Home environment factors associated with child BMI changes during COVID-19 pandemic.

BACKGROUND: The influence of home obesogenic environments, as assessed by the validated Family Nutrition and Physical Activity (FNPA) tool, and child obesity during the COVID pandemic were evaluated using electronic health records in this retrospective cohort study. METHODS: Historical data on BMI and the FNPA screening tool were obtained from annual well-child visits within the Geisinger Health System. The study examined youth ages 2-17 that had a BMI record and an FNPA assessment prior to the pandemic (BMI 3/1/19-2/29/20), 1 BMI record 3 months into the pandemic (6/1/20-12/31/20) and 1 BMI in the second year of the pandemic (1/1/21-12/31/21). Tertiles of obesity risk by FNPA score were examined. Mixed-effects linear regression was used to examine change in BMI slope (kg/m2 per month) pre-pandemic to pandemic using FNPA summary and subscales scores as predictors and adjusting for confounding factors. RESULTS: The analyses included 6,746 children (males: 51.7%, non-Hispanic white: 86.6%, overweight:14.8%, obesity:10.3%, severe obesity: 3.9%; mean(SD) age: 5.7(2.8) years). The rate of BMI change in BMI was greatest from early pandemic compared to pre-pandemic for children in lowest versus highest tertiles of FNPA summary score (0.079 vs. 0.044 kg/m2), FNPA-Eating (0.068 vs. 0.049 kg/m2), and FNPA-Activity (0.078 vs. 0.052 kg/m2). FNPA summary score was significantly associated with change in BMI from the pre-pandemic to early pandemic period (p = 0.014), but not associated with change in BMI during the later pandemic period. CONCLUSIONS: This study provides additional insight into the changes in the rate of BMI change observed among children and adolescents in the United States during the COVID-19 pandemic. The FNPA provides ample opportunity to continue our exploration of the negative impact of the COVID-19 pandemic on the longitudinal growth patterns among children and adolescents.

Comparing enhancements to well-child visits in the prevention of obesity: ENCIRCLE cluster-randomized controlled trial.

BACKGROUND: Obesity disproportionally impacts rural, lower-income children in the United States. Primary care providers are well-positioned to engage parents in early obesity prevention, yet there is a lack of evidence regarding the most effective care delivery models. The ENCIRCLE study, a pragmatic cluster-randomized controlled trial, will respond to this gap by testing the comparative effectiveness of standard care well-child visits (WCV) versus two enhancements: adding a patient-reported outcome (PRO) measure (PRO WCV) and PRO WCV plus Food Care (telehealth coaching and a grocery store tour). METHODS: A total of 2,025 parents and their preschool-aged children (20-60 months of age) will be recruited from 24 Geisinger primary care clinics, where providers are randomized to the standard WCV, PRO WCV, or PRO WCV plus Food Care intervention arms. The PRO WCV includes the standard WCV plus collection of the PRO-the Family Nutrition and Physical Activity (FNPA) risk assessment-from parents. Parents complete the PRO in the patient-portal or in the clinic (own device, tablet, or kiosk), receive real-time feedback, and select priority topics to discuss with the provider. These results are integrated into the child's electronic health record to inform personalized preventive counseling by providers. PRO WCV plus Food Care includes referrals to community health professionals who deliver evidence-based obesity prevention and food resource management interventions via telehealth following the WCV. The primary study outcome is change in child body mass index z-score (BMIz), based on the World Health Organization growth standards, 12 months post-baseline WCV. Additional outcomes include percent of children with overweight and obesity, raw BMI, BMI50, BMIz extended, parent involvement in counseling, health behaviors, food resource management, and implementation process measures. DISCUSSION: Study findings will inform health care systems' choices about effective care delivery models to prevent childhood obesity among a high-risk population. Additionally, dissemination will be informed by an evaluation of mediating, moderating, and implementation factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier (NCT04406441); Registered May 28, 2020.

Metabolomics of Diabetes in Pregnancy.

PURPOSE OF REVIEW: The purpose of this review is to describe ways in which metabolomics may enhance understanding of gestational diabetes mellitus (GDM) etiology and refine current diagnostic criteria. RECENT FINDINGS: Current clinical recommendations suggest screening for GDM between 24 and 28 of gestational weeks using an oral glucose tolerance test. Despite this consensus, there are discrepancies regarding the exact criteria for GDM diagnosis. Further, emerging evidence has unveiled heterogeneous physiological pathways underlying GDM-specifically, GDM with defective insulin secretion vs. sensitivity-that have important implications for disease diagnosis and management. The objectives of this review are threefold. First, we seek to provide a brief summary of current knowledge regarding GDM pathophysiology. Next, we describe the potential role of metabolomics to refine and improve the prediction, screening, and diagnosis of GDM. Finally, we propose ways in which metabolomics may eventually impact clinical care and risk assessment for GDM and its comorbidities.

Childhood Obesity and Early Body Mass Index Gains Associated with COVID-19 in a Large Rural Health System.

OBJECTIVE: To evaluate body mass index (BMI) change among a population of children with a high proportion residing in rural areas across two pandemic time periods. METHODS: Electronic health records were evaluated in a rural health system. INCLUSION CRITERIA: 2-17 years at initial BMI; >2 BMIs during pre-pandemic (January 1, 2018-February 29, 2020); >1 BMI in early pandemic (June 1, 2020-December 31, 2020); and >1 BMI in later pandemic (January 1, 2021-December 31, 2021). Mixed effects linear regression models were used to estimate average monthly rate of change in BMI slope (∆BMI) from pre-pandemic to pandemic and test for effect modification of sex, race/ethnicity, age, BMI, public insurance, and rural address. RESULTS: Among the 40,627 participants, 50.2% were female, 84.6% were non-Hispanic white, 34.9% used public insurance, and 42.5% resided in rural areas. The pre-pandemic proportion of children with overweight, obesity, and severe obesity was 15.6%, 12.8%, and 6.3%, respectively. The ∆BMI nearly doubled during the early pandemic period compared with the pre-pandemic period (0.102 vs 0.055 kg/m2), however, ∆BMI in the later pandemic was lower (0.040 vs 0.055 kg/m2). ∆BMI remained higher in the later pandemic for all race categories compared to Non-Hispanic white. Children with public insurance had higher ∆BMI compared to those with private insurance that remained higher in the later pandemic (0.051 vs 0.035 kg/m2). There was no significant difference between ∆BMI for rural and urban children during pandemic periods. CONCLUSIONS: Despite the decreased ∆BMI among children in the later pandemic, prevalence of obesity and severe obesity remain high. Efforts must continue to be made to limit excess weight gain during childhood and to assess the impact of forces like structural and social factors in both etiology and prevention.

Probing prenatal bisphenol exposures and tissue-specific DNA methylation responses in cord blood, cord tissue, and placenta.

The early-gestational fetal epigenome establishes the landscape for fetal development and is susceptible to disruption via environmental stressors including chemical exposures. Research has explored how cell- and tissue-type-specific epigenomic signatures contribute to human disease, but how the epigenome in each tissue comparatively responds to environmental exposures is largely unknown. This pilot study compared DNA methylation in four previously identified genes across matched cord blood (CB), cord tissue (CT), and placental (PL) samples from 28 mother-infant pairs in tthe Michigan Mother Infant Pairs study; evaluated association between prenatal exposure to bisphenols (BPA, BPF, and BPS) and DNA methylation (DNAm) by tissue type; compared epigenome-wide DNAm of CB and PL; and explored associations between prenatal bisphenol exposures and epigenome-wide DNAm in PL. Bisphenol concentrations were quantified in first-trimester maternal urine. DNAm was assessed at four genes via pyrosequencing in three tissues; epigenome-wide DNAm analysis via Infinium MethylationEPIC array was completed on CB and PL. Candidate gene analysis revealed tissue-specific differences across all genes. In adjusted linear regression, BPA and BPF were associated with DNAm across candidate genes in PL but not CB and CT. Epigenome-wide comparison of matched CB and PL DNAm revealed tissue-specific differences at most CpG sites and modest associations between maternal first-trimester bisphenol exposures and PL but not CB DNAm. These data endorse inclusion of a variety of tissues in prenatal exposure studies. Overlapping and divergent responses in CB, CT, and PL demonstrate their utility in combination to capture a fuller picture of the epigenetic effect of developmental exposures.

A Description of Breast Models Used to Teach Clinical Skills.

Background: Health care trainees lack opportunities to practice breast assessment and clinical skills with patients, making breast models significant for hands-on training. Insufficient training leads to low competence across practitioners in breast health areas of practice, including clinical lactation. The aim of this review was to describe types of breast models used to teach clinical skills of the breast across breast health areas. The secondary aims were to describe education interventions that included each model and identify whether multiple skin tones were available in models. Methods: Authors conducted a scoping review to identify which types of breast models are used to teach clinical skills across breast health areas of practice and determine gaps in literature regarding how clinical lactation skills are taught. The literature search was conducted in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, MedLine, and ProQuest. Inclusion criteria were students/professionals engaging in breast model simulation. Eighteen studies were reviewed. Authors extracted data on participants, breast health area, breast model, intervention, evaluation, general outcomes, skin tone, and research design. Results: The most common skill area was clinical breast exam (n = 7), while least was breastfeeding education (n = 1). Most models were commercial (n = 12). Zero studies described skin tone. Generally, breast model simulations were correlated with increased clinical skills and confidence regardless of model used. Conclusions: Despite demonstrated gain of skills, this review reveals inconsistent use of breast models and evaluation, exclusion of diverse skin tones, and lack of breast models reported to teach clinical lactation skills.

An Application of Kane's Validity Framework to Evaluate Formative and Summative Assessment Instruments for Telesimulations in Clinical Lactation.

INTRODUCTION: Health professional learners have limited exposure to breastfeeding patients from diverse backgrounds in clinical rotations. Instead, simulation-based training is used for lactation skills training. There are no validated or standardized simulations and assessment rubrics for lactation. In this pilot, breastfeeding telesimulations with standardized patients (SPs) wearing a high-fidelity breast model matching their skin tone were developed. The validity of Formative and Summative Assessment Rubrics (FAR, SAR) were assessed following Kane's validity framework. The objective was to provide initial evidence for the validity of the FAR and SAR as constructs of competence in lactation support at the entry to practice or practice level. METHODS: Three breastfeeding case scenarios, FAR, and SAR were developed and evaluated with clinical lactation specialists (evaluators, n = 17) and SPs. The FAR was used in practice telesimulations where SPs' (n = 14) performance and telesimulation feasibility were assessed. The FAR was updated in preparation for a pilot study where medical students (n = 13) completed the 3 telesimulations. In the pilot, the updated FAR was used by SPs (n = 6) to assess medical students' performance of clinical skills. After the pilot, rubrics were updated after focus groups with SPs and discussions with evaluators. Evaluators (n = 3) graded students' posttelesimulation documentations using the SAR. Cronbach ɑ level and the intraclass correlation coefficient were assessed iteratively to collect evidence for the scoring, generalizability, and extrapolation of the FAR and SAR according to Kane's framework. RESULTS: The FAR and SAR were found to have acceptable internal consistency and moderate to high interrater reliability (intraclass correlation coefficient, 0.55-0.94), which provided evidence for scoring and generalizability of the instruments. Evaluators agreed that SPs' performances were realistic (5.6/6), and SPs' feedback was organized (5.5/6) and helpful (5.6/6), which provided evidence for extrapolation. CONCLUSIONS: Initial evidence for validity of scoring, generalization, and extrapolation FAR and SAR (according to Kane's framework) in assessing health professional learner's performance of clinical lactation skills has been presented. These results from a pilot study suggest that the FAR and SAR are reliable instruments for assessing learners' clinical performance in a breastfeeding-focused telesimulation where the SP wears a high-fidelity breast model matching their skin tone. Additional studies will be required to collect evidence according to all 4 categories of Kane's framework for the validity of the FAR and SAR.

Patient-reported outcome measures can advance population health, but is access to instruments and use equitable?

Patient reported outcome measures (PROM) can engage patients and clinicians to improve health outcomes. Their population health impact may be limited by systematic barriers inhibiting access to completion. In this analysis we evaluated the association between individual parent/child characteristics and clinic factors with parental completion of a locally developed PROM, the Early Healthy Lifestyles (EHL) questionnaire. Participants included parent-child dyads who presented at 14 pediatric clinics for regularly scheduled well-child visits (WCV) prior to age 26 months. EHL items include feeding practices, diet, play time, screen exposure, and sleep. Completion was categorized at patient- (i.e., parent-child dyad) and clinic-levels. Parents completed the 15-item EHL in the patient portal before arrival or in the clinic; ninety-three percent of EHL questionnaires were completed in the clinic vs. 7% in the patient portal. High-completers completed EHL for half of WCVs; low-completers completed at least once; and non-completers never completed. Clinics were classified by EHL adoption level (% high completion): High-adoption: >50%; Moderate-adoption: 10%-50%; and Low-adoption: <10%. Individual-level factors had negligible impact on EHL completion within moderate/low EHL adoption sites; high-adoption sites were used to evaluate infant and maternal factors in association with EHL completion using hierarchical logistic regression. Noncompletion of EHL was significantly associated (p < 0.05) with infant use of public insurance (OR = 1.92 [1.42, 2.59]), >1 clinic site for WCV (OR = 1.83 [1.34, 2.50]), non-White birth mother (OR = 1.78 [1.28, 2.47]), and body weight <2,500 grams or gestational age <34 weeks (OR = 1.74 [1.05, 2.90]). The number of WCVs, a proxy for clinic size, was evaluated but was not associated with completion. Findings indicate potential disparities between populations exposed to, completing, and benefitting from these tools.

Gestational exposure to high fat diets and bisphenol A alters metabolic outcomes in dams and offspring, but produces hepatic steatosis only in dams.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. Perinatal development is a critical window for altered, lifelong health trajectory, and evidence supports the role of perinatal programming in chronic metabolic diseases. To examine the impact of diet and bisphenol A (BPA) on the developmental trajectory of NAFLD in offspring, we exposed dams from pre-gestation through lactation to a human-relevant dose of oral BPA coupled with intake of high fat Western or Mediterranean-style diets. We assessed hepatic steatosis by quantifying hepatic triglycerides (TGs) and metabolic health by measuring body weight, relative organ weights, and serum hormone levels in dams and offspring at postnatal day 10 (PND10) and 10-months of age. In dams, consumption of the Western or Mediterranean diet increased hepatic TGs 1.7-2.4-fold, independent of BPA intake. Among offspring, both perinatal diet and BPA exposure had a greater impact on metabolic outcomes than on hepatic steatosis. At PND10, serum leptin levels were elevated 2.6-4.8-fold in pups exposed to the Mediterranean diet, with a trend for sex-specific effects on body and organ weights. At 10-months, sex-specific increases in organ weight and hormone levels were observed in mice perinatally exposed to Western + BPA or Mediterranean + BPA. These findings suggest lifestage-specific interaction of perinatal exposures to experimental diets and BPA on offspring metabolic health without effects on NAFLD later in life. Importantly, alterations in dam phenotype by diet and BPA exposure appear to impact offspring health trajectory, emphasizing the need to define dam diet in assessing effects of environmental exposures on offspring health.

Maternal and neonatal one-carbon metabolites and the epigenome-wide infant response.

Maternal prenatal status, as encapsulated by that to which a mother is exposed through diet and environment, is a key determinant of offspring health and disease. Alterations in DNA methylation (DNAm) may be a mechanism through which suboptimal prenatal conditions confer disease risk later in life. One-carbon metabolism (OCM) is critical to both fetal development and in supplying methyl donors needed for DNAm. Plasma concentrations of one-carbon metabolites across maternal first trimester (M1), maternal term (M3), and infant cord blood (CB) at birth were tested for association with DNAm patterns in CB from the Michigan Mother and Infant Pairs (MMIP) pregnancy cohort. The Illumina Infinium MethylationEPIC BeadChip was used to quantitatively evaluate DNAm across the epigenome. Global and single-site DNAm and metabolite models were adjusted for infant sex, estimated cell type proportions, and batch as covariates. Change in mean metabolite concentration across pregnancy (M1 to M3) was significantly different for S-adenosylhomocysteine (SAH), S-adenosylmethionine (SAM), betaine, and choline. Both M1 SAH and CB SAH were significantly associated with the global distribution of DNAm in CB, with indications of a shift toward less methylation. M3 SAH and CB SAH also displayed significant associations with locus-specific DNAm in infant CB (FDR<0.05). Our findings underscore the role of maternal one-carbon metabolites in shifting the global DNAm pattern in CB and emphasizes the need to closely evaluate how dietary status influences cellular methylation potential and ultimately offspring health.

Clinical features and outcomes of women with unstable ischemic heart disease: observations from metabolic efficiency with ranolazine for less ischemia in non-ST-elevation acute coronary syndromes-thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36).

BACKGROUND: The pathobiological basis of ischemic heart disease and thus the manifestations and response to therapy can differ between women and men. In prior studies, sex-based treatment differences have been observed with the antiischemic ranolazine, with a possibly diminished effect in women. METHODS AND RESULTS: We conducted a prospectively planned analysis of the clinical, biomarker, angiographic, and continuous ECG features and 1-year outcomes of women with unstable ischemic heart disease randomized to ranolazine or placebo in Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36). Compared with men (n=4269), women (n=2291) were older with more risk factors (P<0.001). On presentation, women were less likely than men to have significant epicardial coronary artery disease (no stenosis >or=50% on angiography, 19.4% versus 8.6%; P<0.001) or elevated troponin (57.1% versus 68.9%; P<0.001). Yet, women were more likely to have an elevated B-type natriuretic peptide (47.0% versus 40.2%; P<0.001), worse median angina frequency scores (80 versus 100; P<0.001), and an ischemic episode on continuous ECG administered during the first 7 days (22.5% versus 19.3%; P=0.0025). Women and men were at similar adjusted risk for the primary end point of cardiovascular death, myocardial infarction, or recurrent ischemia (adjusted hazard ratio, 1.11; 95% confidence interval, 0.96 to 1.29; P=0.15). Ranolazine was associated with a significant reduction in recurrent ischemia in women (13.0% versus 18.2%; hazard ratio, 0.71; 95% confidence interval, 0.57 to 0.88; P=0.002). CONCLUSIONS: Women with a clinical syndrome consistent with unstable ischemic heart disease, despite having less obstructive coronary artery disease, were more likely than men to report anginal episodes and had more recorded ischemic periods on continuous ECG. In this setting, ranolazine may be a particularly useful antiischemic agent in women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00099788.

Relations between bleeding and outcomes in patients with ST-elevation myocardial infarction in the ExTRACT-TIMI 25 trial.

AIMS: To evaluate the association of bleeding with mortality in ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We studied 20 323 patients with STEMI receiving fibrinolytic therapy and an antithrombin in ExTRACT-TIMI 25. Relationships between in-hospital bleeding, patient characteristics, treatments, and in-hospital cardiovascular complications with mortality were evaluated using Cox models. Likelihood ratios estimated each variable's model contribution. High 30-day mortality after major bleeding (n = 309, 37.6% mortality) was driven by the poor prognosis of intracranial haemorrhage (ICH; n = 143, 65.4% mortality, model contribution 7.8%). The adjusted hazard ratios (HRs) for 30-day death for any major bleeding and for ICH were 2.9 [2.4-3.6] and 10.3 [8.2-12.8], respectively. Neither non-ICH major nor minor bleeding was associated with 30-day death after adjustment. Cardiogenic shock (HR 13.5, 61% contribution) and age (HR 1.6/decade, 17% contribution) were most strongly correlated with 30-day death. Among 30-day survivors, age (HR 1.6/decade, contribution 43%) and heart rate (HR 1.2 per 10 b.p.m., contribution 18%) were most strongly associated with mortality between Days 31 and 365. CONCLUSION: Cardiogenic shock, age, and ICH were important independent correlates of 30-day and 1-year mortality in STEMI patients receiving fibrinolytic therapy. In-hospital non-ICH major and minor bleeding were not independently associated with increased mortality at 30 days or 1 year.

One-year outcomes after a strategy using enoxaparin vs. unfractionated heparin in patients undergoing fibrinolysis for ST-segment elevation myocardial infarction: 1-year results of the ExTRACT-TIMI 25 trial.

AIMS: To determine the impact of a strategy using enoxaparin for up to 8 days compared with unfractionated heparin (UFH) for 48 h as an adjunct to fibrinolysis for ST-segment elevation myocardial infarction (STEMI) on 1-year clinical outcomes. METHODS AND RESULTS: Follow-up at 1 year (n = 20 275) was conducted by telephone in the ExTRACT-TIMI 25 trial to ascertain the endpoints of death, MI, and disabling stroke. The primary endpoint of death or non-fatal MI occurred in 1614 (15.8%) and 1732 (17.0%) of patients allocated to enoxaparin and UFH, respectively [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.86-0.98, P = 0.01]. The enoxaparin strategy significantly reduced non-fatal MI at 1 year (5.7 vs. 6.8%, HR 0.82, 95% CI 0.73-0.92, P < 0.001). The risks of death (10.5 vs. 10.6%, HR 0.98, 95% CI 0.91-1.07) and disabling stroke (1.1 vs. 1.2%, HR 0.97, 95% CI 0.75-1.26) were not reduced. The composite of death, MI, or disabling stroke favoured enoxaparin (HR 0.91, 95% CI 0.85-0.98, P = 0.007). CONCLUSION: Compared with UFH for 48 h, a strategy using enoxaparin as an adjunct to fibrinolysis resulted in a sustained reduction in death or MI at 1 year with no additional benefit after 30 days. Mortality was not reduced at 1 year with the enoxaparin strategy. The study was registered at ClinicalTrials.gov, NCT00077792.

Patients with acute coronary syndromes and elevated levels of natriuretic peptides: the results of the AVANT GARDE-TIMI 43 Trial.

AIMS: Elevated natriuretic peptides (NPs) are associated with an increased cardiovascular risk following acute coronary syndromes (ACSs). However, the therapeutic implications are still undefined. We hypothesized that early inhibition of renin-angiotensin-aldosterone system (RAAS) in patients with preserved left ventricular function but elevated NPs but following ACS would reduce haemodynamic stress as reflected by a greater reduction NP compared with placebo. METHODS AND RESULTS: AVANT GARDE-TIMI 43 trial, a multinational, double-blind trial, randomized 1101 patients stabilized after ACS without clinical evidence of heart failure or left ventricular function

The Efficacy of Hybrid Telesimulation with Standardized Patients in Teaching Medical Students Clinical Lactation Skills: A Pilot Study.

Introduction: Medical students lack competencies in clinical lactation. We determined the effect of hybrid telesimulation with a standardized patient (SP) on medical students' clinical performance in lactation support. We assessed students' engagement and satisfaction with the experience. Materials and Methods: Undergraduate medical students (n = 13) completed (1) preparatory case scenarios with multiple-choice questions and (2) three telesimulations with SPs wearing a high-fidelity breast model. Students had the option to complete the Encounter Documentation. SPs used the Formative Assessment Rubric (FAR) to evaluate students' interpersonal skills and clinical lactation experts used the Summative Assessment Rubric to evaluate documentation skills. Investigators collected satisfaction data from a focus group and written evaluation. Dunn's multiple comparison and Freidman tests were used to measure differences in FAR scores between cases and telesimulations. Qualitative data were analyzed using thematic analysis. Results: Most students (70%) attempted case questions multiple times and scores improved (p < 0.0001) between attempts. FAR scores suggest students were prepared for telesimulations (5.5/6-pt Likert) and interpersonal skills were appropriate (5.4/6), with no differences by case (p = 0.11). FAR scores increased between telesimulation 1-2 (+24.5/114, p = 0.002) and 2-3 (+17.5/114, p = 0.014). Students were satisfied with the experience and would recommend it to classmates (both 4.6/6). Thematic analysis revealed feedback regarding interpersonal skills was helpful. Conclusions: Medical students must develop skills to support breastfeeding in virtual settings. Telesimulation can be incorporated into existing curricula to support clinical lactation competencies.

Effect of the novel thienopyridine prasugrel compared with clopidogrel on spontaneous and procedural myocardial infarction in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38: an application of the classification system from the universal definition of myocardial infarction.

BACKGROUND: Prasugrel is a novel thienopyridine that reduces new or recurrent myocardial infarctions (MIs) compared with clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. This effect must be balanced against an increased bleeding risk. We aimed to characterize the effect of prasugrel with respect to the type, size, and timing of MI using the universal classification of MI. METHODS AND RESULTS: We studied 13 608 patients with acute coronary syndrome undergoing percutaneous coronary intervention randomized to prasugrel or clopidogrel and treated for 6 to 15 months in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). Each MI underwent supplemental classification as spontaneous, secondary, or sudden cardiac death (types 1, 2, and 3) or procedure related (Types 4 and 5) and examined events occurring early and after 30 days. Prasugrel significantly reduced the overall risk of MI (7.4% versus 9.7%; hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.67 to 0.85; P<0.0001). This benefit was present for procedure-related MIs (4.9% versus 6.4%; HR, 0.76; 95% CI, 0.66 to 0.88; P=0.0002) and nonprocedural (type 1, 2, or 3) MIs (2.8% versus 3.7%; HR, 0.72; 95% CI, 0.59 to 0.88; P=0.0013) and consistently across MI size, including MIs with a biomarker peak > or =5 times the reference limit (HR. 0.74; 95% CI, 0.64 to 0.86; P=0.0001). In landmark analyses starting at 30 days, patients treated with prasugrel had a lower risk of any MI (2.9% versus 3.7%; HR, 0.77; P=0.014), including nonprocedural MI (2.3% versus 3.1%; HR, 0.74; 95% CI, 0.60 to 0.92; P=0.0069). CONCLUSIONS: Treatment with prasugrel compared with clopidogrel for up to 15 months in patients with acute coronary syndrome undergoing percutaneous coronary intervention significantly reduces the risk of MIs that are procedure related and spontaneous and those that are small and large, including new MIs occurring during maintenance therapy.

Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial.

BACKGROUND: Ranolazine is a novel antianginal shown in an exploratory analysis in patients with diabetes mellitus and chronic angina to be associated with a decline in hemoglobin A(1c) (HbA(1c)). We designed a prospective evaluation of the effect of ranolazine on hyperglycemia as part of a randomized, double-blind, placebo-controlled outcomes trial. METHODS AND RESULTS: We compared HbA(1c) (percentage) and the time to onset of a > or =1% increase in HbA(1c) among 4918 patients with acute coronary syndrome randomized to ranolazine or placebo in the MERLIN-TIMI 36 trial. Ranolazine significantly reduced HbA(1c) at 4 months compared with placebo (5.9% versus 6.2%; change from baseline, -0.30 versus -0.04; P<0.001). In patients with diabetes mellitus treated with ranolazine, HbA(1c) declined from 7.5 to 6.9 (change from baseline, -0.64; P<0.001). Diabetic patients were more likely to achieve an HbA(1c) <7% at 4 months with ranolazine compared with placebo (59% versus 49%; P<0.001) and were less likely to have a > or =1% increase in HbA(1c) (14.2% versus 20.6% at 1 year; hazard ratio, 0.63; 95% confidence interval, 0.51 to 0.77; P<0.001). Moreover, ranolazine reduced recurrent ischemia in diabetic patients (hazard ratio, 0.75; 95% confidence interval, 0.61 to 0.93; P=0.008). Notably, in patients without diabetes mellitus at baseline, the incidence of new fasting glucose >110 mg/dL or HbA(1c) > or =6% was reduced by ranolazine (31.8% versus 41.2%; hazard ratio, 0.68; 95% confidence interval, 0.53 to 0.88; P=0.003). Reported hypoglycemia did not increase with ranolazine (P=NS). CONCLUSIONS: Ranolazine significantly improved HbA(1c) and recurrent ischemia in patients with diabetes mellitus and reduced the incidence of increased HbA(1c) in those without evidence of previous hyperglycemia. The mechanism of this effect is under investigation.

Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial.

BACKGROUND: Mechanical reperfusion with stenting for ST-elevation myocardial infarction (STEMI) is supported by dual antiplatelet treatment with aspirin and clopidogrel. Prasugrel, a potent and rapid-acting thienopyridine, is a potential alternative to clopidogrel. We aimed to assess prasugrel versus clopidogrel in patients undergoing percutaneous coronary intervention (PCI) for STEMI. METHODS: We undertook a double-blind, randomised controlled trial in 707 sites in 30 countries. 3534 participants presenting with STEMI were randomly assigned by interactive voice response system either prasugrel (60 mg loading, 10 mg maintenance [n=1769]) or clopidogrel (300 mg loading, 75 mg maintenance [n=1765]) and were unaware of the allocation. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Efficacy analyses were by intention to treat. Follow-up was to 15 months, with secondary analyses at 30 days. This trial is registered with ClinicalTrials.gov, number NCT00097591. FINDINGS: At 30 days, 115 (6.5%) individuals assigned prasugrel had met the primary endpoint compared with 166 (9.5%) allocated clopidogrel (hazard ratio 0.68 [95% CI 0.54-0.87]; p=0.0017). This effect continued to 15 months (174 [10.0%] vs 216 [12.4%]; 0.79 [0.65-0.97]; p=0.0221). The key secondary endpoint of cardiovascular death, myocardial infarction, or urgent target vessel revascularisation was also significantly reduced with prasugrel at 30 days (0.75 [0.59-0.96]; p=0.0205) and 15 months (0.79 [0.65-0.97]; p=0.0250), as was stent thrombosis. Treatments did not differ with respect to thrombolysis in myocardial infarction (TIMI) major bleeding unrelated to coronary-artery bypass graft (CABG) surgery at 30 days (p=0.3359) and 15 months (p=0.6451). TIMI life-threatening bleeding and TIMI major or minor bleeding were also similar with the two treatments, and only TIMI major bleeding after CABG surgery was significantly increased with prasugrel (p=0.0033). INTERPRETATION: In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding.

Otamixaban for the treatment of patients with non-ST-elevation acute coronary syndromes (SEPIA-ACS1 TIMI 42): a randomised, double-blind, active-controlled, phase 2 trial.

BACKGROUND: Otamixaban is an intravenous direct factor Xa inhibitor. We aimed to assess its efficacy and safety in non-ST-elevation acute coronary syndromes and to identify the optimum dose range for further assessment in a phase 3 study. METHODS: In this double-blind, phase 2 trial undertaken in 196 sites in 36 countries, 3241 patients with non-ST-elevation acute coronary syndromes were randomly assigned via a central, telephone-based interactive voice response system to one of five doses of otamixaban (0.08 mg/kg bolus followed by infusions of 0.035 [n=125], 0.070 [676], 0.105 [662], 0.140 [658], or 0.175 [671] mg/kg/h) or to a control of unfractionated heparin (60 IU/kg intravenous bolus followed by an infusion of 12 IU/kg/h) plus eptifibatide (180 microg/kg intravenous bolus followed by an infusion of 1.0-2.0 microg/kg/min [n=449]). Both investigators and patients were unaware of treatment allocation. Enrolment into the lowest dose group was stopped early at the recommendation of the Data Monitoring Committee. The primary efficacy endpoint was a composite of death, myocardial infarction, urgent revascularisation, or bailout glycoprotein IIb/IIIa inhibitor use up to 7 days. The primary safety endpoint was TIMI major or minor bleeding not related to coronary-artery bypass grafting. Efficacy analyses were by intention to treat; safety analyses were in treated patients. This study is registered with ClinicalTrials.gov, number NCT00317395. FINDINGS: Rates of the primary efficacy endpoint in the five otamixaban doses were 7.2% (nine of 125) with 0.035 mg/kg/h, 4.6% (31/676) with 0.070 mg/kg/h, 3.8% (25/662) with 0.105 mg/kg/h, 3.6% (24/658) with 0.140 mg/kg/h, and 4.3% (29/671) with 0.175 mg/kg/h (p=0.34 for trend). In the control group, the rate was 6.2% (28/449), yielding relative risks for the five otamixaban doses of 1.16 (95% CI 0.56-2.38), 0.74 (0.45-1.21), 0.61 (0.36-1.02), 0.58 (0.34-1.00), and 0.69 (0.42-1.15), respectively. Rates of the primary safety endpoint in the five otamixaban doses were 1.6% (two of 122), 1.6% (11/669), 3.1% (20/651), 3.4% (22/651), and 5.4% (36/664), respectively (p=0.0001 for trend); the rate in the control group was 2.7% (12/448). INTERPRETATION: In patients with non-ST-elevation acute coronary syndromes, otamixaban infusions of 0.100-0.140 mg/kg/h might reduce ischaemic events and have a safety profile similar to unfractionated heparin plus eptifibatide. Further testing in a phase 3 trial is warranted. FUNDING: Sanofi-Aventis.

Prasugrel versus clopidogrel in patients with acute coronary syndromes.

BACKGROUND: Dual-antiplatelet therapy with aspirin and a thienopyridine is a cornerstone of treatment to prevent thrombotic complications of acute coronary syndromes and percutaneous coronary intervention. METHODS: To compare prasugrel, a new thienopyridine, with clopidogrel, we randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. RESULTS: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). We also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P=0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P=0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P=0.23) and fatal bleeding (0.4% vs. 0.1%; P=0.002). CONCLUSIONS: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups. (ClinicalTrials.gov number, NCT00097591 [ClinicalTrials.gov].)