions based on data availability statements by the principal investigators (PIs) of drug and vaccine trials in the context of COVID-19. Searches were conducted on PubMed (NCBI). We considered randomized controlled trial (RCT) publications from January 1, 2020, to October 31, 2021. IPD sharing intentions were inferred based on the data availability statements in the full-text manuscript publications. We included 180 articles. Of these, 81.7% (147/180) of the publications have arrived from the findings of the RCTs alone, 12.8% (23/180) of the publications were protocol publications alone, and 5.6% (10/180) of the RCTs had both published protocol and publication from the trial findings. We have reported IPD sharing intentions separately in RCT protocol publications (n = 23 + 10) and publications from RCT findings (n = 147 + 10). Among RCT protocol publications, one-third (11/33) of the PIs intended to share IPD. In fact, over half of the PIs (52.2%, 82/157) in their published RCT findings intended to share IPD. However, information to share about IPD was missing for 57.6% (19/33) of RCT protocols and 38.2% (60/157) of published RCT findings. Stakeholders must work together to ensure that overarching factors, such as legislation that governs clinical trial practices, are streamlined to bolster IPD sharing mechanisms.

OP92 Impact Of Real-World Evidence On Health Technology Assessment And National Guidance For Interventional Procedures: A UK Perspective

IntroductionThe National Institute for Health and Care Excellence (NICE) interventional procedures programme (IPP) issues guidance on the safety and efficacy of new interventional procedures (IPS). The IPP considers a range of evidence from randomized controlled trials (RCTs) to case series to make final recommendations. Real-world evidence (RWE) can provide additional information on long-term outcomes and patient population characteristics that are not easily captured by RCTs. This study explores the impact of RWE in complementing RCTs on long-term safety and efficacy for national guidance development.MethodsWe review the impact of RWE in IPS guidance (IPG) updates and change in guidance recommendations in the last 5 years. This is done by analyzing NICE guidance updates and supporting evidence. A range of RWE was considered in the supporting evidence, for example, registries and clinical audits.ResultsThe addition of RWE evidence to IPP guidance update has led to significant changes in the recommendations. For example, in one recent IPG, standard arrangements recommendation based on short-term RCT evidence was changed to a research recommendation when RWE showed an increase in long-term adverse effects. In another recent IPG update, special arrangements recommendation based on short-term RCT evidence was changed to a research recommendation when RWE reported long-term inferior efficacy and safety for the new intervention compared to current standard of care. A complete overview of results of the last 5 years will also be presented at the meeting.ConclusionsThese findings indicate that increased availability of RWE in HTA has the potential to impact national guidance recommendations. In addition, it shows how RWE can fill the evidence base gaps created by RCTs. Such data can confirm or contradict the findings of RCTs, or generate questions needing further research, or support disinvestment in non-effective technologies.

Real-World Comparison of Direct Oral Anticoagulants to Warfarin Among Patients with Atrial Fibrillation/Flutter Managed By an Anticoagulation Service

Introduction: The use of warfarin to prevent ischemic stroke in patients with atrial fibrillation/flutter (AF) requires routine international normalized ratio monitoring and frequent dose adjustments to optimize time in therapeutic range (TTR). While TTR are generally low in usual care, anticoagulation services are associated with improved TTR and clinical outcomes. The direct oral anticoagulants (DOAC) are preferred to warfarin for AF as randomized controlled trial (RCT) data have shown they are as effective in preventing stroke with a lower risk of bleeding, particularly intracranial hemorrhage, compared to warfarin. However, the mean TTR for warfarin-treated patients enrolled in these RCT were relatively modest (55-65%); thus, it is unclear if clinical outcomes would differ if patients in the RCT control groups had been managed by an anticoagulation service. The purpose of this study was to evaluate the real-world effectiveness and safety of DOAC compared to warfarin among patients with AF followed by an anticoagulation service. Methods: This was a retrospective, longitudinal cohort study conducted at Kaiser Permanente Colorado, an integrated healthcare delivery system with a pharmacist-managed anticoagulation service. Adult patients diagnosed with AF, newly initiated on a DOAC or warfarin, and enrolled in the service between 11/01/2015 and 12/31/2018 were followed until anticoagulant switch/discontinuation, a study outcome, membership termination, or 01/05/2019, whichever came first. The index date was the date of service enrollment. TTR and percent of days covered (PDC, a measure of medication adherence) were calculated for the warfarin and DOAC patients, respectively. The primary outcome was a composite of all-cause mortality, clinically-relevant bleeding, ischemic stroke, or systemic embolism. Secondary outcomes included the individual components of the primary outcome as well as follow-up healthcare utilization. Multivariate Cox proportional hazards (reported as adjusted hazard ratio [aHR] with 95% confidence interval [CI]) and negative binomial (reported as adjusted incidence rate ratio [aIRR] with 95% CI) regression analyses were performed to assess differences between groups. All aspects of this study were reviewed and approved by the KPCO Institutional Review Board before data collection. Results: There were 2928 patients included with 1537 and 1391 warfarin and DOAC patients, respectively. The cohort was primarily older, male, and white with moderate burden of chronic disease and baseline healthcare utilization. Warfarin patients had a mean TTR of 72% and were more likely to be female and Medicaid beneficiaries and have had dementia, depression, and pulmonary disease comorbidities (all p<0.05). DOAC patients had a mean PDC of 83% and were more likely to have had a baseline hospitalization (p<0.05). With adjustment for age, sex, Charlson comorbidity index, race, Medicaid status, baseline healthcare utilization, dementia, depression and pulmonary disease comorbidities, patients on a DOAC had an associated lower risk of the primary composite outcome (aHR 0.75, 95% CI 0.62 - 0.91), any clinically-relevant bleeding (aHR 0.68, 95% CI 0.51 - 0.92), gastrointestinal bleeding (aHR 0.62, 95% CI 0.46 - 0.54), systemic embolism (aHR 0.59, 95% CI 0.36 - 0.95), and follow-up hospitalization (aIRR 0.76, 95% CI 0.65 - 0.89) (Table). DOAC patients had equivalent risks of ischemic stroke, all-cause mortality, intracerebral bleeding, and follow-up emergency department visits (all p>0.05). Conclusions: This retrospective analysis of a large sample of real-world patients with AF managed by an anticoagulation service identified that DOAC use was associated with improved safety compared to warfarin. Despite high-quality warfarin management, use of DOAC was associated with lower risks of clinically-relevant bleeding, systemic embolism, and hospitalization compared to patients receiving warfarin for AF which reinforce the application of RCT findings to health systems with available anticoagulation management services. Future real-world studies should be conducted to confirm our findings with multiple healthcare delivery systems, a larger sample size, and assessments of the individual DOAC versus warfarin to provide further evidence of the effectiveness and safety of DOAC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D.

Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, randomized controlled trials (RCTs) have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status affects several nonskeletal health outcomes, including Alzheimer’s disease and dementia, autoimmune diseases, cancers, cardiovascular disease, COVID-19, major depressive disorder, type 2 diabetes, arterial hypertension, all-cause mortality, respiratory tract infections, and pregnancy outcomes. We also consider relevant findings from ecological, Mendelian randomization, and mechanistic studies. Although clear discrepancies exist between findings of observational studies and RCTs on vitamin D and human health benefits these findings should be interpreted cautiously. Bias and confounding are seen in observational studies and vitamin D RCTs have several limitations, largely due to being designed like RCTs of therapeutic drugs, thereby neglecting vitamin D’s being a nutrient with a unique metabolism that requires specific consideration in trial design. Thus, RCTs of vitamin D can fail for several reasons: few participants’ having low baseline 25(OH)D concentrations, relatively small vitamin D doses, participants’ having other sources of vitamin D, and results being analyzed without consideration of achieved 25(OH)D concentrations. Vitamin D status and its relevance for health outcomes can usefully be examined using Hill’s criteria for causality in a biological system from results of observational and other types of studies before further RCTs are considered and those findings would be useful in developing medical and public health policy, as they were for nonsmoking policies. A promising approach for future RCT design is adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels suggested by findings from observational studies.

Spin in Randomized Controlled Trials in Obstetrics and Gynecology: A Systematic Review.

Objectives:The objective of this study was to evaluate the extent, type, and severity of spin in randomized controlled trials (RCTs) in obstetrics and gynecology.Data Sources:The top five highest impact journals in obstetrics and gynecology were systematically searched for RCTs with non-significant primary outcomes published between January 1, 2019, and December 31, 2020.Methods:Study selection and data extraction assessment were conducted independently and in duplicate. The extent, type, and severity of spin was identified and reported with previously established methodology, and risk of bias was assessed with the Cochrane Risk-of-Bias 2 Tool independently and in duplicate. Fisher's exact tests were used to evaluate the association between study characteristics, risk of bias, and spin.Results:We identified 1475 publications, of which 59 met our inclusion criteria. Articles evaluated interventions in obstetrics (n = 37, 63%) and gynecology (n = 22, 37%). Spin was not detected in 28 (47%) of the articles: Three (5%) had one, 10 (17%) had two, and 18 (31%) had greater than two occurrences of spin. Compared with articles where no spin was detected, spin was associated with the Cochrane Risk-of-Bias domain pertaining to missing data (p < 0.05). No association was observed with the journal, funding source, number of authors, types of interventions, and whether the study involved gynecology or obstetrics.Conclusions:Spin was detected in nearly half of 1:1 parallel two-arm RCTs in obstetrics and gynecology, highlighting the need for caution in the interpretation of RCT findings, particularly when the primary outcome is nonsignificant.