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1.  Non‐ST‐Elevation Myocardial Infarction in the United States: Contemporary Trends in Incidence, Utilization of the Early Invasive Strategy, and In‐Hospital Outcomes 
Background
There has been a paradigm shift in the definition of timing of early invasive strategy (EIS) for patients admitted with non‐ST‐elevation myocardial infarction (NSTEMI) in the last decade. Data on trends of EIS for NSTEMI and associated in‐hospital outcomes are limited. Our aim is to analyze temporal trends in the incidence, utilization of early invasive strategy, and in‐hospital outcomes of NSTEMI in the United States.
Methods and Results
We analyzed the 2002–2011 Nationwide Inpatient Sample databases to identify all patients ≥40 years of age with the principal diagnosis of acute myocardial infarction (AMI) and NSTEMI. Logistic regression was used for overall, age‐, sex‐, and race/ethnicity‐stratified trend analysis. From 2002 to 2011, we identified 6 512 372 patients with AMI. Of these, 3 981 119 (61.1%) had NSTEMI. The proportion of patients with NSTEMI increased from 52.8% in 2002 to 68.6% in 2011 (adjusted odds ratio [OR; per year], 1.055; 95% confidence interval [CI], 1.054 to 1.056) in the overall cohort. Similar trends were observed in age‐, sex‐, and race/ethnicity‐stratified groups. From 2002 to 2011, utilization of EIS at day 0 increased from 14.9% to 21.8% (Ptrend<0.001) and utilization of EIS at day 0 or 1 increased from 27.8% to 41.4% (Ptrend<0.001). Risk‐adjusted in‐hospital mortality in the overall cohort decreased during the study period (adjusted OR [per year], 0.976; 95% CI, 0.974 to 0.978).
Conclusions
There have been temporal increases in the proportion of NSTEMI and, consistent with guidelines, greater utilization of EIS. This has been accompanied by temporal decreases in in‐hospital mortality and length of stay.
doi:10.1161/JAHA.114.000995
PMCID: PMC4310389  PMID: 25074695
early invasive strategy; in‐hospital mortality; non‐ST‐elevation myocardial infarction; temporal trends
2.  Temporal Trends in Incidence and Outcomes of Peripartum Cardiomyopathy in the United States: A Nationwide Population‐Based Study 
Background
The reported incidence of peripartum cardiomyopathy (PPCM) in the United States varies widely. Furthermore, limited information is available on the temporal trends in incidence and outcomes of PPCM.
Methods and Results
We queried the 2004‐2011 Nationwide Inpatient Sample databases to identify all women aged 15 to 54 years with the diagnosis of PPCM. Temporal trends in incidence (per 10 000 live births), maternal major adverse events (MAE; defined as in‐hospital mortality, cardiac arrest, heart transplant, mechanical circulatory support, acute pulmonary edema, thromboembolism, or implantable cardioverter defibrillator/permanent pacemaker implantation), cardiogenic shock, and mean length of stay were analyzed. From 2004 to 2011, we identified 34 219 women aged 15 to 54 years with PPCM. The overall PPCM rate was 10.3 per 10 000 (or 1 in 968) live births. PPCM incidence increased from 8.5 to 11.8 per 10 000 live births (Ptrend<0.001) over the past 8 years. MAE occurred in 13.5% of patients. There was no temporal change in MAE rate, except a small increase in in‐hospital mortality and mechanical circulatory support (Ptrend<0.05). Cardiogenic shock increased from 1.0% in 2004 to 4.0% in 2011 (Ptrend<0.001). Mean length of stay decreased during the study period.
Conclusion
From 2004 to 2011, the incidence of PPCM has increased in the United States. Maternal MAE rates overall have remained unchanged while cardiogenic shock, utilization of mechanical circulatory support, and in‐hospital mortality have increased during the study period. Further study of the mechanisms underlying these adverse trends in the incidence and outcomes of PPCM are warranted.
doi:10.1161/JAHA.114.001056
PMCID: PMC4309108  PMID: 24901108
incidence; major adverse events; outcomes; peripartum cardiomyopathy; trends
3.  Trends in Incidence, Management, and Outcomes of Cardiogenic Shock Complicating ST‐Elevation Myocardial Infarction in the United States 
Background
Limited information is available on the contemporary and potentially changing trends in the incidence, management, and outcomes of cardiogenic shock complicating ST‐elevation myocardial infarction (STEMI).
Methods and Results
We queried the 2003–2010 Nationwide Inpatient Sample databases to identify all patients ≥40 years of age with STEMI and cardiogenic shock. Overall and age‐, sex‐, and race/ethnicity‐specific trends in incidence of cardiogenic shock, early mechanical revascularization, and intra‐aortic balloon pump use, and inhospital mortality were analyzed. From 2003 to 2010, among 1 990 486 patients aged ≥40 years with STEMI, 157 892 (7.9%) had cardiogenic shock. The overall incidence rate of cardiogenic shock in patients with STEMI increased from 6.5% in 2003 to 10.1% in 2010 (Ptrend<0.001). There was an increase in early mechanical revascularization (30.4% to 50.7%, Ptrend<0.001) and intra‐aortic balloon pump use (44.8% to 53.7%, Ptrend<0.001) in these patients over the 8‐year period. Inhospital mortality decreased significantly, from 44.6% to 33.8% (Ptrend<0.001; adjusted OR, 0.71; 95% CI, 0.68 to 0.75), whereas the average total hospital cost increased from $35 892 to $45 625 (Ptrend<0.001) during the study period. There was no change in the average length of stay (Ptrend=0.394). These temporal trends were similar in patients <75 and ≥75 years of age, men and women, and across each racial/ethnic group.
Conclusions
The incidence of cardiogenic shock complicating STEMI has increased during the past 8 years together with increased use of early mechanical revascularization and intra‐aortic balloon pumps. There has been a concomitant decrease in risk‐adjusted inhospital mortality, but an increase in total hospital costs during this period.
doi:10.1161/JAHA.113.000590
PMCID: PMC3959706  PMID: 24419737
cardiogenic shock; early revascularization; inhospital mortality; ST‐elevation myocardial infarction; trends
4.  Heart failure clinical trials: how do we define success? 
Nature reviews. Cardiology  2013;10(9):492-494.
The selection of end points for clinical trials of heart failure is challenging, with important implications for patients, the medical community, and regulatory agencies. The standards used in clinical research on patients with heart failure influence the effectiveness and value of future clinical trials, and the extent to which they can be translated into clinical practice.
doi:10.1038/nrcardio.2013.115
PMCID: PMC4315498  PMID: 23917464
5.  Outcomes of Medicare Beneficiaries With Heart Failure and Atrial Fibrillation 
JACC. Heart failure  2014;2(1):41-48.
Objective
To examine long-term outcomes of patients hospitalized with heart failure and atrial fibrillation.
Background
Atrial fibrillation is common among patients hospitalized with heart failure. Associations of preexisting and new-onset atrial fibrillation with long-term outcomes are unclear.
Methods
We analyzed 27,829 heart failure admissions between 2006 and 2008 at 281 hospitals in the American Heart Association’s Get With the Guidelines-Heart Failure program linked with Medicare claims. Patients were classified as having preexisting, new-onset, or no atrial fibrillation. We used Cox proportional hazards models to identify factors that were independently associated with all-cause mortality, all-cause readmission, and readmission for heart failure, stroke, and other cardiovascular disease at 1 and 3 years.
Results
After multivariable adjustment, preexisting atrial fibrillation was associated with greater 3-year risks of all-cause mortality (hazard ratio, 1.14; 99% CI, 1.08–1.20), all-cause readmission (1.09; 1.05–1.14), heart failure readmission (1.15; 1.08–1.21), and stroke readmission (1.20; 1.01–1.41), compared with no atrial fibrillation. There was also a greater hazard of mortality at 1 year among patients with new-onset atrial fibrillation (hazard ratio, 1.12; 99% CI, 1.01–1.24). New-onset atrial fibrillation was not associated with a greater risk of the readmission outcomes, compared with no atrial fibrillation. Stroke readmission rates at 1 year were just as high for patients with preserved ejection fraction as for patients with reduced ejection fraction.
Conclusions
Both preexisting and new-onset atrial fibrillation were associated with greater long-term mortality among older patients with heart failure. Preexisting atrial fibrillation was associated with greater risk of readmission.
doi:10.1016/j.jchf.2013.11.002
PMCID: PMC4174273  PMID: 24622118
Atrial Fibrillation; Heart Failure; Medicare; Mortality; Outcome Assessment (Health Care); Patient Readmission
6.  Comparison of Performance Achievement Award Recognition With Primary Stroke Center Certification for Acute Ischemic Stroke Care 
Background
Hospital certification and recognition programs represent 2 independent but commonly used systems to distinguish hospitals, yet they have not been directly compared. This study assessed acute ischemic stroke quality of care measure conformity by hospitals receiving Primary Stroke Center (PSC) certification and those receiving the American Heart Association's Get With The Guidelines‐Stroke (GWTG‐Stroke) Performance Achievement Award (PAA) recognition.
Methods and Results
The patient and hospital characteristics as well as performance/quality measures for acute ischemic stroke from 1356 hospitals participating in the GWTG‐Stroke Program 2010–2012 were compared. Hospitals were classified as PAA+/PSC+ (hospitals n=410, patients n=169 302), PAA+/PSC− (n=415, n=129 454), PAA−/PSC+ (n=88, n=26 386), and PAA−/PSC− (n=443, n=75 565). A comprehensive set of stroke measures were compared with adjustment for patient and hospital characteristics. Patient characteristics were similar by PAA and PSC status but PAA−/PSC− hospitals were more likely to be smaller and nonteaching. Measure conformity was highest for PAA+/PSC+ and PAA+/PSC− hospitals, intermediate for PAA−/PSC+ hospitals, and lowest for PAA−/PSC− hospitals (all‐or‐none care measure 91.2%, 91.2%, 84.3%, and 76.9%, respectively). After adjustment for patient and hospital characteristics, PAA+/PSC+, PAA+/PSC−, and PAA−/PSC+ hospitals had 3.15 (95% CIs 2.86 to 3.47); 3.23 (2.93 to 3.56) and 1.72 (1.47 to 2.00), higher odds for providing all indicated stroke performance measures to patients compared with PAA−/PSC− hospitals.
Conclusions
While both PSC certification and GWTG‐Stroke PAA recognition identified hospitals providing higher conformity with care measures for patients hospitalized with acute ischemic stroke, PAA recognition was a more robust identifier of hospitals with better performance.
doi:10.1161/JAHA.113.000451
PMCID: PMC3835260  PMID: 24125846
acute stroke; measures registry; Primary Stroke Center certification
7.  Digoxin Use and Lower 30-Day All-Cause Readmission for Medicare Beneficiaries Hospitalized for Heart Failure 
The American journal of medicine  2013;127(1):61-70.
BACKGROUND
Heart failure is the leading cause for hospital readmission, the reduction of which is a priority under the Affordable Care Act. Digoxin reduces 30-day all-cause hospital admission in chronic systolic heart failure. Whether digoxin is effective in reducing readmission after hospitalization for acute decompensation remains unknown.
METHODS
Of the 5153 Medicare beneficiaries hospitalized for acute heart failure and not receiving digoxin, 1054 (20%) received new discharge prescriptions for digoxin. Propensity scores for digoxin use, estimated for each of the 5153 patients, were used to assemble a matched cohort of 1842 (921 pairs) patients (mean age, 76 years; 56% women; 25% African American) receiving and not receiving digoxin, who were balanced on 55 baseline characteristics.
RESULTS
30-day all-cause readmission occurred in 17% and 22% of matched patients receiving and not receiving digoxin, respectively (hazard ratio {HR} for digoxin, 0.77; 95% confidence interval {CI}, 0.63–0.95). This beneficial association was observed only in those with ejection fraction <45% (HR, 0.63; 95% CI, 0.47–0.83), but not in those with ejection fraction ≥45% (HR, 0.91; 95% CI, 0.60–1.37; p for interaction, 0.145), a difference that persisted throughout first 12-month post-discharge (p for interaction, 0.019). HRs (95% CIs) for 12-month heart failure readmission and all-cause mortality were 0.72 (0.61–0.86) and 0.83 (0.70–0.98), respectively.
CONCLUSIONS
In Medicare beneficiaries with systolic heart failure, a discharge prescription of digoxin was associated with lower 30-day all-cause hospital readmission, which was maintained at 12 months, and was not at the expense of higher mortality. Future randomized controlled trials are needed to confirm these findings.
doi:10.1016/j.amjmed.2013.08.027
PMCID: PMC3929967  PMID: 24257326
Digoxin; heart failure; hospital readmission
8.  Use of Hydralazine‐Isosorbide Dinitrate Combination in African American and Other Race/Ethnic Group Patients With Heart Failure and Reduced Left Ventricular Ejection Fraction 
Background
Hydralazine‐isosorbide dinitrate (H‐ISDN) therapy is recommended for African American patients with moderate to severe heart failure with reduced ejection fraction (<40%) (HFrEF), but use, temporal trends, and clinical characteristics associated with H‐ISDN therapy in clinical practice are unknown.
Methods and Results
An observational analysis of 54 622 patients admitted with HFrEF and discharged home from 207 hospitals participating in the Get With The Guidelines–Heart Failure registry from April 2008 to March 2012 was conducted to assess prescription, trends, and predictors of use of H‐ISDN among eligible patients. Among 11 185 African American patients eligible for H‐ISDN therapy, only 2500 (22.4%) received H‐ISDN therapy at discharge. In the overall eligible population, 5115 of 43 498 (12.6%) received H‐ISDN at discharge. Treatment rates increased over the study period from 16% to 24% among African Americans and from 10% to 13% among the entire HFrEF population. In a multivariable model, factors associated with H‐ISDN use among the entire cohort included younger age; male sex; African American/Hispanic ethnicity; and history of diabetes, hypertension, anemia, renal insufficiency, higher systolic blood pressure, and lower heart rate. In African American patients, these factors were similar; in addition, being uninsured was associated with lower use.
Conclusions
Overall, few potentially eligible patients with HFrEF are treated with H‐ISDN, and among African‐Americans fewer than one‐fourth of eligible patients received guideline‐recommended H‐ISDN therapy. Improved ways to facilitate use of H‐ISDN therapy in African American patients with HFrEF are needed.
doi:10.1161/JAHA.113.000214
PMCID: PMC3828812  PMID: 23966379
guideline adherence; heart failure; quality; race/ethnicity; registry
9.  Process of Care Performance Measures and Long-Term Outcomes in Patients Hospitalized With Heart Failure 
Medical care  2010;48(3):210-216.
Background
Recent efforts to improve care for patients hospitalized with heart failure have focused on process-based performance measures. Data supporting the link between current process measures and patient outcomes are sparse.
Objective
To examine the relationship between adherence to hospital-level process measures and long-term patient-level mortality and readmission.
Research Design
Analysis of data from a national clinical registry linked to outcome data from the Centers for Medicare & Medicaid Services (CMS).
Subjects
22750 Medicare fee-for-service beneficiaries enrolled in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) between March 2003 and December 2004.
Measures
Mortality at 1 year; cardiovascular readmission at 1 year; and adherence to hospital-level process measures, including discharge instructions, assessment of left ventricular function, prescription of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at discharge, prescription of beta-blockers at discharge, and smoking cessation counseling for eligible patients.
Results
Hospital conformity rates ranged from 52% to 86% across the 5 process measures. Unadjusted overall 1-year mortality and cardiovascular readmission rates were 33% and 40%, respectively. In covariate-adjusted analyses, the CMS composite score was not associated with 1-year mortality (hazard ratio, 1.00; 95% confidence interval, 0.98-1.03; P = .91) or readmission (hazard ratio, 1.01; 95% confidence interval, 0.99-1.04; P = .37). Current CMS process measures were not independently associated with mortality, though prescription of beta-blockers at discharge was independently associated with lower mortality (hazard ratio, 0.94; 95% confidence interval, 0.90-098; P = .004).
Conclusion
Hospital process performance for heart failure as judged by current CMS measures is not associated with patient outcomes within 1 year of discharge, calling into question whether existing CMS metrics can accurately discriminate hospital quality of care for heart failure.
doi:10.1097/MLR.0b013e3181ca3eb4
PMCID: PMC3723387  PMID: 20125043
heart failure; mortality; outcome and process assessment (health care); patient readmission
10.  Relation of Serum Magnesium Levels and Postdischarge Outcomes in Patients Hospitalized for Heart Failure (from the EVEREST Trial) 
The American journal of cardiology  2013;112(11):1763-1769.
Serum magnesium levels may be impacted by neurohormonal activation, renal function, and diuretics. The clinical profile and prognostic significance of serum magnesium level concentration in patients hospitalized for heart failure (HF) with reduced ejection fraction is unclear. In this retrospective analysis of the placebo group of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan trial, we evaluated 1,982 patients hospitalized for worsening HF with ejection fractions ≤40%. Baseline magnesium levels were measured within 48 hours of admission and analyzed as a continuous variable and in quartiles. The primary end points of all-cause mortality (ACM) and cardiovascular mortality or HF rehospitalization were analyzed using Cox regression models. Mean baseline magnesium level was 2.1 ± 0.3 mg/dl. Compared with the lowest quartile, patients in the highest magnesium level quartile were more likely to be older, men, have lower heart rates and blood pressures, have ischemic HF origin, and have higher creatinine and natriuretic peptide levels (all p <0.003). During a median follow-up of 9.9 months, every 1-mg/dl increase in magnesium level was associated with higher ACM (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.35 to 2.32; p <0.001) and the composite end point (HR 1.44; 95% CI 1.15 to 1.81; p = 0.002). However, after adjustment for known baseline covariates, serum magnesium level was no longer an independent predictor of either ACM (HR 0.94, 95% CI 0.69 to 1.28; p = 0.7) or the composite end point (HR 1.01, 95% CI 0.79 to 1.30; p = 0.9). In conclusion, despite theoretical concerns, baseline magnesium level was not independently associated with worse outcomes in this cohort. Further research is needed to understand the importance of serum magnesium levels in specific HF patient populations.
doi:10.1016/j.amjcard.2013.07.020
PMCID: PMC4158384  PMID: 24095030
11.  Visual Assessment of Brain Magnetic Resonance Imaging Detects Injury to Cognitive Regulatory Sites in Patients with Heart Failure 
Journal of cardiac failure  2013;19(2):94-100.
Background
Heart failure (HF) patients exhibit depressive and executive function impairments that contribute to HF mortality. Using specialized magnetic resonance imaging (MRI) analysis procedures, brain changes appear in areas regulating these functions (mammillary bodies, hippocampi, and frontal cortex). However, specialized MRI procedures are not part of standard clinical assessment for HF (which is usually a visual evaluation), and it is unclear whether visual examination can detect changes in these structures.
Methods and Results
Using brain MRI, we visually examined the mammillary bodies and frontal cortex for global and hippocampi for global and regional tissue changes in 17 HF and 50 control subjects. Significant global changes emerged in the right mammillary body (HF vs. control scores; 1.18±1.13 vs. 0.52±0.74; P=.024), right hippocampus (1.53±0.94 vs. 0.80±0.86; P=0.005), and left frontal cortex (1.76±1.03 vs. 1.24±0.77; P=0.034) between groups. Comparison of the visual method with specialized MRI techniques corroborates right hippocampal and left frontal cortical, but not mammillary body, atrophy.
Conclusions
Visual examination of brain MRI can detect damage in HF in areas regulating depression and executive function, including the right hippocampus and left frontal cortex. Visual MRI assessment may facilitate evaluation of injury to these structures and the assessment of the impact of potential treatments for this damage.
doi:10.1016/j.cardfail.2012.12.001
PMCID: PMC4249656  PMID: 23384634
Mammillary body; hippocampus; frontal cortex; atrophy
12.  Home Monitoring for Heart Failure Management 
With a prevalence of 5.8 million in the United States alone, heart failure (HF) is a common syndrome associated with substantial morbidity, mortality, and health-care expenditures. Close to 1 million HF hospitalizations occur annually in the United States, with the majority of these resulting from worsening congestion in patients previously diagnosed with HF. An estimated 37.2 billion dollars is spent each year on HF in the United States. These statistics emphasize the need to develop and implement more effective strategies to assess, monitor, and treat HF. It has also become increasingly apparent that interventions geared towards identifying and monitoring sub-clinical congestion would be of value in the home management of chronic HF. Earlier identification and treatment of congestion together with improved care coordination, management of comorbid conditions, and enhanced patient self-management may help to prevent hospitalizations in patients with chronic HF. Such home monitoring extends from the promotion of self-care and home visitations, to telemedicine and remote monitoring of external or implantable devices. This paper will discuss the challenges in monitoring patients with HF, review clinical trials testing different monitoring strategies in HF, and highlight ongoing investigations into the optimal approaches to home monitoring for HF.
doi:10.1016/j.jacc.2011.09.044
PMCID: PMC3254025  PMID: 22222071
heart failure; ambulatory monitoring; home care; telemedicine; disease management
13.  Relation Between Body Mass Index, Exercise Training, and Outcomes in Chronic Systolic Heart Failure 
The American journal of cardiology  2011;108(12):1754-1759.
Exercise training (ET) in heart failure (HF), as demonstrated in the HF-ACTION trial, was associated with improved exercise tolerance and health status, and a trend towards reduced mortality or hospitalizations. This analysis of the HF-ACTION cohort examines the effect of ET in overweight and obese compared to normal HF subjects. 2,314 of 2,331 systolic HF subjects randomized to aerobic ET vs. usual care in HF-ACTION were analyzed to determine the effect of ET on all cause mortality, hospitalizations, exercise parameters, quality of life (QOL), and body weight changes by subgroups of body mass index (BMI). Strata included normal weight (BMI 18.5 – 24.9 kg/m2), overweight (BMI 25.0 – 29.9 kg/m2), obese I (BMI 30 – 34.9 kg/m2), obese II (BMI 35-39.9 kg/m2), and obese III (BMI ≥ 40 kg/m2). At enrollment, 19.4% of subjects were normal weight, 31.3% overweight, and 49.4% obese. Higher BMI was associated with a non-significant increase in all cause mortality or hospitalization. ET was associated with non-significant reductions in all cause mortality or hospitalization in each weight category (HR 0.98, 0.95, 0.92, 0.89, and 0.86 in normal weight, overweight, obese I, obese II, and obese III categories, respectively [all p>0.05]). Modeled improvement in exercise capacity (peak oxygen consumption) and QOL in the ET group was seen in all BMI categories. In conclusion, aerobic ET in HF was associated with a non-significant trend towards decreased mortality and hospitalizations and a significant improvement in QOL across the range of BMI categories.
doi:10.1016/j.amjcard.2011.07.051
PMCID: PMC3229667  PMID: 21907317
heart failure; body mass index; exercise
14.  Pro-HEART – A Randomized Clinical Trial to Test the Effectiveness of a High Protein Diet Targeting Obese Individuals with Heart Failure: Rationale, Design and Baseline Characteristics 
Contemporary clinical trials  2013;36(2):10.1016/j.cct.2013.08.004.
There is ample research to support the potential benefits of a high protein diet on clinical outcomes in overweight/obese, diabetic subjects. However, nutritional management of overweight/obese individuals with heart failure (HF) and type 2 diabetes mellitus (DM) or metabolic syndrome (MS) is poorly understood and few clinical guidelines related to nutritional approaches exist for this subgroup. This article describes the design, methods, and baseline characteristics of study participants enrolled in Pro-HEART, a randomized clinical trial to determine the short term and long term effects of a high protein diet (30% protein [~110 g/day], 40% carbohydrates [150 g/day], 30% fat [~50 g/day]) versus a standard protein diet (15% protein [~55 g/day], 55% carbohydrates [~200 g/day], 30% fat [~50 g/day]) on body weight and adiposity, cardiac structure and function, functional status, lipid profile, glycemic control, and quality of life. Between August, 2009 and May, 2013, 61 individuals agreed to participate in the study; 52 (85%) - mean age 58.2 ± 9.8 years; 15.4% Blacks; 57.7% Whites; 19.2% Hispanics; 7.7% Asians; 73.1% male; weight 112.0 ± 22.6 kilograms- were randomized to a 3-month intensive weight management program of either a high protein or standard protein diet; data were collected at baseline, 3 months, and 15 months. This study has the potential to reveal significant details about the role of macronutrients in weight management of overweight/obese individuals with HF and DM or MS.
doi:10.1016/j.cct.2013.08.004
PMCID: PMC3844022  PMID: 23958597
Heart failure; Obesity; Nutrition; Clinical trial
15.  Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial 
Maggioni, Aldo P. | Greene, Stephen J. | Fonarow, Gregg C. | Böhm, Michael | Zannad, Faiez | Solomon, Scott D. | Lewis, Eldrin F. | Baschiera, Fabio | Hua, Tsushung A. | Gimpelewicz, Claudio R. | Lesogor, Anastasia | Gheorghiade, Mihai | Ramos, Silvina | Luna, Alejandra | Miriuka, Santiago | Diez, Mirta | Perna, Eduardo | Luquez, Hugo | Pinna, Jorge Garcia | Castagnino, Jorge | Alvarenga, Pablo | Ibañez, Julio | Blumberg, Eduardo Salmon | Dizeo, Claudio | Guerrero, Rodolfo Ahuad | Schygiel, Pablo | Milesi, Rodolfo | Sosa, Carlos | Hominal, Miguel | Marquez, Lilia Lobo | Poy, Carlos | Hasbani, Eduardo | Vico, Marisa | Fernandez, Alberto | Vita, Nestor | Vanhaecke, Johan | De Keulenaer, Gilles | Striekwold, Harry | Vervoort, Geert | Vrolix, Mathias | Henry, Philippe | Dendale, Paul | Smolders, Walter | Marechal, Patrick | Vandekerckhove, Hans | Oliveira, Mucio | Neuenschwande, Fernando | Reis, Gilmar | Saraiva, Jose | Bodanese, Luiz | Canesin, Manoel | Greco, Oswaldo | Bassan, Roberto | Marino, Roberto Luis | Giannetti, Nadia | Moe, Gordon | Sussex, Bruce | Sheppard, Richard | Huynh, Thao | Stewart, Robert | Haddad, Haissam | Echeverria, Luis | Quintero, Adalberto | Torres, Adriana | Jaramillo, Mónica | Lopez, Mónica | Mendoza, Fernan | Florez, Noel | Cotes, Carlos | Garcia, Magali | Belohlavek, Jan | Hradec, Jaromir | Peterka, Martin | Gregor, Pavel | Monhart, Zdenek | Jansky, Petr | Kettner, Jiri | Reichert, Petr | Spinar, Jindrich | Brabec, Tomas | Hutyra, Martin | Solar, Miroslav | Pietilä, Mikko | Nyman, Kai | Pajari, Risto | Cohen, Ariel | Galinier, Michel | Gosse, Philippe | Livarek, Bernard | Neuder, Yannick | Jourdain, Patrick | Picard, François | Isnard, Richard | Hoppe, Uta | Kaeaeb, Stefan | Rosocha, Stefan | Prondzinsky, Roland | Felix, Stephan | Duengen, Hans-Dirk | Figulla, Hans-Reiner | Fischer, Sven | Behrens, Steffen | Stawowy, Philipp | Kruells-Muench, Juergen | Knebel, Fabian | Nienaber, Christoph | Werner, Dierk | Aron, Wilma | Remppis, Bjoern | Hambrecht, Rainer | Kisters, Klaus | Werner, Nikos | Hoffmann, Stefan | Rossol, Siegbert | Geiss, Ernst | Graf, Kristof | Hamann, Frank | von Scheidt, Wolfgang | Schwinger, Robert | Tebbe, Ulrich | Costard-Jaeckle, Angelika | Lueders, Stephan | Heitzer, Thomas | Leutermann-Oei, Marie-Louise | Braun-Dullaeus, Ruediger | Roehnisch, Jens-Uwe | Muth, Gerhard | Goette, Andreas | Rotter, Achim | Ebelt, Henning | Olbrich, Hans-Georg | Mitrovic, Veselin | Hengstenberg, Christian | Schellong, Sebastian | Zamolyi, Karoly | Vertes, Andras | Matoltsy, Andras | Palinkas, Attila | Herczeg, Bela | Apro, Dezso | Lupkovics, Geza | Tomcsanyi, Janos | Toth, Kalman | Mathur, Atul | Banker, Darshan | Bharani, Anil | Arneja, Jaspal | Khan, Aziz | Gadkari, Milind | Hiremath, Jagdish | Patki, Nitin | Kumbla, Makund | Santosh, M.J. | Ravikishore, A.G. | Abhaichand, Rajpal | Maniyal, Vijayakukmar | Nanjappa, Manjunath | Reddy, P. Naveen | Chockalingam, Kulasekaran | Premchand, Rajendra | Mahajan, Vijay | Lewis, Basil | Wexler, Dov | Shochat, Michael | Keren, Andre | Omary, Muhamad | Katz, Amos | Marmor, Alon | Lembo, Giuseppe | Di Somma, Salvatore | Boccanelli, Alessandro | Barbiero, Mario | Pajes, Giuseppe | De Servi, Stefano | Greco, Dott Cosimo | De Santis, Fernando | Floresta, Agata | Visconti, Luigi Oltrona | Piovaccari, Giancarlo | Cavallini, Claudio | Di Biase, Matteo | Masini, Dott Franco | Vassanelli, Corrado | Viecca, Maurizio | Cangemi, Dott Francesco | Pirelli, Salvatore | Borghi, Claudio | Volpe, Massimo | Branzi, Angelo | Percoco, Dott Giovanni | Severi, Silvia | Santini, Alberto | De Lorenzi, Ettore | Metra, Marco | Zacà, Valerio | Mortara, Andrea | Tranquilino, Francisco P. | Babilonia, Noe A. | Ferrolino, Arthur M. | Manlutac, Benjamin | Dluzniewski, Miroslaw | Dzielinska, Zofia | Nowalany-Kozie, Ewa | Mazurek, Walentyna | Wierzchowiecki, Jerzy | Wysokinski, Andrzej | Szachniewicz, Joanna | Romanowski, Witold | Krauze-Wielicka, Magdalena | Jankowski, Piotr | Berkowski, Piotr | Szelemej, Roman | Kleinrok, Andrzej | Kornacewicz-Jac, Zdzislawa | Vintila, Marius | Vladoianu, Mircea | Militaru, Constantin | Dan, Gheorghe | Dorobantu, Maria | Dragulescu, Stefan | Kostenko, Victor | Vishnevsky, Alexandr | Goloschekin, Boris | Tyrenko, Vadim | Gordienko, Alexander | Kislyak, Oxana | Martsevich, Sergey | Kuchmin, Alexey | Karpov, Yurii | Fomin, Igor | Shvarts, Yury | Orlikova, Olga | Ershova, Olga | Berkovich, Olga | Sitnikova, Maria | Pakhomova, Inna | Boldueva, Svetlana | Tyurina, Tatiana | Simanenkov, Vladimir | Boyarkin, Mikhail | Novikova, Nina | Tereschenko, Sergey | Zadionchenko, Vladimir | Shogenov, Zaur | Gordeev, Ivan | Moiseev, Valentin | Wong, Raymond | Ong, Hean Yee | Le Tan, Ju | Goncalvesova, Eva | Kovar, Frantisek | Skalina, Ivan | Kasperova, Viera | Hojerova, Silvia | Szentivanyi, Miroslav | Stancak, Branislav | Babcak, Marian | Kycina, Peter | Poliacik, Pavol | Toth, Peter | Sirotiakova, Jana | de Sa, Esteban Lopez | Bueno, Manuel Gomez | Selles, Manuel Martinez | Cabrera, Jose Angel | Freire, Ramon Bover | Gonzalez Juanatey, Jose Ramon | Comin, Josep | Soriano, FranciscoRidocci | Lopez, Alejandro | Vicho, Raul | Lama, Manuel Geraldia | Schaufelberger, Maria | Brunotte, Richard | Ullman, Bengt | Hagerman, Inger | Cizinsky, Stella | Cherng, Wen-Jin | Yu, Wen-Chung | Kuo, Chi-Tai | Chang, Kuan-Cheng | Lai, Wen-Ter | Kuo, Jen-Yuan | Ural, Dilek | Badak, Ozer | Akin, Mustafa | Yigit, Zerrin | Yokusoglu, Mehmet | Yilmaz, Mehmet | Abaci, Adnan | Ebinc, Haksun | Perlman, Richard | Parish, David | Bergin, James | Burnham, Kenneth | Brown, Christopher | Lundbye, Justin | Williams, Celeste | Eisen, Howard | Juneman, Elizabeth | Joseph, Susan | Peberdy, Mary Ann | Peura, Jennifer | Gupta, Vishal | Habet, Kalim | French, William | Mody, Freny | Graham, Susan | Hazelrigg, Monica | Chung, Eugene | Dunlap, Stephanie | Nikolaidis, Lazaros | Najjar, Samer | Katz, Richard | Murali, Srinivas | Izzo, Joseph L. | Callister, Tracy | Phillips, Roland | Lippolis, Nicholas | Winterton, John | Meymandi, Sheba | Heilman, Karl | Oren, Ron | Zolty, Ronald | Brottman, Michael | Gunawardena, D.R. | Adams, Kirkwood | Barnard, Denise | Klapholz, Marc | Fulmer, James
European Heart Journal  2013;34(40):3117-3127.
Aims
The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM).
Methods and results
ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64–0.99; DM: HR: 1.16, 95% CI: 0.91–1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50–0.94; DM: HR: 1.64, 95% CI: 1.15–2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71–1.93; DM: HR: 2.39, 95% CI: 1.30–4.42; P = 0.07 for interaction).
Conclusion
This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without DM.
doi:10.1093/eurheartj/eht342
PMCID: PMC3800848  PMID: 23999456
Aliskiren; Diabetes; Outcomes; Post-discharge
16.  Patterns, Predictors, Variations, and Temporal Trends in Emergency Medical Service Hospital Prenotification for Acute Ischemic Stroke 
Background—
Emergency medical services (EMS) hospital prenotification of an incoming stroke patient is guideline recommended as a means of increasing the timeliness with which stroke patients are evaluated and treated. Still, data are limited with regard to national use of, variations in, and temporal trends in EMS prenotification and associated predictors of its use.
Methods and Results—
We examined 371 988 patients with acute ischemic stroke who were transported by EMS and enrolled in 1585 hospitals participating in Get With The Guidelines—Stroke from April 1, 2003, through March 31, 2011. Prenotification occurred in 249 197 EMS‐transported patients (67.0%) and varied widely by hospital (range, 0% to 100%). Substantial variations by geographic regions and by state, ranging from 19.7% in Washington, DC, to 93.4% in Montana, also were noted. Patient factors associated with lower use of prenotification included older age, diabetes mellitus, and peripheral vascular disease. Prenotification was less likely for black patients than for white patients (adjusted odds ratio 0.94, 95% confidence interval 0.92–0.97, P<0.0001). Hospital factors associated with greater EMS prenotification use were absence of academic affiliation, higher annual volume of tissue plasminogen activator administration, and geographic location outside the Northeast. Temporal improvements in prenotification rates showed a modest general increase, from 58.0% in 2003 to 67.3% in 2011 (P temporal trend <0.0001).
Conclusions—
EMS hospital prenotification is guideline recommended, yet among patients transported to Get With The Guidelines—Stroke hospitals it is not provided for 1 in 3 EMS‐arriving patients with acute ischemic stroke and varies substantially by hospital, state, and region. These results support the need for enhanced implementation of stroke systems of care. (J Am Heart Assoc. 2012;1:e002345 doi: 10.1161/JAHA.112.002345.)
doi:10.1161/JAHA.112.002345
PMCID: PMC3487363  PMID: 23130167
stroke; emergency medicine; hospitals; registries
17.  Action Potential-Evoked Calcium Release Is Impaired in Single Skeletal Muscle Fibers from Heart Failure Patients 
PLoS ONE  2014;9(10):e109309.
Background
Exercise intolerance in chronic heart failure (HF) has been attributed to abnormalities of the skeletal muscles. Muscle function depends on intact excitation-contraction coupling (ECC), but ECC studies in HF models have been inconclusive, due to deficiencies in the animal models and tools used to measure calcium (Ca2+) release, mandating investigations in skeletal muscle from HF patients. The purpose of this study was to test the hypothesis that Ca2+ release is significantly impaired in the skeletal muscle of HF patients in whom exercise capacity is severely diminished compared to age-matched healthy volunteers.
Methods and Findings
Using state-of-the-art electrophysiological and optical techniques in single muscle fibers from biopsies of the locomotive vastus lateralis muscle, we measured the action potential (AP)-evoked Ca2+ release in 4 HF patients and 4 age-matched healthy controls. The mean peak Ca2+ release flux in fibers obtained from HF patients (10±1.2 µM/ms) was markedly (2.6-fold) and significantly (p<0.05) smaller than in fibers from healthy volunteers (28±3.3 µM/ms). This impairment in AP-evoked Ca2+ release was ubiquitous and was not explained by differences in the excitability mechanisms since single APs were indistinguishable between HF patients and healthy volunteers.
Conclusions
These findings prove the feasibility of performing electrophysiological experiments in single fibers from human skeletal muscle, and offer a new approach for investigations of myopathies due to HF and other diseases. Importantly, we have demonstrated that one step in the ECC process, AP-evoked Ca2+ release, is impaired in single muscle fibers in HF patients.
doi:10.1371/journal.pone.0109309
PMCID: PMC4195605  PMID: 25310188
18.  Prediabetes is not an independent risk factor for incident heart failure, other cardiovascular events or mortality in older adults: Findings from a population-based cohort study 
International journal of cardiology  2013;168(4):3616-3622.
Background
Whether prediabetes is an independent risk factor for incident heart failure (HF) in non-diabetic older adults remains unclear.
Methods
Of the 4602 Cardiovascular Health Study participants, age ≥ 65 years, without baseline HF and diabetes, 2157 had prediabetes, defined as fasting plasma glucose (FPG) 100–125 mg/dL. Propensity scores for prediabetes, estimated for each of the 4602 participants, were used to assemble a cohort of 1421 pairs of individuals with and without prediabetes, balanced on 44 baseline characteristics.
Results
Participants had a mean age of 73 years, 57% were women, and 13% African American. Incident HF occurred in 18% and 20% of matched participants with and without prediabetes, respectively (hazard ratio {HR} associated with prediabetes, 0.90; 95% confidence interval {CI}, 0.76–1.07; p = 0.239). Unadjusted and multivariable-adjusted HRs (95% CIs) for incident HF associated with prediabetes among 4602 pre-match participants were 1.22 (95% CI, 1.07–1.40; p = 0.003) and 0.98 (95% CI, 0.85–1.14; p = 0.826), respectively. Among matched individuals, prediabetes had no independent association with incident acute myocardial infarction (HR, 1.02; 95% CI, 0.81–1.28; p = 0.875), angina pectoris (HR, 0.93; 95% CI, 0.77–1.12; p = 0.451), stroke (HR, 0.86; 95% CI, 0.70–1.06; p = 0.151) or all-cause mortality (HR, 0.99; 95% CI, 0.88–1.11; p = 0.840).
Conclusions
We found no evidence that prediabetes is an independent risk factor for incident HF, other cardiovascular events or mortality in community-dwelling older adults. These findings question the wisdom of routine screening for prediabetes in older adults and targeted interventions to prevent adverse outcomes in older adults with prediabetes.
doi:10.1016/j.ijcard.2013.05.038
PMCID: PMC3939803  PMID: 23731526
Prediabetes; Diabetes; Heart failure; Older adults; Propensity-matched study
19.  Prevention of heart failure in older adults may require higher levels of physical activity than needed for other cardiovascular events 
International journal of cardiology  2013;168(3):1905-1909.
Background
Little is known if the levels of physical activity required for the prevention of incident heart failure (HF) and other cardiovascular events vary in community-dwelling older adults.
Methods
We studied 5503 Cardiovascular Health Study (CHS) participants, age ≥65 years, free of baseline HF. Weekly metabolic equivalent task-minutes (MET-minutes), estimated using baseline total leisure-time energy expenditure, were used to categorize participants into four physical activity groups: inactive (0 MET-minutes; n=489; reference), low (1–499; n=1458), medium (500–999; n=1086) and high (≥1000; n=2470).
Results
Participants had a mean (±SD) age of 73 (±6) years, 58% were women, and 15% African American. During 13 years of follow-up, centrally-adjudicated incident HF occurred in 26%, 23%, 20%, and 19% of participants with no, low, medium and high physical activity, respectively (trend p <0.001). Compared with inactive older adults, age-sex-race-adjusted hazard ratios (95% confidence intervals) for incident HF associated with low, medium and high physical activity were 0.87 (0.71–1.06; p=0.170), 0.68 (0.54–0.85; p=0.001) and 0.60 (0.49–0.74; p<0.001), respectively (trend p <0.001). Only high physical activity had significant independent association with lower risk of incident HF (HR, 0.79; 95% CI, 0.64–0.97; p=0.026). All levels of physical activity had significant independent association with lower risk of incident acute myocardial infarction (AMI), stroke and cardiovascular mortality.
Conclusion
In community-dwelling older adults, high level of physical activity was associated with lower risk of incident HF, but all levels of physical activity were associated with lower risk of incident AMI, stroke, and cardiovascular mortality.
doi:10.1016/j.ijcard.2012.12.053
PMCID: PMC4142221  PMID: 23380700
Physical activity; MET-minutes; Incident heart failure; Older adults
20.  Rate-Control versus Rhythm-Control Strategies and Outcomes in Septuagenarian Patients with Atrial Fibrillation 
The American journal of medicine  2013;126(10):10.1016/j.amjmed.2013.04.021.
Background
The prevalence of atrial fibrillation substantially increases after 70 years of age. However, the effect of rate-control versus rhythm-control strategies on outcomes in these patients remains unclear.
Methods
In the randomized Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 4060 patients (mean age, 70, range, 49–80 years) with paroxysmal and persistent atrial fibrillation were randomized to rate-control versus rhythm-control strategies. Of these, 2248 were 70–80 years, of whom 1118 were in the rate-control group. Propensity scores for rate-control strategy were estimated for each of the 2248 patients and were used to assemble a cohort of 937 pairs of patients receiving rate-control versus rhythm-control strategies, balanced on 45 baseline characteristics.
Results
Matched patients had a mean age of 75 years, 45% were women, 7% were non-white, and 47% had prior hospitalizations due to arrhythmias. During 3.4 years of mean follow-up, all-cause mortality occurred in 18% and 23% of matched patients in the rate-control and rhythm-control groups, respectively (hazard ratio {HR} associated with rate-control, 0.77; 95% confidence interval {CI}, 0.63–0.94; p=0.010). HRs (95% CIs) for cardiovascular and non-cardiovascular mortality associated with rate-control were 0.88 (0.65–1.18) and 0.62 (0.46–0.84), respectively. All-cause hospitalization occurred in 61% and 68% of rate-control and rhythm-control patients, respectively (HR, 0.76; 95% CI, 0.68–0.86). HRs (95% CIs) for cardiovascular and non-cardiovascular hospitalization were 0.66 (0.56–0.77) and 1.07 (0.91–1.27).
Conclusion
In septuagenarian patients with atrial fibrillation, compared with rhythm-control, a rate-control strategy was associated with significantly lower mortality and hospitalization.
doi:10.1016/j.amjmed.2013.04.021
PMCID: PMC3818786  PMID: 24054956
atrial fibrillation; rate control; rhythm control; hospitalization; mortality; propensity score; older adults
21.  Anemia and Associated Clinical Outcomes in Patients with Heart Failure Due to Reduced Left Ventricular Systolic Function 
Clinical cardiology  2013;36(10):611-620.
Background
Anemia is associated with decreased functional capacity, reduced quality of life, and worsened outcomes among patients with heart failure (HF) due to reduced left ventricular ejection fraction (HFREF). We sought to evaluate the independent effect of anemia on clinical outcomes among those with HFREF.
Methods
The HF-ACTION trial was a prospective, randomized trial of exercise therapy versus usual care in 2331 patients with HFREF. Patients with New York Heart Association class 2–4 HF and left ventricular ejection fractions of ≤ 35% were recruited. Hemoglobin (Hb) was measured up to one year prior to entry and was stratified by quintile. Anemia was defined as baseline Hb < 13 g/dl and <12 g/dl in men and women, respectively. Hb was assessed in two models; a global prediction model that had been previously developed and a modified model including variables associated with anemia and the studied outcomes.
Results
Hemoglobin was available at baseline in 1763 subjects (76% of total study population); their median age was 59.0 years, 73% were male, and 62% were Caucasian. The prevalence of anemia was 515/1763 (29%). Older age, female gender, African American race, diabetes, hypertension, and lower estimated glomerular filtration rates were all more frequent in lower Hb quintiles. Over a median follow-up of 30 months, the primary outcome of all-cause mortality or all-cause hospitalization occurred in 78% of those with anemia and 64% in those without, p<0.001. The secondary outcomes of all-cause mortality alone, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or HF hospitalization occurred in 23 % vs 15%, 67% vs 54%, and 44 vs 29%, respectively, p<0.001. Heart failure hospitalizations occurred in 36% vs 22%, and urgent outpatient visits for HF exacerbations occurred in 67% and 55%, respectively, p<0.001. For the global model, there was an association observed for anemia and all-cause mortality or hospitalization, adjusted hazard ratio (HR)=1.15, 95% CI 1.01–1.32, p=0.04, but other outcomes were not significant at p<0.05. In the modified model, the adjusted HR for anemia and the primary outcome of all-cause mortality or all-cause hospitalization was 1.25, 95% CI 1.10–1.42, p<0.001. There were independent associations between anemia and all-cause death, HR=1.11, 95% CI 0.87–1.42, p=0.38; cardiovascular death or cardiovascular hospitalization, HR=1.16, 95% CI 1.01–1.33, p=0.035; and cardiovascular death and heart failure hospitalization, HR=1.27, 95% CI 1.06–1.51, p=0.008.
Conclusions
Anemia modestly is associated with increased rates of death, hospitalization, and HF exacerbation in patients with chronic HFREF. After adjusting for other important covariates, anemia is independently associated with an excess hazard for all-cause mortality and all-cause hospitalization. Anemia is also associated with combinations of cardiovascular death and cardiovascular/heart failure hospitalizations as composite endpoints.
doi:10.1002/clc.22181
PMCID: PMC4008125  PMID: 23929781
heart failure; chronic kidney disease; anemia; glomerular filtration rate; renal insufficiency; hospitalization; mortality
22.  Incremental Reduction in Risk of Death Associated With Use of Guideline-Recommended Therapies in Patients With Heart Failure: A Nested Case-Control Analysis of IMPROVE HF 
Background
Several therapies are guideline-recommended to reduce mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction, but the incremental clinical effectiveness of these therapies has not been well studied. We aimed to evaluate the individual and incremental benefits of guideline-recommended HF therapies associated with 24-month survival.
Methods and Results
We performed a nested case-control study of HF patients enrolled in IMPROVE HF. Cases were patients who died within 24 months and controls were patients who survived to 24 months, propensity-matched 1:2 for multiple prognostic variables. Logistic regression was performed, and the attributable mortality risk from incomplete application of each evidence-based therapy among eligible patients was calculated. A total of 1376 cases and 2752 matched controls were identified. β-Blocker and cardiac resynchronization therapy were associated with the greatest 24-month survival benefit (adjusted odds ratio for death 0.42, 95% confidence interval (CI), 0.34–0.52; and 0.44, 95% CI, 0.29–0.67, respectively). Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, implantable cardioverter-defibrillators, anticoagulation for atrial fibrillation, and HF education were also associated with benefit, whereas aldosterone antagonist use was not. Incremental benefits were observed with each successive therapy, plateauing once any 4 to 5 therapies were provided (adjusted odds ratio 0.31, 95% CI, 0.23–0.42 for 5 or more versus 0/1, P<0.0001).
Conclusions
Individual, with a single exception, and incremental use of guideline-recommended therapies was associated with survival benefit, with a potential plateau at 4 to 5 therapies. These data provide further rationale to implement guideline-recommended HF therapies in the absence of contraindications to patients with HF and reduced left ventricular ejection fraction. (J Am Heart Assoc. 2012;1:16-26.)
doi:10.1161/JAHA.111.000018
PMCID: PMC3487312  PMID: 23130115
guideline-recommended therapies; heart failure; nested case-control studies; survival benefit
23.  Relationship of National Institutes of Health Stroke Scale to 30-Day Mortality in Medicare Beneficiaries With Acute Ischemic Stroke 
Background
The National Institutes of Health Stroke Scale (NIHSS), a well-validated tool for assessing initial stroke severity, has previously been shown to be associated with mortality in acute ischemic stroke. However, the relationship, optimal categorization, and risk discrimination with the NIHSS for predicting 30-day mortality among Medicare beneficiaries with acute ischemic stroke has not been well studied.
Methods and Results
We analyzed data from 33102 fee-for-service Medicare beneficiaries treated at 404 Get With The Guidelines-Stroke hospitals between April 2003 and December 2006 with NIHSS documented. The 30-day mortality rate by NIHSS as a continuous variable and by risk-tree determined or prespecified categories were analyzed, with discrimination of risk quantified by the c-statistic. In this cohort, mean age was 79.0 years and 58% were female. The median NIHSS score was 5 (25th to 75th percentile 2 to 12). There were 4496 deaths in the first 30 days (13.6%). There was a strong graded relation between increasing NIHSS score and higher 30-day mortality. The 30-day mortality rates for acute ischemic stroke by NIHSS categories were as follows: 0 to 7, 4.2%; 8 to 13, 13.9%; 14 to 21, 31.6%; 22 to 42, 53.5%. A model with NIHSS alone provided excellent discrimination whether included as a continuous variable (c-statistic 0.82 [0.81 to 0.83]), 4 categories (c-statistic 0.80 [0.79 to 0.80]), or 3 categories (c-statistic 0.79 [0.78 to 0.79]).
Conclusions
The NIHSS provides substantial prognostic information regarding 30-day mortality risk in Medicare beneficiaries with acute ischemic stroke. This index of stroke severity is a very strong discriminator of mortality risk, even in the absence of other clinical information, whether used as a continuous or categorical risk determinant. (J Am Heart Assoc. 2012;1:42-50.)
doi:10.1161/JAHA.111.000034
PMCID: PMC3487316  PMID: 23130117
ischemic stroke; National Institutes of Health Stroke Scale; mortality; registries
24.  Timing and Duration of Interventions in Clinical Trials for Hospitalized Heart Failure Patients 
Circulation. Heart failure  2013;6(5):10.1161/CIRCHEARTFAILURE.113.000518.
doi:10.1161/CIRCHEARTFAILURE.113.000518
PMCID: PMC3845809  PMID: 24046476
heart failure; clinical trial; prognosis; hospitalization
25.  Use and Associated Risks of Concomitant Aspirin Therapy with Oral Anticoagulation in Patients with Atrial Fibrillation: Insights from the ORBIT-AF Registry 
Circulation  2013;128(7):721-728.
Background
The role of concomitant aspirin therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant aspirin use and its association with clinical outcomes among AF patients treated with OAC.
Methods and Results
The Outcomes Registry for Better Informed Treatment (ORBIT) of Atrial Fibrillation registry enrolled 10,126 AF patients from 176 US practices from June, 2010 through August, 2011. The study population was limited to those on OAC (n=7,347).
Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant aspirin therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% (n=2543) of AF patients on OAC also received aspirin (OAC+ASA). Patients receiving OAC+ASA were more likely male (66% vs. 53%, p<0.0001) and had more comorbid illness than those on OAC alone. Over one-third (39%) of OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated ATRIA bleeding risk scores (≥5). Major bleeding (adjusted HR 1.53, 95% CI 1.20–1.96) and bleeding hospitalizations (adjusted HR 1.52, 95% CI 1.17–1.97) were significantly higher in those on OAC+ASA versus OAC alone. Rates of ischemic events were low.
Conclusions
Patients with AF receiving OAC are often treated with concomitant aspirin, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant aspirin outweigh the risks in AF patients already on OAC.
doi:10.1161/CIRCULATIONAHA.113.002927
PMCID: PMC3908483  PMID: 23861512
atrial fibrillation; anticoagulants; aspirin; hemorrhage; outcomes research

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