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Differences between patients hospitalized for heart failure with reduced ejection fraction (HFrEF) vs HF with preserved EF (HFpEF) are not well-characterized, particularly as pertains to in-hospital decongestion and longitudinal patient-reported outcomes. The objective of this analysis was to compare patient-reported and clinical outcomes between patients hospitalized with HFrEF vs HFpEF.The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial enrolled 7141 patients hospitalized for HF with reduced or preserved EF. We assessed the association between an EF ≤ 40% vs an EF40% with in-hospital decongestion, risk of rehospitalization and mortality, and quality of life as measured by the EuroQOL 5 Dimensions (EQ-5D). Among 5800 patients (81%) with complete EF data, 4782 (82%) had an EF ≤40% and 1018 (18%) had an EF40%. Both groups demonstrated similar rates of decongestion by weight change and urine volume through 24 hours, a similar risk of 30-day mortality and HF rehospitalization, and a similar 180-day mortality. Patients with HFpEF had worse EQ-5D scores at hour 24 (median 0.76, [interquartile range (IQR) 0.51-0.84] vs 0.78 [IQR 0.57-0.84]; P = .01) that persisted through discharge (0.81 [IQR 0.69-0.86] vs 0.83 [IQR 0.71-1.00]; P.001) and the 30-day follow-up (0.78 [IQR 0.60-0.85] vs 0.83 [IQR 0.71-1.00]; P.001). After adjustment, these differences were attenuated and not statistically significant.In this large, multinational cohort of patients hospitalized for HF, patients with an EF ≤ 40% vs an EF40% experienced similar in-hospital decongestion and postdischarge clinical outcomes. Patients with an EF40% reported worse in-hospital and postdischarge patient-reported health status, but these measures were similar to HFrEF after accounting for other clinical factors.

Background Many patients with heart failure (HF) have severely reduced ejection fraction but do not meet threshold for consideration of advanced therapies (ie, stage D HF). The clinical profile and health care costs associated with these patients in US practice is not well described. Methods and Results We examined patients hospitalized for worsening chronic heart failure with reduced ejection fraction ≤40% from 2014 to 2019 in the GWTG‐HF (Get With The Guidelines‐Heart Failure) registry, who did not receive advanced HF therapies or have end‐stage kidney disease. Patients with severely reduced EF defined as EF ≤30% were compared with those with EF 31% to 40% in terms of clinical profile and guideline‐directed medical therapy. Among Medicare beneficiaries, postdischarge outcomes and health care expenditure were compared. Among 113 348 patients with EF ≤40%, 69% (78 589) had an EF ≤30%. Patients with severely reduced EF ≤30% tended to be younger and were more likely to be Black. Patients with EF ≤30% also tended to have fewer comorbidities and were more likely to be prescribed guideline‐directed medical therapy (“triple therapy” 28.3% versus 18.2%, P P =0.11). Conclusions Among patients hospitalized for worsening chronic heart failure with reduced ejection fraction in US clinical practice, most patients have severely reduced EF ≤30%. Despite younger age and modestly higher use of guideline‐directed medical therapy at discharge, patients with severely reduced EF face heightened postdischarge risk of death and HF hospitalization.

Background: Basilar artery occlusion (BAO) is a devastating condition without definitive evidence to guide treatment. Whereas the association between faster treatment times with endovascular therapy (EVT) and better outcomes in anterior circulation is well established, whether this relationship exists for patients with BAO is not well delineated. Methods: We used individual-level patient data from the Get With The Guidelines–Stroke nationwide US registry prospectively collected from January 2015 to December 2019. We identified individuals with BAO treated with EVT within 24 hours of symptom onset. The primary outcomes examined were in-hospital mortality, discharge home, ambulatory at discharge, independent at discharge (modified Rankin Scale score 0 to 2), substantial reperfusion (modified Thrombolysis in Cerebral Infarction score 2b or 3), and symptomatic intracranial hemorrhage. Using logistic regression models, we evaluated the association between time from symptom onset to treatment with EVT and outcomes. Results: Among 3015 patients with BAO treated with EVT, the mean age was 65.9 years, 38.8% were women, and the median National Institutes of Health Stroke Scale score at presentation was 17 (interquartile range, 8–26). Median onset to EVT time was 406 minutes (interquartile range, 252–688). From 2015 to 2019, there was an overall increase in the median onset to EVT times (380–411 minutes; P =0.016) but no significant change in the proportion of patients treated within 6 hours of symptom onset (48.4%–44.0%; P =0.17). After risk adjustment for patient and hospital-level factors, there were significantly lower odds of in-hospital mortality (adjusted odds ratio [aOR], 0.55 [95% CI, 0.45–0.68]) and symptomatic intracranial hemorrhage (aOR, 0.52 [95% CI, 0.32–0.84]) and significantly higher odds of ambulation at discharge (aOR, 1.72 [95% CI, 1.37–2.16]), discharge home (aOR, 2.19 [95% CI, 1.73–2.77]), and independence at discharge (aOR, 2.21 [95% CI, 1.66–2.95]) when onset to EVT time was ≤6 hours compared with >6 hours. The fastest decay in good outcomes per hour occurred within 6 hours of symptom onset. Conclusions: Among patients receiving EVT for BAO, faster treatment from symptom onset was associated with improved outcomes. These findings support efforts to achieve rapid treatment with EVT for patients with BAO.

Background Stable chest pain is a common indication for cardiac catheterization. We assessed the prognostic value of the Prospective Multicenter Imaging Study for Evaluation (PROMISE) Minimal-Risk Tool in identifying patients who are at very low risk of obstructive coronary artery disease (CAD) or downstream cardiovascular adverse outcomes. Methods We applied the PROMISE Minimal-Risk Tool to consecutive patients without known CAD who underwent elective cardiac catheterization for stable angina from January 1, 2000 to December 31, 2014 in the Duke Databank for Cardiovascular Disease (DDCD). Patients with scores >0.46 (top decile of lowest-risk from the PROMISE cohort) were classified as low-risk. Logistic regression modeling compared likelihood of freedom from obstructive coronary artery disease on index angiography, 2-year survival, and 2-year survival free of myocardial infarction (MI) and MI/revascularization between low- and non low-risk patients. Alternative cut points to define low- risk patients were also explored. Results Among 6251 patients undergoing cardiac catheterization for stable chest pain, 1082 (17.3%) were low-risk per the PROMISE minimal-risk tool. Among low risk patients, obstructive coronary artery disease was observed in 14.9% and left main disease (≥ 50% Stenosis) was rare (0.9%). Compared with other patients, low risk patients had a higher likelihood of freedom from obstructive coronary disease on index catheterization (85.1% vs. 44.2%, OR 4.84, 95% CI 4.06-5.77). Low risk patients had significantly higher survival (98.2% vs. 94.4%, OR 3.18, 95% CI 1.99-5.08), MI-free survival (97.2% vs. 91.9%, OR 3.03, 95% CI 2.07-4.45), and MI/revascularization-free survival (86.2 vs. 59.9%, OR 4.19, 95% CI 3.48-5.05) at 2 years than non-low risk patients. Operating characteristics for predicting the outcomes of interest varied modestly depending on the low-risk cut-point used but the positive predictive value for 2 year freedom from death was >98% regardless. Conclusion The PROMISE minimal-risk tool identifies 17% of stable chest pain patients referred to cardiac catheterization as low risk. These patients have a low prevalence of obstructive CAD and better survival than non-low risk patients. While this suggests that these patients are unlikely to benefit from catheterization, further research is needed to confirm a favorable downstream prognosis with medical management alone.

Decongestion is a primary goal during hospitalizations for decompensated heart failure (HF). However, data surrounding the preferred route and strategy of diuretic administration are limited with varying results in prior studies.This is a retrospective analysis using patients from ASCEND-HF with a stable diuretic strategy in the first 24 hours following randomization. Patients were divided into three groups: intravenous (IV) continuous, IV bolus and oral strategy. Baseline characteristics, in-hospital outcomes, 30-day composite cardiovascular mortality or HF rehospitalization and 180-day all-cause mortality were compared across groups. Inverse propensity weighted modeling was used for adjustment.Among 5,738 patients with a stable diuretic regimen in the first 24 hours (80% of overall ASCEND trial), 3,944 (68.7%) patients received IV intermittent bolus administration of diuretics, 799 (13.9%) patients received IV continuous therapy and 995 (17.3%) patients with oral administration. Patients in the IV continuous group had a higher baseline creatinine (IV continuous 1.4 [1.1-1.7]; intermittent bolus 1.2 [1.0-1.6]; oral 1.2 [1.0-1.4] mg/dL; P0.001) and high NTproBNP (IV continuous 5,216 [2,599-11,603]; intermittent bolus 4,944 [2,339-9,970]; oral 3,344 [1,570-7,077] pg/mL; P0.001). There was no difference between IV continuous and intermittent bolus group in weight change, total urine output and change in renal function till 10 days/discharge (adjusted P0.05 for all). There was no difference in 30 day mortality and HF readmission (adjusted OR 1.08 [95%CI: 0.74, 1.57]; P = 0.701) and 180 days mortality (adjusted OR 1.04 [95%CI: 0.75, 1.43]; P = 0.832).In a large cohort of patients with decompensated HF, there were no significant differences in diuretic-related in-hospital, or post-discharge outcomes between IV continuous and intermittent bolus administration. Tailoring appropriate diuretic strategy to different states of acute HF and congestion phenotypes needs to be further investigated.

Aims Associations between growth differentiation factor‐15 (GDF‐15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP‐1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF‐15 and change in GDF‐15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF‐15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF‐15 were more likely to be male and have more co‐morbidities. After adjustment, an increase in GDF‐15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF‐15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF‐15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF‐15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF‐15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF‐15 trajectory in informing risk of heart failure disease progression.

Background: Hospitalization for heart failure (HF) is associated with increased risk of death among patients with chronic HF. The degree to which hospitalization for HF is a distinct biologic entity with independent prognostic value versus a marker of higher risk chronic HF patients is unclear. Methods: After excluding patients with new-onset HF, the ASCEND-HF trial (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) included 4205 patients hospitalized for worsening chronic HF with reduced or preserved ejection fraction. The present analysis compared patients by presence or absence of prior HF hospitalization within 12 months and by timing of prior HF hospitalization relative to index hospitalization. Associations with 180-day all-cause mortality were assessed, including adjustment for 27 prespecified clinical factors. Results: Overall, 2241 (53.3%) patients had a HF hospitalization within the prior 12 months and 1964 (46.7%) did not. Mortality rates at 180 days were 15.5% and 11.9%, respectively. In unadjusted analyses, prior HF hospitalization was associated with increased risk of 180-day mortality (HR, 1.35 [95% CI, 1.14–1.59]; P P =0.064). Similarly, after adjustment, compared with patients without prior hospitalization, prior HF hospitalization was not associated with mortality, irrespective of timing (0–4 months: HR, 1.10 [95% CI, 0.87–1.39], P =0.41; 4–8 months: HR, 0.95 [95% CI, 0.70–1.27]; P =0.72; 8–12 months: HR, 1.06 [95% CI, 0.74–1.51], P =0.77; >12 months: HR, 0.81 [95% CI, 0.63–1.06], P =0.12). Conclusions: In this cohort of patients hospitalized for worsening HF, prior HF hospitalization was not associated with 180-day mortality after comprehensively accounting for patient characteristics measured during the index patient visit. Clinical confounders measured at the point-of-care may explain previously observed associations between prior HF hospitalization and mortality, and these clinical factors may be a more direct means of predicting patient survival. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00475852.

Background Whether exposure to a single general anaesthetic (GA) in early childhood causes long-term neurodevelopmental problems remains unclear. Methods PubMed/MEDLINE, Embase, CINAHL, Web of Science, and the Cochrane Library were searched from inception to October 2019. Studies evaluating neurodevelopmental outcomes and prospectively enrolling children exposed to a single GA procedure compared with unexposed children were identified. Outcomes common to at least three studies were evaluated using random-effects meta-analyses. Results Full-scale intelligence quotient (FSIQ); the parentally reported Child Behavior Checklist (CBCL) total, externalising, and internalising problems scores; and Behavior Rating Inventory of Executive Function (BRIEF) scores were assessed. Of 1644 children identified, 841 who had a single exposure to GA were evaluated. The CBCL problem scores were significantly higher (i.e. worse) in exposed children: mean score difference (CBCL total: 2.3 [95% confidence interval {CI}: 1.0–3.7], P=0.001; CBCL externalising: 1.9 [95% CI: 0.7–3.1], P=0.003; and CBCL internalising problems: 2.2 [95% CI: 0.9–3.5], P=0.001). Differences in BRIEF were not significant after multiple comparison adjustment. Full-scale intelligence quotient was not affected by GA exposure. Secondary analyses evaluating the risk of these scores exceeding predetermined clinical thresholds found that GA exposure was associated with increased risk of CBCL internalising behavioural deficit (risk ratio [RR]: 1.47; 95% CI: 1.08–2.02; P=0.016) and impaired BRIEF executive function (RR: 1.68; 95% CI: 1.23–2.30; P=0.001). Conclusions Combining results of studies utilising prospectively collected outcomes showed that a single GA exposure was associated with statistically significant increases in parent reports of behavioural problems with no difference in general intelligence.

Purpose We aimed to 1) describe characteristics of patients with heart failure with preserved ejection fraction (HFpEF) enrolled in RELAX stratified by normal or elevated baseline serum uric acid (sUA) level; 2) evaluate the association between sUA level and surrogate clinical measures; and 3) assess associations between changes in sUA level over time and changes in surrogate clinical measures. Methods We analyzed 212 patients with HFpEF and normal or elevated (>6 mg/dL) baseline sUA measurements from the RELAX trial. Variables examined included clinical characteristics, cardiopulmonary exercise testing, 6-minute walk testing, quality of life, echocardiography, and serum biomarker testing. Baseline characteristics between groups were compared and scatter plots with quadratic regression lines and linear regression modeling were used to assess the relationship between baseline sUA and clinical measures. Kaplan–Meier curves were used to describe composite death or cardiovascular/renal hospitalization. Results The prevalence of elevated baseline sUA was 68.9%. Patients with elevated sUA had more baseline comorbidities and poorer functional status on cardiopulmonary exercise testing than those without. After adjustment, significant associations between baseline sUA levels and cystatin C, N-terminal pro B-type natriuretic peptide, high-sensitivity troponin I, and high-sensitivity C-reactive protein were identified. Higher baseline sUA was also associated with worsening peak VO2, 6-minute walk testing, and left ventricular mass. No significant association was found between baseline sUA levels and the composite of death or cardiovascular/renal hospitalization at 24 weeks. Conclusion sUA is an important marker of comorbidities and functional status in patients with HFpEF. Clinical trials of sUA-lowering therapies in patients with HFpEF are promising.

Clinical guidelines recommend titration of angiotensin converting enzyme inhibitors (ACEi) and beta-blockers among patients with heart failure with reduced ejection fraction (HFrEF) to maximally tolerated doses. Patient characteristics associated with dose titration and clinical outcomes subsequent to dose titration remain poorly characterized.Among 1999 ambulatory patients with chronic HFrEF in the HF-ACTION trial, use and dosing of ACEi and evidence-based beta-blockers were examined at baseline and 6-month follow-up. Multivariable logistic regression models were used to assess factors associated with dose escalation (medication initation or dosing increase) or dose de-escalation (medication discontinuation or dosing decrease). Cox proportional hazard regression models were used to examine associations between dose trajectory group (stable target, stable sub-target, dose escalation, and dose de-escalation) and subsequent mortality and hospitalization outcomes.For both ACEi and beta-blockers, hospitalization for heart failure in the 6 months prior to enrollment (odds ratio [OR] 2.32 [95% confidence interval 1.58-3.42]) for ACEi; 1.42 [1.05-1.9] for beta-blockers) and higher systolic blood pressure (OR 1.01 [1.00-1.03] per 1 mmHg increase for ACEi; 1.01 [1.00-1.02] for beta-blockers) were associated with dose escalation. Hospitalization 6 months prior to enrollment for any cause (including HF or non-HF causes) was associated with dose de-escalation (OR 1.60 [1.14-2.25] for ACEi; 1.67 [1.20-2.33] for beta-blockers). After adjustment for patient characteristics, compared with stable target dosing, dose de-escalation of either medication was associated with greater all-cause mortality (adjusted hazard ratio [aHR] 1.64 [1.11-2.42] for ACEi; 1.62 [1.04-2.53] for beta-blockers). Compared with stable target dosing, both dose de-escalation (aHR 1.98 [1.36-2.87]) and stable sub-target dosing (aHR 1.49 [1.18-1.87]) of beta-blockers were associated with greater cardiovascular mortality or hospitalization for heart failure.Among outpatients with chronic HFrEF, patient characteristics including recent hospitalization status and blood pressure were associated with odds of subsequent escalation and de-escalation of ACEi and beta-blocker therapy. Compared with patients receiving guildeline-recommended target doses, dose de-escalation of either medication and sub-target dosing of beta-blockers were associated with greater morbidity and mortality over long-term follow-up.

BACKGROUND: While left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear. METHODS AND RESULTS: We evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10–22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P

Background In patients hospitalized with acute heart failure (AHF), low urine sodium concentration (U Na) after diuretic treatment may identify patients at risk for longer length of stay (LOS) and adverse events. We investigated the prognostic significance of 24‐hour cumulative postdiuretic urine sodium concentration in a multicenter clinical trial population. Methods The Renal Optimization Strategies Evaluation AHF (ROSE AHF) trial randomized 360 patients with AHF and renal dysfunction receiving intravenous diuretic to dopamine, nesiritide, or placebo. Sodium concentration was measured in cumulative urine sample collected during the first 24 hours after randomization in 298 patients. Based on prior studies, lower U Na was defined as ≤60 mmol/L. Results Lower U Na was present in 142 (48%) patients, who had longer LOS (7 days vs 5 days, P

Background and Purpose: Patients with prestroke mobility impairment (PSMI) were excluded from endovascular clinical trials. There are limited data regarding safety and outcomes of endovascular thrombectomy in this population. We used a large, national data set (Get With The Guidelines–Stroke) to evaluate the safety and outcomes of endovascular thrombectomy in patients with PSMI. Methods: We included patients who underwent endovascular thrombectomy in the Get With The Guidelines–Stroke registry between 2015 and 2019. PSMI was defined as the inability to ambulate independently. Generalized estimating equations for logistic regression models were used to evaluate the association between PSMI and outcomes. Results: Of 56 762 patients treated with endovascular thrombectomy, 2919 (5.14%) had PSMI. PSMI was not associated with symptomatic intracranial hemorrhage (6.0% versus 5.4%; P =0.979). In-hospital death or discharge to hospice occurred in 32.3% of patients with PSMI versus 17.5% without PSMI (adjusted odds ratio, 1.45 [1.32–1.58]). Conclusions: While procedural adverse outcomes were no higher in patients with PSMI, further study is necessary to determine clinical benefit in this population.

Worsening heart failure (HF) often requires hospitalization but in some cases may be managed in the outpatient or emergency department (ED) settings. The predictors and clinical significance of ED visits without admission vs hospitalization are unclear.The ASCEND-HF trial included 2661 US patients hospitalized for HF with reduced or preserved ejection fraction. Clinical characteristics were compared between patients with a subsequent all-cause ED visit (with ED discharge) within 30 days vs all-cause readmission within 30 days. Factors associated with each type of care were assessed in multivariable models. Multivariable models landmarked at 30 days evaluated associations between each type of care and subsequent 150-day mortality.Through 30-day follow-up, 193 patients (7%) had ED discharge, 459 (17%) had readmission, and 2009 (76%) had neither urgent visit. Patients with ED discharge vs readmission were similar with respect to age, sex, systolic blood pressure, ejection fraction, and coronary artery disease, whereas ED discharge patients had a modestly lower creatinine (P.01). Among patients with either event within 30 days, a higher creatinine and prior HF hospitalization were associated with a higher likelihood of readmission, as compared with ED discharge (P.02). Landmarked at 30 days, rates of death during the subsequent 150 days were 21.0% for patients who were readmitted and 11.4% for patients discharged from the ED. Compared with patients who were readmitted, ED discharge was independently associated with lower 150-day mortality (adjusted hazard ratio 0.58, 95% confidence interval 0.36-0.92, P = .02).In this cohort of US patients hospitalized for HF, worse renal function and prior HF hospitalization were associated with a higher likelihood of early postdischarge readmission, as compared with ED discharge. Although subsequent mortality was high after discharge from the ED, this risk of mortality was significantly lower than patients who were readmitted to the hospital.

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.

The significance of recovered left ventricular ejection fraction (LVEF) in LVAD recipients, outside of pump explantation, is unclear.Patients undergoing first LVAD implantation at Duke University Hospital between 2006 and 2017 were evaluated for LVEF recovery up to 2 years following implant. Occurrence of gastrointestinal bleeding (GIB), hospitalization for heart failure (HF), pump thrombosis and death were assessed before and after LVEF recovery.Of 286 patients who met inclusion criteria, 9.8% reached a "threshold" of recovery with an LVEF ≥ 40%. 17.4% achieved "relative" recovery with an increase in LVEF ≥ 10% since LVAD implantation. For either definition, recovered patients had a lower incidence of a composite endpoint of GIB, HF hospitalization, pump thrombosis, or death compared to patients without recovery. Patients with "threshold" recovery had 4.7 events per 100 patient-years (95% CI, 0.7-33.6) compared to 48.8 events per 100 patient-years (95% CI, 39.5-60.3) without "threshold" recovery [p = .020]. Those with "relative" recovery had 14.1 events per 100 patient-years [95% CI, 5.9-33.8] versus 50.7 events per 100 patient-years (95% CI, 40.7-63.0) without "relative" recovery [p = 0.005]. However, improved outcomes in the "relative" recovery group were limited to those who also met the "threshold" definition. Importantly, among patients who achieved "threshold" recovery, the incidence of the composite endpoint declines in the postrecovery period, suggesting that LVEF recovery mechanistically results in improved outcomes.An LVEF ≥ 40% associates with better outcomes in LVAD recipients. Methods to promote recovery could reduce morbidity and mortality related to LVAD support.

The etiology of atrial fibrillation (AF) is multifactorial and incompletely understood.The purpose of this study was to evaluate the association between coronary artery disease (CAD) affecting atrial tissue and AF.Patients from a single center with obstructive CAD during cardiac catheterization (January 1, 2007, through December 1, 2013) were included in a matched case-control analysis on the basis of the presence or absence of new-onset AF within 12 months of catheterization. Quantitative measurements of stenosis severity were performed for the sinoatrial nodal artery, atrioventricular (AV) nodal artery, and right intermediate atrial artery (RIAA) as well as the right coronary, left circumflex, and left anterior descending proximal to the takeoff for each atrial level artery. A multivariable logistic regression model identified factors associated with AF.Of 1794 patients, 115 (6%) developed AF within 1 year of catheterization. The matched cohort included 110 patients with and 110 patients without AF within 12 months of catheterization. Higher odds of AF at 1 year were associated with increasing lesion stenosis severity in the RIAA (odds ratio [OR] 1.41 per 10% increase in lesion severity above 50%; 95% confidence interval [CI] 1.01-1.97; P = .047) and AV nodal artery (OR 1.58 per 10% increase in lesion severity above 50%; 95% CI 1.00-2.49; P = .050). Odds of AF diagnosis during the year after catheterization increased with the number of atrial arteries with50% lesion (OR 1.53 for each additional artery; 95% CI 1.08-2.15; P = .015).In patients with obstructive CAD, disease of the AV nodal artery and RIAA as well as a higher burden of CAD within all arteries supplying blood flow to the atrial myocardium were associated with higher odds of new-onset AF at 1 year.

Background In a randomized control trial, Palliative Care in Heart Failure (PAL-HF) improved heart failure–related quality of life, though cost-effectiveness remains unknown. The aim of this study was to evaluate the cost-effectiveness of the PAL-HF trial, which provided outpatient palliative care to patients with advanced heart failure. Methods and Results Outcomes for usual care and PAL-HF strategies were compared using a Markov cohort model over 36 months from a payer perspective. The model parameters were informed by PAL-HF trial data and supplemented with meta-analyses and Medicare administrative data. Outcomes included hospitalization, place of death, Medicare expenditures, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Simulated mortality rates were the same for PAL-HF and usual care cohorts, at 89.7% at 36 months. In the base case analysis, the PAL-HF intervention resulted in an incremental gain of 0.03 QALYs and an incremental cost of $964 per patient for an incremental cost-effectiveness ratio of $29,041 per QALY. In 1-way sensitivity analyses, an intervention cost of up to $140 per month is cost effective at $50,000 per QALY. Of 1000 simulations, the PC intervention had a 66.1% probability of being cost effective at a $50,000 willingness-to-pay threshold assuming no decrease in hospitalization. In a scenario analysis, PAL-HF decreased payer spending through reductions in noncardiovascular hospitalizations. Conclusions These results from this single-center trial are encouraging that palliative care for advanced heart failure is an economically attractive intervention. Confirmation of these findings in larger multicenter trials will be an important part of developing the evidence to support more widespread implementation of the PAL-HF palliative care intervention.

The 2018 cholesterol guidelines of the American Heart Association and the American College of Cardiology (AHA/ACC) changed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) eligibility criteria for primary prevention to include multiple risk enhancers and novel intensive lipid-lowering therapies for secondary prevention.This study sought to determine how guideline changes affected identification for preventive therapy in young adults with premature myocardial infarction (MI).The study identified adults presenting with first MI at Duke University Medical Center in Durham, North Carolina. Statin therapy eligibility was determined using the 2013 ACC/AHA and 2018 AHA/ACC guidelines criteria. The study also determined potential eligibility for intensive lipid-lowering therapies (very high risk) under the 2018 AHA/ACC guidelines, by assessing the composite of all-cause death, recurrent MI, or stroke rates in adults considered "very high risk" versus not.Among 6,639 patients with MI, 41% were 55 years of age ("younger"), 35% were 55 to 65 years of age ("middle-aged"), and 24% were 66 to 75 years of age ("older"). Younger adults were more frequently smokers (52% vs. 38% vs. 22%, respectively) and obese (42% vs. 34% vs. 31%, respectively), with metabolic syndrome (21% vs. 19% vs. 17%, respectively) and higher low-density lipoprotein cholesterol (117 vs. 107 vs. 103 mg/dl, respectively) (p trend 0.01 for all). Pre-MI, fewer younger adults met guideline indications for 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor (statin) therapy than middle-aged and older adults. The 2018 guideline identified fewer younger adults eligible for statin therapy at the time of their MI than the 2013 guideline (46.4% vs. 56.7%; p 0.01). Younger patients less frequently met very high-risk criteria for intensive secondary prevention lipid-lowering therapy (28.3% vs. 40.0% vs. 81.4%, respectively; p 0.01). Over a median 8 years of follow-up, very high-risk criteria were associated with increased risk of major adverse cardiovascular events in individuals 55 years of age (hazard ratio: 2.09; 95% confidence interval: 1.82 to 2.41; p 0.001), as was the case in older age groups (p interaction = 0.54).Most younger patients with premature MI are not identified as statin candidates before their event on the basis of the 2018 guidelines, and most patients with premature MI are not recommended for intensive post-MI lipid management.

Background: The FIGHT (Functional Impact of GLP-1 [glucagon-like peptide-1] for Heart Failure Treatment) trial randomized 300 patients with heart failure with reduced ejection fraction (HFrEF) and a recent hospitalization for heart failure to liraglutide versus placebo. While there was no difference in the primary outcome (rank score of time to death, time to rehospitalization for heart failure, and change in NT-proBNP [N-terminal pro-B-type natriuretic peptide]), there was a significant increase in cystatin C among patients randomized to liraglutide raising concern of adverse renal outcomes. We performed a post hoc analysis of FIGHT to investigate whether liraglutide was associated with worsening renal function (WRF). Methods: The relationship between randomization to liraglutide and WRF was evaluated using logistic regression models. Two hundred seventy-four patients (91%) had complete data to assess for WRF defined as: increase in SCr ≥0.3 mg/dL, or ≥25% decrease in estimated glomerular filtration rate, or an increase in cystatin C ≥0.3 mg/L from baseline to 180-days. Results: Patients with WRF (n=113, 41%), compared with those without, were older, had more comorbidities, and lower utilization of guideline-directed medical treatment. Logistic regression models showed that age and baseline cystatin C levels were associated with WRF. In adjusted models, liraglutide was not associated with excess risk of WRF compared with placebo (odds ratio, 1.02 [95% CI, 0.62–1.67]). There was also no difference in the rank score when WRF was added as a fourth-tier outcome. Conclusions: Liraglutide was not associated with WRF among patients with HFrEF and a recent hospitalization for heart failure. These data support the relative renal safety profile of liraglutide among patients with HFrEF. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01800968.

Background: Heart rate and systolic blood pressure (SBP) are prognostic markers in heart failure (HF) with reduced ejection fraction (HFrEF). Their combination in rate pressure product (RPP) as well as their role in heart failure with preserved ejection fraction (HFpEF) remains unclear.Hypothesis: RPP and its components are associated with HFpEF outcomes.Methods: We performed an analysis of Acute Study of Clinical Effectiveness of Nesiritide in Subjects With Decompensated Heart Failure (ASCEND-HF; http://www.clinicaltrials.gov NCT00475852), which studied 7141 patients with acute HF. HFpEF was defined as left ventricular ejection fraction >= 40%. Outcomes were assessed by baseline heart rate, SBP, and RPP, as well as the change of these variables using adjusted Cox models.Results: After multivariable adjustment, in-hospital change but not baseline heart rate, SBP, and RPP were associated with 30-day mortality/HF hospitalization (hazard ratio [HR]: 1.17 per 5-bpm heart rate, HR: 1.20 per 10-mm Hg SBP, and HR: 1.02 per 100 bpm x mm Hg RPP; all P Conclusions: An increase in heart rate and SBP from baseline to discharge was associated with increased 30-day mortality/HF hospitalization in HFpEF patients with acute exacerbation. These findings suggest value in monitoring the trend of vital signs during HFpEF hospitalization.

Background and Purpose Patients with prior stroke are at greater risk for recurrent cardiovascular events post-acute coronary syndromes (ACS) and may have a different risk/benefit profile with antithrombotic therapy than patients without prior stroke. Methods We studied 7391 patients with ACS from APPRAISE-2, stratified by the presence or absence of prior stroke. Baseline characteristics and outcomes of cardiovascular death, myocardial infarction (MI), or stroke were compared between groups. Interactions between prior stroke, treatment assignment (apixaban vs placebo), and outcomes were tested before and after multivariable adjustment with Cox proportional hazards models. Results A total of 902 patients (12%) had prior stroke. Those with prior stroke were older (69 vs 67 years), had more hypertension (91% vs 77%), peripheral vascular disease (22% vs18%), and impaired renal function (38% vs 30%) but less diabetes (44% vs 48%) than those without prior stroke. Patients with prior stroke vs no prior stroke had higher unadjusted rates of cardiovascular death (4.8% vs 4.0%), MI (11.2% vs 7.1%), and ischemic stroke (3.2% vs 0.9%). Patients with prior stroke assigned to apixaban had similar rates of the composite of cardiovascular death, MI, or stroke compared with those assigned to placebo (HR 1.39; 95% CI 0.92–2.08). Patients without prior stroke assigned to apixaban had similar rates of cardiovascular death, MI, or ischemic stroke compared with those assigned to placebo (HR 0.87; 95% CI 0.73–1.04; P-interaction = .041). Median follow-up was 240 days. Conclusions Patients with prior stroke are at higher risk for recurrent cardiovascular events post-ACS and had a differential risk/benefit profile with oral anticoagulation.

Background The anaesthetic dose causing neurotoxicity in animals has been evaluated, but the relationship between duration of volatile anaesthetic (VA) exposure and neurodevelopment in children remains unclear. Methods Data were obtained from the Western Australian Pregnancy Cohort (Raine) Study, with language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E] and Total [CELF-T]) and cognition (Coloured Progressive Matrices [CPM]) assessed at age 10 yr. Medical records were reviewed, and children divided into quartiles based on total VA exposure duration before age three yr. The association between test score and exposure duration quartile was evaluated using linear regression, adjusting for patient characteristics and comorbidity. Results Of 1622 children with available test scores, 148 had documented VA exposure and were split into the following quartiles: ≤25, >25 to ≤35, >35 to ≤60 and >60 min. Compared with unexposed children, CELF-T scores for children in the first and second quartiles did not differ, but those in the third and fourth quartiles had significantly lower scores ([3rd quartile – Unexposed] -5.3; 95% confidence interval [CI], (-10.2 – -0.4), [4th quartile – Unexposed] -6.2; 95% CI, (-11.6 – -0.9). CELF-E showed similar findings, but significant differences were not found in CELF-R or CPM for any quartile. Conclusions Children with VA exposures ≤35 min did not differ from unexposed children, but those with exposures >35 min had lower total and expressive language scores. It remains unclear if this is a dose-response relationship, or if children requiring longer exposures for longer surgeries have other clinical reasons for lower scores.

Background Patients with impaired glucose tolerance have an elevated risk of cardiovascular (CV) death; however, the causes and risk factors associated with non-CV deaths are poorly understood. Methods The NAVIGATOR trial enrolled 9,306 participants with impaired glucose tolerance and CV disease or at high CV risk, with a median follow-up of 6.4 years. Using this population, we identified (1) the proportion of deaths attributed to CV, non-CV, and unknown causes, and (2) the risk factors associated with non-CV death. Results During the NAVIGATOR trial follow-up, 622 patients died. Investigators reported 244 (39.2%) CV deaths, 313 (50.3%) non-CV deaths, and 65 (10.5%) deaths of unknown cause. Myocardial infarction was the leading cause of investigator-reported death (57/622 [9.2%]). Among non-CV deaths, the most commonly identified cause related to malignancy (177/313 [56.5%]). Using adjudicated causes of death, Cox proportional hazard models identified 3 independent prognostic markers that increased the risk of non-CV death: history of non–melanoma skin cancer (hazard ratio 2.67 [95% CI 1.65-4.33]; P < .0001), white blood cell count (1 unit N5000/mm3; 1.10 [1.02-1.18]; P = .011), and serum potassium levels (per 1 mmol/L above any value; 1.67 [1.302.15]; P < .0001). Conclusions Despite the high baseline CV risk among patients in the NAVIGATOR trial, the most common cause of death was non-CV. The high burden of non-CV death in this population has potential implications for future CV event–driven trials.

Background Patients with heart failure (HF) with preserved ejection fraction (HFpEF) and obesity display a number of pathophysiologic features that may render them more or less vulnerable to negative effects of decongestion on renal function, including greater right ventricular remodeling, plasma volume expansion and pericardial restraint. We aimed to contrast the renal response to decongestion in obese compared to nonobese patients with HFpEF Methods and Results National Institutes of Health heart failure network studies that enrolled patients with acute decompensated HFpEF (EF ≥ 50%) were included (DOSE, CARRESS, ROSE, and ATHENA). Obese HFpEF was defined as a body mass index ≥ 30 kg/m2. Compared to nonobese HFpEF (n = 118), patients with obese HFpEF (n = 214) were an average of 9 years younger (71 vs 80 years, 0.5 mg/dL) (9 vs 0%, P = 0.002). Conclusions Despite being nearly a decade younger, obese patients with HFpEF experience greater deterioration in renal function during decongestion than do nonobese patients with HFpEF. Further study to elucidate the complex relationships between volume distribution, cardiorenal hemodynamics and adiposity in HFpEF is needed.

Background We sought to study the prevalence of high‐sensitivity troponin and its association with cardiac structure and outcomes in ambulatory and hospitalized patients with heart failure with a preserved ejection fraction ( HF p EF ). Methods and Results A post hoc analysis utilized data from HF p EF patients: DOSE (Diuretic Optimization Strategies Evaluation) and CARRESS ‐ HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) enrolled patients hospitalized with acute HF p EF , and RELAX (Phosphodiesterase‐5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) enrolled ambulatory patients with HF p EF . High‐sensitivity troponin I (hs‐TnI) was measured in hospitalized patients at baseline, at 72 to 96 hours, on day 7, and on day 60. In ambulatory patients hs‐TnI was measured at baseline and at week 24. In the ambulatory cohort, correlations between hs‐TnI and cardiac structure and function were assessed. The association between hs‐TnI and a 60‐day composite of emergency room visits, readmissions, and death was assessed for hospitalized patients using multivariable Cox proportional hazard models. The study population included 139 hospitalized and 212 ambulatory patients with HF p EF and hs‐TnI measured at baseline. The median (25th, 75th percentiles) baseline troponin was 17.6 (11.1, 41.0) ng/L in hospitalized patients and 9.5 (5.3, 19.7) ng/L in ambulatory patients ( P 99% percentile upper reference limit was 86% in hospitalized patients and 53% among ambulatory patients, with stable elevation in ambulatory patients during follow‐up. HF p EF patients with a hs‐TnI above the median were older with worse left ventricular hypertrophy and diastolic dysfunction. Continuously valued hs‐TnI (per doubling) was associated with increased risk of composite end point (adjusted hazard ratio 1.20, 95% confidence interval 1.00‐1.43; P =0.042). Conclusions Hs‐TnI is commonly elevated among both hospitalized and ambulatory patients with HF p EF . Increased hs‐TnI levels are associated with worse cardiac structure and increased risk of adverse events.

Background— Psychosocial factors may influence adherence with exercise training for heart failure (HF) patients. We aimed to describe the association between social support and barriers to participation with exercise adherence and clinical outcomes. Methods and Results— Of patients enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), 2279 (97.8%) completed surveys to assess social support and barriers to exercise, resulting in the perceived social support score (PSSS) and barriers to exercise score (BTES). Higher PSSS indicated higher levels of social support, whereas higher BTES indicated more barriers to exercise. Exercise time at 3 and 12 months correlated with PSSS ( r = 0.09 and r = 0.13, respectively) and BTES ( r =−0.11 and r =−0.12, respectively), with higher exercise time associated with higher PSSS and lower BTES (All P P =0.035), which corresponded to a borderline association between increasing BTES and cardiovascular death or HF hospitalization in the exercise group (hazard ratio 1.25, 95% confidence interval 0.99, 1.59), but no association in the usual care group (hazard ratio 0.83, 95% confidence interval 0.66, 1.06). Conclusions— Poor social support and high barriers to exercise were associated with lower exercise time. PSSS did not impact the effect of exercise training on outcomes. However, for cardiovascular death or HF hospitalization, exercise training had a greater impact on patients with lower BTES. Given that exercise training improves outcomes in HF patients, assessment of perceived barriers may facilitate individualized approaches to implement exercise training therapy in clinical practice. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00047437.

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. Country income data in gross national income per capita in current US dollars from the year 2007 (ie, the year trial enrollment began) were abstracted from the World Bank. Patients were grouped by enrolling country income level (ie, high [>$11 455], upper middle [$3706–$11 455], lower middle [$936–$3705], and low [P P for interaction, 0.03). Conclusions: In this global acute heart failure trial, patients from higher income countries had lower rates of protocol completion, higher rates of adverse events, and similar mortality rates. After adjustment for race, geographic region, and clinical factors, enrollment from a higher income country was associated with worse clinical outcomes, driven by higher rates of rehospitalization. Variation in enrolling country income level may influence study end points and trial performance independent of geographic region. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00475852.

AIMS A 5-point change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) is commonly considered to be a clinically significant difference in health status in patients with heart failure. We evaluated how the magnitude of change relates to subsequent clinical outcomes. METHODS AND RESULTS Using data from the HF-ACTION trial of exercise training in chronic heart failure (n = 2331), we used multivariable Cox regression with piecewise linear splines to examine the relationship between change in KCCQ overall summary score from baseline to 3 months (range 0-100; higher scores reflect better health status) and subsequent all-cause mortality/hospitalization. Among 2038 patients with KCCQ data at the 3-month visit, KCCQ scores increased from baseline by ≥5 points for 45%, scores decreased by ≥5 points for 23%, and scores changed by

Background Underlying inflammation has been increasingly recognized in heart failure with a preserved ejection fraction ( HF p EF ). In this study we tested the hypothesis that pro‐inflammatory biomarkers are elevated in patients with acutely decompensated HF p EF ( AD ‐ HF p EF ) compared with patients with stable HF p EF (S‐ HF p EF ). Methods and Results Using a post hoc analysis the serum biomarkers tumor necrosis factor‐alpha, high‐sensitivity C‐reactive protein interleukin 6 and pentraxin 3 ( PTX 3) and clinical, demographic, echocardiographic‐Doppler and clinical outcomes data were analyzed in HF p EF patients enrolled in NHLBI Heart Failure Research Network clinical trials which enrolled patients with either AD ‐ HF p EF or S‐ HF p EF . Compared to S‐ HF p EF , AD ‐ HF p EF patients had higher levels of PTX 3 (3.08 ng/ mL versus 1.27 ng/ mL , P interleukin ‐6 (4.14 pg/ mL versus 1.71 pg/ mL , P tumor necrosis factor‐alpha (11.54 pg/ mL versus 8.62 pg/ mL , P =0.0015), and high‐sensitivity C‐reactive protein (11.90 mg/ dL versus 3.42 mg/ dL , P interleukin ‐6 and PTX 3 levels were significantly higher in AD ‐ HF p EF compared with S‐ HF p EF patients admitted for decompensated HF within the previous year. PTX 3 was positively correlated with left atrial volume index ( r =0.41, P =0.0017) and left ventricular mass ( r =0.26, P =0.0415), while tumor necrosis factor‐alpha was inversely correlated with E/A ratio ( r =−0.31, P =0.0395). Conclusions Levels of pro‐inflammatory biomarkers are strikingly higher in AD ‐ HF p EF compared with S‐ HF p EF patients. PTX 3 and tumor necrosis factor‐alpha are correlated with echocardiographic‐Doppler evidence of diastolic dysfunction. Taken together these data support the concept that a heightened pro‐inflammatory state has a pathophysiologic role in the development of AD ‐ HF p EF .

Background/aims The Food and Drug Administration Amendments Act mandates that applicable clinical trials report basic summary results to the ClinicalTrials.gov database within 1 year of trial completion or termination. We aimed to determine the proportion of pulmonary trials reporting basic summary results to ClinicalTrials.gov and assess factors associated with reporting. Methods We identified pulmonary clinical trials subject to the Food and Drug Administration Amendments Act (called highly likely applicable clinical trials) that were completed or terminated between 2008 and 2012 and reported results by September 2013. We estimated the cumulative percentage of applicable clinical trials reporting results by pulmonary disease category. Multivariable Cox regression modeling identified characteristics independently associated with results reporting. Results Of 1450 pulmonary highly likely applicable clinical trials, 380 (26%) examined respiratory neoplasms, 238 (16%) asthma, 175 (12%) chronic obstructive pulmonary disease, and 657 (45%) other respiratory diseases. Most (75%) were pharmaceutical highly likely applicable clinical trials and 71% were industry-funded. Approximately 15% of highly likely applicable clinical trials reported results within 1 year of trial completion, while 55% reported results over the 5-year study period. Earlier phase highly likely applicable clinical trials were less likely to report results compared to phase 4 highly likely applicable clinical trials (phases 1/2 and 2 (adjusted hazard ratio 0.41 (95% confidence interval: 0.31-0.54)), phases 2/3 and 3 (adjusted hazard ratio 0.55 (95% confidence interval: 0.42-0.72)) and phase not applicable (adjusted hazard ratio 0.43 (95% confidence interval: 0.29-0.63)). Pulmonary highly likely applicable clinical trials without Food and Drug Administration oversight were less likely to report results compared with those with oversight (adjusted hazard ratio 0.65 (95% confidence interval: 0.51-0.83)). Conclusion A total of 15% of pulmonary clinical highly likely applicable clinical trials report basic summary results to ClinicalTrials.gov within 1 year of trial completion. Strategies to improve reporting are needed within the pulmonary community.

BACKGROUND: The PLATelet inhibition and patient Outcomes (PLATO) trial showed that treatment with ticagrelor reduced the rate of death due to vascular causes, myocardial infarction and stroke when compared to clopidogrel in patients with ST-elevation or non-ST-elevation acute coronary syndrome (ACS). While the comparative benefit of ticagrelor over clopidogrel increased over time, event rates accrued in both groups during the study period. The purpose of our biomarker-based exploratory analysis was to determine whether long-term platelet inhibition may be associated with platelet adaptation. METHODS: A sample of 4000 participants from the PLATO trial also consented to participate in a prospectively designed Biomarker Substudy. Blood samples were procured at baseline, immediately prior to hospital discharge and at one month and six months. Markers of platelet activity, including platelet count, serum CD40-ligand and soluble P-selectin were analyzed. Mean levels were compared at discharge, 1 month and 6 months following study drug initiation – first for all patients and subsequently stratified by treatment group. A linear mixed model was used to estimate the short-term change rate (baseline to 1 month) and long-term change rate (1 month to 6 month) for each biomarker. A Cox proportional hazards model was used to calculate hazard ratios for each change in biomarker over the two time periods examined: baseline to one month and one month to six months. RESULTS: Prior to randomized treatment (baseline), sCD40 ligand and sP-selectin levels were elevated above the normal range of the assay (0.39 ug/L and 33.5 ug/L, respectively). The mean level of each biomarker was significantly different at one month compared to baseline (p

Lower serum chloride (Cl) levels are strongly associated with increased long-term mortality after admission for acute heart failure (AHF). However, the therapeutic implications of serum Cl levels during AHF are unknown. We sought to determine the short-term clinical response and post-discharge outcomes associated with serum Cl levels in AHF. Serum Cl was measured at randomization (N=358) and during hospitalization from patients with AHF in the in the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial. Outcomes included diuretic response and renal function at 72 hours and death and rehospitalization at 60 and 180-days. Baseline Cl tertiles were: 84–98 meq/L; 99–102 meq/L; and 103–117 meq/L. Baseline Cl level was associated with diuretic efficiency (P0.05). Chloride change correlated with weight change (rho 0.18, P=0.001), cystatin C change (rho −0.35, P0.05 for all). In conclusion, serum Cl levels in AHF were inversely associated with loop diuretic response and were prognostic. However, changes in Cl levels were associated with parameters of decongestion, but not with clinical outcomes.

The incidence of and factors associated with sudden cardiac death (SCD) early after an acute heart failure (HF) hospital admission have not been well defined.We assessed SCD and ventricular arrhythmias in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial, which included patients with acute HF with reduced or preserved ejection fraction. SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated from randomization through 30 days and were combined into a composite endpoint. Baseline characteristics associated with this composite were determined by logistic regression. RSCD and VT/VF were included as time-dependent variables in a Cox model evaluating the association of these variables with 180-day all-cause mortality. Among 7011 patients, the 30-day all-cause mortality rate was 3.8%; SCD accounted for 17% of these deaths. The 30-day composite event rate was 1.8% (n = 121). Ten patients had more than one event with 30-day Kaplan-Meier event rates of 0.6% for SCD [95% confidence interval (CI) 0.5%-0.9%, n = 43], 0.4% for RSCD (95% CI 0.2%-0.5%, n = 24), and 0.9% for VT/VF (95% CI 0.7%-1.2%, n = 64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, and longer QRS duration were associated with SCD, RSCD, or VT/VF. A RSCD or VT/VF event was associated with higher 180-day mortality (adjusted hazard ratio 6.6, 95% CI 4.8-9.1, P 0.0001).Approximately 2% of patients admitted for acute HF experienced SCD, RSCD, or VT/VF within 30 days of admission, and SCD accounted for 17% of all deaths within 30 days.

Increased physical activity is known to be beneficial in people with type 2 diabetes mellitus (T2DM), but it is not known whether individuals change their activity levels after T2DM diagnosis. The present Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2816 participants with the requisite data. Participants were relatively inactive at baseline, taking a median (interquartile range) of 5488 (3258-8361) steps/day, which decreased after T2DM diagnosis by a mean (s.e.) of 258 (64) steps/day (p < 0.0001); however, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged [mean (s.e.) of 103 (87) fewer steps/day; p = 0.23]. Awareness of T2DM diagnosis had no impact on the trajectory of activity established before the diagnosis.

We used baseline data from the NAVIGATOR trial to (1) identify risk factors for diabetes progression in those with impaired glucose tolerance and high cardiovascular risk, (2) create models predicting 5-year incident diabetes, and (3) provide risk classification tools to guide clinical interventions. Multivariate Cox proportional hazards models estimated 5-year incident diabetes risk and simplified models examined the relative importance of measures of glycemia in assessing diabetes risk. The C-statistic was used to compare models; reclassification analyses compare the models' ability to identify risk groups defined by potential therapies (routine or intensive lifestyle advice or pharmacologic therapy). Diabetes developed in 3,254 (35%) participants over 5 years median follow-up. The full prediction model included fasting and 2-hour glucose and hemoglobin A1c (HbA1c) values but demonstrated only moderate discrimination for diabetes (C = 0.70). Simplified models with only fasting glucose (C = 0.67) or oral glucose tolerance test values (C = 0.68) had higher C statistics than models with HbA1c alone (C = 0.63). The models were unlikely to inappropriately reclassify participants to risk groups that might receive pharmacologic therapy. Our results confirm that in a population with dysglycemia and high cardiovascular risk, traditional risk factors are appropriate predictors and glucose values are better predictors than HbA1c, but discrimination is moderate at best, illustrating the challenges of predicting diabetes in a high-risk population. In conclusion, our novel risk classification paradigm based on potential treatment could be used to guide clinical practice based on cost and availability of screening tests. © 2013 Elsevier Inc. All rights reserved.

Intra-aortic balloon pumps (IABPs) provide primarily left ventricular support, yet few data detail the efficacy of this temporary mechanical circulatory support device in patients with concomitant right ventricular failure. We compared the efficacy of IABPs in cardiogenic shock patients with isolated left ventricular versus biventricular failure.IABP-treated cardiogenic shock patients were identified from our center between 2006 and 2012, with patients stratified by either isolated left ventricular failure or biventricular failure. We compared baseline characteristics and 72-hour and 30-day outcomes between groups. Outcomes of interest included escalation of mechanical circulatory support, a clinical definition of IABP failure, and death.Among 107 patients, 60 patients (56%) had isolated left ventricular failure compared with 47 patients (44%) having biventricular failure. Patients with isolated left ventricular failure were older and more likely to have coronary artery disease ( p0.05, both). Patients with biventricular failure more often required escalation of mechanical circulatory support at both 72 hours (21% vs. 2%, p0.001) and 30 days (36% vs. 30%). However, there was no significant difference between groups for failure of IABP therapy at 72 hours ( p=0.27) or at 30 days ( p=0.62) and death at 30 days ( p=0.98). In adjusted analysis, there was no significant difference between groups with regard to risk for a clinical definition of IABP failure at 30 days (odds ratio=0.85, 95% confidence interval (0.27, 2.69)).IABP-treated cardiogenic shock patients with biventricular failure more often required early escalation of mechanical circulatory support. However, there were no significant differences by type of ventricular failure with regard to 30-day outcomes.

Background Red blood cell distribution width (RDW) strongly predicts clinical outcomes among patients with coronary disease and heart failure. The factors underpinning this association are unknown. Methods In 6,447 individuals enrolled in the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study who had undergone coronary angiography between 2001 and 2007, we used Cox proportional hazards modeling to examine the adjusted association between RDW and death, and death or myocardial infarction (MI). Multiple linear regression using the R 2 model selection method was then used to identify clinical factors associated with variation in RDW. Results Median follow-up was 4.2 (interquartile range 2.3-5.9) years, and the median RDW was 13.5% (interquartile range 12.9%-14.3%, clinical laboratory reference range 11.5%-14.5%). Red blood cell distribution width was independently associated with death (adjusted hazard ratio 1.13 per 1% increase in RDW, 95% CI 1.09-1.17), and death or MI (adjusted hazard ratio 1.12, 95% CI 1.08-1.16). Twenty-seven clinical characteristics and laboratory measures were assessed in the multivariable linear regression model; a final model containing 18 variables explained only 21% of the variation in RDW. Conclusions Although strongly associated with death and death or MI, only one-fifth of the variation in RDW was explained by routinely assessed clinical characteristics and laboratory measures. Understanding the latent factors that explain variation in RDW may provide insight into its strong association with risk and identify novel targets to mitigate that risk.

Background Little is known about the use of drugs or procedures for management of atrial flutter (AFl) in routine clinical practice. We describe the extent of use of conversion therapies during AFl hospitalizations. Methods We examined hospitalizations for primary diagnoses of AFl using hospital claims from January 2000 to December 2004. Patients who received antiarrhythmic drugs, ablation, and/or electrical cardioversion for AFl were categorized as receiving a conversion therapy. Characteristics associated with use of conversion therapy versus no conversion therapy were determined. Results The study cohort included 19,825 hospitalizations. Of these, 13,059 (65.9%) included in-hospital use of ≥1 conversion therapies. Care by a noncardiologist (adjusted odds ratio [OR] 0.37, 95% CI 0.33-0.41), female sex (adjusted OR 0.84, 95% CI 0.79-0.90), nonwhite race (adjusted OR 0.83, 95% CI 0.74-0.92), and increasing age >70 years (adjusted OR 0.88, 95% CI 0.85-0.91) were associated with lower odds of conversion versus no-conversion therapy. Cardiomyopathy (adjusted OR 1.33, 95% CI 1.17-1.51), heart failure (adjusted OR 1.17, 95% CI 1.06-1.28), coronary artery disease (adjusted OR 1.14, 95% CI 1.05-1.22), secondary diagnosis of atrial fibrillation (adjusted OR 1.28, 95% CI 1.18-1.38), and hospitalization in 2000 or 2001 versus later years (adjusted OR 1.22, 95% CI 1.12-1.33) were associated with greater odds of conversion therapy versus no conversion therapy. Conclusion One or more methods of conversion to sinus rhythm were used in two thirds of the hospitalizations with a primary diagnosis of AFl. Greater use of conversion therapies in patients with other heart disease were expected; however, lower use among elderly persons, females, and racial minorities may indicate some disparities in use and warrant further study.

This pilot study was undertaken to evaluate the hypotheses that there are differences in pediatric pain management (PPM) knowledge across resident specialties, that questions in the form of multiple-choice items could detect such differences, and that resident knowledge of analgesic-related adverse drug events (ADEs) would be greater than knowledge of PPM. Questions were based on two general categories of knowledge within acute pain management in hospitalized children: pediatric pain assessment and treatment, and identification of analgesic-related ADEs. As part of the pilot nature of this study, a convenience sample of 60 residents completed a 10-item PPM knowledge assessment prior to a PPM lecture. Twenty-six were pediatric residents (43%), 19 were orthopedic residents (32%), and 15 were anesthesiology residents (25%). All items had content validity. When controlling for resident year, performance by resident specialty was significantly different between anesthesia and orthopedics (P=0.006) and between anesthesia and pediatrics (P0.001). Resident knowledge of analgesic-related ADEs was not greater than knowledge of PPM. The most difficult topics were opioid equianalgesia, assessment of the cognitively impaired child, and maximal acetaminophen doses. Repeated administration of the PPM knowledge assessment at multiple institutions will allow further evaluation of our initial findings, and with directed educational interventions, provide opportunity for measurement of improvement.

Heart failure (HF) guidelines recommend that beta blockers be titrated to achieve the target doses shown to be effective in major clinical trials, if tolerated. Little is known, however, regarding the doses of beta blockers used in patients with HF in routine clinical practice before, during, and after hospitalization for HF. The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) enrolled 5,791 patients admitted with HF in a registry with prespecified 60- to 90-day follow-up at 91 academic and community hospitals throughout the United States. Among 2,373 patients with systolic HF eligible for beta blockers at discharge, 1,350 (56.9%) were receiving beta-blocker therapy before admission and continued on therapy, and 632 (26.6%) were newly started. The mean total daily dose for beta blockers before hospital admission was1/2 the recommended target dose (carvedilol 21.5 +/- 17.8 mg and metoprolol succinate 69.2 +/- 51.9 mg), with infrequent up- or down-titration during the HF hospitalization. More than 2/3 of patients had no change in their beta-blocker doses in the first 60 to 90 days after hospital discharge. At 60- to 90-day postdischarge follow-up, only 17.5% and 7.9% of patients were being treated with recommended target doses of carvedilol and metoprolol succinate, respectively. In conclusion, these data reveal that the doses of beta blockers applied in clinical practice are substantially less that the doses achieved in randomized clinical trials in HF and recommended in national guidelines. In the first 60 to 90 days after hospital discharge, little up-titration in beta-blocker dosing occurs. Further efforts are needed to help understand and overcome this beta-blocker titration gap.

The objective of this study was to prospectively evaluate beta-blocker use at hospital discharge as an indicator of quality of care and outcomes in patients with heart failure (HF).Data from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry for patients hospitalized with HF from 259 hospitals were prospectively collected and analyzed. HF medication contraindications, intolerance, and use at hospital discharge were assessed, along with 60- to 90-day follow-up data in a prespecified cohort. There were 20,118 patients with left ventricular systolic dysfunction. At discharge, 90.6% of patients were eligible to receive beta-blockers, and 83.7% were eligible to receive an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Eligible patients discharged with beta-blockers were significantly more likely to be treated at follow-up than those not discharged with beta-blockers (93.1% vs 30.5%; P.0001). Discharge use of beta-blockers in eligible patients was associated with a significant reduction in the adjusted risk of death (hazard ratio: 0.48; 95% confidence interval: 0.32-0.74; P.001) and death/rehospitalization (odds ratio: 0.74; 95% confidence interval: 0.55-0.99; P = .04), although we cannot completely exclude the possibility of residual confounding.Discharge beta-blocker use in HF appeared to be well tolerated, improved treatment rates, and was associated with substantially lower postdischarge mortality risk. These data provide additional evidence that supports beta-blocker use at hospital discharge in eligible patients as an HF performance measure.

It is now well established that many general anesthetics have a variety of effects on the developing brain in animal models. In contrast, human cohort studies show mixed evidence for any association between neurobehavioural outcome and anesthesia exposure in early childhood. In spite of large volumes of research, it remains very unclear if the animal studies have any clinical relevance; or indeed how, or if, clinical practice needs to be altered. Answering these questions is of great importance given the huge numbers of young children exposed to general anesthetics. A recent meeting in Genoa brought together researchers and clinicians to map a path forward for future clinical studies. This paper describes these discussions and conclusions. It was agreed that there is a need for large, detailed, prospective, observational studies, and for carefully designed trials. It may be impossible to design or conduct a single study to completely exclude the possibility that anesthetics can, under certain circumstances, produce long-term neurobehavioural changes in humans; however , observational studies will improve our understanding of which children are at greatest risk, and may also suggest potential underlying etiologies, and clinical trials will provide the strongest evidence to test the effectiveness of different strategies or anesthetic regimens with respect to better neurobehavioral outcome.

Contemporary studies suggest an association between venous thromboembolism and a higher incidence of major cardiovascular events, mostly attributed to arterial atherothrombosis. Using data from the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, we assessed the association of venous thromboembolism with major cardiovascular events.In NAVIGATOR, patients with impaired glucose tolerance were randomly allocated to receive valsartan or placebo and nateglinide or placebo in addition to lifestyle modification. Baseline characteristics and prior history of venous thromboembolism were assessed. After adjusting for important baseline covariates, Cox proportional hazards regression models were used to assess the association between venous thromboembolism and major cardiovascular outcomes.Of the 9306 patients enrolled, 129 (1.4%) had a history of venous thromboembolism. Patients with venous thromboembolism were older, more frequently white and female, and had a higher body mass index. Patients with venous thromboembolism had higher 5-year event rates for the composite of death, myocardial infarction, and stroke, as compared with patients without venous thromboembolism (10.7% vs 5.9%; P.001; adjusted hazard ratio 2.12; 95% confidence interval, 1.36-3.31; P = .001).In patients with impaired glucose tolerance at high risk for cardiovascular events, the prevalence of venous thromboembolism was rare but associated with worse long-term cardiovascular outcomes, including arterial events. Venous thromboembolism is a marker of risk, and attention should be paid to this high-risk group of patients.

OBJECTIVES The purpose of this study was to evaluate mortality and readmission rates of heart failure (HF) patients after major noncardiac surgery. BACKGROUND There is a lack of generalizable outcome data on HF patients undergoing major noncardiac surgery because previous studies have been limited to a few academic centers or have not focused on this group of patients. METHODS Using the 1997 to 1998 Standard Analytic File 5% Sample of Medicare beneficiaries, we identified patients with HF who underwent major noncardiac surgery. A multivariable logistic regression model was used to provide adjusted mortality and readmission rates in patients after noncardiac surgery. Patients with coronary artery disease (CAD) and all other remaining patients (Control) who had similar surgery served as reference groups. RESULTS Of 23,340 HF patients and 28,710 CAD patients, 1,532 (6.56%) HF patients and 1,757 (6.12%) CAD patients underwent major noncardiac surgery. There were 44,512 patients in the Control group with major noncardiac surgery. After accounting for demographic characteristics, type of surgery, and comorbid conditions, the risk-adjusted operative mortality (death before discharge or within 30 days of surgery) was HF 11.7%, CAD 6.6%, and Control 6.2% (HF vs. CAD, p < 0.001; CAD vs. Control, p = 0.518). The risk-adjusted 30-day readmission rate was HF 20.0%, CAD 14.2%, and Control 11.0% (p < 0.001). CONCLUSIONS In patients 65 years of age and older, HF patients undergoing major noncardiac surgery suffer substantial morbidity and mortality despite advances in perioperative care, whereas patients with CAD without HF have similar mortality compared with a more general population.

a Brazilian Clinical Research Institute, Sao Paulo, Brazil b Duke Translational Medicine Institute, Duke University Medical Center, Durham, NC, United States c Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, United States d BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, UK e Diabetes Trials Unit, Oxford Center for Diabetes, Endocrinology, and Metabolism, University of Oxford, Oxford, UK f San Antonio, TX, United States

Objective The cardiometabolic risk cluster metabolic syndrome (MS) includes ≥ 3 of elevated fasting glucose, hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-c), and increased waist circumference. Each can be affected by physical activity and diet. Our objective was to determine whether determine whether baseline physical activity and/or diet behavior impact MS in the course of a large pharmaceutical trial. Materials/Methods This was an observational study from NAVIGATOR, a double-blind, randomized (nateglinide, valsartan, both, or placebo), controlled trial between 2002 and 2004. We studied data from persons (n = 9306) with impaired glucose tolerance and cardiovascular disease (CVD) or CVD risk factors; 7118 with pedometer data were included in this analysis. Physical activity was assessed with 7-day pedometer records; diet behavior was self-reported on a 6-item survey. An MS score (MSSc) was calculated using the sum of each MS component, centered around the Adult Treatment Panel III threshold, and standardized according to sample standard deviation. Excepting HDL-c, assessed at baseline and year 3, MS components were assessed yearly. Follow-up averaged 6 years. Results For every 2000-step increase in average daily steps, there was an associated reduction in average MSSc of 0.29 (95% CI -0.33 to -0.25). For each diet behavior endorsed, there was an associated reduction in average MSSc of 0.05 (95% CI -0.08 to -0.01). Accounting for the effects of pedometer steps and diet behavior together had minimal impact on parameter estimates with no significant interaction. Relations were independent of age, sex, race, region, smoking, family history of diabetes, and use of nateglinide, valsartan, aspirin, antihypertensive, and lipid-lowering agent. Conclusions Baseline physical activity and diet behavior were associated independently with reductions in MSSc such that increased attention to these lifestyle elements provides cardiometabolic benefits. Thus, given the potential to impact outcomes, assessment of physical activity and diet should be performed in pharmacologic trials targeting cardiometabolic risk.

Background The role of dysglycemia as an additional risk factor for atrial fibrillation (AF) is controversial. Therefore, it was of interest to assess risk factors for incident AF in a large, representative population of patients with cardiovascular risk factors and impaired glucose tolerance but not overt diabetes in NAVIGATOR. Methods Predictors of incident AF were analyzed in 8,943 patients without AF at baseline by Cox proportional hazards regression. Study treatments (valsartan vs no valsartan and nateglinide vs no nateglinide) and the time-dependent covariate for progression to type 2 diabetes mellitus were added separately to the model. Results The median age of the 8,943 patients included in the present analysis of the NAVIGATOR trial was 63 years. Half of those patients were men, 6,922 (77.4%) had a history of hypertension, and 255 (2.9%) had heart failure. The median glycated hemoglobin was 6%. During the study, 613 of the 8,943 patients without AF at baseline presented with at least 1 episode of AF (6.9% 5-year incidence). Besides established predictors of incident AF, a 1 mmol/L increment of baseline fasting glucose, but not progression to diabetes, was found to be associated with a 33% increased risk of incident AF. Neither valsartan nor nateglinide affected AF incidence. Conclusions In a trial population with impaired glucose tolerance, fasting plasma glucose and well-known risk factors (age, hypertension, and elevated body weight), but not progression to diabetes, predict risk of AF.

Background— Impaired glucose tolerance and metabolic syndrome are associated with increased risk of heart failure (HF). However, predictors associated with the increased risk of incident HF have not been well characterized. We aimed to identify independent predictors of incident HF hospitalization among patients with impaired glucose tolerance. Methods and Results— In Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR), 9306 research participants with impaired glucose tolerance and ≥1 cardiovascular risk factors were randomized to valsartan versus placebo and nateglinide versus placebo in a 2×2 factorial manner, with a median follow-up of 6.5 years. Using a multivariable Cox proportional hazards model, we analyzed the relationships among baseline clinical factors and the outcome of incident HF hospitalization in patients without history of HF. Significant predictors were identified by forward selection. Increasing age, history of coronary heart disease, and atrial fibrillation or flutter were among several known independent predictors of incident HF hospitalization. Increased waist circumference (hazard ratio per 10 cm, 1.37; 95% confidence interval, 1.21–1.55; P P Conclusions— Among research participants with impaired glucose tolerance, there are several easily identifiable predictors of incident HF hospitalization, including traditional risk factors and novel indices of central adiposity and increased urinary albumin–creatinine ratio, which enable further risk stratification and help distinguish patients who could benefit from more aggressive risk factor management.