Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials.

Background: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed.

Relationship Between Enrolling Country Income Level and Patient Profile, Protocol Completion, and Trial End Points.

Background: Globalization of clinical trials fosters inclusion of higher and lower income countries, but the influence of enrolling country income level on heart failure trial performance is unclear. This study sought to evaluate associations between enrolling country income level, acute heart failure patient profile, protocol completion, and trial end points.

Methods And Results: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial included 7141 patients with acute heart failure from 30 countries.

The TMAO-Producing Enzyme Flavin-Containing Monooxygenase 3 Regulates Obesity and the Beiging of White Adipose Tissue.

Emerging evidence suggests that microbes resident in the human intestine represent a key environmental factor contributing to obesity-associated disorders. Here, we demonstrate that the gut microbiota-initiated trimethylamine N-oxide (TMAO)-generating pathway is linked to obesity and energy metabolism. In multiple clinical cohorts, systemic levels of TMAO were observed to strongly associate with type 2 diabetes.

Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.

Background: Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins.

Methods: We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.

mutations in early- and late-onset Alzheimer disease.

Objective: To characterize the clinical and molecular effect of mutations in the sortilin-related receptor () gene.

Methods: We performed whole-exome sequencing in early-onset Alzheimer disease (EOAD) and late-onset Alzheimer disease (LOAD) families followed by functional studies of select variants. The phenotypic consequences associated with mutations were characterized based on clinical reviews of medical records.

A Genetic Response Score for Hydrochlorothiazide Use: Insights From Genomics and Metabolomics Integration.

Hydrochlorothiazide is among the most commonly prescribed antihypertensives; yet, <50% of hydrochlorothiazide-treated patients achieve blood pressure (BP) control. Herein, we integrated metabolomic and genomic profiles of hydrochlorothiazide-treated patients to identify novel genetic markers associated with hydrochlorothiazide BP response. The primary analysis included 228 white hypertensives treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study.

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans.

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.

Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.

Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease.

Objective: The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk.

Methods: Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls.

Zika Virus Infection in Pregnant Women in Rio de Janeiro.

Background: Zika virus (ZIKV) has been linked to central nervous system malformations in fetuses. To characterize the spectrum of ZIKV disease in pregnant women and infants, we followed patients in Rio de Janeiro to describe clinical manifestations in mothers and repercussions of acute ZIKV infection in infants.

Methods: We enrolled pregnant women in whom a rash had developed within the previous 5 days and tested blood and urine specimens for ZIKV by reverse-transcriptase-polymerase-chain-reaction assays.

Altered Maturation Status and Possible Immune Exhaustion of CD8 T Lymphocytes in the Peripheral Blood of Patients Presenting With Acute Coronary Syndromes.

Objective: Inflammation in response to oxidized lipoproteins is thought to play a key role in acute coronary syndromes (ACS), but the pattern of immune activation has not been fully characterized. We sought to perform detailed phenotypic and functional analysis of CD8 T lymphocytes from patients presenting with ACS to determine activation patterns and potential immunologic correlates of ACS.

Approach And Results: We used polychromatic flow cytometry to analyze the cytokine production profiles of naïve, effector, and memory CD8 T cells in patients with ACS compared with control subjects with stable coronary artery disease.

Acute Heart Failure and Atrial Fibrillation: Insights From the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) Trial.

Background: Patients with acute heart failure (AHF) frequently have atrial fibrillation (AF), but how this affects patient-reported outcomes has not been well characterized.

Methods And Results: We examined dyspnea improvement and clinical outcomes in 7007 patients in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. At baseline, 2677 (38.

Relationship Between Cancer and Cardiovascular Outcomes Following Percutaneous Coronary Intervention.

Background: Cardiovascular disease and cancer increasingly coexist, yet relationships between cancer and long-term cardiovascular outcomes post-percutaneous coronary intervention (PCI) are not well studied.

Methods And Results: We examined stented PCI patients at Duke (1996-2010) using linked data from the Duke Information Systems for Cardiovascular Care and the Duke Tumor Registry (a cancer treatment registry). Our primary outcome was cardiovascular mortality.

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.

Background: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.

Methods: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.

Compliance with results reporting at ClinicalTrials.gov.

Background: The Food and Drug Administration Amendments Act (FDAAA) mandates timely reporting of results of applicable clinical trials to ClinicalTrials.gov. We characterized the proportion of applicable clinical trials with publicly available results and determined independent factors associated with the reporting of results.

Utility of socioeconomic status in predicting 30-day outcomes after heart failure hospitalization.

Background: An individual's socioeconomic status (SES) is associated with health outcomes and mortality, yet it is unknown whether accounting for SES can improve risk-adjustment models for 30-day outcomes among Centers for Medicare & Medicaid Services beneficiaries hospitalized with heart failure.

Methods And Results: We linked clinical data on hospitalized patients with heart failure in the Get With The Guidelines-Heart Failure database (January 2005 to December 2011) with Centers for Medicare & Medicaid Services claims and county-level SES data from the 2012 Area Health Resources Files. We compared the discriminatory capabilities of multivariable models that adjusted for SES, patient, and hospital characteristics to determine whether county-level SES data improved prediction or changed hospital rankings for 30-day all-cause mortality and rehospitalization.

Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial.

Background: In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.

Simultaneous consideration of multiple candidate protein biomarkers for long-term risk for cardiovascular events.

Background: Although individual protein biomarkers are associated with cardiovascular risk, rarely have multiple proteins been considered simultaneously to identify which set of proteins best predicts risk.

Methods And Results: In a nested case-control study of 273 death/myocardial infarction (MI) cases and 273 age- (within 10 years), sex-, and race-matched and event-free controls from among 2023 consecutive patients (median follow-up 2.5 years) with suspected coronary disease, plasma levels of 53 previously reported biomarkers of cardiovascular risk were determined in a core laboratory.

Check it, change it: a community-based, multifaceted intervention to improve blood pressure control.

Background: Although home blood pressure (BP) monitoring interventions have shown potential in selected populations, it is unclear whether such strategies can be generalized. We sought to determine whether a multifaceted BP control program that uses a web-based health portal (Heart360), community health coaches, and physician assistant guidance could improve hypertension control in a diverse community setting.

Methods And Results: Between September 12, 2010, and November 11, 2011 Check It, Change It, a community-based hypertension quality improvement program, enrolled 1756 patients with hypertension from 8 clinics in Durham County, NC.

Hypotension during hospitalization for acute heart failure is independently associated with 30-day mortality: findings from ASCEND-HF.

Background: Outcomes associated with episodes of hypotension while hospitalized with acute decompensated heart failure are not well understood.

Methods And Results: Using data from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), we assessed factors associated with in-hospital hypotension and subsequent 30-day outcomes. Patients were classified as having symptomatic or asymptomatic hypotension.

Saphenous vein graft failure after coronary artery bypass surgery: insights from PREVENT IV.

Background: Coronary artery bypass grafting success is limited by vein graft failure (VGF). Understanding the factors associated with VGF may improve patient outcomes.

Methods And Results: We examined 1828 participants in the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial undergoing protocol-mandated follow-up angiography 12 to 18 months post-coronary artery bypass grafting or earlier clinically driven angiography.

Clinical trials in peripheral vascular disease: pipeline and trial designs: an evaluation of the ClinicalTrials.gov database.

Background: Tremendous advances have occurred in therapies for peripheral vascular disease (PVD); until recently, however, it has not been possible to examine the entire clinical trial portfolio of studies for the treatment of PVD (both arterial and venous disease).

Methods And Results: We examined interventional trials registered in ClinicalTrials.gov from October 2007 through September 2010 (n=40,970) and identified 676 (1.

Nesiritide, renal function, and associated outcomes during hospitalization for acute decompensated heart failure: results from the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF).

Background: Contradictory results have been reported on the effects of nesiritide on renal function in patients with acute decompensated heart failure. We studied the effects of nesiritide on renal function during hospitalization for acute decompensated heart failure and associated outcomes.

Methods And Results: A total of 7141 patients were randomized to receive either nesiritide or placebo and creatinine was recorded in 5702 patients at baseline, after infusion, discharge, peak/nadir levels until day 30.

Effects of an antisense oligonucleotide inhibitor of C-reactive protein synthesis on the endotoxin challenge response in healthy human male volunteers.

Background: C-reactive protein (CRP) binds to damaged cells, activates the classical complement pathway, is elevated in multiple inflammatory conditions, and provides prognostic information on risk of future atherosclerotic events. It is controversial, however, as to whether inhibiting CRP synthesis would have any direct anti-inflammatory effects in humans.

Methods And Results: A placebo-controlled study was used to evaluate the effects of ISIS 329993 (ISIS-CRPR x) on the acute-phase response after endotoxin challenge in 30 evaluable subjects.

Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).

Background: Nonvalvular atrial fibrillation is common in elderly patients, who face an elevated risk of stroke but difficulty sustaining warfarin treatment. The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). This prespecified secondary analysis compares outcomes in older and younger patients.