Early Commencement and Long-Term Continuation of Tolvaptan Treatment Attenuate Functional Impairment of Renal Vasopressin V2 Receptors and Improve Clinical Outcomes in Patients with Heart Failure.

Preserved urinary excretion of aquaporin 2, an index for the function of vasopressin V2 receptor (V2-R), has been reported to predict a favorable response of heart failure patients to treatment with tolvaptan. In this study, we investigated the long-term effects of tolvaptan treatment on clinical outcomes and V2-R function in patients with acute decompensated heart failure (ADHF). We enrolled 90 consecutive patients who were hospitalized in Sapporo Medical University Hospital for ADHF and treated with tolvaptan in the BOREAS-ADHF registry and analyzed patients who continued taking tolvaptan after discharge. The effect of tolvaptan treatment on rehospitalization for HF or death was investigated according to whether the V2-R function was preserved (first morning urine osmolarity ≥ 352 mOsm/L, High-Uosm) or impaired (Uosm < 352 mOsm/L, Low-Uosm). During a median follow-up period of 443 days, significantly fewer patients in the High-Uosm group experienced adverse events than did patients in the Low-Uosm group (P < 0.001). Among the patients with High-Uosm, early commencement of tolvaptan administration (on or before day 7 of hospitalization, Early/High-Uosm) significantly reduced adverse events compared to late administration (after day 7 of hospitalization, Late/High-Uosm). Uosm measured during the long-term follow-up period after discharge was significantly reduced compared to that before commencement of tolvaptan administration in the Late/High-Uosm group (from 468 ± 88 to 395 ± 108 mOsm, -18.3 ± 19.6%, P < 0.05) but not in the Early/High-Uosm group (from 478 ± 115 to 455 ± 133 mOsm, -0.50 ± 35.3%, P = 0.66). These findings indicate that early commencement and long-term continuation of tolvaptan treatment attenuate functional impairment of V2-R and improve clinical outcomes in ADHF patients with preserved V2-R function.

Aquaretics Use in Acute Decompensated Heart Failure (ADHF) Patients: A Literature Review.

This is a literature review of the use of aquaretic in patients with acute decompensated heart failure (ADHF), including the physiologic function of vasopressin and its mechanism of action in heart failure patients, and aquaretic drugs with their respective risks and benefits.Vasopressin is one of several hormones that can cause hyponatremia and worsen congestion in ADHF patients. Aquaretics are a class of drugs that have an antagonistic effect on vasopressin receptors, especially V2R. Aquaretics use in ADHF patients can provide relief for congestive symptoms with no serious adverse effects. In-depth additional understanding regarding aquaretics may be useful for clinical judgments in treating ADHF patients.

Effects of Hydrochlorothiazide and Metformin on Aquaresis and Nephroprotection by a Vasopressin V2 Receptor Antagonist in ADPKD: A Randomized Crossover Trial.

BACKGROUND AND OBJECTIVES: The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers. RESULTS: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone. CONCLUSIONS: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.

Lower Urinary Tract Symptoms: What's New in Medical Treatment?

CONTEXT: Pharmacological treatment is a cornerstone in the management of patients with lower urinary tract symptoms (LUTS). OBJECTIVE: To review emerging evidence in the medical treatment of LUTS. EVIDENCE ACQUISITION: An Embase/Pubmed-based literature search was conducted in December 2017, screening for randomized controlled trials (RCTs), prospective and retrospective series, animal model studies, and reviews on medical treatment of LUTS. EVIDENCE SYNTHESIS: The main medical innovation in recent years in overactive bladder (OAB) has been the approval of the first ß3-adrenoceptor agonists (mirabegron) and intradetrusor onabotulinum toxin A, while several other drugs such as antiepileptics, phosphodiesterase inhibitors, or other ß3-agonists have brought promising results in phase 3 trials. Intraprostatic injections of various drugs for LUTS/benign prostatic hyperplasia have been investigated, but results of phase 3 trials are still pending, while combination therapies of phosphodiesterase type 5 inhibitors+α-blockers or finasteride have been proved as superior to single therapies in RCTs conducted in these patients. Two new formulations of desmopressin have been approved for nocturia in the USA (desmopressin nasal spray) and Europe/Canada/Australia (desmopressin orally disintegrated tablet). Fedovapagon, a vasopressin V2 receptor agonist, has recently completed a large phase 3 trial in male patients with nocturia. Other phase 3 trials are ongoing in bladder pain syndrome (AQX 11-25, a SHIP-1 activator) and in neurogenic detrusor overactivity (mirabegron and abobotulinum toxin A). CONCLUSIONS: Medical treatment of LUTS is a very active research field with recently approved drugs for nocturia (desmopressin acetate nasal spray/orally disintegrated tablet) and numerous emerging drugs currently investigated in OAB, LUTS/benign prostatic hyperplasia, nocturia, bladder pain syndrome, and neurogenic detrusor overactivity. PATIENT SUMMARY: Medical treatment of lower urinary tract symptoms is a very active research field with recently approved drugs for nocturia (desmopressin acetate nasal spray/orally disintegrated tablet) and numerous emerging drugs in overactive bladder, nocturia, neurogenic detrusor overactivity, bladder pain syndrome, or benign prostatic hyperplasia.

Traumatismo craneoencefálico e hiponatremia, una asociación a tener en cuenta / Brain trauma and hyponatremia, an association to consider

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Obesidad hipotalámica tras intervención quirúrgica de un craneofaringioma: tratamiento con un análogo del péptido similar al glucagón tipo 1 / Hypothalamic obesity after craniopharyngioma surgery: Treatment with a long acting glucagon like peptide 1 derivated

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Síndrome de Cushing por hiperplasia suprarrenal macronodular bilateral con receptores aberrantes / Cushing's syndrome in a patient with macronodular adrenal hyperplasia secondary to aberrant hormone receptors

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Tratamiento farmacológico en la insuficiencia cardiaca aguda / Drug therapy for acute heart failure

La insuficiencia cardiaca aguda es una de las causas de hospitalización más frecuentes y continúa conllevando dificultades para la elección del mejor tratamiento para mejorar la evolución clínica del paciente. Según lo indicado por las guías internacionales, en cuanto los pacientes con insuficiencia cardiaca aguda llegan al servicio de urgencias, el enfoque terapéutico habitual tiene como objetivo la mejoría de los signos y síntomas, corregir la sobrecarga de volumen y mejorar la hemodinámica cardiaca aumentando la perfusión de los órganos vitales. El tratamiento recomendado para tratar de manera inmediata la insuficiencia cardiaca aguda se caracteriza por el uso de diuréticos intravenosos, oxigenoterapia y vasodilatadores. Aunque estas medidas alivian los síntomas del paciente, no tienen una influencia favorable en la mortalidad a corto y largo plazo. Por consiguiente, hay una necesidad acuciante de nuevos fármacos para el tratamiento de la insuficiencia cardiaca aguda, lo que hace que la investigación en este campo aumente en todo el mundo (AU)

Acute heart failure is globally one of most frequent reasons for hospitalization and still represents a challenge for the choice of the best treatment to improve patient outcome. According to current international guidelines, as soon as patients with acute heart failure arrive at the emergency department, the common therapeutic approach aims to improve their signs and symptoms, correct volume overload, and ameliorate cardiac hemodynamics by increasing vital organ perfusion. Recommended treatment for the early management of acute heart failure is characterized by the use of intravenous diuretics, oxygen, and vasodilators. Although these measures ameliorate the patient's symptoms, they do not favorably impact on short- and long-term mortality. Consequently, there is a pressing need for novel agents in acute heart failure treatment with the result that research in this field is increasing worldwide (AU)

Eficacia de tolvaptán en pacientes ingresados por insuficiencia cardiaca e hiponatremia refractaria. Experiencia en la práctica clínica diaria / Efficacy of tolvaptan in patients hospitalized for heart failure with refractory hyponatremia. Clinical experience in daily practice

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Evaluation of lixivaptan in euvolemic and hypervolemic hyponatremia and heart failure treatment.

INTRODUCTION: Lixivaptan is a selective vasopressin type 2 (V2) receptor antagonist that induces aquaresis, the electrolytes sparing excretion of water. Its ability to correct hyponatremia has been demonstrated in experimental animal studies as well as in clinical trials in humans. Recently, three Phase III, double-blind, randomized, placebo-controlled studies have been completed. In two studies, patients with euvolemic hyponatremia were enrolled, one in the inpatient and the other in the outpatient setting and the third study involved patients with hypervolemic hyponatremia hospitalized for decompensated heart failure (HF). The trials confirmed the efficacy of lixivaptan in raising serum sodium but raised concern about its safety in patients hospitalized with decompensated HF. AREAS COVERED: The authors review original publications on lixivaptan and summarize their findings. Specifically, the authors present information regarding its structure, pharmacodynamics and kinetics, metabolism as well as its efficacy and safety in laboratory animals and human studies. Furthermore, the FDA website was accessed to obtain information presented at the September 13, 2012 meeting of the Cardiovascular and Renal Drugs Advisory Committee. EXPERT OPINION: The published data indicate that lixivaptan raises sodium levels in hyponatremic patients and supports its use in patients with euvolemic hyponatremia. However, the authors note that more safety data are still needed specifically in patients with decompensated HF.

Atrial fibrillation or flutter on initial electrocardiogram is associated with worse outcomes in patients admitted for worsening heart failure with reduced ejection fraction: findings from the EVEREST Trial.

BACKGROUND: Heart failure (HF) complicated by atrial fibrillation/flutter (AF/AFL) is associated with worse outcomes. However, the clinical profile and outcomes of patients following hospitalization for HF with AF/AFL on initial electrocardiogram (ECG) has not been well studied. METHODS: EVEREST was a randomized trial of vasopressin-2 receptor blockade, in addition to standard therapy, in 4133 patients hospitalized with HF with ejection fraction ≤40%. A post hoc analysis was performed comparing the clinical characteristics and outcomes [all-cause mortality and cardiovascular mortality/HF hospitalization] of patients with AF/AFL versus sinus rhythm (SR) on baseline ECG, which were centrally analyzed. Times to events were compared using log-rank tests and Cox regression models. RESULTS: Of the 4133 patients, 1195 (29%) were classified with AF/AFL and 2071(50%) with SR. The remaining patients (21%) were excluded because ECGs were unavailable (n = 106), rhythm was paced (n = 727), or junctional/other supraventricular (n = 34). AF/AFL patients were older, with increased weight, faster heart rate, higher blood urea nitrogen, and natriuretic peptide levels compared to SR patients. Anticoagulation was prescribed in 67% of AF/AFL patients on discharge. AF/AFL patients were less likely to receive ß-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (all P < .05). After risk adjustment, AF/AFL was associated with increased mortality (hazard ratio 1.23; 95% CI, 1.04-1.46) and cardiovascular mortality/HF hospitalization (hazard ratio 1.26; 95% CI, 1.07-1.47). CONCLUSION: AF/AFL on initial ECG in patients hospitalized with HF with reduced ejection fraction is associated with lower use of evidence-based therapies and increased mortality and rehospitalization compared to patients in SR.

La onda R prominente en V1 pero no en V2 es un signo específico de infarto transmural lateral grande / A prominent R wave in V 1 but not in V2 is a specific sign of a large lateral transmural infarction

Introducción y objetivos. Si no hay hipertrofia ventricular derecha o bloqueo de rama del haz, se considera que la presencia de una onda R prominente en V1 o V2 refleja un infarto de miocardio de la pared lateral. Hemos investigado las diferencias existentes en cuanto a localización, tamaño y extensión transmural del infarto entre los pacientes con una onda R prominente en V1 y los que presentan una onda R prominente en V2. Métodos. Estudiamos a 50 pacientes con un primer infarto previo que había afectado a la pared inferior y/o lateral del ventrículo izquierdo utilizando resonancia magnética con contraste. Resultados. Se observó la presencia de una onda R prominente en V1 en 8 pacientes (16%) y en V2 en 23 pacientes (46%). En las imágenes de resonancia magnética, el infarto afectaba a la pared inferior en 11 pacientes (22%), la pared lateral en 6 (12%) y ambas en 33 (66%). La sensibilidad de la presencia de una onda R prominente en V1 para la detección de un infarto de cara lateral fue baja (17,9%), mientras que la especificidad fue alta (90,9%). La sensibilidad y la especificidad de una onda R prominente en V2 fueron del 46,2 y el 54,5% respectivamente. En los pacientes con una onda R prominente en V1, el tamaño del infarto y la extensión lateral y transmural fueron mayores que en los pacientes que no mostraban este patrón (p < 0,005, p < 0,001 y p < 0,05 respectivamente); en cambio, el tamaño del infarto y la extensión transmural en la pared inferior y en su segmento posterobasal no mostraron diferencias significativas. En los pacientes con una onda R prominente en V2, el tamaño del infarto y la extensión lateral y transmural no fueron diferentes de lo observado en los pacientes sin ese patrón. Conclusiones. Tan sólo la presencia de una onda R prominente en V1 constituye un signo específico de un infarto lateral grande y transmural (AU)

Introduction and objectives. In the absence of right ventricular hypertrophy or bundle-branch block, a prominent R wave in V1 or V2 is considered to reflect a lateral myocardial infarction. We investigated the differences in infarct location, size and transmural extent between patients with prominent R wave in V1 and those with prominent R wave in V2. Methods. We studied 50 patients with a previous first infarction involving left ventricular inferior and/or lateral wall at contrast-enhanced magnetic resonance. Results. A prominent R wave in V1 was present in 8 patients (16%), in V2 in 23 (46%). At magnetic resonance, the infarction involved the inferior wall in 11 patients (22%), the lateral wall in 6 (12%), and both walls in 33 patients (66%). The sensitivity of a prominent R wave in V1 in detecting a lateral infarction was low (17.9%), while the specificity was high (90.9%). The sensitivity and specificity of a prominent R wave in V2 were 46.2% and 54.5%, respectively. In patients with a prominent R wave in V1, infarct size and lateral and transmural extent were greater than in patients without this pattern (P<.005, <.001, and <.05, respectively); conversely, infarct size and transmural extent in the inferior wall and in its basal-posterior segment were not significantly different. In patients with a prominent R wave in V2, infarct size, lateral and transmural extent were not different from patients without this pattern. Conclusions. Only a prominent R wave in V1 is a specific sign of large and transmural lateral infarction (AU)

Gender does not affect postdischarge outcomes in patients hospitalized for worsening heart failure with reduced ejection fraction (from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan [EVEREST] Trial).

Women have traditionally been underrepresented in heart failure (HF) trials, and their baseline characteristics and outcomes after hospitalization for HF are unclear. We retrospectively analyzed the clinical characteristics and outcomes of patients according to gender in the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. EVEREST randomized 4,133 patients hospitalized for HF and ejection fraction of ≤40% to tolvaptan or placebo, in addition to standard therapy. The median follow-up was 9.9 months. Log-rank tests and multivariate Cox regression models were used to compare the hazards of all-cause mortality and cardiovascular mortality or HF hospitalization. Women constituted 1,058 (26%) of the study population. The baseline characteristics were similar except that the women were older with more hypertension and diabetes and less chronic renal insufficiency, previous myocardial infarction, previous coronary revascularization, and baseline defibrillator implantation (all p <0.001). The baseline use of evidence-based HF medical therapies was similar between genders (all p >0.30). Despite a high event rate, no difference was seen in all-cause mortality (men 27% vs women 24%, multivariate hazard ratio 1.04, p = 0.61) or cardiovascular mortality plus HF hospitalization (men 42% vs women 39%, multivariate hazard ratio 1.11, p = 0.10) on univariate analysis or after adjusting for baseline covariates. In conclusion, women hospitalized for worsening HF with an ejection fraction of ≤40% were older, had more hypertension, and had received fewer procedure-based interventions than men but had relatively similar HF medication usage and clinical findings. After hospitalization for HF, women have a similarly high risk of long-term HF morbidity and mortality compared with men.

Shock séptico. Actualización en tratamiento con suero salino hipertónico y hormona antidiurética-vasopresina / Septic shock. Update of treatment using hypertonic saline and antidiuretic hormone-vasopressin

La seguridad en el uso del suero salino hipertónico ha sido comprobada por estudios en el campo de la reanimación con pequeños volúmenes para el shock hipovolémico y en el tratamiento de la hipertensión intracraneal. En el ámbito del shock séptico, ha sido poco experimentado en seres humanos. Existen efectos inmunomodulatorios beneficiosos detectados en estudios preclínicos. Las interacciones con el eje hipofisario-adrenal y con la secreción de la hormona antidiurética son diversas y sugerentes, pero insuficientemente entendidas. Por otra parte, la vasopresina ejerce acciones cardiovasculares, osmorreguladoras, sobre la coagulación y también sobre el eje hipotálamo-hipofisario-adrenal. En el shock séptico hay un déficit relativo de vasopresina. Su uso en estos pacientes no parece presentar ventajas en cuanto a la mortalidad, pero puede ser beneficioso en pacientes en riesgo de insuficiencia renal aguda o en aquellos que reciben corticoides. La terlipresina es un análogo de la vasopresina que también se ha estudiado. La sinergia entre la vasopresina y el suero salino hipertónico es una hipótesis que se fundamenta, sobre todo, en estudios preclínicos. El uso del suero salino hipertónico en el shock séptico sigue siendo experimental, aunque prometedor, y debe quedar restringido al campo de los ensayos clínicos controlados(AU)

Safety in the use of small volumes of hypertonic saline solution for hypovolaemic shock and in the treatment of intracranial hypertension has been demonstrated in studies in the field of resuscitation. There is little experience of this for septic shock in humans. Beneficial immunomodulatory effects have been detected in pre-clinical studies. Interactions with the pituitary-adrenal axis and with the secretion of anti-diuretic hormone are varied and suggestive, but are not sufficiently understood. On the other hand, vasopressin has cardiovascular, osmoregulatory, and coagulation effects, and also acts on the hypothalamic-pituitary-adrenal axis. There is a relative deficit of vasopressin in septic shock. Its use in these patients does seem to have any advantages as regards mortality, but may be beneficial in patients at risk from acute renal failure, or those who receive corticosteroids. Terlipressin is a vasopressin analogue that has also been studied. The synergy between vasopressin and hypertonic saline is a hypothesis that is mainly supported in pre-clinical studies. The use of hypertonic saline solution in septic shock, although promising, is still experimental, and must be restricted to the field of controlled clinical trials(AU)

A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90 days: analysis from the EVEREST trial.

Hospitalization for worsening chronic heart failure results in high post-discharge mortality, morbidity, and cost. However, thorough characterization, soon after discharge of patients with early post-discharge events has not been previously performed. The objectives of this study were to describe the baseline, in-hospital, and post-discharge clinical, laboratory, and neurohormonal profiles of patients hospitalized for worsening heart failure with reduced ejection fraction (EF) who die or are re-admitted for cardiovascular (CV) causes within 90 days of initial hospitalization. Retrospective analysis of 4,133 patients hospitalized for worsening heart failure with EF ≤40% in the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial, which randomized patients to tolvaptan or placebo, both in addition to standard therapy. Clinical and laboratory parameters were obtained within 48 h of admission, during hospitalization, and post-discharge weeks 1, 4, 8, and every 8 weeks thereafter for a median of 9.9 months. Patients with events within 90 days were compared with those with later/no events. All-cause mortality (ACM) and CV re-hospitalization were independently adjudicated. Within 90 days of admission, 395 patients (9.6%) died and 801 patients (19.4%) were re-hospitalized for CV causes. Significant baseline and longitudinal differences were seen between groups with early versus later (>90 days) or no events at 12 months post-randomization. Post-discharge outcomes were similar in the tolvaptan and placebo groups. Patients with early post-discharge events experienced clinically significant worsening in signs and symptoms, laboratory values, and neurohormonal parameters soon after discharge. Identifying these abnormalities may facilitate efforts to reduce post-discharge mortality and re-hospitalization.

The therapeutic use of vaptans for the treatment of dilutional hyponatremia.

Hyponatremia is a very common electrolyte abnormality. Dilutional hyponatremia is very difficult to treat effectively due to the complications of conventional treatment. Arginine-vasopressin (AVP) plays an integral role in circulatory and water homeostasis. AVP is a hormone released in response to increases in plasma tonicity or decreases in plasma volume in an attempt to maintain the plasma osmolality between 284 and 295 mOsm/L. AVP receptor antagonists or "vaptans" are a new class of drugs that allow for the safe and efficacious treatment of dilutional hyponatremia. Conivaptan, a mixed V1a/V2 receptor antagonist, and tolvaptan, a selective V2 receptor antagonist, are the only 2 vaptans approved by the US Food and Drug Administration.

Vasopressin and vasopressin antagonists in heart failure and hyponatremia.

Increased synthesis of arginine vasopressin (AVP) plays a critical role in fluid retention and hyponatremia in patients with heart failure. The AVP receptor antagonists constitute a new class of agents that are promising in the management of hyponatremia and congestion. Three of these agents--conivaptan, tolvaptan, and lixivaptan--have been studied in clinical settings. All are effective in inducing aquaresis (ie, electrolyte-free water excretion) and normalizing serum sodium concentration. They are well tolerated without causing electrolyte disorders, hypotension, or renal impairment. Conivaptan has been approved by the US Food and Drug Administration for short-term intravenous treatment of euvolemic hyponatremia of variable etiology but has not been adequately studied in heart failure. The addition of tolvaptan to standard therapy in hospitalized patients with heart failure has led to symptomatic improvement and decreased body weight, but there is no long-term clinical benefit. Early data on lixivaptan in heart failure suggest a dose-dependent aquaresis effect, and larger studies are under way.

Malformación cavernomatosa de la vena porta / Cavernomatous malformation of the portal vein

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