G.M. Felker

Effect of Nesiritide in Patients with Acute Decompensated Heart Failure

BACKGROUND Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Prospective assessment of the occurrence of anemia in patients with heart failure: Results from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) Registry

BACKGROUND Although a potentially important pathophysiologic factor in heart failure, the prevalence and predictors of anemia have not been well studied in unselected patients with heart failure. METHODS The Study of Anemia in a Heart Failure Population (STAMINA-HFP) Registry prospectively studied the prevalence of anemia and the relationship of hemoglobin to health-related quality of life and outcomes among patients with heart failure. A random selection algorithm was used to reduce bias during enrollment of patients seen in specialty clinics or clinics of community cardiologists with experience in heart failure. In this initial report, data on prevalence and correlates of anemia were analyzed in 1,076 of the 1,082 registry patients who had clinical characteristics and hemoglobin determined by finger-stick at baseline. RESULTS Overall (n = 1,082), the registry patients were 41% female and 73% white with a mean age (+/-SD) of 64 +/- 14 years (68 +/- 13 years in community and 57 +/- 14 years in specialty sites, P < .001). Among the 1,076 patients in the prevalence analysis, mean hemoglobin was 13.3 +/- 2.1 g/dL (median 13.2 g/dL); and anemia (defined by World Health Organization criteria) was present in 34%. Age identified patients at risk for anemia, with 40% of patients >70 years affected. CONCLUSIONS Initial results from the STAMINA-HFP Registry suggest that anemia is a common comorbidity in unselected outpatients with heart failure. Given the strong association of anemia with adverse outcomes in heart failure, this study supports further investigation concerning the importance of anemia as a therapeutic target in this condition.

Prospective evaluation of the association between hemoglobin concentration and quality of life in patients with heart failure

BACKGROUND Reduced hemoglobin has been associated with adverse outcomes in heart failure, but the relationship of hemoglobin to health-related quality of life in outpatients with this syndrome has not been well studied. METHODS We used data from the prospective, observational Study of Anemia in a Heart Failure Population Registry, which randomly selected outpatients with heart failure from specialty or community cardiology clinics. Hemoglobin was determined by finger stick at baseline and during medically indicated follow-up visits. Health-related quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire and the Minnesota Living with Heart Failure Questionnaire at 3-month intervals for 12 months. RESULTS Adjusted regression analysis demonstrated a significant, direct, linear relationship between hemoglobin and health-related quality of life from baseline through 12 months follow-up on all Kansas City Cardiomyopathy Questionnaire domains (all P < .001) and the Summary and Physical domains of the Minnesota Living with Heart Failure Questionnaire (all P < .05). Adjusted categorical analysis of the change in Kansas City Cardiomyopathy Questionnaire Clinical scores associated with change in hemoglobin from baseline to 6 months also showed a significant relationship between increasing hemoglobin and improved health status (5.9 +/- 1.8 units for a hemoglobin increase of >or=1 g/dL, 0.7 +/- 1.2 units for change in hemoglobin <1 g/dL, and -2.6 +/- 1.4 units for a >or=1 g/dL decrease in hemoglobin, P < .001). CONCLUSIONS These prospective, observational results indicate that reduced hemoglobin is associated with poorer quality of life in patients with heart failure. Additional studies will be required to establish if this is a cause-and-effect relationship.

Prevalence of AAV1 neutralizing antibodies and consequences for a clinical trial of gene transfer for advanced heart failure

Adeno-associated virus serotype 1 (AAV1) has many advantages as a gene therapy vector, but the presence of pre-existing neutralizing antibodies (NAbs) is an important limitation. This study was designed to determine: (1) characteristics of AAV NAbs in human subjects, (2) prevalence of AAV1 NAbs in heart failure patients and (3) utility of aggressive immunosuppressive therapy in reducing NAb seroconversion in an animal model. NAb titers were assessed in a cohort of heart failure patients and in patients screened for a clinical trial of gene therapy with AAV1 carrying the sarcoplasmic reticulum calcium ATPase gene (AAV1/SERCA2a). AAV1 NAbs were found in 59.5% of 1552 heart failure patients. NAb prevalence increased with age (P=0.001) and varied geographically. The pattern of NAb titers suggested that exposure is against AAV2, with AAV1 NAb seropositivity due to crossreactivity. The effects of immunosuppression on NAb formation were tested in mini-pigs treated with immunosuppressant therapy before, during and after a single AAV1/SERCA2a infusion. Aggressive immunosuppression did not prevent formation of AAV1 NAbs. We conclude that immunosuppression is unlikely to be a viable solution for repeat AAV1 dosing. Strategies to reduce NAbs in heart failure patients are needed to increase eligibility for gene transfer using AAV vectors.

Reduction in Body Weight but Worsening Renal Function with Late Ultrafiltration for Treatment of Acute Decompensated Heart Failure

Objectives: The safety, effectiveness and indications for ultrafiltration (UF) are not well established. We hypothesized that UF would not worsen renal function in patients with heart failure (HF) who were not responding to medical therapy. Methods: Data was collected for patients who underwent UF between 2006 and 2010 (n = 72, median age 61 years, 54% males, 61% Caucasian, 54% left ventricular ejection fraction ≥40%). Results: Baseline GFR was 38 ml/min/ 1.73 m2. All patients were initially treated with loop diuretics and 58% required a thiazide-like diuretic or vasoactive agent. UF resulted in total fluid removal of 11.3 liters and weight loss was 9.7 kg. The median decrease in eGFR during UF was 4.5 ml/min/m2 (IQR –13, 0; p <0.01) and 43% of patients experienced a ≥20% decrease in eGFR. Ten percent of patients required dialysis and 13% died, received a ventricular assist device/cardiac transplant or were discharged to hospice. Conclusions: In a cohort of HF patients who did not respond to medical therapy, UF was associated not only with a significant reduction of body weight and fluid removal, but also acute worsening of renal function. Further research to identify the appropriate population for UF, long-term outcomes and the intensity of treatment is required if UF is to gain wide acceptance for HF management.

Effects of serelaxin on the outcome of patients with or without substantial peripheral edema: A subgroup analysis from the RELAX-AHF trial

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.

Dysphagia in the setting of left ventricular assist device hemolysis.

A 69-year-old man with advanced heart failure treated with a continuous-flow left ventricular assist device presented for evaluation of dark urine and severe dysphagia. Because of evidence of ongoing intravascular hemolysis with device dysfunction, there was a clinical suspicion for pump thrombosis. He had progressive end-organ dysfunction and was therefore treated with tissue plasminogen activator with prompt resolution in hemolysis and dysphagia. Although symptoms of smooth muscle dystonia could represent worsening heart failure in the setting of device failure, the observation may also be related to intravascular hemolysis as described in the prototypic hemolytic disease, paroxysmal nocturnal hemoglobinuria.

Pulmonary Hypertension in the Era of Mechanical Circulatory Support.

Left heart disease (LHD) represents the most common cause of pulmonary hypertension (PH), and is associated with worse prognosis compared with LHD without PH. In addition, PH due to LHD may prevent patients from receiving heart transplantation, because of risk of perioperative right ventricular failure. Current literature lacks comprehensive descriptions and management strategies of PH due to LHD. In this review, we summarize the literature that is available to highlight the definition, pathogenesis, and prognosis of PH due to LHD. Furthermore, we discuss the use of mechanical circulatory support (MCS) in this population. Finally, we provide recommendations regarding the management and reassessment of PH due to LHD in the specific context of MCS.

Liraglutide and weight loss among patients with advanced heart failure and a reduced ejection fraction: insights from the FIGHT trial: Liraglutide and weight loss among patients with advanced HF and a HFrEF

Obesity is present in up to 45% of patients with heart failure (HF). Liraglutide, a glucagon‐like peptide‐1 (GLP‐1) receptor antagonist, facilitates weight loss in obese patients. The efficacy of liraglutide as a weight loss agent among patients with HF and reduced ejection fraction (HFrEF) and a recent acute HF hospitalization remains unknown.

Successful Organ Donation After Long‐Term Circulatory Support With Nonpulsatile Mechanical Support

To the Editor: In cardiac transplantation, eligible patients are “bridged” using mechanical circulatory support (MCS) systems until a cardiac allograft becomes available. Contemporary MCS devices sustain systemic circulation by a continuous flow (CF) mechanism that generates nonphysiological, nonpulsatile flow to vital organs (1–3). We present an unconventional case of orthotopic liver transplantation (OLT) from a patient with end-stage heart failure being treated with a nonpulsatile MCS device. A 56-year-old man with end-stage nonischemic cardiomyopathywasmanagedwithaCFleftventricularassistdevice (LVAD). The LVAD (HeartMate II, Thoratec Inc., Pleasanton, CA, USA) was implanted 22 months earlier as a bridge to cardiac transplantation. MCS resulted in progressive improvement in his exercise tolerance, quality of life and end-organ function. However, the patient had been hospitalized repeatedly for refractory intravascular hemolysis related to thrombus contained within the LVAD. After failing multiple other pharmacological therapies, he was readmitted to hospital, treated with intravenous heparin and listed for emergent cardiac transplantation (UNOS status 1A). While awaiting a suitable allograft the patient became acutely unresponsive, computed tomography of the brain revealed a large left frontal intraparenchymal hemorrhage with tonsillar herniation. Neurosurgical intervention was deemed unlikely to reverse the injury, thus, the local organ procurement organization was contacted at the family’s request. Brain death was confirmed and the patient was considered a suitable donor for a patient listed for OLT. He was taken to the operating room where his liver was inspected (intraoperative biopsy revealed minimal steatosis) and subsequently procured. When the donor hepatic artery was anastomosed to the recipient’s hepatic vasculature there was minimal pulsatility following reperfusion. After a new anastomosis was fashioned and papaverine-soaked gelfoam was placed around this vessel, pulsatility improved and the arterial conduit enlarged. The remainder of the surgery was unremarkable and total ischemic time was less than