Prespecified Subgroup Analysis Research Articles

OR28-4 Efficacy and Safety of Tirzepatide Versus Semaglutide in a Hispanic or Latino Population: A Prespecified Subgroup Analysis of SURPASS-2

Abstract Tirzepatide, a dual GIP/GLP-1 receptor agonist, demonstrated clinically meaningful reductions in HbA1c and body weight that were significantly greater compared with semaglutide in patients with type 2 diabetes on background metformin. In a pre-specified subgroup analysis, we evaluated the efficacy and safety of tirzepatide in the Hispanic or Latino population of SURPASS-2. In this open-label, 40-week, Phase 3 study (N=1878; mean baseline HbA1c 8.28%; BMI 34.2 kg/m2; Hispanic or Latino ethnicity 70%) participants were randomized 1: 1: 1: 1 to tirzepatide (5, 10, 15 mg; doses were double-blinded) or semaglutide (1 mg). Efficacy analyses included all randomised patients who received ≥1 treatment dose (modified intention-to-treat [mITT] population) while patients were on treatment without rescue therapy and excluding patients who discontinued study drug due to inadvertent enrollment (efficacy estimand). Safety analyses were performed in the mITT population, including all data from the start of treatment to the end of the safety follow-up. The least square mean (LSM) change from baseline was calculated within each subgroup using a mixed model for repeated measurements (MMRM) with country, baseline value, treatment group, visit, and treatment-by-visit interaction as the fixed effect, and patient as the random effect. MMRM for weight change also included baseline HbA1c group (≤8.5%, >8.5%) as a covariate. In patients of Hispanic or Latino ethnicity, the LSM change from baseline in HbA1c at 40 weeks was -2.11%, -2.46%, and -2.47% with tirzepatide 5, 10, and 15 mg, respectively, and -1.93% with semaglutide (all p<0.001). The respective changes in patients not of Hispanic or Latino ethnicity were -2.03%, -2.14%, -2.43%, and -1.69% (all p<0.001). Reductions in HbA1c were significantly greater for all tirzepatide doses compared with semaglutide in patients of both Hispanic or Latino and non-Hispanic or Latino ethnicity (all p≤0.027). In Hispanic or Latino patients, body weight change was -6.9 kg with tirzepatide 5 mg, -9.7 kg with 10 mg, -10.5 kg with 15 mg, and -5.6 kg with semaglutide (all p<0.001). In non-Hispanic or Latino patients, the changes from baseline in body weight were -9.9 kg, -11.6 kg, -17.1 kg, and -7.5 kg, for the tirzepatide doses and semaglutide, respectively, (all p<0.001). In both subgroups, reductions in body weight were significantly greater than semaglutide with all tirzepatide doses (all p≤0.013). The most common adverse events were gastrointestinal in the tirzepatide and semaglutide arms, including nausea (Hispanic or Latino 11-17% and 13%; non-Hispanic or Latino 32-36% and 29%), diarrhoea (10-13% and 10%; 15-24% and 17%) and vomiting (4-7% and 7%; 10-16% and 12%). Consistent with the primary SURPASS-2 results, in a Hispanic or Latino population with type 2 diabetes, tirzepatide demonstrated greater reductions from baseline in HbA1c and body weight than the selective GLP-1 receptor agonist semaglutide, with a comparable safety profile. Presentation: Tuesday, June 14, 2022 10:30 a.m. - 10:45 a.m.

ODP274 Shift work is associated with normal weight obesity in community-dwelling adults

Abstract Objective Shift working is known to be associated with metabolic syndrome and increased cardiovascular risk. In this study, we aimed to investigate whether shift work is associated with normal weight obesity (NWO), defined as normal weight with high body fat percentage. Method: From the national representative Korea National Health and Nutrition Examination Survey dataset (KNHANES 2008-2011), data of 3800 full-time workers with age≥ 19 years and body mass index (BMI)≤ 25 kg/m 2 were analyzed. In this study, we defined NWO was defined as BMI≤25 kg/m 2 and body fat (BF)percentage≥25% in men and≥37% in women according to the most strict threshold from literature review. Working patterns were classified into 'daytime', 'other than daytime', and 'shift time' based on the self-reported survey data. Multivariable logistic regression was performed to evaluate the relationship between shift time workers and NWO. Prespecified subgroup analysis were analyzed to determine the consistency of the result. Result: Shift work was associated with elevated odds of NWO than daytime work (adjusted odds ratio [aOR] 1.47, 95% CI 1. 04-2. 09) and night/evening work (aOR 1.87, 95% CI 1.11-3.14), after adjustment for working form, working hours, age, sex, BMI, vitamin D, homeostatic model assessment for insulin resistance, and other sociodemographic factors. In the subgroup analysis, association between shift work and NWO were consistent, and, those age ≥ 60 years (aOR 2.23, p=0. 043; p for interaction=0. 097) or working hours ≥ 56 hours per week (aOR 2. 00, p=0. 013; p for interaction=0. 057) showed a tendency to increase the risk. Conclusion Shift working was associated with NWO in Korean community-dwelling adults, independent of age, sex, BMI, and other covariates. Keywords: Shift work, Obesity, Normal weight obesity, Body fat percentage, KNHANES Presentation: No date and time listed

Identifying relative efficacy of components of prehabilitation in adult surgical patients: protocol for a systematic review and component network meta-analysis

IntroductionPrehabilitation is a high-priority intervention for patients, the public, clinicians and health systems. However, existing knowledge syntheses are generally low quality and do not provide insights regarding the relative efficacy...

362P Intracranial activity of dacomitinib in treatment naïve advanced EGFR mutated non-small cell lung cancer (NSCLC): Prespecified subgroup analysis of the ATORG-003 trial

Dacomitinib is a second generation EGFR tyrosine kinase inhibitor approved as first-line therapy in advanced EGFR mutated NSCLC. In the phase 3 ARCHER 1050 trial, PFS and OS were improved with dacomitinib compared to gefitinib. However, patients (pts) with central nervous system (CNS) metastases (mets) were ineligible to enroll into the study. ATORG-003 is an ongoing investigator-initiated single-arm phase 2 trial evaluating a dose titration strategy to improve the safety and tolerability of dacomitinib whilst maintaining efficacy.

Sex differences among patients receiving ticagrelor monotherapy or aspirin after coronary bypass surgery: A prespecified subgroup analysis of the TiCAB trial

BackgroundThere is limited evidence on the association of sex with outcomes among patients undergoing coronary bypass surgery (CABG) and treated with ticagrelor monotherapy or aspirin. MethodsThis was a pre-specified sub-analysis of TiCAB, an investigator-initiated placebo-controlled randomized trial. Primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, stroke, or repeat revascularization 1 year after CABG. Safety endpoint was BARC type 2, 3 or 5 bleeding. ResultsA total of 280 (15.0%) women and 1579 (85.0%) men were included. Compared with men, women were older (66.1 ± 10.2 vs. 70.1 ± 9.3 years) with more acute presentation (17.0% vs 21.1%). The incidence of the primary endpoint was similar between women and men (9.2% vs. 8.9%, HR 1.08, 95%CI 0.71–1.66, P = 0.71). Cardiovascular death occurred more often in women (2.9% vs 1.0%, adjusted HR 2.87, 95%CI 1.23–6.70, P = 0.02). The incidence of bleeding was similar between the sexes (2.2% vs. 2.5%, HR 0.91, 95% CI 0.51–1.65, P = 0.77). Ticagrelor vs aspirin was associated with a similar risk of the primary endpoint in women (10.6% vs. 7.9%, HR 1.39, 95%CI 0.63–3.05, P = 0.42) and men (9.5% vs. 8.2%, HR 1.15, 95%CI 0.82–1.62, P = 0.41;pinteraction = 0.69), and a similar risk of bleeding in women (2.9% vs. 1.4%, HR 2.09, 95%CI 0.38–11.41, P = 0.40) and men (2.2% vs. 2.8%, HR 0.80, 95%CI 0.42–1.52, P = 0.49;pinteraction = 0.35). ConclusionsAmong women and men undergoing CABG, ticagrelor monotherapy was associated with a similar risk of the primary efficacy endpoint and bleeding compared with aspirin. The risk of cardiovascular death was increased in women irrespective of antiplatelet therapy.

Intraoperative electrocorticography using high-frequency oscillations or spikes to tailor epilepsy surgery in the Netherlands (the HFO trial): a randomised, single-blind, adaptive non-inferiority trial

Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year. The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom [defined as Engel 1A-B] vs seizure recurrence [Engel 1C-4]). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673. Between Oct 10, 2014, and Jan 31, 2020, 78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference -23·5%, 90% CI -39·1 to -7·9; for the 48 patients with temporal lobe epilepsy, the risk difference was -25·5%, -45·1 to -6·0, and for the 30 patients with extratemporal lobe epilepsy it was -20·3%, -46·0 to 5·4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of -7·9% (90% CI -20·7 to 4·9; adjusted risk difference -12·5%, -31·0 to 5·9, for temporal lobe epilepsy and 5·8%, -7·7 to 19·5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died. HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy. UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.

The impact of circadian rhythms on the immune response to influenza vaccination in middle-aged and older adults (IMPROVE): a randomised controlled trial

BackgroundVaccination is important in influenza prevention but the immune response wanes with age. The circadian nature of the immune system suggests that adjusting the time of vaccination may provide an opportunity to improve immunogenicity. Our previous cluster trial in Birmingham suggested differences between morning and afternoon vaccination for some strains in the influenza vaccine in older adults. Whether this effect is also seen in a younger age group with less likelihood of compromised immunity is unknown. We therefore conducted an individual-based randomized controlled trial in Guangzhou to test the hypothesis that influenza vaccination in the morning induces a stronger immune response in older adults than afternoon vaccination. We included adults in middle age to determine if the effect was also seen in younger age groups.ResultsOf the 418 participants randomised, 389 (93.1%, 191 middle-aged adults aged 50–60 years and 198 older adults aged 65–75 years) were followed up. Overall, there was no significant difference between the antibody titers (geometric mean /95% CI) after morning vs afternoon vaccination (A/H1N1: 39.9 (32.4, 49.1) vs. 33.0 (26.7, 40.7), p = 0.178; A/H3N2: 92.2 (82.8, 102.7) vs. 82.0 (73.8, 91.2), p = 0.091; B: 15.8 (13.9, 17.9) vs. 14.4 (12.8, 16.3), p = 0.092), respectively. However, in pre-specified subgroup analyses, post-vaccination titers for morning versus afternoon vaccination in the 65–75 years subgroup were (A/H1N1): 49.5 (36.7, 66.6) vs. 32.9 (24.7, 43.9), p = 0.050; (A/H3N2): 93.5 (80.6, 108.5) vs. 73.1 (62.9, 84.9), p = 0.021; (B): 16.6 (13.8, 20.1) vs. 14.4 (12.3, 17.0), p = 0.095, respectively. Among females, antibody titers for morning versus afternoon vaccination were (A/H1N1): 46.9 (35.6, 61.8) vs. 31.1 (23.8, 40.7), p = 0.030; (A/H3N2): 96.0 (83.5, 110.3) vs. 84.7 (74.4, 96.5), p = 0.176; (B): 14.8 (12.7, 17.3) vs. 13.0 (11.3, 14.9), p = 0.061, respectively. In the 50–60 years old subgroup and males, there were no significant differences between morning and afternoon vaccination.ConclusionsMorning vaccination may enhance the immunogenicity to influenza vaccine in adults aged over 65 and women. An intervention to modify vaccination programs to vaccinate older individuals in the morning is simple, cost free and feasible in most health systems.

Techniques for Mesoappendix Transection and Appendix Resection When Performing Acute Appendectomy: Insights from the SnapAppy Group Audit

Introduction: Surgically managed appendicitis exhibits great heterogeneity regarding mesoappendix transection, and appendix amputation from its base. It is unclear whether a particular surgical technique provides an outcome benefit or reduces complication. Methods: We undertook a pre-specified subgroup analysis of all patients who underwent laparoscopic appendectomy at index admission during the SnapAppy time-bound prospective multi-institutional non-randomized observational cohort study between November 1st 2020 - August 31st 2021 at 71 centers in 14 countries. Poisson regression models were employed for investigating the association between different surgical techniques for mesoappendix as well as stump management and postoperative complication while adjusting for potential confounding. Results: A total of 2,252 patients were included in the analyses of the technique used for dividing the mesoappendix, 69% by electrocautery and 31% by energy device. 3,729 patients were included for analyses of the management of the stump. The appendix was amputated using looped ligatures in 37%, staples in 38%, and clips in 25% of cases. After adjusting for confounders, the risk of postoperative complication was reduced by 42% when an energy device was used for handling the mesoappendix [adjusted incidence rate ratio (95% CI): 0.58 (0.41-0.82), p = 0.002]; however, no difference was detected between the techniques used for dividing the appendix at its base. Conclusion: Safe mesoappendix transection and appendix resection are accomplished using heterogeneous techniques. Energy devices are associated with a lower rate of overall complication while no differences were observed when comparing the techniques used for dividing the appendix base.

Olanzapine/samidorphan combination consistently mitigates weight gain across various subgroups of patients.

A combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM) has been approved in the United States for the treatment of adults with schizophrenia or adults with bipolar I disorder. In a phase 3 study in adults with schizophrenia (ENLIGHTEN-2), OLZ/SAM treatment was associated with significantly less weight gain compared with olanzapine. Prespecified subgroup analyses explored the consistency of the weight mitigation effect of OLZ/SAM vs olanzapine across demographic subgroups in ENLIGHTEN-2. The multicenter, randomized, double-blind ENLIGHTEN-2 study (NCT02694328) included outpatients aged 18-55years with a diagnosis of schizophrenia based on DSM-5 criteria, a body mass index (BMI) of 18 to 30kg/m2, and stable body weight (self-reported change ≤5% for ≥3months before study entry). Patients were randomized 1:1 to receive OLZ/SAM or olanzapine for 24weeks. Co-primary endpoints (previously reported) were percent change in body weight and proportion of patients with at least 10% weight gain from baseline at week 24. Prespecified exploratory subgroup analyses by sex, age, self-reported race, and baseline BMI were conducted. At week 24, treatment with OLZ/SAM resulted in numerically less percent weight gain than with olanzapine across all subgroups evaluated. The proportion of patients with at least 10% weight gain was smaller in each subgroup treated with OLZ/SAM vs olanzapine. In these exploratory subgroup analyses from the ENLIGHTEN-2 study, weight-mitigating effects of OLZ/SAM vs olanzapine were observed consistently across patient subgroups and were in line with results from the overall study population.

Effectiveness and safety of a time to isolation strategy of cryoballoon ablation of atrial fibrillation: A systematic review and meta-analysis.

We conducted a systematic review and meta-analysis of randomized and observational studies with a control group to evaluate the effectiveness and safety of a time to isolation (TTI)-based strategy of cryoballoon ablation (CBA) in the treatment of atrial fibrillation (AF). Three electronic databases (MEDLINE, Cochrane Central Register of Controlled Trials, and Embase) without language restrictions were searched. The intervention assessed was a TTI-based strategy of CBA in the treatment of AF. TTI was defined as the time from the start of freezing to the last recorded pulmonary veins' potential. The comparison of interest was intended conventional protocol of CBA. The primary endpoint was freedom from atrial arrhythmia. Nine studies were deemed eligible (N = 2289 patients). Eight studies reported freedom from atrial arrhythmia and pooled results showed a marginally similar success rate between thetwo protocols (odds ratio [OR]: 1.24; 95% confidence interval [CI]: 0.98-1.56). A prespecified subgroup analysis verified that a high dose TTI strategy (with >120 s duration of cryotherapy post-TTI) compared to the conventional protocol could significantly increase the patients without atrial arrhythmia during follow-up (OR: 1.39; 95% CI: 1.05-1.83). TTI strategy could also significantly decrease total procedure time (SMD:-26.24 min; 95% CI: -36.90 to -15.57) and phrenic nerve palsy incidence (OR: 0.49; 95% CI: 0.29-0.84). Moderate confidence evidence suggests that an individualized CBA dosing strategy based on TTI and extended (>2 minpost-TTI) duration of CBA is accompanied by fewer recurrences post-AFablation.

Thiazide Diuretics and Fracture Risk: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Thiazide diuretics are commonly used antihypertensive agents. Until today, whether their use reduces fracture risk remains unclear. Our objective was to conduct a systematic review of thiazide diuretics' effects on fractures and bone mineral density (BMD) in randomized clinical trials (RCT) of adults. MEDLINE, EMBASE, CENTRAL, and the WHO's ICTRP registry were searched from inception to July 31, 2019. Two reviewers assessed studies for eligibility criteria: (i) RCTs; (ii) including adults; (iii) comparing thiazides, alone or in combination; (iv) to placebo or another medication; and (v) reporting fractures or BMD. Conference abstracts and studies comparing thiazides to antiresorptive or anabolic bone therapy were excluded. Bias was assessed using Cochrane Collaboration's Risk of Bias Tool-2. The primary outcome was fracture at any anatomical site. Secondary outcomes were osteoporotic fractures, hip fractures, and BMD at femoral neck, lumbar spine, and/or total hip. Fractures were pooled as risk ratios (RRs) using random-effect models. Prespecified subgroup analyses and post hoc sensitivity analyses were conducted. From 15,712 unique records screened, 32 trials (68,273 patients) met eligibility criteria. Thiazides were associated with decreased fractures at any site (RR=0.87, 95% confidence interval [CI] 0.77-0.98; I 2 = 0%) and osteoporotic fractures (RR=0.80; 95% CI 0.69-0.94; I 2 = 0%). Results were consistent in most subgroups and sensitivity analyses. Few studies reported hip fractures, and no association was found between thiazides and this outcome (RR=0.84; 95% CI 0.67-1.04; I 2 = 0%). Only four studies reported BMD; a meta-analysis was not conducted because BMD reporting was inconsistent. Trials were deemed at low (3 studies, weight=3%), some concerns (16 studies; 71%), or high (11 studies; 26%) risk of bias for the primary outcome. In conclusion, thiazide diuretics decreases the risk of fractures at any and at osteoporotic sites in a meta-analysis of RCTs. Additional studies are warranted in patients with high fracture risk. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Cardiac impairment in Long Covid 1-year post SARS-CoV-2 infection

Abstract Background Long Covid is associated with multiple symptoms and impairment in multiple organs [1]. Cardiac impairment has been reported to varying degrees by varying methodologies in cross-sectional studies. Using cardiovascular magnetic resonance (CMR), we investigated the 12-month trajectory of cardiac impairment in individuals with Long Covid. Purpose We conducted a prospective, longitudinal, 1-year study in individuals with Long Covid to investigate 1) the characteristics and trajectory of cardiac impairment; 2) the impact of acute hospitalisation for COVID-19 on cardiac impairment; and 3) pathways for designing and improving clinical management for individuals at risk of cardiac impairment. Methods 534 individuals with Long Covid underwent baseline CMR (quantitative T1 and T2 mapping, cardiac mass, volumes, function, and strain) and multi-organ MRI at 6 months (IQR 4.3,7.3) since first post-COVID-19 symptoms. If abnormal findings were reported at baseline, individuals were rescanned at 12.6 months (IQR 11.4, 14.2) (n=330). Symptoms, standardised questionnaires, and blood samples were collected at both timepoints (Figure 1). Cardiac impairment was defined as one or more of: low left or right ventricular ejection fraction (LVEF and RVEF), high left or right ventricular end diastolic volume (LVEDV and RVEDV), impaired left ventricular global longitudinal strain (GLS), or elevated native T1 in ≥3 cardiac independent AHA segments. A significant change over time was reported by comparison with 92 healthy controls. Results The technical success of this multiorgan assessment in a non-acute setting was 99.1% at baseline, and 98.3% at follow-up, with 99.6% and 98.8% for CMR, respectively. Of individuals with Long Covid, 19% had cardiac impairment at baseline; 70% had complete paired data at 12 months. Of those with paired data, 58% presented with ongoing cardiac impairment at 12 months. High sensitivity cardiac troponin I and B-type natriuretic peptide were not predictive of CMR findings, symptoms, or clinical outcomes. At baseline, low LVEF, high RVEDV and reduced GLS were associated with cardiac impairment; however, while elevated T1 was associated with less symptom severity at 12 months, individuals with low LVEF at baseline were associated with ongoing cardiac impairment 1 year post-infection (Figure 2). Conclusion Cardiac impairment, other than myocarditis, is present in 1 in 5 individuals with Long Covid at 6 months, persisting in over half of those at 12 months. Cardiac-related blood biomarkers are unable to identify cardiac impairment in Long COVID. Subtypes of disease (based on symptoms, examination, and investigations) and predictive biomarkers are yet to be established. Interventional trials with pre-specified subgroup analyses are required to inform therapeutic options. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Radical (EU) and Innovative UK (UK national) (and others)

S1325 Association of Alcohol Consumption With Diastolic Hypertension in Patients With Mild Liver Stiffness: Analysis of the National Health and Nutrition Examination Survey 2017-2020

Introduction: While excessive alcohol consumption is associated with arterial hypertension. Cirrhotic patient’s risk for hypertension remains unclear due to both vasodilatation and vasoconstriction effect. We aim to examine the association between alcohol consumption and hypertension in patients with different degrees of liver fibrosis. Methods: A cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) 2017 to March 2020 included adult participants. Association between alcohol consumption and both systolic and diastolic hypertension (SHTN and DHTN) defined as SBP and DBP ≥120 and ≥80 mmHg, respectively were analyzed by multivariate logistic regression. Prespecified subgroup analyses were performed to investigate potential effect modifiers. Results: A total of 9,693 patients were identified (mean age 50±19 years old; 51% female; 35% white). Among the participants with Fibroscan results, they were stratified into 3 groups based on the number of alcohol drinks per day (0-1 drink per day (G1), 2,126 [36%]; 1-4 drinks per day (G2), 2,612 [45%]; > 4 drinks per day (G3), 1,125 [20%]). After controlling for age, race, gender, body mass index, diabetic status, hyperlipidemic status, serum creatinine, urinary albumin:creatinine ratio, and fibrotic liver stage (< F2 = mild and ≥F2 = significant with fibrosis scores of < 7.5 and ≥7.5 kPa, respectively), the G2 and G3 had greater the odds of having SHTN but not statistically significant. (ORG21.26; P 0.155; 95%CI 0.9076, 1.760; ORG3 1.30, P 0.180, 95%CI 0.886, 1.909). Both G2 and G3 were significantly more likely to develop DHTN (ORG2 1.53, P 0.018, 95%CI 1.076, 2.172; OR3G3 1.88, P0.002 95%CI 1.259, 2.802). Subgroup analysis revealed a significant increased odds of developing DHTN in G2 and G3 only for those with mild fibrosis (< F2; ORG2 1.45, P 0.048, 95%CI 1.004, 2.151; OR G3 1.83, P 0.006, 95%CI 1.186, 2.833). The magnitude and direction of the association were similar for participants with significant fibrosis (≥F2; ORG21.64, P 0.363, 95%CI 0.566, 4.728; OR G3 1.86, P 0.308, 95%CI 0.564, 6.168; Figure A). The alcohol – SHTN association remains no statistical significance in all subgroups (Figure B). There was no effect modification observed between alcohol consumption and key covariates. Conclusion: In this study, there is an association between alcohol intake and DHTN in mild fibrotic liver patients. Longitudinal studies are required to further evaluate this association and possible underlying mechanisms.Figure 1.: Distribution of diastolic (A) and systolic (B) hypertension stratified by the amount of alcohol consumption per day and the severity of liver fibrosis

High doses of enteral docosahexaenoic acid omega-3 supplementation for prevention of bronchopulmonary dysplasia in very preterm infants: a protocol for a systematic review and meta-analysis

IntroductionDocosahexaenoic acid (DHA) supplementation in the neonatal period has been proposed to prevent bronchopulmonary dysplasia (BPD) in very preterm infants. We aim to determine the effects of an enteral supplementation...

Vitamin D Supplementation and the Incidence of Cataract Surgery in Older Australian Adults

Observational studies suggest that higher serum 25-hydroxy vitamin D (25(OH)D) concentration may be associated with lower risk of cataract. However, no randomized controlled trials have assessed the effect of vitamin D supplementation on the incidence of cataract. We aimed to assess whether vitamin D supplementation reduces the incidence of cataract surgery. We conducted an ancillary study of the D-Health Trial, a randomized, double-masked, placebo-controlled trial of monthly vitamin D conducted from 2014 through 2020 within the Australian general population. We invited 421 207 men and women 60 to 84 years of age to participate; including an additional 1896 volunteers, 40 824 expressed interest. Those with hypercalcemia, hyperparathyroidism, kidney stones, osteomalacia, or sarcoidosis or those who were taking more than 500 international units (IU) supplemental vitamin D per day were excluded. A total of 21 315 were randomized, and 1390 participants did not fulfil the eligibility criteria for this analysis (linked data available, no cataract within first 6 months), leaving 19 925 included. The median follow-up was 5 years. Participants took 60 000 IU of vitamin D3 (n= 10 662) or placebo (n= 10 653) orally once per month for a maximum of 5 years. The primary outcome for this analysis was the first surgical treatment for cataract, ascertained through linkage to universal health insurance records and hospital data. Among 19 925 participants eligible for this analysis (mean age, 69.3 years; 46% women) 3668 participants (18.4%) underwent cataract surgery during follow-up (vitamin D: n= 1841 [18.5%]; placebo: n= 1827 [18.3%] ). The incidence of cataract surgery was similar between the two groups (incidence rate, 41.6 and 41.1 per 1000 person-years in the vitamin D and placebo groups, respectively; hazard ratio, 1.02; 95% confidence interval, 0.95-1.09). In prespecified subgroup analyses, the effect of vitamin D supplementation on the incidence of cataract surgery was not modified by age, sex, body mass index, predicted serum 25(OH)D concentration, or ambient ultraviolet radiation. Routinely supplementing older adults who live in an area with a low prevalence of vitamin D deficiency with high-dose vitamin D is unlikely to reduce the need for cataract surgery. Proprietary or commercial disclosure may be found after the references.

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial

BackgroundNeutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19.MethodsIn a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012.FindingsBetween June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57–0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug.InterpretationBrensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19.FundingSponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.

Efficacy and Safety of Belimumab in Patients With Lupus Nephritis: Subgroup Analyses of a Phase 3 Randomized Trial in the East Asian Population

Belimumab improved kidney outcomes in patients with active lupus nephritis (LN) in BLISS-LN, leading to its approval in the United States and the European Union. As data on treatment of East Asian patients with LN are limited, we evaluated the efficacy and safety of belimumab in the BLISS-LN East Asian subgroup. Prespecified subgroup analysis of BLISS-LN, a phase 3, placebo-controlled, randomized 104-week trial. Adults with biopsy-proven, active LN were randomized (1:1) to belimumab or placebo, plus standard therapy. Patients were administered intravenous belimumab 10mg/kg, or placebo, plus standard therapy (oral glucocorticoids and either cyclophosphamide for induction followed by azathioprine for maintenance, or mycophenolate mofetil for both induction and maintenance). At the investigator's discretion, 1-3 intravenous pulses of methylprednisolone, 500-1,000mg each, could be administered during induction. The primary end point was primary efficacy renal response (PERR; ie, urinary protein-creatinine ratio≤0.7g/g, estimated glomerular filtration rate no more than 20% below preflare value or≥60mL/min/1.73m2, and no treatment failure) at week 104. Key secondary end points included complete renal response (CRR; urinary protein-creatinine ratio<0.5g/g, estimated glomerular filtration rate no more than 10% below preflare value or≥90mL/min/1.73m2, and no treatment failure) at week 104; PERR at week 52; time to kidney-related event or death; and safety. PERR and CRR were analyzed using a logistic regression model, and time to a kidney-related event or death was analyzed using a Cox proportional hazards regression model. 142 patients from mainland China, Hong Kong, South Korea, and Taiwan were included (belimumab, n=74; placebo, n=68). At week 104, more belimumab than placebo patients achieved PERR (53% vs 37%; OR, 1.76 [95% CI, 0.88-3.51]) and CRR (35% vs 25%; OR, 1.73 [95% CI, 0.80-3.74]). At week 52, more belimumab than placebo patients achieved PERR (62% vs 37%; OR, 2.74 [95% CI, 1.33-5.64]). Belimumab reduced the risk of a kidney-related event or death compared with placebo at any time (HR, 0.37 [95% CI, 0.15-0.91]). Safety was similar across treatment groups. Small sample size and lack of formal significance testing. Safety and efficacy profiles were consistent with BLISS-LN overall population, supporting benefits of belimumab treatment in the East Asian subgroup with LN. This study was funded by GSK (GSK study no. BEL114054). Registered at ClinicalTrials.gov with study number NCT01639339.

Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-analysis

Recently developed ketone (monoester or salt) supplements acutely elevate blood β-hydroxybutyrate (BHB) exogenously without prolonged periods of fasting or carbohydrate restriction. Previous (small-scale) studies have found a blood glucose-lowering effect of exogenous ketones. This study aimed to systematically review available evidence and conduct meta-analyses of studies reporting on exogenous ketones and blood glucose. We searched 6 electronic databases on 13 December 2021 for randomized and nonrandomized trials of any length that reported on the use of exogenous ketones. We calculated raw mean differences (MDs) in blood BHB and glucose in 2 main analyses: 1) after compared with before acute ingestion of exogenous ketones and 2) following acute ingestion of exogenous ketones compared with a comparator supplement. We pooled effect sizes using random-effects models and performed prespecified subgroup analyses to examine the effect of potential explanatory factors, including study population, exercise, blood BHB, and supplement type, dosing, and timing. Risk of bias was examined using Cochrane's risk-of-bias tools. Studies that could not be meta-analyzed were summarized narratively. Forty-three trials including 586 participants are summarized in this review. Following ingestion, exogenous ketones increased blood BHB (MD=1.73 mM; 95% CI: 1.26, 2.21mM; P <0.001) and decreased mean blood glucose (MD = -0.54mM; 95% CI: -0.68, -0.40mM; P <0.001). Similarly, when compared with placebo, blood BHB increased (MD=1.98mM; 95% CI: 1.52, 2.45mM; P <0.001) and blood glucose decreased (MD = -0.47mM; 95% CI: -0.57, -0.36mM; P <0.001). Across both analyses, significantly greater effects were seen with ketone monoesters compared with salts (P <0.001). The available evidence indicates that acute ingestion of exogenous ketones leads to increased blood BHB and decreased blood glucose. Limited evidence on prolonged ketone supplementation was found.

390P Impact of age on treatment strategies in RAS/BRAF wild-type metastatic colorectal cancer (mCRC): A prespecified subgroup analysis of the GERCOR-PRODIGE STRATEGIC-1 phase III study

Nearly half of patients (pts) with CRC are over 70 years old in clinical practice. STRATEGIC-1 compared FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab (Arm A) to OPTIMOX-bevacizumab followed by FOLFIRI-bevacizumab and EGFR monoclonal antibody +/- irinotecan (Arm B) in pts with previously untreated RAS/BRAF wild-type unresectable mCRC. To elucidate the impact of age on treatment efficacy, we evaluated duration of disease control (DDC) and overall survival (OS). A subgroup analysis of pts ≥70 years old was preplaned. Pts were divided into two age groups, <70 and ≥70 years, at the time of diagnosis. DDC and OS were expressed by the Kaplan-Meier method and compared by log-rank testing and Cox regression. In the general population (N=263), 187 pts (71%) and 76 pts (29%) were <70 and ≥70 years old, respectively. In Arm A (N=131) and in Arm B (N=132), 35 pts (27%) and 41 pts (31%) were ≥70 years old, respectively. Subgroup analysis showed that age had similar prognostic value in terms of DDC (22.0 months in younger vs 25.3 months in elderly [HR=0.91, 0.66-1.25; P=0.553]) and OS (36.5 months vs 34.9 months [HR=1.08, 0.78-1.48; P=0.648], respectively). Although OS was significantly improved in Arm A (HR=1.45, 1.02-2.08; P=0.039) in <70 pts, median OS was better in Arm B in ≥70 pts (42.1 vs 33.7 months; but statistically non-significant [P=0.161]). The effect of age on the treatment efficacy is shown in Table.Table: 390PPts <70 yearsPts ≥70 yearsArm AArm BHR (95%CI)PArm AArm BHR (95%CI)PNo.96913541DDC, median (months)22.820.91.05 (0.75-1.48)0.76422.528.90.83 (0.48-1.42)0.483OS, median (months)42.631.71.45 (1.02-2.08)0.03933.742.10.90 (0.53-1.53)0.161 Open table in a new tab These results confirm the polychemotherapy regimens efficiency associated to targeted therapies despite of the age, but elderly were underrepresented in trial compared to real life. The best choice of first-line chemotherapy in older pts remains unclear. The COLAGE GERCOR study, assessing the quality of life in elderly treated by FOLFOX-bevacizumab vs the standard first-line treatment (capecitabine-bevacizumab), and further studies are needed to better target elderly with mCRC.

AZTEC—azithromycin therapy for prevention of chronic lung disease of prematurity: a statistical analysis plan for clinical outcomes

BackgroundThe AZTEC trial is a multi-centre, randomised, placebo-controlled trial of azithromycin to improve survival without development of chronic lung disease of prematurity (CLD) in preterm infants. The statistical analysis plan for the clinical outcomes of the AZTEC trial is described.Methods and designA double-blind, randomised, placebo-controlled trial of a 10-day course of intravenous azithromycin (20 mg/kg for 3 days; 10 mg/kg for 7 days) administered to preterm infants born at < 30 weeks’ gestational age across UK tertiary neonatal units. Following parental consent, infants are randomly allocated to azithromycin or placebo, with allocated treatment starting within 72 h of birth. The primary outcome is survival without moderate/severe CLD at 36 weeks’ postmenstrual age (PMA). Serial respiratory fluid and stool samples are being collected up to 21 days of life. The target sample size is 796 infants, which is based on detecting a 12% absolute difference in survival without moderate/severe CLD at 36 weeks’ PMA (90% power, two-sided alpha of 0.05) and includes 10% loss to follow-up.ResultsBaseline demographic and clinical characteristics will be summarised by treatment arm and in total. Categorical data will be summarised by numbers and percentages. Continuous data will be summarised by mean, standard deviation, if data are normal, or median, interquartile range, if data are skewed. Tests of statistical significance will not be undertaken for baseline characteristics. The primary analysis, on the intention to treat (ITT) population, will be analysed using multilevel logistic regression, within a multiple imputation framework. Adjusted odds ratios, 95% confidence intervals, and p-values will be presented. For all other analyses, the analysis population will be based on the complete case population, which is a modified ITT population. All analyses will be adjusted for gestational age and treatment arm and account for any clustering by centre and/or multiple births as a random effect.ConclusionWe describe the statistical analysis plan for the AZTEC trial, including the analysis principles, definitions of the key clinical outcomes, methods for primary analysis, pre-specified subgroup analysis, sensitivity analysis, and secondary analysis. The plan has been finalised prior to the completion of recruitment.Trial registrationISRCTN registry ISRCTN11650227. Registered on 31 July 2018.