Use Of Vasopressin Receptor Antagonists Research Articles

Korean Society of Nephrology 2022 recommendations on controversial issues in diagnosis and management of hyponatremia.

The Korean Society for Electrolyte and Blood Pressure Research, in collaboration with the Korean Society of Nephrology, has published a clinical practice guideline (CPG) document for hyponatremia treatment. The document is based on an extensive evidence-based review of the diagnosis, evaluation, and treatment of hyponatremia with the multidisciplinary participation of representative experts in hyponatremia with methodologist support for guideline development. This CPG consists of 12 recommendations (two for diagnosis, eight for treatment, and two for special situations) based on eight detailed topics and nine key questions. Each recommendation begins with statements graded by the strength of the recommendations and the quality of the evidence. Each statement is followed by rationale supporting the recommendations. The committee issued conditional recommendations in favor of rapid intermittent bolus administration of hypertonic saline in severe hyponatremia, the use of vasopressin receptor antagonists in heart failure with hypervolemic hyponatremia, and syndrome of inappropriate antidiuresis with moderate to severe hyponatremia, the individualization of desmopressin use, and strong recommendation on the administration of isotonic fluids as maintenance fluid therapy in hospitalized pediatric patients. We hope that this CPG will provide useful recommendations in practice, with the aim of providing clinical support for shared decision-making to improve patient outcomes.

Korean Society of Nephrology 2022 Recommendations on controversial issues in diagnosis and management of hyponatremia.

The Korean Society for Electrolyte and Blood Pressure Research, in collaboration with the Korean Society of Nephrology, has published a clinical practice guideline (CPG) document for hyponatremia treatment. The document is based on an extensive evidence-based review of the diagnosis, evaluation, and treatment of hyponatremia with the multidisciplinary participation of representative experts in hyponatremia with methodologist support for guideline development. This CPG consists of 12 recommendations (two for diagnosis, eight for treatment, and two for special situations) based on eight detailed topics and nine key questions. Each recommendation begins with statements graded by the strength of the recommendations and the quality of the evidence. Each statement is followed by rationale supporting the recommendations. The committee issued conditional recommendations in favor of rapid intermittent bolus administration of hypertonic saline in severe hyponatremia, the use of vasopressin receptor antagonists in heart failure with hypervolemic hyponatremia, and syndrome of inappropriate antidiuresis with moderate to severe hyponatremia, the individualization of desmopressin use, and strong recommendation on the administration of isotonic fluids as maintenance fluid therapy in hospitalized pediatric patients. We hope that this CPG will provide useful recommendations in practice, with the aim of providing clinical support for shared decision-making to improve patient outcomes.

Korean Society of Nephrology 2022 Recommendations on Controversial Issues in Diagnosis and Management of Hyponatremia.

The Korean Society for Electrolyte and Blood Pressure Research, in collaboration with the Korean Society of Nephrology, has published a clinical practice guideline (CPG) document for hyponatremia treatment. The document is based on an extensive evidence-based review of the diagnosis, evaluation, and treatment of hyponatremia with the multidisciplinary participation of representative experts in hyponatremia with methodologist support for guideline development. This CPG consists of 12 recommendations (two for diagnosis, eight for treatment, and two for special situations) based on eight detailed topics and nine key questions. Each recommendation begins with statements graded by the strength of the recommendations and the quality of the evidence. Each statement is followed by rationale supporting the recommendations. The committee issued conditional recommendations in favor of rapid intermittent bolus administration of hypertonic saline in severe hyponatremia, the use of vasopressin receptor antagonists in heart failure with hypervolemic hyponatremia, and syndrome of inappropriate antidiuresis with moderate to severe hyponatremia, the individualization of desmopressin use, and strong recommendation on the administration of isotonic fluids as maintenance fluid therapy in hospitalized pediatric patients. We hope that this CPG will provide useful recommendations in practice, with the aim of providing clinical support for shared decision-making to improve patient outcomes.

Vasopressin Receptor Antagonists in Hyponatremia: Uses and Misuses.

Decreases in the concentration of sodium in plasma constitute hyponatremia, the commonest electrolyte disorder in clinical medicine. It is now well established that its presence conveys an increased mortality risk even when the decrement is mild. In addition, recent evidence suggests that chronic and apparently asymptomatic hyponatremia is associated with increased morbidity including neurocognitive deficits and bone fractures. Furthermore, hyponatremia is associated with higher health care-related expenses. Consequently, exploring new therapeutic strategies that increase plasma sodium in a safe and effective manner is of paramount importance. In this regard, there are scant data to support the use of traditional management strategies for hyponatremia (fluid restriction, salt tablets, loop diuretics, and normal saline). Furthermore, data from a large hyponatremia registry reveal the limited efficacy of these therapies. More recently vasopressin receptor antagonists provide a promising treatment for hyponatremia by targeting its most common mechanism, namely, increased vasopressin activity. However, uncertainty still lingers as to the optimal indications for the use of vasopressin receptor antagonists in hyponatremia and a few reports have described complications resulting from their misuse. This review summarizes the appropriate and inappropriate uses of vasopressin receptor antagonists in the treatment of hyponatremia.

Vasopressin and Vasopressin Antagonists in Heart Failure.

Despite the introduction of multiple new pharmacological agents over the past three decades in the field of heart failure (HF), overall prognosis remains poor. Hyponatremia is prevalent in HF patients and has been suggested as a contributor to poor response to standard therapy. Elevated levels of arginine vasopressin (AVP), a peptide hormone produced in the hypothalamus, play a role in development of hyponatremia, and AVP and its surrogate, copeptin, are related to changes in osmolality, hemodynamics, neuro-hormones as well as in overall outcome in HF patients. Of current pharmacological interest are the selective and non-selective vasopressin receptor antagonists (VRAs), which inhibit vasoconstriction and cardiac remodeling mediated by the V1a receptors in smooth blood vessels, and water retention (increased urine osmolality and decreased water excretion) by increasing aquaporin-2 water channels mediated by the V2 receptors in the renal collecting tubules. The optimal use of VRAs is yet to be determined, especially in patients with congestive HF. Although long-term effects on improvement in mortality have not been shown in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial, the only long-term outcome trial to date, many short-term studies indicate beneficial aquaretic- and hemodynamic-effects of the VRAs. In contrast to loop diuretics, these new agents tend to increase urine flow and the excretion of electrolyte-free water (so-called aquaresis) in patients with HF, without substantial changes in sodium or potassium excretion. This chapter reviews the role of AVP and copeptin in HF, and the treatment potential of VRAs in HF.

Hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH): therapeutic decision-making in real-life cases.

Despite being the most common electrolyte disturbance encountered in clinical practice, the diagnosis and treatment of hyponatremia (defined as a serum sodium concentration <135 mmol/L) remains far from optimal. This is extremely troubling because not only is hyponatremia associated with increased morbidity, length of hospital stay and hospital resource use, but it has also been shown to be associated with increased mortality. The reasons for this poor management may partly lie in the heterogeneous nature of the disorder; hyponatremia presents with a variety of possible etiologies, differing symptomology and fluid volume status, thereby making its diagnosis potentially complex. In addition, a general lack of awareness of the clinical impact of the disorder, a fear of adverse outcomes through overcorrection of sodium levels, and a lack of effective targeted treatments until recent years, may all have contributed to a reticence to actively treat cases of hyponatremia. There is therefore a clear unmet need to further educate physicians on the pathophysiology, diagnosis and management of this important condition. Through the use of a variety of real-world cases of patients with hyponatremia secondary to the syndrome of inappropriate secretion of antidiuretic hormone—a condition that accounts for approximately one-third of all cases of hyponatremia—this supplement aims to provide a comprehensive overview of the challenges faced in diagnosing and managing hyponatremia. These cases will also help to illustrate how some of the limitations of traditional therapies may be overcome with the use of vasopressin receptor antagonists.

PREVELANC OF HYPONATREMIA AND ITS ASSOCIATION WITH DEVELOPMENT AND SEVERITY OF COMPLICATIONS IN CIRRHOTIC PATIENTS

Hyponatremia is common in advanced liver cirrhosis. Recently it has attracted an interest as a possible prognostic factor for liver cirrhosis complications. This study was conducted to assess the prevalence of hyponatremia in complicated cirrhotic patients admitted to medical ICU and to identify its relationship to development and severity of these complications. 200 patients with liver cirrhosis were included in this study. According to serum sodium, they were classified into three groups: group 1 with serum sodium ≤130 meq/L (severe hyponatremia), group 2 with serum sodium from 131 to 135 meq/L (mild hyponatremia) and group 3 with serum sodium ≥136 meq/L (normo-natremia). Demographic, clinical, and laboratory variables were prospectively recorded for analysis. In our studyThe prevalence of total hyponatremia was 131/200 patients (65.5%) and those with severe hyponatremia were 91/200 (45.5%) .There was a statistically significant increase in frequency of occurance (p>0.01) and relative risk each of ascites (1.3fold),intractable ascites (9.5fold), spontaneous bacterial peritonitis (2.6fold), hepatic hydrothorax (1.5fold) and hepatic encephalopathy (2.8fold), in hyponatremic groups compared to normonatremic one while there was no significant difference regarding hepatorenal syndrome, esophageal varices and variceal bleeding between different groups. Also there was a statistically significant negative correlation betwee serum sodium level and the two scoring systems: Child-Pugh score (r =-0.690, p<0.001) and Model for End – stage Liver Disease (MELD) score(r =-0.586, p<0.001 ). We can conclude that In critically ill patients with liver cirrhosis, the prevalence of total hyponatremia(Na ≤ 135 meq/L) was 65.5% while those with severe hyponatremia (Na ≤130) was 45.5%. Low serum sodium level was associated with high complications of liver cirrhosis. The relative risk of occurance, frequencies and severity of ascitis, intractable ascitis, hepatic hydrothorax, hepatic encephalopathy and spontineous bacterial peritonitis were increased in cirrhotic patients especially those with serum sodium levels ≤ 130 meq/L.So the Management of hyponatremia may decrease the incidence and severity of the liver cirrhosis complications with better quality of their life. Thus more interest should be tried towards the use of vasopressin receptor antagonists as a line of treatment of complicated cirrhotic patients with hyponatremia without salt overload

Short-term Efficacy and Safety of Vasopressin Receptor Antagonists for Treatment of Hyponatremia

Background We performed a meta-analysis to systematically measure efficacy and safety of vasopressin receptor antagonists (VRAs) tested in randomized controlled trials for treatment of hyponatremia. Methods MEDLINE, ClinicalTrials.gov, and scientific abstracts were searched without language restriction. Two authors independently screened citations and extracted data on patient characteristics, quality of reports, and efficacy and safety endpoints. Results Eleven trials were identified (1094 patients). By meta-analysis, VRAs achieved a net increase in serum sodium concentration ([Na +] serum) relative to placebo of 3.3 mEq/L at day 1 (95% confidence interval [CI], 2.7-3.8), and 4.2 mEq/L at day 2 (95% CI, 3.6-4.8), persisting at days 3-5. Larger net increases in [Na +] serum at days 1-4 were observed in euvolemic hyponatremia and with higher doses. VRAs induced a net increase in effective water clearance relative to placebo of 1244 mL at day 1 (95% CI, 920-1567), persisting at days 2 and 4. VRAs were associated with odds ratios of 3.0 for overly rapid correction of [Na +] serum ( P <.001), 7.8 for development of hypernatremia ( P <.001), 3.3 for thirst development ( P <.001), and 2.2 for postural hypotension ( P = .04). Conclusions Short-term use of VRAs in treating hyponatremia was successful at raising [Na +] serum. Additional experience is required to guide their optimal use and minimize safety concerns.

Hyponatremia and the Use of Vasopressin Receptor Antagonists In Critically Ill Patients

Hyponatremia in critically ill patients is a common and challenging problem. Increased levels of arginine vasopressin almost always contribute to the etiology. Inhibition of the vasopressin receptor with a vasopressin receptor antagonist (vaptan) is a novel approach to the treatment of hyponatremia. Vaptans are well suited to the treatment of chronic hyponatremia associated with syndrome of inappropriate anti-diuretic hormone secretion (SIADH) and hypervolemic states like cirrhosis or congestive heart failure. No data are available on the use of vaptans in acute hyponatremia, and they are not indicated in hypovolemic hyponatremia. The focus of this review is the treatment of critically ill patients with hyponatremia with vaptans and other measures.

Targeting Hyponatremia and Hemodynamics in Acute Decompensated Heart Failure: Is There a Role for Vasopressin Antagonists?

Current treatment of acute decompensated heart failure (ADHF) has not reduced the significant morbidity or mortality associated with this disease, and has promoted drug development aimed at neurohormonal targets. Hypervolemic hyponatremia, which is linked to the nonosmotic release of arginine vasopressin, is associated with a poor prognosis in patients with heart failure (HF). Vasopressin acts on V(2) and V(1a) receptors to cause water retention and vasoconstriction, respectively. Clinical trials have demonstrated that vasopressin receptor antagonists (VRAs) are effective in treating hypervolemic hyponatremia in ADHF without a negative impact on renal function. The small hemodynamic benefit seen with VRA use appeared to result from V(2)-receptor antagonist-induced increase in urine output rather than from a vasodilatory drug effect. VRA use in ADHF trials was associated with minimal symptomatic improvement and no impact on morbidity or mortality. At present, clinical trial evidence does not support the routine use of VRAs in ADHF. Given the favorable renal profile of VRAs, studies on the possible benefit of VRAs in ADHF patients with renal insufficiency and diuretic resistance appear warranted.

Vasopressin-2 Antagonists for Treatment of Hyponatremia in Cirrhosis - A Systematic Review and Meta-Analysis

Purpose: Hyponatremia is a common electrolyte abnormality in patients with cirrhosis and affects their outcome. Vasopressin-2 (V2) receptor antagonists increase free water clearance and are useful for treatment of hyponatremia. Randomized controlled trials (RCTs) have shown conflicting data on efficacy and safety of V2 receptor antagonists in the treatment of hyponatremia in cirrhotic patients. A systematic review and meta-analysis of all RCTs was performed to assess safety and efficacy of V2 receptor antagonists in the treatment of hyponatremia in patients with cirrhosis. Methods: Pub Med, Ovid, Cochrane reviews, EMBASE and ISI web of science databases were searched for all RCTs on treatment of hyponatremia using V2 receptor antagonists. Studies including patients with hyponatremia of different causes but not reporting data on cirrhotics were excluded. Data was extracted into a predefined Excel spreadsheet for patient demographics, sample size (in treated and control patients), type and dose of V2 receptor antagonist, change [post treatment - baseline (mean±SD)] on various outcomes (Table), and adverse effects. Data were entered into comprehensive meta-analysis 9.2 software and analyzed using random effects model. Heterogeneity and publication bias across the studies (reported if > 2 studies) were assessed using Chi-2 and Egger's tests respectively. Meta-regression was performed to assess heterogeneity for year of publication, type and dose of drug, baseline serum sodium, time at which change is reported (12-168 hrs), and percent males.Table: [324] Pooled data on vasopressin-2 receptor antagonists for treatment of hyponatremia in cirrhosisResults: Total 6 studies (n=342, 169 treated) were analyzed. Pooled data showed a significant increase in serum sodium with a decrease in urine osmolality (Table). However, there was no change in other parameters. The drugs were safe with similar proportion of patients among treated and control groups experiencing adverse effects with pooled OR of 1.29 (95% CI 0.73-2.25); P=0.93. Most common side effect was increased thirst. There was marked heterogeneity but no publication bias across the studies. Meta regression showed that the year of study publication along with type and dose of the drug contributed to data heterogeneity. Conclusion: Vasopressin-2 receptor antagonists are effective and safe for treatment of hyponatremia in patients with cirrhosis. Further studies are needed to determine efficacy and safety of long-term use of vasopressin receptor antagonists for treatment of hyponatremia in patients with cirrhosis.

Hyponatremia in Heart Failure: Revisiting Pathophysiology and Therapeutic Strategies

Hyponatremia is frequently encountered in patients with heart failure (HF), and its association with adverse outcomes is well-established in this population. While hyponatremia is an independent marker for severity of HF, it is not certain whether it has a causal impact on the progression of the disease. There are no universally accepted consensus guidelines regarding therapeutic strategies for HF-associated hyponatremia and volume overload; current societal guidelines do not address management of this complication. Whereas thiazide diuretics are known to induce or worsen hyponatremia in this setting through a number of mechanisms, loop diuretics can be considered a readily available first-line pharmacologic therapy. Consistent with pathophysiology of the disease and mechanisms of action of loop diuretics, available clinical evidence supports such an approach provided that patients can be closely monitored. Use of vasopressin receptor antagonists is an emerging therapeutic strategy in this setting, and the efficacy of these agents has so far been shown in a number of clinical studies. These agents can be reserved for patients with HF in whom initial appropriate loop diuretic therapy fails to improve serum sodium levels.

Vasopressin-receptor antagonists in heart failure

The role of arginine vasopressin in heart failure and the use of vasopressin receptor antagonists in the treatment of heart failure are reviewed. Arginine vasopressin (AVP) functions in the regulation of plasma osmolarity and blood pressure. In heart failure, AVP worsens heart failure by causing vasoconstriction of arteries and veins, potentially contributing to remodeling of the left ventricle and causing fluid retention and worsening of hyponatremia. Two V(2)-receptor antagonists, tolvaptan and lixivaptan, and one combined V(1a)- and V(2)-receptor antagonist, conivaptan, have shown promise for use in patients with heart failure. All three agents have been shown to increase free water excretion and increase serum sodium levels while maintaining serum potassium levels. They have not been shown to decrease renal function or the glomerular filtration rate and are well tolerated, with thirst being the major adverse effect during clinical trials. Because of their effects on sodium, vasopressin antagonists need to be carefully monitored to ensure that serum sodium levels do not increase too quickly and put the patient at risk for overcorrection or osmotic demyelination syndrome. In addition, patients need to be monitored for signs of dehydration secondary to increased urine excretion. To date, studies have not consistently shown improvements in patient symptoms or weight reduction. However, early data suggest that at least one agent, tolvaptan, does not alter mortality. Based on data from available clinical trials, vasopressin antagonists may offer a new treatment option for patients with congestive heart failure. However, these agents do not currently appear to delay the progression of heart failure or decrease mortality.

Evaluation and management of hyponatremia: an emerging role for vasopressin receptor antagonists

Vasopressin-2 receptor antagonists, collectively known as the 'vaptans', provide a new approach to the treatment of hyponatremia; therefore, an updated Review of the pathophysiology of hyponatremia is particularly timely. After briefly defining hyponatremia and introducing its clinical aspects and complications, we present an approach to the diagnosis and evaluation of hyponatremia that is based primarily on the often-underused concept of free water clearance and, more specifically, the electrolyte-free water clearance. Then we review the use of vasopressin receptor antagonists in the management of hyponatremia from the standpoint of their pharmacology, their mechanism of action, and available efficacy data from clinical trials.