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Because signs of congestion are associated with adverse outcomes in patients with acute heart failure (AHF), attempts were made to decongest patients as much as possible with diuretic agents (loop diuretic agents, thiazides, acetazolamide) or mechanical devices. Those interventions improved signs of congestion but failed to meaningfully improve patients' symptoms, improve quality of life, or reduce early readmissions or deaths. Recent studies have shown that implementation of guideline-directed medical therapies after an AHF admission led to both more decongestion and improved symptoms, quality of life, and outcomes. Therefore, for most patients with AHF whose symptoms and congestion can be controlled with loop diuretic agents, the main focus should be rapid guideline-directed medical therapy uptitration. Enhanced decongestion, ie, adding a second-line diuretic agent to a loop diuretic agent, should be reserved for those patients who do not respond to loop diuretic agents. [Display omitted] • Congestion in patients with AHF is associated with poor outcomes and frequent hospital readmissions. • Enhanced decongestion leads to minimal improvement in symptoms or outcomes in patients with AHF. • Greater focus on GDMT after discharge can improve outcomes for patients hospitalized with AHF. [ABSTRACT FROM AUTHOR]

Istaroxime was shown, in a small study, to increase systolic blood pressure (SBP) in patients with pre-cardiogenic shock (CS) due to acute heart failure (AHF). In the current analysis, we describe the effects of 2 doses of istaroxime 1.0 (Ista-1) and 1.5 µg/kg/min (Ista-1.5). The target dose of istaroxime, administered in a double-blind, placebo-controlled fashion, was 1.5 µg/kg/min in the first cohort (n = 24), and it was reduced to 1.0 µg/kg/min in subsequent patients (n = 36). Ista-1 was associated with numerically larger effects on SBP area under the curve, with a 93.6% relative increase from baseline during the first 6 hours with Ista-1 vs 39.5% for Ista-1.5, and with a 49.4% and 24.3% relative increase, respectively, at 24 hours. Compared to placebo, Ista-1.5 had more worsening HF events until day 5 and fewer days alive out of hospital (DAOH) through day 30. Ista-1 had no worsening HF events, and DAOH to day 30 were significantly increased. Effects on echocardiographic measures were similar, although decreases in left ventricular end systolic and diastolic volumes were numerically larger in the Ista-1 group. Ista-1, but not Ista-1.5, showed numerically smaller creatinine increases and larger decreases in natriuretic peptides as compared to placebo. There were 5 serious adverse events in Ista-1.5 (4 of which were cardiac) but only 1 in Ista-1. In patients with pre-CS due to AHF, istaroxime 1.0 µg/kg/min induced beneficial effects on SBP and DAOH. Clinical benefits appear to be reached at dosages less than 1.5 ug/kg/min. [ABSTRACT FROM AUTHOR]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2006.02.038 Byline: Gad Cotter (a), G. Michael Felker (a), Kirkwood F. Adams (b), Olga Milo-Cotter (a), Christopher M. O'Connor (a) Abstract: Despite significant advancement in chronic heart failure (HF), no breakthroughs have occurred in the last 2 decades in our understanding of the pathophysiology, classification, and treatment of acute HF (AHF). Traditional thinking, which has been that this disorder is a result of gradual fluid accumulation on a background of chronic HF, has been called into question by recent large registries enrolling less selected patient populations. It is increasingly recognized that many patients with this syndrome are elderly, have relatively preserved ejection fraction, and have mild or no preexisting chronic HF. In this review, we propose 2 primary subtypes of AHF: (1) acute decompensated cardiac failure, characterized by deterioration of cardiac performance over days to weeks leading to decompensation; and (2) acute vascular failure, characterized by acute hypertension and increased vascular stiffness. Registry data suggest that the latter is the more common form of AHF in the general population, although the former is often overrepresented in studies focused in academic tertiary care centers. Regardless of the clinical subtype, a variety of pathophysiologic mechanisms may play a role in this disorder, many of which remain poorly understood. In this review, we describe current understanding of the pathophysiology of AHF, including a critical evaluation of the data supporting both traditional and novel mechanisms, and suggest a framework for integrating these mechanisms into an overall model of AHF. Author Affiliation: (a) Duke University Medical Center, the Duke Clinical Research Institute, Durham, NC (b) University of North Carolina, Chapel Hill, NC Article History: Received 19 October 2005; Accepted 12 February 2006

STRONG-HF demonstrated the safety and efficacy of rapid up-titration of guideline-directed medical therapy (GDMT) with high intensity care (HIC) compared to usual care in patients hospitalized for acute HF. We examined the impact on treatment and outcome of protocol-specified safety indicators used to guide up-titration in the HIC arm. These included eGFR <30ml/min/1.73m2, serum K+ >5.0 mmol/L, systolic blood pressure [SBP] <95mmHg, heart rate <55 bpm, NT-proBNP level >10% higher than pre-discharge level. More than one safety indicator could have been noted for each patient. Three-hundred-thirteen of the 542 patients in the HIC arm (57.7%) met at least one safety indicator at any follow-up visit 1 to 6 weeks after discharge. The most common indicator was a NT-proBNP increase of > 10% (41.1%) followed by K > 5.0 mmol/L (27.5%), SBP < 95 mmHg (9.4%), heart rate < 55 bpm (8.5%) and eGFR < 30 ml/min/1.73m2 (5.2%). As compared to those without, patients meeting at least one safety indicator had more severe HF symptoms, lower SBP and higher heart rate at baseline. Patients meeting at least one safety indicator achieved a lower average percentage of GDMT optimal doses (mean difference vs the HIC arm patients not reaching any safety indicator, -11.0% [95% CI -13.6 to -8.4%], P<0.001, Figure 1). SBP < 95 mmHg and eGFR < 30 ml/min/1.73m2 were associated with the least GDMT up-titration. The primary endpoint of 180-day all-cause death or HF re-admission occurred in 15.0% of patients with any safety indicator versus 14.2% of those without (adjusted hazard ratio [HR] 0.84, 95% CI 0.48 to 1.46, P=0.54). The risk of 180-day all-cause mortality was also not significantly different, as was the risk of 180-day HF readmission. With respect to the impact of each safety indicator, considered alone, on outcomes, no single safety indicator was significantly associated with the primary endpoint. A drop of SBP < 95 mmHg was associated with a trend towards increased 180-day all-cause mortality (adjusted HR 2.68 [95% CI 0.94 to 7.64]; P = 0.0653). eGFR drop < 30 ml/min/1.73m2 was associated with a higher risk of 180-day HF readmission (adjusted HR 3.60 [95% CI 1.22 to 10.60]; P = 0.0203). NT-proBNP increase, increased potassium and reduced pulse were not associated with outcomes. The occurrence of a safety indicator was associated with a smaller 90-day improvement in EQ-5D VAS (adjusted mean difference -3.32 points, 95% CI -5.97 to -0.66, P=0.015). Among patients with AHF enrolled in STRONG-HF in the HIC arm, the occurrence of safety indicators led to slightly lower GDMT doses over time and less improvement in quality of life but not an increase in 180-day HF readmission or death when appropriately addressed by a specific protocol. [ABSTRACT FROM AUTHOR]

Background: In international trials, glucagon-like protein-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2Is) were effective in improving cardiovascular (CV) outcomes.Methods: We assessed the effect of GLP-1RAs and SGLT2Is treatment effect on CV endpoints by geographical region in multiple international trials using random effects weighted least squares meta-regressions.Results: The estimated effects of both SGLT2Is and GLP-1RAs on major adverse CV events (MACE) in North America (SGLT2Is n = 12,399, HR 0.90, 95% CI 0.81-1.01; GLP-1RAs n = 12,515, HR 0.95, 95% CI 0.83- 1.09) and in Europe (SGLT2Is n = 19,435, HR 0.93, 95% CI 0.85-1.02; GLP-1RAs n = 22,812, HR 0.88, 95% CI 0.79-0.99) were numerically lower but not statistically different to the rest of the world (ROW) (SGLT2Is n = 15,127, HR 0.83, 95% CI 0.75-0.92, p-value for interaction 0.26; GLP-1RAs n = 17,494, HR 0.82, 95% CI 0.73-0.92, p-value for interaction 0.28). Effects of SGLT2Is on heart failure readmission or CV death varied significantly by region (P = 0.0094). The effect of SGLT2Is was significantly smaller in Europe (n = 18,653, HR 0.86, 95% CI 0.78-0.95) than in the ROW (n = 12,463, HR 0.68, 95% CI 0.61-0.76, P = 0.0024). The smaller effect in North America (n = 9776, HR 0.76, 95% CI 0.66-0.87) did not differ significantly from that in the ROW (P = 0.2370).Conclusion: The effects of SGLT2Is on HF events are larger in the ROW. Further analyses and studies are needed to better elucidate the differential effects of SGLTIs and GLP-1RAs by geographical regions. [ABSTRACT FROM AUTHOR]

Background: Elevated plasma interleukin-6 (IL-6) concentrations are frequently observed in patients with acute heart failure (AHF). However, the predictive value of serial IL-6 measurements beyond brain natriuretic peptide (BNP) remains poorly characterized.Methods and Results: This was a retrospective analysis of the PROTECT cohort (2033 patients with AHF). Plasma IL-6 and BNP levels were determined on days 1, 2, 7 and 14 after admission for AHF in 1591 (78.3%), 1462 (71.9%), 1445 (71.1%) and 1451 (71.4%) patients, respectively. The primary endpoint was 180-day all-cause mortality. The median day-1 IL-6 concentration was 11.1 pg/mL (IQR: 6.6, 20.9) and decreased to 10.1 pg/mL (IQR: 5.6-18.5) at day-7. Higher cross-sectional IL-6 concentrations at all time-points predicted the primary endpoint, independent of a risk model for this cohort and changes in BNP. Each doubling of IL-6 between day-1 and day-7 predicted the primary endpoint independent of baseline IL-6 concentrations, the risk model, baseline BNP and changes in BNP [HR (95% CI): 1.18 (1.07-1.30), p=0.0013]. Collectively, 214 (17%) patients experienced at least a doubling of their IL-6 concentrations between day-1 and day-7.Conclusions: We demonstrate that the temporal evolution patterns of IL-6 in patients with AHF have additive prognostic value independent of changes in BNP. [ABSTRACT FROM AUTHOR]

Acute heart failure (AHF) is a life-threatening condition with a dramatic burden in terms of symptoms, morbidity and mortality. It is a specific syndrome requiring urgent, life-saving treatment. Multiple specific pathophysiologic mechanisms may be involved, including congestion, inflammation, and neurohormonal activation. This process eventually leads to symptoms, end-organ damage, and adverse outcomes. Clinical presentation varies, but it almost universally includes worsening of congestion associated with different degrees of hypoperfusion. Due to substantial early symptoms burden and high morbidity and mortality, patients with AHF require intensive monitoring and intravenous treatment. However, beyond variable improvement in congestion, none of the available intravenous therapies for AHF was shown to improve longer term outcomes. Although oral treatment with guideline-directed therapies for stable patients with HF and reduced ejection fraction (HFrEF) before discharge may fully prevent subsequent episodes, proof that this strategy may benefit patients is lacking. First, most patients with AHF have preserved EF (HFpEF) where no therapies have been shown to be effective. Second, all therapies developed for patients with HFrEF were tested for efficacy on outcomes in patients who were stable without recent AHF. Hence, the implementation of these chronic therapies during an AHF episode is untested. Third, the problem to better treat AHF patients in their early phase remains crucial with treatment strategies largely untested, yet. Further studies targeting AHF specific mechanisms, such as inflammation and end-organ damage, and finding effective intravenous drugs remain therefore warranted. [ABSTRACT FROM AUTHOR]

Background: Changes in renal function have been associated with differential outcomes in patients with acute heart failure (HF). However, individual trajectories of changes in renal function are unknown, and it is unclear whether they relate to different clinical characteristics and clinical outcomes. Our aim was to investigate the prognostic importance of individual trajectories of change in renal function in acute HF.Methods: This was a retrospective, observational analysis from the double-blind, randomized, placebo-controlled PROTECT trial in patients with acute HF. We identified and internally validated 8 different renal trajectories among 1897 patients by visual inspection of inhospital serum creatinine changes. The primary outcome measure was all-cause mortality at 180 days. Mean age was 70 ± 12 years; 70% were male, and mean baseline estimated glomerular filtration rate was 49.0 mL/min/1.73m2.Results: A total of 8 different trajectories was established. The most prevalent trajectories were an inhospital bump (19.0%), a sustained increase (17.6%) and a dip (14.5%) in serum creatinine. Overall, the clinical characteristics of patients in different trajectories were remarkably similar. Crude 180-day mortality rates ranged from 12.0% in the trajectory, with no significant changes to 18.3% in the trajectory of sustained increase without significant differences. Overall, after multivariable adjustment, there was no trajectory of changes in renal function that was associated with significantly better or worse outcomes.Conclusions: Trajectories of changes in renal function in acute HF differ considerably on the patient level. Despite these differences, clinical characteristics and outcomes were similar, therefore, questioning the prognostic importance of changes in renal function in acute HF. [ABSTRACT FROM AUTHOR]

Background: Symptoms and signs of heart failure (HF) are the most common reasons for admission to hospital for acute HF (AHF) and are used routinely throughout admission to assess the severity of disease and response to therapy.Methods and Results: The data were collected in The Sub-Saharan Africa Survey on Heart Failure (THESUS-HF) study, a prospective, multicenter, observational survey of AHF from 9 countries in sub-Saharan Africa. A total of 1006 patients, ≥12 years of age, hospitalized for AHF were recruited. Symptoms and signs of HF and changes in dyspnea and well-being, relative to admission, were assessed at entry and on days 1, 2, and 7 (or on discharge if earlier) and included oxygen saturation, degree of edema and rales, body weight, and level of orthopnea. The patient determined dyspnea and general well-being, whereas the physician determined symptoms and signs of HF, as well as improvements in vital sign measurement, throughout the admission. After multivariable adjustment, baseline rales and changes to day 7 or discharge in general well-being predicted death or HF hospitalization through day 60, and baseline orthopnea, edema, rales, oxygen saturation, and changes to day 7 or on discharge in respiratory rate and general well-being were predictive of death through day 180.Conclusions: In AHF patients in sub-Saharan Africa, symptoms and signs of HF improve throughout admission, and simple assessments, including edema, rales, oxygen saturation, respiratory rate, and asking the patient about general well-being, are valuable tools in patients' clinical assessment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Proenkephalin (pro-ENK) has emerged as a novel biomarker associated with both renal function and cardiac function. However, its clinical and prognostic value have not been well evaluated in symptomatic patients with heart failure.Methods and Results: The association between pro-ENK and markers of renal function was evaluated in 95 patients with chronic heart failure who underwent renal hemodynamic measurements, including renal blood flow (RBF) and glomerular filtration rate (GFR) with the use of 131I-Hippuran and 125I-iothalamate clearances, respectively. The association between pro-ENK and clinical outcome in acute heart failure was assessed in another 1589 patients. Pro-ENK was strongly correlated with both RBF (P < .001) and GFR (P < .001), but not with renal tubular markers. In the acute heart failure cohort, pro-ENK was a predictor of death through 180 days, heart failure rehospitalization through 60 days, and death or cardiovascular or renal rehospitalization through day 60 in univariable analyses, but its predictive value was lost in a multivariable model when other renal markers were entered in the model.Conclusions: In patients with chronic and acute heart failure, pro-ENK is strongly associated with glomerular function, but not with tubular damage. Pro-ENK provides limited prognostic information in patients with acute heart failure on top of established renal markers. [ABSTRACT FROM AUTHOR]

Background: The length of hospital stay (LOS) is important in patients admitted for acute heart failure (AHF) because it prolongs an unpleasant experience for the patients and adds substantially to health care costs.Methods and Results: We examined the association between LOS and baseline characteristics, 10-day post-discharge HF readmission, and 90-day post-discharge mortality in 1347 patients with AHF enrolled in the VERITAS program. Longer LOS was associated with greater HF severity and disease burden at baseline; however, most of the variability of LOS could not be explained by these factors. LOS was associated with a higher HF risk of both HF readmission (odds ratio for 1-day increase: 1.08; 95% confidence interval [CI] 1.01-1.16; P = .019) and 90-day mortality (hazard ratio for 1-day increase: 1.05; 95% CI 1.02-1.07; P < .001), although these associations are partially explained by concurrent end-organ damage and worsening heart failure during the first days of admission.Conclusions: In patients who have been admitted for AHF, longer length of hospital stay is associated with a higher rate of short-term mortality.Clinical Trial Registration: VERITAS-1 and -2: Clinicaltrials.gov identifiers NCT00525707 and NCT00524433. [ABSTRACT FROM AUTHOR]

Background: Vanoxerine is an oral, 1,4-dialkylpiperazine derivative antiarrhythmic drug being evaluated for pharmacological cardioversion of atrial fibrillation (AF).Objective: The purpose of this study was to evaluate the safety and efficacy of vanoxerine for the restoration of sinus rhythm in subjects with recent onset AF or atrial flutter (AFL).Methods: RESTORE SR (randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm) was a prospective, multinational, randomized, double-blind, placebo-controlled trial that randomized subjects to a single oral dose of vanoxerine 400 mg or placebo (2:1 allocation).Results: A total of 41 subjects were randomized in the study (placebo [n = 15] and vanoxerine [n = 26]). The study was terminated prematurely because of safety concerns. Overall, 61% (23 of 38) of the treated cohort had a history of AF/AFL and 66% (27 of 41) had structural heart disease (SHD). The primary efficacy end point-conversion to sinus rhythm through 24 hours-occurred in 20% (3 of 15) in the placebo arm vs 69% (18 of 26) in the vanoxerine arm (P = .0024). The mean length of stay was 4.2 ± 2.9 days in the placebo arm vs 4.7 ± 3.2 days in the vanoxerine arm (P = .6561). The primary safety end point (all-cause death, ventricular fibrillation/tachycardia requiring intervention, or torsades de pointes) occurred in no patient in the placebo arm vs 11.5% (3 of 26) in the vanoxerine arm. All 3 patients had torsades de pointes and underlying SHD.Conclusion: Vanoxerine is an oral, mixed ion channel blocker with IKr, INa, and L-type calcium channel activity. While oral therapy with 400 mg of vanoxerine appears effective for the termination of recent onset AF/AFL, its use was associated with a significant risk of ventricular proarrhythmia in patients with SHD. [ABSTRACT FROM AUTHOR]

Background Acute heart failure (HF) is common in the elderly, but the association of age with clinical outcomes and prognostic factors has not been examined thoroughly. Methods and Results We analyzed the clinical and laboratory characteristics and the outcomes of 1,347 patients with acute HF enrolled in the VERITAS trial. Subjects were subdivided based on their median age of 72 years. Older patients had a higher prevalence of comorbidities and a higher prevalence of hypertension and atrial fibrillation. During a mean follow-up of 149 ± 61 days, 432 patients (32.1%) reached the composite end point of death, in-hospital worsening HF, or HF rehospitalization by 30 days, and 135 patients (10.4%) died by 90 days, with a worse outcome in elderly patients in both cases. At multivariable analysis, different variables were related with each of these outcomes in elderly compared with younger patients. Regarding deaths at 90 days, plasma urea nitrogen and hemoglobin levels were predictive only in the younger patients, whereas respiratory rate and albumin levels were associated with mortality only in the older patients. Conclusions Elderly patients with acute HF have different clinical characteristics and poorer outcomes. Prognostic variables differ in elderly compared with younger patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: Elevated plasma concentrations of liver function tests are prevalent in patients with chronic heart failure (HF). Little is known about liver function in patients with acute HF. We aimed to assess the prevalence and prognostic value of serial measurements of liver function tests in patients admitted with acute decompensated HF. METHODS: We investigated liver function tests from all 234 patients from the Relaxin for the Treatment of Patients With Acute Heart Failure study at baseline and during hospitalization. The end points were worsening HF through day 5, 60-day mortality or rehospitalization, and 180-day mortality. RESULTS: Mean age was 70 ± 10 years, 56% were male, and most patients were in New York Heart Association functional class III/IV (73%). Abnormal liver function tests were frequently found for alanine transaminase (ALT; 12%), aspartate transaminase (AST; 21%), alkaline phosphatase (12%), and total bilirubin (19%), and serum albumin (25%) and total protein (9%) were decreased. In-hospital changes were very small. On a continuous scale, baseline ALT and AST were associated with 180-day mortality (hazard ratios [HRs; per doubling] 1.52 [P = .030] and 1.97 [P = .013], respectively) and worsening HF through day 5 (HRs [per doubling] 1.72 [P = .005] and 1.95 [P = .008], respectively). Albumin was associated with 180-day mortality (HR 0.86; P = .001) but not with worsening HF (HR 0.95; P = .248). Total protein was associated with only worsening HF (HR 0.91; P = .004). CONCLUSIONS: Abnormal liver function tests are often present in patients with acute HF and are associated with an increased risk for mortality, rehospitalization, and in-hospital worsening HF. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to assess the predictive utility of 12-lead electrocardiogram (ECG) abnormalities among Africans with acute heart failure (HF). METHODS AND RESULTS: We used the Sub-Saharan Africa Survey of Heart Failure, a multicenter prospective cohort study of 1,006 acute HF patients, and regression models to relate baseline ECG findings to all-cause mortality and readmission during a 6-month follow-up period. Of 814 ECGs available, 523 (49.0% male) were obtained within 15 days of admission, among which 97.7% showed abnormalities. Mean age was 52.0 years and median follow-up was 180 days, with 77 deaths (Kaplan-Meier 17.5%) through day 180 and 63 patients with death or readmission to day 60. QRS width, QT duration, bundle branch block, and ischemic changes were not associated with outcomes. Increasing ventricular rate was associated with increasing risk of both outcomes (hazard ratio [HR] 1.07 per 5 beats/min increase for 60-day death or readmission, 95% confidence interval [CI] 1.02-1.12; P = .0047), and the presence of sinus rhythm was associated with lower risk (HR 0.58, 95% CI 0.34-0.97; P = .0385). There was a strong association between survival and heart rate in patients in sinus rhythm, with heart rate >119 beats/min conveying the worst mortality risk. CONCLUSIONS: ECG abnormalities are almost universal among Africans with acute HF, which may add to the immediate diagnosis of patients presenting with dyspnea. Although some ECG findings have prognostic value for risk of adverse outcomes, most of them are nonspecific and add little to the risk stratification of these patients. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure. Background: Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage. Methods: The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies. Results: Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro–brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion. Conclusions: Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission. [Copyright &y& Elsevier]

Abstract: Background: Current treatment for acute decompensated heart failure (ADHF) is associated with incomplete resolution of symptoms and signs, recurrent symptoms of heart failure in-hospital and after discharge and high mortality. Studies have consistently demonstrated an association between worsening renal function in ADHF and adverse outcomes. Adenosine A1 receptor antagonists, such as rolofylline, appear in preliminary studies to produce potentially beneficial effects on natriuresis, diuresis, renal blood flow, and glomerular filtration rate. In a previous dose-finding study, rolofylline 30 mg intravenously daily for 3 days was associated with symptom improvement, less worsening of renal function, and trends toward lower 60-day rates of death or readmission for cardiovascular or renal causes. Methods and Results: This manuscript describes the rationale underlying the design of the phase 3 PROTECT (Placebo-controlled Randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal funcTion) trial. Conclusion: Rolofylline 30 mg or matching placebo was given intravenously as a 4-hour continuous infusion on 3 consecutive days and the hospital course was assessed by measurements dyspnea, clinical status, renal function, and subsequent morbidity and mortality in a large population of patients with ADHF with renal impairment. [Copyright &y& Elsevier]

Abstract: Background: The most common outcome currently assessed in acute heart failure trials (AHF) is dyspnea improvement. Worsening hear failure (WHF) is a new outcome measure that incorporates failure to improve or recurrent symptoms of AHF requiring rescue intravenous therapy, mechanical circulatory or ventilatory support, or readmission because of AHF, occurring within 30 days of AHF admission. Methods and Results: Retrospective data analysis of 120 patients with AHF requiring hemodynamic monitoring who enrolled in the placebo arm of 2 prospective randomized studies. The incidence of WHF was 42% at 30 days from enrollment. Most WHF events occurred in-hospital during the first 7 days after admission (early WHF). Thirty-day readmission from AHF was an infrequent event in the present cohort (5.0%). The strongest hemodynamic predictors of WHF were cardiac power at baseline and its change during the initial 6hours of monitoring. Other hemodynamic parameters associated with WHF events were blood pressure and its increase, cardiac output, and pulmonary wedge pressure change during the initial 6hours of monitoring. WHF was found to be a strong predictor of 6-month mortality. Conclusions: WHF is a common morbid event clustered mostly during the first week of AHF admission and is associated with higher 6-month mortality. The hemodynamic measurements associated with WHF are similar to those predicting adverse outcome in AHF and cardiogenic shock (low cardiac power, higher pulmonary capillary wedge pressure, and vascular resistance), emphasizing the notion that early WHF should become an important AHF-specific outcome measure. [Copyright &y& Elsevier]

Abstract: Background: Rolofylline, an adenosine A1 receptor antagonist, facilitates diuresis and preserves renal function in patients with acute heart failure (AHF) with renal impairment. Although not powered around any specific hypothesis, this pilot study was designed to identify an efficacious dose while refining inclusion criteria and end points. Methods: A total of 301 patients hospitalized for AHF with an estimated creatinine clearance of 20 to 80 mL/min and elevated natriuretic peptide levels were enrolled within 24 hours of presentation to placebo or rolofylline 10, 20, or 30 mg administered as 4-hour infusions for 3 days in addition to intravenously administered loop diuretics. Post hoc analyses for end points chosen for subsequent Phase III studies were performed. Results: Compared with placebo, rolofylline produced trends toward greater proportions of patients with marked or moderately improved dyspnea and fewer patients with worsening heart failure or renal function. Serum creatinine increased in patients receiving placebo and remained stable or tended to decrease in those receiving rolofylline. On day 14 the absolute differences between placebo and rolofylline for change in creatinine increased with increasing rolofylline dose, reflecting the lesser increase in creatinine in rolofylline-treated patients (r = −0.12, P = .030). Treatment with 30 mg, the dose selected for the pivotal trials, was associated with a trend toward reduced 60-day mortality or readmission for cardiovascular or renal cause (hazard ratio, 0.55; 95% confidence interval, 0.28–1.04). Conclusion: These results demonstrate that adenosine A1 receptor blockade with rolofylline can prevent renal impairment in patients with AHF and may positively affect acute symptoms and 60-day outcome. A 2000-patient trial of this agent is now under way. [Copyright &y& Elsevier]

Abstract: Background: Previous studies suggested a higher incidence of acute heart failure (AHF) during cold months in regions with cold climate. We examined the daily incidence of AHF by same-day trough temperature and humidity in a warmer region. Methods and Results: All admissions for AHF (340 patients) to a city hospital, providing the sole emergency medical care to a geographical region of approximately 500,000 people were recorded. Patients were followed through admission and for 6 months after discharge. Low minimal trough temperature was associated with an increase in the same-day AHF incidence. Lowest tercile trough night temperatures were associated with higher AHF incidence (3.5 ± 2.1 versus 2.4 ± 1.6, events/24 hours, P = .012). This association was mainly from increased AHF events in nights with the predetermined trough temperature of <7°C (4 ± 2.1 versus 2.5 ± 1.7, events/24 hours, P = .0013). This association persisted even after excluding the coldest consecutive 30 days from the analysis. Humidity was not associated with increased AHF event rate. In a post-hoc analysis we have observed doubling of 6-month mortality in patients admitted with AHF during days with lower trough night temperature, despite no apparent worse baseline characteristics or disease severity at admission. Conclusions: AHF rate is increased during days with lower trough night temperature. If confirmed, these results may have implications on issues related to climate control in houses of the elderly or patients susceptible to heart failure. [Copyright &y& Elsevier]

Reports on a randomized study in the United States, which evaluated the effect of gradually increasing dosages of captopril or losartan on early clinical outcome, in patients on continuous intravenous nitrates during the treatment of angina pectoris, in an attempt to prevent nitrate tolerance. Information on the patients who had unstable angina pectoris; Definition of unstable angina pectoris; Results of the study.

Comprehensive uptitration of neurohormonal blockade targets fundamental mechanisms underlying development of congestion and may be an additional approach for decongestion after acute heart failure (AHF). This hypothesis was tested in the STRONG-HF (Safety, Tolerability, and Efficacy of Rapid Optimization, Helped by N-Terminal Pro–Brain Natriuretic Peptide Testing of Heart Failure Therapies) trial. In STRONG-HF, patients with AHF were randomized to the high-intensity care (HIC) arm with fast up-titration of neurohormonal blockade or to usual care (UC). Successful decongestion was defined as an absence of peripheral edema, pulmonary rales, and jugular venous pressure <6 cm. At baseline, the same proportion of patients in both arms had successful decongestion (HIC 48% vs UC 46%; P = 0.52). At day 90, higher proportion of patients in the HIC arm (75%) experienced successful decongestion vs the UC arm (68%) (P = 0.0001). Each separate component of the congestion score was significantly better in the HIC arm (all, P < 0.05). Additional markers of decongestion also favored the HIC: weight reduction (adjusted mean difference: −1.36 kg; 95% CI: −1.92 to −0.79 kg), N-terminal pro–B-type natriuretic peptide level, and lower orthopnea severity (all, P < 0.001). More effective decongestion was achieved despite a lower mean daily dose of loop diuretics at day 90 in the HIC arm. Among patients with successful decongestion at baseline, those in the HIC arm had a significantly better chance of sustaining decongestion at day 90. Successful decongestion in all subjects was associated with a lower risk of 180-day HF readmission or all-cause death (HR: 0.40; 95% CI: 0.27-0.59; P < 0.0001). In STRONG-HF, intensive uptitration of neurohormonal blockade was associated with more efficient and sustained decongestion at day 90 and a lower risk of the primary endpoint. [ABSTRACT FROM AUTHOR]

Liver biopsies are a critical component of pivotal studies in non-alcoholic steatohepatitis (NASH), constituting inclusion criteria, risk stratification factors and endpoints. We evaluated the reliability of NASH Clinical Research Network scoring of liver biopsies in a NASH clinical trial. Digitized slides of 678 biopsies from 339 patients with paired biopsies randomized into the EMMINENCE study – examining a novel insulin sensitizer (MSDC-0602K) in NASH – were read independently by 3 hepatopathologists blinded to treatment code and scored using the NASH CRN histological scoring system. Various endpoints were computed from these scores. Inter-reader linearly weighted kappas were 0.609, 0.484, 0.328, and 0.517 for steatosis, fibrosis, lobular inflammation, and ballooning, respectively. Inter-reader unweighted kappas were 0.400 for the diagnosis of NASH, 0.396 for NASH resolution without worsening fibrosis, and 0.366 for fibrosis improvement without worsening NASH. In the current study, 46.3% of the patients included in the study based on 1 hepatopathologist's qualifying reading were deemed not to meet the study's histologic inclusion criteria by at least 1 of the 3 hepatopathologists. The MSDC-0602K treatment effect was lowest for those histologic features with lower inter-reader reliability. Simulations show that the lack of reliability of endpoints and inclusion criteria can drastically reduce study power – from >90% in a well-powered study to as low as 40%. The reliability of hepatopathologists' liver biopsy evaluation using currently accepted criteria is suboptimal. This lack of reliability may affect NASH pivotal studies by introducing patients who do not meet NASH study entry criteria, misclassifying fibrosis subgroups, and attenuating apparent treatment effects. Since liver biopsy analysis plays such an important role in clinical studies of non-alcoholic steatohepatitis, it is important to understand the reliability of hepato-pathologist readings. We examined both inter- and intra-reader variability in a large data set of paired liver biopsies from a clinical trial. We found very poor inter-reader and modest intra-reader variability. This result has important implications for entry criteria, fibrosis stratification, and the ability to measure a treatment effect in clinical trials. • Liver biopsy is a critical inclusion criteria and outcome measure in NASH studies. • Reader variability was tested in 678 biopsies from a NASH study of MSDC-0602K. • Kappas were poor for the diagnosis of NASH, its resolution and fibrosis improvement. • Almost half of the patients would have been excluded from entry by 1 of the readers. • Poor reliability allows improper entry, misclassification, and diminishes treatment effect. [ABSTRACT FROM AUTHOR]

Background: Acute heart failure (AHF) remains a major public health burden with a high prevalence and poor prognosis. Relaxin is a naturally occurring peptide hormone that increases cardiac output, arterial compliance, and renal blood flow during pregnancy. The RELAX-AHF-1 study will evaluate the effect of RLX030 (recombinant form of human relaxin 2) on symptom relief and clinical outcomes in patients with AHF. Methods: The protocol includes a completed phase 2 234-patient dose-finding study (Pre-RELAX-AHF) and an ongoing phase 3 1,160-patient trial (RELAX-AHF-1). Patients with AHF and systolic blood pressure >125 mm Hg are randomized within 16 hours of presentation to a 48-hour IV infusion of RLX030 or placebo. The 30 μg/kg per day dose of RLX030 was chosen for RELAX-AHF-1 based on effects on dyspnea, clinical outcomes, and safety observed in Pre-RELAX-AHF. Primary efficacy end points in RELAX-AHF-1 are (1) the area under the curve of change of the dyspnea Visual Analog Scale from baseline through day 5 and (2) whether the patient reports moderately to markedly better dyspnea at 6, 12, and 24 hours. Secondary efficacy end points include days alive and out of the hospital through day 60 and cardiovascular death or rehospitalization for heart failure or renal failure through day 60. Patients will be followed up through day 180 for mortality. As of September 19, 2011, 978 patients have been enrolled. Conclusions: Pre-RELAX-AHF results suggested that infusion of RLX030 may accelerate dyspnea relief and improve prognosis in patients hospitalized with AHF. RELAX-AHF-1 will further evaluate these effects. [ABSTRACT FROM AUTHOR]