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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.  A propensity‐matched study of the effect of diabetes on the natural history of heart failure: variations by sex and age 
Heart  2007;93(12):1584-1590.
Background
Poor prognosis in heart failure (HF) patients with diabetes is often attributed to increased co‐morbidity and advanced disease. Further, this effect may be worse in women.
Objective
To determine whether the effect of diabetes on outcomes and the sex‐related variation persisted in a propensity score‐matched HF population, and whether the sex‐related variation was a function of age.
Methods
Of the 7788 HF patients in the Digitalis Investigation Group trial, 2218 had a history of diabetes. Propensity score for diabetes was calculated for each patient using a non‐parsimonious logistic regression model incorporating all measured baseline covariates, and was used to match 2056 (93%) diabetic patients with 2056 non‐diabetic patients.
Results
All‐cause mortality occurred in 135 (25%) and 216 (39%) women without and with diabetes (adjusted HR = 1.67; 95% CI = 1.34 to 2.08; p<0.001). Among men, 535 (36%) and 609 (41%) patients without and with diabetes died from all causes (adjusted HR = 1.21; 95% CI = 1.07 to 1.36; p = 0.002). Sex–diabetes interaction (overall adjusted p<0.001) was only significant in patients ⩾65 years (15% absolute risk increase in women; multivariable p for interaction = 0.005), but not in younger patients (2% increase in women; p for interaction = 0.173). Risk‐adjusted HR (95% CI) for all‐cause hospitalisation for women and men were 1.49 (1.28 to 1.72) and 1.21 (1.11 to 1.32), respectively, also with significant sex–diabetes interaction (p = 0.011).
Conclusions
Diabetes‐associated increases in morbidity and mortality in chronic HF were more pronounced in women, and theses sex‐related differences in outcomes were primarily observed in elderly patients.
doi:10.1136/hrt.2006.113522
PMCID: PMC2095739  PMID: 17488764
3.  The MGTX Experience: Challenges in Planning and Executing an International, Multicenter Clinical Trial 
Journal of neuroimmunology  2008;201-202:80-84.
We present our experience planning and launching a multinational, NIH/NINDS funded study of thymectomy in myasthenia gravis. We highlight the additional steps required for international sites and analyze and contrast the time investment required to bring U.S. and non-U.S. sites into full regulatory compliance. Results show the mean time for non- U.S. centers to achieve regulatory approval was significantly longer (mean 13.4 ± 0.96 months) than for U.S. sites (9.67 ± 0.74 months; p = 0.003, t-test). The delay for non- U.S. sites was mainly attributable to Federalwide Assurance certification and State Department clearance.
doi:10.1016/j.jneuroim.2008.05.031
PMCID: PMC2654214  PMID: 18675464
Myasthenia gravis; thymectomy; regulatory approval
4.  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
5.  The MRI Rule of Five: Predicting the Occurrence of Relapse 
Background
Clinical intuition suggests that a sharp increase in the number of enhancing lesions should signal an increased risk of relapse. The Rule of Five recommends that subjects exhibiting at least five lesions over the baseline level be referred for closer monitoring. This rule has been used as an informal safety criterion with limited formal evaluation.
Objective
To determine the best threshold for the Rule and to demonstrate its predictive validity for risk of subsequent relapses for MS trials.
Methods
We used logistic regression modeling to apply the Rule to patient data from a Phase II clinical trial. Predictive validity was ascertained using rate ratios and ROC curves.
Results
We found that, for these data, a threshold of five lesions over the baseline constituted the best definition of a threshold. Overall, 35% of subjects broke the Rule at least once. Breaking the rule increased the odds of imminent relapse by a factor of 3.2 (95% Confidence Interval: 1.8 to 5.5).
Conclusion
Breaking the Rule of Five was found to be a significant predictor of an imminent relapse. Length of follow-up and the number of lesions discovered via MRI were also significant predictors of relapse.
doi:10.1177/1352458513485147
PMCID: PMC4128343  PMID: 23612880
Multiple sclerosis; relapsing-remitting; magnetic resonance imaging scans; safety monitoring; logistic regression
6.  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
7.  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
8.  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
9.  Evaluation of a Frequentist Hierarchical Model to Estimate Prevalence when sampling from a large geographic area using Pool Screening 
Communications in statistics: theory and methods  2013;42(19):10.1080/03610926.2011.633732.
We present a frequentist Bernoulli-Beta hierarchical model to relax the constant prevalence assumption underlying the traditional prevalence estimation approach based on pooled data. This assumption is called into question when sampling from a large geographic area. Pool screening is a method that combines individual items into pools. Each pool will either test positive (at least one of the items is positive) or negative (all items are negative). Pool screening is commonly applied to the study of tropical diseases where pools consist of vectors (e.g. black flies) that can transmit the disease. The goal is to estimate the proportion of infected vectors.
Intermediate estimators (model parameters) and estimators of ultimate interest (pertaining to prevalence) are evaluated by standard measures of merit, such as bias, variance and mean squared error making extensive use of expansions. Using the hierarchical model an investigator can determine the probability of the prevalence being below a prespecified threshold value, a value at which no reemergence of the disease is expected. An investigation into the least biased choice of the α parameter in the Beta (α, β) prevalence distribution leads to the choice of α = 1.
doi:10.1080/03610926.2011.633732
PMCID: PMC3862083  PMID: 24347808
10.  Digoxin Reduces 30-Day All-Cause Hospital Admission in Older Patients with Chronic Systolic Heart Failure 
The American journal of medicine  2013;126(8):701-708.
BACKGROUND
Heart failure is a leading cause of hospital admission and readmission in older adults. The new United States healthcare reform law has created provisions for financial penalties for hospitals with higher-than-expected 30-day all-cause readmission rates for hospitalized Medicare beneficiaries ≥65 years with heart failure. We examined the effect of digoxin on 30-day all-cause hospital admission in older patients with heart failure and reduced ejection fraction.
METHODS
In the main Digitalis Investigation Group (DIG) trial, 6800 ambulatory patients with chronic heart failure (ejection fraction ≤45%) were randomly assigned to digoxin or placebo. Of these, 3405 were ≥65 years (mean age, 72 years, 25% women, 11% non-whites). The main outcome in the current analysis was 30-day all-cause hospital admission.
RESULTS
In the first 30 days after randomization, all-cause hospitalization occurred in 5.4% (92/1693) and 8.1% (139/1712) of patients in the digoxin and placebo groups, respectively, (hazard ratio {HR} when digoxin was compared with placebo, 0.66; 95% confidence interval {CI}, 0.51–0.86; p=0.002). Digoxin also reduced both 30-day cardiovascular (3.5% vs. 6.5%; HR, 0.53; 95% CI, 0.38–0.72; p<0.001) and heart failure (1.7 vs. 4.2%; HR, 0.40; 95% CI, 0.26–0.62; p<0.001) hospitalizations, with similar trends for 30-day all-cause mortality (0.7% vs. 1.3%; HR, 0.55; 95% CI, 0.27–1.11; p=0.096). Younger patients were at lower risk of events but obtained similar benefits from digoxin.
CONCLUSIONS
Digoxin reduces 30-day all-cause hospital admission in ambulatory older patients with chronic systolic heart failure. Future studies need to examine its effect on 30-day all-cause hospital readmission in hospitalized patients with acute heart failure.
doi:10.1016/j.amjmed.2013.02.001
PMCID: PMC3926199  PMID: 23490060
Digoxin; heart failure; 30-day all-cause hospital admission
11.  Effects of enalapril in systolic heart failure patients with and without chronic kidney disease: Insights from the SOLVD Treatment trial 
International journal of cardiology  2012;167(1):151-156.
Background
Angiotensin-converting enzyme inhibitors improve outcomes in systolic heart failure (SHF). However, doubts linger about their effect in SHF patients with chronic kidney disease (CKD).
Methods
In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, 2569 ambulatory chronic HF patients with left ventricular ejection fraction ≤35% and serum creatinine level ≤2.5 mg/dL were randomized to receive either placebo (n=1284) or enalapril (n=1285). Of the 2502 patients with baseline serum creatinine data, 1036 had CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2).
Results
Overall, during 35 months of median follow-up, all-cause mortality occurred in 40% (502/1252) and 35% (440/1250) of placebo and enalapril patients, respectively (hazard ratio {HR}, 0.84; 95% confidence interval {CI}, 0.74–0.95; p=0.007). All-cause mortality occurred in 45% and 42% of patients with CKD (HR, 0.88; 95% CI, 0.73–1.06; p=0.164), and 36% and 31% of non-CKD patients (HR, 0.82; 95% CI, 0.69–0.98; p=0.028) in the placebo and enalapril groups, respectively (p for interaction=0.615). Enalapril reduced cardiovascular hospitalization in those with CKD (HR, 0.77; 95% CI, 0.66–0.90; p<0.001) and without CKD (HR, 0.80; 95% CI, 0.70–0.91; p<0.001). Among patients in the enalapril group, serum creatinine elevation was significantly higher in those without CKD (0.09 versus 0.04 mg/dL in CKD; p=0.003) during first year of follow-up, but there was no differences in changes in systolic blood pressure (mean drop, 7 mmHg, both) and serum potassium (mean increase, 0.2 mEq/L, both).
Conclusions
Enalapril reduces mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD.
doi:10.1016/j.ijcard.2011.12.056
PMCID: PMC3395757  PMID: 22257685
enalapril; heart failure; chronic kidney disease
12.  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
13.  Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial 
European Heart Journal  2013;34(20):1489-1497.
Aims
Digoxin is recommended for long-term rate control in paroxysmal, persistent, and permanent atrial fibrillation (AF). While some analyses suggest an association of digoxin with a higher mortality in AF, the intrinsic nature of this association has not been examined in propensity-matched cohorts, which is the objective of the current study.
Methods and results
In Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), 4060 patients with paroxysmal and persistent AF were randomized to rate (n = 2027) vs. rhythm (n = 2033) control strategies. Of these, 1377 received digoxin as initial therapy and 1329 received no digoxin at baseline. Propensity scores for digoxin use were estimated for each of these 2706 patients and used to assemble a cohort of 878 pairs of patients receiving and not receiving digoxin, who were balanced on 59 baseline characteristics. Matched patients had a mean age of 70 years, 40% were women, and 11% non-white. During the 3.4 years of the mean follow-up, all-cause mortality occurred in 14 and 13% of matched patients receiving and not receiving digoxin, respectively [hazard ratio (HR) associated with digoxin use: 1.06; 95% confidence interval (CI): 0.83–1.37; P = 0.640]. Among matched patients, digoxin had no association with all-cause hospitalization (HR: 0.96; 95% CI: 0.85–1.09; P = 0.510) or incident non-fatal cardiac arrhythmias (HR: 0.90; 95% CI: 0.37–2.23; P = 0.827). Digoxin had no multivariable-adjusted or propensity score-adjusted associations with these outcomes in the pre-match cohort.
Conclusions
In patients with paroxysmal and persistent AF, we found no evidence of increased mortality or hospitalization in those taking digoxin as baseline initial therapy.
doi:10.1093/eurheartj/eht120
PMCID: PMC3659306  PMID: 23592708
Atrial fibrillation; Digoxin; Hospitalization; Mortality; Propensity score
14.  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
15.  Effect of oral digoxin in high-risk heart failure patients: a pre-specified subgroup analysis of the DIG trial† 
European Journal of Heart Failure  2013;15(5):551-559.
Aims
In the Digitalis Investigation Group (DIG) trial, digoxin reduced mortality or hospitalization due to heart failure (HF) in several pre-specified high-risk subgroups of HF patients, but data on protocol-specified 2-year outcomes were not presented. In the current study, we examined the effect of digoxin on HF death or HF hospitalization and all-cause death or all-cause hospitalization in high-risk subgroups during the protocol-specified 2 years of post-randomization follow-up.
Methods and results
In the DIG trial, 6800 ambulatory patients with chronic HF, normal sinus rhythm, and LVEF ≤45% (mean age 64 years, 26% women, 17% non-whites) were randomized to receive digoxin or placebo. The three high-risk groups were defined as NYHA class III–IV symptoms (n = 2223), LVEF <25% (n = 2256), and cardiothoracic ratio (CTR) >55% (n = 2345). In all three high-risk subgroups, compared with patients in the placebo group, those in the digoxin group had a significant reduction in the risk of the 2-year composite endpoint of HF mortality or HF hospitalization: NYHA III–IV [hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.57–0.75; P < 0.001], LVEF <25% (HR 0.61; 95% CI 0.53–0.71; P < 0.001), and CTR >55% (HR 0.65; 95% CI 0.57–0.75; P < 0.001). Digoxin-associated HRs (95% CI) for 2-year all-cause mortality or all-cause hospitalization for subgroups with NYHA III–IV, LVEF <25%, and CTR >55% were 0.88 (0.80–0.97; P = 0.012), 0.84 (0.76–0.93; P = 0.001), and 0.85 (0.77–0.94; P = 0.002), respectively.
Conclusions
Digoxin improves outcomes in chronic HF patients with NYHA class III–IV, LVEF <25%, or CTR >55%, and should be considered in these patients.
doi:10.1093/eurjhf/hft010
PMCID: PMC3707428  PMID: 23355060
Digoxin; Heart Failure; High risk; Morbidity; Mortality
16.  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
17.  Renin-Angiotensin Inhibition in Diastolic Heart Failure and Chronic Kidney Disease 
The American journal of medicine  2013;126(2):150-161.
BACKGROUND
The role of renin-angiotensin inhibition in older patients with diastolic heart failure and chronic kidney disease remains unclear.
METHODS
Of the 1340 patients (age ≥65 years), with diastolic heart failure (ejection fraction ≥45%) and chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), 717 received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Propensity scores for the use of these drugs, estimated for each of the 1340 patients, were used to assemble a cohort of 421 pairs of patients, receiving and not receiving these drugs, who were balanced on 56 baseline characteristics.
RESULTS
During more than 8 years of follow-up, all-cause mortality occurred in 63% and 69% of matched patients with chronic kidney disease receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (hazard ratio {HR}, 0.82; 95% confidence interval {CI}, 0.70–0.97; p=0.021). There was no association with heart failure hospitalization (HR, 0.98; 95% CI, 0.82–1.18; p=0.816). Similar mortality reduction (HR, 0.81; 95% CI, 0.66–0.995; p=0.045) occurred in a subgroup of matched patients with an estimated glomerular filtration rate <45 ml/min/1.73 m2. Among 207 pairs of propensity-matched patients without chronic kidney disease, the use of these drugs was not associated with mortality (HR, 1.03; 95% CI, 0.80–1.33; p=0.826) or heart failure hospitalization (HR, 0.99; 95% CI, 0.76–1.30; p=0.946).
CONCLUSIONS
A discharge prescription for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant reduction in all-cause mortality in older patients with diastolic heart failure and chronic kidney disease including those with more advanced chronic kidney disease.
doi:10.1016/j.amjmed.2012.06.031
PMCID: PMC3575519  PMID: 23331442
Angiotensin-converting enzyme inhibitors; Angiotensin receptor blockers; Chronic kidney disease; Diastolic heart failure
18.  Aldosterone Antagonists and Outcomes in Real-World Older Patients with Heart Failure and Preserved Ejection Fraction 
JACC. Heart failure  2013;1(1):40-47.
Objectives
The purpose of this study was to examine the clinical effectiveness of aldosterone antagonists in older patients with heart failure and preserved ejection fraction (HF-PEF).
Background
Aldosterone antagonists improve outcomes in HF and reduced EF. However, their role in HF-PEF remains unclear.
Methods
Of the 10,570 hospitalized older (age ≥65 years) HF-PEF (EF ≥40%) patients in Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) trial, 8013 had no prior aldosterone antagonist use and no current contraindications, of whom 492 (6% of 8013) received new prescriptions for aldosterone antagonists. We assembled a matched cohort of 487 pairs of patients receiving and not receiving aldosterone antagonists, who had similar propensity to receive these drugs, and were balanced on 116 baseline characteristics.
Results
Patients had a mean age of 80 years, a mean EF of 54%, 59% were women, and 8% were African American. During 2.4 year of mean follow-up (through December, 2008), the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 392 (81%) and 393 (81%) patients receiving and not receiving aldosterone antagonists, respectively (hazard ratio {HR}, 0.97; 95% confidence interval {CI}, 0.84–1.11; p=0.628). Aldosterone antagonists had no association with all-cause mortality (HR, 1.03; 95% CI, 0.89–1.20; p=0.693) or HF hospitalization (HR, 0.88; 95% CI, 0.73–1.07; p=0.188). Among 8013 pre-match patients, multivariable-adjusted HR for primary composite endpoint associated with aldosterone antagonist use was 0.93 (95% CI, 0.83–1.03; p=0.144).
Conclusions
In older HF-PEF patients, aldosterone antagonists had no association with clinical outcomes. Findings from the ongoing randomized controlled TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial will provide further insights into their effect in HF-PEF.
doi:10.1016/j.jchf.2012.08.001
PMCID: PMC3694622  PMID: 23814702
Aldosterone antagonists; Heart failure; Preserved ejection fraction
19.  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
20.  Angiotensin receptor blockers and outcomes in real-world older patients with heart failure and preserved ejection fraction: a propensity-matched inception cohort clinical effectiveness study 
European Journal of Heart Failure  2012;14(10):1179-1188.
Aims
To examine the clinical effectiveness of angiotensin receptor blockers (ARBs) in older patients with heart failure and preserved ejection fraction (HF-PEF).
Methods and results
Of the 10 570 hospitalized HF-PEF patients, aged ≥65 years, EF ≥40%, in OPTIMIZE-HF (2003–2004), linked to Medicare data (up to 31 December 2008), 3806 were not receiving angiotensin-converting enzyme inhibitors or prior ARB therapy. Of these, 303 (8%) patients received new discharge prescriptions for ARBs. Propensity scores for the receipt of ARBs, estimated for each of the 3806 patients, were used to assemble a cohort of 296 pairs of patients receiving and not receiving ARBs, who were balanced on 114 baseline characteristics. Patients had a mean age of 80 years, mean EF of 55%, 69% were women, and 12% were African American. During 6 years of follow-up, the primary composite endpoint of all-cause mortality or HF hospitalization occurred in 79% (235/296) and 81% (241/296) of patients receiving and not receiving ARBs, respectively [hazard ratio (HR) associated with ARB use 0.88, 95% confidence interval (CI) 0.74–1.06; P = 0.179]. ARB use had no association with individual endpoints of all-cause mortality (HR 0.93, 95% CI 0.76–1.14; P = 0.509), HF hospitalization (HR 0.90, 95% CI, 0.72–1.14; P = 0.389), or all-cause hospitalization (HR 0.91, 95% CI 0.77–1.08; P = 0.265). These associations remained unchanged when we compared any (prevalent and new prescriptions) ARB use vs. non-use in a separately assembled propensity-matched cohort of 1137 pairs of HF-PEF patients.
Conclusions
In real-world older HF-PEF patients, ARB use was not associated with improved clinical outcomes.
doi:10.1093/eurjhf/hfs101
PMCID: PMC3448391  PMID: 22759445
Angiotensin receptor blockers; Heart failure; Preserved ejection fraction
21.  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
22.  In-Hospital Cardiology Consultation and Evidence-Based Care for Nursing Home Residents with Heart Failure 
Objectives
To determine the association between cardiology consultation and evidence-based care for nursing home (NH) residents with heart failure (HF).
Participants
Hospitalized NH residents (n= 646) discharged from 106 Alabama hospitals with a primary discharge diagnosis of HF during 1998–2001.
Design
Observational.
Measurements of Evidence-Based Care
Pre-admission estimation of left ventricular ejection fraction (LVEF) for patients with known HF (n=494), in-hospital LVEF estimation for HF patients without known LVEF (n=452), and discharge prescriptions of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEIs-or-ARBs) to systolic HF (LVEF <45%) patients discharged alive who were eligible to receive those drugs (n=83). Eligibility for ACEIs-or-ARBs was defined as lack of prior allergy or adverse effect, serum creatinine <2.5 mg/dL, serum potassium <5.5 mEq/L, and systolic blood pressure >100 mm Hg.
Results
Pre-admission LVEF was estimated in 38% and 12% of patients receiving and not receiving cardiology consultation, respectively (adjusted odds ratio {AOR}, 3.49; 95% CI, 2.16–5.66; p <0.001). In-hospital LVEF was estimated in 71% and 28% of patients receiving and not receiving cardiology consultation, respectively (AOR, 6.01; 95% CI, 3.69–9.79; p <0.001). ACEIs-or-ARBs were prescribed to 62% and 82% of patients receiving and not receiving cardiology consultation, respectively (AOR, 0.24; 95% CI, 0.07–0.81; p=0.022).
Conclusion
In-hospital cardiology consultation was associated with significantly higher odds of LVEF estimation among NH residents with HF. However, it did not translate into higher odds of discharge prescriptions for ACEIs-or-ARBs to NH resident with systolic HF who were eligible for the receipt of these drugs.
doi:10.1016/j.jamda.2011.09.001
PMCID: PMC3750116  PMID: 21982687
heart failure; nursing home residents; cardiology consultation; evidence-based care
23.  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
24.  Impairment of activities of daily living and incident heart failure in community-dwelling older adults 
European Journal of Heart Failure  2012;14(6):581-587.
Aims
Instrumental activities of daily living (IADLs) are tasks that are necessary for independent community living. These tasks often require intact physical and cognitive function, the impairment of which may adversely affect health in older adults. In the current study, we examined the association between IADL impairment and incident heart failure (HF) in community-dwelling older adults.
Methods and results
Of the 5795 community-dwelling adults, aged ≥65 years, in the Cardiovascular Health Study, 5511 had data on baseline IADL and were free of prevalent HF. Of these, 1333 (24%) had baseline IADL impairment, defined as self-reported difficulty with one or more of the following tasks: using the telephone, preparing food, performing light and heavy housework, managing finances, and shopping. Propensity scores for IADL impairment, estimated for each of the 5511 participants, were used to assemble a cohort of 1038 pairs of participants with and without IADL impairment who were balanced on 42 baseline characteristics. Centrally adjudicated incident HF occurred in 26% and 21% of matched participants with and without IADL impairment, respectively, during >12 years of follow-up [matched hazard ratio (HR) 1.33; 95% confidence interval (CI) 1.11–1.59; P = 0.002]. Unadjusted and multivariable-adjusted HRs for incident HF before matching were 1.77 (95% CI 1.56–2.01; P < 0.001) and 1.33 (95% CI 1.15–1.54; P < 0.001), respectively. IADL impairment was also associated with all-cause mortality (matched HR 1.19; 95% CI 1.06–1.34; P = 0.004).
Conclusion
Among community-dwelling older adults free of baseline HF, IADL impairment is a strong and independent predictor of incident HF and mortality.
doi:10.1093/eurjhf/hfs034
PMCID: PMC3359859  PMID: 22492539
Instrumental activities of daily living; Incident heart failure; Propensity score
25.  Renin-angiotensin inhibition in systolic heart failure and chronic kidney disease 
The American Journal of Medicine  2012;125(4):399-410.
Background
The role of renin-angiotensin inhibition in older systolic heart failure patients with chronic kidney disease remains unclear.
Methods
Of the 1665 patients, age ≥65 years, with systolic heart failure (ejection fraction <45%) and chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), 1046 received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Propensity scores for the receipts of these drugs, estimated for each of the 1665 patients, were used to assemble a matched cohort of 444 pairs of patients receiving and not receiving these drugs who were balanced on 56 baseline characteristics.
Results
During over 8 years of follow-up, all-cause mortality occurred in 75% and 79% of matched patients with chronic kidney disease receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (hazard ratio {HR}, 0.86; 95% confidence interval {CI}, 0.74–0.996; p=0.045). There was no significant association with heart failure hospitalization (HR, 0.86; 95% CI, 0.72–1.03; p=0.094). Similar mortality reduction (HR, 0.83; 95% CI, 0.70–1.00; p=0.046) occurred in a subgroup of matched patients with estimated glomerular filtration rate <45 ml/min/1.73 m2. Among 171 pairs of propensity-matched patients without chronic kidney disease, the use of these drugs was associated with significant reduction in all-cause mortality (HR, 0.72; 95% CI, 0.55–0.94; p=0.015) and heart failure hospitalization (HR, 0.71; 95% CI, 0.52–0.95; p=0.023).
Conclusions
Discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant modest reduction in all-cause mortality in older systolic heart failure patients with chronic kidney disease including those with more advanced chronic kidney disease.
doi:10.1016/j.amjmed.2011.10.013
PMCID: PMC3324926  PMID: 22321760
systolic heart failure; chronic kidney disease; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers

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