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Van Der Meer P.,University of Groningen | Postmus D.,University of Groningen | Ponikowski P.,Klinika Kardiologii | Cleland J.G.,University of Hull | And 10 more authors.
Journal of the American College of Cardiology | Year: 2013

Objectives: The study sought to investigate the clinical correlates and prognostic role of anemia and changes in hemoglobin in patients hospitalized for acute decompensated heart failure (AHF). Background: Anemia is related to a poor outcome in patients with heart failure. In addition, an increase in hemoglobin during hospitalization might be a sign of effective decongestion and therefore related to improved outcome. Methods: This is a post hoc analysis of the PROTECT (Placebo-Controlled Randomized Study of the Selective Adenosine A1 Receptor Antagonist Rolofylline for Patients Hospitalized with Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function) study in 1,969 patients with AHF and mild to moderate impaired renal function. Hemoglobin levels were measured daily for the first 4 days and at day 7. The endpoint was 180-day all-cause mortality. Results: Anemia at baseline was observed in 50.3% of the patients. During follow-up, 359 patients (18.2%) died. Hemoglobin increased in 69.1% and was associated with a better renal function at baseline and more weight loss, but was associated with a deterioration of renal function (p = 0.01), whereas total dose diuretics was lower in patients with hemoconcentration (p < 0.01). Interaction analysis showed that greater weight loss and better baseline renal function were associated with a more rapid increase in hemoglobin concentration (p < 0.01 for both). The absolute change in hemoglobin (g/dl) independently predicted outcome (hazard ratio: 0.66; 95% confidence interval: 0.51 to 0.86; p = 0.002), whereas baseline hemoglobin levels did not. Conclusions: Patients with AHF and preserved renal function are decongested better, as shown by an increase in hemoglobin. A rapid increase in hemoglobin during the first week is independently associated with a favorable outcome, despite a slight decrease in renal function. © 2013 American College of Cardiology Foundation.


Voors A.A.,University of Groningen | Dittrich H.C.,NovaCardia Inc. | Massie B.M.,University of California at San Francisco | Delucca P.,Merck And Co. | And 10 more authors.
Journal of the American College of Cardiology | Year: 2011

Objectives: This study sought to assess the effects of rolofylline on renal function in patients with acute heart failure (AHF) and renal dysfunction randomized in PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function). Background: Small studies have indicated that adenosine A1 receptor antagonists enhance diuresis and may improve renal function in patients with chronic heart failure or AHF. Methods: A total of 2,033 patients with AHF, volume overload, estimated creatinine clearance between 20 and 80 ml/min, and elevated natriuretic peptide levels were randomized (2:1) within 24 h of hospital presentation to rolofylline 30 mg/day or intravenous placebo for up to 3 days. Creatinine was measured daily until discharge or day 7 and on day 14. Persistent worsening renal function was defined as an increase in serum creatinine <0.3 mg/dl at both days 7 and 14, or initiation of hemofiltration or dialysis or death by day 7. Results: At baseline, mean ± SD estimated creatinine clearance was 51.0 ± 20.5 ml/min in the placebo group and 50.4 ± 20.0 ml/min in the rolofylline group. Changes in creatinine and estimated creatinine clearance were similar between placebo- and rolofylline-treated patients during hospitalization and at day 14. After 4 days, mean body weight was reduced by 2.6 and 3.0 kg in placebo and rolofylline patients, respectively (p = 0.005). Persistent worsening renal function occurred in 13.7% of the placebo group and 15.0% of the rolofylline group (odds ratio vs. placebo: 1.11 [95% confidence interval: 0.85 to 1.46]; p = 0.44). Conclusions: In this large, phase III clinical trial, the adenosine A1 receptor antagonist rolofylline did not prevent persistent worsening renal function in AHF patients with volume overload and renal dysfunction. (A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function [PROTECT-1], NCT00328692; and [PROTECT-2], NCT00354458) © 2011 American College of Cardiology Foundation.


Background - Acute heart failure is a common reason for admission, and outcome is often poor. Improved prognostic risk stratification may assist in the design of future trials and in patient management. Using data from a large randomized trial, we explored the prognostic value of clinical variables, measured at hospital admission for acute heart failure, to determine whether a few selected variables were inferior to an extended data set. Methods and Results - The prognostic model included 37 clinical characteristics collected at baseline in PROTECT, a study comparing rolofylline and placebo in 2033 patients admitted with acute heart failure. Prespecified outcomes at 30 days were death or rehospitalization for any reason; death or rehospitalization for cardiovascular or renal reasons; and, at both 30 and 180 days, all-cause mortality. No variable had a c-index >0.70, and few had values >0.60; c-indices were lower for composite outcomes than for mortality. Blood urea was generally the strongest single predictor. Eighteen variables contributed independent prognostic information, but a reduced model using only 8 items (age, previous heart failure hospitalization, peripheral edema, systolic blood pressure, serum sodium, urea, creatinine, and albumin) performed similarly. For prediction of all-cause mortality at 180 days, the model c-index using all variables was 0.72 and for the simplified model, also 0.72. Conclusions - A few simple clinical variables measured on admission in patients with acute heart failure predict a variety of adverse outcomes with accuracy similar to more complex models. However, predictive models were of only moderate accuracy, especially for outcomes that included nonfatal events. Better methods of risk stratification are required. © 2013 American Heart Association, Inc.


Schmitter D.,Momentum | Cotter G.,Momentum Research Inc. | Voors A.A.,University of Groningen
Heart Failure Reviews | Year: 2014

Biomarkers play an important role in heart failure. They provide us information about the mechanisms involved in specific types of heart failure and can identify patients at higher risk. Although the majority of biomarker studies in heart failure focus on their prognostic value, the clinical applicability of prognostication in heart failure needs to be established. However, biomarkers can be used for many other purposes. For example, they can help us with the diagnosis of heart failure, and they can be used to select our therapy, leading to personalized tailored therapy. Finally, when biomarkers are causally involved in the disease process, they can even become targets for therapy. The present paper reviews the established and potential value of the novel heart failure biomarkers, mid-regional atrial natriuretic peptide, soluble ST2, growth differentiation factor 15, galectin-3, renal tubular damage markers, and microRNAs. Their potential clinical value will be discussed and compared with the reference markers, the natriuretic peptides. © 2013 Springer Science+Business Media New York.


Voors A.A.,University of Groningen | Davison B.A.,Momentum Research Inc. | Teerlink J.R.,University of California at San Francisco | Felker G.M.,Duke Clinical Research Institute | And 9 more authors.
European Journal of Heart Failure | Year: 2014

Aims We studied the characteristics and clinical outcome related to diuretic response and the effects of serelaxin in patients hospitalized for acute heart failure (AHF).Methods and results RELAX-AHF was a double-blind, placebo-controlled trial, enrolling 1161 patients admitted to hospital for AHF who were randomized to 48 h i.v infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. Diuretic response was defined as Δ weight kg/[(total i.v. dose)/40 mg] + [(total oral dose)/80 mg)] furosemide (or equivalent loop diuretic dose) up to day 5. Median diuretic response was -0.42 (-1.00, -0.14) kg/40 mg. A poor diuretic response was independently associated with Western-like region (Western Europe, North America, Israel, and Poland), lower diastolic blood pressure, the absence of oedema, higher blood urea nitrogen, and lower levels of aspartate aminotransferase and potassium (all P < 0.01). Randomization to serelaxin was associated with lower doses of i.v. loop diuretics and slightly less weight loss, resulting in a neutral effect on diuretic response. Worse diuretic response was independently associated both with less relief of dyspnoea, measured with a visual analogue scale (VAS) at day 5 (primary endpoint; P = 0.0002), and with a higher risk of cardiovascular death or rehospitalization for heart failure or renal failure through day 60 (secondary endpoint, P < 0.0001), but not with increased 180-day cardiovascular mortality (P = 0.507).Conclusions In patients hospitalized for AHF, a poor diuretic response was associated with a poor in-hospital and early post-discharge clinical outcome. Serelaxin had a neutral effect on diuretic response. Trial registration: NCT00520806. © 2014 The Authors European Journal of Heart Failure.


Felker G.M.,Duke University | Teerlink J.R.,University of California at San Francisco | Butler J.,Emory University | Hernandez A.F.,Duke University | And 11 more authors.
Journal of the American College of Cardiology | Year: 2014

Background Little is known about mode of death after acute heart failure (AHF) hospitalization. In the RELAX-AHF (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure) study, serelaxin, the recombinant form of human relaxin-2, reduced post-discharge mortality at 180 days in selected patients with AHF.Objectives The goal of this study was to assess the effect of serelaxin on specific modes of death in patients with AHF.Methods The RELAX-AHF study randomized 1,161 patients with AHF to 48 h of therapy with intravenous serelaxin or placebo. Patients were followed for vital status through 180 days. A blinded clinical events committee reviewed all deaths and adjudicated a cause of death on the basis of pre-specified criteria. Cox proportional hazard models were used to assess the effect of serelaxin on each mode of death, on the basis of pre-specified groupings of mode of death.Results There were 107 deaths (9.3%): 37 (35%) due to HF, 25 (23%) due to sudden death, 15 (14%) due to other cardiovascular (CV) causes, 19 (18%) due to non-CV causes, and 11 (10%) classified as unknown. The treatment effect of serelaxin was most pronounced on other CV deaths (hazard ratio [HR]: 0.29; 95% CI: 0.12 to 0.73; p = 0.005) and sudden death (HR: 0.46; 95% CI: 0.20 to 1.07; p = 0.065). There was no apparent impact of serelaxin treatment on HF deaths or non-CV deaths.Conclusions In the RELAX-AHF study, the effects of serelaxin on mortality were primarily driven by reduction in mortality from other CV causes and sudden death, without apparent impact on HF deaths. (Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure [RELAX-AHF]; NCT00520806). © 2014 by the American College of Cardiology Foundation.


Colombo P.C.,Columbia University | Ganda A.,Columbia University | Lin J.,Columbia University | Onat D.,Columbia University | And 4 more authors.
Heart Failure Reviews | Year: 2012

Although inflammation is a physiologic response designed to protect us from infection, when unchecked and ongoing it may cause substantial harm. Both chronic heart failure (CHF) and chronic kidney disease (CKD) are known to cause elaboration of several pro-inflammatory mediators that can be detected at high concentrations in the tissues and blood stream. The biologic sources driving this chronic inflammatory state in CHF and CKD are not fully established. Traditional sources of inflammation include the heart and the kidneys which produce a wide range of proinflammatory cytokines in response to neurohormones and sympathetic activation. However, growing evidence suggests that non-traditional biomechanical mechanisms such as venous and tissue congestion due to volume overload are also important as they stimulate endotoxin absorption from the bowel and peripheral synthesis and release of proinflammatory mediators. Both during the chronic phase and, more rapidly, during acute exacerbations of CHF and CKD, inflammation and congestion appear to amplify each other resulting in a downward spiral of worsening cardiac, vascular, and renal functions that may negatively impact patients' outcome. Anti-inflammatory treatment strategies aimed at attenuating end organ damage and improving clinical prognosis in the cardiorenal syndrome have been disappointing to date. A new therapeutic paradigm may be needed, which involves different anti-inflammatory strategies for individual etiologies and stages of CHF and CKD. It may also include specific (short-term) anti-inflammatory treatments that counteract inflammation during the unsettled phases of clinical decompensation. Finally, it will require greater focus on volume overload as an increasingly significant source of systemic inflammation in the cardiorenal syndrome. © 2011 Springer Science+Business Media, LLC.


Metra M.,University of Brescia | Davison B.,Momentum Research Inc | Bettari L.,University of Brescia | Sun H.,Momentum Research Inc | And 8 more authors.
Circulation: Heart Failure | Year: 2012

Background-Worsening renal function (WRF), traditionally defined as an increase in serum creatinine levels <0.3 mg/dL, is a frequent finding in patients with acute heart failure (AHF) and has been associated with poorer outcomes in some but not all studies. We hypothesized that these discrepancies may be caused by the interaction between WRF and congestion in AHF patients. Methods and Results-We measured serum creatinine levels on a daily basis during the hospitalization and assessed the persistence of signs of congestion at discharge in 599 consecutive patients admitted at our institute for AHF. They had a postdischarge mortality and mortality or AHF readmission rates of 13% and 43%, respectively, after 1 year. Patients were subdivided into 4 groups according to the development or not of WRF and the persistence of <1 sign of congestion at discharge. Patients with WRF and no congestion had similar outcomes compared with those with no WRF and no congestion, whereas the risk of death or of death or AHF readmission was increased in the patients with persistent congestion alone and in those with both WRF and congestion (hazard ratio, 5.35; 95% confidence interval, 3.0 -9.55 at univariable analysis; hazard ratio, 2.44; 95% confidence interval, 1.24-4.18 at multivariable analysis for mortality; hazard ratio, 2.14; 95% confidence interval, 1.39 -3.3 at univariable analysis; and hazard ratio, 1.39; 95% confidence interval, 0.88 -2.2 at multivariable analysis for mortality and rehospitalizations). Conclusions-WRF alone, when detected using serial serum creatinine measurements, is not an independent determinant of outcomes in patients with AHF. It has an additive prognostic value when it occurs in patients with persistent signs of congestion. © 2011 American Heart Association, Inc.


Cotter G.,Momentum Research Inc. | Milo O.,Momentum Research Inc. | Davison B.A.,Momentum Research Inc.
Current Heart Failure Reports | Year: 2014

Acute heart failure (AHF) is one of the most common causes of hospital admission. Despite the very high short-term morbidity and mortality and high costs associated with the condition, little progress has been made toward an understanding of the complex mechanisms of AHF, and particularly the spike in mortality after AHF admission. This manuscript addresses certain hypotheses for the pathophysiology of increased mortality after an AHF episode, specifically exploring the role of neurohormonal and inflammatory activation, congestion, and end-organ damage occurring during the first hours and days of an AHF episode. The results of the recently published RELAX-AHF (Relaxin in Acute Heart Failure) study may hold the key to understanding these intricate mechanisms. In the study, congestion and end-organ damage, which were strongly associated with increased 180-day mortality, were relieved by early administration of serelaxin, which was also associated with reduction in 180-day mortality. Hence, it is possible that early treatment of AHF, including decongestion and prevention of damage to end organs, including kidneys, heart, and liver, is critical to preventing mortality in AHF. This may require a change in our strategic approach to the management of patients admitted with AHF, setting them apart from patients with chronic heart failure (HF), and developing specific treatment strategies for AHF patients beyond simply implementing therapies proven to be effective in chronic HF. © 2013 Springer Science+Business Media New York.


Sun H.,Momentum Research Inc | Davison B.A.,Momentum Research Inc | Cotter G.,Momentum Research Inc | Pencina M.J.,University of North Carolina at Chapel Hill | And 2 more authors.
Circulation: Heart Failure | Year: 2012

Background-To assess concomitant simultaneous effects on multiple end points using global statistical methods in phase II acute heart failure studies. Methods and Results-Using simulations we have assessed different statistical methods to evaluate concomitant effects of a new intervention on dyspnea relief (using 2 measures), length of hospital stay, worsening heart failure to 5 days, mortality, and heart failure readmission to 30 days. Treatment effect scenarios included large (20% to 28% relative improvements) and very large (30% to 43% relative improvements) effects among others. Placebo responses and correlations among end points typical in recent acute heart failure clinical trials were used. Powers for the average Z score exceeded 70% with =75 patients per group for 35% relative improvement across all 6 end points. Assessing dyspnea alone generally provides lower power than the average Z score approach, with power deducted ̃50% under most of scenarios. Other approaches generally provide lower power than the average Z score method. Conclusions-Assessing the effects of new therapies on multiple clinical end points using the average Z score enables detection of therapeutic efficacy using sample sizes of 100 to 150 patients per group, approximately double the power achievable assessing the effects on dyspnea alone. © 2012 American Heart Association, Inc.

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