Controlled Trial Evidence Research Articles

Key requirements for achieving EU-wide programme change

Abstract Issue Across the world, thousands of projects aim for equitable improvement in health for people who are experiencing ongoing avoidable stigma, discrimination and disadvantage however very little change is often achieved. Description of the problem In this presentation we explore key requirements for project-level change to ensure EU-wide programme change is achieved. Results The two most common causes of project failure are a) the innovation is not suitable, needed or wanted (also called theory failure) or b) implementation failure. This presentation shares strategies to mitigate risks of project failure through co-design processes and communication, drawing from 30 years of experience from the entire implementation process from ideation to scale up. These experiences include projects from over 30 countries, including partnerships with the World Health Organization, governments and industry focused on health literacy, self-management, care pathways, workplace health, hospital services redesign, First Nations health and migrant health. Common success factors include balancing top-down needs with co-designed inputs and with previous preferred or good practice (which may have come from controlled trial evidence generated in different contexts). The intervention must co-implemented to serve stakeholder’s needs at all levels, from citizens to decision makers. Lessons The United Nations (UN) and private sector apply system-wide approaches to affect large scale change. This knowledge is valuable for large public health programmes aiming to integrate equity and diversity in project processes to minimize implementation failure.

A Review and Economic Analysis of the Dapivirine Vaginal Ring as HIV Pre-Exposure Prophylaxis for Women, to Inform South African Public-Sector Guidelines.

South Africa has a high HIV incidence and oral pre-exposure prophylaxis (PrEP) is available as public-sector standard of care. Access to alternative prevention methods for women may further reduce HIV acquisition. South African public sector. We performed a systematic search for high-quality up-to-date guidelines recommending dapivirine rings as PrEP using the Grading of Recommendations Assessment, Development, and Evaluation -Adolopment process. We appraised the systematic review and randomized controlled trial (RCT) evidence underpinning the selected guideline's recommendations and conducted a cost-effectiveness analysis. The Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework guided the adaptation of source guideline recommendations, according to our local context. We identified the 2021 World Health Organization PrEP Guidelines, informed by 2 placebo-controlled RCTs, which were included in a contemporaneous systematic review. There were 23 fewer HIV acquisitions per 1000 clients with dapivirine ring vs placebo (95% confidence interval: 10 to 34), with no increase in adverse events (moderate certainty evidence). We found no RCTs comparing dapivirine to oral PrEP or among adolescent/pregnant/breastfeeding clients. Dapivirine is less cost-effective than oral PrEP at $14.59/ring, at the current price. The source guideline recommendation was adapted for the local context. Dapivirine ring seems to be less efficacious than oral PrEP, although comparative studies are lacking. Data on adolescents and pregnancy are also lacking, currently limiting the use of dapivirine as an alternative for women unable to take oral PrEP. At the current price, dapivirine is not cost-effective and unaffordable for inclusion in the South African Essential Medicines List.

The Potential Effectiveness of Front-of-Pack Nutrition Labeling for Improving Population Diets.

Nutrition labeling on the front of food packages can support more healthful purchase decisions and encourage favorable reformulation. This systematic literature review applied Cochrane methods to synthesize and appraise the evidence on the effectiveness of front-of-pack labeling (FOPL) on diet-related outcomes and food reformulation to inform policy recommendations. The search was conducted on 11 academic and gray literature databases, from inception to July 2022. Evidence was synthesized using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation), vote counting, and meta-analyses, where appropriate. Overall, 221 articles were included in the review. The randomized controlled trial evidence suggested that, compared with when no FOPL was present, FOPL likely improved consumer understanding of the nutritional quality/content of foods (moderate certainty of evidence), and the healthfulness of food choices (moderate certainty) and purchases (moderate certainty). Interpretive FOPL had a greater effect on these outcomes compared with noninterpretive systems (moderate certainty). There was inconsistency in the best-performing interpretive FOPL system.

Feasibility of Indirect Treatment Comparisons Between Niraparib Plus Abiraterone Acetate and Other First-Line Poly ADP-Ribose Polymerase Inhibitor Treatment Regimens for Patients with BRCA1/2 Mutation-Positive Metastatic Castration-Resistant Prostate Cancer.

Poly(ADP-ribose) polymerase inhibitors (PARPi) are a novel option to treat patients with metastatic castration-resistant prostate cancer (mCRPC). Niraparib plusabiraterone acetate and prednisone (AAP) is indicated for BRCA1/2 mutation-positive mCRPC. Niraparib plus AAP demonstrated safety and efficacy in the phase 3 MAGNITUDE trial (NCT03748641). In the absence of head-to-head studies comparing PARPi regimens, the feasibility of conducting indirect treatment comparisons (ITC) to inform decisions for patients with first-line BRCA1/2 mutation-positive mCRPC has been explored. A systematic literature review was conducted to identify evidence from randomized controlled trials on relevant comparators to inform the feasibility of conducting ITCs via network meta-analysis (NMA) or population-adjusted indirect comparisons (PAIC). Feasibility was assessed based on network connectivity, data availability in the BRCA1/2 mutation-positive population, and degree of within- and between-study heterogeneity or bias. NMAs between niraparib plus AAP and other PARPi regimens (olaparib monotherapy, olaparib plus AAP, and talazoparib plus enzalutamide) were inappropriate due to the disconnected network, differences in trial populations related to effect modifiers, or imbalances within BRCA1/2 mutation-positive subgroups. The latter issue, coupled with the lack of a common comparator (except for olaparib plus AAP), also rendered anchored PAICs infeasible. Unanchored PAICs were either inappropriate due to lack of population overlap (vs. olaparib monotherapy) or were restricted by unmeasured confounders and small sample size (vs. olaparib plus AAP). PAIC versus talazoparib plus enzalutamide was not possible due to lack of published arm-level baseline characteristics and sufficient efficacy outcome data in the relevant population. The current randomized controlled trial evidence network does not permit robust comparisons between niraparib plus AAP and other PARPi regimens for patients with 1L BRCA-positive mCRPC. Decision-makers should scrutinize any ITC results in light of their limitations. Real-world evidence combined with clinical experience should inform treatment recommendations in this indication.

A Randomized Controlled Trial Comparing Automated Peritoneal Dialysis and Hemodialysis for Urgent-Start Dialysis in ESRD

Peritoneal dialysis (PD) shows promise for urgent-start dialysis in end-stage renal disease (ESRD), with automated PD (APD) having advantages. However, there is limited multicenter randomized controlled trial (RCT) evidence comparing APD with temporary hemodialysis (HD) for this indication in China. This multicenter RCT enrolled 116 patients with ESRD requiring urgent dialysis from 11 hospitals, randomized to APD or HD. Patients underwent a 2-week treatment with APD or HD via a temporary central venous catheter (CVC), followed by a maintenance PD. Outcomes were assessed over 12 months during 8 visits. The primary outcome was dialysis-related complications. The 1-year incidence of dialysis-related complications was significantly lower in the APD group than in the HD group (25.9% vs. 56.9%, P= 0.001). No significant differences were found between the groups in terms of PD catheter survival rates (P= 0.388), peritonitis-free survival rates (P= 0.335), and patient survival rates (P= 0.329). In terms of health economics, the total direct medical cost of the initial hospitalization for patients with ESRD was significantly lower in the APD group (27,008.39 CNY) than in the HD group (42,597.54 CNY) (P= 0.001), whereas the duration of the first hospital stay showed no significant difference (P= 0.424). For patients with ESRD needing urgent initiation of dialysis, APD was associated with a lower incidence of dialysis-related complications and lower initial hospitalization costs compared with HD, with no significant differences in PD catheter survival rate, peritonitis-free survival rates, or patient survival rates. These findings can guide clinical decision-making for the optimal dialysis modality for patients requiring urgent dialysis initiation.

Interventions for primary prevention of cardiovascular disease: umbrella review of systematic reviews.

Cardiovascular diseases are the leading cause of death globally. The aim of this overview of systematic reviews was to compare the effectiveness of different pharmacological and non-pharmacological interventions for the primary prevention of cardiovascular disease. A structured search of the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE and the Database of Abstracts of Reviews of Effects archive was conducted to find systematic reviews that reported the effect of various pharmacological and non-pharmacological interventions for the primary prevention of cardiovascular disease from inception to March 2021. References of included studies were also checked. The included systematic reviews' methodological quality was assessed using the Assessment of Multiple Systematic Reviews 2 instrument (range, 0-16). The outcomes of each included review's meta-analysis were extracted and described narratively. This study analysed 95 systematic reviews, including 41 on non-pharmacological interventions and 54 on pharmacological interventions for cardiovascular health. The majority of the reviews focused on lipid-lowering interventions (n = 25) and antiplatelet medications (n = 21), followed by nutritional supplements, dietary interventions, physical activity, health promotion and other interventions. Only 1 of the 10 reviews addressing cardiovascular mortality showed a potential benefit, while the others found no effect. Antiplatelets were found to have a beneficial effect on all-cause mortality in 2 out of 12 meta-analyses and on major cardiovascular disease events in 8 out of 17 reviews. Lipid-lowering interventions showed beneficial effects on cardiovascular disease mortality, all-cause mortality and major cardiovascular disease events in varying numbers of the reviews. Glucose-lowering medications demonstrated significant benefits for major cardiovascular events, coronary heart disease events and mortality. However, the combination of dietary interventions, physical activities, nutritional supplements and polypills showed little or no significant benefit for major cardiovascular outcomes or mortality. More research is needed to determine whether the effect of treatment varies depending on population characteristics. The findings of this review should be interpreted with caution because the majority of studies of non-pharmacological interventions compare primary prevention with usual care, which may include recommended pharmacological treatment in higher-risk patients (e.g. statins and/or antihypertensive medications, etc.). In addition, randomised controlled trial evidence may be better suited to the study of pharmacological interventions than dietary and lifestyle interventions. This umbrella review captured the variability in different interventions on randomised controlled trial evidence on interventions for primary prevention of cardiovascular disease and identified areas that may benefit from further research. Specifically, this review focused on randomised controlled trial evidence on interventions for primary prevention of cardiovascular disease. Researchers may use these findings as a resource to direct new intervention studies and network meta-analyses to compare the efficacy of various interventions based on these findings. This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme as award number 17/148/05.

The Current Landscape of Ventricular Tachycardia Trials: A Systematic Review of Registered Studies

Although there are evolving techniques and technologies for treating ventricular tachycardia (VT), the current landscape of clinical trials for managing VT remains understudied. The objective of this study was to provide a systematic characterisation of the interventional management of VT through an analysis of the ClinicalTrials.gov, clinicaltrialsregister.eu, anzctr.org.au and chictr.org.cndatabases. We queried all phase II to IV interventional trials registered up to November 2023 that enrolled patients with VT. Published, completed but unpublished, terminated, or ongoing trials were included for final analysis. Of the 698 registered studies, 135 were related to VT, with 123 trials included in the final analysis. Among these trials, 25 (20%) have been published, enrolling a median of 35 patients (interquartile range [IQR] 20-132) over a median of 43 months (IQR 19-62). Out of the published trials, 14 (56%) were randomised, and 12 (48%) focused on catheter ablation. Twenty-two (18%) have been completed but remain unpublished, even after a median of 36 months (IQR 15-60). Furthermore, 27 (22%) trials were terminated or withdrawn, with the most common cause being poor enrolment. Currently, 49 (40%) trials are ongoing and novel non-ablative technologies, such as radioablation and autonomic modulation, account for 35% and 8% of ongoing trials, respectively. Our analysis revealed that many registered trials remain unpublished or incomplete, and randomised controlled trial evidence is limited to only a few studies. Furthermore, many ongoing trials are focused on non-catheter ablation-based strategies. Therefore, larger pragmatic trials are needed to create stronger evidence in the future.

Assessing the one-month mortality impact of civilian-setting prehospital transfusion: A systematic review and meta-analysis.

Based on convincing evidence for outcomes improvement in the military setting, the past decade has seen evaluation of prehospital transfusion (PHT) in the civilian emergency medical services (EMS) setting. Evidence synthesis has been challenging, due to study design variation with respect to both exposure (type of blood product administered) and outcome (endpoint definitions and timing). The goal of the current meta-analysis was to execute an overarching assessment of all civilian-arena randomized controlled trial (RCT) evidence focusing on administration of blood products compared to control of no blood products. The review structure followed the Cochrane group's Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). Using the Transfusion Evidence Library (transfusionevidencelibrary.com), the multidatabase (e.g. PubMed, EMBASE) Harvard On-Line Library Information System (HOLLIS), and GoogleScholar, we accessed many databases and gray literature sources. RCTs of PHT in the civilian setting with a comparison group receiving no blood products with 1-month mortality outcomes were identified. In assessing a single patient-centered endpoint-1-month mortality-we calculated an overall risk ratio (RR) estimate. Analysis of three RCTs yielded a model with acceptable heterogeneity (I2 = 48%, Q-test p = 0.13). Pooled estimate revealed civilian PHT results in a statistically nonsignificant (p = 0.38) relative mortality reduction of 13% (RR 0.87, 95% CI 0.63-1.19). Current evidence does not demonstrate 1-month mortality benefit of civilian-setting PHT. This should give pause to EMS systems considering adoption of civilian-setting PHT programs. Further studies should not only focus on which formulations of blood products might improve outcomes but also focus on which patients are most likely to benefit from any form of civilian-setting PHT.

Vagus nerve stimulation for enhanced stroke recovery after intracerebral hemorrhage: illustrative case.

Randomized controlled trial (RCT) evidence has revealed the efficacy of vagus nerve stimulation (VNS) paired with rehabilitation therapy, over therapy alone, for upper-limb functional recovery after ischemic stroke. However, this technique has not yet been described for the recovery of chronic motor deficits after hemorrhagic stroke. Three years after left putaminal intracerebral hemorrhagic stroke with chronic upper-limb functional deficits, a patient was treated with VNS for enhanced stroke recovery. VNS was paired with 6 weeks of in-clinic physical therapy, resulting in upper-limb functional improvement of 14 points on the Fugl-Meyer Assessment Upper Extremity (FMA-UE) index for stroke recovery (maximum score of 66 equating to normal function). This improvement was more than 1 standard deviation above the improvement documented in the first successful RCT of VNS paired with therapy for ischemic stroke (5.0 ± 4.4 improvement on FMA-UE). VNS is a promising therapy for enhanced recovery after hemorrhagic stroke and may offer greater improvement in function compared to that after ischemic stroke. Improvement in function can occur years after the time of intracerebral hemorrhage.

Cost effectiveness analysis for commonly used human cell and tissue products in the management of diabetic foot ulcers.

This study considers the cost-effectiveness of commonly used cellular, acellular, and matrix‑like products (CAMPs) of human origin also known as human cell and tissue products (HCT/Ps) in the management of diabetic foot ulcers. We developed a 1-year economic model assessing six CAMPs [cryopreserved placental membrane with viable cells (vCPM), bioengineered bilayered living cellular construct (BLCC), human fibroblast dermal substitute (hFDS), dehydrated human amnion chorion membrane (dHACM), hypothermically stored amniotic membrane (HSAM) and human amnion membrane allograft (HAMA) which had randomized controlled trial evidence compared with standard of care (SoC). CAMPs were compared indirectly and ranked in order of cost-effectiveness using SoC as the baseline, from a CMS/Medicare's perspective. The mean cost, healed wounds (hw) and QALYs per patient for vCPM is $10,907 (0.914 hw, 0.783 QALYs), for HAMA $11,470 (0.903 hw, 0.780 QALYs), for dHACM $15,862 (0.828 hw, 0.764 QALYs), for BLCC $18,430 (0.816 hw, 0.763 QALYs), for hFDS $19,498 (0.775 hw, 0.757 QALYs), for SoC $19,862 (0.601 hw, 0.732 QALYs) and $24, 214 (0.829, 0.763 QALYs) for HSAM respectively. Over 1 year, vCPM results in cheaper costs overall and better clinical outcomes compared to other CAMPs. Following probabilistic sensitivity analysis, vCPM has a 60%, HAMA 40% probability of being cost-effective then dHACM, hFDS, BLCC, and lastly HSAM using a $100,000/healed wound or QALY threshold. All CAMPs were shown to be cost-effective when compared to SoC in managing DFUs. However, vCPM appears to be the most cost-effective CAMP over the modelled 52 weeks followed by HAMA, dHACM, hFDS, BLCC, and HSAM. We urge caution in interpreting the results because we currently lack head-to-head evidence comparing all these CAMPs and therefore suggest that this analysis be updated when more direct evidence of CAMPs becomes available.

An 8-Week Vitamin D3–Fortified Fruit Drink Supplementation Increases Serum Ferritin Concentration: A Randomized Controlled Trial in Malaysian Women With Low Iron Stores

BackgroundThere is limited randomized controlled trial evidence to support the association between vitamin D deficiency and anemia risk, highlighting the necessity for further investigations into the role of vitamin D in influencing iron status. ObjectiveThe aim of this study was to determine the effect of vitamin D3–fortified fruit drink consumption (4,000 IU) on vitamin D and iron status biomarkers among iron-deficient women (serum ferritin of <20 μg/L [to convert μg/L ferritin to ng/mL, multiply by 1]). DesignAn 8-week double-blind randomized controlled trial was conducted. Subjects/settingA total of 45 healthy, nonpregnant, nonlactating subjects aged 18 through 40 years (mean [SD] 25.3 [4.6] years) were included in the study, excluding those who donated blood 6 months prior, regularly consumed nutritional supplements, or had gastrointestinal or iron metabolic disorders. InterventionSubjects were randomly assigned to receive either vitamin D3–fortified fruit drink or a placebo. Main outcome measuresMeasurements of 25-hydroxyvitamin D (25[OH]D), serum ferritin, high-sensitivity C-reactive protein, and full blood count concentrations were obtained at baseline, interim, and post intervention. Statistical analysesA mixed model, repeated measures analysis of variance was used to analyze the intervention effect. ResultsAttrition rate for the study was 13%, with 6 dropouts, and 39 subjects completed the study. Daily consumption of vitamin D3–fortified fruit drink in the intervention group resulted in significant increases in 25(OH)D and serum ferritin concentrations compared with the placebo group. The intervention group showed significantly higher mean (SD) changes (Δ) in both 25(OH)D (Δ 76.4 [30.2] nmol/L [to convert nmol/L 25(OH)D to ng/mL, multiply by .4] vs Δ –1.3 [10.7] nmol/L; P = .001) and serum ferritin concentrations (Δ 2.2 [4.2] μg/L vs Δ –0.3 [3.4] μg/L; P = .048) between baseline and post intervention. The other iron status biomarkers were not affected by the intervention. ConclusionsOur study found that daily vitamin D3–fortified fruit drink supplementation for 8 weeks effectively improved 25(OH)D and iron stores, indicated by increased serum ferritin concentrations, in iron-deficient women. Further research is needed to evaluate its safety, efficacy, feasibility, and optimal food fortification in diverse populations.

Low-dose interleukin 2 antidepressant potentiation in unipolar and bipolar depression: Safety, efficacy, and immunological biomarkers

Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.

Maternal and neonatal morbidity associated with Fetal Pillow® use at full dilatation caesarean: A retrospective cohort.

To investigate associations of the Fetal Pillow® with maternal and neonatal morbidity. Retrospective cohort. Two tertiary maternity units, New Zealand. Full dilatation singleton, term, cephalic caesarean section, with three comparisons: at Unit A (1) before versus after introduction of the Fetal Pillow® (1 Jaunary 2016-31 October 2021); (2) with versus without the Fetal Pillow® after introduction (27 July 2017-31 October 2021); and (3) between Unit A and Unit B during the same time period (1 January 2019-31 October 2021). The Fetal Pillow® is unavailable at Unit B. Cases were ascertained and clinical data were extracted from electronic clinical databases and records. Outcome data were adjusted and presented as adjusted odds ratios (aOR) with 95% CI. Primary outcome "any" uterine incision extension; secondary outcomes included major extension (into adjacent structures), and a composite neonatal outcome. In all, 1703 caesareans were included; 375 with the device and 1328 without. Uterine incision extension rates were: at Unit A before versus after introduction: 26.8% versus 24.8% (aOR 0.88, 95% CI 0.65-1.19); at Unit A with the Fetal Pillow® versus without: 26.1% versus 23.8% (aOR 1.14, 95% CI 0.83-1.57); and at Unit A versus Unit B: 24.2% versus 29.2% (aOR 0.73, 95% CI 0.54-0.99). No differences were found in major extensions, or neonatal composite outcome. Despite the relatively large size of this study, it could not rule out either a positive or a negative association between use of the Fetal Pillow® and uterine extensions, major uterine incision extensions, and neonatal morbidity. Randomised controlled trial evidence is required to assess efficacy.

Effects of mindfulness-based interventions on cognition in people with multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials.

Cognitive impairment affects up to 65% of people with multiple sclerosis (PwMS), undermining functional independence and quality of life. The objective of this study is to synthesize existing randomized controlled trial (RCT) evidence on the effects of Mindfulness-based interventions (MBIs) on cognitive function in PwMS. A systematic literature search was conducted to identify RCTs assessing MBIs effects on cognitive functioning in PwMS. Using pre-defined criteria, two independent reviewers screened titles, abstracts, and extracted data from included studies. Meta-analysis was performed, where possible, using a random effects model. Narrative synthesis was undertaken. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidance was followed. PROSPERO_ID:(CRD42021286429). Twelve eligible RCTs were identified, n=700 PwMS. MBIs included both standardized and tailored interventions, in-person and virtually. A variety of measures of cognitive functioning were reported. Five studies (n=254 PwMS) were included in meta-analysis; pooled results suggested MBIs effectively improved scores on the Paced Auditory Serial Addition Test (PASAT)-2 (SMD=0.38; 95% CI 0.06-0.71; I2 63%; p=0.02), whereas improvements were of borderline significance on the PASAT-3 (SMD=0.32; 95% CI -0.01-0.64; I2 65%; p=0.06), and, although trending to positive, were statistically insignificant on the Perceived Deficits Questionnaire (SMD=0.34; 95 CI -0.05-0.74; I2 0%; p=0.09) and Symbol Digits Modality Test (SMD=0.25; 95% CI -0.15-0.66; I2 0%; p=0.21). Preliminary findings in meta-analysis are inconsistent but suggest potential benefits from MBI training on cognitive functioning in PwMS. High quality RCTs are necessary to test more definitively the impact of MBIs on cognitive functioning in PwMS. PROSPERO, identifier CRD42021286429.

The fragility index in randomised controlled trials of interventions for aneurysmal subarachnoid haemorrhage: A systematic review.

Fragility analysis supplements the p-value and risk of bias assessment in the interpretation of results of randomised controlled trials. In this systematic review we determine the fragility index (FI) and fragility quotient (FQ) of randomised trials in aneurysmal subarachnoid haemorrhage. This is a systematic review registered with PROSPERO (ID: CRD42020173604). Randomised controlled trials in adults with aneurysmal subarachnoid haemorrhage were analysed if they reported a statistically significant primary outcome of mortality, function (e.g. modified Rankin Scale), vasospasm or delayed neurological deterioration. We identified 4825 records with 18 randomised trials selected for analysis. The median fragility index was 2.5 (inter-quartile range 0.25-5) and the median fragility quotient was 0.015 (IQR 0.02-0.039). Five of 20 trial outcomes (25%) had a fragility index of 0. In seven trials (39.0%), the number of participants lost to follow-up was greater than or equal to the fragility index. Only 16.7% of trials are at low risk of bias. Randomised controlled trial evidence supporting management of aneurysmal subarachnoid haemorrhage is weaker than indicated by conventional analysis using p-values alone. Increased use of fragility analysis by clinicians and researchers could improve the translation of evidence to practice.

Natural Experiment Outcomes Studies in Rotor Wing Air Medical Transport: Systematic Review and Meta-Analysis of Before-and-After and Helicopter-Unavailable Publications From 1970 to 2022

ObjectiveHelicopter emergency medical services (HEMS) is widely used for prehospital and interfacility transport, but there is a paucity of HEMS outcomes data from studies using randomized controlled trial designs. In the absence of robust randomized controlled trial evidence, judgments regarding HEMS potential benefit must be informed by observational data. Within the study design set of observational analyses, the natural experiment (NE) is notable for its high potential methodologic quality; NE designs are occasionally denoted “quasi-experimental.” The aim of this study is to examine all NE outcomes studies in the HEMS literature and to discern what lessons can be learned from these potentially high-quality observational data. MethodsHEMS NE studies were identified during the development of a new HEMS Outcomes Assessment Research Database (HOARD). HOARD was constructed using a broad-ranging search of published and gray literature resources (eg, PubMed, Embase, and Google Scholar) that used variations of the terms “helicopter EMS,” “air ambulance,” and “air medical transport.” Among the 221 studies ultimately included in HOARD, 16 NE publications describing 13 sets of observational data comprising myriad diagnostic groups were identified. Of these 16 HEMS NEs, 4 HEMS NE studies assessing trauma outcomes were used in a meta-analysis. A meta-analysis was also performed of 4 HEMS NE studies. ResultsAlthough the disparity of studies (in terms of both case mix and end points) precluded the generation of a pooled effect estimate of an adjusted mortality benefit of HEMs versus ground emergency medical services, HEMS was found to be associated with outcomes improvement in 8 of the 13 cohorts. ConclusionThe weight of the NE evidence supports a conclusion of some form of HEMS-mediated outcomes improvement in a variety of patient types. Meta-analysis of 4 HEMS NE studies assessing trauma outcomes generated a model with acceptable heterogeneity (I2 = 43%, Q test: P = .16), which significantly (P < .01) favored HEMS use with a pooled HEMS survival odd ratio estimate of 1.66 (95% confidence interval, 1.23-2.22).

Ablative and non-surgical therapies for early and very early hepatocellular carcinoma: a systematic review and network meta-analysis.

A wide range of ablative and non-surgical therapies are available for treating small hepatocellular carcinoma in patients with very early or early-stage disease and preserved liver function. To review and compare the effectiveness of all current ablative and non-surgical therapies for patients with small hepatocellular carcinoma (≤ 3 cm). Systematic review and network meta-analysis. Nine databases (March 2021), two trial registries (April 2021) and reference lists of relevant systematic reviews. Eligible studies were randomised controlled trials of ablative and non-surgical therapies, versus any comparator, for small hepatocellular carcinoma. Randomised controlled trials were quality assessed using the Cochrane Risk of Bias 2 tool and mapped. The comparative effectiveness of therapies was assessed using network meta-analysis. A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence. Where comparisons based on randomised controlled trial evidence were not robust or no randomised controlled trials were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis. The feasibility of undertaking economic modelling was explored. A workshop with patients and clinicians was held to discuss the findings and identify key priorities for future research. Thirty-seven randomised controlled trials (with over 3700 relevant patients) were included in the review. The majority were conducted in China or Japan and most had a high risk of bias or some risk of bias concerns. The results of the network meta-analysis were uncertain for most comparisons. There was evidence that percutaneous ethanol injection is inferior to radiofrequency ablation for overall survival (hazard ratio 1.45, 95% credible interval 1.16 to 1.82), progression-free survival (hazard ratio 1.36, 95% credible interval 1.11 to 1.67), overall recurrence (relative risk 1.19, 95% credible interval 1.02 to 1.39) and local recurrence (relative risk 1.80, 95% credible interval 1.19 to 2.71). Percutaneous acid injection was also inferior to radiofrequency ablation for progression-free survival (hazard ratio 1.63, 95% credible interval 1.05 to 2.51). Threshold analysis showed that further evidence could plausibly change the result for some comparisons. Fourteen eligible non-randomised studies were identified (n ≥ 2316); twelve had a high risk of bias so were not included in updated network meta-analyses. Additional non-randomised data, made available by a clinical advisor, were also included (n = 303). There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated. However, the updated analyses suggested that microwave ablation and resection are superior to percutaneous ethanol injection and percutaneous acid injection for some outcomes. Further research on stereotactic ablative radiotherapy was recommended at the workshop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials. Many studies were small and of poor quality. No comparative studies were found for some therapies. The existing evidence base has limitations; the uptake of specific ablative therapies in the United Kingdom appears to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness. However, there is evidence that percutaneous ethanol injection and percutaneous acid injection are inferior to radiofrequency ablation, microwave ablation and resection. PROSPERO CRD42020221357. This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme (NIHR award ref: NIHR131224) and is published in full in Health Technology Assessment; Vol. 27, No. 29. See the NIHR Funding and Awards website for further award information.

2722. Risk of Infectious Adverse Events of Venetoclax Therapy in the Treatment of Hematologic Malignancies: A Systematic Review and Bayesian Meta-Analysis of Randomized Controlled Trials

Abstract Background Venetoclax is a small molecule inhibitor of BCL-2 used in the treatment of acute myelogenous leukemia and chronic lymphocytic leukemia. Recent post-marketing studies on venetoclax suggested that it may predispose to opportunistic infections (OIs). We sought to systematically review the randomized controlled trial (RCT) evidence on venetoclax to assess whether it predisposes patients to infectious adverse events (IAEs) and neutropenia. Methods We systematically reviewed the RCTs comparing venetoclax therapy to active (i.e., a regimen with additional anti-cancer agents) or placebo controls in patients with hematologic malignancies, irrespective of treatment line. Data on IAEs and neutropenia were pooled by Bayesian meta-analysis and we computed the probability of any increased risk in infectious or neutropenic complications (Risk Ratio [RR] &amp;gt;1). Subgroup analyses were conducted based on treatment line, use of an inactive comparator, malignancy type, and prophylaxis strategy. Additionally, we pooled the incidence rates of fatal OIs between venetoclax and comparator arms and compared them by univariate meta-regression. Results Seven RCTs were included comprising 2067 patients. In venetoclax versus comparator regimens there was a 81.1% probability of any increase in IAEs (RR=1.14, 95% Confidence Interval [95%CI]=0.76-1.66). The probabilities of venetoclax increasing the risk of grade 3-5 and fatal IAEs were 86.6% (RR=1.16, 95%CI=0.86-1.55) and 81.1% (RR=1.40, 95%CI=0.66-2.94), respectively. There was a 97.2% likelihood that venetoclax increased the risk of grade 3-5 neutropenia (RR=1.44, 95%CI=1.01-2.10). Venetoclax treatment did not increase the incidence of fatal OIs (P=0.55). Conclusion Our results suggest that venetoclax likely increases the risk of high-grade neutropenia and IAEs overall, but not fatal OIs. However, our analyses did not identify any specific IAEs that would benefit from routine anti-infective prophylaxis or pre-emptive testing. Disclosures Michael Sebag, MD, PhD, Amgen: Advisor/Consultant|BMS: Advisor/Consultant|Focus Therapeutics: Advisor/Consultant|Gilead: Advisor/Consultant|Janssen: Advisor/Consultant|Novartis: Advisor/Consultant|Pfizer: Advisor/Consultant|Sanofi: Advisor/Consultant Matthew Cheng, MD, Amplyx Pharmaceuticals: Grant/Research Support|AstraZeneca: Advisor/Consultant|AstraZeneca: Honoraria|Cidara Therapeutics: Grant/Research Support|GEn1E lifesciences: Advisor/Consultant|GEn1E lifesciences: Stocks/Bonds|Kanvas Biosciences, Inc.: Board Member|Kanvas Biosciences, Inc.: Pending patents|Kanvas Biosciences, Inc.: Ownership Interest|Merck: Honoraria|nomic bio: Advisor/Consultant|nomic bio: Stocks/Bonds|Pfizer: Honoraria|Scynexis Inc.: Grant/Research Support|Takeda: Advisor/Consultant|Takeda: Honoraria

The Fifth Croatia Stuttering Symposium: Part I. Treatments for early stuttering

PurposeThe Fifth Croatia Stuttering Symposium in 2022 continued the Fourth Croatia Stuttering Symposium 2019 theme of the connection between research and clinical practice. At the 2022 Symposium, there were 145 delegates from 21 countries. This paper documents the contents of the first of three Symposium modules. MethodsThe module topic was that three treatments for early childhood stuttering are supported by randomized controlled trial evidence. A clinical situation was considered where a parent of a 3-year-old child asked what results to expect of stuttering treatment. ResultsA distinguished scholar presented a 5-minute video interpretation of the research concerning the randomized controlled trial evidence for the three treatments. Three master clinicians then each presented a 2-minute video demonstration of how those research findings might be applied in a clinical situation. Following that, the convenors moderated a discussion between the distinguished scholar, master clinicians, and delegates regarding the research and how it applies to clinical practice.

Hypertensive Emergency: Parenteral Antihypertensives and Population Data.

Review parenteral therapeutic choices in treatment of hypertensive crises by mechanism of action and summarize recent literature on the management of hypertensive crises. Recent data have documented the safety and efficacy of labetalol and nicardipine in treatment of hypertensive crises as well as characterized the hypertensive emergency population to a much greater extent. Based on recent data, hypertensive emergencies are seen in 0.5% of all emergency room visits. Ischemic stroke and heart failure/pulmonary edema are the most common forms of organ damage seen in hypertensive emergencies. There are many therapeutic choices in treatment of hypertensive crises with varied mechanisms of action. Large randomized, controlled trial evidence is lacking in this therapeutic area; however, recent data have documented the safety and efficacy of labetalol and nicardipine.