Sadiya S. Khan

Clinical course and predictive value of congestion during hospitalization in patients admitted for worsening signs and symptoms of heart failure with reduced ejection fraction: Findings from the EVEREST trial

AIMS Signs and symptoms of congestion are the most common cause for hospitalization for heart failure (HHF). The clinical course and prognostic value of congestion during HHF has not been systemically characterized. METHODS AND RESULTS A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 h of admission (median ~24 h) for worsening HF with an EF ≤ 40% and two or more signs or symptoms of fluid overload [dyspnoea, oedema, or jugular venous distension (JVD)] for a median follow-up of 9.9 months. Clinician-investigators assessed patients daily for dyspnoea, orthopnoea, fatigue, rales, pedal oedema, and JVD and rated signs and symptoms on a standardized 4-point scale ranging from 0 to 3. A modified composite congestion score (CCS) was calculated by summing the individual scores for orthopnoea, JVD, and pedal oedema. Endpoints were HHF, all-cause mortality (ACM), and ACM + HHF. Multivariable Cox regression models were used to evaluate the risk of CCS at discharge on outcomes at 30 days and for the entire follow-up period. The mean CCS obtained after initial therapy decreased from the mean ± SD of 4.07 ± 1.84 and the median (25th, 75th) of 4 (3, 5) at baseline to 1.11 ± 1.42 and 1 (0, 2) at discharge. At discharge, nearly three-quarters of study participants had a CCS of 0 or 1 and fewer than 10% of patients had a CCS >3. B-type natriuretic peptide (BNP) and amino terminal-proBNP, respectively, decreased from 734 (313, 1523) pg/mL and 4857 (2251, 9642) pg/mL at baseline to 477 (199, 1079) pg/mL, and 2834 (1218, 6075) pg/mL at discharge/Day 7. A CCS at discharge was associated with increased risk (HR/point CCS, 95% CI) for a subset of endpoints at 30 days (HHF: 1.06, 0.95-1.19; ACM: 1.34, 1.14-1.58; and ACM + HHF: 1.13, 1.03-1.25) and all outcomes for the overall study period (HHF: 1.07, 1.01-1.14; ACM: 1.16, 1.09-1.24; and ACM + HHF 1.11, 1.06-1.17). Patients with a CCS of 0 at discharge experienced HHF of 26.2% and ACM of 19.1% during the follow-up. CONCLUSION Among patients admitted for worsening signs and symptoms of HF and reduced EF, congestion improves substantially during hospitalization in response to standard therapy alone. However, patients with absent or minimal resting signs and symptoms at discharge still experienced a high mortality and readmission rate.

Clinical Trials of Pharmacological Therapies in Acute Heart Failure Syndromes Lessons Learned and Directions Forward

Acute heart failure syndromes (AHFS) are characterized by a gradual or rapid onset of new or worsening signs and/or symptoms of heart failure (HF) requiring urgent therapy, usually resulting in hospitalization.1,2 The societal burden of AHFS is substantial, with >1 million hospitalizations annually in the United States and similar relative numbers in Europe.2–6 Ongoing epidemiological trends, such as the aging population, improved survival after myocardial infarction, and a decrease in sudden death due to defibrillator therapy, suggest that the prevalence of chronic HF resulting in hospitalization will continue to increase during the coming decades.7 The prognosis after hospitalization for AHFS remains bleak, with rates of death or recurrent hospitalization at 6 months approaching 50%,8–10 outcomes that have changed little in recent years despite improvements in the management of chronic HF.11 Hidden within these oft-cited statistics is a notable paradox—signs and symptoms of AHFS (dyspnea, edema, etc) are successfully treated in the majority of patients, but postdischarge outcomes remain dismal, and attempts to develop new short-term therapies for AHFS have largely been unsuccessful. Since our initial publication in 2005,1 4 large, international phase III development programs—tezosentan,12 levosimendan,13 tolvaptan,14 and rolofylline15—have failed to convincingly demonstrate the safety and efficacy of these agents in AHFS. Even for drugs approved for AHFS treatment (milrinone and nesiritide in the United States and levosimendan in parts of Europe), there have been persistent concerns about safety.16–18 Broadly speaking, the pharmacological armamentarium for AHFS—loop diuretics, vasodilators, and inotropes—is largely unchanged from the 1970s.19 Although substantial efforts in the last decade to develop improved AHFS therapies have yielded disappointing results, we believe that as a scientific community, we are now better equipped to conduct future studies. Hospitalization for AHFS is now recognized as a critical clinical …

Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial

Abnormal liver function tests (LFTs) are common in ambulatory heart failure (HF). The aim of this study was to characterize abnormal LFTs during index hospitalization.

Impact of diabetes on epidemiology, treatment, and outcomes of patients with heart failure

The prevalence of patients with concomitant heart failure (HF) and diabetes mellitus (DM) continues to increase with the general aging of the population. In patients with chronic HF, prevalence of DM is 24% compared with 40% in those hospitalized with worsening HF. Patients with concomitant HF and DM have diverse pathophysiologic, metabolic, and neurohormonal abnormalities that potentially contribute to worse outcomes than those without comorbid DM. In addition, although stable HF outpatients with DM show responses that are similar to those of patients without DM undergoing evidence-based therapies, it is unclear whether hospitalized HF patients with DM will respond similarly to novel investigational therapies. These data support the need to re-evaluate the epidemiology, pathophysiology, and therapy of HF patients with concomitant DM. This paper discusses the role of DM in HF patients and underscores the potential need for the development of targeted therapies.

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.

Toward engineering a human neoendothelium with circulating progenitor cells.

Tissue‐engineered vascular grafts may one day provide a solution to many of the limitations associated with using synthetic vascular grafts. However, identifying a suitable cell source and polymer scaffold to recreate the properties of a native blood vessel remains a challenge. In this work, we assess the feasibility of using endothelial progenitor cells (EPCs) found in circulating blood to generate a functional endothelium on poly(1,8‐octanediol‐co‐citrate) (POC), a biodegradable elastomeric polyester. EPCs were isolated from human blood and biochemically differentiated into endothelial‐like cells (HE‐like) in vitro. The differentiated cell phenotype and function was confirmed by the appearance of the characteristic endothelial cell (EC) cobblestone morphology and positive staining for EC markers, von Willebrand factor, vascular endothelial cadherin, flk‐1, and CD31. In addition, HE‐like cells cultured on POC express endothelial nitric oxide synthase at levels comparable to aortic ECs. Furthermore, as with mature endothelial cells, HE‐like cell populations show negligible expression of tissue factor. Similarly, HE‐like cells produce and secrete prostacyclin and tissue plasminogen activator at levels comparable to venous and aortic ECs. When compared to fibroblast cells, HE‐like cells cultured on POC show a decrease in the rate of plasma and whole‐blood clot formation as well as a decrease in platelet adhesion. Finally, the data show that HE‐like cells can withstand physiological shear stress of 10 dynes/cm2 when cultured on POC‐modified expanded poly(tetrafluoroethylene) vascular grafts. Collectively, these data are the foundation for future clinical studies in the creation of an autologous endothelial cell‐seeded vascular graft. STEM CELLS 2010;28:318–328

Characterization of Porcine Circulating Progenitor Cells: Toward a Functional Endothelium

The lack of available healthy vessels, significant patient morbidity, and high costs hinders the successful clinical utilization of autologous endothelial cells (ECs). Herein we assess the feasibility of using endothelial progenitor cells (EPC) found in circulating blood to engineer a functional endothelium on poly(1,8-octanediol-co-citrate) (POC), a hemocompatible and biodegradable elastomer used in vascular tissue engineering. EPCs were isolated from porcine blood and biochemically differentiated into porcine endothelial (PE)-like cells in vitro. Once differentiated, EC phenotype and function on POC were assessed according to the presence of the EC-specific markers von Willebrand factor, platelet EC adhesion molecule, and vascular endothelial cadherin; metabolism of acetylated low-density lipoprotein; secretion of the anti-thrombogenic factors nitric oxide and prostacyclin; and inhibition of platelet adhesion and clotting processes in vitro. The effects of PE-like cells on porcine aortic smooth muscle cells (PASMCs) were also investigated via co-culture. PE-like cells on POC had phenotype, function, and clotting responses similar to those of primary aortic ECs. The presence of PE-like cells resulted in a 71 +/- 20% decrease in PASMC proliferation; a 52 +/- 2% decrease in the protein:deoxyribonucleic acid ratio; and an elongated, spindle-shaped morphology indicative of a shift from the proliferative to the contractile phenotype. These data suggest that EPCs and POC can provide the basis for a functional tissue-engineered endothelium.

EVEREST study: Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan

Acute heart failure syndromes are a common cause of emergency department visits and hospitalization in North America and Europe. Although in-hospital mortality is relatively low, the postdischarge mortality and rehospitalization rates can be as high as 10–15 and 30%, respectively, within 60–90 days following discharge. It appears that the main reason for admission and readmission for heart failure is related to congestion manifested by dyspnea, jugular venous distension and edema. Often, congestion is associated with dilutional hyponatremia that is difficult to treat. Hyponatremia is an important predictor of increased mortality and the available therapies to treat congestion and/or hyponatremia are often ineffective and/or unsafe. Accordingly, there is an unmet need to develop a new agent that effectively relieves congestion due to high filling pressure without worsening renal function and improving or normalizing serum sodium in hyponatremic patients. This paper provides an overview of a new compound, tolvaptan, an oral selective V2-vasopressin antagonist in light of the recently published Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. The biochemical and pharmacological properties are discussed in conjunction with its clinical efficacy and safety, exploring the potential role of tolvaptan in the management of acute heart failure syndromes presenting with or without hyponatremia.

Effects of tolvaptan on physician-assessed symptoms and signs in patients hospitalized with acute heart failure syndromes: Analysis from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) Trials

BACKGROUND A rapid and sustained relief of heart failure (HF) symptoms and signs is an important goal of management in patients hospitalized for acute HF syndromes (AHFS). To date, no novel therapy in AHFS have been shown to improve signs and symptoms throughout hospitalization. This study explores the clinical effects of tolvaptan, a vasopressin-2-receptor antagonist, in addition to standard medical therapies on physician-assessed signs and symptoms in hospitalized AHFS patients. METHODS The EVEREST trial randomized 4,133 patients admitted with worsening HF and reduced ejection fraction (≤ 40%) within 48 hours after hospital admission. On each inpatient day, investigators assessed dyspnea, orthopnea, fatigue, jugular venous distension (JVD), rales, and pedal edema by predefined ordinal scales. Responder analyses were performed for each sign and symptom, with significant clinical response defined as a change in one point on the measurement scale. RESULTS Post hoc analysis demonstrated greater likelihood of clinical improvement in physician-assessed dyspnea, edema, orthopnea, and JVD among tolvaptan-treated subjects (P < .05) as early as inpatient day 1. This difference was observed throughout hospitalization only for JVD and orthopnea through day 3. CONCLUSION The addition of tolvaptan to standard therapy for AHFS improves physician-assessed signs and symptoms during hospitalization without serious adverse short- or long-term effects.

Management of comorbid diabetes mellitus and worsening heart failure.

Type 2 diabetes mellitus affects 25.8 million adults in the United States and accounts for attributable health care costs exceeding