Current treatment practice and outcomes. Report of the hyponatremia registry.

Current management practices for hyponatremia (HN) are incompletely understood. The HN Registry has recorded diagnostic measures, utilization, efficacy, and outcomes of therapy for eu- or hypervolemic HN. To better understand current practices, we analyzed data from 3087 adjudicated adult patients in the registry with serum sodium concentration of 130 mEq/l or less from 225 sites in the United States and European Union. Common initial monotherapy treatments were fluid restriction (35%), administration of isotonic (15%) or hypertonic saline (2%), and tolvaptan (5%); 17% received no active agent. Median (interquartile range) mEq/l serum sodium increases during the first day were as follows: no treatment, 1.0 (0.0-4.0); fluid restriction, 2.0 (0.0-4.0); isotonic saline, 3.0 (0.0-5.0); hypertonic saline, 5.0 (1.0-9.0); and tolvaptan, 4.0 (2.0-9.0). Adjusting for initial serum sodium concentration with logistic regression, the relative likelihoods for correction by 5 mEq/l or more (referent, fluid restriction) were 1.60 for hypertonic saline and 2.55 for tolvaptan. At discharge, serum sodium concentration was under 135 mEq/l in 78% of patients and 130 mEq/l or less in 49%. Overly rapid correction occurred in 7.9%. Thus, initial HN treatment often uses maneuvers of limited efficacy. Despite an association with poor outcomes and availability of effective therapy, most patients with HN are discharged from hospital still hyponatremic. Studies to assess short- and long-term benefits of correction of HN with effective therapies are needed.

Prospective evaluation of the association between cardiac troponin T and markers of disturbed erythropoiesis in patients with heart failure.

BACKGROUND: Elevated cardiac troponin T is a well-documented marker of cardiomyocyte damage and poor prognosis in patients with heart failure. We prospectively evaluated the relationship between this marker and hematopoietic disturbances in heart failure. METHODS: Data were analyzed from 254 patients in the UNITE-HF Biomarker Registry, a prospective, observational, multicenter study of the clinical and biomarker correlates of anemia in heart failure. Logistic regression modeling assessed relationships between detectable troponin T and indices of hematologic function including anemia and red cell distribution width. RESULTS: Anemia (hemoglobin≤12 g/dL) was present in 65 of the 254 study patients, and detectable troponin T was found in 39. Anemia was a significant independent predictor of detectable troponin T in models that considered a number of clinical characteristics including renal function, functional class, heart rate, and systolic blood pressure (odds ratio 2.57, 95% CI 1.09-6.09, P=.032). Likewise, detectable troponin T was directly and independently related to red cell distribution width in similar multivariable analyses (odds ratio 1.36 per unit increase, 95% CI 1.08-1.71, P=.008). CONCLUSIONS: Anemia and increasing red cell distribution width were independently associated with elevated troponin T, a marker of cardiomyocyte injury or death in patients with heart failure.

Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure.

BACKGROUND: Adverse outcomes have recently been linked to elevated red cell distribution width (RDW) in heart failure. Our study sought to validate the prognostic value of RDW in heart failure and to explore the potential mechanisms underlying this association. METHODS AND RESULTS: Data from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry, a prospective, multicenter cohort of ambulatory patients with heart failure supported multivariable modeling to assess relationships between RDW and outcomes. The association between RDW and iron metabolism, inflammation, and neurohormonal activation was studied in a separate cohort of heart failure patients from the United Investigators to Evaluate Heart Failure (UNITE-HF) Biomarker registry. RDW was independently predictive of outcome (for each 1% increase in RDW, hazard ratio for mortality 1.06, 95% CI 1.01-1.12; hazard ratio for hospitalization or mortality 1.06; 95% CI 1.02-1.10) after adjustment for other covariates. Increasing RDW correlated with decreasing hemoglobin, increasing interleukin-6, and impaired iron mobilization. CONCLUSIONS: Our results confirm previous observations that RDW is a strong, independent predictor of adverse outcome in chronic heart failure and suggest elevated RDW may indicate inflammatory stress and impaired iron mobilization. These findings encourage further research into the relationship between heart failure and the hematologic system.

Utility of natriuretic peptide testing in the evaluation and management of acute decompensated heart failure.

The B-type natriuretic peptide (BNP) and the amino-terminal fragment of proBNP (NT-proBNP) are increased in heart failure in proportion to severity of symptoms, degree of left ventricular dysfunction, and elevation of cardiac filling pressures. These natriuretic peptides (NPs) are increasingly used for diagnostic and prognostic purposes in acute heart failure. While NP levels on admission provide independent prognostic information, serial determinations during hospitalization and at discharge better reflect adequacy of treatment and prognosis. The addition of BNP and NT-proBNP to usual clinical decision making enhances detection of high-risk patients who need aggressive follow-up and adjustment of treatment.

Clinical applications of N-terminal pro B-type natriuretic peptide in heart failure and other cardiovascular diseases.

N-terminal fragment of pro B-type natriuretic peptide (NT-proBNP) has emerged as an important adjunct in the management of heart failure (HF) and other cardiovascular diseases. NT-proBNP is a 76-amino acid peptide created during cleavage of the precursor molecule, Pro B-type natriuretic peptide (ProBNP). NT-proBNP is of significant diagnostic value in patients presenting with possible HF and is an important prognostic factor in this condition and other cardiovascular diseases. Ongoing research supports the potential value of this biomarker in non-cardiovascular disease. This review will describe clinical applications of NT-proBNP in HF and a broad range of other conditions.

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.

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.

Does clinician's knowledge of B-type natriuretic peptide levels translate to improvement of quality of life and less hospitalization days in patients with heart failure?

This pilot study was conducted to determine whether clinicians' knowledge of b-type natriuretic peptide (BNP) levels in individuals with heart failure (HF) correlates with better outcomes including quality of life (QOL) and hospital length of stay (LOS) over a 90-day period. HF clinic patients were randomized into 2 groups: clinician aware (BNP group; n=50) or blinded to BNP levels (control group; n=42). BNP levels were measured at baseline using the BNP Immunoassay Kit. QOL was measured by the Minnesota Living with Heart Failure (MLWHF) questionnaire, and hospital LOS were measured at baseline and 90 days. There was no significant difference in BNP levels between groups. Compared with baseline scores (46.87+/-29.63), mean QOL scores at 90 days (37.46+/-28.67) were not significantly different for both groups. Hospital LOS was also similar for both groups (mean=3 days). BNP levels were significantly correlated with New York Heart Association classification (P=.05), ejection fraction (P=0.0001), creatinine levels (P=0.05), and overall Minnesota Living with Heart Failure Questionnaire scores (P=.01). Clinician's knowledge of BNP levels is not associated with better outcomes of QOL or hospital LOS in HF patients. However, BNP levels are correlated with functional status and physiological parameters. Further research is needed to determine whether other factors influence QOL and hospital LOS of HF patients.

Current Management of Hyponatremia in Acute Heart Failure: A Report From the Hyponatremia Registry for Patients With Euvolemic and Hypervolemic Hyponatremia (HN Registry).

BACKGROUND: Hyponatremia (HN) occurs commonly in patients with acute heart failure and confers a worse prognosis. Current HN treatment varies widely, with no consensus. This study recorded treatment practices currently used for patients hospitalized with acute heart failure and HN. METHODS AND RESULTS: Data were collected prospectively from 146 US sites on patients hospitalized with acute heart failure and HN (serum sodium concentration [Na+] ≤130 mEq/L) present at admission or developing in the hospital. Baseline variables, HN treatment, and laboratory values were recorded. Of 762 patients, median [Na+] was 126 mEq/L (interquartile range, 7) at baseline and increased to 130 mEq/L at discharge. Fluid restriction was the most commonly prescribed therapy (44%), followed by no specific HN treatment beyond therapy for congestion (23%), isotonic saline (5%), tolvaptan (4%), and hypertonic saline (2%). Median rate of change in [Na+] varied by treatment (0.5 [interquartile range, 1.0] to 2.3 [8.0] mEq/L/d) and median treatment duration ranged from 1 (interquartile range, 1) to 6 (5) days. Fluid restriction and no specific HN treatment resulted in similar changes in [Na+], and were least effective in correcting HN. Few patients (19%) had [Na+] ≥135 mEq/L at discharge. CONCLUSIONS: The most commonly used treatment approaches for HN (fluid restriction and no specific treatment) in acute heart failure increased [Na+] minimally, and most patients remained hyponatremic at discharge.

Agents that stabilise atherosclerotic plaque.

The concept of plaque stabilisation was developed to explain how medications could decrease adverse coronary events without a substantial reduction in the regression of atherosclerosis. With this concept, a comprehensive view of atherosclerosis is now appreciated. A number of imaging modalities are employed to study atherosclerosis; most identify luminal diameter or stenosis, wall thickness and plaque volume. A number of antiatherosclerotic agents have been studied as well to prove this hypothesis. However, the ultimate goal of medical treatment is to cure or prevent diseases caused by atherosclerosis.

Renin-angiotensin system antagonism and lipid-lowering therapy in cardiovascular risk management.

The renin-angiotensin system (RAS) and dyslipidaemia have been shown to be involved in the genesis and progression of atherosclerosis. Manipulation of the RAS has been effective in modifying human coronary artery disease progression. Similarly, the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors or statins have been shown to reduce cholesterol and lower cardiovascular events in primary and secondary prevention trials in coronary artery disease. In addition to their primary mode of action, statins and blockers of the RAS possess common additional properties that include restoration of endothelial activity and inhibition of cellular proliferation. This article reviews the current data on the common properties of these classes of drugs in which the beneficial effects extend beyond their antihypertensive and lipid-lowering properties.

Long-term anticoagulation in the extreme elderly with the newer antithrombotics: safe or sorry?

BACKGROUND AND OBJECTIVES: The prevalence of atrial fibrillation (AF) doubles in the extreme elderly and is higher than in the rest of the population. Warfarin therapy to prevent thromboembolic events secondary to AF is often underutilized and under-prescribed in this subgroup, due to the fear of bleeding and other complications. Newer oral anticoagulants such as rivaroxaban and dabigatran offer alternative therapeutic options for the extreme elderly. We review the clinical trial data of these newer agents in the extreme elderly population. SUBJECTS AND METHODS: THE PRIMARY LITERATURE WAS IDENTIFIED THROUGH PUBMED, USING THE FOLLOWING SEARCH TERMS: anticoagulation, rivaroxaban, dabigatran, warfarin, elderly, AF, bleeding, stroke, and aging. Additional references were identified through the review of references from the articles obtained. We included clinical studies evaluating anticoagulation therapies in AF. Selection emphasis was placed on those evaluating anticoagulation in the elderly population. RESULTS: Dabigatran and rivaroxaban have predictable, dose-proportional pharmacokinetic and pharmacodynamic properties, which make them favorable options for the elderly. Fewer monitoring parameters and drug interactions allow for the greater ease of use. A landmark trial shows that the rate of intracranial hemorrhage with dabigatran is lower in this population compared to warfarin. However, the data is based on a small number of subjects enrolled in the clinical trials. As such, the real-world use of these agents may not replicate the published rates of bleeding and thrombosis in the study populations. CONCLUSION: More research is needed in this area, specifically in this population, before newer agents such as rivaroxaban and dabigatran are widely recommended for use in the extreme elderly patients.

Evaluation of costs associated with tolvaptan-mediated hospital length of stay reduction among US patients with the syndrome of inappropriate antidiuretic hormone secretion, based on SALT-1 and SALT-2 trials.

BACKGROUND: Two randomized clinical trials, the Study of Ascending Levels of Tolvaptan in Hyponatremia 1 and 2 (SALT-1 and SALT-2), showed that tolvaptan was an efficacious and safe therapy for the treatment of hyponatremic patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). HYPOTHESIS: This study evaluated the potential cost savings associated with tolvaptan usage based on the SALT-1 and SALT-2 trials. METHODS: Hospital length of stay (LOS) reduction associated with tolvaptan versus placebo was evaluated among hyponatremic patients with the SIADH (serum sodium < 135 mEq/L) from the combined data of the SALT-1 and SALT-2 trials. The Healthcare Cost and Utilization Project 2009 Nationwide Inpatient Sample database was used to estimate hospital cost and LOS for hospitalizations of adult (age ≥ 18 years) patients with the SIADH. A cost-offset model was constructed to evaluate the impact of tolvaptan on hospital cost and LOS, with univariate and multivariate Monte Carlo sensitivity analyses. RESULTS: In the SALT-1 and SALT-2 trials, patients with the SIADH receiving tolvaptan had a shorter hospital LOS than patients receiving placebo (4.98 vs 6.19 days, respectively). There were 21 718 hospitalizations for the SIADH identified from the Healthcare Cost and Utilization Project Nationwide 2009 Inpatient Sample database, with a mean LOS of 5.7 days and mean total hospital costs of $8667. Using an inpatient tolvaptan treatment duration of 4 days, with a daily wholesale acquisition cost of $250, the cost-offset model estimated an LOS reduction among SIADH hospitalizations of 1.11 days. The total cost offset, including tolvaptan drug cost, was estimated to be $694 per admission. The cost-neutral break-even duration of tolvaptan therapy is 6.78 days. Univariate and multivariate sensitivity analyses demonstrated consistent cost reduction associated with tolvaptan usage. Ten thousand cycles of Monte Carlo simulation showed the 95% CI for cost offset to be $73 to $1405. CONCLUSION: Based on the SALT-1 and SALT-2 trials, tolvaptan usage is associated with a shorter hospital LOS than placebo among patients with the SIADH. Including the drug cost for 4 days of inpatient tolvaptan therapy, tolvaptan is associated with an estimated mean hospital cost reduction of $694 per admission in the United States.

Evaluation of costs associated with tolvaptan-mediated length-of-stay reduction among heart failure patients with hyponatremia in the US, based on the EVEREST trial.

BACKGROUND: The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial showed that tolvaptan use improved heart failure (HF) signs and symptoms without serious adverse events. OBJECTIVE: To evaluate the potential cost savings associated with tolvaptan usage among hospitalized hyponatremic HF patients. METHODS: The Healthcare Cost and Utilization Project (HCUP) 2008 Nationwide Inpatient Sample (NIS) database was used to estimate hospital cost and length of stay (LOS), for diagnosis-related group (DRG) hospitalizations of adult (age ≥18 years) HF patients with complications and comorbidities or major complications and comorbidities. EVEREST trial data for patients with hyponatremia were used to estimate tolvaptan-associated LOS reductions. A cost offset model was constructed to evaluate the impact of tolvaptan on hospital cost and LOS, with univariate and multivariate Monte Carlo sensitivity analyses. RESULTS: Tolvaptan use among hyponatremic EVEREST trial HF patients was associated with shorter hospital LOS than placebo patients (9.72 vs 11.44 days, respectively); 688,336 hospitalizations for HF DRGs were identified from the HCUP NIS database, with a mean LOS of 5.4 days and mean total hospital costs of $8415. Using an inpatient tolvaptan treatment duration of 4 days with a wholesale acquisition cost of $250 per day, the cost offset model estimated a LOS reduction among HF hospitalizations of 0.81 days and an estimated total cost saving of $265 per admission. Univariate and multivariate sensitivity analysis demonstrated that cost reduction associated with tolvaptan usage is consistent among variations of model variables. CONCLUSIONS: The estimated LOS reduction and cost savings projected by the cost offset model suggest a clinical and economic benefit to tolvaptan use in hyponatremic HF patients. STUDY LIMITATIONS: The EVEREST trial data may not generalize well to the US population. Clinical trial patient profiles and relative LOS reductions may not be applicable to real-world patient populations.

Update on tolvaptan for the treatment of hyponatremia.

Tolvaptan is a member of a new class of drugs, called the vaptans, that antagonize receptors of the neurohormone arginine vasopressin. From a clinical perspective, tolvaptan has been shown to be efficacious in the treatment of hyponatremia, whether it is idiopathic or disease related, and it may have a more favorable benefit/risk profile than other treatment modalities. From an economic perspective, tolvaptan is an expensive drug for treating hyponatremia, but recent economic cost-offset models provide evidence that tolvaptan can be cost effective. The cost-effectiveness of tolvaptan is driven by reduced healthcare resource usage and hospitalization costs. More comparative research of tolvaptan versus other pharmacotherapies and analyses of patients treated with tolvaptan in the real world are needed to better determine the benefits of tolvaptan usage to patient outcome, and more accurately assess its value in the treatment of hyponatremia, an independent predictor of morbidity, mortality and cost.

Hyponatremia in acute decompensated heart failure: mechanisms, prognosis, and treatment options.

Hyponatremia is common and is increasingly recognized as an independent prognostic marker that adversely affects morbidity and mortality in various disease states, including heart failure. In acute decompensated heart failure (ADHF), the degree of hyponatremia often parallels the severity of cardiac dysfunction and is further exacerbated by any reduction in glomerular filtration rate and arginine vasopressin dysregulation. A recent study showed that even modest improvement of hyponatremia may have survival benefits. Although management of hyponatremia in ADHF has traditionally focused on improving cardiac function and fluid restriction, the magnitude of improvement of serum sodium is fairly slow and unpredictable. In this article, we discuss the mechanisms of hyponatremia in ADHF, review its evolving prognostic significance, and evaluate the efficacy of various treatments for hyponatremia, including the recently approved vasopressin receptor antagonists for managing hyponatremia among patients hospitalized for ADHF.

Loop diuretic therapy in heart failure: the need for solid evidence on a fluid issue.

BACKGROUND: Heart failure (HF) is a common condition associated with substantial cost, morbidity, and mortality. Because results of clinical trials in the acute decompensated heart failure (ADHF) setting have been mostly neutral, loop diuretics remain the mainstay of treatment. HYPOTHESIS: Loop diuretic use may be associated with unfavorable outcomes. METHODS: A MEDLINE literature search was performed to identify articles relating to heart failure and loop diuretics. The current evidence on the risks and benefits of loop diuretics for the treatment of ADHF is reviewed. RESULTS: Loop diuretics are associated with symptomatic improvements in congestion, urine output, and body weight, but have shown no long-term mortality benefit. Loop diuretics, especially at high doses, are associated with worsened renal function and other poor outcomes. CONCLUSIONS: Loop diuretics still prove useful in HF treatment, but risk-benefit analysis of these agents in the treatment of ADHF requires a well-designed prospective study.

Clinical utility of tolvaptan in the management of hyponatremia in heart failure patients.

Hyponatremia is an electrolyte disorder frequently observed in several clinical settings and common in hospitalized patients with decompensated heart failure (HF). It is caused by deregulation of arginine vasopressin (AVP) homeostasis associated with water retention in hypervolemic or in euvolemic states. While hypervolemic hypotonic hyponatremia is also seen in advanced liver cirrhosis, renal failure, and nephrotic syndrome, the bulk of evidence associating this electrolyte disorder to increasing morbidity and mortality can be found in the HF literature. Hospitalized HF patients with low serum sodium concentration have lower short-term and long-term survival, longer hospital stay and increased readmission rates. Conventional therapeutic approaches, ie, restriction of fluid intake, saline and diuretics, can be effective, but often the results are unpredictable. Recent clinical trials have demonstrated the effectiveness of nonpeptide AVP receptor antagonists (vaptans) in the treatment of hyponatremia. The vaptans induce aquaresis, an electrolyte-sparing excretion of free water resulting in the correction of serum sodium concentrations and plasma osmolality, without activation of the renin-angiotensin-aldosterone system (RAAS) or changes in renal function and blood pressure. Further prospective studies in a selected congestive HF population with hyponatremia, using clinical-status titrated dose of tolvaptan, are needed to determine whether serum sodium normalization will be translated into a better long-term prognosis. This review will focus on recent clinical trials with tolvaptan, an oral V(2) receptor antagonist, in HF patients. The ability of tolvaptan to safely increase serum sodium concentration without activating the RAAS or compromising renal function and electrolyte balance makes it an attractive agent for treating hyponatremic HF patients.

Mortality reduction with beta-blockers in ischemic cardiomyopathy patients undergoing coronary artery bypass grafting.

Coronary artery bypass grafting (CABG) in patients with systolic heart failure (HF) carries high morbidity and mortality rates. Reducing perioperative mortality with beta-blockers (BBs) may help improve outcomes. Analysis of 4903 patients who underwent isolated CABG surgery was performed. In-hospital mortality of systolic HF patients who received BBs was 2.03%; systolic HF patients who did not receive BBs had a mortality of 5.20%. Thirty-day mortality was 2.98% in the patients with systolic HF who received BBs and 6.16% in the patients who did not. beta-Blockade did not affect the mortality in patients with preserved systolic function. Cardiogenic shock was a predictor of increased mortality in patients with systolic HF, while BBs reduced mortality. BBs are associated with decreased in-hospital and 30-day mortality in patients with systolic HF. BB therapy should be considered in patients with systolic HF who are undergoing CABG.