Prespecified Subgroup Analysis Research Articles

Salt Substitution and Recurrent Stroke and Death: A Randomized Clinical Trial.

The direct effect of consumption of salt substitutes on recurrent stroke and mortality among patients with stroke remains unclear. To evaluate the effects of salt substitutes vs regular salt on the incidence of recurrent stroke and mortality among patients with stroke. The Salt Substitute and Stroke Study (SSaSS), an open-label, cluster randomized clinical trial, was conducted in 600 northern Chinese villages (clusters). Patients who self-reported a hospital diagnosis of stroke were included in this prespecified subgroup analysis. Data were analyzed from November 2023 to August 2024. Participants were assigned to use either a salt substitute, consisting of 75% sodium chloride and 25% potassium chloride by mass, or regular salt. The primary outcome was recurrent stroke. After excluding 5746 persons without a baseline history of stroke, 15 249 patients with stroke (mean [SD] age, 64.1 [8.8] years; 6999 [45.9%] female; 8250 male [54.1%]) were included. Over a median (IQR) follow-up of 61.2 (60.9-61.6) months, the mean difference in systolic blood pressure was -2.05 mm Hg (95% CI, -3.03 to -1.08 mm Hg). A total of 2735 recurrent stroke events (691 fatal and 2044 nonfatal) and 3242 deaths were recorded. Recurrent stroke was significantly lower in the salt substitute vs regular salt group (rate ratio [RR], 0.86; 95% CI, 0.77-0.95; P = .005), with larger effects on hemorrhagic stroke (relative reduction, 30%; P = .002). Death rates were also significantly lower (RR, 0.88; 95% CI, 0.82-0.96; P = .003), with larger effects on stroke-related deaths (relative reduction 21%; P = .01). No significant difference was observed for hyperkalemia (RR, 1.01; 95% CI, 0.74-1.38; P = .96). Results of this cluster trial demonstrate that salt substitution was safe, along with reduced risks of stroke recurrence and death, which underscores large health gains from scaling up this low-cost intervention among patients with stroke. ClinicalTrials.gov Identifier: NCT02092090.

Comparison of percutaneous versus cutdown access in patients after endovascular abdominal aortic repair: a randomized controlled trial (SWEET-EVAR trial).

The optimal choice of either percutaneous or cutdown access for endovascular abdominal aortic repair (EVAR) remains uncertain due to insufficient evidence, particularly regarding patient-centered outcomes (PCOs). This study aimed at comparing both clinician-reported outcomes (ClinROs) and PCOs of percutaneous versus cutdown access in patients after EVAR. The study was a single-blind, single-center, non-inferiority, randomized controlled trial. After eligibility screening, patients diagnosed with abdominal aortic diseases were randomly assigned to either the intervention group receiving percutaneous EVAR or the control group receiving cutdown EVAR. Primary ClinRO was access-related complications, and primary PCO was time return to normal life/work. Overall, 120 patients (containing 240 accesses) were allocated to either intervention group (n =62) or control group (n =58). Percutaneous EVAR (10/124, 8.1%) was non-inferior and not superior to cutdown EVAR (17/116, 14.7%) regarding access-related complications (P =0.110; OR: 0.521, 95% CI: 0.225-1.157). As for PCOs, the recovery time back to normal life or work was superior in percutaneous EVAR compared to cutdown EVAR (16 vs. 28days, P =0.025; median difference: 7days, 95% CI: 0-13days). Moreover, percutaneous access did better in other PCOs, including a reduction in the duration of access-related pain (4 vs. 8days, P =0.001), decreased use of analgesics for access-related pain (0/61, 0% vs. 6/55, 10.9%; P =0.026), and improved quality of life scores at 2 weeks following EVAR (0.876 vs. 0.782; P =0.022). Prespecified subgroup analyses demonstrated percutaneous access significantly reduced the incidence of access-related complications compared to cutdown access in patients with thick subcutaneous tissue (1/42, 2.4% vs. 7/32, 21.9%; P =0.026). In patients without massive common femoral artery calcification, percutaneous access may accelerate postoperative recovery and enhance patient experience and quality of life following EVAR, but did not provide obvious advantages regarding access-related complications.

Neoadjuvant immune checkpoint blockade in resectable hepatocellular carcinoma: A systematic review and meta-analyisis.

590 Background: Hepatocellular carcinoma (HCC) presents a significant therapeutic challenge due to its high recurrence rates after curative-intent resection. Neoadjuvant immune checkpoint blockade (ICB) has emerged as a promising strategy to improve tumor control by modulating the immune microenvironment prior to surgery. This systematic review and meta-analysis aim to assess the safety and efficacy of neoadjuvant ICB in improving clinical outcomes for patients with resectable HCC. Methods: A systematic search of PubMed, EMBASE, and Cochrane databases was conducted to identify clinical trials examining neoadjuvant ICB in resectable HCC. Primary endpoints included pathological complete response (pCR), major pathological response (mPR), overall response rate (ORR), and grade 3-4 treatment-related adverse events (TRAE). Prespecified subgroup analyses were conducted for studies combining ICB with tyrosine kinase inhibitors (TKIs) or dual ICB therapies. Pooled proportions were calculated using a random-effects model via the R package "meta." Inter-study heterogeneity was assessed using the I² statistic and test for subgroup differences were conducted. Results: Out of 1,321 studies screened, 14 clinical trials involving 252 patients with resectable HCC were included. Most studies were phase II trials (57%), and patient median age ranged from 57.5 to 68.0 years, with 88.3% of patients being male. The pooled prevalence of mPR was 32% (95% CI, 24–42%; I² = 9%)while pCR was achieved in 24% (95% CI, 17–34%; I² = 29%)of patients. The ORR was 27% (95% CI, 18–39%; I² = 49%), and severe adverse events (grade 3-4 TRAE) had a pooled prevalence of 24% (95% CI, 17–34%; I² = 16%). Subgroup analysis of trials combining ICB with TKIs showed an ORR 34% (95% CI, 20–55%; I² = 60%), an mPR rate of 27% (95% CI, 19–40%; I² = 0%), and a pCR rate of 20% (95% CI, 14–30%; I² = 0%). Dual ICB therapies demonstrated a higher mPR rate of 42% (95% CI, 26–67%; I² = 16%) and a pCR rate of 41% (95% CI, 29–59%; I² = 29%), but were associated with a higher incidence of severe TRAE (41%; 95% CI, 29–60%; I² = 0%). Conclusions: Neoadjuvant ICB demonstrates promising efficacy in resectable HCC, particularly when combined with TKIs or dual ICB therapies. While dual ICB enhances pathological response rates, it is associated with higher rates of severe TRAE. These results highlight the need of further studies to optimize combination strategies that balance efficacy and safety for patients with resectable HCC.

Apixaban versus aspirin for stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack: subgroup analysis of the ARTESiA randomised controlled trial.

People with subclinical atrial fibrillation are at increased risk of stroke, albeit to a lesser extent than those with clinical atrial fibrillation, leading to an ongoing debate regarding the benefit of anticoagulation in these individuals. In the ARTESiA trial, the direct-acting oral anticoagulant apixaban reduced stroke or systemic embolism compared with aspirin in people with subclinical atrial fibrillation, but the risk of major bleeding was increased with apixaban. In a prespecified subgroup analysis of ARTESiA, we tested the hypothesis that people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack, who are known to have an increased risk of recurrent stroke, would show a greater benefit from oral anticoagulation for secondary stroke prevention compared with those without a history of stroke or transient ischaemic attack. ARTESiA is a double-blind, double-dummy, randomised controlled trial conducted at 247 sites in 16 countries across Europe and North America. Adults aged 55 years or older with device-detected subclinical atrial fibrillation lasting from 6 min to 24 h and a CHA2DS2-VASc score of 3 or higher were randomly assigned using an interactive web-based system to oral apixaban 5 mg twice per day or oral aspirin 81 mg once per day. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding, assessed as absolute risk differences. Analyses were by intention to treat. ARTESiA is registered with ClinicalTrials.gov (NCT01938248) and is completed; this report presents a prespecified subgroup analysis in people with a history of stroke or transient ischaemic attack. Between May 7, 2015, and July 30, 2021, 4012 people with subclinical atrial fibrillation were randomly allocated either apixaban (n=2015) or aspirin (n=1997). A history of stroke or transient ischaemic attack was present in 346 (8·6%) participants (172 assigned to apixaban and 174 to aspirin), among whom the annual rate of stroke or systemic embolism was 1·20% (n=7; 95% CI 0·48 to 2·48) with apixaban versus 3·14% (n=18; 1·86 to 4·96) with aspirin; (hazard ratio [HR] 0·40, 95% CI 0·17 to 0·95). In participants without a history of stroke or transient ischaemic attack (n=3666; 1843 assigned to apixaban and 1823 to aspirin), the annual rate of stroke or systemic embolism was 0·74% (n=48; 95% CI 0·55 to 0·98) with apixaban versus 1·07% (n=68; 95% CI 0·83 to 1·36) with aspirin (HR 0·69, 95% CI 0·48 to 1·00). The absolute risk difference in incidence of stroke or systemic embolism at 3·5 years of follow-up was 7% (95% CI 2 to 12) in participants with versus 1% (0 to 3) in participants without a history of stroke or transient ischaemic attack. The annual rate of major bleeding in participants with a history of stroke or transient ischaemic attack was 2·26% with apixaban (n=13; 95% CI 1·21 to 3·87) versus 1·16% with aspirin (n=7; 0·47 to 2·39; HR 1·94, 95% CI 0·77 to 4·87). The absolute risk difference in major bleeding events at 3·5 years was 3% (-1 to 8) in individuals with a versus 1% (-1 to 2) in those without a history of stroke or transient ischaemic attack. Treatment with the direct-acting oral anticoagulant apixaban in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack led to a 7% absolute risk reduction in stroke or systemic embolism over 3·5 years, compared with a 1% absolute risk reduction for individuals without a previous history of stroke or transient ischaemic attack. The corresponding absolute increase in major bleeding was 3% and 1%, respectively. Apixaban could be considered for secondary stroke prevention in people with subclinical atrial fibrillation and a history of stroke or transient ischaemic attack. The Canadian Institutes of Health Research, Bristol-Myers Squibb-Pfizer Alliance, Heart and Stroke Foundation of Canada, Canadian Stroke Prevention and Intervention Network, Hamilton Health Sciences, Accelerating Clinical Trials Network, Population Health Research Institute, and Medtronic.

Abstract TP115: Differences in the Medical Management of Post-Stroke Sequelae Among Patients Treated with Mechanical Thrombectomy vs Intravenous Thrombolysis

Background: Mechanical thrombectomy (MT) as treatment for acute ischemic stroke (AIS) has demonstrated superior functional outcomes compared to intravenous thrombolysis (IVT). Yet AIS survivors often experience a range of unstudied post-stroke complications which negatively affect patient reported outcomes. To inform clinical practice, we assessed 90-day differences in the medical management of common stroke post-complications among patients treated with MT vs. IVT. Methods: A retrospective cohort of hospitalized AIS patients treated with IVT or MT were identified from Electronic Medical Records of 92 large healthcare organizations (01/2015-09/2024). Matched propensity scores were used to adjust for baseline differences across 36 factors. Outcomes included the use of medication(s) for the management of fatigue, spasticity, mood, sleep, seizure, neurogenic bowel&neurogenic bladder. Pre-specified subgroup analyses included differences in post-stroke sequelae management stratified by NIHSS scores of ≤9 (mild AIS) or >9 (moderate/severe AIS)&differences in post-stroke sequelae between AIS patients treated with MT vs MT + IVT. Results: The final cohort consisted of n=87,819 AIS patients treated with either IVT (n=82,534) or MT (n=5,285). PS matching resulted in 5,285 matched pairs with good balance across all baseline covariates. At 90-days, AIS patients treated with MT were more likely to receive medications for spasticity (RR: 1.15, 95%CI: 1.01, 1.31), mood (RR: 1.06, 95%CI: 1.01, 1.13)&neurogenic bowel (RR: 1.11, 95%CI: 1.09, 1.14) (Table 1). Approximately 7% (n=6,344) of AIS patients had NIHSS scores – PS matching resulted in 877 matched pairs with NIHSS ≤9&848 matched pairs with NIHSS>9. Following stratification, AIS patients treated with MT were significantly more likely to receive treatment of neurogenic bowel&bladder (Table 2). For the MT vs MT + IVT comparison, patients treated with MT were 5% less likely to receive treatment for neurogenic bowel RR: 0.95 (95%CI: 0.92, 0.99) among 1,900 matched pairs (Table 3). Discussion: Using real world data, AIS patients treated with MT (vs IVT) were more likely to receive treatment for spasticity, mood&neurogenic bowel. Among patients with documented NIHSS scores, differences remained significant for treatment of neurogenic bowel and bladder after stratifying by stroke severity. Healthcare providers should screen for these post-stroke sequelae, which substantially affect quality of life for AIS survivors.

Plant-based diets and the risk of lung cancer: a large prospective cohort study.

Plant-based diets are increasingly recognized for cancer prevention, yet their specific impact on lung cancer (LC) risk remains insufficiently examined. This study aims to assess the relationship between plant-based diets adherence and the incidence of LC. Data from the Prostate, Lung, Colorectal, and Ovarian cancer screening trial were analyzed. The plant-based diet index (PDI) was developed to assess adherence to plant-based diets. Multivariable Cox regression model was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic spline (RCS) model was performed to examine risk across the PDI spectrum. Prespecified subgroup analyses identified potential modifiers, and sensitivity analyses tested the association's robustness. Of the 98,459 participants included, 1,642 developed LC over an average follow-up of 8.83 years. Higher PDI scores were associated with a lower LC risk (HR quartile 4 vs. 1: 0.75, 95% CI: 0.65-0.87, P trend < 0.001), evident in both non-small cell lung cancer (HR quartile 4 vs. 1: 0.76, 95% CI: 0.65-0.88, P trend < 0.001) and small cell lung cancer (HR quartile 4 vs. 1: 0.73, 95% CI: 0.49-1.09, P trend = 0.046). RCS analyses further confirmed these relationships. The association was stronger among participants with lower BMI, smokers, those without a history of emphysema or diabetes, those without a family history of LC, and those with lower physical activity (all P trend < 0.001). Sensitivity analyses consistently supported these findings. Our findings reveal an inverse correlation between PDI and LC risk, supporting the potential benefits of plant-based diets in LC prevention. ClinicalTrials.gov ID: NCT00339495 (URL: https://www. gov/study/NCT00339495 ).

Aerobic exercise to alleviate primary dysmenorrhea in adolescents and young women: A systematic review and meta-analysis of randomized controlled trials.

Aerobic exercise has been confirmed to alleviate primary dysmenorrhea (PD) in adolescents and young women. However, the effect of the aerobic exercise type and dosage on PD alleviation was unclear. This research aims to assess the effect of aerobic exercise on PD and investigate the dose-response relationships. Systematic literature searches of Web of Science, Embass, Cochrane Library, PubMed, PsycNET, CINAHL, CNKI, Baidu Scholar, Google Scholar, and other Complimentary Medicine Database. PICOS standards were adopted in this research: participants were nonathlete women with PD; intervention was aerobic exercise of at least one menstruation cycle; comparator was any comparator; outcomes were pain intensity or pain duration; and study type was randomized controlled trials. The Cochrane Collaboration risk of bias tool was used to assess the quality of the research. Random-effect meta-analysis was conducted for pain intensity and pain duration, with prespecified subgroup analyses based on aerobic exercise components. The strength of the evidence was assessed using GRADE. This systematic review and meta-analysis was registered in PROSPERO (CRD42024533544). The study identified 16 eligible studies, with 15 involving adolescents, totaling 918 participants aged 15 to 43, with an average age of 21.26 ± 13.15. The results confirmed that aerobic exercise can alleviate PD's pain intensity (standard mean difference (SMD) = -1.728 (p = 0.00), 95% CI [-2.26 to -1.31]) and pain duration (weighted mean difference (WMD) = -12.53 h, p = 0.01, 95% CI: -21.38 to -3.68). However, the heterogeneity of these two results was high. Subgroup analysis showed that Pilates (SMD = -3.17, 95% CI [-4.26 to -2.07]), low intensity (SMD = -1.64, 95% CI [-2.10 to -1.19]), 31-45 min duration (SMD = -3.05, 95% CI [-5.36 to -0.75]), ≤2 times per week frequency (SMD = -2.24, 95% CI [-3.36 to -1.12]), and a period cycle of 2 menstrual cycles (SMD = -2.21, 95% CI [-3.13 to -1.28]) had the maximum effect size. Aerobic exercise was able to alleviate pain intensity and pain duration in adolescents and young women with PD. Moderate-quality evidence indicates that Pilates, low intensity, 46-60 min, ≤two times per week, or two menstrual cycles showed more efficiency in alleviating PD. Due to the limited data, future research should prioritize conducting randomized controlled trials of aerobic exercise interventions in younger age groups to develop personalized treatment strategies for adolescents.

Aspirin versus Clopidogrel monotherapy beyond 1 month after complex percutaneous coronary intervention: A pre-specified subgroup analysis of the STOPDAPT-3 trial.

There were no previous studies comparing aspirin versus P2Y12 inhibitor monotherapy following short dual antiplatelet therapy (DAPT) after complex percutaneous coronary intervention (PCI). We conducted a prespecified subgroup analysis based on complex PCI in the 1-year results of the STOPDAPT-3 trial, which randomly compared 1-month DAPT followed by aspirin monotherapy (aspirin group) to 1-month prasugrel monotherapy followed by clopidogrel monotherapy (clopidogrel group). The main analysis in the present study was the 30-day landmark analysis. The co-primary endpoints were cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) and major bleeding (Bleeding Academic Research Consortium 3 or 5). In the 30-day landmark analysis (N=5833), there were 1415 patients (24.3%) who underwent complex PCI. There was a significant interaction between complex PCI and the effect of aspirin group relative to clopidogrel group for cardiovascular events (complex PCI: 3.3% versus 5.2%, non-complex PCI, 4.3% versus 3.6%, interaction P=0.04) and net adverse clinical events (complex PCI: 4.8% versus 7.2%, non-complex PCI: 5.3% versus 4.4%, interaction P=0.02), but not for bleeding events (complex PCI: 2.1% versus 2.7%, non-complex PCI: 1.7% versus 1.4%, interaction P=0.35). There was a significant interaction between complex PCI and the effect of aspirin monotherapy relative to clopidogrel monotherapy beyond 1 month and up to 1 year for cardiovascular events due to numerically lower risk of aspirin monotherapy in patients with complex PCI, while the effect of aspirin monotherapy relative to clopidogrel monotherapy was not different for bleeding regardless of complex PCI. Clinical trial registration: ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3 [STOPDAPT-3]; NCT04609111.

Safety and efficacy of early initiation of sodium-glucose co-transporter inhibitors 2 in patients hospitalized for acute heart failure: A meta-analysis of randomized controlled trials.

Data on the early use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with acute heart failure (HF) are conflicting, and mostly evaluating soft endpoints (i.e., indices of congestion, renal function, ejection fraction, and diuresis). The aim was to perform a meta-analysis of randomized controlled trials (RCTs) to assess their impact after an HF decompensation event. Two electronic databases were screened for eligible studies. Efficacy endpoints were all-cause death, cardiovascular death, HF hospitalization, length of hospital stay, and N-terminal pro-B-type natriuretic peptide (nt-proBNP). Safety endpoints included acute kidney injury (AKI), volume depletion, ketoacidosis, hypotension, hypoglycemia, non-cardiovascular death, urinary tract infection, genital infections, serious adverse events (AE), and AE leading to treatment discontinuation. Two pre-specified subgroup analyses were planned according to the specific SGLT2i and clinical setting [i.e., acute myocardial infarction (MI) versus non-acute MI]. 16 RCTs enrolling 15,073 patients were considered. Early initiation of SGLT2i significantly reduced the risk of HF hospitalizations [Risk ratio (RR) 0.79, 95 % Confidence interval (CI) 0.72-0.87], AKI (RR 0.76, 95 % CI 0.59-0.99), and nt-proBNP levels (MD -354 pg/mL). No significant difference was detected for any of the other endpoints. In the pre-specified subgroup analysis, a significant interaction was found between the SGLT2i type and the risk of AKI, in favor of empagliflozin. In patients recently hospitalized for acute HF, early administration of SGLT2i was associated with fewer readmissions for HF and AKI, as well as decongestant effects, without raising any safety concern.

The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial

ObjectiveTo evaluate whether the immunomodulatory drug thymosin α1 reduces mortality in adults with sepsis.DesignMulticentre, double blinded, placebo controlled phase 3 trial.Setting22 centres in China, September 2016 to December 2020.Participants1106 adults...

Early Versus Delayed Antihypertensive Treatment After Acute Ischemic Stroke by Hypertension History.

We performed a prespecified subgroup analysis of the CATIS-2 trial (China Antihypertensive Trial in Acute Ischemic Stroke II) to compare the effect of early versus delayed antihypertensive treatment on death and disability in patients with and without medical history of hypertension. CATIS-2 is a multicenter randomized clinical trial conducted in 106 hospitals in China. The trial randomized 4810 patients with acute ischemic stroke within 24 to 48 hours of symptom onset and elevated systolic blood pressure between 140 and <220 mm Hg to receive antihypertensive treatment immediately after randomization or to discontinue antihypertensive medications for 7 days and then receive treatment on day 8. The primary outcome was a combination of death or functional dependency (modified Rankin Scale score ≥3) at 90 days. At the 90-day follow-up, the primary outcome of death or functional dependency was not different between early- and delayed-treatment groups according to the history of hypertension; the odds ratios (95% CIs) associated with the early-treatment group were 1.11 (0.91-1.36) and 1.38 (0.92-2.08) for participants with and without a history of hypertension. However, the ordinal logistic regression showed that early antihypertensive treatment was associated with the odds of a higher modified Rankin Scale score in patients without hypertension (odds ratio, 1.35 [95% CI, 1.01-1.82]), but not in those with hypertension (odds ratio, 0.95 [95% CI, 0.82-1.10]; P=0.04 for interaction). Early antihypertensive treatment did not reduce the odds of dependency or death at 90 days by hypertension history among patients with ischemic stroke but worsened functional outcomes for patients without hypertension in the ordinal analysis. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03479554.

Safety and efficacy of long-acting cabotegravir/rilpivirine versus standard oral antiretroviral therapy: a systematic review and meta-analysis.

In 2023, there were 39.9 million people living with HIV (PLWH) worldwide and 630 000 deaths related to HIV. New strategies are needed, and long-acting antiretrovirals (LAAs) are now widely considered to have great potential to help end the HIV epidemic. This systematic review and meta-analysis compare the safety and efficacy of LAA versus standard oral treatment (SOT) for HIV. PubMed and Embase databases, supplemented by ClinicalTrials.gov and grey literature, were searched. Randomized controlled trials (RCTs) reporting efficacy and/or safety of LAA versus SOT for PLWH until June 2024 were included. Efficacy (HIV RNA < 50 copies/mL) and HIV RNA ≥ 50 copies/mL, adverse events (AEs), treatment discontinuation, CD4 count, metabolic parameters and drug resistance were assessed. Prespecified subgroup analyses were conducted. The risk of bias was assessed with Cochrane RoB 2.0. Certainty of evidence was assessed using GRADE. Six RCTs were eligible for inclusion, involving 2829 participants. LAA was non-inferior to SOT in suppressing HIV RNA < 50 copies/mL [Risk Difference (RD), -0.00; 95% CI, -0.03-0.02; P = 0.83; I2 = 51%; high quality of evidence (QoE)]. LAA was associated with higher drug resistance (percentage pooled estimate, 57%; 95% CI, 33%-78% versus 9%; 95% CI, 2%-30%; moderate QoE) and risk of grade 1-4 AEs than SOT [Risk Ratio (RR), 1.22; 95% CI, 1.12-1.33; P < 0.001; I2 = 62%; moderate QoE]. LAA has non-inferior efficacy compared to SOT. However, participants receiving LAA were at a higher risk of developing drug resistance, cross-resistance and AEs.

Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial.

There are no approved oral disease-modifying treatments for Alzheimer's disease (AD). The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement. ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial. Multicenter - 52 medical research centers/hospitals in 5 countries. 508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934. The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model. Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related. Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs.

AFFORDABLE, ACCESSIBLE HEARING CARE AMONG INDIVIDUALS WITH COGNITIVE IMPAIRMENT: LESSONS FROM THE HEARS RCT

Abstract Hearing loss is highly prevalent and associated with adverse health outcomes but undertreated among individuals with cognitive impairment, particularly African Americans. The incorporation of community health worker (CHW)-partnered models may increase access and reduce disparities. The HEARS intervention is a hearing care intervention delivered by CHWs that provides a low-cost amplification device. This pre-specified subgroup analysis based within the HEARS randomized controlled trial (RCT) aims to assess whether cognitive impairment modified the effect of the HEARS intervention among community-dwelling older adults. The analysis was stratified by cognitive status using the total Montreal Cognitive Assessment (MoCA) score (□25: cognitive impairment; post hoc sensitivity analysis using □22). Among 149 randomized participants with MoCA data, 100 individuals were cognitively impaired (Mean adjusted MoCA: 21(SD 3.5; 52% African American; 70% low-income). At 3-months post-intervention, communication function significantly improved among individuals with cognitive impairment compared with control, with an estimated average treatment effect of -13.92 HHIE-S change (95% CI:-16.84,-10.86), comparable to those without cognitive impairment (-11.47; 95% CI:-18.04,-4.17). Post hoc sensitivity analysis using a □22 MoCA cut-off for cognitive impairment yielded similar findings. Among individuals with cognitive impairment, the HEARS intervention, compared with waitlist control, significantly improved communication function. The improvements were comparable to participants without cognitive impairment and similar in magnitude to improvements documented for older adults who received conventional hearing care. To the authors’ knowledge, this trial was the largest trial to date of a hearing care intervention in the U.S. of African American older adults and low-income older adults with cognitive impairment.

Fractional Flow Reserve Directed Percutaneous Coronary Intervention Optimization Using High-Definition Intravascular Ultrasound in Non-ST-Segment Elevation Acute Coronary Syndrome Versus Chronic Coronary Syndrome.

Intravascular ultrasound (IVUS)-guided optimization of suboptimal fractional flow reserve (FFR) following percutaneous coronary intervention (PCI) results in a significant increase in both post-PCI FFR and minimal lumen and stent areas (MLA and MSA, respectively). However, the impact of clinical presentation with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) versus chronic coronary syndrome (CCS) on the efficacy of PCI optimization remains unknown. This was a prespecified subgroup analysis of the FFR REACT trial comparing IVUS-guided PCI optimization versus no further treatment in 291 patients with a post-PCI FFR < 0.90. Post-PCI physiology and pre optimization IVUS findings were compared between patients presenting with NSTE-ACS versus CCS, as well as optimization strategy, final FFR and IVUS findings. Out of 291 patients, 130 (44.7%) presented with NSTE-ACS. Median post-PCI FFR was similar in patients with NSTE-ACS and CCS (0.85 for both, p = 0.55). Pre optimization IVUS findings did not differ significantly between both groups and subsequent optimization strategy was comparable (p = 0.71). In both NSTE-ACS and CCS, optimization resulted in a significant increase (p < 0.01 for all) of similar magnitude in median FFR (0.02 vs. 0.03, p = 0.80), MLA (0.37 vs. 0.50 mm2, p = 0.46) and MSA (0.29 vs. 0.32 mm2, p = 0.61), respectively. The clinical impact of IVUS-guided optimization on 2-year target vessel failure showed no signs of heterogeneity based on clinical presentation (interaction p = 0.36). In patients undergoing FFR-directed IVUS-guided optimization, post-PCI FFR, pre optimization IVUS findings and optimization strategy did not differ significantly between patients presenting with either NSTE-ACS or CCS, with comparable improvements in FFR, MLA and MSA.

Effect of nebivolol on erectile function: a systematic review and meta-analysis of randomized controlled trials.

Historically, β-blockers have been associated with erectile dysfunction (ED). Nebivolol, a third-generation β-blocker, may have had no negative effect on erectile function because of its vasodilating properties. However, the evidence level was considered either as low or very low. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to determine the effect of nebivolol on erectile function. All published RCTs were searched through PubMed, Cochrane Library, Web of Science, and Embase until October 2023. Review Manager version 5.3.0 was used for statistical analysis. Sensitivity analyses were performed by excluding each study using Stata 17 software. The primary outcome was the International Index of Erectile Function (IIEF)-5 score. We excluded publication types, including letters, reviews, and meta-analyses. We identified four RCTs in this meta-analysis. All included studies compared the effects of nebivolol vs metoprolol on erectile function. Eight parallel groups with 397 individuals reported IIEF-5 scores. A random-effect model revealed that the IIEF-5 score was significantly higher in the nebivolol group (MD 1.81, 95%CI 0.95-2.68, P<.0001, I2 = 99%). We conducted a sensitivity analysis by removing each individual study and observed that there was no significantly different result. Furthermore, we conducted a prespecified subgroup analysis based on the dosage of metoprolol, patients with ED at the time of enrollment, and disease type. Subgroup analysis revealed that heterogeneity significantly decreased, and the result of the IIEF-5 score was stable and consistent. Our results provides stronger evidence that nebivolol significantly reduced the risk of ED occurrence or progression. Our meta-analysis included high-quality RCTs and conducted a predetermined subgroup analysis. However, the main limitations are the limited number of included studies and their heterogeneity. Our meta-analysis provided stronger evidence that nebivolol significantly reduced the risk of ED occurrence or progression compared with metoprolol, irrespective of whether the patient had ED or not. This meta-analysis could serve as an important reference for future studies in this field.

Vestibular Infant Screening-Rehabilitation (VIS-REHAB): protocol for a randomised controlled trial on Vestibular Rehabilitation Therapy (VRT) in vestibular-impaired children

IntroductionA vestibular deficit can have a substantial impact on the overall development of children. Therefore, it is of utmost importance that vestibular-impaired problems are treated early and effectively through Vestibular...

Transient brain ischemic symptoms and the presence of ischemic lesions at neuroimaging: Results from the READAPT study.

According to the literature, about one third of patients with brain ischemic symptoms lasting <24 h, which are classified as Transient ischemic attacks (TIAs) according to the traditional "time-based" definition, show the presence of acute ischemic lesions at neuroimaging. Recent evidence has shown that the presence of acute ischemic lesions at neuroimaging may impact on the outcome of patients with transient ischemic symptoms treated with dual antiplatelet treatment (DAPT). This uncertainty is even more compelling in recent years as short-term DAPT has become the standard treatment for any non-cardioembolic TIA or minor ischemic stroke. This is a pre-specified subgroup analysis from a prospective multicenter real-world study (READAPT). The analysis included patients with time-based TIA-that is, those with ischemic symptoms lasting <24 h-who started DAPT. In the whole population, we assessed the presence of acute brain ischemic lesions at neuroimaging and their association with the ABCD2 score. To assess the impact of acute brain ischemic lesions on 90-day prognosis, we performed a propensity score matching of patients with and without those lesions. We adopted a primary effectiveness outcome which was a composite of new stroke/TIA events and death due to vascular causes at 90 days. We included 517 patients-324 (62.7%) male-with a median (interquartile range-IQR) age of 74 (IQR = 65-81) years; 144 patients (27.9%) had acute brain ischemic lesions at neuroimaging. The proportion of patients with brain ischemic lesions did not vary according to the ABCD2 score. At follow-up, 4 patients with brain ischemic lesions (2.8%) and 21 patients without lesions (5.6%) reported the primary effectiveness outcome, which was similar between the groups before (p = 0.178) and after matching (p = 0.518). In our population, patients with transient ischemic symptoms and acute ischemic lesions at brain magnetic resonance imaging (MRI) had a risk of recurrent ischemic events similar to those without lesions. The risk of recurrent ischemic events was low in both groups.

Impact of Mild Hypothermia As Adjunctive Therapy in Patients With ST-Elevation Myocardial Infarction: A Meta-Analysis and Trial Sequential Analysis of Randomized Controlled Trials.

The prevention of reperfusion injury remains an unmet need in ST-elevation myocardial infarction (STEMI) patients. Several randomized controlled trials (RCTs) evaluated mild hypothermia as adjunctive therapy during STEMI, with conflicting results. To summarize the evidence about the efficacy and safety of mild hypothermia in patients with STEMI, as well as its conclusiveness through a trial sequential analysis (TSA). PubMed and Scopus electronic databases were screened for eligible studies until August 12, 2024. Efficacy endpoints were all-cause death, infarct size (IS), left ventricular ejection fraction (LVEF), the occurrence of microvascular obstruction (MVO), thrombolysis in myocardial infarction (TIMI) flow grade 3, and the resolution of ST-segment elevation (i.e., > 50-70% from baseline) after the procedure. Safety endpoints included: the incidence of atrial fibrillation (AF), infections, any bleeding, major bleeding, acute and subacute stent thrombosis (STh), cardiogenic shock/pulmonary oedema, and ventricular fibrillation/tachycardia. "Door-to-balloon time" was indicated as the procedural endpoint. Two pre-specified subgroup analyses were planned according to the mean ischemic time and the site of hypothermia induction (intra-coronary vs. extra-coronary). A TSA was run to explore whether the effect estimate of each efficacy outcome could be influenced by further studies. Ten RCTs were included. Hypothermia did not provide a benefit for any of the specified efficacy endpoints. Furthermore, it enhanced the risk of infection, the risk of STh in patients with a mean ischemic time of less than 4 h, and the risk of AF in patients undergoing extra-coronary hypothermia. Finally, it was also associated with an increased "door-to-balloon time", and a trend toward an increased risk of any bleeding. No significant difference was found for the other endpoints. TSA showed conclusive evidence of an absence of benefit of hypothermia on IS, MVO, LVEF, and TIMI three flow. Mild hypothermia is not beneficial and causes relevant delays in clinical management of STEMI patients, raising safety issues mainly related to the occurrence of STh, AF, and infections.

School-age growth and development following infant feeding and/or water, sanitation, and hygiene interventions in rural Zimbabwe: long-term follow-up of a cluster-randomised trial

Few trials have explored long-term effects of interventions designed to reduce child stunting. We evaluated school-age outcomes in rural Zimbabwean children who received cluster-randomised water, sanitation and hygiene (WASH) and/or infant and young child feeding (IYCF) interventions from pregnancy up to 18 months of age. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial enrolled pregnant women from two rural Zimbabwean districts (Chirumanzu and Shurugwi) between 2012 and 2015, and cluster-randomised them using a 2×2 factorial design to standard-of-care, WASH, IYCF, or combined WASH & IYCF, with a co-primary outcome of height-for-age Z-score and haemoglobin at 18 months (clinicaltrials.govNCT01824940). Children who were HIV-unexposed, age 7 years, and still living in Shurugwi district were eligible for this follow-up study (registered at PACTR 202201828512110) and measured between 1st April 2021 and 30th September 2022. The primary outcome at 7 years was cognitive function using the Kaufman Assessment Battery for Children (KABC-II). Secondary outcomes were executive function, literacy and numeracy, fine motor skills, socioemotional function, handgrip strength, broad jump distance, shuttle-run test distance, anthropometry, lean mass index, and skinfold thicknesses. Study nurses conducting assessments were blinded to intervention arm. Analysis followed a pre-registered statistical analysis plan. Intention-to-treat analyses using generalized estimating equations were used to assess the long-term effects of WASH and IYCF on each outcome, leveraging the factorial trial design. A pre-specified subgroup analysis by child sex was also performed. Among 3989 HIV-negative women, 3676 children were assessed at age 18 months; of these, 1002 (510 female) were assessed at mean (SD) age 7.3 (0.2) years. There was no effect of IYCF or WASH on the KABC-II score or secondary cognitive outcomes, except a small improvement in socioemotional function in WASH arms (-0.98 points, 95% CI-1.73,-0.22, p=0.01). Children in IYCF arms had higher handgrip strength (0.28Kg, 95% CI 0.02, 0.53, p=0.03); however, in the pre-specified subgroup analysis, improved handgrip strength was seen only in boys (0.53Kg, 95% CI 0.19, 0.87 p=0.002). There were no significant effects of either intervention on other outcomes. Early-life IYCF and WASH led to few functional benefits by school-age. Interventions that are more comprehensive, delivered for longer, and include nurturing care should be considered to improve long-term cognitive and physical function. Wellcome [220671/Z/20/Z, 108065/Z/15/Z]; NIH [R61HD103101]; Thrasher [15250]; and IMMANA [3.02].