Faricimab for neovascular age-related macular degeneration and diabetic macular edema: from preclinical studies to phase 3 outcomes.

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD); however, vision gains and anatomical improvements are not sustained over longer periods of treatment, suggesting other relevant targets may be needed to optimize treatments. Additionally, frequent intravitreal injections can prove a burden for patients and caregivers. Angiopoietin-2 (Ang-2) has been explored as an additional therapeutic target, due to the involvement of Ang-2 in DME and nAMD pathogenesis.

TENAYA and LUCERNE: Two-Year Results from the Phase 3 Neovascular Age-Related Macular Degeneration Trials of Faricimab with Treat-and-Extend Dosing in Year 2.

Purpose: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A.

Design: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.

Efficacy, durability, and safety of faricimab in patients from Asian countries with neovascular age-related macular degeneration: 1-Year subgroup analysis of the TENAYA and LUCERNE trials.

Purpose: To evaluate 1-year efficacy, durability, and safety of faricimab among patients from Asian countries in the TENAYA/LUCERNE trials of neovascular age-related macular degeneration (nAMD).

Methods: Treatment-naïve patients with nAMD were randomly assigned (1:1) to faricimab 6.0 mg up to every 16 weeks (Q16W), based on disease activity at weeks 20 and 24, or aflibercept 2.

A hybrid automated event adjudication system for clinical trials.

Introduction: In clinical trials, event adjudication is a process to review and confirm the accuracy of outcomes reported by site investigators. Despite efforts to automate the communication between a clinical-data-and-coordination center and an event adjudication committee, the review and confirmation of outcomes, as the core function of the process, still fully rely on human labor. To address this issue, we present an automated event adjudication system and its application in two randomized controlled trials.

TENAYA and LUCERNE: Rationale and Design for the Phase 3 Clinical Trials of Faricimab for Neovascular Age-Related Macular Degeneration.

Purpose: To describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD).

Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.

Background: Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).

Methods: TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide.

Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective Proxima A and B Clinical Trials.

Purpose: To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD).

Design: Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials.

Participants: Eligible patients were aged ≥50 years.

Efficacy and Safety of Rivaroxaban Versus Aspirin in Embolic Stroke of Undetermined Source and Carotid Atherosclerosis.

Background and Purpose- The sources of emboli in patients with embolic stroke of undetermined source (ESUS) are multiple and may not respond uniformly to anticoagulation. In this exploratory subgroup analysis of patients with carotid atherosclerosis in the NAVIGATE (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism)-ESUS trial, we assessed whether the treatment effect in this subgroup is consistent with the overall trial population and investigated the association of carotid atherosclerosis with recurrent ischemic stroke. Methods- Carotid atherosclerosis was analyzed either as the presence of mild (ie, 20%-49%) atherosclerotic stenosis or, separately, as the presence of carotid plaque.

Frequency and features of embolic stroke of undetermined source in young adults.

Introduction: The sources of emboli in those with embolic stroke of undetermined source may differ in old and young. We assessed the frequency, features and potential embolic sources of younger vs. older embolic stroke of undetermined source patients in the embolic stroke of undetermined source Global Registry.

Recurrent Stroke With Rivaroxaban Compared With Aspirin According to Predictors of Atrial Fibrillation: Secondary Analysis of the NAVIGATE ESUS Randomized Clinical Trial.

Importance: The NAVIGATE ESUS randomized clinical trial found that 15 mg of rivaroxaban per day does not reduce stroke compared with aspirin in patients with embolic stroke of undetermined source (ESUS); however, it substantially reduces stroke risk in patients with atrial fibrillation (AF).

Objective: To analyze whether rivaroxaban is associated with a reduction of recurrent stroke among patients with ESUS who have an increased risk of AF.

Design, Setting, And Participants: Participants were stratified by predictors of AF, including left atrial diameter, frequency of premature atrial contractions, and HAVOC score, a validated scheme using clinical features.

Effects of blood pressure and lipid lowering on cognition: Results from the HOPE-3 study.

Objective: To assess whether long-term treatment with candesartan/hydrochlorothiazide, rosuvastatin, or their combination can slow cognitive decline in older people at intermediate cardiovascular risk.

Methods: The Heart Outcomes Prevention Evaluation-3 (HOPE-3) study was a double-blind, randomized, placebo-controlled clinical trial using a 2 × 2 factorial design. Participants without known cardiovascular disease or need for treatment were randomized to candesartan (16 mg) plus hydrochlorothiazide (12.

The cost implication of primary prevention in the HOPE 3 trial.

Aims: The Heart Outcomes Prevention Evaluation-3 (HOPE-3) found that rosuvastatin alone or with candesartan and hydrochlorothiazide (HCT) (in a subgroup with hypertension) significantly lowered cardiovascular events compared with placebo in 12 705 individuals from 21 countries at intermediate risk and without cardiovascular disease. We assessed the costs implications of implementation in primary prevention in countries at different economic levels.

Methods And Results: Hospitalizations, procedures, study and non-study medications were documented.

Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.

Background: Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

Background: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin.

Methods: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source.

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

Background: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS.

Aims: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups.

Long-term Effects of Statins, Blood Pressure-Lowering, and Both on Erectile Function in Persons at Intermediate Risk for Cardiovascular Disease: A Substudy of the Heart Outcomes Prevention Evaluation-3 (HOPE-3) Randomized Controlled Trial.

Background: It is unclear whether modifying cholesterol, blood pressure, or both affect erectile dysfunction. Also, there are concerns that erectile dysfunction is worsened by common medications used to treat these risk factors. In this study, we evaluated the effect of: (1) cholesterol-lowering with a statin; (2) pharmacologic blood pressure reduction; and (3) their combination, on erectile function.

Embolic strokes of undetermined source: Prevalence and patient features in the ESUS Global Registry.

Background: Recent evidence supports that most non-lacunar cryptogenic strokes are embolic. Accordingly, these strokes have been designated as embolic strokes of undetermined source (ESUS).

Aims: We undertook an international survey to characterize the frequency and clinical features of ESUS patients across global regions.

Age disparity in diagnostic evaluation of stroke patients: Embolic Stroke of Undetermined Source Global Registry Project.

Incomplete evaluation of stroke patients may result in an unclear diagnosis. Our objective was to determine if older stroke patients more often undergo incomplete diagnostic evaluations versus younger patients in an international cohort. The Embolic Stroke of Undetermined Source Global Registry was a retrospective cohort of consecutive stroke patients evaluated at 19 stroke centers in 19 countries.

The persistence of maternal vitamin D deficiency and insufficiency during pregnancy and lactation irrespective of season and supplementation.

Background: Pregnancy and lactation comprise a critical window spanning all seasons during which maternal vitamin D status potentially may influence the long-term health of the newborn. Women typically receive calcium/vitamin D supplementation through antenatal vitamins, but there has been limited serial evaluation of maternal vitamin D status across this critical window.

Design/patients/measurements: In this prospective observational cohort study, 467 women in Toronto, Canada, underwent measurement of serum 25-hydroxy vitamin D (25-OH-D) at mean 29·7 ± 2·9 weeks' gestation, 3 months postpartum and 12 months postpartum, enabling serial assessment across 3 seasons.

Postpartum microalbuminuria after gestational diabetes: the impact of current glucose tolerance status.

Context: It has been reported that women with a history of gestational diabetes mellitus (GDM) have an increased risk of microalbuminuria compared with that of their peers. Because previous GDM predicts an increased risk of prediabetes, which itself is associated with microalbuminuria, we hypothesized that current glucose intolerance may confound any association between GDM and microalbuminuria.

Objective: The purpose of this study was to evaluate the relative impact of gestational and current dysglycemia on postpartum microalbuminuria in a cohort of women reflecting the full spectrum of gestational glucose tolerance from normal to mildly abnormal to GDM.

Prediction of hypertension based on the genetic analysis of longitudinal phenotypes: a comparison of different modeling approaches for the binary trait of hypertension.

For the analysis of the longitudinal hypertension family data, we focused on modeling binary traits of hypertension measured repeatedly over time. Our primary objective is to examine predictive abilities of longitudinal models for genetic associations. We first identified single-nucleotide polymorphisms (SNPs) associated with any occurrence of hypertension over the study period to set up covariates for the longitudinal analysis.

Delivery by Caesarean section and infant cardiometabolic status at one year of age.

Objective: Disruption of the gut microbiome has been associated with overweight/obesity, insulin resistance, and type 2 diabetes. Recently, it has been reported that Caesarean section disrupts the normal gut microbiome of neonates. As such, these data have raised the intriguing possibility that CS could lead to an adverse cardiometabolic risk profile early in life.

Liraglutide and the preservation of pancreatic β-cell function in early type 2 diabetes: the LIBRA trial.

Objective: Clinical studies evaluating the effects of medications on β-cell function in type 2 diabetes (T2DM) are compromised by an inability to determine the actual baseline degree of β-cell dysfunction independent of the reversible dysfunction induced by hyperglycemia (glucotoxicity). Short-term intensive insulin therapy (IIT) is a strategy for eliminating glucotoxicity before randomization. This study determined whether liraglutide can preserve β-cell function over 48 weeks in early T2DM following initial elimination of glucotoxicity with IIT.

Each degree of glucose intolerance in pregnancy predicts distinct trajectories of β-cell function, insulin sensitivity, and glycemia in the first 3 years postpartum.

Objective: Glucose intolerance in pregnancy predicts an increased risk of future type 2 diabetes mellitus (T2DM) that is proportional to the severity of antepartum dysglycemia (i.e., highest in women with gestational diabetes mellitus [GDM], followed by those with milder dysglycemia).