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1.  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
2.  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
3.  Design and rationale of studies of neurohormonal blockade and outcomes in diastolic heart failure using OPTIMIZE-HF registry linked to Medicare data 
International journal of cardiology  2011;166(1):230-235.
Background
Heart failure (HF) is the leading cause of hospitalization for Medicare beneficiaries. Nearly half of all HF patients have diastolic HF or HF with preserved ejection fraction (HF-PEF). Because these patients were excluded from major randomized clinical trials of neurohormonal blockade in HF there is little evidence about their role in HF-PEF.
Methods
The aims of the American Recovery & Reinvestment Act-funded National Heart, Lung, and Blood Institute-sponsored “Neurohormonal Blockade and Outcomes in Diastolic Heart Failure” are to study the long-term effects of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists in four separate propensity-matched populations of HF-PEF patients in the OPTIMIZE-HF (Organized Program to Initiate Life-Saving Treatment in Hospitalized Patients with Heart Failure) registry. Of the 48,612 OPTIMIZE-HF hospitalizations occurring during 2003–2004 in 259 U.S. hospitals, 20,839 were due to HF-PEF (EF ≥40%). For mortality and hospitalization we used Medicare national claims data through December 31, 2008.
Results
Using a two-step (hospital-level and hospitalization-level) probabilistic linking approach, we assembled a cohort of 11,997 HF-PEF patients from 238 OPTIMIZE-HF hospitals. These patients had a mean age of 75 years, mean EF of 55%, were 62% women, 15% African American, and were comparable with community-based HF-PEF cohorts in key baseline characteristics.
Conclusions
The assembled Medicare-linked OPTIMIZE-HF cohort of Medicare beneficiaries with HF-PEF with long-term outcomes data will provide unique opportunities to study clinical effectiveness of various neurohormonal antagonists with outcomes in HF-PEF using propensity-matched designs that allow outcome-blinded assembly of balanced cohorts, a key feature of randomized clinical trials.
doi:10.1016/j.ijcard.2011.10.089
PMCID: PMC3465528  PMID: 22119116
Diastolic heart failure; neurohormonal antagonists; OPTIMIZE-HF; Medicare
4.  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
5.  Angiotensin-Converting Enzyme Inhibitors and Outcomes in Heart Failure and Preserved Ejection Fraction 
The American journal of medicine  2013;126(5):401-410.
BACKGROUND
The role of angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure and preserved ejection fraction remains unclear.
METHODS
Of the 10,570 patients ≥65 years with heart failure and preserved ejection fraction (≥40%) in OPTIMIZE-HF (2003–2004) linked to Medicare (through December, 2008), 7304 were not receiving angiotensin receptor blockers and had no contraindications to ACE inhibitors. After excluding 3115 patients with pre-admission ACE inhibitor use, the remaining 4189 were eligible for new discharge prescriptions for ACE inhibitors, and 1706 received them. Propensity scores for the receipt of ACE inhibitors, calculated for each of the 4189 patients, were used to assemble a cohort of 1337 pairs of patients, balanced on 114 baseline characteristics.
RESULTS
Matched patients had a mean age of 81 years, mean ejection fraction of 55%, 64% were women and 9% African American. Initiation of ACE inhibitor therapy was associated with lower risk of the primary composite endpoint of all-cause mortality or heart failure hospitalization during 2.4 years of median follow-up (hazard ratio {HR}, 0.91; 95% confidence interval {CI}, 0.84–0.99; p=0.028), but not with individual endpoints of all-cause mortality (HR, 0.96; 95% CI, 0.88–1.05; p=0.373) or heart failure hospitalization (HR, 0.93; 95% CI, 0.83–1.05; p=0.257).
CONCLUSION
In hospitalized older patients with heart failure and preserved ejection fraction not receiving angiotensin receptor blockers, discharge initiation of ACE inhibitor therapy was associated with a modest improvement in the composite endpoint of total mortality or heart failure hospitalization, but had no association with individual endpoint components.
doi:10.1016/j.amjmed.2013.01.004
PMCID: PMC3656660  PMID: 23510948
ACE inhibitors; Heart Failure; Preserved Ejection Fraction
6.  Reduced right ventricular ejection fraction and increased mortality in chronic systolic heart failure patients receiving beta-blockers: Insights from the BEST trial 
Background
Right ventricular ejection fraction (RVEF) <20% is an independent predictor of poor outcomes in patients with advanced chronic systolic heart failure (HF). The aim of this study was to examine if the adverse effect of abnormally reduced RVEF varies by the receipt of beta-blockers.
Methods
In the Beta-Blocker Evaluation of Survival Trial (BEST), 2708 patients with chronic advanced HF and left ventricular ejection fraction <35%, receiving standard background therapy with renin-angiotensin inhibition, digoxin, and diuretics, were randomized to receive bucindolol or placebo. Of these 2008 had data on baseline RVEF, and 14% (146/1017) and 13% (125/991) of the patients receiving bucindolol and placebo respectively had RVEF <20%.
Results
Among patients in the placebo group, all-cause mortality occurred in 33% and 43% of patients with RVEF ≥20% and <20% respectively (unadjusted hazard ratios {HR}, 1.33; 95% confidence intervals {CI}, 0.99–1.78; p =0.055 and adjusted HR, 0.99; 95% CI, 0.71–1.37; p =0.934). Among those receiving bucindolol, all-cause mortality occurred in 28% and 49% of patients with RVEF ≥20% and <20% respectively (unadjusted HR, 2.15; 95% CI, 1.65–2.80; p <0.001 and adjusted HR, 1.50; 95% CI, 1.08–2.07; p =0.016). These differences were statistically significant (unadjusted and adjusted p for interaction, 0.016 and 0.053 respectively).
Conclusions
In ambulatory patients with chronic advanced systolic HF receiving renin-angiotensin inhibition, digoxin, and diuretics, RVEF <20% had no intrinsic association with mortality. However, in those receiving additional therapy with bucindolol, RVEF <20% had a significant independent association with increased risk of mortality.
doi:10.1016/j.ijcard.2011.05.051
PMCID: PMC3395778  PMID: 21704392
Heart failure; Right ventricle; Bucindolol; Mortality; Morbidity
7.  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
8.  Baseline Characteristics, Quality of Care, and Outcomes of Younger and Older Medicare Beneficiaries Hospitalized with Heart Failure: Findings from the Alabama Heart Failure Project 
Background
Most studies of heart failure (HF) in Medicare beneficiaries have excluded patients age <65 years. We examined baseline characteristics, quality of care, and outcomes among younger and older Medicare beneficiaries hospitalized with HF in the Alabama Heart Failure Project.
Methods
Of the 8049 Medicare beneficiaries discharged alive with a primary discharge diagnosis of HF in 1998–2001 from 106 Alabama hospitals, 991 (12%) were younger (age <65 years). After excluding 171 patients discharge to hospice care, 7867 patients were considered eligible for left ventricular systolic function (LVSF) evaluation and 2211 patients with left ventricular ejection fraction <45% and without contraindications were eligible for angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy.
Results
Nearly half of the younger HF patients (45% versus 22% for ≥65 years; p<0.001) were African American. LVSF was evaluated in 72%, 72%, 70% and 60% (overall p<0.001) and discharge prescriptions of ACE inhibitors or ARBs were given to 83%, 77%, 75% and 75% of eligible patients (overall p=0.013) among those <65, 65–74, 75–84 and ≥85 years, respectively. During 9 years of follow-up, all-cause mortality occurred in 54%, 61%, 71% and 80% (overall p<0.001) and hospital readmission due to worsening HF occurred in 65%, 60%, 55% and 48% (overall p<0.001) of those <65, 65–74, 75–84 and ≥85 years, respectively.
Conclusion
Medicare beneficiaries <65 years with HF, nearly half of whom were African American, generally received better quality of care, had lower mortality, but had higher re-hospitalizations due to HF.
doi:10.1016/j.ijcard.2011.05.003
PMCID: PMC3395759  PMID: 21621285
heart failure; age; Medicare; quality of care; outcomes
9.  Bucindolol, systolic blood pressure, and outcomes in systolic heart failure: a prespecified post hoc analysis of BEST 
BACKGROUND
In the Beta-Blocker Evaluation of Survival Trial (BEST) trial, systolic blood pressure (SBP) ≤120 mm Hg was an independent predictor of poor prognosis in ambulatory patients with chronic systolic heart failure (HF). Because SBP is an important predictor of response to beta-blocker therapy, the BEST protocol had pre-specified a post hoc analysis to determine if the effect of bucindolol varied by baseline SBP.
METHODS
In the BEST, 2706 patients with chronic systolic (left ventricular ejection fraction <35%) HF and New York Heart Association class III (92%) or IV (8%) symptoms and receiving standard background therapy were randomized to receive either bucindolol (n=1354) or placebo (n=1354). Of these, 1751 had SBP ≤120 mm Hg and 955 had SBP >120 mm Hg at baseline.
RESULTS
Among patients with SBP >120 mm Hg, all-cause mortality occurred in 28% and 22% of patients receiving placebo and bucindolol, respectively (hazard ratio when bucindolol was compared with placebo, 0.77; 95% confidence interval, 0.59–0.99; P=0.039). In contrast, among those with SBP ≤120 mm Hg, 36% and 35% of patients in the placebo and bucindolol groups died, respectively (hazard ratio, 0.95; 95% confidence interval, 0.81–1.12; P=0.541). Hazard ratios (95% confidence intervals) for HF hospitalization associated with bucindolol use were 0.70 (0.56–0.89; P=0.003) and 0.82 (0.71–0.95; P=0.008) for patients with SBP >120 and ≤120 mm Hg, respectively.
CONCLUSION
Bucindolol, a nonselective beta-blocker with weak alpha-blocking properties, significantly reduced HF hospitalization in systolic HF patients regardless of baseline SBP. However, bucindolol reduced mortality only in those with SBP >120 mm Hg.
doi:10.1016/j.cjca.2011.07.004
PMCID: PMC3769783  PMID: 21982425
Bucindolol; systolic blood pressure; outcomes; heart failure
10.  Association between smoking and outcomes in older adults with atrial fibrillation 
Tobacco smoking is a risk factor for atrial fibrillation (AF), but little is known about the impact of smoking in patients with AF. Of the 4060 patients with recurrent AF in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 496 (12%) reported having smoked during the past two years. Propensity scores for smoking were estimated for each of the 4060 patients using a multivariable logistic regression model and were used to assemble a matched cohort of 487 pairs of smokers and nonsmokers, who were balanced on 46 baseline characteristics. Cox and logistic regression models were used to estimate the associations of smoking with all-cause mortality and all-cause hospitalization, respectively, during over 5 years of follow-up. Matched participants had a mean age of 70 ± 9 years (± S.D.), 39% were women, and 11% were non-white. All-cause mortality occurred in 21% and 16% of matched smokers and nonsmokers, respectively (when smokers were compared with nonsmokers, hazard ratio = HR = 1.35; 95% confidence interval = 95% CI = 1.01–1.81; p = 0.046). Unadjusted, multivariable-adjusted and propensity-adjusted HR (95% CI) for all-cause mortality associated with smoking in the pre-match cohort were: 1.40 (1.13–1.72; p = 0.002), 1.45 (1.16–1.81; p = 0.001), and 1.39 (1.12–1.74; p = 0.003), respectively. Smoking had no association with all-cause hospitalization (when smokers were compared with nonsmokers, odds ratio = OR = 1.21; 95% CI = 0.94–1.57, p = 0.146). Among patients with AF, a recent history of smoking was associated with an increased risk of all-cause mortality, but had no association with all-cause hospitalization.
doi:10.1016/j.archger.2011.05.027
PMCID: PMC3358565  PMID: 21733581
Atrial fibrillation; Smoking; Mortality; Propensity score
11.  Rheumatic heart disease and risk of incident heart failure among community-dwelling older adults: a prospective cohort study 
Annals of Medicine  2011;44(3):253-261.
Background
Little is known about the association of rheumatic heart disease (RHD) with incident heart failure (HF) among older adults.
Design
Cardiovascular Health Study, a prospective cohort study.
Methods
Of the 4751 community-dwelling adults ≥65 years, free of prevalent HF at baseline, 140 had RHD, defined as self-reported physician-diagnosed RHD along with echocardiographic evidence of left-sided valvular disease. Propensity scores for RHD, estimated for each of the 4751 participants, were used to assemble a cohort of 720, in which 124 and 596 participants with and without RHD respectively were balanced on 62 baseline characteristics.
Results
Incident HF developed in 33% and 22% of matched participants with and without RHD respectively during 13 years of follow-up (hazard ratio when RHD was compared to no-RHD, 1.60; 95% confidence interval, 1.13–2.28; P=0.008). Pre-match unadjusted, multivariable-adjusted and propensity-adjusted hazard ratios (95% confidence intervals) for RHD-associated incident heart failure were 2.04 (1.54–2.71; P<0.001), 1.32 (1.02–1.70; P=0.034) and 1.55 (1.14–2.11; P=0.005) respectively. RHD was not associated with all-cause mortality (HR, 1.09; 95% CI, 0.82–1.45; P=0.568).
Conclusion
RHD is an independent risk factor for incident HF among community-dwelling older adults free of HF, but has no association with mortality.
doi:10.3109/07853890.2010.530685
PMCID: PMC3116996  PMID: 21254894
Heart failure; rheumatic heart disease; older adults
12.  Effect of Warfarin on Outcomes in Septuagenarian Patients with Atrial Fibrillation 
The American Journal of Cardiology  2011;109(3):370-377.
Anticoagulation has been shown to reduce ischemic stroke in atrial fibrillation (AF). However, concerns remain regarding their safety and efficacy in those ≥70 years of age who comprise most AF patients. Of the 4060 patients (mean age, 65 years; range, 49–80 years) in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 2248 (55% of 4060) were 70–80 years of age, 1901 of whom were receiving warfarin. Propensity score for warfarin use, estimated for each of the 2248 patients, were used to match 227 of the 347 no-warfarin patients (in 1:1, 1:2 or 1:3 sets) with 616 warfarin patients, who were balanced on 45 baseline characteristics. All-cause mortality occurred in 18% and 33% of matched patients receiving and not receiving warfarin, respectively, during up to six (mean, 3.4) years of follow-up (hazard ratio {HR} when warfarin use was compared with its non-use, 0.58; 95% confidence interval {CI}, 0.43–0.77; p<0.001). All-cause hospitalization occurred in 64% and 67% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use, 0.93; 95% CI, 0.77–1.12; p=0.423). Ischemic stroke occurred in 4% and 8% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use, 0.57; 95% CI, 0.31–1.04; p=0.068). Major bleeding occurred in 7% and 10% of matched patients receiving and not receiving warfarin, respectively (HR associated with warfarin use, 0.73; 95% CI, 0.44–1.22; p=0.229). In conclusion, warfarin use was associated with reduced mortality in septuagenarian AF patients but had no association with hospitalization or major bleeding.
doi:10.1016/j.amjcard.2011.09.023
PMCID: PMC3390022  PMID: 22118824
atrial fibrillation; warfarin; mortality; propensity score; older adults
13.  Outcomes in younger and older adults with chronic advanced systolic heart failure: a propensity-matched study 
International Journal of Cardiology  2010;154(2):128-133.
Background
Older age is an independent predictor of all-cause mortality in patients with mild to moderate heart failure (HF). Whether older age is also an independent predictor of mortality in patients with more advanced HF is unknown.
Methods
Of the 2707 Beta-Blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF (New York Heart Association class III/IV and left ventricular ejection fraction <35%), 1091 were elderly (≥65 years). Propensity scores for older age, estimated for each of the 2707 patients, were used to assemble a cohort of 603 pairs of younger and older patients, balanced on 66 baseline characteristics.
Results
All-cause mortality occurred in 33% and 36% of younger and older matched patients respectively during 4 years of follow-up (hazard ratio {HR} associated with age ≥65 years, 1.05; 95% confidence interval {CI}, 0.87—1.27; P=0.614). HF hospitalization occurred in 38% and 40% of younger and older matched patients respectively (HR, 1.01; 95% CI, 0.84–1.21; P=0.951). Among 603 pairs of unmatched and unbalanced patients, all-cause mortality occurred in 28% and 36% of younger and older patients respectively (HR, 1.34; 95% CI, 1.10–1.64; P=0.004) and HF hospitalization occurred in 34% and 40% of younger and older unmatched patients respectively (HR, 1.24; 95% CI, 1.03–1.50; P=0.024).
Conclusion
Significant bivariate associations suggest that older age is a useful marker of poor outcomes in patients with advanced chronic systolic HF. However, lack of significant independent associations suggests that older age per se has no intrinsic effect on outcomes in these patients.
doi:10.1016/j.ijcard.2010.09.006
PMCID: PMC3116091  PMID: 20947188
Age; heart failure; mortality; hospitalization
14.  A Propensity-Matched Study of the Association of Diabetes Mellitus with Incident Heart Failure and Mortality among Community-Dwelling Older Adults 
The American Journal of Cardiology  2011;108(12):1747-1753.
Diabetes mellitus (DM) is a risk factor for incident heart failure (HF) in older adults. However, to what extent this association is independent of other risk factors remains unclear. Of the 5464 community-dwelling adults ≥65 years in the Cardiovascular Health Study without baseline HF, 862 had DM (fasting plasma glucose levels ≥126 mg/dl, or treatment with insulin or oral hypoglycemic agents). Propensity scores for DM were estimated for each of the 5464 participants and were used to assemble a cohort of 717 pairs of participants with and without DM, who were balanced on 65 baseline characteristics. Incident HF occurred in 31% and 26% of matched participants with and without DM, respectively, during over 13 years of follow-up (hazard ratio {HR} when DM was compared with no DM, 1.45; 95% confidence interval {CI}, 1.14–1.86; p=0.003). Among the 5464 pre-match participants, unadjusted and multivariable-adjusted HRs for incident HF associated with DM were 2.22 (95% CI, 1.94–2.55; p<0.001) and 1.52 (95% CI, 1.30–1.78; p<0.001), respectively. All-cause mortality occurred in 57% and 47% of matched participants with and without DM respectively (HR, 1.35; 95% CI, 1.13–1.61; p=0.001). Among matched participants, DM-associated HRs for incident peripheral arterial disease, incident acute myocardial infarction and incident stroke were 2.50 (95% CI, 1.45–4.32; p=0.001), 1.37 (95% CI, 0.97–1.93; p=0.072), and 1.11 (95% CI, 0.81–1.51; p=0.527), respectively. In conclusion, the association of DM with incident HF and all-cause mortality in community-dwelling older adults without HF is independent of major baseline cardiovascular risk factors.
doi:10.1016/j.amjcard.2011.07.046
PMCID: PMC3324944  PMID: 21943936
heart failure; diabetes mellitus; mortality; older adults; propensity-matched
15.  Intrinsic Association of Widowhood With Mortality in Community-Dwelling Older Women and Men: Findings From a Prospective Propensity-Matched Population Study 
Objectives.
Widowhood is associated with increased mortality. However, to what extent this association is independent of other risk factors remains unclear. In the current study, we used propensity score matching to design a study to examine the independent association of widowhood with outcomes in a balanced cohort of older adults in the United States.
Methods.
We used public-use copies of the Cardiovascular Health Study data obtained from the National Heart, Lung, and Blood Institute. Of the 5,795 community-dwelling older men and women aged 65 years and older in Cardiovascular Health Study, 3,820 were married and 1,436 were widows or widowers. Propensity scores for widowhood, estimated for each of the 5,256 participants, were used to assemble a cohort of 819 pairs of widowed and married participants who were balanced on 74 baseline characteristics. The 1,638 matched participants had a mean (± standard deviation) age of 75 (±6) years, 78% were women, and 16% African American.
Results.
All-cause mortality occurred in 46% (374/819) and 51% (415/819) of matched married and widowed participants, respectively, during more than 11 years of median follow-up (hazard ratio associated with widowhood, 1.18; 95% confidence interval, 1.03–1.36; p = .018). Hazard ratios (95% confidence intervals) for cardiovascular and noncardiovascular mortalities were 1.07 (0.87–1.32; p = .517) and 1.28 (1.06–1.55; p = .011), respectively. Widowhood had no independent association with all-cause or heart failure hospitalization or incident cardiovascular events.
Conclusions.
Among community-dwelling older adults, widowhood was associated with increased mortality, which was independent of confounding by baseline characteristics and largely driven by an increased noncardiovascular mortality. Widowhood had no independent association with hospitalizations or incident cardiovascular events.
doi:10.1093/gerona/glr144
PMCID: PMC3252210  PMID: 21903611
Widowhood; Spousal loss; Mortality; Hospitalization; Older adults
16.  Heart failure is a risk factor for incident driving cessation among community-dwelling older adults: Findings from a prospective population study 
Journal of Cardiac Failure  2011;17(12):1035-1040.
Background
Heart failure (HF) patients often depend on driving for access to specialty care. We analyzed a public-use copy of the Cardiovascular Health Study (CHS) data to determine if HF is a risk factor for driving cessation and to identify other risk factors for driving cessation among those with HF.
Methods and results
Of the 5383 community-dwelling drivers ≥65 years (mean age, 73 years, 55% women, 13% African American), 839 had HF: 246 had baseline prevalent HF and 593 developed incident HF before driving cessation during 9 years of follow-up. Incident driving cessation occurred at rates of 3980 and 3709 per 10,000 person-years of follow-up for those with and without HF, respectively (unadjusted hazard ratio {HR} associated with HF as a time-varying variable, 2.13; 95% confidence interval {CI}, 1.83–2.47; p<0.001). This association remained unchanged after multivariable risk adjustment (HR, 1.43; 95% CI, 1.21–1.68; p<0.001). Among the 839 older drivers with HF, independent predictors for incident driving cessation were age ≥75 years (HR, 1.99; 95% CI, 1.44–2.73; p<0.001), female gender (HR, 1.93; 95% CI, 1.37–2.74; p<0.001), difficulty walking half a mile (HR, 1.47; 95% CI, 1.04–2.08; p=0.028), vision problems (HR, 1.47; 95% CI, 1.07–2.02; p=0.018), and stroke as a time-varying covariate (HR, 1.96; 95% CI, 1.38–2.79; p<0.001).
Conclusion
HF is an independent risk factor for incident driving cessation among community-dwelling older drivers. Several patient characteristics predicted driving cessation in older HF patients, which may be targets for interventions to prevent driving cessation among these patients.
doi:10.1016/j.cardfail.2011.08.014
PMCID: PMC3324852  PMID: 22123368
Heart failure; incident driving cessation; older adults; population study
17.  Isolated diastolic hypotension and incident heart failure in older adults 
Hypertension  2011;58(5):895-901.
Aging is often associated with increased systolic blood pressure and decreased diastolic blood pressure. Isolated systolic hypertension or an elevated systolic blood pressure without an elevated diastolic blood pressure is a known risk factor for incident heart failure in older adults. In the current study, we examined whether isolated diastolic hypotension, defined as a diastolic blood pressure <60 mm Hg and a systolic blood pressure ≥100 mm Hg, is associated with incident heart failure. Of the 5795 Medicare-eligible community-dwelling adults age ≥65 years in the Cardiovascular Health Study, 5521 were free of prevalent heart failure at baseline. After excluding 145 individuals with baseline systolic blood pressure <100 mm Hg, the final sample included 5376 participants, of whom 751 (14%) had isolated diastolic hypotension. Propensity scores for isolated diastolic hypotension were calculated for each of the 5376 participants and used to match 545 and 2348 participants with and without isolated diastolic hypotension, respectively who were balanced on 58 baseline characteristics. During over 12 years of median follow-up, centrally-adjudicated incident heart failure developed in 25% and 20% of matched participants with and without isolated diastolic hypotension respectively (hazard ratio associated with isolated diastolic hypotension, 1.33; 95% confidence interval, 1.10–1.61; p=0.004). Among the 5376 pre-match individuals, multivariable-adjusted hazard ratio for incident heart failure associated with isolated diastolic hypotension was 1.29 (95% confidence interval, 1.09–1.53; p=0.003). As in isolated systolic hypertension, among community-dwelling older adults without prevalent heart failure, isolated diastolic hypotension is also a significant independent risk factor for incident heart failure.
doi:10.1161/HYPERTENSIONAHA.111.178178
PMCID: PMC3390027  PMID: 21947466
aging; blood pressure; diastolic; heart failure; pulse pressure
18.  Left Ventricular Diastolic Function and Exercise Capacity in Community-Dwelling Adults ≥ 65 Years of Age without Heart Failure 
The American Journal of Cardiology  2011;108(5):735-740.
Left ventricular diastolic dysfunction (LVDD) has been reported to have strong correlation with exercise capacity. However, this relationship has not been studied extensively in community-dwelling older adults. Data on pulse and tissue Doppler echocardiographic estimates of resting early (E) and atrial (A) transmitral peak inflow and early (Em) mitral annular velocities, and six-minute walk test were obtained from 89 community-dwelling older adults (mean age, 74; range, 65 -93 years; 54% women), without a history of heart failure. Overall, 47% had cardiovascular morbidity and 60% had normal diastolic function (E/A 0.75 -1.5 and E/Em <10). Among the 36 individuals with LVDD, 83%, 14% and 3% had grade I (E/A<0.75, regardless of E/Em), II (E/A 0.75–1.5 and E/Em ≥10) and III (E/A>1.5 and E/Em ≥10) LVDD respectively. Those with LVDD were older (77 versus 73 years; p=0.001) and tended to have a higher prevalence of cardiovascular morbidity (58% versus 40%; p=0.083). LVDD negatively correlated with six-minute walk distance (1013 versus 1128 feet; R=−0.25; p=0.017). This association remained significant despite adjustment for cardiovascular morbidity (R=−0.35; p=0.048), but lost significance when adjusted for age (R=−0.32; p=0.105), both age and cardiovascular morbidity (R=−0.38; p=0.161), and additional adjustment for sex, race, body mass index, and systolic blood pressure (R=−0.44; p=0.365). In conclusion, most community-dwelling older adults without heart failure had normal left ventricular diastolic function or grade-I LVDD. Although LVDD was associated with decreased performance on a six-minute walk test, that association was no longer evident after adjustment for age, body mass index and cardiovascular morbidity.
doi:10.1016/j.amjcard.2011.04.025
PMCID: PMC3324348  PMID: 21704282
Left Ventricular Diastolic Function; Exercise Capacity; Older Adults; Cardiovascular Morbidity
19.  Relationship between Stage of Kidney Disease and Incident Heart Failure in Older Adults 
American Journal of Nephrology  2011;34(2):135-141.
Background
The relationship between stage of chronic kidney disease (CKD) and incident heart failure (HF) remains unclear.
Methods
Of the 5,795 community-dwelling adults ≥65 years in the Cardiovascular Health Study, 5,450 were free of prevalent HF and had baseline estimated glomerular filtration rate (eGFR: ml/min/1.73 m2) data. Of these, 898 (16%) had CKD 3A (eGFR 45–59 ml/min/1.73 m2) and 242 (4%) had CKD stage ≥3B (eGFR <45 ml/min/1.73 m2). Data on baseline proteinuria were not available and 4,310 (79%) individuals with eGFR ≥60 ml/min/1.73 m2 were considered to have no CKD. Propensity scores estimated separately for CKD 3A and ≥3B were used to assemble two cohorts of 1,714 (857 pairs with CKD 3A and no CKD) and 557 participants (148 CKD ≥3B and 409 no CKD), respectively, balanced on 50 baseline characteristics.
Results
During 13 years of follow-up, centrally-adjudicated incident HF occurred in 19, 24 and 38% of pre-match participants without CKD (reference), with CKD 3A [unadjusted hazard ratio (HR) 1.40; 95% confidence interval (CI) 1.20–1.63; p < 0.001] and with CKD ≥3B (HR 3.37; 95% CI 2.71–4.18; p < 0.001), respectively. In contrast, among matched participants, incident HF occurred in 23 and 23% of those with CKD 3A and no CKD, respectively (HR 1.03; 95% CI 0.85–1.26; p = 0.746), and 36 and 28% of those with CKD ≥3B and no CKD, respectively (HR 1.44; 95% CI 1.04–2.00; p = 0.027).
Conclusions
Among community-dwelling older adults, CKD is a marker of incident HF regardless of stage; however, CKD ≥3B, not CKD 3A, has a modest independent association with incident HF.
doi:10.1159/000328905
PMCID: PMC3136373  PMID: 21734366
Chronic kidney disease; Heart failure
21.  Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients with Chronic Mild to Moderate Heart Failure 
The American journal of cardiology  2011;107(8):1208-1214.
We studied the impact of baseline systolic blood pressure (SBP) on outcomes in mild to moderate chronic systolic and diastolic heart failure (HF) patients in the Digitalis Investigation Group trial using propensity-matched design. Of the 7788 patients, 7785 had baseline SBP data and 3538 had SBP ≤120 mm Hg. Propensity scores for SBP ≤120 mm Hg, calculated for each of the 7785 patients, were used to assemble a matched cohort of 3738 patients with SBP ≤120 and >120 mm Hg who were well-balanced on 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBP ≤120 and >120 mm Hg respectively during 5 years of follow-up (hazard ratio {HR} when SBP ≤120 was compared with >120 mm Hg, 1.10; 95% confidence interval {CI}, 0.99–1.23; p=0.088). HRs (95% CIs) for cardiovascular and HF mortality associated with SBP ≤120 mm Hg were 1.15 (1.01–1.30; p=0.031) and 1.30 (1.08–1.57; p=0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBP ≤120 and >120 mm Hg respectively (HR for SBP ≤120 was compared with >120 mm Hg, 1.13; 95% CI, 1.03–1.24; P=0.008). HRs (95% CIs) for all-cause and HF hospitalization associated with SBP ≤120 mm Hg were 1.10 (1.02–1.194; p=0.017) and 1.21 (1.07–1.36; p=0.002). In conclusion, in patients with mild to moderate chronic systolic and diastolic HF, baseline SBP ≤120 mm Hg was associated with increased cardiovascular and HF mortality and all-cause, cardiovascular and HF hospitalization that was independent of other baseline characteristics.
doi:10.1016/j.amjcard.2010.12.020
PMCID: PMC3072746  PMID: 21296319
heart failure; systolic blood pressure; mortality; hospitalization
22.  Gender-Related Dissociation in Outcomes in Chronic Heart Failure: Reduced Mortality but Similar Hospitalization in Women 
Background
The impact of gender on major natural history endpoints in heart failure (HF) has not been examined in a propensity-matched study.
Methods
Of the 7788 chronic systolic and diastolic HF patients in the Digitalis Investigation Group trial 1926 were women. Propensity scores for female gender were used to assemble a cohort of 1669 pairs of men and women who were well-balanced on 32 measured baseline characteristics. Matched hazard ratios (HR) and 95% confidence intervals (CI) for outcomes associated with female gender were calculated using stratified Cox regression models.
Results
All-cause mortality occurred in 36% (rate, 1256/10,000 person-years) and 30% (rate, 1008/10,000 person-years) of matched men and women respectively during 5 years of follow up (HR when women were compared with men, 0.82, 95% CI, 0.72–0.94, P=0.004). Female gender was also associated with reduced cardiovascular mortality (matched HR, 0.85; 95% CI, 0.73–0.99, P=0.037) and a trend toward reduced non-cardiovascular mortality (matched HR, 0.73; 95% CI, 0.53–1.00; P=0.053). All-cause hospitalization occurred in 67% (rate, 4003/10,000 person-years) and 65% (rate, 3762/10,000 person-years) matched male and female patients respectively (HR for women, 1.03, 95% CI, 0.93–1.15, P=0.538). Female gender was not associated with cardiovascular or HF hospitalization but was associated with hospitalization due to unstable angina pectoris (matched HR, 1.38; 95%CI, 1.11–1.72; P=0.003) and stroke (matched HR, 0.65; 95%CI, 0.46–0.92; P=0.014).
Conclusions
In patients with chronic HF, female gender has a significant independent association with improved survival but has no association with all-cause, cardiovascular, or HF hospitalizations.
doi:10.1016/j.ijcard.2009.10.019
PMCID: PMC2888923  PMID: 19939481
Heart failure; gender; unstable angina pectoris; mortality; hospitalization
23.  Relationship between left and right ventricular ejection fractions in chronic advanced systolic heart failure: insights from the BEST trial 
European Journal of Heart Failure  2010;13(4):392-397.
Aims
Abnormally low right ventricular ejection fraction (RVEF) is a predictor of poor outcomes in chronic heart failure (HF) patients with low left ventricular ejection fraction (LVEF). However, little is known about the relationship between LVEF and RVEF in these patients.
Methods and results
Of the 2707 Beta-blocker Evaluation of Survival Trial (BEST) participants with ambulatory chronic HF, New York Heart Association class III–IV symptoms, and LVEF ≤35%, 2008 patients had gated-equilibrium radionuclide angiographic data on baseline LVEF and RVEF. Patients were categorized into quartiles by LVEF ≥29% (n= 507), 23–28% (n= 513), 17–22% (n= 538), and <17% (n= 450). Logistic regression models were used to determine the association of LVEF quartiles (reference, ≥29%) with abnormally low RVEF (<20%). The prevalence of RVEF <20% for patients with LVEF quartiles ≥29, 23–28, 17–22, and <17% were 3, 6, 15, and 32%, respectively. Unadjusted odds ratios [95% confidence intervals (CIs)] for RVEF <20% (vs. ≥20%) associated with LVEF quartiles 23–28, 17–22, and <17% (reference, ≥29%) were 2.18 (1.14–4.17; P= 0.018), 6.32 (3.54–11.30; P< 0.001), and 16.67 (9.46–29.39; P< 0.001), respectively. Respective multivariable-adjusted odds ratios (95% CIs) were 1.82 (0.94–3.54; P= 0.076), 4.55 (2.48–8.35; P< 0.001), and 10.53 (5.70–19.44; P< 0.001), respectively. Heart failure symptoms and signs had unadjusted associations with low RVEF, but lacked intrinsic associations.
Conclusion
In patients with advanced systolic HF, LVEF has a strong dose-dependent relationship with RVEF which is independent of other characteristics, and low LVEF is useful as a surrogate marker of abnormally low RVEF in these patients.
doi:10.1093/eurjhf/hfq206
PMCID: PMC3063564  PMID: 21097899
Chronic heart failure; Right ventricular ejection fraction; Left ventricular ejection fraction
24.  Evidence of a “Heart Failure Belt” in the Southeastern United States 
The American journal of cardiology  2011;107(6):935-937.
The Southeastern region of the United States is known as the “Stroke Belt” because of the excess stroke mortality in this region as compared to the rest of the country. However, whether a similar geographic variation in heart failure mortality exists is unknown. Using the CDC WONDER’s publicly-available compressed mortality data files and the 2000 United States population as the standard, we estimated age-adjusted heart failure and stroke mortality rates per 100,000 for individuals of all ages, both sexes and all races during 1979–1998 in the United States, and mapped them at the state level. The age-adjusted heart failure mortality rate for the six contiguous Southeastern states (Alabama, Arkansas, Mississippi, Oklahoma, Louisiana, and Georgia) was 31.0/100,000, which was 69% higher than the national rate of 18.3/100,000. This geographic disparity was similar among African Americans (32.9/100,000 in the Southeast versus 21.7/100,000 nationally) and whites (30.8/100,000 in the Southeast versus 18.1/100,000 nationally). These findings suggest that in addition to the “Stroke Belt”, the Southeastern region of the United States may also be burdened by a “Heart Failure Belt”. To better understand the causes of the excess stroke mortality in the “Stroke Belt”, the National Institutes of Health has funded the REasons for Geographic and Racial Differences in Stroke (REGARDS) study (N=30,239, over half from the Southeastern region), which provide a unique opportunity to study the underlying causes of excess heart failure mortality in the “Heart Failure Belt”.
doi:10.1016/j.amjcard.2010.11.012
PMCID: PMC3057326  PMID: 21247536
heart failure; mortality; southeastern states
25.  Hyperuricaemia, chronic kidney disease, and outcomes in heart failure: potential mechanistic insights from epidemiological data 
European Heart Journal  2011;32(6):712-720.
Aim
To determine if the association between hyperuricaemia and poor outcomes in heart failure (HF) varies by chronic kidney disease (CKD).
Methods and results
Of the 2645 systolic HF patients in the Beta-Blocker Evaluation of Survival Trial with data on baseline serum uric acid, 1422 had hyperuricaemia (uric acid ≥6 mg/dL for women and ≥8 mg/dL for men). Propensity scores for hyperuricaemia, estimated for each patient, were used to assemble a matched cohort of 630 pairs of patients with and without hyperuricaemia who were balanced on 75 baseline characteristics. Associations of hyperuricaemia with outcomes during 25 months of median follow-up were examined in all patients and in those with and without CKD (estimated glomerular filtration rate of <60 mL/min/1.73 m2). Hyperuricaemia-associated hazard ratios (HRs) and 95% confidence intervals (CI) for all-cause mortality and HF hospitalization were 1.44 (1.12–1.85, P = 0.005) and 1.27 (1.02–1.58, P = 0.031), respectively. Hazard ratios (95% CIs) for all-cause mortality among those with and without CKD were 0.96 (0.70–1.31, P = 0.792) and 1.40 (1.08–1.82, P = 0.011), respectively (P for interaction, 0.071), and those for HF hospitalization among those with and without CKD were 0.99 (0.74–1.33, P = 0.942) and 1.49 (1.19–1.86, P = 0.001), respectively (P for interaction, 0.033).
Conclusion
Hyperuricaemia has a significant association with poor outcomes in HF patients without CKD but not in those with CKD, suggesting that hyperuricaemia may predict poor outcomes when it is primarily a marker of increased xanthine oxidase activity, but not when it is primarily due to impaired renal excretion of uric acid.
doi:10.1093/eurheartj/ehq473
PMCID: PMC3056205  PMID: 21199831
Heart failure; Hyperuricaemia; Chronic kidney disease; Outcomes

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