John E.A. Blair

Assessing and grading congestion in acute heart failure: a scientific statement from the Acute Heart Failure Committee of the Heart Failure Association of the European Society of Cardiology and endorsed by the European Society of Intensive Care Medicine

Patients with acute heart failure (AHF) require urgent in‐hospital treatment for relief of symptoms. The main reason for hospitalization is congestion, rather than low cardiac output. Although congestion is associated with a poor prognosis, many patients are discharged with persistent signs and symptoms of congestion and/or a high left ventricular filling pressure. Available data suggest that a pre‐discharge clinical assessment of congestion is often not performed, and even when it is performed, it is not done systematically because no method to assess congestion prior to discharge has been validated. Grading congestion would be helpful for initiating and following response to therapy. We have reviewed a variety of strategies to assess congestion which should be considered in the care of patients admitted with HF. We propose a combination of available measurements of congestion. Key elements in the measurement of congestion include bedside assessment, laboratory analysis, and dynamic manoeuvres. These strategies expand by suggesting a routine assessment of congestion and a pre‐discharge scoring system. A point system is used to quantify the degree of congestion. This score offers a new instrument to direct both current and investigational therapies designed to optimize volume status during and after hospitalization. In conclusion, this document reviews the available methods of evaluating congestion, provides suggestions on how to properly perform these measurements, and proposes a method to quantify the amount of congestion present.

Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: Results from efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan (EVEREST) program

BACKGROUND The postdischarge rehospitalization and death rates are high in patients with acute heart failure (HF) syndromes despite optimization of standard therapy for chronic HF. To the best of our knowledge, there has been no systematic analysis of the causes of death and rehospitalization in this patient population. METHODS This was a prespecified analysis of adjudicated cause-specific all-cause mortality and cardiovascular (CV) hospitalization in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, a randomized, double-blind, placebo-controlled study in patients hospitalized with worsening HF and left ventricular ejection fraction < or =40% comparing tolvaptan, an oral vasopressin receptor antagonist to placebo, in addition to standard care. RESULTS Of the 4,133 randomized, there were 5,239 rehospitalizations and 1,080 deaths during a median of 9.9 months. Of all deaths, 41.0% were due to HF, 26.0% due to sudden cardiac death (SCD), 2.6% due to acute myocardial infarction (MI), 2.2% due to stroke, and 13.2% due to non-CV causes. Of all hospitalizations, 39.2% were non-CV, whereas 46.3% were for HF, and a minority of hospitalizations was due to stroke, MI, arrhythmia, or other CV causes. CONCLUSIONS Despite close follow-up and evidence-based therapy within a clinical trial, rehospitalization and death remain high. Although most deaths were from HF, one quarter of patients had SCD. In addition, there were almost as many non-CV hospitalizations as HF hospitalizations. Knowledge of the causes of death and rehospitalization may be essential for proper management and early initiation of therapy.

Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program.

OBJECTIVES Our aim was to examine continental and regional differences in baseline characteristics and post-discharge clinical outcomes in the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) trial. BACKGROUND Continental and regional differences in clinical trials of acute heart failure syndromes (AHFS) have not been well studied. METHODS We analyzed data from the EVEREST trial, which randomized 4,133 patients hospitalized for worsening (HF) and left ventricular ejection fraction < or =40% to oral tolvaptan, a vasopressin antagonist, or placebo and followed for a median of 9.9 months. Baseline characteristics, mortality, and outcomes were analyzed across North America (n = 1,251), South America (n = 688), Western Europe (564 patients), and Eastern Europe (n = 1,619). RESULTS There were major differences between the 4 groups in the severity, etiology, and management of HF. Unadjusted 1-year mortality and cardiovascular mortality/HF hospitalization were 30.4% and 52.5% in North America, 27.2% and 41.6% in South America, 27.1% and 47.3% in Western Europe, and 20.5% and 35.3% in Eastern Europe. After adjustment, South American patients had the highest overall mortality (hazard ratio: 1.42, 95% confidence interval: 1.15 to 1.76), while Eastern European patients had the lowest cardiovascular death and HF hospitalization rate (hazard ratio: 0.84, 95% confidence interval: 0.73 to 0.97), compared with patients in North America. CONCLUSIONS Major continental and regional differences in HF severity, etiology, and management exist among AHFS patients, resulting in varied post-discharge outcomes, despite pre-defined selection criteria. These differences should be taken into account when planning global trials in AHFS. (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan [EVEREST]; NCT00071331).

Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: A Randomized Controlled Trial in Patients Hospitalized With Heart Failure

OBJECTIVES We examined the hemodynamic, echocardiographic, and neurohormonal effects of intravenous istaroxime in patients hospitalized with heart failure (HF). BACKGROUND Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase. METHODS One hundred twenty patients admitted with HF and reduced systolic function were instrumented with a pulmonary artery catheter within 48 h of admission. Three sequential cohorts of 40 patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 microg/kg/min, the second 1.0 microg/kg/min, and the third 1.5 microg/kg/min istaroxime or placebo. RESULTS All doses of istaroxime lowered pulmonary capillary wedge pressure (PCWP), the primary end point (mean +/- SD: -3.2 +/- 6.8 mm Hg, -3.3 +/- 5.5 mm Hg, and -4.7 +/- 5.9 mm Hg compared with 0.0 +/- 3.6 mm Hg with placebo; p < 0.05 for all doses). Istaroxime significantly decreased heart rate (HR) and increased systolic blood pressure (SBP). Cardiac index increased and left ventricular end-diastolic volume decreased significantly only with 1.5 microg/kg/min. On echocardiography, left ventricular end diastolic volume and deceleration time improved with 1.5 microg/kg/min. There were no changes in neurohormones, renal function, or troponin I. Adverse events were not life threatening and were dose related. CONCLUSIONS In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available inotropes, istaroxime increased SBP and decreased HR. (A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function [HORIZON-HF]; NCT00616161).

Handcarried Ultrasound Measurement of the Inferior Vena Cava for Assessment of Intravascular Volume Status in the Outpatient Hemodialysis Clinic

Accurate intravascular volume assessment is critical in the treatment of patients who receive chronic hemodialysis (HD) therapy. Clinically assessed dry weight is a poor surrogate of intravascular volume; however, ultrasound assessment of the inferior vena cava (IVC) is an effective tool for volume management. This study sought to determine the feasibility of using operators with limited ultrasound experience to assess IVC dimensions using hand-carried ultrasounds (HCU) in the outpatient clinical setting. The IVC was assessed in 89 consecutive patients at two outpatient clinics before and after HD. Intradialytic IVC was recorded during episodes of hypotension, chest pain, or cramping. High-quality IVC images were obtained in 79 of 89 patients. Despite that 89% of patients presented at or above dry weight, 39% of these patients were hypovolemic by HCU. Of the 75% of patients who left HD at or below goal weight, 10% were still hypervolemic by HCU standards. Hypovolemic patients had more episodes of chest pain and cramping (33 versus 14%, P = 0.06) and more episodes of hypotension (22 versus 3%, P = 0.02). The clinic with a higher prevalence of predialysis hypovolemia had significantly more intradialytic adverse events (58 versus 27%; P = 0.01). HCU measurement of the IVC is a feasible option for rapid assessment of intravascular volume status in an outpatient dialysis setting by operators with limited formal training in echocardiography. There is a poor relationship between dry weight goals and IVC collapsibility. Practice variation in the maintenance of volume status is correlated with significant differences in intradialysis adverse events.

Changes in renal function during hospitalization and soon after discharge in patients admitted for worsening heart failure in the placebo group of the EVEREST trial

AIM To provide an in-depth clinical characterization and analysis of outcomes of the patients hospitalized for heart failure (HF) who subsequently develop worsening renal function (WRF) during hospitalization or soon after discharge. METHODS AND RESULTS Of the 4133 patients hospitalized with worsening HF and reduced left ventricular ejection fraction (LVEF) (≤40%) in the EVEREST trial, 2072 were randomized to tolvaptan, a selective vasopressin-2 receptor antagonist, and 2061 were randomized to placebo, both in addition to standard therapy. This analysis included the 2021 (98%) patients in the placebo group with a complete set of renal function parameters. Renal function parameters and clinical variables were measured prospectively during hospitalization and after discharge. Worsening renal function was defined as an increase in sCr ≥0.3 mg/dL during the in-hospital (randomization to discharge or Day 7) and post-discharge (discharge or Day 7 to 4 weeks post-discharge) periods. Blood pressure (BP), body weight (BW), natriuretic peptides (NPs), and congestion score were correlated with WRF. The prognostic value of baseline renal function at admission and WRF during hospitalization and post-discharge on long-term outcomes were assessed using a Cox proportional hazards model adjusted for other baseline covariates. At randomization, 53.2% of patients had moderately or severely reduced estimated glomerular filtration rate (eGFR) (<60.0 mL/min/1.73 m2). Worsening renal function was observed in 13.8% in-hospital and 11.9% post-discharge. Worsening renal function during hospitalization and post-discharge was associated with greater reductions in BP, BW, and NPs. Baseline renal dysfunction as well as in-hospital and post-discharge WRF were predictive of a composite endpoint of cardiovascular (CV) mortality/HF rehospitalization. CONCLUSION The prevalence of renal dysfunction is high in patients hospitalized for HF with reduced LVEF. Worsening renal function may occur not only during hospitalization, but also in the early post-discharge period. Since worsening renal function during hospitalization is associated with a significant decrease in signs and symptoms of congestion, body weight and natriuretic peptides, which are good prognostic indicators, worsening renal function during hospitalization as an endpoint in clinical trials should be re-evaluated.

Weight changes after hospitalization for worsening heart failure and subsequent re-hospitalization and mortality in the EVEREST trial

AIMS Increases in body weight (BW) are important determinants for hospitalization in ambulatory patients with heart failure (HF), but have not yet been explored in patients hospitalized for worsening HF. We explore the relationship between change in BW after hospitalization for worsening HF and risk for repeat hospitalization and mortality in the EVEREST trial. METHODS AND RESULTS The EVEREST trial randomized 4133 patients hospitalized for worsening HF and low ejection fraction (< or =40%) to tolvaptan, a vasopressin antagonist, or placebo. Following discharge, BW was assessed at 1, 4, and 8 weeks, and every 8 weeks thereafter. A time-dependent Cox proportional Hazard model explored the relationship between change in BW at 60, 120, and 180 days from discharge and the risks of HF hospitalization, cardiovascular (CV) hospitalization, and all-cause mortality. For subjects re-hospitalized for heart failure at 60, 120, and 180 days after discharge, mean BW increase prior to the event was 1.96, 2.07, and 1.97 kg, respectively, compared with 0.74, 0.90, and 1.04 kg in patients without re-hospitalization (P < 0.001 all groups). A similar pattern was observed with CV hospitalization. However, increases in BW were not predictive of all-cause mortality. CONCLUSION Increases in BW after hospitalization for worsening HF was predictive of repeat hospitalization events, but not mortality in the post-discharge period.

Usefulness of hand-carried ultrasound to predict elevated left ventricular filling pressure.

Detection of increased left ventricular filling pressure (LVFP) is paramount in the evaluation and treatment of patients with left heart failure, yet difficult to assess directly at the bedside. Although inferior vena cava (IVC) examination can detect increased right atrial pressure, a used surrogate for high LVFP, this assumption has not been directly tested. We evaluated whether assessment of IVC size and respirophasic variation could be used to predict increased LVFP. Seventy-two patients with chronic heart failure underwent right heart catheterization and limited echocardiographic examination focused on the IVC. IVC size and collapsibility were evaluated for their ability to predict a wedge pressure>or=15 mm Hg. In conclusion, an IVC maximum dimension of 2.0 cm and IVC collapsibility of 45% were the optimal cutoffs to predict an increased pulmonary capillary wedge pressure, with sensitivities of 75% and 83% and specificities of 83% and 71%, respectively.

Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na–K-ATPase inhibition: a new promising treatment for acute heart failure syndromes?

Acute heart failure syndromes (AHFS) are associated with the rapid onset of heart failure (HF) signs and symptoms. Hospitalizations for AHFS continue to rise and are associated with significant mortality and morbidity. Several pharmacological agents are currently approved for the treatment of AHFS, but their use is associated with an increase in short-term mortality. There is a need for new agents that can be given in the acute setting with increased efficacy and safety. Istaroxime is a unique agent with both inotropic and lusitropic properties which is currently being studied for the treatment of AHFS. Istaroxime inhibits the sodium–potassium adenosine triphosphatase (ATPase) and stimulates the sarcoplasmic reticulum calcium ATPase isoform 2 (SERCA-2) thereby improving contractility and diastolic relaxation. Early data from human studies reveal that istaroxime decreases pulmonary capillary wedge pressure (PCWP) and possibly improves diastolic function without causing a significant change in heart rate (HR), blood pressure, ischemic or arrhythmic events. Most commonly reported side effects were related to gastrointestinal intolerance and were dose related. In conclusion, istaroxime is a novel agent being investigated for the treatment of AHFS whose mechanism of action and cellular targets make it a promising therapy. Further studies with longer infusion times in patients with hypotension are required to confirm its efficacy and safety.

Heart Failure in North America

Heart failure is a major health problem that affects patients and healthcare systems worldwide. Within the continent of North America, differences in economic development, genetic susceptibility, cultural practices, and trends in risk factors and treatment all contribute to both inter-continental and within-continent differences in heart failure. The United States and Canada represent industrialized countries with similar culture, geography, and advanced economies and infrastructure. During the epidemiologic transition from rural to industrial in countries such as the United States and Canada, nutritional deficiencies and infectious diseases made way for degenerative diseases such as cardiovascular diseases, cancer, overweight/obesity, and diabetes. This in turn has resulted in an increase in heart failure incidence in these countries, especially as overall life expectancy increases. Mexico, on the other hand, has a less developed economy and infrastructure, and has a wide distribution in the level of urbanization as it becomes more industrialized. Mexico is under a period of epidemiologic transition and the etiology and incidence of heart failure is rapidly changing. Ethnic differences within the populations of the United States and Canada highlight the changing demographics of each country as well as potential disparities in heart failure care. Heart failure with preserved ejection fraction makes up approximately half of all hospital admissions throughout North America; however, important differences in demographics and etiology exist between countries. Similarly, acute heart failure etiology, severity, and management differ between countries in North America. The overall economic burden of heart failure continues to be large and growing worldwide, with each country managing this burden differently. Understanding the inter-and within-continental differences may help improve understanding of the heart failure epidemic, and may aid healthcare systems in delivering better heart failure prevention and treatment.