Sue Hee Sung

The Cardiovascular Research Network: A New Paradigm for Cardiovascular Quality and Outcomes Research

Background—A clear need exists for a more systematic understanding of the epidemiology, diagnosis, and management of cardiovascular diseases. More robust data are also needed on how well clinical trials are translated into contemporary community practice and the associated resource use, costs, and outcomes. Methods and Results—The National Heart, Lung, and Blood Institute recently established the Cardiovascular Research Network, which represents a new paradigm to evaluate the epidemiology, quality of care, and outcomes of cardiovascular disease and to conduct future clinical trials using a community-based model. The network includes 15 geographically distributed health plans with dedicated research centers, National Heart, Lung, and Blood Institute representatives, and an external collaboration and advisory committee. Cardiovascular research network sites bring complementary content and methodological expertise and a diverse population of ≈11 million individuals treated through various health care delivery models. Each site’s rich electronic databases (eg, sociodemographic characteristics, inpatient and outpatient diagnoses and procedures, pharmacy, laboratory, and cost data) are being mapped to create a standardized virtual data warehouse to facilitate rapid and efficient large-scale research studies. Initial projects focus on (1) hypertension recognition and management, (2) quality and outcomes of warfarin therapy, and (3) use, outcomes, and costs of implantable cardioverter defibrillators. Conclusions—The Cardiovascular Research Network represents a new paradigm in the approach to cardiovascular quality of care and outcomes research among community-based populations. Its unique ability to characterize longitudinally large, diverse populations will yield novel insights into contemporary disease and risk factor surveillance, management, outcomes, and costs. The Cardiovascular Research Network aims to become the national research partner of choice for efforts to improve the prevention, diagnosis, treatment, and outcomes of cardiovascular diseases.

Atrial fibrillation and outcomes in heart failure with preserved versus reduced left ventricular ejection fraction

Background Atrial fibrillation (AF) and heart failure (HF) are 2 of the most common cardiovascular conditions nationally and AF frequently complicates HF. We examined how AF has impacts on adverse outcomes in HF‐PEF versus HF‐REF within a large, contemporary cohort. Methods and Results We identified all adults diagnosed with HF‐PEF or HF‐REF based on hospital discharge and ambulatory visit diagnoses and relevant imaging results for 2005–2008 from 4 health plans in the Cardiovascular Research Network. Data on demographic features, diagnoses, procedures, outpatient pharmacy use, and laboratory results were ascertained from health plan databases. Hospitalizations for HF, stroke, and any reason were identified from hospital discharge and billing claims databases. Deaths were ascertained from health plan and state death files. Among 23 644 patients with HF, 11 429 (48.3%) had documented AF (9081 preexisting, 2348 incident). Compared with patients who did not have AF, patients with AF had higher adjusted rates of ischemic stroke (hazard ratio [HR] 2.47 for incident AF; HR 1.57 for preexisting AF), hospitalization for HF (HR 2.00 for incident AF; HR 1.22 for preexisting AF), all‐cause hospitalization (HR 1.45 for incident AF; HR 1.15 for preexisting AF), and death (incident AF HR 1.67; preexisting AF HR 1.13). The associations of AF with these outcomes were similar for HF‐PEF and HF‐REF, with the exception of ischemic stroke. Conclusions AF is a potent risk factor for adverse outcomes in patients with HF‐PEF or HF‐REF. Effective interventions are needed to improve the prognosis of these high‐risk patients.

Effectiveness and Safety of Digoxin Among Contemporary Adults With Incident Systolic Heart Failure

Background—Clinical guidelines recommend digoxin for patients with symptomatic systolic heart failure (HF) receiving optimal medical therapy, but this recommendation is based on limited, older trial data. We evaluated the effectiveness and safety of digoxin in a contemporary cohort of patients with incident systolic HF. Methods and Results—We identified adults with incident systolic HF between 2006 and 2008 within Kaiser Permanente Northern California who had no prior digoxin use. We used multivariable extended Cox regression to examine the association between new digoxin use and risks of death and HF hospitalization, controlling for medical history, laboratory results, medications, HF disease severity, and the propensity for digoxin use. We also conducted analyses stratified by sex and concurrent &bgr;-blocker use. Among 2891 newly diagnosed patients with systolic HF, 529 (18%) received digoxin. During a median 2.5 years of follow-up, incident digoxin use was associated with higher rates of death (14.2 versus 11.3 per 100 person-years) and HF hospitalization (28.2 versus 24.4 per 100 person-years). In multivariable analysis, incident digoxin use was associated with higher mortality (hazard ratio, 1.72; 95% confidence interval, 1.25–2.36) but no significant difference in the risk of HF hospitalization (hazard ratio, 1.05; 95% confidence interval, 0.82–1.34). Results were similar in analyses stratified by sex and &bgr;-blocker use. Conclusions—Digoxin use in patients with incident systolic HF was independently associated with a higher risk of death but no difference in HF hospitalization.

Contemporary Prevalence and Correlates of Incident Heart Failure with Preserved Ejection Fraction

BACKGROUND We assessed the prevalence of preserved left ventricular ejection fraction in patients with incident heart failure and differences in the demographic and clinical characteristics that may differentiate patients presenting with heart failure with preserved versus reduced left ventricular ejection fraction. METHODS We identified all patients with newly diagnosed heart failure between 2005 and 2008 from 4 sites in the Cardiovascular Research Network on the basis of hospital discharge and ambulatory visit diagnoses, and assigned a category of preserved, borderline, or reduced left ventricular ejection fraction using data from electronic databases and chart review. RESULTS We identified 11,994 patients with incident heart failure; of these, 6210 (51.8%) had preserved left ventricular ejection fraction, 1870 (15.6%) had borderline systolic dysfunction, and 3914 (32.6%) had reduced left ventricular ejection fraction. For those with heart failure with preserved left ventricular ejection fraction, the mean age was 74.7 years and 57.1% were women; for those with borderline systolic dysfunction, the mean age was 71.6 years and 38.4% were women; and for those with reduced left ventricular ejection fraction, the mean age was 69.1 years and 32.6% were women. Compared with white patients, black patients were less likely to have heart failure with preserved systolic function. Those with a history of coronary artery bypass surgery, mitral or aortic valvular disease, atrial fibrillation or flutter, or a diagnosis of hypertension were more likely to have heart failure with preserved systolic function, as were those with a diverse range of noncardiac comorbid conditions, including chronic lung disease, chronic liver disease, a history of a hospitalized bleed, a history of a mechanical fall, a diagnosis of depression, and a diagnosis of dementia. Patients with a history of acute myocardial infarction and a history of ventricular fibrillation or ventricular tachycardia were less likely to have heart failure with preserved left ventricular ejection fraction. Patients with higher systolic blood pressures at baseline and lower low-density lipoprotein levels were more likely to have heart failure with preserved left ventricular ejection fraction, as were those with lower hemoglobin levels and the lowest glomerular filtration rates. CONCLUSIONS Heart failure with preserved left ventricular ejection fraction is the most common form of the heart failure syndrome among patients newly presenting with this condition, and women and older adults are especially affected. Evidence-based treatment strategies apply to less than one third of patients with newly diagnosed heart failure.

Chronic Kidney Disease and Outcomes in Heart Failure With Preserved Versus Reduced Ejection Fraction The Cardiovascular Research Network PRESERVE Study

Background— There is scant evidence on the effect that chronic kidney disease (CKD) confers on clinically meaningful outcomes among patients with heart failure with preserved left ventricular ejection fraction (HF-PEF). Methods and Results— We identified a community-based cohort of patients with HF. Electronic medical record data were used to divide into HF-PEF and reduced left ventricular EF on the basis of quantitative and qualitative estimates. Level of CKD was assessed by estimated glomerular filtration rate (eGFR) and by dipstick proteinuria. We followed patients for a median of 22.1 months for outcomes of death and hospitalization (HF-specific and all-cause). Multivariable Cox regression estimated the adjusted relative-risk of outcomes by level of CKD, separately for HF-PEF and HF with reduced left ventricular EF. We identified 14 579 patients with HF-PEF and 9762 with HF with reduced left ventricular EF. When compared with patients with eGFR between 60 and 89 mL/min per 1.73 m2, lower eGFR was associated with an independent graded increased risk of death and hospitalization. For example, among patients with HF-PEF, the risk of death was nearly double for eGFR 15 to 29 mL/min per 1.73 m2 and 7× higher for eGFR<15 mL/min per 1.73 m2, with similar findings in those with HF with reduced left ventricular EF. Conclusions— CKD is common and an important independent predictor of death and hospitalization in adults with HF across the spectrum of left ventricular systolic function. Our study highlights the need to develop new and effective interventions for the growing number of patients with HF complicated by CKD.

Longitudinal study of implantable cardioverter-defibrillators: methods and clinical characteristics of patients receiving implantable cardioverter-defibrillators for primary prevention in contemporary practice

Background—Implantable cardioverter-defibrillators (ICDs) are increasingly used for primary prevention after randomized, controlled trials demonstrating that they reduce the risk of death in patients with left ventricular systolic dysfunction. The extent to which the clinical characteristics and long-term outcomes of unselected, community-based patients with left ventricular systolic dysfunction undergoing primary prevention ICD implantation in a real-world setting compare with those enrolled in the randomized, controlled trials is not well characterized. This study is being conducted to address these questions. Methods and Results—The study cohort includes consecutive patients undergoing primary prevention ICD placement between January 1, 2006 and December 31, 2009 in 7 health plans. Baseline clinical characteristics were acquired from the National Cardiovascular Data Registry ICD Registry. Longitudinal data collection is underway, and will include hospitalization, mortality, and resource use from standardized health plan data archives. Data regarding ICD therapies will be obtained through chart abstraction and adjudicated by a panel of experts in device therapy. Compared with the populations of primary prevention ICD therapy randomized, controlled trials, the cohort (n=2621) is on average significantly older (by 2.5–6.5 years), more often female, more often from racial and ethnic minority groups, and has a higher burden of coexisting conditions. The cohort is similar, however, to a national population undergoing primary prevention ICD placement. Conclusions—Patients undergoing primary prevention ICD implantation in this study differ from those enrolled in the randomized, controlled trials that established the efficacy of ICDs. Understanding a broad range of health outcomes, including ICD therapies, will provide patients, clinicians, and policy makers with contemporary data to inform decision-making.

Risk Factors for Adverse Outcomes by Left Ventricular Ejection Fraction in a Contemporary Heart Failure Population

Background—Although heart failure (HF) is a syndrome with important differences in response to therapy by left ventricular ejection fraction (LVEF), existing risk stratification models typically group all HF patients together. The relative importance of common predictor variables for important clinical outcomes across strata of LVEF is relatively unknown. Methods and Results—We identified all members with HF between 2005 and 2008 from 4 integrated healthcare systems in the Cardiovascular Research Network. LVEF was categorized as preserved (LVEF ≥50% or normal), borderline (41%–49% or mildly reduced), and reduced (⩽40% or moderately to severely reduced). We used Cox regression models to identify independent predictors of death and hospitalization by LVEF category. Among 30 094 ambulatory adults with HF, mean age was 74 years and 46% were women. LVEF was preserved in 49.5%, borderline in 16.2%, and reduced in 34.3% of patients. During a median follow-up of 1.8 years (interquartile range, 0.8–3.1), 8060 (26.8%) patients died, 8108 (26.9%) were hospitalized for HF, and 20 272 (67.4%) were hospitalized for any reason. In multivariable models, nearly all tested covariates performed similarly across LVEF strata for the outcome of death from any cause, as well as for HF-related and all-cause hospitalizations. Conclusions—We found that in a large, diverse contemporary HF population, risk assessment was strikingly similar across all LVEF categories. These data suggest that, although many HF therapies are uniquely applied to patients with reduced LVEF, individual prognostic factor performance does not seem to be significantly related to level of left ventricular systolic function.

The Complex Relationship of Race to Outcomes in Heart Failure with Preserved Ejection Fraction

BACKGROUND An improved understanding of racial differences in the natural history, clinical characteristics, and outcomes of heart failure will have important clinical and public health implications. We assessed how clinical characteristics and outcomes vary across racial groups (whites, blacks, and Asians) in adults with heart failure with preserved ejection fraction. METHODS We identified all adults with heart failure with preserved ejection fraction between 2005 and 2008 from 4 health systems in the Cardiovascular Research Network using hospital principal discharge and ambulatory visit diagnoses. RESULTS Among 13,437 adults with confirmed heart failure with preserved ejection fraction, 85.9% were white, 7.6% were black, and 6.5% were Asian. After adjustment for potential confounders and use of cardiovascular therapies, compared with whites, blacks (adjusted hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.62-0.85) and Asians (HR, 0.75; 95% CI, 0.64-0.87) had a lower risk of death from any cause. Compared with whites, blacks had a higher risk of hospitalization for heart failure (HR, 1.48; 95% CI, 1.29-1.68); no difference was observed for Asians compared with whites (HR, 1.01; 95% CI, 0.86-1.18). Compared with whites, no significant differences were detected in risk of hospitalization for any cause for blacks (HR, 1.03; 95% CI, 0.95-1.12) and Asians (HR, 0.93; 95% CI, 0.85-1.02). CONCLUSIONS In a diverse population with heart failure with preserved ejection fraction, we observed complex relationships between race and important clinical outcomes. More detailed studies of large populations are needed to fully characterize the epidemiologic picture and to elucidate potential pathophysiologic and treatment-response differences that may relate to race.

Long-term Outcomes Associated With Implantable Cardioverter Defibrillator in Adults With Chronic Kidney Disease

Importance Chronic kidney disease (CKD) is common in adults with heart failure and is associated with an increased risk of sudden cardiac death. Randomized trials of participants without CKD have demonstrated that implantable cardioverter defibrillators (ICDs) decrease the risk of arrhythmic death in selected patients with reduced left ventricular ejection fraction (LVEF) heart failure. However, whether ICDs improve clinical outcomes in patients with CKD is not well elucidated. Objective To examine the association of primary prevention ICDs with risk of death and hospitalization in a community-based population of potentially ICD-eligible patients who had heart failure with reduced LVEF and CKD. Design, Settings, and Participants This noninterventional cohort study included adults with heart failure and an LVEF of 40% or less and measures of serum creatinine levels available from January 1, 2005, through December 31, 2012, who were enrolled in 4 Kaiser Permanente health care delivery systems. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min/1.73 m2. Patients who received and did not receive an ICD were matched (1:3) on CKD status, age, and high-dimensional propensity score to receive an ICD. Follow-up was completed on December 31, 2013. Data were analyzed from 2015 to 2017. Exposures Placement of an ICD. Main Outcomes and Measures All-cause death, hospitalizations due to heart failure, and any-cause hospitalizations. Results A total of 5877 matched eligible adults with CKD (1556 with an ICD and 4321 without an ICD) were identified (4049 men [68.9%] and 1828 women [31.1%]; mean [SD] age, 72.9 [8.2] years). In models adjusted for demographics, comorbidity, and cardiovascular medication use, no difference was found in all-cause mortality between patients with CKD in the ICD vs non-ICD groups (adjusted hazard ratio, 0.96; 95% CI, 0.87-1.06). However, ICD placement was associated with increased risk of subsequent hospitalization due to heart failure (adjusted relative risk, 1.49; 95% CI, 1.33-1.60) and any-cause hospitalization (adjusted relative risk, 1.25; 95% CI, 1.20-1.30) among patients with CKD. Conclusions and Relevance In a large, contemporary, noninterventional study of community-based patients with heart failure and CKD, ICD placement was not significantly associated with improved survival but was associated with increased risk for subsequent hospitalization due to heart failure and all-cause hospitalization. The potential risks and benefits of ICDs should be carefully considered in patients with heart failure and CKD.

Outcomes in adults with acute pulmonary embolism who are discharged from emergency departments: the Cardiovascular Research Network Venous Thromboembolism study.

Author Affiliations: Section on Cardiology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (Qureshi, Soliman); Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina (O’Neal); School of Medicine, Department of Medicine, University of Alabama at Birmingham (Khodneva, Safford); School of Public Health, Department of Biostatistics, University of Alabama at Birmingham (Judd); School of Public Health, Department of Epidemiology, University of Alabama at Birmingham (Muntner); Epidemiological Cardiology Research Center, Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina (Soliman).