Defining Advanced Heart Failure: A Systematic Review of Criteria Used in Clinical Trials.

BACKGROUND: Enrollment criteria used in advanced heart failure (HF) clinical trials might identify a common set of widely accepted quantitative characteristics as the basis of a consensus definition for advanced HF, which is currently lacking. METHODS: We reviewed all clinical trials investigating interventions in patients with advanced HF as of July 31, 2015. Eligible publications (N = 134) reported original data from clinical trials explicitly defining advanced HF in adults. RESULTS: New York Heart Association (NYHA) class was the most common criterion (119 trials, 88.8%; classes ranged from II to IV), followed by left ventricular ejection fraction (LVEF) (84 trials, 62.7%; cutoff range, 20% to 45%; mode 35%). Other criteria included inotrope-dependent status (12.7%), peak oxygen consumption (10.4%), ≥1 previous HF admissions (10.4%), cardiac index (10.4%), pulmonary capillary wedge pressure (9.0%), left ventricular end-diastolic diameter (6.0%), and transplant listing status (5.2%). Cutoff points for quantitative criteria varied considerably. Previous HF admission was more frequently required in recent trials (P = .007 for temporal trend), whereas use of hemodynamic criteria decreased over time (P = .050 for temporal trend). Average LVEF among participants increased over time. CONCLUSIONS: There is considerable variation in the definition of advanced HF for clinical trial purposes. Beyond NYHA and LVEF, a wide array of criteria has been used, with little consistency both in criteria selection and quantitative cutoff points.

Echocardiography in Acute Heart Failure: Current Perspectives.

In contrast to chronic heart failure (HF), the use of echocardiography in acute HF (AHF) is less well defined, both in clinical practice and in clinical trials. Current guidelines recommend the utility of echocardiography as an adjunct diagnostic tool in the clinical setting of new-onset or decompensated HF. However, despite its unique advantages as the only practical imaging modality in AHF, echocardiography poses unique challenges in this setting. Data from early-phase clinical studies and trials provide evidence that echocardiographic end points can be clinically meaningful surrogate end points as a means to track response to treatment in AHF; however, the optimal timing and selection of echocardiographic measures is under active investigation. In addition, despite a number of studies indicating that certain echocardiographic measures of cardiac function are predictive of post-discharge prognosis, the role of echocardiography as a tool for patient classification and risk determination in AHF is less well defined. Importantly, it is unclear whether echocardiography can be used to phenotype and select AHF patients for interventions. In this article, we (1) appraise the current evidence for use of echocardiographic measures in AHF, (2) identify knowledge gaps regarding optimal use of echocardiography in AHF, and (3) assess the evidence for echocardiography as a prognosis determination and risk stratification tool in AHF.

Trends in Heart Failure Clinical Trials From 2001-2012.

BACKGROUND: A systematic assessment of the temporal trends in heart failure (HF) clinical trials is lacking. METHODS AND RESULTS: A total of 154 phase II-IV HF trials including 162,725 patients published from 2001 to 2012 in 8 high-impact-factor journals were reviewed. The median number of participants and sites per trial were 367 (interquartile range [IQR] 133-1450) and 38 (5-101), respectively. Median enrollment duration was 2.2 (1.5-3.3) years. The majority of studies investigated treatment for chronic HF (82.5%) and investigated HF with reduced ejection fraction (EF) (71.4%), whereas 27 trials (17.5%) enrolled patients with mixed EF and 9 (5.8%) enrolled HF with preserved EF patients alone. Enrollment rates did not significantly change over time (median 0.49 patients site(-1) month(-1), IQR 0.34-0.98; P = .53). Trials meeting their primary end point decreased over time from 73.5% in 2001-2003 to 52.5% in 2010-2012 (P = .08) and were more often smaller and used nonmortality end points. Industry trials were larger with shorter enrollment duration, more concentrated in North America, and more likely to be positive. Trials conducted exclusively outside North America and Western Europe had the highest enrollment rates (median 1.95 patients site(-1) month(-1), IQR 1.34-4.11). CONCLUSIONS: Contemporary HF clinical trials display slow enrollment rates and decreased rates of positive outcomes over time. Positive trials tended to be smaller size with a higher proportion of surrogate end points.

Nitrite therapy improves left ventricular function during heart failure via restoration of nitric oxide-mediated cytoprotective signaling.

RATIONALE: Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury. OBJECTIVE: No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy. METHODS AND RESULTS: Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kß signaling early in the progression of hypertrophy and heart failure. CONCLUSIONS: These results support the emerging concept that nitrite therapy may be a viable clinical option for increasing NO levels and may have a practical clinical use in the treatment of heart failure.

Trends in characteristics of cardiovascular clinical trials 2001-2012.

BACKGROUND: Efficient conduct of clinical trials is essential for the timely generation of critical medical knowledge. METHODS: We systematically assessed size, duration, enrollment rates, and geographic distribution of randomized cardiovascular trials published between 2001 and 2012 in the 8 highest-impact journals in general medicine and cardiology. RESULTS: Of the 1,224 trials, 27.0% were conducted in North America, 36.5% in Western Europe, and 7.7% in other countries, and 28.8% were multiregional. Trials enrolled a median of 452 patients (interquartile range 167-1,530) in 20 sites (2-76). Median duration was 2.1 (1.3-3.3) years, with an estimated enrollment rate of 1.1 (0.5-3.5) patients/site per month. Between 2001-2003 and 2009-2012, the proportion of North American trials decreased from 34.5% to 25.7% (P = .006), whereas that of multiregional trials (from 26.0% to 30.3%; P = .046) and trials conducted in other countries (from 4.6% to 10.3%; P = .012) increased. Over time, trials involved more patients (from 400 to 500 [median]; P = .032) and sites (from 20 to 22; P = .049), multiregional trials involved more countries (from 12 to 18; P = .031), and enrollment rate declined from 1.2 to 0.9 patients/site per month (P = .017). The proportion of trials meeting their primary end point ("positive") decreased from 69% to 57% (P < .001). Trials with higher enrollment rates were more likely to be positive (odds ratio 1.20 per doubling, 95% CI 1.12-1.29), as were industry-sponsored compared with government-sponsored trials (odds ratio 2.62, 95% CI 1.67-4.12). CONCLUSIONS: From 2001 to 2012, cardiovascular clinical trials have become larger, more global, and less likely to meet their primary end point. Enrollment rates have declined, requiring more sites and regions.

Improving cardiovascular clinical trials conduct in the United States: recommendation from clinicians, researchers, sponsors, and regulators.

Advances in medical therapies leading to improved patient outcomes are in large part related to successful conduct of clinical trials that offer critical information regarding the efficacy and safety of novel interventions. The conduct of clinical trials in the United States, however, continues to face increasing challenges with recruitment and retention. These trends are paralleled by an increasing shift toward more multinational trials where most participants are enrolled in countries outside the United States, bringing into question the generalizability of the results to the American population. This manuscript presents the perspectives and recommendations from clinicians, researchers, sponsors, and regulators who attended a meeting facilitated by the Food and Drug Administration to improve upon the current clinical trial trends in the United States.

Inotrope use and outcomes among patients hospitalized for heart failure: impact of systolic blood pressure, cardiac index, and etiology.

BACKGROUND: Inotropes are widely used in hospitalized systolic heart failure (HF) patients, especially those with low systolic blood pressure (SBP) or cardiac index. In addition, inotropes are considered to be harmful in nonischemic HF. METHODS AND RESULTS: We examined the association of in-hospital inotrope use with (1) major events (death, ventricular assist device, or heart transplant) and (2) study days alive and out of hospital during the first 6 months in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness, which excluded patients with immediate need for inotropic therapy. Predefined subgroups of interest were baseline SBP <100 versus ≥ 100 mm Hg, cardiac index <1.8 vs ≥ 1.8 L min(-1) m(-2), and ischemic versus nonischemic HF etiology. Inotropes were frequently used in both the <100 mm Hg (88/165 [53.3%]) and the ≥ 100 mm Hg (106/262 [40.5%]) SBP subgroups and were associated with higher risk for major events in both subgroups (adjusted hazard ratio [HR] 2.85, 95% confidence interval [CI] 1.59-5.12 [P < .001]; and HR 1.86, 95% CI 1.02-3.37 [P = .042]; respectively). Risk with inotropes was more pronounced among those with cardiac index ≥ 1.8 L min(-1) m(-2) (n = 114; HR 4.65, 95% CI 1.98-10.9; P < .001) vs <1.8 L min(-1) m(-2) (n = 82; HR 1.48, 95% CI 0.61-3.58; P = .39). Event rates were higher with inotropes in both ischemic (n = 215; HR 2.64, 95% CI 1.49-4.68; P = .001) and nonischemic (n = 216; HR 2.19, 95% CI 1.18-4.07; P = .012) patients. Across all subgroups, patients who received inotropes spent fewer study days alive and out of hospital. CONCLUSIONS: In the absence of cardiogenic shock or end-organ hypoperfusion, inotrope use during hospitalization for HF was associated with unfavorable 6-month outcomes, regardless of admission SBP, cardiac index, or HF etiology.

Frailty and risk for heart failure in older adults: the health, aging, and body composition study.

OBJECTIVE: The aim of this study was to assess the association between frailty and risk for heart failure (HF) in older adults. BACKGROUND: Frailty is common in the elderly and is associated with adverse health outcomes. Impact of frailty on HF risk is not known. METHODS: We assessed the association between frailty, using the Health ABC Short Physical Performance Battery (HABC Battery) and the Gill index, and incident HF in 2825 participants aged 70 to 79 years. RESULTS: Mean age of participants was 74 ± 3 years; 48% were men and 59% were white. During a median follow up of 11.4 (7.1-11.7) years, 466 participants developed HF. Compared to non-frail participants, moderate (HR 1.36, 95% CI 1.08-1.71) and severe frailty (HR 1.88, 95% CI 1.02-3.47) by Gill index was associated with a higher risk for HF. HABC Battery score was linearly associated with HF risk after adjusting for the Health ABC HF Model (HR 1.24, 95% CI 1.13-1.36 per SD decrease in score) and remained significant when controlled for death as a competing risk (HR 1.30; 95% CI 1.00-1.55). Results were comparable across age, sex, and race, and in sub-groups based on diabetes mellitus or cardiovascular disease at baseline. Addition of HABC Battery scores to the Health ABC HF Risk Model improved discrimination (change in C-index, 0.014; 95% CI 0.018-0.010) and appropriately reclassified 13.4% (net-reclassification-improvement 0.073, 95% CI 0.021-0.125; P = .006) of participants (8.3% who developed HF and 5.1% who did not). CONCLUSIONS: Frailty is independently associated with risk of HF in older adults.

Acute heart failure: patient characteristics and pathophysiology.

The number of hospitalizations for acute heart failure (HF) continues to increase and it remains the most common discharge diagnosis among Medicare beneficiaries. Prognosis after hospitalization for HF is poor, with high in-hospital mortality and even higher post-discharge mortality and rehospitalization rates. It is a complex clinical syndrome that varies widely with respect to clinical presentation and underlying pathophysiology. This paper reviews what is documented in the literature regarding the known pathophysiologic mechanisms reported in patients hospitalized for HF.

Epidemiology and importance of renal dysfunction in heart failure patients.

Renal dysfunction (RD) is a frequent comorbid condition and a major determinant of outcomes in patients with heart failure (HF). It is likely that the etiology of RD in patients with HF is much more complex than we first thought and represents a matrix of independent, albeit interacting, pathophysiological pathways with effects on both the kidney and the heart that share a common denominator: aging and inflammation. Renal dysfunction in HF has been attributed, among others, to biochemical, hormonal, and hemodynamic factors, coupled with pharmacological interventions. Regardless of the cause, the development of RD or worsening renal function is common in patients with HF, and is associated with increased morbidity and mortality. There is increasing evidence, however, that transient increases in creatinine in the setting of acute HF are not prognostically important, whereas persistent deterioration does portend a higher mortality in this patient population. In addition, congestion seems to play an important role in the course of renal deterioration, and the combination of congestion and worsening renal function is the most significant clinical prognosticator in HF patients. This review aims to provide an update on the epidemiology and prognostic significance of RD in HF patients, in both the acute and the chronic setting.

Classification of patients hospitalized for heart failure.

Despite low inpatient mortality and effective symptomatic management, patients hospitalized for heart failure (HHF) experience high postdischarge mortality and rehospitalization rates. HHF represents a widely heterogeneous population with distinct clinical subsets that may require tailored management approaches. Despite this, however, HHF patients are almost uniformly managed with intravenous diuretics, with low uptake of new therapies during hospitalization. This article proposes a practical approach to classifying HHF patients that is focused on guiding individualized inpatient and postdischarge management. HHF is not a single disease but a manifestation of several cardiac and noncardiac processes and thus should be approached as such.

Cigarette smoking exposure and heart failure risk in older adults: the Health, Aging, and Body Composition Study.

BACKGROUND: Although there is evidence linking smoking and heart failure (HF), the association between lifetime smoking exposure and HF in older adults and the strength of this association among current and past smokers is not well known. METHODS: We examined the association between smoking status, pack-years of exposure, and incident HF risk in 2,125 participants of the Health, Aging, and Body Composition Study (age 73.6 ± 2.9 years, 69.7% women, 54.2% whites) using proportional hazard models. RESULTS: At inception, 54.8% of participants were nonsmokers, 34.8% were past smokers, and 10.4% were current smokers. During follow-up (median 9.4 years), HF incidence was 11.4 per 1,000 person-years in nonsmokers, 15.2 in past smokers (hazard ratio [HR] vs nonsmokers 1.33, 95% CI 1.01-1.76, P = .045), and 21.9 in current smokers (HR 1.93, 95% CI 1.30-2.84, P = .001). After adjusting for HF risk factors, incident coronary events, and competing risk for death, a dose-effect association between pack-years of exposure and HF risk was observed (HR 1.09, 95% CI 1.05-1.14, P < .001 per 10 pack-years). Heart failure risk was not modulated by pack-years of exposure in current smokers. In past smokers, HR for HF was 1.05 (95% CI 0.64-1.72) for 1 to 11 pack-years, 1.23 (95% CI 0.82-1.83) for 12 to 35 pack-years, and 1.64 (95% CI 1.11-2.42) for >35 pack-years of exposure in fully adjusted models (P < .001 for trend) compared with nonsmokers. CONCLUSIONS: In older adults, both current and past cigarette smoking increase HF risk. In current smokers, this risk is high irrespective of pack-years of exposure, whereas in past smokers, there was a dose-effect association.

Echocardiographic evaluation of left ventricular structure and function: new modalities and potential applications in clinical trials.

Advances in modern echocardiography for quantification of cardiac structure and function have not been translated in clinical trial or practice applications to date. Imaging endpoints are especially well-suited for early trials with investigational therapies for heart failure as most drugs and devices approved for heart failure have shown favorable effects on cardiac structure and function also. Echocardiography is versatile and can be performed in most clinical settings. The modest interobserver and test-retest reproducibility of specific structural and functional parameters with conventional echocardiography can be improved on by using contemporary modalities, including 3-dimensional (3D) echocardiography for assessment of volumes and ejection fraction and speckle tracking for detailed functional assessment of the ventricles with mechanics-based parameters (strain and strain rate). The appropriate imaging endpoints (global vs. regional, systolic vs. diastolic) should be tailored to the specific research question and the mode of action of the therapy under investigation. The newer echocardiographic modalities, namely 3D echocardiography and speckle tracking, are more demanding in terms of equipment and personnel and therefore are better suited for implementation in experienced research centers with central interpretation. However, these modalities provide the best opportunity currently available to demonstrate treatment effects on the myocardium with investigational therapies and provide mechanistic insights for future directions.

Cardiopulmonary rehabilitation enhances heart rate recovery in patients with COPD.

BACKGROUND: Autonomic dysfunction is present early in the course of COPD, and is associated with adverse outcomes. We utilized heart rate recovery, a simple and validated index of autonomic balance, to investigate the effects of exercise training on autonomic dysfunction in patients with COPD. METHODS: We evaluated 45 stable subjects with COPD who participated in a 36-session exercise-based cardiopulmonary rehabilitation program. Subjects underwent maximal cardiopulmonary exercise testing at baseline and after completion of the rehabilitation program. We recorded exercise testing parameters and heart rate during rest, exercise, and recovery. Heart rate recovery was calculated as heart rate at peak exercise minus heart rate at the first minute of recovery. RESULTS: Thirty-nine subjects (age 66.3 ± 7.8 y, 90% male, body mass index 27.1 ± 4.1 kg/m(2), FEV(1) 45.7 ± 18.7%) completed the program. In these subjects, heart rate recovery increased from 16.2 ± 8.0 beats/min to 18.4 ± 8.4 beats/min (P = .01), resting heart rate decreased from 88.0 ± 10.7 beats/min to 83.3 ± 10.5 beats/min (P = .004), and heart rate at anaerobic threshold decreased from 109.0 ± 12.5 beats/min to 105.5 ± 11.7 beats/min (P = .040). In addition, oxygen consumption (V(O(2))) increased from 14.3 ± 3.7 mL/kg/min to 15.2 ± 3.8 mL/kg/min at peak exercise, and from 9.7 ± 2.4 mL/kg/min to 10.4 ± 2.6 mL/kg/min at anaerobic threshold (both P = .02), while the V(O(2))/t slope increased from -0.32 ± 0.16 mL/kg/min(2) to -0.38 ± 0.19 mL/kg/min(2) (P = .003). Parameters of ventilatory performance improved also. CONCLUSIONS: In subjects with COPD, exercise-based rehabilitation improves heart rate recovery, modestly though, which indicates a degree of attenuated autonomic dysfunction. Exercise and muscular oxidative capacity, as expressed by V(O(2))/t slope, is also improved.

From risk factors to structural heart disease: the role of inflammation.

Elevated levels of circulating proinflammatory cytokines and adipokines have been repeatedly associated with increased risk for clinically manifest (Stage C) heart failure in large cohort studies. However, the role of low-grade, subclinical inflammatory activity in the transition from risk factors (Stage A heart failure) to structural heart disease (Stage B heart failure) is less well understood. Recent evidence suggests that chronic low-grade inflammatory activity is involved in most mechanisms underlying progression of structural heart disease, including ventricular remodeling after ischemic injury, response to pressure and volume overload, and myocardial fibrosis. Inflammation also contributes to progression of peripheral vascular changes.

Serum albumin concentration and heart failure risk The Health, Aging, and Body Composition Study.

BACKGROUND: How serum albumin levels are associated with risk for heart failure (HF) in the elderly is unclear. METHODS: We evaluated 2,907 participants without HF (age 73.6 +/- 2.9 years, 48.0% male, 58.7% white) from the community-based Health ABC Study. The association between baseline albumin and incident HF was assessed with standard and competing risks proportional hazards models controlling for HF predictors, inflammatory markers, and incident coronary events. RESULTS: During a median follow-up of 9.4 years, 342 (11.8%) participants developed HF. Albumin was a time-dependent predictor of HF, with significance retained for up to 6 years (baseline hazard ratio [HR] per -1 g/L 1.14, 95% CI 1.06-1.22, P < .001; annual rate of HR decline 2.1%, 95% CI 0.8%-3.3%, P = .001). This association persisted in models controlling for HF predictors, inflammatory markers, and incident coronary events (baseline HR per -1 g/L 1.13, 95% CI 1.05-1.22, P = .001; annual rate of HR decline 1.8%, 95% CI 0.5%-3.0%, P = .008) and when mortality was accounted for in adjusted competing risks models (baseline HR per -1 g/L 1.13, 95% CI 1.05-1.21, P = .001; annual rate of HR decline 1.9%, 95% CI 0.7%-3.1%, P = .002). The association of albumin with HF risk was similar in men (HR per -1 g/L 1.13, 95% CI 1.05-1.23, P = .002) and women (HR per -1 g/L 1.12, 95% CI 1.04-1.22, P = .005) and in whites and blacks (HR per -1 g/L 1.13, 95% CI 1.04-1.22, P< .01 for both races) in adjusted models. CONCLUSIONS: Low serum albumin levels are associated with increased risk for HF in the elderly in a time-dependent manner independent of inflammation and incident coronary events.

Metabolic abnormalities in adults with cystic fibrosis.

BACKGROUND AND OBJECTIVE: Survival of patients with cystic fibrosis (CF) has improved, resulting in increased exposure of patients to cardiovascular risk factors. Diabetes mellitus is common in patients with CF; however, less is known about lipid abnormalities in this population. In this study, the prevalence of lipid abnormalities was investigated in a contemporary population of adults with CF. METHODS: Clinical and laboratory data on 221 adult patients with CF were collected retrospectively. Fasting serum glucose levels and lipid profiles were recorded. The age-specific values for healthy individuals, as reported by the National Health and Nutrition Examination Surveys, were used for comparison. RESULTS: The mean age of the patients was 30 +/- 10 years, 55.1% were men and the mean FEV(1)% was 68 +/- 25%. Sixty-nine patients (31.2%) had CF-related diabetes mellitus and 52 (23.5%) were receiving insulin therapy. In addition, 36 patients (16.3%) had impaired glucose tolerance. Triglyceride levels were similar to those of historical control subjects (mean +/- SEM, 1.37 +/- 0.05 and 1.39 +/- 0.02 mmol/L, respectively, P = 0.75). However, in the 30-39 years age group of CF patients, triglyceride levels were increased relative to those of their control counterparts (1.79 +/- 0.14 vs 1.38 +/- 0.04 mmol/L, P = 0.006). Total cholesterol levels were lower in the CF patients compared with control subjects, across all age groups. CONCLUSIONS: Abnormalities of glucose metabolism are highly prevalent in CF patients, and are accompanied by hypertriglyceridaemia in the 30-39 years age group. Prospective studies are required to confirm lipid abnormalities and investigate possible cardiovascular complications in patients with CF.

Right ventricular function in adult patients with Eisenmenger physiology: insights from quantitative echocardiography.

BACKGROUND: The favorable outcomes of Eisenmenger syndrome (ES) relative to other forms of pulmonary arterial hypertension (PAH) have been partially attributed to a unique adaptation of the right ventricle (RV). However, conventional measures of RV function may not adequately express this adaptation. METHODS: We studied 23 patients with ES (age 43 ± 17 years, 16 women, pulmonary artery systolic pressure [PASP] 93 ± 26 mmHg), 25 patients with PAH (age 44 ± 13 years, 17 women, PASP 92 ± 19 mmHg), and 25 subjects without known structural disease (age 45 ± 16 years, 17 women). We evaluated long- and short-axis function of the RV with two-dimensional strain and anatomical M-mode echocardiography, respectively. RESULTS: Long-axis function of the RV was comparable between patients with ES and PAH although depressed relative to controls (global strain, -15.6 ± 4.7, -14.9 ± 4.3, and -22.4 ± 2.8%, respectively, P < 0.001; global RV systolic strain rate, -0.77 ± 0.26, -0.84 ± 0.24, and -1.11 ± 0.21 1/sec, respectively, P < 0.001). However, short-axis RV function was significantly better in patients with ES versus those with PAH and preserved relative to controls (RV fractional shortening by anatomical M-mode, median [interquartile range], 21%[14-33%], 14%[10-16%], and 26%[22-36%], respectively, P = 0.002 for ES vs. PAH, P = 0.09 for ES vs. controls). This differential was not reflected in conventional measures of RV function (fractional area change, 32 ± 10 vs. 29 ± 8% in ES and PAH, respectively, P = 0.26). CONCLUSION: In patients with ES, the RV is characterized by preserved short-axis function, despite a depressed long-axis function. Thus, conventional assessment of RV function might not be suitable for patients with ES.

Low- Versus Moderate-Sodium Diet in Patients With Recent Hospitalization for Heart Failure: The PROHIBIT (Prevent Adverse Outcomes in Heart Failure by Limiting Sodium) Pilot Study.

BACKGROUND: We conducted a pilot study to assess feasibility, on-study retention, trends in natriuretic peptide levels, quality of life, and safety of a 12-week feeding trial with 1500- versus 3000-mg daily sodium meals in high-risk patients with heart failure. METHODS: Of 196 patients with recent (≤2 weeks) hospitalization for heart failure, ejection fraction ≤40%, on optimal medical therapy, functionally independent, and able to communicate, 83 (47%) consented to participate. Of these, 27 (age, 62±11 years; 22 men; 20 white; ejection fraction, 26±8%) had 24-hour urine sodium ≥3000 mg and agreed to randomly receive either 1500-mg (N=12) or 3000-mg (N=15) sodium meals. RESULTS: On-study retention at 12 weeks was 77% (82% versus 73%; P=0.53); 6 patients (2 in 1500-mg, 4 in 3000-mg arm) withdrew before study completion. Food satisfaction questionnaires indicated that both diets were well tolerated. Quality of life improved in the 1500-mg arm at 12 weeks but did not change in the 3000-mg arm. Average compliance with meals was 52% (based on urinary sodium) and was not significantly different between arms (42% versus 60%; P=0.25). Study meals reduced 24-hour urinary sodium by 137±21 mmol (1500-mg arm) and 82±16 mmol (3000-mg arm), both P<0.001; between-arms difference was 55 mmol (95% CI, 3-107; P=0.037). NT-proBNP (N-terminal pro-B-type natriuretic peptide) was not affected. Hospitalizations and low blood pressure events did not differ significantly between arms. Serum creatinine decreased more (by 0.17 mg/dL [95% CI, 0.06-0.28]; P=0.003) in the 1500-mg arm. Creatinine increases >0.5 mg/dL over baseline only occurred in 1 patient in the 3000-mg arm. CONCLUSIONS: Even with prepared meals, investigating optimal dietary sodium in heart failure comes with challenges, including need for extensive screening, reluctance to participate, and compliance issues. Because both diets reduced urinary sodium without adverse safety or quality of life signals, a larger trial, with modifications to improve participation and compliance, would be ethical and feasible. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02467296.

Serum ST2 and hospitalization rates in Caucasian and African American outpatients with heart failure.

BACKGROUND: Limited data exist on the association between circulating suppression of tumorigenicity 2 (ST2) and recurrent hospitalizations and emergency department (ED) encounters in outpatients with heart failure (HF). In addition, data on ST2 in African American patients with HF are scarce. METHODS: We evaluated 307 outpatients with HF (age, 57 ±â€¯12 years; 64.2% men; 51.5% Caucasian, 45.6% African American; median ejection fraction, 35%; ischemic etiology, 41.4%). Median ST2 was 37.8 ng/mL (29.6-51.4). RESULTS: After a median of 3.1 years, there were 584 hospitalizations (224 for HF) and 335 ED visits (80 for HF). Patients (N = 176; 57.3%) with elevated (>35 ng/mL) ST2 had 2-fold higher hospitalization rates in adjusted models (rate ratio [RR] 1.97; 95% CI 1.38-2.82; P < 0.001), driven by 3.5-fold higher HF hospitalization rates (adjusted RR 3.56; 95% CI 1.69-7.49; P < 0.001). These associations persisted after adjusting for baseline B-type natriuretic peptide levels. Findings were similar for elevated ST2 and ED visit rates. Elevated ST2 was associated with the composite of death or HF hospitalization (109 patients; 3-year estimate: 35.4%); risk was 5-fold higher in the first 6 months but declined gradually. The higher hospitalization rates and composite endpoint risk associated with elevated ST2 was similar in African Americans and Caucasians. In landmark analyses in a subset of patients, 6-month (N = 112) and 12-month (N = 149) changes in ST2 levels from baseline added prognostic information. CONCLUSIONS: Elevated ST2 in outpatients with HF portends higher healthcare resources utilization and higher risk for accelerated disease progression, regardless of race, especially in the first 6 months.