Robert Clare

Predictors of mortality after discharge in patients hospitalized with heart failure: An analysis from the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF)

BACKGROUND Patients with heart failure (HF) are at high risk for mortality and rehospitalization in the early period after hospital discharge. We developed clinical models predictive of short-term clinical outcomes in a broad patient population discharged after hospitalization for HF. METHODS The Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry is a comprehensive hospital-based registry and performance-improvement program for patients hospitalized with HF. Follow-up data were scheduled to be prospectively collected at 60 to 90 days postdischarge in a prespecified 10% sample. For the 4,402 patients included in this analysis, 19 prespecified potential predictor variables were used in a stepwise Cox proportional hazards model for all-cause mortality. Logistic regression including 45 potential variables was used to model mortality or rehospitalization. RESULTS The 60- to 90-day postdischarge mortality rate was 8.6% (n = 481), and 29.6% (n = 1,715) were rehospitalized. Factors predicting early postdischarge mortality include age, serum creatinine, reactive airway disease, liver disease, lower systolic blood pressure, lower serum sodium, lower admission weight, and depression. Use of statins and beta-blockers at discharge was associated with significantly decreased mortality. The C-index of the model was 0.74. The most important predictors for the combined end point of death or rehospitalization were admission serum creatinine, systolic blood pressure, admission hemoglobin, discharge use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and pulmonary disease. From this analysis, 8 factors identified to carry significant risk were selected for use in a point scoring system to predict the risk of mortality within 60 days after discharge, with a C-index of 0.72. CONCLUSIONS A substantial risk of mortality and mortality or rehospitalization is present in the first 60 to 90 days after discharge from a hospitalization for HF. Several factors were identified that signal high-risk patients. Application of these findings with a simple algorithm can distinguish patients who are low risk from those at high risk who may benefit from closer monitoring and aggressive evidence-based treatment.

Analyses of cancer data from three ezetimibe trials.

BACKGROUND Five years of statin therapy lowers low-density lipoprotein (LDL) cholesterol substantially and, over a 5-year period, results in reductions in the incidence of cardiovascular events. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677) has raised the hypothesis that adding ezetimibe to statin therapy for larger LDL cholesterol reductions might increase the incidence of cancer. METHODS We compared the results of a hypothesis-generating analysis of the incidence of cancer in the SEAS trial of ezetimibe plus simvastatin in 1873 patients (mean follow-up after ezetimibe or matching placebo was begun, 4.1 years) with a hypothesis-testing analysis of cancer data from the two large ongoing trials of this regimen: the Study of Heart and Renal Protection (SHARP) (NCT00125593) with 9264 patients (mean follow-up, 2.7 years) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878), currently with 11,353 patients (mean follow-up, 1.0 year). RESULTS In the SEAS trial, assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P=0.61) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P=0.07), but there were also fewer, although not significantly fewer, other cases of cancer (216, vs. 254 in the control group; P=0.08). There was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up. CONCLUSIONS The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer. Follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably.

Galectin-3 in Ambulatory Patients with Heart Failure: Results from the HF-ACTION Study

Background— Galectin-3 is a soluble s-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P <0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: . Unique identifier: [NCT00047437][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00047437&atom=%2Fcirchf%2F5%2F1%2F72.atomBackground— Galectin-3 is a soluble ß-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P<0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Factors Related to Morbidity and Mortality in Patients with Chronic Heart Failure with Systolic Dysfunction: The HF-ACTION Predictive Risk Score Model

Background— We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation. Methods and Results— In a cohort of 2331 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing) study (New York Heart Association class II–IV, left ventricular ejection fraction ⩽0.35, randomized to exercise training and usual care versus usual care alone, median follow-up of 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite end point of death or all-cause hospitalization and the secondary end point of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise test was the most important predictor of both the primary end point and all-cause death. Additional important predictors for the primary end point risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire symptom stability score, higher serum urea nitrogen, and male sex (all P<0.0001). Important additional predictors for the mortality risk model were higher serum urea nitrogen, male sex, and lower body mass index (all P<0.0001). Conclusions— Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic heart failure with systolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor Insights From the Platelet Inhibition and Patient Outcomes Trial

Background— The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. Methods and Results— We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04–1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07–1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79–1.23; ticagrelor, HR, 0.89; 95% CI, 0.73–1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12–1.49; ticagrelor, HR, 1.30; 95% CI, 1.14–1.49). Conclusions— The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events. Clinical Trial Registration— . Unique identifier: [NCT00391872][1]. # Clinical Perspective {#article-title-47} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00391872&atom=%2Fcirculationaha%2F125%2F8%2F978.atomBackground— The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. Methods and Results— We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04–1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07–1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79–1.23; ticagrelor, HR, 0.89; 95% CI, 0.73–1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12–1.49; ticagrelor, HR, 1.30; 95% CI, 1.14–1.49). Conclusions— The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Galectin-3 in Ambulatory Patients With Heart FailureClinical Perspective

Background— Galectin-3 is a soluble s-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P <0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: . Unique identifier: [NCT00047437][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00047437&atom=%2Fcirchf%2F5%2F1%2F72.atomBackground— Galectin-3 is a soluble ß-galactoside–binding lectin released by activated cardiac macrophages. Elevated levels of galectin-3 have been found to be associated with adverse outcomes in patients with heart failure. We evaluated the association between galectin-3 and long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study. Methods and Results— HF-ACTION was a randomized, controlled trial of exercise training in patients with chronic heart failure caused by left ventricular systolic dysfunction. Galectin-3 was assessed at baseline in a cohort of 895 HF-ACTION subjects with stored plasma samples available. The association between galectin-3 and clinical outcomes was assessed using a series of Cox proportional hazards models. Higher galectin-3 levels were associated with other measures of heart failure severity, including higher New York Heart Association class, lower systolic blood pressure, higher creatinine, higher amino-terminal proB-type natriuretic peptide (NTproBNP), and lower maximal oxygen consumption. In unadjusted analysis, there was a significant association between elevated galectin-3 levels and hospitalization-free survival (unadjusted hazard ratio, 1.14 per 3-ng/mL increase in galectin-3; P<0.0001). In multivariable modeling, the prognostic impact of galectin-3 was significantly attenuated by the inclusion of other known predictors, and galectin-3 was no longer a significant predictor after the inclusion of NTproBNP. Conclusions— Galectin-3 is elevated in ambulatory heart failure patients and is associated with poor functional capacity and other known measures of heart failure severity. In univariate analysis, galectin-3 was significantly predictive of long-term outcomes, but this association did not persist after adjustment for other predictors, especially NTproBNP. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

International variation in and factors associated with hospital readmission after myocardial infarction.

CONTEXT ST-segment elevation myocardial infarction (STEMI) treatment has improved outcomes and shortened hospital stay. Recently, 30-day readmission rates have been proposed as a metric for care of patients with STEMI. However, international rates and predictors of 30-day readmission after STEMI have not been studied. OBJECTIVE To determine international variation in and predictors of 30-day readmission rates after STEMI and country-level care patterns. DESIGN, SETTING, AND PATIENTS Post hoc analysis of the Assessment of Pexelizumab in Acute Myocardial Infarction trial that enrolled 5745 patients with STEMI at 296 sites in the United States, Canada, Australia, New Zealand, and 13 European countries from July 13, 2004, to May 11, 2006. Multivariable logistic regression analysis was used to identify independent predictors of all-cause and nonelective 30-day postdischarge readmission. MAIN OUTCOME MEASURES Predictors of 30-day postdischarge all-cause and nonelective readmissions. RESULTS Of 5571 patients with STEMI who survived to hospital discharge, 631 (11.3%) were readmitted within 30 days. Thirty-day readmission rates were higher for the United States than other countries (14.5% vs 9.9%; P < .001). Median length of stay was shortest for US patients (3 days; interquartile range, 2-4 days) and longest for Germany (8 days; interquartile range, 6-11 days). In multivariable regression, the predictors of 30-day readmission included multivessel disease (odds ratio [OR], 1.97; 95% CI, 1.65-2.35) and US location (OR, 1.68; 95% CI, 1.37-2.07). Excluding elective readmission for revascularization, US enrollment was still an independent predictor of readmission (OR, 1.53; 95% CI, 1.20-1.96). After adjustment of the models for country-level median length of stay, US location was no longer an independent predictor of 30-day all-cause or nonelective readmission. Location in the United States was not a predictor of in-hospital death (OR, 0.88; 95% CI, 0.60-1.30) or 30-day postadmission death (OR, 1.0; 95% CI, 0.72-1.39). CONCLUSIONS In this multinational study, there was variation across countries in 30-day readmission rates after STEMI, with readmission rates higher in the United States than in other countries. However, this difference was greatly attenuated after adjustment for length of stay.

6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure.

OBJECTIVES The goal of this study was to compare the prognostic efficacy of the 6-min walk (6MW) and cardiopulmonary exercise (CPX) tests in stable outpatients with chronic heart failure (HF). BACKGROUND CPX and 6MW tests are commonly applied as prognostic gauges for systolic HF patients, but few direct comparisons have been conducted. METHODS Stable New York Heart Association (NYHA) functional class II and III systolic HF patients (ejection fraction ≤ 35%) from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were studied. 6MW distance (6MWD) and CPX indices (peak oxygen consumption [VO(2)] and ventilatory equivalents for exhaled carbon dioxide [VE/VCO(2)] slope) were compared as predictors of all-cause mortality/hospitalization and all-cause mortality over 2.5 years of mean follow-up. RESULTS A total of 2,054 HF-ACTION participants underwent both CPX and 6MW tests at baseline (median age 59 years; 71% male; 64% NYHA functional class II and 36% NYHA functional class III/IV). In unadjusted models and in models that included key clinical and demographic covariates, C-indices of 6MWD were 0.58 and 0.65 (unadjusted) and 0.62 and 0.72 (adjusted) in predicting all-cause mortality/hospitalization and all-cause mortality, respectively. C-indices for peak VO(2) were 0.61 and 0.68 (unadjusted) and 0.63 and 0.73 (adjusted). C-indices for VE/VCO(2) slope were 0.56 and 0.65 (unadjusted) and 0.61 and 0.71 (adjusted); combining peak VO(2) and VE/VCO(2) slope did not improve the C-indices. Overlapping 95% confidence intervals and modest integrated discrimination improvement values confirmed similar prognostic discrimination by 6MWD and CPX indices within adjusted models. CONCLUSIONS In systolic HF outpatients, 6MWD and CPX indices demonstrated similar utility as univariate predictors for all-cause hospitalization/mortality and all-cause mortality. However, 6MWD or CPX indices added only modest prognostic discrimination to models that included important demographic and clinical covariates.

Factors Related to Morbidity and Mortality in Patients With Chronic Heart Failure With Systolic DysfunctionClinical Perspective

Background— We aimed to develop a multivariable statistical model for risk stratification in patients with chronic heart failure with systolic dysfunction, using patient data that are routinely collected and easily obtained at the time of initial presentation. Methods and Results— In a cohort of 2331 patients enrolled in the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise TraiNing) study (New York Heart Association class II–IV, left ventricular ejection fraction ⩽0.35, randomized to exercise training and usual care versus usual care alone, median follow-up of 2.5 years), we performed risk modeling using Cox proportional hazards models and analyzed the relationship between baseline clinical factors and the primary composite end point of death or all-cause hospitalization and the secondary end point of all-cause death alone. Prognostic relationships for continuous variables were examined using restricted cubic spline functions, and key predictors were identified using a backward variable selection process and bootstrapping methods. For ease of use in clinical practice, point-based risk scores were developed from the risk models. Exercise duration on the baseline cardiopulmonary exercise test was the most important predictor of both the primary end point and all-cause death. Additional important predictors for the primary end point risk model (in descending strength) were Kansas City Cardiomyopathy Questionnaire symptom stability score, higher serum urea nitrogen, and male sex (all P<0.0001). Important additional predictors for the mortality risk model were higher serum urea nitrogen, male sex, and lower body mass index (all P<0.0001). Conclusions— Risk models using simple, readily obtainable clinical characteristics can provide important prognostic information in ambulatory patients with chronic heart failure with systolic dysfunction. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.

Quality of Care of and Outcomes for African Americans Hospitalized With Heart Failure: Findings From the OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) Registry

OBJECTIVES We sought to examine the characteristics, quality of care, and clinical outcomes for a large cohort of African-American patients hospitalized with heart failure (HF) in centers participating in a quality improvement initiative. BACKGROUND Heart failure in African Americans is characterized by variations in natural history, lesser response to evidence-based therapies, and disparate health care. We hypothesized that a performance improvement program will achieve similar adherence to quality measures in African Americans admitted with HF compared with non-African Americans. METHODS The OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure) registry-based performance-improvement program includes a pre-specified 10% subgroup with 60- to 90-day follow-up. Data on quality of care measures and outcomes were analyzed for 8,608 African-American patients compared with 38,501 non-African-American patients. RESULTS African Americans were significantly younger and more likely to receive evidence-based medications but less likely to receive discharge instructions and smoking cessation counseling. In multivariable analyses, African-American race was an independent predictor of lower in-hospital mortality (odds ratio 0.71; 95% confidence interval 0.57 to 0.87; p < 0.001) but similar hospital length of stay. After multivariable adjustment, post-discharge outcomes were similar for American-American and non-African-American patients, but African-American race was associated with higher angiotensin-converting enzyme inhibitor prescription and left ventricular function assessment; no other HF quality indicators were influenced by race. CONCLUSIONS In the context of a performance-improvement program, African Americans with HF received similar or better treatment with evidence-based medications, less discharge counseling, had better in-hospital survival, and similar adjusted risk of follow-up death/repeat hospital stay.