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Background Despite oral anticoagulation, patients with atrial fibrillation (AF) remain at risk of ischemic stroke and systemic embolism (SE) events. For patients whose residual risk is sufficiently high, additional therapies might be useful to mitigate stroke risk. Methods and Results Individual patient data from 5 landmark trials testing oral anticoagulation in AF were pooled in A Collaboration Between Multiple Institutions to Better Investigate Non‐Vitamin K Antagonist Oral Anticoagulant Use in AF (COMBINE AF). We calculated the rate of ischemic stroke/SE among oral anticoagulation–treated patients with a CHA2DS2‐VASc score≥2, across strata of CHA2DS2‐VASc score, stroke history, and AF type, as either paroxysmal or nonparoxysmal. We included 71 794 patients with AF (median age 72 years, interquartile range, 13 years, 61.3% male) randomized to a direct oral anticoagulant or vitamin K antagonist, and followed for a mean of 2.1 (±0.8) years. The median CHA2DS2‐VASc score was 4 (interquartile range, 3–5), 18.8% had a prior stroke, and 76.4% had nonparoxysmal AF. The overall rate of stroke/SE was 1.33%/y (95% CI, 1.27–1.39); 1.38%/y (95% CI, 1.31–1.45) for nonparoxysmal AF, and 1.15%/y (95% CI, 1.05–1.27) for paroxysmal AF. The rate of ischemic stroke/SE increased by a rate ratio of 1.36 (95% CI, 1.32–1.41) per 1‐point increase in CHA2DS2‐VASc, reaching 1.67%/y (95% CI, 1.59–1.75) ≥4 CHA2DS2‐VASc points. Patients with both nonparoxysmal AF and CHA2DS2‐VASc ≥4 had a stroke/SE rate of 1.75%/y (95% CI, 1.66–1.85). In patients with a prior stroke, the risk was 2.51%/y (95% CI, 2.33–2.71). Conclusions AF type, CHA2DS2‐VASc score, and stroke history can identify patients with AF, who despite oral anticoagulation have a residual stroke/SE risk of 1.5% to 2.5% per year. Evaluation of additional stroke/SE prevention strategies in high‐risk patients is warranted.

Abstract Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.

Abstract The management of perioperative acute myocardial infarction (AMI) following oncologic neurosurgery requires balancing competing risks of myocardial ischemia and postoperative bleeding. There are limited human data to establish the safest timing of antiplatelet or anticoagulation therapy following neurosurgical procedures. For patients with malignancy experiencing AMI in the acute postoperative period, staged percutaneous coronary intervention (PCI) with upfront coronary aspiration thrombectomy followed by delayed completion PCI may offer an opportunity for myocardial salvage while minimizing postoperative bleeding risks. CYP2C19 genotyping and platelet aggregation studies can help confirm adequate platelet inhibition once antiplatelet therapy is resumed.

Abstract Aims We aim to explore the relationship of heart failure (HF) and diabetes with cardiovascular (CV) death or hospitalization for HF (HHF) and to study the clinical utility of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) in an unselected patient population with atrial fibrillation (AF). Methods and results Patients with AF admitted to a tertiary academic center between January 2005 and July 2019 were identified through a search of electronic health records. We used Cox regression models adjusted for age, sex, estimated glomerular filtration rate, diabetes, HF, body mass index, prior myocardial infarction, coronary artery disease, hypertension, smoking, C‐reactive protein, and low‐density lipoprotein cholesterol. To select the most informative variables, we performed a least absolute shrinkage and selection operator Cox regression with 10‐fold cross‐validation. In total, 7412 patients (median age 70 years, 39.7% female) were included in this analysis and followed over a median of 4.5 years. Both diabetes [adjusted (Adj.) HR 1.87, 95% CI 1.55–2.25] and HF (Adj. HR 2.57, 95% CI 2.22–2.98) were significantly associated with CV death/HHF after multivariable adjustment. Compared with patients with diabetes, HF patients had a higher risk of HHF but a similar risk of CV and all‐cause death. NT‐proBNP showed good discriminatory performance (area under the curve 0.78, 95% CI 0.77–0.80) and the addition of NT‐proBNP to the covariates used for adjustment resulted in a significant area under the curve improvement (Δ = 0.04, P

Background Patients with acute coronary syndrome (ACS) are recognized by guidelines as remaining at high risk for adverse outcomes. Evidence from contemporary, representative ACS populations in a clinical practice setting is necessary to identify subgroups and strategies for improving patient outcomes. We aimed to describe event rates and risk factors in an ACS population over prolonged follow‐up for cardiovascular end points. Methods and Results We identified 239 234 patients in the Optum Research Database (57.2% men; mean [standard deviation] age, 69.2 [12.2] years) with evidence of an ACS hospitalization (index ACS) during January 1, 2005 through December 30, 2018. Subgroups were based on index ACS event (myocardial infarction/unstable angina and revascularization status) and the Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention. The 5‐year event rate for the primary end point representing nonfatal myocardial infarction, nonfatal ischemic stroke, and cardiovascular death was 33.4% (95% CI, 33.1%–33.7%; P

Background Patients who undergo percutaneous coronary intervention (PCI) are at increased risk for recurrent cardiovascular events despite aggressive medical therapy. Methods and Results This post hoc analysis focused on the subset of patients with prior PCI enrolled in REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, randomized, double‐blind, placebo‐controlled trial of icosapent ethyl versus placebo. Icosapent ethyl was added to statins in patients with low‐density lipoprotein cholesterol

Background: An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. Objectives: The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Methods: Within IMPROVE-IT, 17,708 patients post–acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy. Results: In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68). Conclusions: Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878)

Abstract For more than half a century, low-density lipoprotein cholesterol (LDL-C) has been recognized as a major risk factor for incident atherosclerotic cardiovascular disease. The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9) in 2003, which prevents LDL-C receptor recycling, identified a new target for drug intervention. Recently, two large-scale randomized clinical outcomes trials involving fully human anti-PCSK9 monoclonal antibodies tested the hypothesis that targeting this pathway would reduce cardiovascular events. Both the FOURIER (Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk) and ODYSSEY OUTCOMES trials met their primary efficacy endpoints, confirming findings reported earlier that major adverse cardiovascular events can be reduced by a further lowering of LDL-C beyond that achieved with statin therapy. In both trials, there were incremental reductions in LDL-C of > 50% from baseline, with no major safety concerns, over the trials’ median follow-up time (2.2 and 2.8 years, respectively). While there were differences in design, lipid management and overall results, key messages from both studies were similar. However, post-publication, additional questions have arisen, especially regarding drug effects over the long-term, including a potential mortality benefit.

Background Unlike patients with low ejection fraction after an acute coronary syndrome (ACS), little is known about the long‐term incidence and influence of cardiovascular events before sudden death among stabilized patients after ACS. Methods and Results A total of 18 144 patients stabilized within 10 days after ACS in IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) were studied. Cumulative incidence rates (IRs) and IRs per 100 patient‐years of sudden death were calculated. Using Cox proportional hazards, the association of ≥1 additional postrandomization cardiovascular events (myocardial infarction, stroke, and hospitalization for unstable angina or heart failure) with sudden death was examined. Early (≤1 year after ACS) and late sudden deaths (>1 year) were compared. Of 2446 total deaths, 402 (16%) were sudden. The median time to sudden death was 2.7 years, with 109 early and 293 late sudden deaths. The cumulative IR was 2.47% (95% CI, 2.23%–2.73%) at 7 years of follow‐up. The risk of sudden death following a postrandomization cardiovascular event (150/402 [37%] sudden deaths; median 1.4 years) was greater (IR/100 patient‐years, 1.45 [95% CI, 1.23–1.69]) than the risk with no postrandomization cardiovascular event (IR/100 patient‐years, 0.27 [95% CI, 0.24–0.30]). Postrandomization myocardial infarction (hazard ratio [HR], 3.64 [95% CI, 2.85–4.66]) and heart failure (HR, 4.55 [95% CI, 3.33–6.22]) significantly increased future risk of sudden death. Conclusions Patients stabilized within 10 days of an ACS remain at long‐term risk of sudden death with the greatest risk in those with an additional cardiovascular event. These results refine the long‐term risk and risk effectors of sudden death, which may help clinicians identify opportunities to improve care. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878.

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer’s disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p’s>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer’s disease.

Non-vitamin K antagonist oral anticoagulants (NOACs) have a half-life of around 12 h. We aimed to clarify if there was any effect modification by dosing (once- or twice-daily) regimens in Asian patients. Methods: Phase III randomized controlled trials of NOACs compared with warfarin in Asian patients with atrial fibrillation (AF) were identified and extracted from PubMed, CENTRAL, and CINAHL databases through November 2016. Outcomes were pooled by dosing regimens with the Mantel-Haenszel fixed-effects model. The risk ratio (RR) and 95% confidence interval (CI) were calculated. Effect differences between once- and twice-daily NOACs were assessed with Bucher indirect comparisons using common estimates, once heterogeneity was low, and with the Bayesian method. Results: From 6 trials, there was no effect modification by dosing regimens in the risk of stroke or systemic embolism across ethnicities (all interaction P > 0.05). Both dosing regimens were associated with a greater reduction in the risk of major bleeding in Asian patients (RR, 0.63 (95% CI, 0.47–0.85) and 0.57 (95% CI, 0.43–0.75), for once- and twice-daily NOACs, respectively). In Asian patients, risks of hemorrhagic stroke and intracranial hemorrhage were lower with once- (RR, 0.41 (95% CI, 0.21–0.80) and 0.29 (95% CI, 0.16–0.53)) and twice-daily NOACs (RR, 0.25 (95% CI, 0.12–0.51) and 0.38 (95% CI, 0.23–0.65)), compared with warfarin. There was no effect difference favoring any of NOAC regimens evaluated by Bucher and Bayesian methods. Conclusion: In Asian patients with AF, NOACs, regardless of dosing regimens, have a similar feature of preserved efficacy with improved safety compared with warfarin.

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.

Background Anticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse. Methods and Results The ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230–771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78–3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07–2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83–1.42). Relative outcomes with higher‐dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism (HR, 0.60 [95% CI, 0.31–1.15] for malignancy versus HR, 0.89 [95% CI, 0.76–1.05] for no malignancy; interaction P=0.25) and major bleeding (HR, 0.98 [95% CI, 0.69–1.40] for malignancy versus HR, 0.79 [95% CI, 0.69–1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher‐dose edoxaban versus warfarin in patients with malignancy (HR, 0.54; 95% CI, 0.31–0.93) compared with no malignancy (HR, 1.02; 95% CI, 0.88–1.18; interaction P=0.026). Conclusions In patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

BackgroundIMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) showed that adding the nonstatin ezetimibe to statin therapy further reduced cardiovascular events in patients after an acute coronary syndrome. In a prespecified analysis, we explore results stratified by sex. Methods and ResultsIn IMPROVE‐IT, patients with acute coronary syndrome and low‐density lipoprotein cholesterol of 50 to 125 mg/dL were randomized to placebo/simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg. They were followed up for a median of 6 years for the primary composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, coronary revascularization ≥30 days, and stroke. Among 18 144 patients in IMPROVE‐IT, 4416 (24%) were women. At 12 months, the addition of ezetimibe to simvastatin significantly reduced low‐density lipoprotein cholesterol from baseline compared with simvastatin monotherapy in men and women equally (absolute reduction, 16.7 mg/dL in men and 16.4 mg/dL in women). Women receiving ezetimibe/simvastatin had a 12% risk reduction over those receiving placebo/simvastatin for the primary composite end point (hazard ratio, 0.88; 95% confidence interval, 0.79–0.99) compared with a 5% reduction for men (hazard ratio, 0.95; 95% confidence interval, 0.90–1.01; P=0.26 for interaction). When the total number of primary events was considered, women had an 18% reduction with the addition of ezetimibe (relative risk, 95% confidence interval, 0.81; 0.71–0.94) and men had a 6% reduction (relative risk, 0.94; 95% confidence interval, 0.87–1.02; P=0.08 for interaction). The addition of ezetimibe did not increase the rates of safety events in either women or men. ConclusionsIMPROVE‐IT demonstrated that the benefit of adding ezetimibe to statin is present in both women and men, with a good safety profile supporting the use of intensive, combination, lipid‐lowering therapy to optimize cardiovascular outcomes. Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00202878.

BackgroundUnderstanding the relative risk of cardiovascular versus noncardiovascular death is important for designing clinical trials. These risks may differ depending on patient age, sex, and type of acute coronary syndrome (ACS). Methods and ResultsIMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) was a randomized controlled trial of simvastatin plus either ezetimibe or placebo following stabilized ACS. Cause of death was adjudicated by an independent committee. We compared the cumulative incidence of cardiovascular and noncardiovascular death for patients with unstable angina/non‐ST‐segment elevation myocardial infarction (UA/NSTEMI) and ST‐segment elevation myocardial infarction (STEMI), in those

BackgroundThe impact of different types of extracranial bleeding events on health‐related quality of life and health‐state utility among patients with atrial fibrillation is not well understood. Methods and ResultsThe ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) Trial compared edoxaban with warfarin with respect to the prevention of stroke or systemic embolism in atrial fibrillation. Data from the EuroQol‐5D (EQ‐5D‐3L) questionnaire, prospectively collected at 3‐month intervals for up to 48 months, were used to estimate the impact of different categories of bleeding events on health‐state utility over 12 months following the event. Longitudinal mixed‐effect models revealed that major gastrointestinal bleeds and major nongastrointestinal bleeds were associated with significant immediate decreases in utility scores (−0.029 [−0.044 to −0.014; P

BackgroundDigoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF). Methods and ResultsIn the ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation‐Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow‐up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10–2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P>0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36–2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all‐cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P

Background: Data from over 4 decades have reported a higher incidence of silent infarction among patients with diabetes mellitus (DM), but recent publications have shown conflicting results regarding the correlation between DM and presence of pain in patients with acute coronary syndromes (ACS). Objective: Our primary objective was to analyze the association between DM and precordial pain at hospital arrival. Secondary analyses evaluated the association between hyperglycemia and precordial pain at presentation, and the subgroup of patients presenting within 6 hours of symptom onset. Methods: We analyzed a prospectively designed registry of 3,544 patients with ACS admitted to a Coronary Care Unit of a tertiary hospital. We developed multivariable models to adjust for potential confounders. Results: Patients with precordial pain were less likely to have DM (30.3%) than those without pain (34.0%; unadjusted p = 0.029), but this difference was not significant after multivariable adjustment, for the global population (p = 0.84), and for subset of patients that presented within 6 hours from symptom onset (p = 0.51). In contrast, precordial pain was more likely among patients with hyperglycemia (41.2% vs 37.0% without hyperglycemia, p = 0.035) in the overall population and also among those who presented within 6 hours (41.6% vs. 32.3%, p = 0.001). Adjusted models showed an independent association between hyperglycemia and pain at presentation, especially among patients who presented within 6 hours (OR = 1.41, p = 0.008). Conclusion: In this non-selected ACS population, there was no correlation between DM and hospital presentation without precordial pain. Moreover, hyperglycemia correlated significantly with pain at presentation, especially in the population that arrived within 6 hours from symptom onset.

BackgroundRecent findings suggest that atrial fibrillation is associated with sudden cardiac death (SCD). We examined the incidence, characteristics, and factors associated with SCD in patients with atrial fibrillation. Methods and ResultsSCD was defined as witnessed death ≤60 minutes from the onset of new symptoms or unwitnessed death 1 to 24 hours after being observed alive, without another known cause of death. Predictors of SCD were examined using multivariate competing risks models. Over 2.8 years (median), 2349 patients died (40.5 per 1000 patient‐years), of which 1668 (71%) were cardiovascular deaths. SCD was the most common cause of cardiovascular death (n=749; median age 73 years; 70.6% male). Most SCD events occurred out of hospital (92.8%) and without prior symptoms (66.0%). Predictors of SCD included low ejection fraction, heart failure, and prior myocardial infarction (P

BackgroundElderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF‐TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age. Methods and ResultsTwenty‐one thousand one‐hundred and five patients enrolled in the ENGAGE AF‐TIMI 48 trial were stratified into 3 prespecified age groups:

BackgroundWe studied the concomitant use of single antiplatelet therapy (SAPT) on the efficacy and safety of the anti‐Xa agent edoxaban in patients with atrial fibrillation (AF). Methods and ResultsENGAGE AF‐TIMI 48 was a randomized trial that compared 2 dose regimens of edoxaban with warfarin. We studied both the approved higher‐dose edoxaban regimen (HDER; 60 mg daily reduced by one half in patients with anticipated increased drug exposure), as well as a lower‐dose edoxaban regimen (LDER; 30 mg daily, also reduced by one half in patients with anticipated increased drug regimen). SAPT (aspirin in 92.5%) was administered at the discretion of the treating physician. Cox proportional hazard regressions stratified by SAPT at 3 months with treatment as a covariate were performed. The 4912 patients who received SAPT were more frequently male, with histories of coronary artery disease and diabetes, and had higher CHADS2Vasc and HAS BLED scores than did the 14 997 patients not receiving SAPT. When compared to patients not receiving SAPT, those receiving SAPT had a higher incidence of major bleeding; (adjusted hazard ratio [HRadj]=1.46; 95% CI, 1.27–1.67, P

APOE encodes a cholesterol transporter, and the ε4 allele is associated with higher circulating cholesterol levels, ß-amyloid burden, and risk of Alzheimer's disease. Prior studies demonstrated no significant differences in objective or subjective cognitive function for patients receiving the PCSK9 inhibitor evolocumab vs. placebo added to statin therapy. There is some evidence that cholesterol-lowering medications may confer greater cognitive benefits in APOE ε4 carriers. Thus, the purpose of this study was to determine whether APOE genotype moderates the relationships between evolocumab use and cognitive function. APOE-genotyped patients (N = 13,481; 28% ε4 carriers) from FOURIER, a randomized, placebo-controlled trial of evolocumab added to statin therapy in patients with stable atherosclerotic cardiovascular disease followed for a median of 2.2 years, completed the Everyday Cognition Scale (ECog) to self-report cognitive changes from the end of the trial compared to its beginning; a subset (N = 835) underwent objective cognitive testing using the Cambridge Neuropsychological Test Automated Battery as part of the EBBINGHAUS trial. There was a dose-dependent relationship between APOE ε4 genotype and patient-reported memory decline on the ECog in the placebo arm (p = .003 for trend across genotypes; ε4/ε4 carriers vs. non-carriers: OR = 1.46, 95% CI [1.03, 2.08]) but not in the evolocumab arm (p = .50, OR = 1.18, 95% CI [.83,1.66]). However, the genotype by treatment interaction was not significant (p = .30). In the subset of participants who underwent objective cognitive testing with the CANTAB, APOE genotype did not significantly modify the relationship between treatment arm and CANTAB performance after adjustment for demographic and medical covariates, (p's>.05). Although analyses were limited by the low population frequency of the ε4/ε4 genotype, this supports the cognitive safety of evolocumab among ε4 carriers, guiding future research on possible benefits of cholesterol-lowering medications in people at genetic risk for Alzheimer's disease.