Browsing by Author "Greenberg, Barry H."

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    Characteristics and clinical outcomes of patients with acute heart failure with a supranormal left ventricular ejection fraction
    (Wiley, 2023) van Essen, Bart J.; Tromp, Jasper; Ter Maaten, Jozine M.; Greenberg, Barry H.; Gimpelewicz, Claudio; Felker, G. Michael; Davison, Beth A.; Severin, Thomas; Pang, Peter S.; Cotter, Gad; Teerlink, John R.; Metra, Marco; Voors, Adriaan A.; Emergency Medicine, School of Medicine
    Aim: Recent data suggest that guideline-directed medical therapy of patients with heart failure (HF) with reduced ejection fraction (HFrEF) might improve clinical outcomes in patients with HF up to a left ventricular ejection fraction (LVEF) of 55-65%, whereas patients with higher LVEF do not seem to benefit. Recent data have shown that LVEF may have a U-shaped relation with outcome, with poorer outcome also in patients with supranormal values. This suggests that patients with supranormal LVEF may be a distinctive group of patients. Methods and results: RELAX-AHF-2 was a multicentre, placebo-controlled trial on the effects of serelaxin on 180-day cardiovascular (CV) mortality and worsening HF at day 5 in patients with acute HF. Echocardiograms were performed at hospital admission in 6128 patients: 155 (2.5%) patients were classified as HF with supranormal ejection fraction (HFsnEF; LVEF >65%), 1440 (23.5%) as HF with preserved ejection fraction (HFpEF; LVEF 50-65%), 1353 (22.1%) as HF with mildly reduced ejection fraction (HFmrEF; LVEF 41-49%) and 3180 (51.9%) as HFrEF (LVEF <40%). Patients with HFsnEF compared to HFpEF were more often women, had higher prevalence of non-ischaemic HF, had lower levels of natriuretic peptides, were less likely to be treated with beta-blockers and had higher blood urea nitrogen plasma levels. All-cause mortality was not statistically different between groups, although patients with HFsnEF had the highest numerical rate. A declining trend was seen in the proportion of 180-day deaths due to CV causes from HFrEF (290/359, 80.8%) to HFsnEF (14/24, 58.3%). The reverse was observed with death from non-CV causes. No treatment effect of serelaxin was observed in any of the subgroups. Conclusions: In this study, only 2.5% of patients were classified as HFsnEF. HFsnEF was primarily characterized by female sex, lower natriuretic peptides and a higher risk of non-CV death.
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    Day vs night: Does time of presentation matter in acute heart failure? A secondary analysis from the RELAX-AHF trial
    (Elsevier, 2017-05) Pang, Peter S.; Teerlink, John R.; Boer-Martins, Leandro; Gimpelewicz, Claudio; Davison, Beth A.; Wang, Yi; Voors, Adriaan A.; Severin, Thomas; Ponikowski, Piotr; Hua, Tsushung A.; Greenberg, Barry H.; Filippatos, Gerasimos; Felker, G. Michael; Cotter, Gad; Metra, Marco; Department of Emergency Medicine, IU School of Medicine
    Background Signs and symptoms of heart failure can occur at any time. Differences between acute heart failure (AHF) patients who present at nighttime vs daytime and their outcomes have not been well studied. Our objective was to determine if there are differences in baseline characteristics and clinical outcomes between AHF patients presenting during daytime vs nighttime hours within an international, clinical trial. Methods This is a post hoc analysis of the RELAX AHF trial, which randomized 1,161 AHF patients to serelaxin vs placebo, both in addition to usual AHF therapy. Prespecified end points of the primary trial were used: dyspnea, 60-day heart failure/renal failure rehospitalization or cardiovascular (CV) death, and 180-day CV death. Both unadjusted and adjusted analyses for outcomes stratified by daytime vs nighttime presentation were performed. Results Of the 1,161 RELAX-AHF patients, 775 (66.8%) patients presented during daytime and 386 (33.2%) at nighttime. Baseline characteristics were largely similar, although daytime patients were more likely to be male, have greater baseline body weight, have higher New York Heart Association class, have history of atrial fibrillation, and have more peripheral edema compared with nighttime patients. No differences in dyspnea relief or 60-day outcomes were observed. However, daytime presentation was associated with greater risk for 180-day CV death after adjustment (hazard ratio 2.28, 95% CI 1.34-3.86; c statistic = 0.82, 95% CI 0.78-0.86). Conclusion In this secondary analysis of the RELAX-AHF trial, baseline characteristics suggest that daytime-presenting patients may have more gradual worsening of chronic HF. Patients with AHF who presented at night had less risk for 180-day CV death, but similar risk for 60-day CV death or rehospitalization and symptom improvement for patients who presented during the daytime.
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    Effects of serelaxin in acute heart failure patients with renal impairment: results from RELAX-AHF
    (Springer, 2016-09) Liu, Licette C. Y.; Voors, Adriaan A.; Teerlink, John R.; Cotter, Gad; Davison, Beth A.; Felker, G. Michael; Filippatos, Gerasimos; Chen, Yakuan; Greenberg, Barry H.; Ponikowski, Piotr; Pang, Peter S.; Prescott, Margaret F.; Hua, Tsushung A.; Severin, Thomas M.; Metra, Marco; Department of Emergency Medicine, IU School of Medicine
    Background Serelaxin showed beneficial effects on clinical outcome and trajectories of renal markers in patients with acute heart failure. We aimed to study the interaction between renal function and the treatment effect of serelaxin. Methods In the current post hoc analysis of the RELAX-AHF trial, we included all patients with available estimated glomerular filtration rate (eGFR) at baseline (n = 1132). Renal impairment was defined as an eGFR <60 ml/min/1.73 m2 estimated by creatinine. Results 817 (72.2 %) patients had a baseline eGFR <60 ml/min/1.73 m2. In placebo-treated patients, baseline renal impairment was related to a higher 180 day cardiovascular (HR 3.12, 95 % CI 1.33–7.30) and all-cause mortality (HR 2.81, 95 % CI 1.34–5.89). However, in serelaxin-treated patients, the risk of cardiovascular and all-cause mortality was less pronounced (HR 1.19, 95 % CI 0.54 –2.64; p for interaction = 0.106, and HR 1.15 95 % CI 0.56–2.34 respectively; p for interaction = 0.088). In patients with renal impairment, treatment with serelaxin resulted in a more pronounced all-cause mortality reduction (HR 0.53, 95 % CI 0.34–0.83), compared with patients without renal impairment (HR 1.30, 95 % CI 0.51–3.29). Conclusion Renal dysfunction was associated with higher cardiovascular and all-cause mortality in placebo-treated patients, but not in serelaxin-treated patients. The observed reduction in (cardiovascular) mortality in RELAX-AHF was more pronounced in patients with renal dysfunction. These observations need to be confirmed in the ongoing RELAX-AHF-2 trial.
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    Effects of serelaxin on the outcome of patients with or without substantial peripheral edema: A subgroup analysis from the RELAX-AHF trial
    (Elsevier, 2017-08) Gimpelewicz, Claudio; Metra, Marco; Cleland, John G. F.; Szecsödy, Peter; Chang Wun, Chuan-Chuan; Boer-Martins, Leandro; Cotter, Gad; Davison, Beth A.; Felker, G. Michael; Filippatos, Gerasimos; Greenberg, Barry H.; Pang, Peter S.; Ponikowski, Piotr; Severin, Thomas; Voors, Adrian A.; Teerlink, John R.; Department of Emergency Medicine, IU School of Medicine
    Background Acute heart failure (AHF) is a heterogeneous disorder, with most of the patients presenting with breathlessness along with varying degrees of peripheral edema. The presence of peripheral edema suggests that volume overload is the cause of decompensation leading to AHF, whereas breathlessness in the absence of edema may reflect a “vascular phenotype.” This analysis investigated the characteristics, therapeutic response, and outcome of patients with AHF, with and without overt peripheral edema in the RELAX-AHF trial. Methods Physician-assessed edema scores at baseline were used to categorize the population into those with no/mild edema (score 0 or 1+) and moderate/severe edema (score 2+ or 3+). The effect of serelaxin vs placebo was assessed within each subgroup. Results Patients with moderate/severe edema (n = 583; 50.5%) were more likely to have severe dyspnea, orthopnea (>30°), rales (≥1/3), and elevated jugular venous pressure (>6 cm) than the patients with little or no peripheral edema (n=571; 49.5%). The relative benefits of serelaxin in terms of reduction in breathlessness, lower diuretic requirements, decreased length of initial hospital stay and days in intensive care unit/cardiac care unit, and improved prognosis (180-day cardiovascular and all-cause mortality) were generally similar for patients with or without peripheral edema. However, because patients with moderate/severe peripheral edema had worse outcomes, the absolute benefit was generally greater than in patients with no/mild edema. Conclusions Overall, patients with AHF and moderate/severe peripheral edema have a worse prognosis but appear to receive similar relative benefit and perhaps greater absolute benefit from serelaxin administration.
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    Growth differentiation factor 15 (GDF-15) in patients admitted for acute heart failure: results from the RELAX-AHF study
    (Wiley, 2015-11) Cotter, Gad; Voors, Adriaan A.; Prescott, Margaret F.; Felker, G. Michael; Filippatos, Gerasimos; Greenberg, Barry H.; Pang, Peter S.; Ponikowski, Piotr; Milo, Olga; Hua, Tsushung A.; Qian, Min; Severin, Thomas M.; Teerlink, John R.; Metra, Marco; Davison, Beth A.; Department of Emergency Medicine, IU School of Medicine
    Background Growth differentiation factor 15 (GDF-15) was found to be upregulated in patients with chronic heart failure (HF) and associated with disease severity, however, data on patients with acute heart failure (AHF) is lacking. Methods and results Levels of GDF-15 were measured at pre-specified time-points (baseline and at days 2, 5, 14, and 60) in patients enrolled in the placebo-controlled RELAXin in Acute Heart Failure (RELAX-AHF) study, which examined the effect of serelaxin in 1161 patients with AHF, systolic blood pressure >125 mmHg, and mild to moderate renal impairment. Neither baseline nor changes in GDF-15 were associated with the degree of dyspnoea or dyspnoea relief. After adjustment for baseline characteristics, baseline GDF-15 was not associated with the composite endpoint of heart failure or renal failure (HF/RF) readmission at 60 days/cardiovascular (CV) death or CV death at 180 days. In contrast, larger increases in GDF-15 levels at days 2 and 14 were associated with a greater risk of 60-day HF/RF rehospitalizations/CV death and CV death at 180 days. Serelaxin treatment was associated with significantly larger decreases of GDF-15 at days 2 and 5 than placebo. Conclusions In AHF patients enrolled in the RELAX-AHF study, increases in GDF-15 levels, but not baseline measurements, were associated with a greater likelihood of adverse outcomes. Serelaxin administration was associated with greater decreases in GDF-15 compared with placebo.
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    Serial high sensitivity cardiac troponin T measurement in acute heart failure: insights from the RELAX-AHF study
    (Wiley, 2015-12) Felker, G. Michael; Mentz, Robert J.; Teerlink, John R.; Voors, Adriaan A.; Pang, Peter S.; Ponikowski, Piotr; Greenberg, Barry H.; Filippatos, Gerasimos; Davison, Beth A.; Cotter, Gad; Prescott, Margaret F.; Hua, Tsushung A.; Lopez-Pintado, Sara; Severin, Thomas; Metra, Marco; Department of Emergency Medicine, IU School of Medicine
    Aims Troponin elevation is common in acute heart failure (AHF) and may be useful for prognostication; however, available data are mixed and many previous studies used older, less sensitive assays. We examined the association between serial measurements of high-sensitivity cardiac troponin T (hs-cTnT) and outcomes in RELAX-AHF. Methods and results Hs-cTnT was measured at baseline and days 2, 5, and 14. We assessed the relationship between baseline, peak and peak change hs-cTnT with dyspnoea relief by visual analogue scale, cardiovascular death, or HF/renal hospitalization to 60 days and cardiovascular mortality to 180 days. Models were adjusted for clinical variables and treatment assignment. Whether baseline troponin status affected the treatment effect of serelaxin was assessed using interactions terms. In 1074 patients, the median baseline troponin was 0.033 µg/L, and 90% of patients were above the 99th upper reference limit (URL). Patients with hs-cTnT >median were more likely to be men with ischaemic heart disease, worse renal function, and higher N-terminal pro-brain natriuretic peptide. Higher baseline or peak hs-cTnT and greater peak change were associated with worse outcomes independent of adjustment for covariates, but relationships were generally strongest for 180-day cardiovascular mortality (hazard ratio per doubling of baseline hs-cTnT = 1.36, 95% confidence interval 1.15–1.60). Troponin was most strongly associated with death from heart failure or from other cardiovascular causes. The treatment effect of serelaxin did not differ by baseline troponin levels. Conclusion Hs-cTnT was elevated above the 99% URL in the majority of AHF patients. Baseline, peak, and peak change hs-cTnT were associated with worse outcomes, with the strongest relationship with 180-day cardiovascular mortality.
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    Use of High-Sensitivity Troponin T to Identify Patients With Acute Heart Failure at Lower Risk for Adverse Outcomes
    (Elsevier, 2016-07) Pang, Peter S.; Teerlink, John R.; Voors, Adriaan A.; Ponikowski, Piotr; Greenberg, Barry H.; Filippatos, Gerasimos; Felker, G. Michael; Davison, Beth A.; Cotter, Gad; Kriger, Joshua; Prescott, Margaret F.; Hua, Tsushung A.; Severin, Thomas; Metra, Marco; Department of Emergency Medicine, IU School of Medicine
    Objectives The aim of this study was to determine if a baseline high-sensitivity troponin T (hsTnT) value ≤99th percentile upper reference limit (0.014 μg/l [“low hsTnT”]) identifies patients at low risk for adverse outcomes. Background Approximately 85% of patients who present to emergency departments with acute heart failure are admitted. Identification of patients at low risk might decrease unnecessary admissions. Methods A post-hoc analysis was conducted from the RELAX-AHF (Serelaxin, Recombinant Human Relaxin-2, for Treatment of Acute Heart Failure) trial, which randomized patients within 16 h of presentation who had systolic blood pressure >125 mm Hg, mild to moderate renal impairment, and N-terminal pro–brain natriuretic peptide ≥1,600 ng/l to serelaxin versus placebo. Linear regression models for continuous endpoints and Cox models for time-to-event endpoints were used. Results Of the 1,076 patients with available baseline hsTnT values, 107 (9.9%) had low hsTnT. No cardiovascular (CV) deaths through day 180 were observed in the low-hsTnT group compared with 79 CV deaths (7.3%) in patients with higher hsTnT. By univariate analyses, low hsTnT was associated with lower risk for all 5 primary outcomes: 1) days alive and out of the hospital by day 60; 2) CV death or rehospitalization for heart failure or renal failure by day 60; 3) length of stay; 4) worsening heart failure through day 5; and 5) CV death through day 180. After multivariate adjustment, only 180-day CV mortality remained significant (hazard ratio: 0.0; 95% confidence interval: 0.0 to 0.736; p = 0.0234; C-index = 0.838 [95% confidence interval: 0.798 to 0.878]). Conclusions No CV deaths through day 180 were observed in patients with hsTnT levels ≤0.014 μg/l despite high N-terminal pro–brain natriuretic peptide levels. Low baseline hsTnT may identify patients with acute heart failure at very low risk for CV mortality.