Background In Alzheimer's disease (AD) clinical trials, efficacy inference is traditionally based on the last visit (e.g., 18 months). However, recent studies suggest that disease-modifying treatment effects may emerge as early as 3 months post-baseline.Objective To explore this further, our study aimed to assess the increased statistical power achieved by incorporating all or multiple post-baseline visits to estimate treatment effect, compared to relying solely on the last visit.Methods We developed explicit formulas for the basis functions of the natural cubic spline model, ensuring compatibility with standard SAS procedures. Through simulations using disease progression trajectories from Clarity-AD and TRAILBLAZER-ALZ 2 trials, we comprehensively evaluated various models in terms of power and type I error. Additionally, we offer SAS codes that to facilitate seamless implementation of different modeling approaches.Results Simulations based on ClarityAD and TRAILBLAZER-ALZ 2 disease trajectories demonstrated that models incorporating multiple or all post-baseline visits yield greater power than those using only the last visit, while maintaining Type I error control. Furthermore, when three post-baseline visits were included, adding more visits resulted in minimal power gains.Conclusions Our findings support prioritizing statistical models that incorporate multiple or all post-baseline visits for treatment efficacy inference, as they offer greater efficiency than models relying solely on the last visit.

Background Tenaya Therapeutics is developing TN-201, the first AAV9-mediated gene therapy for the leading cause of genetic HCM, MYBPC3-associated hypertrophic cardiomyopathy (MYBPC3+ HCM). Patients with high levels of preexisting neutralizing antibodies (NAbs) to AAVs may fail to achieve desired transgene expression and/or be at risk of an inflammatory response. There have been no studies assessing AAV9 seroprevalence in MYBPC3+ HCM patients. Methods Tenaya initiated the first observational seroprevalence study of MYBPC3+ HCM patients at US HCM clinics, enrolling participants 18-65 years of age with HCM and with one or more MYBPC3 mutation. Demographics, medical histories, symptom burden, and a single blood draw were collected. NAb titers were assessed via assay. Participants with preexisting NAb titers <1:40 were classified as seronegative to AAV9. Total antibody (TAb) titer to AAV9 was also assessed to compare with NAb titers. Results By March 2024, 104 participants had enrolled in this study. Median age was 48 years (IQR: 35-56 years) and 65% were male. The majority of participants (57%) had nonobstructive HCM, which included patients post-myectomy. Available data indicate that 78% (69/88) of participants with MYBPC3+ HCM were AAV9 seronegative. Preexisting AAV9 TAb titer strongly correlated with AAV9 NAb. AAV9 serostatus did not vary by gender, age, race, geography, clinical state, or medical history. Conclusion Results suggest that MYBPC3+ HCM patients in the US have low levels of pre-existing AAV9 NAbs and that most would meet current NAb eligibility for clinical studies of TN-201 gene therapy. Tenaya is enrolling patients in MyPEAK-1, a Phase 1b/2a trial evaluating the safety, tolerability, and exploratory efficacy measures of TN-201 in MYBPC3+ HCM.

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.

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.

Background 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). Method 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. Results 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). Conclusion 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.

Background 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. Method 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. Results 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%. Conclusion 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.

Introduction: TD-0714 is an orally active, potent, and selective inhibitor of human neprilysin (NEP) in development for the treatment of a range of cardiorenal diseases including chronic heart failure (CHF) and chronic kidney disease (CKD). A significant population of these patients exhibit moderate to severe renal impairment. NEP inhibitors exhibiting non-renal excretion and a once-daily dosing regimen may provide optimal therapy for such patients. A multiple dose, double–blind, placebo–controlled, dose–escalation study in healthy subjects was conducted to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of TD–0714. Methods: Forty healthy adult subjects (n = 10/group) were randomized to one of four cohorts and received a daily oral dose of TD–0714 (10 to 200 mg) or placebo in a 4:1 ratio for 14 days. In addition, ten elderly healthy subjects were randomized to receive either 100 mg TD-0714 or placebo in a 4:1 ratio. Safety and tolerability were evaluated by monitoring treatment-emergent adverse events (TEAE), ECG, vital signs and laboratory parameters. PK and corresponding PD response (cGMP and ANP), were assessed. Results: TD-0714 was generally well tolerated up to the highest dose level tested (200 mg). No SAEs were reported. No clinically significant effects on vital signs or ECG parameters were observed. One subject at the lowest dose level (10 mg) exhibited an asymptomatic increase in liver enzymes (ALT, AST). This subject was subsequently rechallenged at the same dose level (10 mg QD for 14days) and no elevations in liver enzymes were observed upon rechallenge. No clinically relevant changes in laboratory parameters were observed in any other subjects during the study. PK (Cmax and AUC) of TD-0714 was dose–proportional from 10 mg to 200 mg, no accumulation was observed from day 1 to day 14 and renal excretion remained low at <1% of the administered dose. In addition, PK of TD-0714 was similar in elderly vs adult subjects. Dose-dependent increases in plasma and urine cGMP levels were observed. The increases in cGMP were sustained for 24 hr after a single dose and remained significantly above the baseline for the entire 24 hr interval on day 14 indicating that sustained cGMP elevations are achieved at steady state. Maximal PD effects were observed at doses of ≥50 mg based on plasma cGMP on day 14. Conclusions: Multiple doses of TD-0714 from 10 to 200 mg were generally well tolerated. PK was dose-proportional with negligible renal elimination. PD effects consistent with NEP target engagement were sustained for and remained significantly over baseline during the entire dosing interval at steady state. The TD-0714 PK and PD profiles continue to support the potential for once-daily administration and predictable exposure in patients with cardiorenal diseases across all levels of renal function.

AIMS:Clinical utility of QTc prolongation as a predictor for sudden cardiac death (SCD) has not been definitely established. Ranolazine causes modest QTc prolongation, yet it shows antiarrhythmic properties. We aimed to determine the association between prolonged QTc and risk of SCD, and the effect of ranolazine on this relationship.METHODS AND RESULTS:The relationship between baseline QTc and SCD was studied in 6492 patients with non-ST elevation acute coronary syndrome (NSTEACS) randomized to placebo or ranolazine in the MERLIN-TIMI 36 trial. In the placebo group, an abnormal QTc interval (≥450 ms in men, ≥470 ms in women) was associated with a two-fold increased risk of SCD (hazard ratio, HR, 2.3, P = 0.005) after adjustment for other risk factors (age ≥75 years, NYHA class III/IV, high TIMI risk score, ventricular tachycardia ≥8 beats, digitalis, and antiarrhythmics). In the ranolazine group, the association between abnormal QTc and SCD was similar to placebo, but not significant (HR 1.8, P = 0.074). There was no significant difference between placebo and ranolazine in the risk for SCD in patients with abnormal QTc (HR 0.78, P = 0.48). When QTc was used as a continuous variable, for every 10 ms increase in QTc, hazard rate for SCD increased significantly by 8% (P = 0.007) in the placebo group, and only by 2.9% (P = 0.412; P for interaction=0.25) in the ranolazine group.CONCLUSION:In NSTEACS patients treated with placebo, prolonged QTc was a significant independent predictor for SCD. Ranolazine, compared with placebo, was not associated with increased risk for SCD in patients with prolonged QTc.

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.Conclusion-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.

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. Conclusion— 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.

Background: Among pts with NSTEACS, recurrent ischemia and ventricular arrhythmias detected on continuous ECG (cECG) remain common clinical events with uncertain clinical significance. Methods: We determined the risk associated with the presence of ischemia (> 1mm ST depression lasting > 1min) and NSVT (> 4beats) alone or combined on 7-day cEKG in 6355 pts with NSTEACS. Pts were categorized into 4 groups: No ischemia or NSVT, NSVT alone, Ischemia alone or Both ischemia and NSVT. Median clinical follow-up was 348 days. Results: A total of 43.6% pts had no VT or ischemia; 31.2% had NSVT alone; 18.5% had ischemia alone; and 6.8% had both NSVT and ischemia. Pts with either NSVT or ischemia on cECG were at increased risk of CV outcomes (Table ). In a MV analysis, recurrent ischemia alone increased the risk of all CV outcomes while NSVT alone increased the risk of CVD, SCD, and subsequent heart failure. Pts with both ischemia and NSVT were at high-risk for CVD (10.1 v 3.0%, p<0.001), SCD (7.8 v 0.9%, p<0.001), recurrent MI (15.4 v 6.2%, p<0.001) and heart failure (13.0 v 3.0%, p<0.001) compared to pts with neither. In pts with both ischemia and NSVT, 47.1% of SCD occurred within 90d (Figure ). Conclusion: In more than 6300 pts with NSTEACS, the presence of either ischemia or NSVT alone or particularly in combination was independently associated with poor CV outcomes, including a particularly high risk for early SCD. These findings raise the question whether such pts should be considered for ICD implantation. Sudden Cardiac Death 1-yr Clinical Outcomes(%) by NSVT or Ischemia detected on cECG monitoring

Background Adenosine and regadenoson increase heart rate (HR) when used as stress agents to produce coronary hyperemia due to direct sympathetic stimulation. We hypothesized that the HR response will be lower in patients with than in those without diabetes mellitus (DM).Methods We studied the HR response (percentage maximal increase) in 2,000 patients in The ADenoscan Versus regAdenosoN Comparative Evaluation for Myocardial Perfusion Imaging (ADVANCE MPI 1 and 2) Trials with known DM status.Results There were 643 patients with a history of DM (65.4 +/- 0.4 years, 32% women) and 1,357 patients with no DIM (65.5 +/- 0.3 years, 29% women). Compared with non-DM, the DM group had higher HR at baseline (68.4 +/- 0.48 vs 65.2 +/- 0.31 beat/min, P < .001) and smaller HR response after adenosine or regadenoson administration (29.4% +/- 0.64% vs 36.1% +/- 0.54%, P < .001). Insulin therapy was associated with further blunting in the HR response (25.9% +/- 1.0% vs 31.2% +/- 0.8%, P < .001). After adjusting for R-blocker intake, baseline HR, age, gender, renal function, systolic blood pressure, and left ventricular systolic function, DM independently accounted for a decrease in the HR response.Conclusions The HIR response to adenosine and regadenoson in patients with DIM is blunted. If additional studies confer an agreement between traditional tests for determination of autonomic neuropothy and this measure, then examination of HR response to these agents during myocardial perfusion imaging might add prognostic power. (Am Heart J 2009; 157:771-6.)

INTRODUCTION: In pts with NSTEACS from MERLIN-TIMI 36, non-sustained ventricular tachycardia (NSVT) lasting ≥4 beats was associated with higher risk of sudden cardiac death (SCD), and ranolazine (R...