The clinical effects of vasopressin receptor antagonists in heart failure

The neurohormone arginine vasopressin (AVP) is a promising target in the treatment of heart failure because AVP promotes congestion and hyponatremia, each of which is associated with poor outcomes. Diuretics are standard therapy for heart failure, but they have several limitations, including worsening renal function and hyponatremia. Blocking AVP leads to effective aquaresis, improvements in hemodynamics and renal function parameters, weight loss, and normalization of serum sodium, without changes in blood pressure or heart rate. In placebo-controlled trials in the inpatient and outpatient setting, the AVP receptor antagonist tolvaptan reduced body weight and edema and normalized serum sodium in patients with heart failure.     

Rationale and design of the treatment of hyponatremia based on lixivaptan in NYHA class III/IV cardiac patient evaluation (THE BALANCE) study

Hyponatremia is a common electrolyte disorder in patients with heart failure (HF) associated with cognitive dysfunction and increased mortality and rehospitalization rates. Loop diuretics worsen renal function, produce neurohormonal activation, and induce electrolyte imbalances. Lixivaptan is a selective, oral vasopressin V(2) -receptor antagonist that improves hyponatremia by promoting electrolyte-free aquaresis without significant side effects. The Treatment of Hyponatremia Based on Lixivaptan in NYHA Class III/IV Cardiac Patient Evaluation (BALANCE) study is a randomized, double-blind, placebo-controlled, phase 3 trial designed to evaluate the effects of lixivaptan on serum sodium in patients hospitalized with worsening heart failure (target N= 650), signs of congestion and serum sodium concentrations <135 mEq/L. Other endpoints include assessment of dyspnea, body weight, cognitive function, and days of hospital-free survival. Patients are randomized 1:1 to lixivaptan or matching placebo for 60 days, with a 30-day safety follow-up. Doses of lixivaptan or placebo are adjusted based on serum sodium and volume status. Lixivaptan was shown to increase serum sodium and reduce body weight, without renal dysfunction or hypokalemia. BALANCE seeks to address unmet questions regarding the use of vasopressin antagonists including their effects on cognitive function and clinical outcomes in patients with hyponatremia and worsening heart failure.     

Treatment of hypervolemic or euvolemic hyponatremia associated with heart failure,cirrhosis, or the syndrome of inappropriate antidiuretic hormone with tolvaptan: A clinical review

Background: Tolvaptan is an oral nonpeptide selective vasopressin V₂-receptor antagonist indicated for the treatment of clinically relevant hypervolemic or euvolemic hyponatremia associated with heart failure, cirrhosis, or syndrome of inappropriate antidiuretic hormone.Objective: The objective of this article was to review the pharmacology, efficacy, and tolerability of tolvaptan in the treatment of hypervolemic or euvolemic hyponatremia, heart failure, and autosomal dominant polycystic kidney disease (ADPKD).Methods: Articles were identified using MEDLINE (1966–February 28, 2010) and EMBASE (1947–February 28, 2010). Abstracts and proceedings from the annual meetings (2007–2009) of the American Heart Association, the European Society of Cardiology, and the American Society of Nephrology were searched to identify additional relevant publications. Searches were conducted using the terms tolvaptan, vasopressin antagonist, heart failure, polycystic kidney disease, hyponatremia, drug interaction, pharmacokinetics, and pharmacology. The reference lists of the identified publications were reviewed for additional references. All clinical trials that assessed the use of tolvaptan in the management of hypervolemic/euvolemic hyponatremia or heart failure in humans were included, regardless of study design.Results: A total of 9 trials were identified. For the treatment of hyponatremia, tolvaptan was associated with significantly increased serum sodium concentrations compared with placebo on treatment days 4 (3.62 [2.68] vs 0.25 [2.08] mmol/L, respectively; P < 0.001) and 30 (6.22 [4.10] vs 1.66 [3.59] mmol/L; P < 0.001). In the clinical trials in patients with heart failure, tolvaptan at doses of 30, 60, and 90 mg/d was associated with mean weight changes of ?1.80, ?2.10, and ?2.05 kg, respectively, versus ?0.60 kg with placebo (P = 0.002, P = 0.002, and P = 0.009). Trials of tolvaptan in humans with ADPKD are ongoing. Overall, mortality rates were not significantly altered with tolvaptan compared with placebo (25.9% vs 26.3%). The most commonly reported adverse events associated with tolvaptan in clinical trials were dry mouth (4.2%–23.0%), thirst (7.7%–40.3%), and polyuria (0.6%–31.7%), all consistent with the mechanism of action of the drug.Conclusion: Based on findings from clinical trials to date, tolvaptan is effective for the correction of hypona-tremia but has not been associated with significant improvements in mortality in patients with heart failure compared with placebo, and its utility in the treatment of ADPKD in humans remains to be determined.     

Baseline characteristics and hospital mortality in the Acute Heart Failure Database (AHEAD) Main registry

Introduction

The prognosis of patients hospitalized with acute heart failure (AHF) is poor and risk stratification may help clinicians guide care. The objectives of the Acute Heart Failure Database (AHEAD) registry are to assess patient characteristics, etiology, treatment and outcome of AHF.

Methods

The AHEAD main registry includes patients hospitalized for AHF in seven centers with a Catheterization Laboratory Service in the Czech Republic. The data were collected from September 2006 to October 2009. The inclusion criteria for the database adhere to the European guidelines for AHF (2005) and patients were systematically classified according to the basic syndromes, type and etiology of AHF.

Results

Of 4,153 patients, 12.7% died during hospitalization. The median length of hospitalization was 7.1 days. Mean age of patients was 71.5 ± 12.4 years; men were younger (68.6 ± 12.4 years) compared to women (75.5 ± 11.5 years) (P < 0.001). De-novo heart failure was seen in 58.3% of the patients. According to the classification of heart failure syndromes, acute decompensated heart failure (ADHF) was reported in 55.3%, hypertensive AHF in 4.4%, pulmonary edema in 18.4%, cardiogenic shock in 14.7%, high output failure in 3.3%, and right heart failure in 3.8%. The mortality of cardiogenic shock was 62.7%, of right AHF 16.7%, of pulmonary edema 7.1%, of high output HF 6.1%, whereas the mortality of hypertensive AHF or ADHF was < 2.5%. According to multivariate analyses, low systolic blood pressure, low cholesterol level, hyponatremia, hyperkalemia, the use of inotropic agents and norepinephrine were predictive parameters for in-hospital mortality in patients without cardiogenic shock. Severe left ventricular dysfunction and renal insufficiency were predictive parameters for mortality in patients with cardiogenic shock. Invasive ventilation and age over 70 years were the most important predictive factors for mortality in both genders with or without cardiogenic shock.

Conclusions

The AHEAD Main registry provides up-to-date information on the etiology, treatment and hospital outcomes of patients hospitalized with AHF. The results highlight the highest risk patients.     

Vasopressin dysregulation and hyponatremia in hospitalized patients

Hyponatremia, which is often due to dysregulation of arginine vasopressin, occurs frequently in hospitalized patients and is associated with increased morbidity and mortality. Nonosmotic secretion of arginine vasopressin is central to the pathophysiology of hyponatremia in patients with euvolemic hyponatremia (due to, for example, the syndrome of inappropriate secretion of antidiuretic hormone) and those with hypervolemic hyponatremia secondary to congestive heart failure or cirrhosis with ascites. Arginine vasopressin-receptor antagonists, a novel class of agents that block the action of arginine vasopressin on V2 receptors in the renal collecting ducts, may provide specific correction of sodium and water imbalance in hyponatremia by promoting free water clearance while sparing electrolytes (aquaresis). Arginine vasopressin antagonism would treat hyponatremia directly, as opposed to other therapies that do not address the effects of arginine vasopressin dysregulation directly.     

Aggressive salt and water restriction in acutely decompensated heart failure: is it worth its weight in salt?

Evaluation of: Aliti GB, Rabelo ER, Clausell N, Rohde LE, Biolo A, Beck-da-Silva L. Aggressive fluid and sodium restriction in acute decompensated heart failure: a randomized clinical trial. JAMA Intern. Med. 173(12), 1058–1064 (2013).

Acute decompensated heart failure (ADHF) is the leading cause of hospitalization worldwide, especially in the elderly, and is associated with a high readmission rate and increased first year mortality . Fluid overload manifested by pulmonary congestion is seen in the majority of patients with ADHF and is believed to be the reason behind most admissions. ADHF is commonly treated with intravenous diuretics aimed to alleviate congestion and restore euvolemia. In fact, current European and American guidelines for heart failure (HF) consider relief of congestion as the first-line therapy in ADHF. Following the same theme of reducing fluid retention, historical approaches have recommended water and salt restriction as an essential non-pharmacological therapy in the management of symptomatic HF. This ‘common sense’ dietary practice was mainly based on experts’ opinions and has been challenged by recent data suggesting that salt or fluid restriction has neutral outcomes in achieving clinical stability and improving signs and symptoms of HF .     

Outcomes of correcting hyponatremia in patients with myocardial infarction

Background

Hyponatremia has significant prognostic implications in patients with heart, failure. However, little data are available regarding its significance in patients presenting with myocardial infarction. In addition, it is not known if correction of hyponatremia impacts outcomes in these patients. The aim of this study was to evaluate the prognostic value of hyponatremia in patients with myocardial infarction and the effect of its correction on all-cause mortality.

Methods

Patients with the discharge diagnosis of myocardial infarction at our institution between 2000 and 2010 with serum sodium levels measured within 24 h of admission were included in this retrospective analysis. Multivariate analysis was used to determine the predictors of all-cause mortality. Cox proportional hazard model was applied to determine the adjusted survival.

Results

A total of 11,562 patients (67.15 ± 14.6 years, males 56.3 %) were included in the analysis. There were a total of 1,535 (13.3 %) deaths within mean follow-up duration of 5.5 ± 3.3 years. There were 425 (27.9 %) deaths in patients with corrected hyponatremia and 155 (55.3 %) deaths in persistent hyponatremia patients. Multivariate analysis indicated that corrected hyponatremia and persistent hyponatremia were independent predictors of all cause mortality (p < 0.0001). When analyzing short-term (30 days) and long-term mortality, corrected hyponatremia group did not have associated long term mortality. Various methods to correct hyponatremia were also analyzed and use of vaptans was associated with decrease in mortality in patients with hyponatremia from 115 to 125 (HR 0.45; 95 % CI 0.26–0.78, p = 0.005).

Conclusion

Our analysis showed that corrected and persistent hyponatremia in patients presenting with myocardial infarction is a predictor of all-cause mortality, major adverse cardiac events and heart failure related 30 day rehospitalization. In certain cases, correction of hyponatremia may actually improve survival of the patients.     

Chronic Heart Failure: Impact of the Current Guidelines

Despite the persistent high mortality, many adults are living with chronic heart failure. Recent updates to the clinical guidelines for managing heart failure provide substantive recommendations on how to treat patients with heart failure with preserved ejection fraction or heart failure with reduced ejection fraction. Key changes in these guidelines include 2 new medications, use of biomarkers, a focus on specific comorbidities, and prevention strategies. This report provides recommendations from the updated 2017 guideline for the management of heart failure for nurse practitioners in caring for patients with chronic heart failure.     

Hyponatremia in critical care patients: Frequency,outcome, characteristics,and treatment with the vasopressin V2-receptor antagonist tolvaptan

Hyponatremia is a common problem in critical care patients and is associated with increased duration of hospital stay and increased morbidity and mortality. The prevalence of hyponatremia in the intensive care unit (ICU) has been reported to be as high as 30% to 40%. Recent studies have found hyponatremia at ICU admission in up to 14% of patients in unselected groups; patients with hyponatremia were at elevated risk of mortality vs normonatremic patients. Most cases in the ICU are euvolemic or hypervolemic hyponatremia, with the syndrome of inappropriate secretion of antidiuretic hormone being a predominant cause. The oral selective vasopressin V₂-receptor antagonist tolvaptan is effective in treating euvolemic and hypervolemic hyponatremia and may be useful in the management of hyponatremic critical care patients. Tolvaptan treatment increases serum sodium via aquaresis—ie, increased electrolyte-free water excretion—and thus presents an advantage in patients with syndrome of inappropriate secretion of antidiuretic hormone or other euvolemic states or hypervolemic hyponatremia. This article provides a review of hyponatremia and of the potential use of tolvaptan in critical care settings. Case reports provide examples of tolvaptan use in correcting severe hyponatremia and associated abnormal mental status and in resolving hyponatremia prior to surgery.     

Loop diuretics in acute heart failure: beyond the decongestive relief for the kidney

Current goals in the acute treatment of heart failure are focused on pulmonary and systemic decongestion with loop diuretics as the cornerstone of therapy. Despite rapid relief of symptoms in patients with acute decompensated heart failure, after intravenous use of loop diuretics, the use of these agents has been consistently associated with adverse events, including hypokalemia, azotemia, hypotension, and increased mortality. Two recent randomized trials have shown that continuous infusions of loop diuretics did not offer benefit but were associated with adverse events, including hyponatremia, prolonged hospital stay, and increased rate of readmissions. This is probably due to the limitations of congestion evaluation as well as to the deleterious effects linked to drug administration, particularly at higher dosage. The impaired renal function often associated with this treatment is not extensively explored and could deserve more specific studies. Several questions remain to be answered about the best diuretic modality administration, global clinical impact during acute and post-discharge period, and the role of renal function deterioration during treatment. Thus, if loop diuretics are a necessary part of the treatment for acute heart failure, then there must be an approach that allows personalization of therapy for optimal benefit and avoidance of adverse events.     

Acute myocardial infarction complicated by cardiogenic shock: role of mechanical circulatory support

Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is the leading cause of in-hospital death for patients admitted with acute coronary syndromes. Expert guidelines for the care of AMI-CS patients recommend early revascularization with intra-aortic balloon pump support. Ventricular assist devices (VADs) offer the advantages of providing greater and longer-term cardiac support than an intra-aortic balloon pump and may improve outcomes when inserted early after heart failure symptoms begin. Pulsatile VADs are versatile and can provide biventricular support but are associated with a higher incidence of serious complications. The newer percutaneous VADs can normalize cardiac index and can be implanted without surgery. Therefore, early implementation of percutaneous VADs and early revascularization may reduce the high mortality of AMI-CS. However, access to revascularization and VAD support, including percutaneous VADs, is currently limited and must improve to more effectively treat AMI-CS patients.     

Acute myocardial infarction complicated by cardiogenic shock: role of mechanical circulatory support

Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is the leading cause of in-hospital death for patients admitted with acute coronary syndromes. Expert guidelines for the care of AMI-CS patients recommend early revascularization with intra-aortic balloon pump support. Ventricular assist devices (VADs) offer the advantages of providing greater and longer-term cardiac support than an intra-aortic balloon pump and may improve outcomes when inserted early after heart failure symptoms begin. Pulsatile VADs are versatile and can provide biventricular support but are associated with a higher incidence of serious complications. The newer percutaneous VADs can normalize cardiac index and can be implanted without surgery. Therefore, early implementation of percutaneous VADs and early revascularization may reduce the high mortality of AMI-CS. However, access to revascularization and VAD support, including percutaneous VADs, is currently limited and must improve to more effectively treat AMI-CS patients.     

Diagnosis and evaluation of heart failure

Heart failure is a common clinical syndrome characterized by dyspnea, fatigue, and signs of volume overload, which may include peripheral edema and pulmonary rales. Heart failure has high morbidity and mortality rates, especially in older persons. Many conditions, such as coronary artery disease, hypertension, valvular heart disease, and diabetes mellitus, can cause or lead to decompensation of chronic heart failure. Up to 40 to 50 percent of patients with heart failure have diastolic heart failure with preserved left ventricular function, and the overall mortality is similar to that of systolic heart failure. The initial evaluation includes a history and physical examination, chest radiography, electrocardiography, and laboratory assessment to identify causes or precipitating factors. A displaced cardiac apex, a third heart sound, and chest radiography findings of venous congestion or interstitial edema are useful in identifying heart failure. Systolic heart failure is unlikely when the Framingham criteria are not met or when B-type natriuretic peptide level is normal. Echocardiography is the diagnostic standard to confirm systolic or diastolic heart failure through assessment of left ventricular ejection fraction. Evaluation for ischemic heart disease is warranted in patients with heart failure, especially if angina is present, given that coronary artery disease is the most common cause of heart failure. (Am Fam Physician. 2012;85(12):1161-1168. Copyright ? 2012 American Academy of Family Physicians.).     

Hyponatremia influences the outcome of patients with acute-on-chronic liver failure: an analysis of the CANONIC study

Introduction

Hyponatremia is a marker of poor prognosis in patients with cirrhosis. This analysis aimed to assess if hyponatremia also has prognostic value in patients with acute-on-chronic liver failure (ACLF), a syndrome characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality.

Methods

We performed an analysis of the Chronic Liver Failure Consortium CANONIC database in 1,341 consecutive patients admitted to 29 European centers with acute decompensation of cirrhosis (including ascites, gastrointestinal bleeding, hepatic encephalopathy, or bacterial infections, or any combination of these), both with and without associated ACLF (301 and 1,040 respectively).

Results

Of the 301 patients with ACLF, 24.3% had hyponatremia at inclusion compared to 12.3% of 1,040 patients without ACLF (P <0.001). Model for end-stage liver disease, Child-Pugh and chronic liver failure-SOFA scores were significantly higher in patients with ACLF and hyponatremia compared to those without hyponatremia. The presence of hyponatremia (at inclusion or during hospitalization) was a predictive factor of survival both in patients with and without ACLF. The presence of hyponatremia and ACLF was found to have an independent effect on 90-day survival after adjusting for the potential confounders. Hyponatremia in non-ACLF patients nearly doubled the risk (hazard ratio (HR) 1.81 (1.33 to 2.47)) of dying at 90 days. However, when considering patients with both factors (ACLF and hyponatremia) the relative risk of dying at 90 days was significantly higher (HR 6.85 (3.85 to 12.19) than for patients without both factors. Patients with hyponatremia and ACLF had a three-month transplant-free survival of only 35.8% compared to 58.7% in those with ACLF without hyponatremia (P <0.001).

Conclusions

The presence of hyponatremia is an independent predictive factor of survival in patients with ACLF. In cirrhosis, outcome of patients with ACLF is dependent on its association with hyponatremia.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0700-0) contains supplementary material, which is available to authorized users.     

慢性心力衰竭患者血钠水平对血浆肾素活性、醛固酮和N末端前脑钠肽水平的影响

目的探讨慢性心力衰竭（心衰）患者血钠水平对血浆。肾素活性（PRA）、醛固酮（ALD）和N末端前脑钠肽（NT．proBNP）水平的影响。方法91例慢性心衰患者,根据治疗前血钠水平分正常血钠组和低血钠组,均在人院第二天清晨卧位采血测定PRA、ALD和NT．proBNP水平,常规治疗心衰及低钠血症一周后以同样的方法采血复查血钠、PRA、ALD和NT-proBNP水平,对上述指标进行统计分析。结果入院时低血钠组PRA、ALD和NT-proBNP比正常血钠组高,差异有统计学意义（P〈0．05l低血钠组患者常规治疗心衰及低钠血症一周后,PRA、ALD和NT-proBNP水平较入院时降低．差异有统计学意义（P〈O．05）正常血钠组常规治疗心衰一周后PRA、ALD和NT．proBNP水平较入院时降低,差异有统计学意义（P〈0．05）;而两组患者治疗前后PRA、ALD和NT．proBNP水平下降值有明显差异（p〈O．05）,低血钠组下降史明显。结论低钠血症可能促进慢性心衰患者PRA、ALD和NT-proBNP分泌增加,心衰伴低钠血症患者的神经内分泌水平激活更明显。低钠血症经治疗血钠水平恢复正常后,神经内分泌激素水平明显降低。     

Hyponatremia, heart failure, and the role of tolvaptan

Hyponatremia-usually defined by serum sodium < 135 mEq/L-is common in heart failure (HF); it remains unclear whether it worsens HF or is merely a marker of more severe disease. Hyponatremia may develop from causes besides HF and symptoms may be mistakenly attributed to HF. Hyponatremia correction may be required for optimal HF management in some cases, and it can prevent neurologic complications. Symptoms, volume status, and onset timing determine treatment, which should correct serum sodium in a controlled manner. Arginine vasopressin is elevated in hypervolemic/euvolemic hyponatremia, favoring water reabsorption despite low serum osmolality. The oral selective V(2)-receptor antagonist tolvaptan blocks arginine vasopressin effects in the renal collecting ducts, promoting aquaresis without increasing sodium/potassium excretion. In clinical trials, tolvaptan significantly increased serum sodium in patients with euvolemic/hypervolemic hyponatremia, including HF. When added to conventional HF treatment, tolvaptan produced early symptomatic benefit, without long-term improvement in an HF population consisting primarily of normonatremic patients. Tolvaptan is approved for treatment of clinically significant hypervolemic/euvolemic hyponatremia (serum sodium < 125 mEq/L or less marked symptomatic hyponatremia that has resisted correction with fluid restriction), but not HF without hyponatremia.     

Current issues for nurse practitioners: Hyponatremia

PURPOSE: To review the assessment, diagnosis, and management of hyponatremia (serum sodium <135 mEq/L), the most common electrolyte disturbance as a result of dysregulation of water balance in hospitalized or institutionalized patients. DATA SOURCES: Comprehensive search using keywords AVP receptor antagonists, hyponatremia, SIADH, conivaptan, tolvaptan, lixivaptan, nurse practitioner, and others was carried out using the National Library of Medicine (PubMed) Web site from which full-text articles were obtained. Meeting abstracts were obtained from scientific sessions including the American Society of Nephrology Renal Week 2004 and the Endocrine Society's 87th Annual Meeting (2005). The Vaprisol (conivaptan hydrochloride injection) package insert was referenced and obtained from FDA.gov. CONCLUSIONS: A diagnosis of hyponatremia requires thorough investigation for underlying causes and prompt treatment to prevent poor patient outcomes. In clinical trials, a new class of drugs called the arginine vasopressin (AVP) receptor antagonists or aquaretics has been shown to be safe and effective for the treatment of hyponatremia. Among this class of agents, intravenous conivaptan hydrochloride, indicated for the treatment of euvolemic hyponatremia in hospitalized patients, is the first drug in class approved for use. IMPLICATIONS FOR PRACTICE: Elderly patients, and those with certain conditions such as heart failure, tuberculosis, cirrhosis, and head injury, may be at increased risk for hyponatremia. In hospitalized patients following surgery and the use of certain medications, hyponatremia is a common condition. A thorough understanding of the physiology of water balance and the risk factors associated with hyponatremia is essential for prompt and effective intervention. Awareness of the limitations of conventional therapies and the availability of new treatment options for hyponatremia allows clinicians to optimize patient care.     

充血性心力衰竭合并低钠血症56例临床分析

目的分析充血性心力衰竭(CHF)合并低钠血症的诱因与治疗体会。方法选取我院收治的56例CHF心功能Ⅲ、Ⅳ级合并血钠<130mmol/L的患者临床资料进行分析。结果过度限盐和反复利尿是引起CHF合并低钠血症主要诱因,低钠血症分为缺钠性低钠血症和稀释性低钠血症,缺钠性低钠血症多见于心衰纠正后水肿减轻,稀释性低钠血症多见于心衰晚期,缺钠性低钠血症治疗效果优于稀释性低钠血症。结论 CHF患者不应盲目忌钠,须给予适量的钠摄入,并严密观察病情变化;在使用利尿剂治疗时应注意及时检查电解质,治疗低钠血症时首先应鉴别是缺钠性低钠血症还是稀释性低钠血症,缺钠性低钠血症治疗以补钠为主,稀释性低钠血症治疗以限水为主,所有患者必须同时纠正心衰治疗。     

Vasopressin antagonists in the management of heart failure

Vasopressin antagonists have been studied in a variety of clinical settings, including patients with acute and chronic heart failure. The clinical trials published to date have sought to describe the clinical and physiologic effects of these agents in an effort to prove clinical efficacy and safety. A variety of agents with varying effects on V2 and V1a vasopressin receptor subtype have been studied. They have been shown to reduce bodyweight and improve serum sodium without worsening renal function. They may also decrease the need for loop diuretic use and may be particularly useful in patients with hyponatremia in the setting of volume overload. Further studies are underway that are powered to assess for morbidity and mortality benefits. The beneficial effects have been well documented but, until outcomes are understood more fully, the use of these agents should be limited to currently approved indications. In the USA, this includes only the treatment of euvolemic hyponatremia.     

Digoxin therapy for heart failure: an update

Digoxin therapy has long been used to treat heart failure; however, its effectiveness was not completely known until recently. Results of the Digitalis Investigation Group trial showed that adding digoxin to standard heart failure therapy had no effect on mortality. However, adding digoxin decreased hospitalizations related to heart failure and improved symptoms in patients treated for heart failure. Reanalyses of the trial's findings have raised new questions about the role of digoxin in heart failure treatment. These new analyses showed that low serum digoxin concentrations used in patients with more severe disease offered the most benefit. Digoxin use in women was associated with increased mortality risk. This finding should be interpreted with caution, however, because it was based on retrospective data, and the cause of this phenomenon has not been fully elucidated. Prospective clinical trials are needed to determine the serum digoxin concentration that is associated with the most clinical benefit and to determine the role of digoxin therapy for women. Digoxin generally does not have a role in the treatment of diastolic heart failure and is not a first-line therapy for managing atrial fibrillation in patients with heart failure.