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IntroductionConcurrent Staphylococcus aureus bacteremia (SAB) worsens outcomes and increases mortality in patients with complicated skin and skin structure infections (cSSSI), hospital-acquired bacterial pneumonia, and ventilator-associated bacterial pneumonia (HABP/VABP). These challenges highlight the need for alternative treatments. Telavancin (TLV), a bactericidal lipoglycopeptide with high in vitro potency, effectively treats patients with cSSSI and HABP/VABP caused by Gram-positive pathogens, particularly S. aureus.MethodsThis retrospective analysis evaluated patients from the Assessment of Telavancin in Complicated Skin and Skin Structure Infections and Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia studies with baseline, concurrent SAB. Differences in the clinical cure rates at test-of-cure and safety outcomes were compared for TLV vs vancomycin (VAN) treatment groups.ResultsA total of 105 patients, 32 cSSSI and 73 HABP/VABP, had baseline, concurrent SAB. The clinical cure rates for all-treated SAB patients in the cSSSI (TLV 57.1% and VAN 54.5%) and HABP/VABP (TLV 54.3% and VAN 47.2%) groups were comparable. For both types of infections, the safety profile of TLV and VAN showed similar incidences of adverse events (AEs), serious AEs, or AEs leading to discontinuation. One VAN-treated patient died in the cSSSI group, and there were 13 deaths in each treatment arm of the HABP/VABP group.ConclusionThis retrospective analysis demonstrated that TLV is clinically comparable in both efficacy and safety to VAN, and, therefore, may be an appropriate therapeutic option for the treatment of patients with HABP/VABP or cSSSI and concurrent SAB. Given the limited sample size in this subgroup, the interpretation of these results is limited.FundingTheravance Biopharma Antibiotics, Inc.

INTRODUCTION: Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods. METHODS: We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial. RESULTS: Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm. DISCUSSION: Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods. Highlights: We explore the statistical considerations of the current method for estimating time savings.We proposed alternative methods that provide time savings estimations based on the observed absolute differences.By using various methods, a more comprehensive estimation of time savings can be achieved. [ABSTRACT FROM AUTHOR]

Longitudinal data from clinical trials are commonly analyzed using mixed models for repeated measures (MMRM) when the time variable is categorical or linear mixed‐effects models (ie, random effects model) when the time variable is continuous. In these models, statistical inference is typically based on the absolute difference in the adjusted mean change (for categorical time) or the rate of change (for continuous time). Previously, we proposed a novel approach: modeling the percentage reduction in disease progression associated with the treatment relative to the placebo decline using proportional models. This concept of proportionality provides an innovative and flexible method for simultaneously modeling different cohorts, multivariate endpoints, and jointly modeling continuous and survival endpoints. Through simulated data, we demonstrate the implementation of these models using SAS procedures in both frequentist and Bayesian approaches. Additionally, we introduce a novel method for implementing MMRM models (ie, analysis of response profile) using the nlmixed procedure. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the MYBPC3 gene are the leading genetic cause of hypertrophic cardiomyopathy (HCM) resulting in reduced functional myosin-binding protein C (MyBP-C) levels. Studies have shown that adult patients with pathogenic sarcomere variant-HCM exhibit higher incidence of major clinical events than genotype-negative HCM patients. With the emergence of gene replacement therapies, characterizing the natural history of MYBPC3 + HCM is essential to inform future development of this class of targeted therapies. We conducted an analysis of all adult MYBPC3 + HCM patients enrolled in SHaRe (Sarcomeric Human Cardiomyopathy Registry) based on their primary diagnosis at the age of 18-39, 40-59, and ≥60 years. As of September 2023, 1493 adult HCM patients with a pathogenic or likely pathogenic variant in MYBPC3 had enrolled in SHaRe, a multicenter registry involving 12 cardiac centers in the US, EU, and Australia. This analysis included 635 patients (42.5%) diagnosed at 18–39 years, 659 (44.1%) at 40–59 years, and 199 (13.3%) at ≥60 years. Duration of follow-up in the three cohorts was 8.4, 6.6, and 4.5 years, respectively. Demographics, genotype, first echocardiographic metrics, and time to major clinical events were compared across the three groups. Most patients diagnosed at 18–39 and 40–59 years were males (67.0% and 56.3% respectively), while those diagnosed at ≥60 years were primarily female (59.5%). Family history of HCM and proband status were comparable across cohorts (range of 56.3 – 65.7% and 88.0 – 91.5%, respectively). Patients in the youngest cohort presented with the greatest left ventricular maximal wall thickness (median of 19 mm, 18 mm, and 17 mm for the 18 – 39, 40 – 59, and ≥60 years cohorts, respectively). Symptom burden was comparable across cohorts, as the proportion of patients with NYHA III/IV was 13.1%, 10.5%, and 11.4%, respectively. The prevalence of patients having SRT, syncope and need for transplant or left ventricular assist device (LVAD) were highest in the youngest cohort (see Table). Across all three cohorts, patients experienced atrial fibrillation (AF) at 13.7%, the ventricular arrhythmia (VA) composite at 5.3%, and the heart failure (HF) composite at 9.1%. Adult MYBPC3 + HCM patients of all ages are at risk for serious clinical manifestations including heart failure, arrhythmias, and sudden cardiac death (SCD). These findings underscore the importance of genetic diagnosis and development of targeted therapies to restore MyBP-C levels, which could potentially modify the natural history of the disease. [ABSTRACT FROM AUTHOR]

The drug ranolazine may benefit patients who have chronic chest pain caused by coronary artery disease, according to a study of 823 patients. The patients who took the drug were able to exercise longer on a treadmill and got chest pain less frequently than patients who took a placebo, or inactive substance. Ranolazine reduces the heart's need for oxygen so it can continue to function at low oxygen levels.

Heterozygous MYBPC3 variants are the leading genetic cause of hypertrophic cardiomyopathy (HCM). Pathogenic and likely pathogenic (P/LP) MYBPC3 variants (MYBPC3 +) are predominantly truncating variants and result in reduced functional protein (MyBP-C) levels. Despite a common genetic basis, there is wide variability in disease severity and onset. Prior work demonstrates pediatric-onset HCM associated with sarcomeric mutations has worse outcomes, but limited studies have examined this by genotype. To better understand the natural history of pediatric-onset MYBPC3+ HCM, we analyzed data of all MYBPC3 + HCM patients enrolled in SHaRe (Sarcomeric Human Cardiomyopathy Registry). As of December 2023, 1,713 HCM patients with ≥1 P/LP MYBPC3 variants had been enrolled in SHaRe, a multicenter registry spanning 12 cardiac centers in the US, EU, and Australia. Pediatric-onset (218/1713 patients) and adult-onset MYBPC3 + HCM (1495/1713) were defined as <18 and ≥18 years of age, respectively. Both cohorts were followed for a similar median duration of 7 years. Analysis of demographics, genotype, first echocardiographic metrics, and time to major clinical events was performed and compared across pediatric and adult groups. Compound heterozygosity for MYBPC3 P/LP variants was more common in pediatric disease onset (8.3%) compared to adult-onset (3.7%) (p=0.002). Pediatric-onset MYBPC3 + HCM had more prominent hypertrophy with median left ventricular wall thickness (LVMWT) Z score 11.5 vs 8.9 in adult-onset disease (p=0.006). While the prevalence of overall composite events (i.e. death, transplant, heart failure, or ventricular arrhythmia events) was similar in pediatric- and adult-onset MYBPC3 + HCM patients (16.1% and 20.2%, respectively), events occurred 27 years earlier in the pediatric-onset cohort (median age at event 30.5 vs 57.5 years, p<0.001). Heart failure (HF) composite outcomes and septal reduction therapy (SRT) demonstrated a pattern of similar prevalence between pediatric- and adult-onset disease (HF: 11.5% pediatric and 9.1% adult; SRT: 11.5% pediatric and 13.2% adult) but with earlier onset (HF: median 23 years earlier; SRT: median 23 years earlier, p<0.001). Pediatric-onset MYBPC3+ HCM patients had more severe hypertrophy and showed an earlier age of disease morbidity than adult-onset MYBPC3+ HCM. These results underscore the critical importance of early clinical diagnosis with genetic confirmation to understand prognostic implications and guide treatment. [ABSTRACT FROM AUTHOR]

The broth microdilution (BMD) MIC testing method for telavancin was recently revised BMD (rBMD) to improve accuracy and reproducibility. Staphylococcus aureus isolates from telavancin phase 3 complicated skin and skin-structure infection (cSSSI) studies were tested using the rBMD method. Retesting of 1132 isolates produced MICs ranging from ≤0.015 to 0.12 μg/mL that were 8-fold lower than the original method. All isolates tested remained susceptible to telavancin at the revised susceptibility breakpoint of 0.12 μg/mL. The clinical cure and microbiological eradication rates were 90% (368/409) and 89% (366/409) for telavancin-treated patients, and were similar for patients with methicillin-susceptible and -resistant S. aureus isolates and S. aureus isolates with elevated vancomycin MICs (≥1 μg/mL). The data presented here are aimed to update the literature and better inform clinicians and clinical microbiologists about the revised telavancin MICs, as well as the corresponding clinical and microbiological cure rates for cSSSI patients. [ABSTRACT FROM AUTHOR]

: ObjectivesThe primary objective of the Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial was to determine the dose-response relationship of ranolazine, a potentially new anti-anginal compound, on symptom-limited exercise duration.: BackgroundFatty acids rise precipitously in response to stress, including acute myocardial ischemia. Ranolazine is believed to partially inhibit fatty acid oxidation, shift metabolism toward carbohydrate oxidation, and increase the efficiency of oxygen use.: MethodsPatients (n = 191) with angina-limited exercise discontinued anti-anginal medications and were randomized into a double-blind four-period crossover study of sustained-release ranolazine 500, 1,000, or 1,500 mg, or placebo, each administered twice daily for one week. Exercise testing was performed at the end of each treatment during both trough and peak ranolazine plasma concentrations.: ResultsExercise duration at trough increased with ranolazine 500, 1,000, and 1,500 mg twice daily by 94, 103, and 116 s, respectively, all greater (p < 0.005) than the 70-s increase on placebo. Dose-related increases in exercise duration at peak and in times to 1 mm ST-segment depression at trough and peak and to angina at trough and peak were also demonstrated (all p < 0.005). Ranolazine had negligible effects on heart rate and blood pressure. One year survival rate combining data from the MARISA trial and its open-label follow-on study was 96.3 ± 1.7%.: ConclusionsIn chronic angina patients, ranolazine monotherapy was well tolerated and increased exercise performance throughout its dosing interval at all doses studied without clinically meaningful hemodynamic effects. One-year survival was not lower than expected in this high-risk patient population. This metabolic approach to treating myocardial ischemia may offer a new therapeutic option for chronic angina patients. [Copyright &y& Elsevier]

Introduction: Estimating treatment effects as time savings in disease progression may be more easily interpretable than assessing the absolute difference or a percentage reduction. In this study, we investigate the statistical considerations of the existing method for estimating time savings and propose alternative complementary methods., Methods: We propose five alternative methods to estimate the time savings from different perspectives. These methods are applied to simulated clinical trial data that mimic or modify the Clinical Dementia Rating Sum of Boxes progression trajectories observed in the Clarity AD lecanemab trial., Results: Our study demonstrates that the proposed methods can generate more precise estimates by considering two crucial factors: (1) the absolute difference between treatment arms, and (2) the observed progression rate in the treatment arm., Discussion: Quantifying treatment effects as time savings in disease progression offers distinct advantages. To provide comprehensive estimations, it is important to use various methods., Highlights: We explore the statistical considerations of the current method for estimating time savings. We proposed alternative methods that provide time savings estimations based on the observed absolute differences. By using various methods, a more comprehensive estimation of time savings can be achieved., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Two phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. This post hoc analysis included patients with lesion sizes of ≥75 cm(2) and excluded patients with ulcers or burns (updated all-treated population; n = 1,127). Updated day 3 (early) clinical response was defined as a ≥20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of-cure (TOC) clinical response was defined as a ≥90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of -4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, -0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Most studies examining the relationship between ventricular tachycardia (VT) after acute coronary syndrome and sudden cardiac death (SCD) were performed before widespread use of reperfusion, revascularization, or contemporary medical therapy and were limited to ST-elevation myocardial infarction. The incidence and prognostic implications of VT in patients with non-ST-elevation acute coronary syndrome receiving contemporary care have not been examined., Methods and Results: The Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36) trial randomized 6560 patients hospitalized with a non-ST-elevation acute coronary syndrome to ranolazine or placebo in addition to standard therapy. Continuous ECG recording was performed for the first 7 days after randomization and evaluated in a blinded core laboratory. SCD (n=121) was assessed over a median follow-up of 1 year. A total of 6345 patients (97%) had continuous ECG recordings evaluable for analysis. Compared with patients with no VT (n=2764), there was no increased risk of SCD in patients with only ventricular triplets (n=1978, 31.2%) (1.4% versus 1.2%); however, the risk of SCD was significantly greater in patients with VT lasting 4 to 7 beats (n=1172, 18.5%) (SCD, 2.9%; adjusted hazard ratio, 2.3; P<0.001) and in patients with VT lasting at least 8 beats (n=431, 6.8%) (SCD, 4.3%; adjusted hazard ratio, 2.8; P=0.001). This effect was independent of baseline characteristics and ejection fraction. VT occurring within the first 48 hours after admission was not associated with SCD., Conclusions: Nonsustained VT is common after admission for non-ST-elevation acute coronary syndrome, and even short episodes of VT lasting 4 to 7 beats are independently associated with the risk of SCD over the subsequent year. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788.