As-treated Analysis Research Articles

Transplantation Outcomes with Donor Hearts after Circulatory Death

BackgroundData showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited.MethodsWe conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation.ResultsA total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, −3 percentage points; 90% CI, −10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation.ConclusionsIn this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.)

Perioperative changes in neurocognitive and Alzheimer's disease-related cerebrospinal fluid biomarkers in older patients randomised to isoflurane or propofol for anaesthetic maintenance

BackgroundAnimal studies have shown that isoflurane and propofol have differential effects on Alzheimer's disease (AD) pathology and memory, although it is unclear whether this occurs in humans. MethodsThis was a nested randomised controlled trial within a prospective cohort study; patients age ≥60 yr undergoing noncardiac/non-neurological surgery were randomised to isoflurane or propofol for anaesthetic maintenance. Cerebrospinal fluid (CSF) was collected via lumbar puncture before, 24 h, and 6 weeks after surgery. Cognitive testing was performed before and 6 weeks after surgery. Nonparametric methods and linear regression were used to evaluate CSF biomarkers and cognitive function, respectively. ResultsThere were 107 subjects (54 randomised to isoflurane and 53 to propofol) who completed the 6-week follow-up and were included in the analysis. There was no significant effect of anaesthetic treatment group, time, or group-by-time interaction for CSF amyloid-beta (Aβ), tau, or phospho-tau181p levels, or on the tau/Aβ or p-tau181p/Aβ ratios (all P>0.05 after Bonferroni correction). In multivariable-adjusted intention-to-treat analyses, there were no significant differences between the isoflurane and propofol groups in 6-week postoperative change in overall cognition (mean difference [95% confidence interval]: 0.01 [–0.12 to 0.13]; P=0.89) or individual cognitive domains (P>0.05 for each). Results remained consistent across as-treated and per-protocol analyses. ConclusionsIntraoperative anaesthetic maintenance with isoflurane vs propofol had no significant effect on postoperative cognition or CSF Alzheimer's disease-related biomarkers within 6 weeks after noncardiac, non-neurological surgery in older adults. Clinical trial registrationNCT01993836.

Kidney function loss and albuminuria progression with GLP-1 receptor agonists versus basal insulin in patients with type 2 diabetes: real-world evidence

BackgroundIn clinical trials enrolling patients with type 2 diabetes (T2D) at high cardiovascular risk, many glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improved albuminuria status and possibly mitigated kidney function loss. However, limited data are available regarding the effects of GLP-1 RAs on albuminuria status and kidney function in real-world settings, including populations with a lower baseline cardiovascular and kidney risk. We assessed the association of GLP-1 RAs initiation with long-term kidney outcomes in the Maccabi Healthcare Services database, Israel.MethodsAdults with T2D treated with ≥ 2 glucose-lowering agents who initiated GLP-1 RAs or basal insulin from 2010 to 2019 were propensity-score matched (1:1) and followed until October 2021 (intention-to-treat [ITT]). In an as-treated (AT) analysis, follow-up was also censored at study-drug discontinuation or comparator-initiation. We assessed the risk of a composite kidney outcome, including confirmed ≥ 40% eGFR loss or end-stage kidney disease, and the risk of new macroalbuminuria. Treatment-effect on eGFR slopes was assessed by fitting a linear regression model per patient, followed by a t-test to compare the slopes between the groups.ResultsEach propensity-score matched group constituted 3424 patients, 45% women, 21% had a history of cardiovascular disease, and 13.9% were treated with sodium-glucose cotransporter-2 inhibitors at baseline. Mean eGFR was 90.6 mL/min/1.73 m2 (SD 19.3) and median UACR was 14.6 mg/g [IQR 0.0–54.7]. Medians follow-up were 81.1 months (ITT) and 22.3 months (AT). The hazard-ratios [95% CI] of the composite kidney outcome with GLP-1 RAs versus basal insulin were 0.96 [0.82–1.11] (p = 0.566) and 0.71 [0.54–0.95] (p = 0.020) in the ITT and AT analyses, respectively. The respective HRs for first new macroalbuminuria were 0.87 [0.75–0.997] and 0.80 [0.64–0.995]. The use of GLP-1 RA was associated with a less steep eGFR slope compared with basal insulin in the AT analysis (mean annual between-group difference of 0.42 mL/min/1.73 m2/year [95%CI 0.11–0.73]; p = 0.008).ConclusionInitiation of GLP-1 RAs in a real-world setting is associated with a reduced risk of albuminuria progression and possible mitigation of kidney function loss in patients with T2D and mostly preserved kidney function.

Statistically Adjusting for Wear Time in Randomized Trials of Continuous Glucose Monitors as a Complement to Intent-to-Treat and As-Treated Analyses: Application and Evaluation in Two Trials.

Background: Randomized trials of continuous glucose monitoring (CGM) often estimate treatment effects using standard intent-to-treat (ITT) analyses. We explored how adjusting for CGM-measured wear time could complement existing analyses by estimating the effect of receiving and using CGM 100% of the time. Methods: We analyzed data from two 6-month CGM trials spanning diverse ages, the Wireless Innovation for Seniors with Diabetes Mellitus (WISDM) and CGM Intervention in Teens and Young Adults with Type 1 Diabetes (CITY) Studies. To adjust the ITT estimates for CGM use, as measured by wear time, we used an instrumental variable (IV) approach with the treatment assignment as an instrument. Outcomes included (1) time in range ([TIR] 70-180 mg/dL), time below range ([TBR] ≤70 mg/dL), and time above range ([TAR] ≥250 mg/dL). We estimated outcomes based on CGM use in the last 28 days of the trial and the full trial. Findings: In the WISDM study, the wear time rates over the 28-day window and full trial period were 93.1% (standard deviation [SD]: 20.4) and 94.5% (SD: 11.9), respectively. In the CITY study, the wear time rates over the 28-day window and full trial period were 82.2% (SD: 26.5) and 83.1% (SD: 21.5), respectively. IV-based estimates for the effect of CGM on TIR, TBR, and TAR suggested greater improvements in glycemic management than the ITT counterparts. The magnitude of the differences was proportional to the level of wear time observed in the trials. Interpretation: In trials of CGM use, the effect of variable wear time is non-negligible. By providing adherence-adjusted estimates, the IV approach may have additional utility for individual clinical decision-making.

OA06 Clinical outcomes of filgotinib in patients with rheumatoid arthritis aged ≥65 years: a post hoc subgroup analysis of Phase 2 and 3 clinical trials and ongoing long-term extensions

Abstract Background/Aims Filgotinib (FIL) is a Janus kinase 1 preferential inhibitor approved for treatment of moderate-severe active RA. A numerically higher proportion of patients (pts) ≥65y vs &amp;lt; 65y had an adverse event (AE), serious AE, or serious infection (SI) in the FIL 200 mg (FIL200) group of the pooled phase 2 and 3 safety studies. We report updated data on AEs of special interest (AESIs) and efficacy in these age groups. Methods This post hoc analysis assessed safety and efficacy in pts aged &amp;lt;65y and ≥65y using data from phase 2 DARWIN 1 (NCT01888874) and 2 (NCT01894516); phase 3 FINCH 1 (NCT02889796), 2 (NCT02873936), and 3 (NCT02886728); and DARWIN 3 (NCT02065700) and FINCH 4 (NCT03025308) long-term extension (LTE) trials. All pts with RA fulfilled 2010 ACR/EULAR criteria. Data as of Jan 11, 2022 (DARWIN 3) and Jan 31, 2022 (FINCH 4). Analyses performed on an ad hoc interim analysis data set without additional cleaning. The as-treated analysis set included all available data for pts receiving ≥1 FIL dose (FIL200/FIL 100 mg [FIL100]), including those rerandomized to FIL in the LTE. Censored exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure of AESIs by age category (&amp;lt;65y vs ≥ 65y) are presented. EAIR and 95% confidence intervals (CIs) were calculated. Proportions of pts aged &amp;lt;65y and ≥65y achieving a 20, 50 and 70% improvement in ACR criteria (ACR20/50/70) and DAS28-CRP low disease activity (LDA) at Week 144 in FINCH 4, estimated using observed cases, are reported. Results Patients ≥65y had higher proportions of cardiovascular (CV) risk factors at baseline vs those &amp;lt;65y. EAIRs of AESIs were generally higher in pts aged ≥65y than &amp;lt;65y. In pts aged ≥65y, the EAIRs of adjudicated major adverse cardiovascular events, venous thromboembolisms, SI, and herpes zoster differed between the 2 FIL doses with partly or largely overlapping CIs. The EAIRs of nonmelanoma skin cancer (NMSC), malignancies (excluding NMSC), and treatment-emergent AE (TEAE) leading to death were numerically higher in the ≥65y age group only, with FIL200 vs FIL100. The most reported fatal outcomes with FIL200 in the ≥65y age group were malignancies, cardiac disorders, and infections and infestations. ACR20/50/70 and DAS28-CRP LDA rates in pts aged &amp;lt;65 and ≥65y in FINCH 4 were maintained or numerically higher with FIL200 to Week 144. Conclusion In this post hoc integrated safety analysis, the EAIRs of AESIs were generally higher in pts aged ≥65y than &amp;lt;65y. A numerically higher incidence of NMSC, malignancies (excluding NMSC), and TEAEs leading to death was observed in the FIL200 vs FIL100 group in pts aged ≥65y only. In FINCH 4, efficacy was maintained in both age groups. Limitations include the ad hoc nature of analysis, overlapping CIs, lack of comparator data, and potential LTE bias. Disclosure M.H. Buch: Other; AbbVie, Galapagos, Gilead, Pfizer, Eli Lilly, Merck-Serono, Roche, UCB. B. Combe: Other; AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Gilead, Janssen, Lilly, MSD, Pfizer, Roche-Chugai, Novartis. J.A. Gómez-Puerta: Other; GSK, Galapagos, Pfizer, Janssen, Sanofi, AbbVie, Bristol Myers Squibb, Lilly, Novartis, MSD, Roche. R. Caporali: Other; AbbVie, Celltrion, Fresenius-Kabi, Galapagos, Janssen, Pfizer, Roche, UCB, Eli Lilly, Gilead, Sanofi. J. Gottenberg: Other; AbbVie, Bristol Myers Squibb, Galapagos, Gilead, Lilly, MSD, Novartis, Pfizer. P. Van Hoek: Other; Galapagos. V. Rajendran: Other; Galapagos. P. Stiers: Other; Galapagos. K. Van Beneden: Other; Galapagos. D. Aletaha: Other; Novartis, SoBi, Sanofi, Amgen, Lilly, Merck, Pfizer, Roche, Sandoz, Janssen, AbbVie. G. Burmester: Other; AbbVie, Galapagos, Lilly, MSD, Pfizer, Roche, UCB, Janssen, Gilead Sciences, Inc. R. Westhovens: Other; Celltrion, Galapagos, Gilead. Y. Tanaka: Other; Lilly, AbbVie, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Pfizer, Mitsubishi Tanabe, GlaxoSmithKline, Asahi Kasei, Takeda, Astellas, Janssen, Novartis, Sanofi, UCB, YL Biologics, MSD, Ono, Taisho Toyama, Celltrion, Gilead, Boehringer-Ingelheim, Corrona, Kowa, Amgen, AstraZeneca, AstraZeneca, Eli Lilly.

Implementation and outcomes of dolutegravir-based first-line antiretroviral therapy for people with HIV in South Africa: a retrospective cohort study

There are few data assessing the uptake of first-line dolutegravir among men and women living with HIV in low-income and middle-income countries, and subsequent clinical outcomes in non-trial settings. We aimed to determine dolutegravir uptake in women, and the effect of dolutegravir on clinical outcomes in routine care in South Africa. In this cohort study, we analysed deidentified data from adults receiving first-line antiretroviral therapy (ART) at 59 South African clinics from Dec 1, 2019, to Feb 28, 2022, using two distinct cohorts. In the initiator cohort, we used Poisson regression models to assess the outcome of initiation with dolutegravir-based ART by gender, and associations between dolutegravir use and the outcomes of 12-month retention in care and viral suppression at less than 50 copies per mL. In the transition cohort, comprising adults who received non-dolutegravir-based first-line ART in December, 2019, we used Cox proportional hazards models to assess the outcome of transition to first-line dolutegravir by gender. We then used time-dependent propensity score matching to compare the outcomes of subsequent 12-month retention in care and viral suppression between people who transitioned to dolutegravir and those who had not yet transitioned at the same timepoint. In both the initiation and transition cohort, the primary viral load analysis was an intention-to-treat analysis, with a secondary as-treated analysis that excluded people who changed their ART regimen after baseline. In the initiator cohort, between Dec 1, 2019, and Feb 28, 2022, 45 392 people were initiated on ART. 23 945 (52·8%) of 45 392 were non-pregnant women, 4780 (10·5%) were pregnant women, and 16 667 (36·7%) were men. The median participant age was 31·0 years (IQR 26·0-38·0) and 2401 (5·3%) were receiving tuberculosis treatment at time of ART initiation. 31 264 (68·9%) of 45 392 people were initiated on dolutegravir, 14 102 (31·1%) on efavirenz, and 26 (0·1%) on nevirapine. In a univariable Poisson regression model, pregnant women (risk ratio [RR] 0·57, 95% CI 0·49 to 0·66; risk difference -35·4%, 95% CI -42·3 to -28·5) and non-pregnant women (RR 0·78, 0·74 to 0·82; risk difference -18·4%, -21·6 to -15·2) were less likely to be initiated on dolutegravir than were men. In Poisson models adjusted for age, gender (including pregnancy), time, tuberculosis status, and initiation CD4 count, people initiated on dolutegravir were more likely to be retained in care at 12 months (adjusted RR 1·09, 95% CI 1·04 to 1·14; adjusted risk difference 5·2%, 2·2 to 8·4) and virally suppressed (adjusted RR 1·04, 95% CI 1·01 to 1·06; adjusted risk difference 3·1%, 1·2 to 5·1) compared with those initiated on non-dolutegravir-based regimens. For the transition cohort, on Dec 1, 2019, 180 956 people were receiving non-dolutegravir-based first-line ART at the study clinics, of whom 124 168 (68·6%) were women. The median age was 38 years (IQR 32-45), and the median time on ART was 3·9 years (2·0-6·4) years, with most people receiving efavirenz (178 624 [98·7%] people) and tenofovir (178 148 [98·4%]). By Feb 28, 2022, 121 174 (67·0%) of 180 956 people had transitioned to first-line dolutegravir at a median of 283 days (IQR 203-526). In a univariable Cox regression model the hazard of being transitioned to dolutegravir was lower in women than in men (hazard ratio 0·56, 95% CI 0·56 to 0·57). Among 92 318 propensity score matched people, the likelihood of retention in care was higher among the dolutegravir group compared with matched controls (adjusted RR 1·03, 95% CI 1·02 to 1·03; risk difference 2·5%, 95% CI 2·1 to 2·9). In the dolutegravir group, 33 423 (90·5%) of 36 920 people were suppressed at less than 50 copies per mL compared with 31 648 (89·7%) of 35 299 matched controls (adjusted RR 1·01, 95% CI 1·00 to 1·02; risk difference 0·8%, 95% CI 0·3 to 1·4). Women were less likely to receive dolutegravir than men. As dolutegravir was associated with improved outcomes, roll-out should continue, with a particular emphasis on inclusion of women. Wellcome Trust, Africa Oxford Initiative, International Association of Providers of AIDS Care, and Bill & Melinda Gates Foundation. For the isiZulu translation of the abstract see Supplementary Materials section.

Impact on direct and indirect costs of switching patients with inflammatory bowel disease from intravenous to subcutaneous infliximab (CT-P13)

BackgroundWe aim to compare the real-life direct and indirect costs of switching patients from intravenous to subcutaneous (SC) CT-P13, an infliximab biosimilar, in a tertiary UK Inflammatory Bowel Disease (IBD)...

P731 Effect on direct and indirect costs of switching Inflammatory Bowel Disease patients from intravenous to subcutaneous infliximab (CT-P13)

Abstract Background Infliximab has transformed the management of Inflammatory Bowel Disease (IBD) however it has a significant cost burden. Additionally, demand on our IBD day case infusion unit has tripled in the last 7 years leading to long delays in treatment initiation. Switching patients from intravenous (IV) to subcutaneous (SC) infliximab reduces the demand on infusion units and offers patients more flexibility. We aim to compare the real-life direct (drug price and administration costs) and indirect costs (travel costs and time lost to work for patients) associated with switching patients from IV to SC CT-P13, an infliximab biosimilar, in a tertiary UK IBD centre. Methods We analysed data from all adult IBD patients at Leeds Teaching Hospitals Trust who had been identified as eligible to switch from IV to SC CT-P13. All patients were on a standard dosing regimen (5mg/kg 8 weekly) and were invited to switch via a letter from the IBD lead clinician. Patients were classified as IV or SC based on their decision to switch within 3 months. Figure one demonstrates how direct and indirect costs were calculated. We then compared the calculated annual costs by intention-to-treat (i.e. if all patients had switched from IV to SC) and as-treated (comparing all on IV pre-switch to some on IV and some SC post switch). Results 169 patients were identified as eligible to switch to SC CT-P13, 98 (58%) switched within 3 months. One patient was excluded as they had subsequently moved out of area. Prior to switching, total annual IV cost for 168 patients was calculated as £689,507.04 (direct = £653,671.20, indirect = £35,835.84). In the as-treated analysis after the switch, IV cost for 70 patients was £285,490.02 (direct = £272,363, indirect = £13,127.02) and SC cost for 98 patients was £389,432.81 (direct = £382,200, indirect = £7,232.81) giving a total annual cost for 168 patients of £674,922.83. In this analysis, after a proportion of patients switched to SC CT-P13, annual direct costs to the health service were £891.80 more per year, however indirect costs or cost to the patient were lower resulting in a lower total spend. See figure 2 for a breakdown of direct and indirect costs. Conclusion Our real-world analysis demonstrates that a switch from IV to SC CT-P13 is broadly cost neutral to the health service. Whilst the SC option has higher drug costs, a switch to SC allows for more efficient running of IV induction therapies by reducing demand on the infusion unit and reduces costs to the patient in terms of travel, parking and potential loss of working hours.

Vascular impulse technology versus elevation for reducing the swelling of upper and lower extremity joint fractures

Soft-tissue conditioning due to posttraumatic oedema after complicated joint fractures is a central therapeutic aspect both pre- and postoperatively. On average, 6–10 days pass until the patient is suitable for surgery. This study compares the decongestant effect of vascular impulse technology (VIT) with that of conventional elevation. In this monocentric RCT, 68 patients with joint fractures of the upper (n = 36) and lower (n = 32) extremity were included and randomized after consent in a 1:1 ratio. Variables were evaluated for all fractures together and additionally subdivided into upper or lower extremity for better clinical comparability. Primary endpoint was the time in days from hospital admission to operability. Secondary endpoints were total length of stay, oedema reduction, pain intensity, complications, and revisions. The time from admission until operability was reduced by 1.4 (95% CI − 0.4; 3.1) days in the mITT analysis (p = 0.120) and was statistically significant with 1.7 (95% CI 0.1; 3.3) days in the as-treated sensitivity analysis (pAT = 0.038). Significantly less pain and a faster oedema reduction were found in the intervention group. Due to rare occurrences, nothing can be concluded regarding complications and revisions. Administration of VIT therapy did not lead to a significant reduction in time until operability in the whole population but was superior to elevation for soft-tissue conditioning and pain reduction. However, there was a significant reduction by 2.5 days (95% CI 0.7; 4.3) in the subgroup of lower extremity fractures. VIT therapy therefore seems to be a helpful tool in the treatment of posttraumatic oedema after complex joint fractures of the lower and upper extremity, especially in tibial head and lower leg fractures.

Association of Sodium-Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study.

Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk. Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer's disease and related dementias. Propensity score-weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53-0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69-0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80-1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57-0.76]) than the intention-to-treat analysis. SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted.

Vaginal cleansing before unscheduled cesarean delivery to reduce infection: a randomized clinical trial

Cesarean delivery is the most performed major surgery among women, and surgical-site infections following a cesarean delivery are a significant source of postoperative morbidity. It is unclear if vaginal cleansing before a cesarean delivery decreases post-cesarean delivery infectious morbidity. This study aimed to evaluate if preoperative vaginal cleansing with povidone-iodine among women undergoing a cesarean delivery after labor decreases postoperative infectious morbidity. This randomized clinical trial was conducted from August 3, 2015 to January 28, 2021, with 30 days of follow-up and the final follow-up completed on February 27, 2021. Patients met the inclusion criteria if they underwent a cesarean delivery after regular contractions with cervical dilation, rupture of membranes, or any cesarean delivery performed at >4 cm dilation. Participants were randomly assigned in a 1:1 ratio to either abdominal cleansing plus vaginal cleansing with 1% povidone-iodine or abdominal cleansing alone. The primary outcome was composite infectious morbidity including surgical-site infection, fever, endometritis, and wound complications within 30 days after the cesarean delivery. Secondary outcomes included individual components of the composite, length of hospital stay, postoperative hospitalization or outpatient treatment related to infectious morbidity, and empirical treatment for neonatal sepsis. A total of 608 subjects (304 vaginal cleansing group, 304 control group) were included in the intention-to-treat analysis. Patient characteristics were similar between groups. There was no significant difference in the primary composite outcome between the 2 groups (11.8% vs 11.5%; P=.90; relative risk, 1.0; 95% confidence interval, 0.7-1.6). Individual components of the composite and secondary outcomes were also not significantly different between the groups. Similar findings were observed in the as-treated analysis (11.3% vs 11.8%; P=.9; relative risk, 1.0; 95% confidence interval, 0.7-1.6). Vaginal cleansing with povidone-iodine before an unscheduled cesarean delivery occurring after labor did not reduce the postoperative infectious morbidity. These findings do not support the routine use of vaginal cleansing for women undergoing a cesarean delivery after labor.

Association of Benzodiazepine Treatment for Sleep Disorders With Drug Overdose Risk Among Young People

Benzodiazepines are prescribed for the treatment of adolescent sleep disorders; however, benzodiazepine overdoses occur, often in combination with opioids. To evaluate whether benzodiazepine treatment for sleep disorders, compared with alternative pharmacologic treatments (trazodone, hydroxyzine, zolpidem, zaleplon, and eszopiclone), is associated with increased risk of drug overdose for young people. This cohort study included privately insured people 10 to 29 years of age identified from a US commercial claims database (MarketScan), from January 1, 2009, to December 31, 2018. Young people with a sleep disorder diagnosis initiating benzodiazepine (n = 23 084) or comparator pharmacologic treatments (n = 66 706) were included in the study. Statistical analysis was performed from November 1, 2021, to May 16, 2022. New use of benzodiazepine treatment or comparator pharmacologic treatments (defined as ≥1 year without a prescription for benzodiazepine or comparator medications). Incident diagnosed drug overdoses were identified from inpatient and emergency department records within 6 months of treatment initiation. The propensity score-adjusted cumulative incidence of overdose and hazard ratios (HRs) were estimated with intention-to-treat (analyzed based on initial treatment) and as-treated analyses (added censoring at treatment discontinuation). Results were stratified by prior prescription opioid fill. The cohort included 23 084 young people initiating benzodiazepine treatment (14 444 female participants [62.6%]; mean [SD] age, 23 [4.1] years) and 66 706 initiating a comparator treatment (38 446 female participants [57.6%]; mean [SD] age, 22 [4.4] years). Six months after treatment initiation, 9.7% (95% CI, 9.3%-10.1%) of benzodiazepine users and 12.3% (95% CI, 12.1%-12.6%) of the comparator group were still receiving treatment. The crude incidence of drug overdose at 6 months was 0.9% for benzodiazepine initiators and 0.8% for comparator treatment initiators. In adjusted analyses, an increased risk of drug overdose was associated with benzodiazepines vs comparator treatments (intention-to-treat analysis: HR, 1.25 [95% CI, 1.03-1.51]; as-treated analysis: HR, 1.44 [95% CI, 1.14-1.80]). This association was stronger among young people with a recent prescription opioid fill vs those without a recent prescription opioid fill (as-treated analysis: adjusted HR, 2.01 [95% CI, 1.24-3.25] vs adjusted HR, 1.31 [95% CI, 1.00-1.70]). The findings of this study suggest that benzodiazepines, compared with alternative pharmacologic treatments for common sleep disorders, were associated with an increased risk of drug overdose among young people during the following 6-month period, especially among those with a recent opioid prescription. Drug overdose is an important safety consideration when treating young people with benzodiazepines.

Association between body mass index and localized prostate cancer management and disease-specific quality of life.

The purpose of this work is to describe the association between body mass index (BMI) and (1) management option for localized prostate cancer (PCa) and (2) disease-specific quality of life (ds-QoL) after treatment or active surveillance. We analysed data from men with localized PCa managed with radical prostatectomy (RP), radiation therapy (RT), or active surveillance (AS) in a prospective, population-based cohort study. We evaluated the association between BMI and management option with multivariable multinomial logistic regression analysis. The association between BMI and ds-QoL was assessed using multivariable longitudinal linear regression. Regression models were adjusted for baseline domain scores, demographics, and clinicopathologic characteristics. A total of 2378 men were included (medians [quartiles]: age 64 [59-69] years; BMI 27 kg/m2; 77% were non-Hispanic white); 29% were obese (BMI ≥ 30). Accounting for demographic and clinicopathologic features, BMI ≥ 28 kg/m2 was inversely associated with the likelihood of receiving RP (compared with RT) and became statistically significant at BMI≥33 kg/m2 (maximum adjusted relative risk ratio =0.80, 95% CI 0.67 to 0.95, p= 0.013 for BMI ≥ 33 vs. 25). Conversely, BMI was not significantly associated with the likelihood of receiving AS compared with RT. After stratification by management option, obese men who underwent definitive treatment were not found to have clinically worse ds-QoL. Obese men initially on AS appeared to have worse urinary incontinence than nonobese men, but this was not significant on an as-treated sensitivity analysis. Among men with localized PCa, those with BMI ≥ 33 kg/m2 were less likely to receive surgery than radiation. Obesity was not associated with ds-QoL in men undergoing definitive treatment, nor in men who remained on AS.

406EMF Early Fluid Delivery by Emergency Medical Services for Sepsis Using a Novel Rapid Infusion Device

406EMF Early Fluid Delivery by Emergency Medical Services for Sepsis Using a Novel Rapid Infusion Device

Effect of long-lasting insecticidal nets with and without piperonyl butoxide on malaria indicators in Uganda (LLINEUP): final results of a cluster-randomised trial embedded in a national distribution campaign

Long-lasting insecticidal nets (LLINs) are the foundation of malaria control but resistance of mosquito vectors to pyrethroids threatens their effectiveness. We embedded a cluster-randomised trial into Uganda's 2017-18 campaign to distribute LLINs. LLINs with piperonyl butoxide (PBO) reduced parasite prevalence more effectively than conventional LLINs (without PBO) for 18 months. Here, we report the final 25-month survey results. LLINEUP was a cluster-randomised trial conducted in 48 districts in eastern and western Uganda. 104 health subdistricts (clusters) without ongoing or planned indoor residual spraying with pirimiphos-methyl (Actellic, Basel, Switzerland) were eligible for inclusion in the trial. Clusters were randomly assigned to PBO LLINs (PermaNet 3.0 or Olyset Plus) and conventional LLINs (PermaNet 2.0 or Olyset Net) with proportionate randomisation using STATA version 14.2. LLINs were delivered from March 25, 2017, to March 18, 2018. Between April 23, 2019, and Sept 13, 2019, community surveys were conducted in 50 randomly selected households per cluster; ten households per cluster were randomly selected for entomology surveys. Mosquitoes were collected in the morning from indoor surfaces of households using Prokopack aspirators. Due to COVID-19 restrictions, only 90 of the 104 clusters were surveyed at 25 months. The primary outcome was parasite prevalence by microscopy in children aged 2-10 years, assessed in the as-treated population, determined using the results from the 6-month household survey on the type of LLINs received in each cluster. This trial is registered with ISRCTN, ISRCTN17516395, and is now completed. In the as-treated analysis, two clusters were excluded (no predominant LLIN received) and four were reassigned; 40 PBO LLIN clusters (30 PermaNet 3.0, ten Olyset Plus) and 48 non-PBO LLIN (36 PermaNet 2.0, 12 Olyset Net) were included. Parasite prevalence was 17·1% (506 of 2958 participants) in the PBO group and 19·8% (701 of 3534) in the non-PBO group (prevalence ratio adjusted for baseline 0·80 [95% CI 0·69-0·93], p=0·0048). Comparing within-treatment group parasite prevalence to baseline, parasite prevalence ratios were lower in the PBO groups at all timepoints, but the difference was greatest at 6 months (PBO LLINs parasite prevalence at baseline 28·8% [1001 of 3472, 95% CI 27·3-30·4] vs at 6 months 12·0% [361 of 3009, 10·9-13·2], prevalence ratio [PR] 0·43 [95% CI 0·36-0·52], p<0·0001; non-PBO LLINs parasite prevalence at baseline 25·4% [1015 of 4004, 24·0-26·7] vs 6 months 14·8% [526 of 3551, 13·7-16·0], PR 0·60 [0·54-0·68], p<0·0001) and 25 months (PBO LLINs parasite prevalence at 25 months 17·1% [506 of 2958, 15·8-18·5], PR 0·63 [95% CI 0·57-0·71], p<0·0001; non-PBO LLINs parasite prevalence at 25 months 19·8% [701 of 3534, 18·5-21·2], PR 0·79 [0·73-0·86], p<0·0001). In Uganda, PBO LLINs outperformed pyrethroid-only LLINs for 25 months. WHO concluded that PBO LLINs are more effective against malaria than non-PBO LLINs when resistance to pyrethroids is high and issued a conditional recommendation suggesting PBO LLINs should be deployed in areas of pyrethroid resistance. The Against Malaria Foundation, UK Department for International Development, Innovative Vector Control Consortium, and Bill and Melinda Gates Foundation.

Telemedicine and Spina Bifida Transition: A Pilot Randomized Trial

Transition of care is the planned movement of adolescents and young adults from pediatric to adult health care. Many studies have demonstrated the importance of an organized transition process. The purpose of this study is to determine the efficacy of a telemedicine intervention for improving transition readiness among adolescents with spina bifida. The present study is a randomized, controlled trial, including children 14 years of age and older with myelomeningocele from a multidisciplinary spina bifida clinic. Subjects were randomized to standard care or to an intervention, consisting of video telemedicine contacts at 3, 6, and 9 months from the clinic visit. The primary outcome measure was a change in the Transition Readiness Assessment Questionnaire score from baseline to 1-year follow-up. Twenty-four patients were enrolled in the study and underwent randomization. The mean age at enrollment was 15.8 years. Ten patients (40%) were female, and the majority were White, non-Hispanic (67%). Despite enrolling 24 patients, only 1 patient in the telemedicine group completed any of the planned telemedicine sessions. No other participant completed any telemedicine counseling sessions. The study was stopped early for lack of participation in the intervention. In a single-group, as-treated analysis, there was no significant change in the Transition Readiness Assessment Questionnaire score between enrollment and 1-year follow-up (Δ= 0.36, P= 0.46). However, there were significant improvements in subscores for Managing Medications, Appointment Keeping, and Managing Daily Activities. The primary finding from this study was very low participation in a telemedicine video follow-up intervention among adolescents with myelomeningocele. Based on these results, this strategy alone is unlikely to significantly improve readiness for transition to adult care.

Extended vincristine and dexamethasone pulse therapy may not be necessary for children with TCF3-PBX1 positive acute lymphoblastic leukaemia.

The effect of prolonged pulse therapy with vincristine and dexamethasone (VD) during maintenance therapy on the outcome of paediatric patients with TCF3-PBX1 positive acute lymphoblastic leukaemia (ALL) remains uncertain. We conducted non-inferiority analysis of 263 newly diagnosed TCF3-PBX1 positive ALL children who were stratified and randomly assigned (1:1) to receive seven additional VD pulses (the control group) or not (the experimental group) in the CCCG-ALL-2015 clinical trial from January 2015 to December 2019 (ChiCTR-IPR-14005706). There was no significant difference in baseline characteristics between the two groups. With a median follow-up of 4.2 years, the 5-year event-free survival (EFS) and 5-year overall survival (OS) in the control group were 90.1% (95% confidence interval [CI] 85.1-95.4) and 94.7% (95% CI, 90.9-98.6) comparable to those in the experimental group 89.2% (95% CI 84.1-94.7) and 95.6% (95% CI 91.8-99.6), respectively. Non-inferiority was established as a one-sided 95% upper confidence bound for the difference in probability of 5-year EFS was 0.003, and that for 5-year OS was 0.01 by as-treated analysis. Thus, omission of pulse therapy with VD beyond one year of treatment did not affect the outcome of children with TCF3-PBX1 positive ALL.

Use of low-dose quetiapine increases the risk of major adverse cardiovascular events: results from a nationwide active comparator-controlled cohort study.

At standard doses used for schizophrenia or bipolar disorder, quetiapine has been associated with weight gain and increased levels of triglycerides,to-tal cholesterol and low-density lipoprotein (LDL) cholesterol, which are risk factors for cardiovascular morbidity and mortality. However, this drug is also commonly used off-label at low doses for anxiolytic or hypnotic purposes, and its cardiovascular safety at these doses is unknown. We aimed to assess the risk of major adverse cardiovascular events with use of low-dose quetiapine compared to use of Z-drug hypnotics in a nationwide, active comparator-controlled cohort study. The cohort included new users of either drugs in Denmark from 2003 to 2017, aged 18-85 years, without history of ischemic stroke, myocardial infarction, cancer, and severe mental illness. The main outcome was the occurrence of major adverse cardiovascular events, defined as non-fatal myocardial infarction or ischemic stroke, or death from cardiovascular causes. Selective serotonin reuptake inhibitors (SSRIs) were used as an alternative comparator in sensitivity analyses. Altogether, we compared 60,566 low-dose quetiapine users with 454,567 Z-drug users, followed for 890,198 person-years in intent-to-treat analysis, and 330,334 person-years in as-treated analysis. In intention-to-treat analysis, low-dose quetiapine was associated with an increased risk of major adverse cardiovascular events (adjusted hazard ratio, aHR=1.13, 95% CI: 1.02-1.24, p=0.014) and cardiovascular death (aHR=1.26, 95% CI: 1.11-1.43, p<0.001). In as-treated analysis, continuous low-dose quetiapine use was associated with increased risk of major adverse cardiovascular events (aHR=1.52, 95% CI: 1.35-1.70, p<0.001), non-fatal ischemic stroke (aHR=1.37, 95% CI: 1.13-1.68, p=0.002) and cardiovascular death (aHR=1.90, 95% CI: 1.64-2.19, p<0.001). The risk of major adverse cardiovascular events was greater in women (aHR=1.28, p=0.02) and those aged ≥65 years at initiation (aHR=1.24, p<0.001). Compared to SSRIs, low-dose quetiapine use was associated with an increased risk of major adverse cardiovascular events (aHR=1.42, p<0.001), non-fatal ischemic stroke (aHR=1.27, p=0.0028) and cardiovascular death (aHR=1.72, p<0.001). So, we conclude that the use of low-dose quetiapine is associated with an increased risk of major adverse cardiovascular events, especially in women and the elderly. On the basis of these findings, we suggest that use of off-label low-dose quetiapine for sedative or hypnotic purposes should be discouraged.

Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation

BackgroundThe role of allogeneic hematopoietic cell transplantation (alloHCT) in acute myeloid leukemia (AML) with mutated IDH1/2 has not been defined. Therefore, we analyzed a large cohort of 3234 AML patients in first complete remission (CR1) undergoing alloHCT or conventional chemo-consolidation and investigated outcome in respect to IDH1/2 mutational subgroups (IDH1 R132C, R132H and IDH2 R140Q, R172K).MethodsGenomic DNA was extracted from bone marrow or peripheral blood samples at diagnosis and analyzed for IDH mutations with denaturing high-performance liquid chromatography, Sanger sequencing and targeted myeloid panel next-generation sequencing, respectively. Statistical as-treated analyses were performed using R and standard statistical methods (Kruskal–Wallis test for continuous variables, Chi-square test for categorical variables, Cox regression for univariate and multivariable models), incorporating alloHCT as a time-dependent covariate.ResultsAmong 3234 patients achieving CR1, 7.8% harbored IDH1 mutations (36% R132C and 47% R132H) and 10.9% carried IDH2 mutations (77% R140Q and 19% R172K). 852 patients underwent alloHCT in CR1. Within the alloHCT group, 6.2% had an IDH1 mutation (43.4% R132C and 41.4% R132H) and 10% were characterized by an IDH2 mutation (71.8% R140Q and 24.7% R172K). Variants IDH1 R132C and IDH2 R172K showed a significant benefit from alloHCT for OS (p = .017 and p = .049) and RFS (HR = 0.42, p = .048 and p = .009) compared with chemotherapy only. AlloHCT in IDH2 R140Q mutated AML resulted in longer RFS (HR = 0.4, p = .002).ConclusionIn this large as-treated analysis, we showed that alloHCT is able to overcome the negative prognostic impact of certain IDH mutational subclasses in first-line consolidation treatment and could pending prognostic validation, provide prognostic value for AML risk stratification and therapeutic decision making.

National randomized clinical trial on subdural drainage time after chronic subdural hematoma evacuation.

Placement of a subdural drain reduces recurrence and death after evacuation of chronic subdural hematoma (CSDH), but little is known about optimal drainage duration. In the present national trial, the authors investigated the effect of drainage duration on recurrence and death. In a randomized controlled trial involving all neurosurgical departments in Denmark, patients treated with single burr hole evacuation of CSDH were randomly assigned to 24 hours or 48 hours of postoperative passive subdural drainage. Follow-up duration was 90 days, and the primary study outcome was recurrent hematoma requiring reoperation. Secondary outcome was death. In addition, complications and length of hospital stay were recorded and analyzed. Of the 420 included patients, 212 were assigned 24-hour drainage and 208 were assigned 48-hour drainage. The recurrence rate was 14% in the 24-hour group and 13% in the 48-hour group. Four patients died in the 24-hour group, and 8 patients died in the 48-hour group; this difference was not statistically significant. The ORs (95% CIs) for recurrence and mortality (48 hours vs 24 hours) were 0.94 (0.53-1.66) and 2.07 (0.64-7.85), respectively, in the intention-to-treat analysis. The ORs (95% CIs) for recurrence and mortality per 1-hour increase in drainage time were 1.0005 (0.9770-1.0244) and 1.0046 (0.9564-1.0554), respectively, in the as-treated sensitivity analysis that used the observed drainage times instead of the preassigned treatment groups. The rates of surgical and drain-related complications, postoperative infections, and thromboembolic events were not different between groups. The mean ± SD postoperative length of hospital stay was 7.4 ± 4.3 days for patients who received 24-hour drainage versus 8.4 ± 4.9 days for those who received 48-hour drainage (p = 0.14). The mean ± SD postoperative length of stay in the neurosurgical department was significantly shorter for the 24-hour group (2 ± 0.9 days vs 2.8 ± 1.6 days, p < 0.001). No significant differences in the rates of recurrent hematoma or death during 90-day follow-up were identified between the two groups that randomly received either 24- or 48-hour passive subdural drainage after burr hole evacuation of CSDH.