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Aims We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). Methods and results DECLARE–TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to Conclusions In DECLARE–TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. Clinical trial registration URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.

Objective: Functional HDL (high-density lipoprotein) particles that facilitate cholesterol efflux may be cardioprotective. EL (endothelial lipase) hydrolyzes phospholipids promoting catabolism of HDL and subsequent renal excretion. MEDI5884 is a selective, humanized, monoclonal, EL-neutralizing antibody. We sought to determine the safety, pharmacokinetics, and pharmacodynamic effects of multiple doses of MEDI5884 in patients with stable coronary artery disease. Approach and Results: LEGACY was a phase 2a, double-blind, placebo-controlled, parallel-design trial that randomized 132 patients with stable coronary artery disease receiving high-intensity statin therapy to 3 monthly doses of 1 of 5 dose levels of MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary end point was the safety and tolerability of MEDI5884 through the end of the study (day 151). Additional end points included change in HDL cholesterol and cholesterol efflux from baseline to day 91, hepatic uptake of cholesterol at day 91, changes in various other lipid parameters. The incidence of adverse events was similar between the placebo and MEDI5884 groups. In a dose-dependent manner, MEDI5884 increased HDL cholesterol up to 51.4% ( P P P P =0.04) was observed with MEDI5884. However, at the potential target doses for future studies, there was no meaningful increase in LDL cholesterol or apoB. Conclusions: Inhibition of EL by MEDI5884 increases the quantity and quality of functional HDL in patients with stable coronary artery disease on high-intensity statin therapy without an adverse safety signal at the likely dose to be used. These data support further clinical investigation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03351738.

Background Coronary stent type and risk of stent thrombosis remain important factors affecting recommended duration of dual antiplatelet therapy. We investigated the efficacy and safety of long‐term ticagrelor in patients with prior coronary stenting enrolled in the PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) trial. Methods and Results Patients in PEGASUS‐TIMI 54 had a myocardial infarction 1 to 3 year prior and were randomized 1:1:1 to ticagrelor 60 or 90 mg BID or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke (major adverse cardiovascular events). Stent thrombosis was prospectively adjudicated (Academic Research Consortium definition). Baseline characteristics were compared by most recent stent type (bare metal versus drug‐eluting stent and first‐ versus later‐generation drug‐eluting stent). Treatment arms were compared using Cox proportional hazards models. Of 21 162 patients randomized, 80% (n=16 891) had prior coronary stenting. Following randomization, myocardial infarction was the most frequent ischemic event in patients with prior stenting in the placebo arm, occurring in 5.2% of patients (Type 1: 4.1%), followed by cardiovascular death (2.3%), stroke (1.7%), and stent thrombosis (0.9%). Ticagrelor pooled reduced major adverse cardiovascular events (7.0% versus 8.0%; hazard ratio [HR], 0.85; 95% CI, 0.75–96) regardless of stent type (bare metal stent versus drug‐eluting stent: p interaction =0.767; first versus later generation: p interaction =0.940). The rate of any stent thrombosis was numerically lower with ticagrelor pooled (0.7% versus 0.9%; HR, 0.73; 95% CI, 0.50–1.05) and Thrombolysis in Myocardial Infarction major bleeding was increased (HR, 2.65; 95% CI, 1.90–3.68). Conclusions Long‐term ticagrelor reduces major adverse cardiovascular events in patients with prior myocardial infarction and coronary stenting regardless of stent type, with the benefit driven predominantly by reduction in de novo events. Nonfatal major bleeding is increased with ticagrelor. Registration Information clinicaltrials.gov. Identifier: NCT01225562.

Background: In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the composite end point of cardiovascular death/hospitalization for heart failure (HHF) in a broad population of patients with type 2 diabetes mellitus. However, the impact of baseline left ventricular ejection fraction (EF) on the clinical benefit of sodium-glucose cotransporter 2 inhibition is unknown. Methods: In the DECLARE-TIMI 58 trial, baseline heart failure (HF) status was collected from all patients, and EF was collected when available. HF with reduced EF (HFrEF) was defined as EF Results: Of 17 160 patients, 671 (3.9%) had HFrEF, 1316 (7.7%) had HF without known reduced EF, and 15 173 (88.4%) had no history of HF at baseline. Dapagliflozin reduced cardiovascular death/HHF more in patients with HFrEF (hazard ratio [HR], 0.62 [95% CI, 0.45–0.86]) than in those without HFrEF (HR, 0.88 [95% CI, 0.76–1.02]; P for interaction=0.046), in whom the treatment effect of dapagliflozin was similar in those with HF without known reduced EF (HR, 0.88 [95% CI, 0.66–1.17]) and those without HF (HR, 0.88 [95% CI, 0.74–1.03]). Whereas dapagliflozin reduced HHF both in those with (HR, 0.64 [95% CI, 0.43–0.95]) and in those without HFrEF (HR, 0.76 [95% CI, 0.62–0.92]), it reduced cardiovascular death only in patients with HFrEF (HR, 0.55 [95% CI, 0.34–0.90]) but not in those without HFrEF (HR, 1.08 [95% CI, 0.89–1.31]; P for interaction=0.012). Likewise, dapagliflozin reduced all-cause mortality in patients with HFrEF (HR, 0.59 [95% CI, 0.40–0.88;) but not in those without HFrEF (HR, 0.97 [95% CI, 0.86–1.10]; P for interaction=0.016). Conclusions: In the first sodium-glucose cotransporter 2 inhibitor cardiovascular outcome trial to evaluate patients with type 2 diabetes mellitus stratified by EF, we found that dapagliflozin reduced HHF in patients with and without HFrEF and reduced cardiovascular death and all-cause mortality in patients with HFrEF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Background: Sodium glucose transporter-2 inhibitors reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and a history of atherosclerotic cardiovascular disease. Because of their baseline risk, patients with previous myocardial infarction (MI) may derive even greater benefit from sodium glucose transporter-2 inhibitor therapy. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) randomized 17 160 patients with type 2 diabetes mellitus and either established atherosclerotic cardiovascular disease (n=6974) or multiple risk factors (n=10 186) to dapagliflozin versus placebo. The 2 primary end points were composite of MACE (cardiovascular death, MI, or ischemic stroke) and the composite of cardiovascular death or hospitalization for heart failure. Those with previous MI (n=3584) made up a prespecified subgroup of interest. Results: In patients with previous MI (n=3584), dapagliflozin reduced the relative risk of MACE by 16% and the absolute risk by 2.6% (15.2% versus 17.8%; hazard ratio [HR], 0.84; 95% CI, 0.72–0.99; P =0.039), whereas there was no effect in patients without previous MI (7.1% versus 7.1%; HR, 1.00; 95% CI, 0.88–1.13; P =0.97; P for interaction for relative difference=0.11; P for interaction for absolute risk difference=0.048), including in patients with established atherosclerotic cardiovascular disease but no history of MI (12.6% versus 12.8%; HR, 0.98; 95% CI, 0.81–1.19). There seemed to be a greater benefit for MACE within 2 years after the last acute event ( P for interaction trend=0.007). The relative risk reductions in cardiovascular death/hospitalization for heart failure were more similar, but the absolute risk reductions tended to be greater: 1.9% (8.6% versus 10.5%; HR, 0.81; 95% CI, 0.65–1.00; P =0.046) and 0.6% (3.9% versus 4.5%; HR, 0.85; 95% CI, 0.72–1.00; P =0.055) in patients with and without previous MI, respectively ( P interaction for relative difference=0.69; P interaction for absolute risk difference=0.010). Conclusions: Patients with type 2 diabetes mellitus and previous MI are at high risk of MACE and cardiovascular death/hospitalization for heart failure. Dapagliflozin appears to robustly reduce the risk of both composite outcomes in these patients. Future studies should aim to confirm the large clinical benefits with sodium glucose transporter-2 inhibitors we observed in patients with previous MI. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01730534.

Background: Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)–TIMI 48 trial (NCT00781391) of edoxaban versus warfarin. Methods: A total of 21 105 patients with atrial fibrillation at risk for stroke (CHADS 2 score ≥2) were enrolled in the ENGAGE AF-TIMI 48 trial comparing warfarin with a higher- (60/30 mg daily) or lower- (30/15 mg daily) dose edoxaban regimen. Median follow-up was 2.8 years. Bleeding events occurring among on-treatment patients were examined. Annualized event rates were calculated by the ISTH, TIMI, GUSTO, and BARC scales and compared across treatment arms. Cox proportional hazards for a first bleeding event of each type were calculated for higher-dose edoxaban regimen vs warfarin and lower-dose edoxaban regimen versus warfarin. Results: A total of 10 311 bleeding events were reported. In a comparison of the most severe events in each scale, ISTH major bleeding was the most common (n=1289), followed by TIMI major (n=548), GUSTO severe/life-threatening (n=347), and BARC 3c+5 (n=276) bleeding. Lower bleeding risk with edoxaban compared with warfarin was seen regardless of bleeding scale (higher-dose edoxaban regimen range: hazard ratio [HR], 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 versus HR, 0.80 [95% CI, 0.71–0.91] for ISTH major; lower-dose edoxaban regimen range: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 versus HR, 0.47 [95% CI, 0.41–0.55] for ISTH major). Furthermore, a gradient of more pronounced risk reduction with edoxaban was observed with greater severity of first bleeding event (higher-dose edoxaban regimen: HR, 0.47 [95% CI, 0.35–0.62] for BARC 3c+5 bleeds versus HR, 0.86 [95% CI, 0.81–0.91] for any BARC bleed; lower-dose edoxaban regimen: HR, 0.32 [95% CI, 0.23–0.45] for BARC 3c+5 bleeds versus HR, 0.68 [95% CI, 0.63–0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal bleeding and nongastrointestinal bleeding. Conclusions: Among patients with atrial fibrillation at risk for stroke, there was a >4-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Furthermore, the relative safety of edoxaban compared with warfarin tended to increase with greater severity of bleeding. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Background The effects of anticoagulants at extremes of body weight (BW) are not well described. The aim of this study was to analyze the pharmacokinetics/pharmacodynamics and clinical outcomes in patients randomized to warfarin, higher dose edoxaban (HDER), and lower dose edoxaban (LDER) regimens at extremes of BW in ENGAGE AF-TIMI 48.Methods and Results We analyzed three BW groups: low BW (LBW: 95th percentile, ≥120 kg, N = 1,093). In the warfarin arm, LBW patients had higher rates of stroke/systemic embolism (SSE: 6.5 vs. 4.7 in MBW vs. 1.6% in HBW, P trend Conclusion Patients with LBW in ENGAGE AF-TIMI 48 had in general a more fragile clinical status and poorer international normalized ratio control. The pharmacokinetic/pharmacodynamic profile of edoxaban was consistent across extremes of BW, resulting in similar efficacy compared with warfarin, while major or clinically relevant non-MB and net outcomes were most favorable with edoxaban as compared to warfarin in LBW patients.

Introduction: Among patients with atherosclerotic cardiovascular disease (ASCVD), those with history of PCI represent an important population for potential high risk for cardiovascular (CV) events. We examined the clinical efficacy of the PCSK9 inibitor evolocumab in patients with prior PCI. Methods: FOURIER randomized 27,564 patients with ASCVD on statin therapy to evolocumab or placebo with a median follow-up of 2.2 yrs. The primary end point (PEP) was the composite of CV death, MI, stroke, unstable angina, or coronary revascularization; major coronary events were the composite of coronary death, MI, or coronary revascularization. The risk of events in patients with and without a history of PCI were compared in the placebo arm. The clinical benefit of evolocumab vs. placebo was compared using a Cox proportional hazards model. Results: 17,073 (62%) patients had prior PCI at baseline. Among patients in the placebo arm, those with prior PCI (N=8563) had a 1.6x higher rate of the PEP (16.8 vs 10.7%; adjusted HR 1.61; 95% CI 1.42-1.84 P Conclusions: In a contemporary cohort with ASCVD on statin therapy, patients with prior PCI were at heightened risk for coronary events. Evolocumab was highly effective in this group, reducing major coronary events by 18% with a NNT at 3 years of only 36.

Introduction: Although PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall, their ability to specifically reduce the risk of complex coronary atherosclerosis requiring revascularization has not been explored. Methods: FOURIER was a randomized trial of the PCSK9 inhibitor evolocumab vs. placebo in 27,564 patients with ASCVD on statin therapy (median achieved LDL-C 32 mg/dL vs. 89 mg/dL) followed for a median of 2.2 years. The study database was blindly reviewed to assess characteristics of coronary revascularization procedures. Complex revascularization was the composite of complex PCI (per GLOBAL LEADERS criteria, at least one of: multivessel PCI, 3 or more stents implanted, 3 or more lesions treated, bifurcation PCI with 2 or more stents, or total stent length >60 mm) or CABG. PCI complications included no-reflow, side branch loss, thrombus formation, major dissection, or perforation. The effects of evolocumab on types of revascularization and PCI complications were evaluated using Cox proportional hazards models. Results: 1724 patients underwent revascularization procedures during follow-up. Evolocumab reduced the risk of non-complex PCI by 22% (HR 0.78; 95%CI 0.70-0.88; P Conclusions: Adding evolocumab to statin therapy reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. Together with prior coronary imaging findings, these data suggest very aggressive LDL-C lowering to

This study sought to evaluate the ability of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab to reduce the risk of complex coronary atherosclerosis requiring revascularization.PCSK9 inhibitors induce plaque regression and reduce the risk of coronary revascularization overall.FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) was a randomized trial of the PCSK9 inhibitor evolocumab versus placebo in 27,564 patients with stable atherosclerotic cardiovascular disease on statin therapy followed for a median of 2.2 years. Clinical documentation of revascularization events was blindly reviewed to assess coronary anatomy and procedural characteristics. Complex revascularization was the composite of complex percutaneous coronary intervention (PCI) (as per previous analyses, ≥1 of: multivessel PCI, ≥3 stents, ≥3 lesions treated, bifurcation PCI, or total stent length60 mm) or coronary artery bypass grafting surgery (CABG).In this study, 1,724 patients underwent coronary revascularization, including 1,482 who underwent PCI, 296 who underwent CABG, and 54 who underwent both. Complex revascularization was performed in 632 (37%) patients. Evolocumab reduced the risk of any coronary revascularization by 22% (hazard ratio [HR]: 0.78; 95% CI: 0.71 to 0.86; p 0.001), simple PCI by 22% (HR: 0.78; 95% CI: 0.70 to 0.88; p 0.001), complex PCI by 33% (HR: 0.67; 95% CI: 0.54 to 0.84; p 0.001), CABG by 24% (HR: 0.76; 95% CI: 0.60 to 0.96; p = 0.019), and complex revascularization by 29% (HR: 0.71; 95% CI: 0.61 to 0.84; p 0.001). The magnitude of the risk reduction with evolocumab in complex revascularization tended to increase over time (20%, 36%, and 41% risk reductions in the first, second, and beyond second years).Adding evolocumab to statin therapy significantly reduced the risk of developing complex coronary disease requiring revascularization, including complex PCI and CABG individually. (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER); NCT01764633.).

Importance: Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a life-threatening condition with no proven disease-modifying therapy. Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab reduces circulating LDL-C concentrations by 50% to 60% and Lp(a) by 20% to 30%. Objective: To determine whether evolocumab reduces the risk of AS events in patients with atherosclerotic cardiovascular disease. Interventions: Patients were randomized 1:1 to evolocumab or placebo. Design, Setting, and Participants: Exploratory analysis of the FOURIER trial, which enrolled 27564 patients with stable atherosclerotic cardiovascular disease who were taking statin therapy at 1242 sites in 49 countries from February 2013 to November 2016. Patients were randomized to evolocumab or placebo and followed up for a median (interquartile range) of 2.2 (1.8-2.5) years. This post hoc analysis was performed from September 2019 to February 2020. Main Outcomes and Measures: Site-reported adverse events of new or worsening AS or aortic valve replacement (termed AS events). The adjusted risk of AS events was calculated with a multivariable model including concentrations of Lp(a) and LDL-C corrected for Lp(a) content, plus age, sex, diabetes, hypertension, current smoking, and estimated glomerular filtration rate. Evolocumab efficacy was tested using a Cox proportional hazards model. Results: Aortic stenosis events occurred in 63 patients (48 men [76%]; mean [SD] age, 69 [9] years) over a median of 2.2 years. Elevated Lp(a) concentration was associated with higher rates of AS events (adjusted hazard ratio [aHR], 1.55 [95% CI, 1.17-2.05] per SD; P =.002), including aortic valve replacement (aHR, 2.22 [95% CI, 1.38-3.58] per SD; P =.001), after multivariable adjustment. The corrected LDL-C concentration was not significantly associated with AS events (aHR, 1.23 [95% CI, 0.93-1.61] per SD; P =.14). The overall HR for AS events with evolocumab was 0.66 (95% CI, 0.40-1.09), with no apparent association in the first year (HR, 1.09 [95% CI, 0.48-2.47]) but an HR of 0.48 (95% CI, 0.25-0.93) after the first year of treatment. Conclusions and Relevance: In this exploratory analysis of the FOURIER trial, higher Lp(a) levels, but not Lp(a)-corrected LDL-C levels, were associated with a higher risk of subsequent AS events, including aortic valve replacement. Long-term therapy with evolocumab may reduce AS events, and this raises the possibility that specific pharmacologic lipid-lowering therapy could offer a means to prevent or slow the progression of AS. These exploratory findings merit further investigation with a dedicated randomized clinical trial. Trial Registration: ClinicalTrials.gov Identifier: NCT01764633.

Background: Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes mellitus and its related comorbidities, including hypertension, obesity, and heart failure (HF). SGLT2 (sodium-glucose cotransporter 2) inhibitors have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling, and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes mellitus. We therefore investigated whether SGLT2 inhibitors could also reduce the risk of AF/AFL. Methods: DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) studied the efficacy and safety of the SGLT2 inhibitor dapagliflozin versus placebo in 17 160 patients with type 2 diabetes mellitus and either multiple risk factors for atherosclerotic cardiovascular disease (n=10 186) or known atherosclerotic cardiovascular disease (n=6974). We explored the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using MedDRA preferred terms (“atrial fibrillation,” “atrial flutter”). Results: Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events; 7.8 versus 9.6 events per 1000 patient-years; hazard ratio [HR], 0.81 [95% CI, 0.68–0.95]; P =0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (previous AF/AFL: HR, 0.79 [95% CI, 0.58–1.09]; no AF/AFL: HR, 0.81 [95% CI, 0.67–0.98]; P for interaction 0.89). Similarly, presence of atherosclerotic cardiovascular disease (HR, 0.83 [95% CI, 0.66–1.04]) versus multiple risk factors (HR, 0.78 [95% CI, 0.62–0.99]; P for interaction 0.72) or a history of HF (HF: HR, 0.78 [95% CI, 0.55–1.11]; No HF: HR, 0.81 [95% CI, 0.68–0.97]; P for interaction 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, glycated hemoglobin A 1c , body mass index, blood pressure, or estimated glomerular filtration rate (all P for interaction >0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio, 0.77 [95% CI, 0.64–0.92]; P =0.005). Conclusions: Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with type 2 diabetes mellitus. This effect was consistent regardless of the patient’s previous history of AF, atherosclerotic cardiovascular disease, or HF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01730534.

Background The impact on outcomes of oral anticoagulants in pts at extremes of body weight have not been well-characterized. Aim To analyse the outcomes of pts with atrial fibrillation (AF) enrolled in ENGAGE AF-TMI 48 randomized to warfarin (W) targeting INR 2.0–3.0, higher (HDE) or lower dose regimens of edoxaban (LDE), focusing on subgroups of patients at the extremes of weight. Methods and results Among 21105 pts enrolled in the trial we identified 3 subgroups: 1082 with low body weight (LBW) (95th percentile, >120 kg). Baseline characteristics differed markedly (LWB pts were older and more likely Asian, women, with prior TIA/stroke, renal dysfunction) resulting in a trend towards higher rates of stroke/systemic embolism (SSE: 6.5% vs 4.7% in MBW vs 1.6% in HBW) and major bleeding (MB: 9.3% vs 7.7% in MBW vs 6.5% in HBW) in the warfarin arm. The risks of SSE (Pint = 0.52) were similar between W and HDE regardless of body weight, while the relative reduction in MB was greatest in LBW patients (HR reduction45%, 23%, 1% across weight groups; Pint = 0.35) (Figure). Net clinical outcomes (SEE/major bleeding/death) tended to be most favourable for LBW pts (HR 0.67 [0.50–0.90]; Pint 0.084) (Figure). Main outcomes during follow up Conclusions In ENGAGE AF-TIMI 48 the profile of AF pts with LBW markedly differed suggesting a more fragile clinical status. Use of dose-adjusted edoxaban, as compared to W, was associated with similar efficacy regardless of weight, while bleeding and net outcomes were most favourable in LBW pts.

Summary Background The proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab reduced LDL cholesterol and cardiovascular events in the FOURIER trial. In this prespecified analysis of FOURIER, we investigated the efficacy and safety of evolocumab by diabetes status and the effect of evolocumab on glycaemia and risk of developing diabetes. Methods FOURIER was a randomised trial of evolocumab (140 mg every 2 weeks or 420 mg once per month) versus placebo in 27 564 patients with atherosclerotic disease who were on statin therapy, followed up for a median of 2·2 years. In this prespecified analysis, we investigated the effect of evolocumab on cardiovascular events by diabetes status at baseline, defined on the basis of patient history, clinical events committee review of medical records, or baseline HbA 1c of 6·5% (48 mmol/mol) or greater or fasting plasma glucose (FPG) of 7·0 mmol/L or greater. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularisation. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, or stroke. We also assessed the effect of evolocumab on glycaemia, and on the risk of new-onset diabetes among patients without diabetes at baseline. HbA 1c was measured at baseline then every 24 weeks and FPG was measured at baseline, week 12, week 24, and every 24 weeks thereafter, and potential cases of new-onset diabetes were adjudicated centrally. In a post-hoc analysis, we also investigated the effects on glycaemia and diabetes risk in patients with prediabetes (HbA 1c 5·7–6·4% [39–46 mmol/mol] or FPG 5·6–6·9 mmol/L) at baseline. FOURIER is registered with ClinicalTrials.gov, number NCT01764633. Findings At study baseline, 11 031 patients (40%) had diabetes and 16 533 (60%) did not have diabetes (of whom 10 344 had prediabetes and 6189 had normoglycaemia). Evolocumab significantly reduced cardiovascular outcomes consistently in patients with and without diabetes at baseline. For the primary composite endpoint, the hazard ratios (HRs) were 0·83 (95% CI 0·75–0·93; p=0·0008) for patients with diabetes and 0·87 (0·79–0·96; p=0·0052) for patients without diabetes (p interaction =0·60). For the key secondary endpoint, the HRs were 0·82 (0·72–0·93; p=0·0021) for those with diabetes and 0·78 (0·69–0·89; p=0·0002) for those without diabetes (p interaction =0·65). Evolocumab did not increase the risk of new-onset diabetes in patients without diabetes at baseline (HR 1·05, 0·94–1·17), including in those with prediabetes (HR 1·00, 0·89–1·13). Levels of HbA 1c and FPG were similar between the evolocumab and placebo groups over time in patients with diabetes, prediabetes, or normoglycaemia. Among patients with diabetes at baseline, the proportions of patients with adverse events were 78·5% (4327 of 5513 patients) in the evolocumab group and 78·3% (4307 of 5502 patients) in the placebo group; among patients without diabetes at baseline, the proportions with adverse events were 76·8% (6337 of 8256 patients) in the evolocumab group and 76·8% (6337 of 8254 patients) in the placebo group. Interpretation PCSK9 inhibition with evolocumab significantly reduced cardiovascular risk in patients with and without diabetes. Evolocumab did not increase the risk of new-onset diabetes, nor did it worsen glycaemia. These data suggest evolocumab use in patients with atherosclerotic disease is efficacious and safe in patients with and without diabetes. Funding Amgen.

SummaryDiabetes increases cardiovascular risk and reduces pharmacodynamic response to some oral antiplatelet drugs. This study aimed to determine whether ticagrelor 60 mg twice daily (bid) provided potent and consistent platelet inhibition in patients with vs without diabetes in the PEGASUS-TIMI 54 platelet function substudy. Out of 180 patients studied, 58 patients were randomised to and had received at least four weeks of ticagrelor 60 mg bid, with 20 (34 %) having diabetes, 58 patients received ticagrelor 90 mg bid, with 12 (21 %) having diabetes, and 64 patients received placebo, with 18 (28 %) having diabetes. Blood was sampled pre- and 2 hours post-maintenance dose. In patients treated with ticagrelor 60 mg bid, on-treatment platelet reactivity to ADP, as determined by light transmission aggregometry (LTA), VerifyNow and VASP, was similar in patients with vs without diabetes (LTA post-dose, ADP 20 ?M: 29 ± 14 vs 34 ± 10 %, respectively; p = 0.19). A consistent inhibitory effect of ticagrelor 60 mg bid was observed pre- and post-dose regardless of diabetes status, even in insulin-treated patients. Patients with diabetes did not have an increased incidence of high platelet reactivity in either ticagrelor group. Platelet reactivity was similar in patients with diabetes treated with ticagrelor 60 mg vs 90 mg bid. Pharmacokinetics of ticagrelor were not affected by diabetes status. In conclusion, ticagrelor 60 mg bid is equally effective at reducing platelet reactivity in patients with and without diabetes, yielding a consistently high level of platelet inhibition regardless of diabetes status.

AIMS Klotho, an essential co-receptor for fibroblast growth factor (FGF)-23, has potentially beneficial inhibitory effects on the renin-angiotensin system. Limited data exist on the prognostic value of Klotho and FGF-23 levels in combination or their ability to predict benefit from angiotensin-converting enzyme (ACE) inhibition. METHODS AND RESULTS A total of 3555 patients with stable ischaemic heart disease and left ventricular ejection fraction > 40% enrolled in the PEACE trial of trandolapril vs. placebo had Klotho levels drawn at randomization. Patients were characterized by quartiles of Klotho and FGF-23 concentrations. Six-year Kaplan-Meier rates and adjusted risk were calculated in the placebo arm for the composite of cardiovascular (CV) death or hospitalization for heart failure and its components. Low [quartile (Q) 1-3] Klotho concentration was associated with an increased rate of CV death or hospitalization for heart failure as compared with Q4 (8.2% vs. 4.2%; P = 0.03). After multivariable adjustment for clinical variables and renal and CV biomarkers (estimated glomerular filtration rate, cystatin-C, urine albumin-to-creatinine ratio, FGF-23, high-sensitivity troponin T, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein), low Klotho concentration remained strongly associated with increased risk of CV death or hospitalization for heart failure [adjusted hazard ratio (HR) 2.62; 95% confidence interval (CI) 1.35-5.08; P

Importance Little is known about the heterogeneity in low-density lipoprotein cholesterol levels (LDL-C) lowering with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor medications. Objective To evaluate the interindividual variability in LDL-C reduction with the PCSK9 inhibitor drug evolocumab. Design, Setting, and Participants We examined the percentage change in LDL-C levels from baseline in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, a placebo-controlled randomized clinical trial of the PCSK9 inhibitor evolocumab in patients with stable atherosclerotic cardiovascular disease who were taking statin medications. Patients in either treatment arm who had high baseline LDL-C variability during screening and either did not receive the study drug, altered their background lipid-lowering therapy regimen, or had no LDL-C level sample in week 4 were excluded from the primary analysis. Analyses in the patients were stratified by treatment arm. Data was collected from 2013 to 2016, and data were analyzed from January 2018 to November 2018. Main Outcomes and Measures Interindividual variation in percent reduction in LDL-C with evolocumab. Results There were 27 564 individuals in the cohort; after exclusions for baseline variability (n = 3524) or alterations in background lipid therapy and other causes (n = 2272), 21 768 patients remained. At week 4, the median percent reduction in LDL-C levels from baseline was 66% (interquartile range, 54%-76%; median [interquartile range] baseline value, 90 [79-105] mg/dL; postchange value, 31 [21-44] mg/dL) with evolocumab. During the first year, a total of 10 325 of 10902 patients in the evolocumab group (94.7%) had a reduction 50% or greater in LDL-C levels, 10 669 of 10 902 (97.9%) had a reduction 30% or more, and 10 849 of 10 902 (99.5%) had any reduction in LDL-C levels. Fifty-three patients (0.5%) had no apparent reduction in LDL-C levels. In the placebo arm, the median LDL-C reduction was 4% (interquartile range, 6% increase to 13% reduction; baseline median [IQR] value, 90 [79-106] mg/dL; postchange value, 87 [74-103] mg/dL) at 4 weeks. Waterfall plots showed notable variability in the top and bottom 5% of patients for both evolocumab and placebo groups, with large changes in LDL-C levels in the placebo group (increases of ≥25%, 531 patients [4.9%]; decreases of ≥25%, 985 patients [9.1%]). At 4 weeks, the placebo-adjusted reductions in LDL-C levels with evolocumab were 50% or greater in 9839 of 10 866 patients (90.5%) and 30% or greater in 10 846 of 10 866 patients (99.8%). Results were consistent across clinically relevant subgroups. Conclusions and Relevance There appears to be a highly consistent robust reduction in LDL-C levels with evolocumab use. Trial Registration ClinicalTrials.gov identifier:NCT01764633

Background Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and with varying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance. Methods and Results MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized patients over a median follow‐up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type 2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronary intervention–related (Type 4a) and coronary artery bypass graft–related (Type 5) each accounted for P =0.0055). The benefit was consistent among the subtypes, including a 31% reduction in MIs with a peak troponin ≥100× upper limit of normal (hazard ratio 0.69, 95% confidence interval 0.53–0.92, P =0.0096) and a 40% reduction in ST‐segment elevation MI (hazard ratio 0.60, 95% confidence interval 0.46–0.78, P =0.0002). Conclusions In stable outpatients with prior MI, the majority of recurrent MIs are spontaneous and associated with a high biomarker elevation. Ticagrelor reduces the MI consistently among subtypes and sizes including large MIs and ST‐segment elevation MI. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT01225562.

Background The PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis In Myocardial Infarction 54) trial studied 2 doses of ticagrelor, 90 mg twice a day (bid) and 60 mg bid, for long-term prevention of ischemic events in patients with prior myocardial infarction. Both doses similarly reduced the rate of ischemic events versus placebo. The pharmacokinetics and pharmacodynamics of ticagrelor 60 mg bid have not been studied. Objectives In this study, the authors sought to study the pharmacokinetics and pharmacodynamics for ticagrelor 60 mg compared with 90 mg bid. Methods A total of 180 patients who received >4 weeks of study medication had blood sampling in the morning pre-maintenance dose and again 2 h post-dose. All patients received aspirin. Plasma levels of ticagrelor and its active metabolite AR-C124910XX were determined. P2Y12 inhibition was assessed by the VerifyNow P2Y12 assay (Accumetrics, Inc., San Diego, California) (P2Y12 reaction units [PRU]), light transmittance aggregometry (adenosine diphosphate 5 and 20 μmol/l and arachidonic acid), and vasodilator-stimulated phosphoprotein phosphorylation assays. VerifyNow Aspirin assays and serum thromboxane B2 measurements were performed. Results Mean pre- and post-dose plasma levels of ticagrelor were 35% and 38% lower, respectively, with 60 mg versus 90 mg. Both doses achieved high levels of platelet inhibition pre- and post-dose, with numerically slightly more variability with 60 mg: mean (SD) pre-dose PRU values were 59 ± 63 and 47 ± 43 for ticagrelor 60 and 90 mg, respectively (p = 0.34). High platelet reactivity, determined as PRU >208, was rare with the 60-mg pre-dose and was absent post-dose. Platelet reactivity pre- and post-dose, as measured by light transmittance aggregometry or vasodilator-stimulated phosphoprotein assays, was numerically but not significantly lower with 90 mg than with 60 mg. Aspirin response was not affected by either dose. Conclusions Ticagrelor 60 mg bid achieved high levels of peak and trough platelet inhibition in nearly all patients, similar to that with 90 mg bid, helping to explain the efficacy of the lower ticagrelor dose in PEGASUS-TIMI 54.

IMPORTANCE: The PCSK9 inhibitor evolocumab reduced major vascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, yet the types and sizes of myocardial outcomes in FOURIER have not been previously explored. OBJECTIVE: To assess the types and sizes of myocardial infarction (MI) and the effect of evolocumab on MI by subtype. DESIGN, SETTING, AND PARTICIPANTS: A prespecified analysis of a multicenter double-blind randomized clinical trial. Patients were randomized to evolocumab or placebo and followed up for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Clinical end points were evaluated by the Thrombolysis in Myocardial Infarction clinical events committee. Rates presented are 3-year Kaplan-Meier estimates. Data were collected from 2013 to 2016 and analyzed from June 2017 to December 2019. MAIN OUTCOMES AND MEASURES: Myocardial infarction was defined based on the third universal MI definition, and further classified according to MI type (universal MI subclass, ST-segment elevation myocardial infarction [STEMI] vs non–STEMI) and by MI size (determined by peak troponin level). RESULTS: A total of 27 564 patients were randomized, with a mean (SD) age of 62.5 (9.0) years, and 20 795 (75%) were male. Of these, 1107 patients experienced a total of 1288 MIs. Most MIs (68%) were atherothrombotic (type 1), with 15% from myocardial oxygen supply-demand mismatch (type 2) and 15% percutaneous coronary intervention–related (type 4). Sudden death (type 3) and coronary artery bypass grafting–related (type 5) accounted for a total of 21 MIs (

Despite recent advances in treatment of severe aortic valve stenosis (AS), AS remains a common, life-threatening condition with no proven preventive therapy. Low-density lipoprotein cholesterol (LDL-C) and, particularly, lipoprotein(a) (Lp[a]) have been implicated in the pathobiology of AS. The

In DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58), dapagliflozin reduced the risk of the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF) and of adverse renal outcomes in a broad range of patients with type 2

Aims To investigate the relationship between body mass index (BMI) and outcomes in patients with atrial fibrillation (AF). Methods and results In the ENGAGE AF-TIMI 48 trial, patients with AF were randomized to warfarin (international normalized ratio 2.0–3.0) or edoxaban. The cohort (N = 21 028) included patients across BMI categories (kg/m2): underweight (18.5 kg/m2, while time in therapeutic range for warfarin improved significantly as BMI increased (P Conclusion An increased BMI was independently associated with a lower risk of stroke/SEE, better survival, but increased risk of bleeding. The efficacy and safety profiles of edoxaban were similar across BMI categories ranging from 18.5 to >40.

IMPORTANCE: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with myocardial fibrosis and renin-angiotensin system upregulation, potentially providing prognostic information distinct from standard cardiovascular (CV) biomarkers. OBJECTIVE: To evaluate the association of FGF-23 with recurrent CV events in patients after an acute coronary syndrome (ACS). DESIGN, SETTING, AND PARTICIPANTS: C-terminal FGF-23 was measured in plasma samples using an established enzyme-linked immunosorbent assay system for 4947 patients within 30 days of ACS (median, 14 days) and with 1 additional CV risk factor in the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial of the lipoprotein-associated phospholipase A(2) inhibitor darapladib vs placebo performed from December 1, 2009, to April 24, 2014 (median follow-up, 2.5 years). Analyses were adjusted for clinical risk factors, renal function, and established cardiorenal biomarkers. This secondary analysis was performed from September 25, 2014, to October 1, 2017. EXPOSURE: The FGF-23 concentration at baseline. MAIN OUTCOMES AND MEASURES: The primary end point for this post hoc analysis was the composite of CV death or hospitalization for heart failure. RESULTS: In this study, baseline FGF-23 concentrations were available for 4947 patients (median age, 64.0 years; interquartile range, 59.0-71.0 years; 1276 [25.8%] female). Patients with higher FGF-23 concentrations were older and more likely female, with a greater proportion of hypertension, diabetes, and previous myocardial infarction. After multivariable adjustment for baseline clinical characteristics and established biomarkers (high-sensitivity troponin I, brain-type natriuretic peptide, and high-sensitivity C-reactive protein), FGF-23 concentration in the top quartile was independently associated with an increased risk of CV death or heart failure hospitalization (adjusted hazard ratio [HR], 2.35; 95% CI, 1.82-3.02; P

Background: The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab. Methods: The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (≥40% stenosis in ≥2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared. Results: A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had ≥2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22–1.53), 1.78 (95% CI, 1.59–1.99), and 1.39 (95% CI, 1.24–1.56; all P Conclusions: Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Background: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. Methods: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of Results: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66–0.94; P =0.0098) and without PAD (HR 0.86; 95% CI, 0.80–0.93; P =0.0003; P interaction =0.40). For the key secondary end point, the HRs were 0.73 (0.59–0.91; P =0.0040) for those with PAD and 0.81 (0.73–0.90; P P interaction =0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38–0.88; P =0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events ( P =0.026 for the beta coefficient) that extended down to Conclusions: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.

Background— Despite the known association of diabetes mellitus with cardiovascular events, there are few contemporary data on the long-term outcomes from international cohorts of patients with diabetes mellitus. We sought to describe cardiovascular outcomes at 4 years and to identify predictors of these events in patients with diabetes mellitus. Methods and Results— The Reduction of Atherothrombosis for Continued Health (REACH) registry is an international registry of patients at high risk of atherothrombosis or established atherothrombosis. Four-year event rates in patients with diabetes mellitus were determined with the corrected group prognosis method. Of the 45 227 patients in the REACH registry who had follow-up at 4 years, 43.6% (n=19 699) had diabetes mellitus at baseline. The overall risk and hazard ratio (HR) of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were greater in patients with diabetes compared with patients without diabetes (16.5% versus 13.1%; adjusted HR, 1.27; 95% confidence interval [CI] 1.19–1.35). There was also an increase in both cardiovascular death (8.9% versus 6.0%; adjusted HR, 1.38; 95% CI, 1.26–1.52) and overall death (14.3% versus 9.9%; adjusted HR, 1.40; 95% CI, 1.30–1.51). Diabetes mellitus was associated with a 33% greater risk of hospitalization for heart failure (9.4% versus 5.9%; adjusted odds ratio, 1.33; 95% CI, 1.18–1.50). In patients with diabetes mellitus, heart failure at baseline was independently associated with cardiovascular death (adjusted HR, 2.45; 95% CI, 2.17–2.77; P P Conclusions— Diabetes mellitus substantially increases the risk of death, ischemic events, and heart failure. Patients with both diabetes mellitus and heart failure are at particularly elevated risk of cardiovascular death, highlighting the need for additional therapies in this high-risk population.

Summary Background New oral anticoagulants for stroke prevention in atrial fibrillation were developed to be given in fixed doses without the need for the routine monitoring that has hindered usage and acceptance of vitamin K antagonists. A concern has emerged, however, that measurement of drug concentration or anticoagulant activity might be needed to prevent excess drug concentrations, which significantly increase bleeding risk. In the ENGAGE AF-TIMI 48 trial, higher-dose and lower-dose edoxaban were compared with warfarin in patients with atrial fibrillation. Each regimen incorporated a 50% dose reduction in patients with clinical features known to increase edoxaban drug exposure. We aim to assess whether adjustment of edoxaban dose in this trial prevented excess drug concentration and the risk of bleeding events. Methods We analysed data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. We correlated edoxaban dose, plasma concentration, and anti-Factor Xa (FXa) activity and compared efficacy and safety outcomes with warfarin stratified by dose reduction status. Patients with atrial fibrillation and at moderate to high risk of stroke were randomly assigned in a 1:1:1 ratio to receive warfarin, dose adjusted to an international normalised ratio of 2·0–3·0, higher-dose edoxaban (60 mg once daily), or lower-dose edoxaban (30 mg once daily). Randomisation was done with use of a central, 24 h, interactive, computerised response system. International normalised ratio was measured using an encrypted point-of-care device. To maintain masking, sham international normalised ratio values were generated for patients assigned to edoxaban. Edoxaban (or placebo-edoxaban in warfarin group) doses were halved at randomisation or during the trial if patients had creatinine clearance 30–50 mL/min, bodyweight 60 kg or less, or concomitant medication with potent P-glycoprotein interaction. Efficacy outcomes included the primary endpoint of all-cause stroke or systemic embolism, ischaemic stroke, and all-cause mortality. Safety outcomes included the primary safety endpoint of major bleeding, fatal bleeding, intracranial haemorrhage, and gastrointestinal bleeding. This trial is registered with ClinicalTrials.gov, number NCT00781391. Findings Between Nov 19, 2008 and Nov 22, 2010, 21 105 patients were recruited. Patients who met clinical criteria for dose reduction at randomisation (n=5356) had higher rates of stroke, bleeding, and death compared with those who did not have a dose reduction (n=15 749). Edoxaban dose ranged from 15 mg to 60 mg, resulting in a two-fold to three fold gradient of mean trough drug exposure (16·0–48·5 ng/mL in 6780 patients with data available) and mean trough anti-FXa activity (0·35–0·85 IU/mL in 2865 patients). Dose reduction decreased mean exposure by 29% (from 48·5 ng/mL [SD 45·8] to 34·6 ng/mL [30·9]) and 35% (from 24·5 ng/mL [22·7] to 16·0 ng/mL [14·5]) and mean anti-FXa activity by 25% (from 0·85 IU/mL [0·76] to 0·64 IU/mL [0·54]) and 20% (from 0·44 IU/mL [0·37] to 0·35 IU/mL [0·28]) in the higher-dose and lower-dose regimens, respectively. Despite the lower anti-FXa activity, dose reduction preserved the efficacy of edoxaban compared with warfarin (stroke or systemic embolic event: higher dose p interaction =0·85, lower dose p interaction =0·99) and provided even greater safety (major bleeding: higher dose p interaction 0·02, lower dose p interaction =0·002). Interpretation These findings validate the strategy that tailoring of the dose of edoxaban on the basis of clinical factors alone achieves the dual goal of preventing excess drug concentrations and helps to optimise an individual patient's risk of ischaemic and bleeding events and show that the therapeutic window for edoxaban is narrower for major bleeding than thromboembolism. Funding Daiichi-Sankyo Pharma Development.

The aim of this study was to elucidate protein-protein interactions between tegument proteins of herpes simplex virus type 1 (HSV-1). To do so, we have cloned and expressed in the LexA yeast (Saccharomyces cerevisiae) two-hybrid system, 13 of the 21 currently known tegument proteins of HSV-1. These included the tegument proteins essential for replication in cell lines, UL17, UL36, UL37, UL48, and UL49, and the nonessential tegument proteins US11, UL11, UL14, UL16, UL21, UL41, UL46, and UL47. A total of 104 combinations were screened in the yeast two-hybrid assay, with 9 interactions identified. These included: UL11-UL16, UL36-UL37, UL36-UL48, UL46-UL48, UL47-UL48, and UL48-UL49. The remaining interactions consisted of self-associations that were observed for US11, UL37, and UL49. The interactions UL36-UL37, UL36-UL48, UL37-UL37, UL46-UL48, and UL47-UL48 have not been previously reported for HSV-1. The interaction of UL46-UL48 was verified using an in vitro pull-down assay. The interactions of UL36-UL37 and UL37-UL37 were verified with a coimmunoprecipitation assay. Knowledge of HSV-1 tegument protein-protein interactions will provide insights into the pathways of tegument assembly, and the identified interactions are potential targets for new antiviral drugs.

Lorcaserin, a serotonin 2C receptor agonist, recently demonstrated sustained weight loss without an increased risk of cardiovascular (CV) events or valvulopathy in obese or overweight pts at high CV risk. Here we evaluate the persistence of valvulopathy measures. The CAMELLIA-TIMI 61 trial

Background: Edoxaban, an oral factor Xa inhibitor with 50% renal clearance, was noninferior to well-managed warfarin for stroke or systemic embolism (S/SE) prevention and reduced bleeding in patients with atrial fibrillation. We evaluated the efficacy and safety of edoxaban versus warfarin across the range of baseline creatinine clearance (CrCl) in the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) with a focus on the higher-dose edoxaban regimen (HDER) and the upper range of CrCl. Methods: A total of 14 071 patients with atrial fibrillation at moderate to high risk for stroke were randomized to warfarin or HDER (60 mg daily or a 50% dose reduction to 30 mg daily for CrCl 30–50 mL/min, body weight of ≤60 kg, or use of a potent phosphorylated glycoprotein inhibitor). CrCl Results: The relative risk of S/SE with HDER versus warfarin in patients with CrCl >50 mL/min (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.72–1.04) was similar to that in patients with CrCl ≤50 mL/min (HR, 0.87; 95% CI, 0.65–1.18; P for interaction=0.94). Several exploratory analyses suggested lower relative efficacy for the prevention of S/SE with HDER compared with warfarin at higher levels of CrCl (CrCl ≤50 mL/min: HR, 0.87; 95% CI, 0.65–1.18; CrCl >50–95 mL/min: HR, 0.78; 95% CI, 0.64–0.96; CrCl >95 mL/min: HR, 1.36; 95% CI, 0.88–2.10; P for interaction=0.08). Bleeding rates were lower at all levels of CrCl with HDER ( P for interaction=0.11). Because of the preserved effect on bleeding, the net clinical outcome was more favorable with HDER across the range of CrCl ( P for interaction=0.73). Similar findings were observed in the sensitivity analysis using the CKD-EPI formula. Conclusions: Although there was an apparent decrease in relative efficacy to prevent arterial thromboembolism in the upper range of CrCl, the safety and net clinical benefit of HDER compared with warfarin are consistent across the range of renal function. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Peripheral artery disease (PAD) is associated with heightened ischemic and bleeding risk in patients with prior myocardial infarction (MI).This study evaluated the efficacy and safety of ticagrelor on major cardiovascular (CV) events and major adverse limb events in patients with PAD and a prior MI.PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54) randomized 21,162 patients with prior MI (1 to 3 years) to ticagrelor 90 mg twice daily, ticagrelor 60 mg twice daily, or placebo, all on a background of low-dose aspirin. History of PAD was obtained at baseline. Occurrences of major adverse cardiovascular events (MACE) (defined as CV death, MI, or stroke) and major adverse limb events (MALE) (defined as acute limb ischemia or peripheral revascularization for ischemia) were recorded in follow-up.A total of 1,143 patients (5%) had known PAD. In the placebo arm, those with PAD (n = 404) had higher rates of MACE at 3 years than those without (n = 6,663; 19.3% vs. 8.4%; p 0.001), which persisted after adjusting for baseline differences (adjusted hazard ratio: 1.60; 95% confidence interval: 1.20 to 2.13; p = 0.0013), and higher rates of acute limb ischemia (1.0% vs. 0.1%) and peripheral revascularization procedures (9.15% vs. 0.46%). Whereas the relative risk reduction in MACE with ticagrelor was consistent, regardless of PAD, patients with PAD had a greater absolute risk reduction of 4.1% (number needed to treat: 25) due to their higher absolute risk. The absolute excess of TIMI major bleeding was 0.12% (number needed to harm: 834). The 60-mg dose had particularly favorable outcomes for CV and all-cause mortality. Ticagrelor (pooled doses) reduced the risk of MALE (hazard ratio: 0.65; 95% confidence interval: 0.44 to 0.95; p = 0.026).Among stable patients with prior MI, those with concomitant PAD have heightened ischemic risk. In these patients, ticagrelor reduced MACE, with a large absolute risk reduction, and MALE. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS-TIMI 54]; NCT01225562).

Background. Strength training (ST) is an important health behavior for aging women; it helps maintain strength and function and reduces risk for chronic diseases. This study assessed change in physical fitness following participation in a ST program implemented and evaluated by community leaders. Method. The StrongWomen Program is a nationally disseminated, research-based, community ST program active in 40 states. The Senior Fitness Test is used to assess upper and lower body strength, upper and lower body flexibility, aerobic fitness, and agility; data are collected prior to and following program participation. Results. For these analyses, five states provided deidentified data for 367 female participants, mean age 63 (±11) years. Attendance in approximately 10 weeks of twice-weekly classes was 69.4%. Paired t tests were used to analyze pre–post change. Significant improvements were observed ( p < .01) in all Senior Fitness Test measures. Data are stratified by age-group and compared with published, age-based norms. Conclusions. This study demonstrates that it is feasible for community leaders to conduct pre–post physical fitness evaluations with participants and that participants experienced improvements across several important domains of physical fitness.

Objective: Ticagrelor reduced the risk of CV death, MI or stroke (MACE) in stable patients with prior MI in PEGASUS-TIMI 54. We investigated the efficacy of ticagrelor in reducing different subtypes and sizes of MI. Methods: MIs were adjudicated by the blinded TIMI Clinical Events Committee with definitions consistent with the Third Universal Definition of MI. Each MI was categorized by subtype and fold elevation of peak troponin (Tn) over the upper limit of normal (ULN). Results for both doses of ticagrelor were pooled in comparison to placebo. Results: A total of 1042 MIs occurred in the 21,162 randomized patients over a median follow up of 33 months. The majority (76%) of the MIs were spontaneous (Type 1), with demand MI (Type 2) and PCI-related (Type 4) accounting for 13% and 10% respectively (Figure Left); sudden death MI (Type 3) and CABG-related MI (Type 5) each accounted for Conclusion: In stable outpatients with a history of MI the majority of recurrent MI events are spontaneous and associated with a high biomarker elevation. Ticagrelor significantly reduces the incidence of MI consistently among different subtypes and biomarker sizes, with the greatest absolute reduction in spontaneous MIs, large MIs, and STEMI.

Background: Long-term dual antiplatelet therapy with aspirin plus ticagrelor, a direct-acting reversibly-binding P2Y12 receptor antagonist, was recently shown in the PEGASUS-TIMI 54 trial (NCT01225562) to be superior to aspirin alone in preventing major adverse cardiovascular events in patients with a prior MI. Whereas prior analyses focused on time to first event, we hypothesized that total events including those beyond the first event would also be reduced with ticagrelor. Methods: We evaluated all primary endpoint (PEP) events (CV death, MI, stroke) during a median 33 month follow-up in patients randomized to ticagrelor (60 mg or 90 mg) vs placebo in the PEGASUS-TIMI 54 trial. Negative binomial regression & other sensitivity models were used. Results: Among 21,162 patients, there were 1,830 PEP events (85% first events, n=1,558 and 15% subsequent events, n=272). Of the total PEP events, 1,041 were MIs (56.9%), 338 were strokes (18.5%), and 451 were CV deaths (24.6%). In patients with a PEP event, 86.3% had 1 event, 11.0% had 2 events, and 2.8% had 3 or more events (maximum 6). Total PEP events were reduced 17% with ticagrelor 60 mg vs placebo (incidence-rate ratio [IRR] 0.83, 95% CI 0.72-0.95, p=0.006) and 17% with ticagrelor 90 mg vs placebo (IRR 0.83, 95% CI 0.73-0.95, p=0.007). A Wei-Lin-Weissfeld time-to-event model showed similar reductions. In terms of irreversible harm events, for every 1000 patients treated for 3 years, ticagrelor would prevent 18 primary endpoint events, including (depending on the dose) 5 CV deaths, 8-11 MIs, and 3-4 strokes, and cause only 0 or 1 excess fatal bleeds or ICH (Figure). Conclusions: Patients with prior MI remain at high risk for recurrent vascular events. The addition of ticagrelor to aspirin significantly reduces the burden of total vascular events.

Purpose: The purpose of this study was to assess anthropometry, physical fitness, and serum glucose and lipid levels in college students and to determine the relative impact of fitness level compared with body composition on blood chemistries related to metabolic syndrome. Methods: College students (n = 564; means +/- SD: age = 19.4 +/- 1.1 yr) participating in the Tufts University Longitudinal Health Study between 2000 and 2007 were examined for the relative impact of fitness level compared with body composition on serum glucose, triglycerides, HDL, LDL, and total cholesterol controlling for age and ethnicity. Results: In this college population, 16.2% were overweight or obese, whereas 60% had body fat percentages above desirable levels. Higher percent body fat was associated with increased cholesterol and LDL in both men and women, and with increased triglyceride and decreased HDL in women (P < 0.05). Increased fitness was associated with increased HDL and decreased triglycerides in women and decreased serum glucose in men (P < 0.05). When dichotomized into "fit" and "unfit" groups, students who were fit demonstrated more optimal levels of serum glucose and lipids independent of percent body fat (P < 0.05). Conclusions: Several metabolic risk factors are already evident in a young college population, and both increased body fatness and decreased physical fitness were associated with metabolic risk. Being physically fit can confer an added benefit to a healthy body composition. It is therefore important to encourage both healthy weights and fitness in late adolescence as each play important and independent roles in biochemical parameters associated with increased chronic disease risk

Questions have been raised about interpatient variability in response to PCSK9 inhibitors. FOURIER was a randomized, pbo-controlled trial of the PCSK9i evolocumab, a fully human mAb, in pts w/ ASCVD on a statin. We examined % change in LDL-C at 4 wks. Pts in either arm who did not receive study

Objectives. We tested a community-based intervention designed to reduce cardiovascular disease risk in sedentary midlife and older women who were overweight or obese. Methods. In a randomized controlled trial conducted in 8 counties in Arkansas and Kansas, counties were assigned to the intervention (a 12-week twice-weekly heart health program) group or to the delayed-intervention control group. Ten to fifteen women were selected from each site, and participants' weight, waist circumference, diet, physical activity, and self-efficacy were measured before and after the intervention. Data were analyzed with multiple regressions. Results. Compared with the control group, participants in the intervention group had a significant decrease in body weight (−2.1 kg; 95% confidence interval [CI] = −3.2, −1.0), waist circumference (–2.3 in; 95% CI = −4.2, −0.5), and energy intake (–390 kcal/day; 95% CI = −598, −183); an increase in activity (+1637 steps/day; 95% CI = 712, 2562); and an increase in self-efficacy for dietary and physical activity behaviors. Conclusions. Our results suggest that a community-based program can improve self-efficacy, increase physical activity, and decrease energy intake, resulting in decreased waist circumference and body weight among at-risk women.

Aims We evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of ticagrelor in stable patients with prior myocardial infarction (MI). Methods and results Patients with a history of MI 1–3 years prior from PEGASUS-TIMI 54 were stratified based on estimated glomerular filtration rate (eGFR), with

Objective The objective of this study was to test the hypothesis that community-based environmental change intervention prevents undesirable weight gain in children. Method The method used in this study was a two-year, non-randomized, controlled trial (2003–2005) using community-based participatory methodology in three diverse cities in Massachusetts: one intervention and two socio-demographically-matched control communities (pooled for analysis). Children (n = 1028), with a mean age = 7.61 + 1.04 years participated. Interventions were made to improve energy balance by increasing physical activity options and availability of healthful foods (Year 1). To firmly secure sustainability, the study team supported policies and shifted intervention work to community members (Year 2). Results Change in body mass index z-score (BMIz) was assessed by multiple regression, accounting for clustering within communities and adjusting for baseline covariates. Sex-specific overweight/obesity prevalence, incidence and remission were assessed. Over the two-year period, BMIz of children in the intervention community decreased by − 0.06 [p = 0.005, 95% confidence interval: − 0.08 to − 0.04] compared to controls. Prevalence of overweight/obesity decreased in males (OR = 0.61, p = 0.01) and females (OR = 0.78, p = 0.01) and remission increased in males (OR 3.18, p = 0.03) and females (OR 1.93, p = 0.03) in intervention compared to controls. Conclusion Results demonstrate promise for preventing childhood obesity using a sustainable multi-level community-based model and reinforce the need for wide-reaching environmental and policy interventions.

IMPORTANCE: In the PEGASUS-TIMI 54 trial, treatment with ticagrelor reduced the incidence of cardiovascular death, myocardial infarction, or stroke by 15% to 16% among stable patients compared with placebo. However, more patients prematurely discontinued treatment with ticagrelor than with placebo. OBJECTIVE: To investigate the reasons and timing of discontinuation of treatment with ticagrelor among stable patients prior myocardial infarction. DESIGN, SETTING, AND PARTICIPANTS: In the PEGASUS-TIMI 54 trial, 21 162 stable outpatients with prior myocardial infarction were randomly assigned to 90 mg of ticagrelor twice daily, 60 mg of ticagrelor twice daily, or placebo, with all of the patients receiving a low dose of aspirin. These participants were followed up for a median of 33 months (study start date: October 2010; completion date: December 2014). Discontinuation of treatment was evaluated by treatment arm, cause, and timing. This analysis was initiated in May 2015. MAIN OUTCOME AND MEASURE: Discontinuation of treatment. RESULTS: Over 33 months, 32%, 29%, and 21% of patients receiving 90 mg of ticagrelor, 60 mg of ticagrelor, and placebo, respectively, discontinued treatment (P

Importance p38 Mitogen-activated protein kinase (MAPK)–stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non–ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. Objective To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. Design, Setting, and Patients LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22 000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. Interventions Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. Main Outcomes and Measures The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. Results In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. Conclusions and Relevance Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population. Trial Registration clinicaltrials.gov Identifier:NCT02145468

Peripheral artery disease (PAD) has been associated with heightened ischemic and bleeding risk. In PEGASUS-TIMI 54, a contemporary trial of pts with prior MI, we evaluated ischemic and bleeding risk by concomitant PAD and whether the efficacy and safety of ticagrelor was modified by PAD. PEGASUS

Provision of fortified juices may provide a convenient method to maintain and increase blood fat-soluble vitamins.To determine whether children consuming orange juice fortified with calcium and combinations of vitamins D, E, and A could increase serum 25-hydroxyvitamin D [25(OH)D], α-tocopherol, and retinol levels.A 12-week randomized, double-blind, controlled trial.One hundred eighty participants (aged 8.04±1.42 years) were recruited at Tufts (n=70) and Boston University (n=110) during 2005-2006. Of those recruited, 176 children were randomized into three groups: CaD (700 mg calcium+200 IU vitamin D), CaDEA (700 mg calcium+200 IU vitamin D+12 IU vitamin E+2,000 IU vitamin A as beta carotene), or Ca (700 mg calcium). Children consumed two 240-mL glasses of CaD, CaDEA, or Ca fortified orange juice daily for 12 weeks.Serum 25(OH)D, α-tocopherol, and retinol concentrations.Changes in 25(OH)D, α-tocopherol, retinol, and parathyroid hormone concentrations were examined. Covariates included sex, age, race/ethnicity, body mass index, and baseline 25(OH)D, α-tocopherol, retinol, or parathyroid hormone levels. Multivariate models and repeated measures analysis of variance tested for group differences with pre-post measures (n=141).Baseline 25(OH)D was 68.4±27.7 nmol/L (27.4±11.10 ng/mL) ), with 21.7% of participants having inadequate 25(OH)D (50 nmol/L [20.03 ng/mL]). The CaD group's 25(OH)D increase was greater than that of the Ca group (12.7 nmol/L [5.09 ng/mL], 95% CI 1.3 to 24.1; P=0.029). The CaDEA group's increase in α-tocopherol concentration was greater than that in the Ca or CaD groups (3.79 μmol/L [0.16 μg/mL], 95% CI 2.5 to 5.1 and 3.09 μmol/L [0.13 μg/mL], 95% CI -1.8 to 4.3), respectively (P0.0001). Retinol levels did not change, and body weight remained as expected for growth.Daily consumption of orange juice providing 200 IU vitamin D and 12 IU vitamin E increased 25(OH)D and α-tocopherol concentrations in young children within 12 weeks.

Background There are disproportionately higher rates of overweight and obesity in poor rural communities but studies exploring children’s health-related behaviors that may assist in designing effective interventions are limited. We examined the association between overweight and obesity prevalence of 401 ethnically/racially diverse, rural school-aged children and healthy-lifestyle behaviors: improving diet quality, obtaining adequate sleep, limiting screen-time viewing, and consulting a physician about a child’s weight. Methods A cross-sectional analysis was conducted on a sample of school-aged children (6–11 years) in rural regions of California, Kentucky, Mississippi, and South Carolina participating in CHANGE (Creating Healthy, Active, and Nurturing Growing-up Environments) Program, created by Save the Children, an independent organization that works with communities to improve overall child health, with the objective to reduce unhealthy weight gain in these school-aged children (grades 1–6) in rural America. After measuring children’s height and weight, we17 assessed overweight and obesity (BMI ≥ 85th percentile) associations with these behaviors: improving diet quality18 (≥ 2 servings of fruits and vegetables/day), reducing whole milk, sweetened beverage consumption/day; obtaining19 adequate night-time sleep on weekdays (≥ 10 hours/night); limiting screen-time (i.e., television, video, computer,20 videogame) viewing on weekdays (≤ 2 hours/day); and consulting a physician about weight. Analyses were adjusted 21 for state of residence, children's race/ethnicity, gender, age, and government assistance. Results Overweight or obesity prevalence was 37 percent in Mississippi and nearly 60 percent in Kentucky. Adjusting for covariates, obese children were twice as likely to eat ≥ 2 servings of vegetables per day (OR=2.0,95% CI 1.1-3.4), less likely to consume whole milk (OR=0.4,95% CI 0.2-0.70), Their parents are more likely to be told by their doctor that their child was obese (OR=108.0,95% CI 21.9-541.6), and less likely to report talking to their child about fruits and vegetables a lot/sometimes vs. not very much/never (OR=0.4, 95%CI 0.2-0.98) compared to the parents of healthy-weight children. Conclusions Rural children are not meeting recommendations to improve diet, reduce screen time and obtain adequate sleep. Although we expected obese children to be more likely to engage in unhealthy behaviors, we found the opposite to be true. It is possible that these groups of respondent parents were highly aware of their weight status and have been advised to change their children’s health behaviors. Perhaps given the opportunity to participate in an intervention study in combination with a physician recommendation could have resulted in actual behavior change.

Amid the childhood obesity epidemic, understanding how organized sports participation contributes to meeting physical activity recommendations in children is important. Anthropometrics were measured in children (n = 111; 68% female, 9.1 ± 0.8yr) before one 50-min soccer match. Time spent at different physical activity intensity levels was examined using Actigraph accelerometers. 49% of the match time was spent in sedentary activity (25.4 ± 5.7 min), while 33% of the match (16.9 ± 4.7 min) was spent in moderate-to-vigorous activity (MVPA; p < .001). 22.5% of the children were overweight/obese and spent more time in sedentary activity (+3.2 ± 1.2 min; p < .05) and less time in MVPA (-3.0 ± 1.0 min; p < .01) compared with the normal weight children. These data demonstrate that playing an organized sport such as soccer only meets a portion (~25%) of the 60 min of MVPA recommended and even less of this recommendation is met by overweight/obese children.

Background:Despite the recognized health benefits, few older women participate in strength-training exercises.Methods:The purpose of this study was to examine factors related to older women’s adherence to strength training after participation in the Strong Women Program, a nationally disseminated community program. Adherence was defined as ≥4 months of twice-weekly strength training. Surveys were sent to 970 program participants from 23 states and to participants’ corresponding program leaders. Five-hundred fifty-seven participants responded (57%).Results:Of respondents who completed surveys (527), 79% (415) adhered to strength training; adherers reported a mean of 14.1 ± 9.1 months of strength training. Logistic-regression analysis revealed that exercise adherence was positively associated with age (p = .001), higher lifetime physical activity levels (p = .045), better perceived health (p = .003), leader’s sports participation (p = .028), and leader’s prior experience leading programs (p = .006).Conclusion:These data lend insight to factors that may be related to exercise adherence among midlife and older women.