Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label, randomized controlled trial.

OBJECTIVE: Randomized controlled trials comparing tocilizumab and baricitinib in patients with coronavirus disease 2019 (COVID-19) are needed. This was an open-label, randomized controlled trial aiming to address this unmet need. METHODS: To determine whether baricitinib was non-inferior to tocilizumab, we assessed whether the upper boundary of the two-sided 95% CI of the hazard ratio (HR) did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10. RESULTS: We assigned 251 patients with COVID-19 and a PaO2/FiO2 ratio of <200 to receive either tocilizumab (n = 126) or baricitinib (n = 125) plus standard of care. Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (mechanical ventilation or death for patients who received baricitinib, 39.2% [n = 49/125]; mechanical ventilation or death for patients who received tocilizumab, 44.4% [n = 56/126]; HR, 0.83; 95% CI, 0.56-1.21; p 0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (patients who received baricitinib- discharged alive: 58.4% [n = 73/125] vs. patients who received tocilizumab- discharged alive: 52.4% [n = 66/126]; HR, 0.85; 95% CI, 0.61-1.18; p < 0.001 for non-inferiority). There was no significant difference between the baricitinib and tocilizumab arms in the change in WHO scale at day 10 (0.0 [95% CI, 0.0-0.0] vs. 0.0 [95% CI, 0.0-1.0]; p 0.83). DISCUSSION: In the setting of this trial, baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19.

Tocilizumab improves 28-day survival in hospitalized patients with severe COVID-19: an open label, prospective study.

BACKGROUND: Data on the safety and efficacy profile of tocilizumab in patients with severe COVID-19 needs to be enriched. METHODS: In this open label, prospective study, we evaluated clinical outcomes in consecutive patients with COVID-19 and PaO2/FiO2 < 200 receiving tocilizumab plus usual care versus usual care alone. Tocilizumab was administered at the time point that PaO2/FiO2 < 200 was observed. The primary outcome was 28-day mortality. Secondary outcomes included time to discharge, change in PaO2/FiO2 at day 5 and change in WHO progression scale at day 10. FINDINGS: Overall, 114 patients were included in the analysis (tocilizumab plus usual care: 56, usual care: 58). Allocation to usual care was associated with significant increase in 28-day mortality compared to tocilizumab plus usual care [Cox proportional-hazards model: HR: 3.34, (95% CI: 1.21-9.30), (p = 0.02)]. There was not a statistically significant difference with regards to hospital discharge over the 28 day period for patients receiving tocilizumab compared to usual care [11.0 days (95% CI: 9.0 to 16.0) vs 14.0 days (95% CI: 10.0-24.0), HR: 1.32 (95% CI: 0.84-2.08), p = 0.21]. ΔPaO2/FiO2 at day 5 was significantly higher in the tocilizumab group compared to the usual care group [42.0 (95% CI: 23.0-84.7) vs 15.8 (95% CI: - 19.4-50.3), p = 0.03]. ΔWHO scale at day 10 was significantly lower in the tocilizumab group compared to the usual care group (-0.5 ± 2.1 vs 0.6 ± 2.6, p = 0.005). CONCLUSION: Administration of tocilizumab, at the time point that PaO2/FiO2 < 200 was observed, improved survival and other clinical outcomes in hospitalized patients with severe COVID-19 irrespective of systemic inflammatory markers levels.

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.

Serial Changes in Left Ventricular Ejection Fraction and Outcomes in Outpatients With Heart Failure and Preserved Ejection Fraction.

Limited data exist on the course of left ventricle ejection fraction (LVEF) among outpatients with heart failure (HF) and preserved ejection fraction (HFpEF) and its impact on outcomes. We evaluated 322 consecutive outpatients with confirmed HF, LVEF >40%, no previous LVEF ≤40%, and no specific cardiomyopathies or primary right-sided or valvular heart disease. Median age was 73 years (interquartile range: 63 to 82); 57.1% were women, 50.3% White, and 45.0% Black; median LVEF was 55% (50% to 60%); and 45.6% had coronary artery disease. After a median of 37 months (32 to 38) and 4.5 follow-up echocardiograms (4 to 6) per patient, 11.4% of patients (95% confidence interval [CI] 5.2% to 17.7%) developed LVEF <40%. The average drop in LVEF among these patients was 19.4 units (95%CI 15.0 to 23.8) to an average LVEF of 30.3% (95%CI 27.4% to 33.2%). Baseline systolic blood pressure >130 mm Hg was associated with more LVEF decline. During follow-up, 50 patients died (3-year mortality 15.3%) and 67 additional patients were hospitalized for HF (3-year death plus HF hospitalization 35.6%). Development of LVEF <40% was subsequently followed by 5-fold higher mortality in time-updated models (adjusted HR 4.91; 95%CI 2.00 to 12.0; p = 0.001) and 3.5-fold higher rates of death or HF hospitalization (adjusted HR 3.70; 95%CI 1.67 to 8.19; p = 0.001). Interval coronary events were infrequent (10%) among patients with deteriorated LVEF. The impact of LVEF changes on outcomes was similar in White and Black patients. In conclusion, a proportion of patients with HFpEF will develop reduced LVEF over time. These patients have worse prognosis subsequently.

Definitions of Stage D heart failure and outcomes among outpatients with heart failure and reduced ejection fraction.

BACKGROUND: An operational consensus definition of Stage D heart failure (HF) is currently lacking. METHODS: We evaluated 512 outpatients (median age, 63 years; 35.0% women; 45.5% white and 45.9% black; median ejection fraction was 25%; 67.4% had coronary artery disease) with HF and reduced (≤40%) ejection fraction. We applied 3 hypothetical definitions for Stage D: (1) designation as "Stage D" or "advanced" HF by treating physician; (2) INTERMACS profiles, defining Stage D as profiles 2-6; and (3) European Society of Cardiology Heart Failure Association (ESC-HFA) criteria. RESULTS: Physicians, INTERMACS profiles, and ESC-HFA criteria identified 64 (12.5%), 93 (18.2%), and 67 (13.1%) patients, respectively, as Stage D, with modest concordance between definitions (κ = 0.37). After a median of 3.1 years, 97 patients died (3-year mortality 20.4%). Among patients identified as Stage D by physicians, 3-year mortality was 43.7% vs. 17.0% for non-Stage D patients (age-adjusted hazard ratio [HR] 3.17; 95%CI 1.94-5.18; P < 0.001). The corresponding mortalities for the INTERMACS-based definition were 41.0% vs. 16.2% (HR 3.28; 95%CI 2.11-5.11; P < 0.001) and for ESC-HFA criteria 33.5% vs. 18.6% (HR 2.02; 95%CI 1.22-3.33; P = 0.006); the INTERMACS-based definition provided the best prognostic separation. Results were similar with an alternative INTERMACS-based definition considering only profiles 2-5 as Stage D HF. The INTERMACS-based definition best separated all-cause and HF-specific hospitalization and composite endpoint risk between Stage D and non-Stage D patients also. CONCLUSIONS: INTERMACS profiles provide a practical alternative for the identification of Stage D HF in ambulatory populations with systolic HF. The ESC-HFA criteria offer limited prognostic information.

INTERMACS Profiles and Outcomes Among Non-Inotrope-Dependent Outpatients With Heart Failure and Reduced Ejection Fraction.

OBJECTIVES: This study sought to evaluate INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) profiles for prognostic use among ambulatory non-inotrope-dependent patients with heart failure with reduced ejection fraction (HFrEF). BACKGROUND: Data for INTERMACS profiles and prognoses in ambulatory patients with HFrEF are limited. METHODS: We evaluated 3-year outcomes in 969 non-inotrope-dependent outpatients with HFrEF (EF: ≤40%) not previously receiving advanced HF therapies. Patients meeting an INTERMACS profile at baseline were classified as profile 7 (n = 348 [34.7%]); 146 patients (14.5%) were classified profile 6; and 52 patients (5.2%) were classified profile 4 to 5. Remaining patients were classified "stable Stage C" (n = 423 [42.1%]). RESULTS: Three-year mortality rate was 10.0% among stable Stage C patients compared with 21.8% among INTERMACS profile 7 (hazard ratio [HR] vs. Stage C: 2.45; 95% confidence interval [CI]: 1.64 to 3.66), 26.0% among profile 6 (HR: 3.93; 95% CI: 1.64 to 3.66), and 43.8% among profile 4 to 5 (HR: 6.35; 95% CI: 3.51 to 11.5) patients. Hospitalization rates for HF were 4-fold higher among INTERMACS profile 7 (38 per 100 patient-years; rate ratio [RR] vs. Stage C: 3.88; 95% CI: 2.70 to 5.35), 6-fold higher among profile 6 patients (54 per 100 patient-years; RR: 5.69; 95% CI: 3.72 to 8.71), and 10-fold higher among profile 4 to 5 patients (69 per 100 patient-years; RR: 9.96; 95% CI: 5.15 to 19.3) than stable Stage C patients (11 per 100 patient-years). All-cause hospitalization rates had similar trends. INTERMACS profiles offered better prognostic separation than NYHA functional classifications. CONCLUSIONS: INTERMACS profiles strongly predict subsequent mortality and hospitalization burden in non-inotrope-dependent outpatients with HFrEF. These simple profiles could therefore facilitate and promote advanced HF awareness among clinicians and planning for advanced HF therapies.

Comorbidities, Sociodemographic Factors, and Hospitalizations in Outpatients With Heart Failure and Preserved Ejection Fraction.

Patients with heart failure and preserved ejection fraction (HFpEF) tend to be older and have a high co-morbidity burden. The impact of co-morbid conditions and sociodemographic risk factors on outcomes in these patients has not been quantified. We evaluated 445 consecutive outpatients with HFpEF, defined as established diagnosis of heart failure (HF) with left ventricular ejection fraction at presentation >40% and no previous left ventricular ejection fraction ≤40%. Patients with specific cardiomyopathies, congenital heart disease, primary right-sided disease, valvular disease, or previous advanced HF therapies were excluded. After 2 years, there were 44 deaths and 609 all-cause hospitalizations; of these, 260 (42.7%) were cardiovascular hospitalizations, including HF, and 173 (28.4%) were specifically for HF. The highest attributable risk for hospitalizations was associated with marital status (single, divorced, and widowed had higher hospitalization rates compared with married patients), hypoalbuminemia, diabetes, atrial fibrillation, and renal dysfunction. The proportion of hospitalizations potentially attributable to these factors was 66.6% (95% confidence interval [CI] 56.4 to 74.4) for all-cause hospitalizations, 76.9% (95% CI 65.2 to 84.6) for cardiovascular hospitalizations, and 83.0% (95% CI 70.3 to 90.3) for HF hospitalizations. For composite end points, the proportion was 46.9% (95% CI 34.0% to 57.3%) for death or all-cause hospitalization, 45.7% (95% CI 29.3% to 58.2%) for death or cardiovascular hospitalization, and 43.7% (95% CI 24.2% to 58.2%) for death or HF-related hospitalization. In conclusion, among outpatients with HFpEF, most hospitalizations could be attributed to co-morbidities and sociodemographic factors. Effects of HF therapies on hospitalizations and related end points may be difficult to demonstrate in these patients. Multidisciplinary approaches are more likely to impact hospitalizations in HFpEF.

Progression to Stage D Heart Failure Among Outpatients With Stage C Heart Failure and Reduced Ejection Fraction.

OBJECTIVES: This study sought to estimate the rate of progression to Stage D heart failure (HF) among outpatients with Stage C HF and to identify risk factors for progression. BACKGROUND: The pool of patients who may be candidates for advanced HF therapies is growing. METHODS: We estimated 3-year progression to clinically determined Stage D HF and competing mortality among 964 outpatients with Stage C heart failure with reduced ejection fraction (HFrEF), where ejection fraction is ≤40%. RESULTS: The mean age of patients was 62 ± 15 years; 35% were women; 47% were white; 46% were black, and 7% were of other races; median baseline ejection fraction was 28% (25th to 75th percentile: 20% to 35%); and 47% had ischemic heart disease. After 3.0 years (25th to 75th percentile: 1.7 to 3.2 years), 112 patients progressed to Stage D (3-year incidence: 12.2%; 95% confidence interval [CI]: 10.2% to 14.6%; annualized: 4.5%; 95% CI: 3.8% to 5.5%), and 116 patients died before progression (3-year competing mortality: 12.9%; annualized: 4.7%; 95% CI: 3.9% to 5.6%). By 3 years, 25.1% of patients (95% CI: 22.2% to 28.1%) had either progressed to Stage D or died (annualized: 9.2%; 95% CI: 8.1% to 10.5%). Annualized progression rates were higher in black versus white patients (6.3% vs. 2.7%, respectively; p < 0.001), nonischemic versus ischemic patients (6.1% vs. 2.9%, respectively; p < 0.001), and in New York Heart Association functional class III to IV versus I to II patients (7.5% vs. 1.9%, respectively; p < 0.001) but were similar for men and women (4.7% vs. 4.2%, respectively; p = 0.53). Lower ejection fraction and blood pressure, renal and hepatic dysfunction, and chronic lung disease rates were additional predictors of progression. Predictors of competing mortality were different from those of disease progression. CONCLUSIONS: Among patients with Stage C HFrEF receiving care in a referral center, 4.5% progressed to Stage D HF each year, with earlier progression among black and nonischemic patients. These findings have implications for healthcare planning and resource allocation for these patients.

High-density lipoprotein-associated paraoxonase-1 activity for prediction of adverse outcomes in outpatients with chronic heart failure.

AIMS: Decreased arylesterase (ArylE) activity of paraoxonase-1, a HDL-associated protein with anti-inflammatory and antioxidant properties, has been associated with increased risk of cardiac events in patients with ischaemic heart failure (HF). We aim to investigate the prognostic significance of changes in serum ArylE activity over time. METHODS AND RESULTS: We examined the association between baseline and follow-up serum ArylE activity and HF outcomes (death, cardiac transplantation, or ventricular assist device implantation) in 299 patients with HF enrolled in a prospective cohort study from January 2008 to July 2009, with 145 patients having available follow-up levels at 1 year. A significant drop in ArylE activity on follow-up was defined as a drop of ≥25% vs. baseline levels. Mean baseline and follow-up ArylE activity levels were 110.6 ± 29.9 µmol/min/mL and 106.2 ± 29.9 µmol/min/mL, respectively. After a mean follow-up of 2.8 ± 1.1 years, low baseline ArylE activity was associated with increased risk of adverse HF events [hazard ratio (HR; lowest vs highest tertile) 2.6, 95% confidence interval (CI) 1.3-5.5, P = 0.01] and HF-related hospitalization [incidence rate ratio (lowest vs. highest tertile) 2.1, 95% CI 1.2-4.1, P = 0.016], which remained significant after adjustment for age, male gender, systolic blood pressure, diabetes, creatinine clearance, CAD, and HDL-cholesterol levels. Patients who had a significant drop in ArylE activity on follow-up (n = 18) had a significantly increased risk of HF events (HR 4.9, 95% CI 1.6-14.6, P = 0.005), even after adjustment for baseline levels of ArylE activity. CONCLUSIONS: Reduced baseline ArylE activity and decreased levels on follow-up are associated with adverse outcomes in stable outpatients with HF.

Exercise Capacity, Heart Failure Risk, and Mortality in Older Adults: The Health ABC Study.

INTRODUCTION: Data on the association between exercise capacity and risk for heart failure (HF) in older adults are limited. METHODS: This study examined the association of exercise capacity, and its change over time, with 10-year mortality and incident HF in 2,935 participants of the Health, Aging, and Body Composition Study without HF at baseline (age, 73.6 [SD=2.9] years; 52.1% women; 41.4% black; 58.6% white). This cohort was initiated in 1997-1998 and exercise capacity was evaluated with a long-distance corridor walk test (LDCW) at baseline and Year 4. Outcomes were collected in 2007-2008 and initial analysis performed in 2014. RESULTS: Ten-year incident HF for completers (n=2,245); non-completers (n=331); and those excluded from LDCW for safety reasons (n=359) was 11.4%, 19.2%, and 23.0%, respectively. The corresponding 10-year mortality was 27.9%, 41.1%, and 42.4%. In models accounting for competing mortality, the adjusted subhazard ratio for HF was 1.37 (95% CI=1.00, 1.88; p=0.049) in non-completers and 1.41 (95% CI=1.06, 1.89; p=0.020) in those excluded versus completers. Non-completers (adjusted hazard ratio, 1.49; 95% CI=1.21, 1.84; p<0.001) and those excluded (hazard ratio, 1.27; 95% CI=1.04, 1.55; p=0.016) had elevated mortality. In adjusted models, LDCW performance variables were associated mainly with mortality. Only 20-meter walking speed and resting heart rate retained prognostic value for HF. Longitudinal changes in LDCW did not predict subsequent incident HF or mortality. CONCLUSIONS: Completing an LDCW is strongly associated with lower 10-year mortality and HF risk in older adults. Therefore, walking capacity may serve as an early risk marker.

Depression in heart failure: Can PHQ-9 help?

BACKGROUND: The Patient Health Questionnaire 9 (PHQ-9) is an effective tool for identification and grading of depression symptoms. Data on PHQ-9 utility for patients with heart failure (HF) are limited. METHODS: We evaluated the severity of depression by PHQ-9 at baseline and its association with health care resource utilization (HCRU) rates and quality of life (QoL) in 308 outpatients enrolled in a prospective HF cohort study. Depression symptoms were stratified according to PHQ-9 score as minimal (0-4), mild (5-9), or moderate-to-severe (10-27). RESULTS: Mean age of patients was 57±11years; 65% were men; 50% were white and 47% black; ejection fraction was 30±15%. Over 24±12months (total: 625person-years), there were 41 (13.3%) major clinical events (34 deaths, 5 transplants, 2 ventricular assist device implantations), 633 all-cause admissions (249 [39.3%] for HF), and 362 emergency department (ED) visits. Moderate-to-severe depressive symptoms were associated with 70% more all-cause admissions compared to patients without depressive symptoms and 2.5 times more HF-related admissions. However, less than 50% of patients with moderate-to-severe symptoms were on antidepressants. In adjusted analyses, even mild depressive symptoms were associated with 57% more all-cause admissions compared to patients without depressive symptoms and more than 2-fold higher rate of HF-related admissions. Depressive symptoms were not associated with ED visits. Increasing PHQ-9 score was associated with progressively worse QoL. PHQ-9 was not associated with major clinical events. CONCLUSIONS: PHQ-9 effectively identifies HF patients at risk for increased HCRU and lower QoL. Interventions to reduce depression symptoms may help improve HF outcomes.

Characteristics and Outcomes of Adult Outpatients With Heart Failure and Improved or Recovered Ejection Fraction.

IMPORTANCE: Heart failure (HF) guidelines recognize that a subset of patients with HF and preserved left ventricular ejection fraction (LVEF) previously had reduced LVEF but experienced improvement or recovery in LVEF. However, data on these patients are limited. OBJECTIVE: To investigate the characteristics and outcomes of adult outpatients with HF and improved or recovered ejection fraction (HFrecEF). DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study (inception period, January 1, 2012, to April 30, 2012) with 3-year follow-up at cardiology clinics (including HF subspecialty) in an academic institution. The dates of the analysis were May 21, 2015, to August 10, 2015. Participants were all outpatients 18 years or older who received care for a verified diagnosis of HF not attributed to specific cardiomyopathies or other special causes during the inception period. EXPOSURES: Type of HF at baseline, classified as HF with reduced ejection fraction (HFrEF) (defined as current LVEF ≤40%), HF with preserved ejection fraction (HFpEF) (defined as current and all previous LVEF reports >40%), and HF with recovered ejection fraction (HFrecEF) (defined as current LVEF >40% but any previously documented LVEF ≤40%). MAIN OUTCOMES AND MEASURES: Mortality, hospitalization rates, and composite end points. RESULTS: The study cohort comprised 2166 participants. Their median age was 65 years, 41.4% (896 of 2166) were female, 48.7% (1055 of 2166) were white and 45.2% (1368 of 2166) black, and 63.2% (1368 of 2166) had coronary artery disease. Preserved (>40%) LVEF at inception was present in 816 of 2166 (37.7%) patients. Of these patients, 350 of 2166 (16.2%) had previously reduced (≤40%) LVEF and were classified as having HFrecEF, whereas 466 of 2166 (21.5%) had no previous reduced LVEF and were classified as having HFpEF. The remaining 1350 (62.3%) patients were classified as having HFrEF. After 3 years, age and sex-adjusted mortality was 16.3% in patients with HFrEF, 13.2% in patients with HFpEF, and 4.8% in patients with HFrecEF (P < .001 vs HFrEF or HFpEF). Compared with patients with HFpEF and patients with HFrEF, patients with HFrecEF had fewer all-cause (adjusted rate ratio [RR] vs HFpEF, 0.71; 95% CI, 0.55-0.91; P = .007), cardiovascular (RR, 0.50; 95% CI, 0.35-0.71; P < .001), and HF-related (RR, 0.48; 95% CI, 0.30-0.76; P = .002) hospitalizations and were less likely to experience composite end points commonly used in clinical trials (death or cardiovascular hospitalization and death or HF hospitalization). CONCLUSIONS AND RELEVANCE: Outpatients with HFrecEF have a different clinical course than patients with HFpEF and HFrEF, with lower mortality, less frequent hospitalizations, and fewer composite end points. These patients may need to be investigated separately in outcomes studies and clinical trials.

Renal biomarkers and outcomes in outpatients with heart failure: The Atlanta cardiomyopathy consortium.

BACKGROUND/OBJECTIVES: Cystatin-C and beta-2-microglobulin may be superior to serum creatinine, blood urea nitrogen (BUN), or estimated glomerular filtration rate (eGFR) in patients hospitalized with heart failure (HF). We compared these renal markers in ambulatory HF patients. METHODS: We prospectively evaluated the association of baseline renal markers and eGFR (by 4 different formulas) with (1) the composite of death or HF-related hospitalization and (2) rates of hospitalizations and emergency department (ED) visits in 166 outpatients with HF (57.3±11.6years; 57.2% white, 38.6% black, median left ventricular ejection fraction 27.5% [17.5, 40.0]). RESULTS: After a median of 3.9years, 63 (38.0%) patients met the composite endpoint. There were 458 hospitalizations (177 [38.6%] for HF) and 209 ED visits (51 [24.4%] for HF). Cystatin-based eGFR most consistently predicted (1) the composite endpoint (highest-to-lowest tertile adjusted hazard ratio [HR] 4.92 [95% CI 2.07-11.7; P<0.001]); and (2) hospitalization rates, including HF hospitalizations (highest-to-lowest tertile, adjusted relative rate 5.24 [95% CI 1.61-17.01; P=0.006]). Serum creatinine alone was a strong predictor of the composite endpoint (highest-to-lowest tertile, adjusted HR 3.20 [95% CI, 1.51-6.78; P=0.002]). Only the highest tertile of BUN was associated with rates of ED visits. CONCLUSIONS: In outpatients with HF, cystatin-based eGFR provides consistent prognostication across outcomes, except ED visits. Serum creatinine is an adequate prognosticator of death or HF hospitalization.

Trends in Utilization of Surrogate Endpoints in Contemporary Cardiovascular Clinical Trials.

Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p = 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p = 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p = 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p = 0.27) and intermediate endpoints (74.4% to 71.4%, p = 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes.

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.