Essential team science skills for biostatisticians on collaborative research teams.

Introduction: Despite the critical role that quantitative scientists play in biomedical research, graduate programs in quantitative fields often focus on technical and methodological skills, not on collaborative and leadership skills. In this study, we evaluate the importance of team science skills among collaborative biostatisticians for the purpose of identifying training opportunities to build a skilled workforce of quantitative team scientists. Methods: Our workgroup described 16 essential skills for collaborative biostatisticians. Collaborative biostatisticians were surveyed to assess the relative importance of these skills in their current work. The importance of each skill is summarized overall and compared across career stages, highest degrees earned, and job sectors. Results: Survey respondents were 343 collaborative biostatisticians spanning career stages (early: 24.2%, mid: 33.8%, late: 42.0%) and job sectors (academia: 69.4%, industry: 22.2%, government: 4.4%, self-employed: 4.1%). All 16 skills were rated as at least somewhat important by > 89.0% of respondents. Significant heterogeneity in importance by career stage and by highest degree earned was identified for several skills. Two skills ("regulatory requirements" and "databases, data sources, and data collection tools") were more likely to be rated as absolutely essential by those working in industry (36.5%, 65.8%, respectively) than by those in academia (19.6%, 51.3%, respectively). Three additional skills were identified as important by survey respondents, for a total of 19 collaborative skills. Conclusions: We identified 19 team science skills that are important to the work of collaborative biostatisticians, laying the groundwork for enhancing graduate programs and establishing effective on-the-job training initiatives to meet workforce needs.

PROPHETIC: Prospective Identification of Pneumonia in Hospitalized Patients in the ICU.

BACKGROUND: Pneumonia is the leading infection-related cause of death. The use of simple clinical criteria and contemporary epidemiology to identify patients at high risk of nosocomial pneumonia should enhance prevention efforts and facilitate development of new treatments in clinical trials. RESEARCH QUESTION: What are the clinical criteria and contemporary epidemiology trends that are helpful in the identification of patients at high risk of nosocomial pneumonia? STUDY DESIGN AND METHODS: Within the ICUs of 28 US hospitals, we conducted a prospective cohort study among adults who had been hospitalized >48 hours and were considered high risk for pneumonia (defined as treatment with invasive or noninvasive ventilatory support or high levels of supplemental oxygen). We estimated the proportion of high-risk patients who experienced the development of nosocomial pneumonia. Using multivariable logistic regression, we identified patient characteristics and treatment exposures that are associated with increased risk of pneumonia development during the ICU admission. RESULTS: Between February 6, 2016, and October 7, 2016, 4,613 high-risk patients were enrolled. Among 1,464 high-risk patients (32%) who were treated for possible nosocomial pneumonia, 537 (37%) met the study pneumonia definition. Among high-risk patients, a multivariable logistic model was developed to identify key patient characteristics and treatment exposures that are associated with increased risk of nosocomial pneumonia development (c-statistic, 0.709; 95% CI, 0.686-0.731). Key factors associated with increased odds of nosocomial pneumonia included an admission diagnosis of trauma or cerebrovascular accident, receipt of enteral nutrition, documented aspiration risk, and receipt of systemic antibacterials within the preceding 90 days. INTERPRETATION: Treatment for nosocomial pneumonia is common among patients in the ICU who are receiving high levels of respiratory support, yet more than one-half of patients who are treated do not fulfill standard diagnostic criteria for pneumonia. Application of simple clinical criteria may improve the feasibility of clinical trials of pneumonia prevention and treatment by facilitating prospective identification of patients at highest risk.

Sex Differences in Quality of Life and Clinical Outcomes in Patients With Advanced Heart Failure: Insights From the PAL-HF Trial.

BACKGROUND: Palliative care improves quality of life in patients with heart failure. Whether men and women with heart failure derive similar benefit from palliative care interventions remains unknown. METHODS: In a secondary analysis of the PAL-HF trial (Palliative Care in Heart Failure), we analyzed differences in quality of life among men and women with heart failure and assessed for differential effects of the palliative care intervention by sex. Differences in clinical characteristics and quality-of-life metrics were compared between men and women at serial time points. The primary outcome was change in Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks. RESULTS: Among the 71 women and 79 men, there was a significant difference in baseline Kansas City Cardiomyopathy Questionnaire (24.5 versus 36.2, respectively; P=0.04) but not Functional Assessment of Chronic Illness Therapy-Palliative Care scale (115.7 versus 120.3; P=0.27) scores. Among those who received the palliative care intervention (33 women and 42 men), women's quality-of-life score remained lower than that of men after enrollment. Treated men's scores were significantly higher than those untreated (6-month Kansas City Cardiomyopathy Questionnaire, 68.0 [interquartile range, 52.6-85.7] versus 41.1[interquartile range, 32.0-78.3]; P=0.047), whereas the difference between treated and untreated women was not significantly different (P=0.39). Rates of death and rehospitalization, as well as the composite end point, were similar between treated and untreated women and men. CONCLUSIONS: In the PAL-HF trial, women with heart failure experienced a greater symptom burden and poorer quality of life as compared with men. The change in treated men's Kansas City Cardiomyopathy Questionnaire score between baseline and 24 weeks was significantly higher than those untreated; this trend was not observed in women. Thus, there may be a sex disparity in response to palliative care intervention, suggesting that sex-specific approaches to palliative care may be needed to improve outcomes. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT0158960.

A Novel In-hospital Congestion Score to Risk Stratify Patients Admitted for Worsening Heart Failure (from ASCEND-HF).

Patients hospitalized for heart failure (HF) remain at high risk for early readmission. A post hoc analysis was performed of the biomarker substudy of the ASCEND-HF trial. An in-hospital congestion score was derived using orthopnea, pedal edema, and NT-proBNP levels. Its added prognostic value beyond traditional risk factors was assessed by determining the net reclassification index (NRI). Study participants (n = 884) had a median age (years) of 67 (55-77), 68% were male, and the median (25th-75th) ejection fraction (%) was 26 (20-40). After adjustment, increasing congestion score was associated with 30-day all-cause mortality or HF hospitalization (odds ratio = 1.51, 95% confidence interval [CI] 1.28-1.77, p < 0.001) and 180-day all-cause mortality (hazard ratio = 1.48, 95% CI 1.28-1.72, p < 0.001). However, adding the congestion score to the multivariable model did not significantly impact the NRI. A higher in-hospital congestion score portended a poor short-term prognosis but did not significantly reclassify risk.

Sex Differences in Exercise Capacity and Quality of Life in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of the RELAX and NEAT-HFpEF Trials.

BACKGROUND: Few studies have compared clinical characteristics, echocardiographic parameters, exercise capacity, and quality of life between women and men with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: Subjects in the NIH-sponsored RELAX (N = 216) and NEAT (N = 107) trials completed baseline echocardiography, the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-minute walk test (6MWT). In an exploratory analysis, multivariable linear regression models were used to associate clinical and imaging characteristics with baseline 6MWT distance and MLHFQ score in women and men. Our cohort included 158 (49%) men and 165 (51%) women. Men had higher prevalence of atrial arrhythmias, ischemic heart disease, diabetes, anemia, and left ventricular (LV) hypertrophy. 6MWT and MLHFQ score did not differ between sexes. In multivariable analysis, ischemic heart disease, diastolic dysfunction, and exercise capacity predicted MLHFQ score for men, whereas only age and body mass index predicted MLHFQ score for women. CONCLUSIONS: Men with HFpEF had more comorbidities and LV hypertrophy than women with HFpEF. In men, quality of life was associated with diastolic dysfunction, ischemic heart disease, and exercise capacity. Further research is needed to identify determinants of quality of life in women with HFpEF.

Discordances between predicted and actual risk in obese patients with suspected cardiac ischaemia.

OBJECTIVES: To test the relationship between increasing severity of obesity, calculated risk and observed outcomes. METHODS: Patients with symptoms suggestive of coronary artery disease (CAD) (n=10 003) were stratified according to body mass index (BMI). We compared risk factors, pooled risk scores and physicians' perception of risk. Cox regression tested the association between BMI and (1) presence of obstructive CAD and (2) composite clinical endpoints (death, cardiovascular death, unstable angina hospitalisation and myocardial infarction). RESULTS: BMI was ≥30 kg/m2 in 48% of patients and ≥35 in 20%. Increasingly obese patients were younger, female and non-smoking but with higher prevalence of hypertension, diabetes, black race and sedentary lifestyle. Pooled risk estimates of CAD were highest in those with mid-range BMI. In contrast, physicians' estimation of the likelihood of significant CAD based on clinical impression increased progressively with BMI. For a 10% increase in the Diamond-Forrester probability of CAD, the adjusted OR for obstructive CAD was 1.5 (95% CI 1.4 to 1.5) in patients with BMI <35, but only 1.2 (95% CI 1.1 to 1.3) in those with BMI ≥35 (interaction p<0.001). Framingham Risk Score increased across increasing BMI categories. However, there was a strong and consistent inverse relationship between degree of obesity and all three composite clinical endpoints over a median 25 months of follow-up. CONCLUSIONS: Despite perceptions of higher risk and higher risk scores, increasingly obese patients had obstructive CAD less frequently than predicted and had fewer adverse clinical outcomes. There is a need for risk assessment tools and guidelines that account for obesity. TRIAL REGISTRATION NUMBER: NCT01174550.

Natriuretic Peptide Response and Outcomes in Chronic Heart Failure With Reduced Ejection Fraction.

BACKGROUND: The GUIDE-IT (GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) trial demonstrated that a strategy to "guide" application of guideline-directed medical therapy (GDMT) by reducing amino-terminal pro-B-type natriuretic peptide (NT-proBNP) was not superior to GDMT alone. OBJECTIVES: The purpose of this study was to examine the prognostic meaning of NT-proBNP changes following heart failure (HF) therapy intensification relative to the goal NT-proBNP value of 1,000 pg/ml explored in the GUIDE-IT trial. METHODS: A total of 638 study participants were included who were alive and had available NT-proBNP results 90 days after randomization. Rates of subsequent cardiovascular (CV) death/HF hospitalization or all-cause mortality during follow-up and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall scores were analyzed. RESULTS: A total of 198 (31.0%) subjects had an NT-proBNP ≤1,000 pg/ml at 90 days with no difference in achievement of NT-proBNP goal between the biomarker-guided and usual care arms. NT-proBNP ≤1,000 pg/ml by 90 days was associated with longer freedom from CV/HF hospitalization or all-cause mortality (p < 0.001 for both) and lower adjusted hazard of subsequent HF hospitalization/CV death (hazard ratio: 0.26; 95% confidence interval: 0.15 to 0.46; p < 0.001) and all-cause mortality (hazard ratio: 0.34; 95% confidence interval: 0.15 to 0.77; p = 0.009). Regardless of elevated baseline concentration, an NT-proBNP ≤1,000 pg/ml at 90 days was associated with better outcomes and significantly better KCCQ overall scores (p = 0.02). CONCLUSIONS: Patients with heart failure with reduced ejection fraction whose NT-proBNP levels decreased to ≤1,000 pg/ml during GDMT had better outcomes. These findings may help to understand the results of the GUIDE-IT trial. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment [GUIDE-IT]; NCT01685840).

Effects of obesity on noninvasive test results in patients with suspected cardiac ischemia: Insights from the PROMISE trial.

BACKGROUND: Obesity is a risk factor for coronary artery disease (CAD), but adiposity may mimic symptoms of CAD and reduce the accuracy of diagnostic testing. METHODS: Patients from the PROMISE trial (n = 8889) were classified according to body mass index (BMI). We assessed relationships between BMI, physician's preference of functional test, test positivity, and results of invasive coronary angiography (Cath) using logistic regression models. RESULTS: Nearly half (48%) of the patients had BMI ≥ 30 kg/m2, and 20% had BMI ≥ 35. Providers were more likely to prefer nuclear myocardial perfusion imaging (MPI) over other functional tests as BMI increased. The rate of test positivity with coronary computed tomographic angiography (CTA) was not different (10% vs. 12%) in patients with BMI ≥35 vs. < 35. The same was true for stress echocardiogram and stress electrocardiogram (positivity 8-13%, P > 0.8 for both). In contrast, MPI was significantly more likely to be positive in those with BMI ≥35 vs. <35 (18% vs. 13%; P = 0.001). The likelihood of obstructive CAD at Cath did not differ with BMI ≥35 vs. <35 in patients having CTA (52% vs. 59%, P = 0.22), but among MPI patients, Cath positivity was only 29% with BMI ≥35 vs. 48% with BMI <35 (P = 0.005). Radiation exposure increased with higher BMI in both MPI and CTA groups. CONCLUSIONS: Increasing levels of obesity adversely affect the diagnostic yield of MPI more than CTA. The degree of obesity should be considered when choosing evaluation strategies for patients with chest pain. CLINICAL TRIAL REGISTRATION: PROMISE ClinicalTrials.gov number, NCT01174550.

Clinical factors related to morbidity and mortality in high-risk heart failure patients: the GUIDE-IT predictive model and risk score.

BACKGROUND: Most heart failure (HF) risk scores have been derived from cohorts of stable HF patients and may not incorporate up to date treatment regimens or deep phenotype characterization that change baseline risk over the short- and long-term follow-up period. We undertook the current analysis of participants in the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment) trial to address these limitations. METHODS AND RESULTS: The GUIDE-IT study randomized 894 high-risk patients with HF and reduced ejection fraction (≤ 40%) to biomarker-guided treatment strategy vs. usual care. We performed risk modelling using Cox proportional hazards models and analysed the relationship between 35 baseline clinical factors and the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, the secondary endpoint of all-cause mortality, and the exploratory endpoint of 90-day HF hospitalization or death. Prognostic relationships for continuous variables were examined and key predictors were identified using a backward variable selection process. Predictive models and risk scores were developed. Over a median follow-up of 15 months, the cumulative number of HF hospitalizations and CV deaths was 328 out of 894 patients (Kaplan-Meier event rate 34.5% at 12 months). Frequency of all-cause deaths was 143 out of 894 patients (Kaplan-Meier event rate 12.2% at 12 months). Outcomes for the primary and secondary endpoints between strategy arms of the study were similar. The most important predictor that was present in all three models was the baseline natriuretic peptide level. Hispanic ethnicity, low sodium and high heart rate were present in two of the three models. Other important predictors included the presence or absence of a device, New York Heart Association class, HF duration, black race, co-morbidities (sleep apnoea, elevated creatinine, ischaemic heart disease), low blood pressure, and a high congestion score. CONCLUSION: Risk models using readily available clinical information are able to accurately predict short- and long-term CV events and may be useful in optimizing care and enriching patients for clinical trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID number NCT01685840.

Stress Testing Versus CT Angiography in Patients With Diabetes and Suspected Coronary Artery Disease.

BACKGROUND: The optimal noninvasive test (NIT) for patients with diabetes and stable symptoms of coronary artery disease (CAD) is unknown. OBJECTIVES: The purpose of this study was to assess whether a diagnostic strategy based on coronary computed tomographic angiography (CTA) is superior to functional stress testing in reducing adverse cardiovascular (CV) outcomes (CV death or myocardial infarction [MI]) among symptomatic patients with diabetes. METHODS: PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) was a randomized trial evaluating an initial strategy of CTA versus functional testing in stable outpatients with symptoms suggestive of CAD. The study compared CV outcomes in patients with diabetes (n = 1,908 [21%]) and without diabetes (n = 7,058 [79%]) based on their randomization to CTA or functional testing. RESULTS: Patients with diabetes (vs. without) were similar in age (median 61 years vs. 60 years) and sex (female 54% vs. 52%) but had a greater burden of CV comorbidities. Patients with diabetes who underwent CTA had a lower risk of CV death/MI compared with functional stress testing (CTA: 1.1% [10 of 936] vs. stress testing: 2.6% [25 of 972]; adjusted hazard ratio: 0.38; 95% confidence interval: 0.18 to 0.79; p = 0.01). There was no significant difference in nondiabetic patients (CTA: 1.4% [50 of 3,564] vs. stress testing: 1.3% [45 of 3,494]; adjusted hazard ratio: 1.03; 95% confidence interval: 0.69 to 1.54; p = 0.887; interaction term for diabetes p value = 0.02). CONCLUSIONS: In diabetic patients presenting with stable chest pain, a CTA strategy resulted in fewer adverse CV outcomes than a functional testing strategy. CTA may be considered as the initial diagnostic strategy in this subgroup. (PROspective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).

Predictive Model for High-Risk Coronary Artery Disease.

BACKGROUND: Patients with high-risk coronary artery disease (CAD) may be difficult to identify. METHODS: Using the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) cohort randomized to coronary computed tomographic angiography (n=4589), 2 predictive models were developed for high-risk CAD, defined as left main stenosis (≥50% stenosis) or either (1) ≥50% stenosis [50] or (2) ≥70% stenosis [70] of 3 vessels or 2-vessel CAD involving the proximal left anterior descending artery. Pretest predictors were examined using stepwise logistic regression and assessed for discrimination and calibration. RESULTS: High-risk CAD was identified in 6.6% [50] and 2.4% [70] of patients. Models developed to predict high-risk CAD discriminated well: [50], bias-corrected C statistic=0.73 (95% CI, 0.71-0.76); [70], bias-corrected C statistic=0.73 (95% CI, 0.68-0.77). Variables predictive of CAD in both models included family history of premature CAD, age, male sex, lower glomerular filtration rate, diabetes mellitus, elevated systolic blood pressure, and angina. Additionally, smoking history was predictive of [50] CAD and sedentary lifestyle of [70] CAD. Both models characterized high-risk CAD better than the Pooled Cohort Equation (area under the curve=0.70 and 0.71 for [50] and [70], respectively) and Diamond-Forrester risk scores (area under the curve=0.68 and 0.71, respectively). Both [50] and [70] CAD was associated with more frequent invasive interventions and adverse events than non-high-risk CAD (all P<0.0001). CONCLUSIONS: In contemporary practice, 2.4% to 6.6% of stable, symptomatic patients requiring noninvasive testing have high-risk CAD. A simple combination of pretest clinical variables improves prediction of high-risk CAD over traditional risk assessments. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01174550.

Single-Molecule hsTnI and Short-Term Risk in Stable Patients With Chest Pain.

BACKGROUND: Evaluation of stable symptomatic outpatients with suspected coronary artery disease (CAD) may be challenging because they have a wide range of cardiovascular risk. The role of troponin testing to assist clinical decision making in this setting is unexplored. OBJECTIVES: This study sought to evaluate the prognostic meaning of single-molecule counting high-sensitivity troponin I (hsTnI) (normal range <6 ng/l) among outpatients with stable chest symptoms and suspected CAD. METHODS: Participants with available blood samples in PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) were studied, and hsTnI results were analyzed relative to the primary outcome of death, acute myocardial infarction (MI), or hospitalization for unstable angina by 1 year. The secondary outcome was the composite of cardiovascular death or acute MI. RESULTS: The study sample consisted of 4,021 participants; 98.6% had measurable hsTnI concentrations. The median hsTnI value was 1.6 ng/l. In upper hsTnI quartiles, patients had higher-risk clinical profiles. Higher hsTnI concentrations were associated with greater event probabilities for death, acute MI, or hospitalization for unstable angina. In multivariable models, hsTnI concentrations independently predicted death, acute MI, or hospitalization for unstable angina (hazard ratio: 1.54 per increase in log-hsTnI interquartile range; p < 0.001) and cardiovascular death or acute MI (hazard ratio: 1.52 per increase in log-hsTnI interquartile range; p < 0.001) and were particularly associated with near-term events, compared with longer follow-up. CONCLUSIONS: In symptomatic outpatients with suspected CAD, higher concentrations of hsTnI within the normal range were associated with heightened near-term risk for death, acute MI, or hospitalization. (Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).

High-Sensitivity Troponin I and Coronary Computed Tomography in Symptomatic Outpatients With Suspected CAD: Insights From the PROMISE Trial.

OBJECTIVES: The goal of this study was to examine associations between concentrations of high-sensitivity troponin I (hsTnI) (measured by using a single-molecule counting method) and obstructive coronary artery disease (CAD) in 1,844 stable, symptomatic outpatients with suspected CAD randomized to undergo coronary computed tomography angiography (CTA) in the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial. BACKGROUND: Elevated concentrations of hsTnI are associated with CAD in patients with myocardial infarction. The meaning of hsTnI concentrations in stable symptomatic outpatients is not well understood. METHODS: Clinical characteristics and CTA results (including coronary artery calcium [CAC] scores) were expressed across hsTnI quartiles. Determinants of hsTnI concentration were identified. Multivariable logistic regression identified independent predictors of obstructive CAD50 (≥50% stenosis in any vessel) and CAD70 (≥70% stenosis or ≥50% left main). RESULTS: The median hsTnI concentration was 1.5 ng/l; nearly all (98.5%) subjects had measurable hsTnI, and 6.1% had concentrations ≥99th percentile concentration for this assay (6 ng/l). Higher CAC scores, as well as more prevalent and diffuse CAD, was seen in upper hsTnI quartiles (all p < 0.001). Independent predictors of hsTnI concentrations included age, sex, and CAC score (all p < 0.05). After adjusting for demographic and clinical characteristics, log-transformed hsTnI concentrations were associated with obstructive CAD50 (odds ratio: 1.15 per interquartile range; p = 0.02) and CAD70 (odds ratio: 1.25 per interquartile range; p = 0.001). CONCLUSIONS: In stable symptomatic outpatients undergoing nonemergent coronary CTA for the diagnosis of suspected CAD, higher concentrations of hsTnI were associated with increasing presence and severity of coronary atherosclerosis. (Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).

Relationship between changing patient-reported outcomes and subsequent clinical events in patients with chronic heart failure: insights from HF-ACTION.

AIMS: A 5-point change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) is commonly considered to be a clinically significant difference in health status in patients with heart failure. We evaluated how the magnitude of change relates to subsequent clinical outcomes. METHODS AND RESULTS: Using data from the HF-ACTION trial of exercise training in chronic heart failure (n = 2331), we used multivariable Cox regression with piecewise linear splines to examine the relationship between change in KCCQ overall summary score from baseline to 3 months (range 0-100; higher scores reflect better health status) and subsequent all-cause mortality/hospitalization. Among 2038 patients with KCCQ data at the 3-month visit, KCCQ scores increased from baseline by ≥5 points for 45%, scores decreased by ≥5 points for 23%, and scores changed by <5 points for the remaining 32% of patients. There was a non-linear relationship between change in KCCQ and outcomes. Worsening health status was associated with increased all-cause mortality/hospitalization (adjusted hazard ratio 1.07 per 5-point KCCQ decline; 95% confidence interval 1.03-1.12; P < 0.001). In contrast, improving health status, up to an 8-point increase in KCCQ, was associated with decreased all-cause mortality/hospitalization (adjusted hazard ratio 0.93 per 5-point increase; 95% confidence interval 0.90-0.97; P < 0.001). Additional improvements in health status beyond an 8-point increase in KCCQ was not associated with all-cause death or hospitalization (P = 0.42). CONCLUSION: In patients with heart failure, small changes in KCCQ are associated with changing future risk, but more research will be necessary to understand how different magnitudes of improving health status affect outcomes.

Identifying responders to oral iron supplementation in heart failure with a reduced ejection fraction: a post-hoc analysis of the IRONOUT-HF trial.

BACKGROUND: The IRONOUT-HF trial previously demonstrated that oral iron supplementation minimally increased iron stores and did not improve exercise capacity in patients with heart failure with a reduced ejection fraction (HFrEF) and iron deficiency. METHODS: The IRONOUT-HF trial was a double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy and safety of oral iron polysaccharide compared to matching placebo among patients with HFrEF and iron deficiency. Study participants received oral iron polysaccharide 150 mg twice daily or matching placebo for 16 weeks. Response to oral iron was defined as a ferritin level >300 ng/mL or a ferritin level 100-300 ng/mL with a transferrin saturation >20% at the end of the study. RESULTS: The final analytical cohort included 98 patients with HFrEF and iron deficiency at baseline. Study participants had a median (25, 75) age of 63 years (54 years, 71 years), included 40% women (N = 39). After 16 weeks of therapy, 24 patients (24%) responded to oral iron supplementation while 74 patients (76%) remained iron deficient despite treatment. There was no association between response to oral iron supplementation and improvement in functional status (i.e. peak VO2 or anaerobic threshold), myocardial stress (i.e. NT-proBNP levels), or HRQOL (i.e. Kansas City Cardiomyopathy Questionnaire) at week 16. CONCLUSION: This study failed to identify a subset of responders more likely to derive a clinical benefit from oral iron therapy and does not support its routine use in patients with symptomatic HFrEF and iron deficiency.

Sex differences in management and outcomes of patients with stable symptoms suggestive of coronary artery disease: Insights from the PROMISE trial.

BACKGROUND: Although sex differences exist in the management of acute coronary syndromes, less is known about the management and outcomes of women and men with suspected coronary artery disease being evaluated with noninvasive testing (NIT). METHODS: We investigated sex-based differences in NIT results and subsequent clinical management in 4,720 women and 4,246 men randomized to CT angiography versus stress testing in the PROMISE trial. Logistic regression models assessed relationships between sex and referral for catheterization, revascularization, and aspirin or statin use. Cox regression models assessed the relationship between sex and the composite of all-cause death, myocardial infarction, or unstable angina. RESULTS: Women more often had normal NITs than men (61.0% vs 49.6%, P < .001) and less often had mild (29.3% vs 35.4%, P < .001), moderate (4.0% vs 6.8%, P < .001), or severe abnormalities (5.7% vs 8.3%, P < .001) found on NIT. Women were less likely to be referred for catheterization than men (7.6% vs 12.6%, adjusted OR 0.75 [0.62-0.90]; P = .002). Of those who underwent catheterization within 90 days of randomization (358 women, 534 men), fewer women than men had obstructive coronary artery disease (40.8% vs 60.9%, P < .001). At a 60-day visit, women were significantly less likely than men to report statin use when indicated (adjusted OR 0.81 [0.73-0.91]; P < .001) but were similarly likely to report aspirin use when indicated (adjusted OR 0.78 [0.56-1.08]; P = .13). Over a median follow-up of 25 months, women had better outcomes than men (adjusted OR 0.73 [0.57-0.94]; P = .017). CONCLUSIONS: Although women more frequently had normal NITs compared with men, those with abnormalities on NIT were less likely to be referred for catheterization or to receive statin therapy. The high rates of negative NIT in women, coupled with the better outcomes compared with men, strongly support the need for a sex-specific algorithm to guide NIT and chest pain management.

Renal Function and Exercise Training in AmbulatoryHeart Failure Patients With a Reduced Ejection Fraction.

Patients with chronic kidney disease (CKD) and/or end-stage renal disease are less active and experience significant functional limitations. The impact of a structured aerobic exercise intervention on outcomes in ambulatory heart failure (HF) patients with comorbid CKD is unknown. HF-ACTION enrolled 2,331 outpatients with HF and a reduced ejection fraction (i.e., ≤35%) from April 2003 to February 2007 and randomized them to aerobic exercise training versus usual care. Patients were grouped according to the presence of CKD, defined as an estimated glomerular filtration rate <60 ml/min/1.73 m2. A total of 2,091 patients (90%) had serum creatinine measured and were included in the final analytical cohort. The prevalence of CKD was 41% at baseline. In patients with and without CKD, respectively, the incidence of all-cause death and hospitalization was 75% and 63% over a median follow-up of 30 months. After adjusting for potential confounders, CKD was associated with increased risk of the composite of all-cause mortality and hospitalization (hazard ratio 1.18, 95% confidence interval 1.04 to 1.33; p value ≤0.01). With the exception of a marginally greater improvement in exercise duration in response to aerobic exercise training (estimate ± standard error: 0.9 ± 0.2 minutes vs 1.4 ± 0.1 minutes; p value = 0.01), there was no interaction between treatment arm and CKD on functional status, health-related quality of life, or clinical outcomes (p value ≥0.05 for all interactions). In conclusion, the prevalence of CKD was high in ambulatory reduced ejection fraction patients and was associated with a poorer overall prognosis but not a differential response to aerobic exercise training.

Relationship Between Enrolling Country Income Level and Patient Profile, Protocol Completion, and Trial End Points.

BACKGROUND: Globalization of clinical trials fosters inclusion of higher and lower income countries, but the influence of enrolling country income level on heart failure trial performance is unclear. This study sought to evaluate associations between enrolling country income level, acute heart failure patient profile, protocol completion, and trial end points. METHODS AND RESULTS: The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial included 7141 patients with acute heart failure from 30 countries. Country income data in gross national income per capita in current US dollars from the year 2007 (ie, the year trial enrollment began) were abstracted from the World Bank. Patients were grouped by enrolling country income level (ie, high [>$11 455], upper middle [$3706-$11 455], lower middle [$936-$3705], and low [<$936]). Income data were available for 29 (97%) countries (N=7064). There were 3996 (57%), 1518 (21%), and 1550 (22%) patients from high-income, upper-middle-income, and lower-middle-income countries, respectively. There were no patients from low-income countries. Patients from lower-middle-income countries tended to be younger with fewer comorbidities and lower utilization of guideline-directed therapies. Rates of adverse events (13.8%) and protocol noncompletion (4.9%) during 180-day follow-up were highest among high-income countries (all P <0.01). After adjustment for race, geographic region, and clinical characteristics, compared with lower-middle-income countries, enrollment from higher income countries was associated with increased 30-day mortality or rehospitalization (high income: odds ratio, 1.70; 95% CI, 1.02-2.85; upper-middle-income: odds ratio, 2.16; 95% CI, 1.23-3.81), driven by higher rates of rehospitalization. Mortality was similar at 30 and 180 days. The association between higher country income and the 30-day composite end point was similar across geographic regions, with exception of Latin America ( P for interaction, 0.03). CONCLUSIONS: In this global acute heart failure trial, patients from higher income countries had lower rates of protocol completion, higher rates of adverse events, and similar mortality rates. After adjustment for race, geographic region, and clinical factors, enrollment from a higher income country was associated with worse clinical outcomes, driven by higher rates of rehospitalization. Variation in enrolling country income level may influence study end points and trial performance independent of geographic region. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00475852.