Presentation on theme: "HYPONATREMIA AND THE EMERGING ROLE OF TOLVAPTAN IN CARDIOLOGY"— Presentation transcript:
1HYPONATREMIA AND THE EMERGING ROLE OF TOLVAPTAN IN CARDIOLOGY DR SHREETAL RAJAN NAIR
2HyponatremiaHyponatremia, defined as a serum sodium <135 mEq/L, is the most common electrolyte disorder encountered in hospitalized patients.Is a significant independent predictor of medical prognosis andcosts.
3Prevalence of hyponatremia Prevalence of hyponatremia ([Na+] <135 mEq/L):28% in hospitalized patients21% in hospital clinics and7% in outpatient community care clinicsClin Chim Acta. 2003;337(1-2):
4Prevalence of hyponatremia in hospitalized patients with heart failure or cirrhosis Gheorghiade M, Rossi JS, Cotts W et al. Arch Intern Med. 2007;167(18): ,Angeli P, Wong F, Watson H, Gines P. Hepatology. 2006;44(6):
5Classification of hyponatremia Hypervolemic hyponatremia,Euvolemic hyponatremia,Hypovolemic hyponatremia
6Hypervolemic hyponatremia Dilutional form of hyponatremia, occurs when there is an increase in total body water but a relatively smaller increase in the total serum sodium.3 primary causes of hypervolemic hyponatremia:HF,Cirrhosis of the liver, andRenal disease.Clinical signsevidence of volume expansion, such as the presence of clinically evident edema, ascites, and pulmonary edema
7Euvolemic hyponatremia It occurs when there is an increase in total body water without a corresponding increase in total serum sodium, though the increase in body water is not sufficient to promote clinically evident edema.Causes:Syndrome of inappropriate antidiuretic hormone (SIADH)Patients with euvolemic hyponatremia have no signs of volume depletion or volume expansion.
8Hypovolemic hyponatremia Depletional form of hyponatremia, occurs when there is a decrease in both total body water and total serum sodium, with a disproportionately greater decrease in serum sodium.Hypovolemic hyponatremia is usually due to an excess of fluid loss. It is commonly caused by fluid loss through vomiting or diarrhea or is due to the use of diuretic therapy.Clinical signs of volume depletion include orthostatic decreases in blood pressure, increases in pulse rate, dry mucus membranes, and decreased skin turgor
9Description of hyponatremia Dilutional hyponatremiaDepletional hyponatremiaHypervolemicEuvolemicHypovolemicIncrease in total body water with a relatively smaller increase in the total serum sodium; presence of clinically evident edemaMild to moderate increase in total body water with normal or near normal sodium levels; absence of clinically evident edemaDecrease in total body water with a disproportionately greater decrease in total serum sodium; presence of clinically evident volume depletion
10Causes of hyponatremia Dilutional hyponatremiaDepletional hyponatremiaHypervolemicEuvolemicHypovolemicHeart failure (HF)CirrhosisRenal disease(nephrotic syndromeand renal failure)Glucocorticoid deficiencyHypothyroidismSIADH, resulting from the following:Neurologic or CNS disorders such as mass lesions, inflammatory diseases,degenerative demyelinative diseasesA range of cancers, including lung, pancreatic, prostate/ureteral, uterine, throat, and leukemiaPulmonary diseases, such as infections, respiratory failure, or chronic obstructive pulmonary disease (COPD)AIDS and AIDS-related complex Drug-inducedDiuretic therapyCerebral salt wastingMineralocorticoiddeficiencySalt-wasting nephropathyBicarbonaturia, glucosuria,ketonuriaGastrointestinal losses, includingvomiting and diarrheaThird-space losses suchas bowel obstruction, pancreatitis,muscle trauma, and burnsSweat losses
14VasopressinIs a nine-amino-acid peptide synthesized in the neurosecretory cells of the supraoptic and paraventricular nuclei of the hypothalamus and is stored in the posterior pituitary gland.Upon its release, vasopressin binds to and activates V2-receptors in the renal collecting duct, leading to the insertion of water channels into the wall of the collecting duct by a cAMP-dependent mechanism.This series of events stimulates water reabsorption.Thus, increased vasopressin promotes an increase in electrolyte-free water reabsorption and more concentrated urine as water passively diffuses out of the renal tubule.Circulating vasopressin can also cause vasoconstriction by activating V1a-receptors on smooth muscle cells in blood vessels. V1b-receptors are found on corticotropes, and they contribute to increased ACTH secretion.
15Vasopressin The primary role of vasopressin is to control total body water, electrolyte balance, and blood pressure by regulating vascular tone and water excretion by the kidney.Increased vasopressin levels due to nonosmotic hemodynamic stimuli is the mechanism responsible for water retention and hyponatremia in edema-forming disorders such as HF and cirrhosis.
16Heart failure: HF patients may have increased vasopressin secretion in response to decreases in arterial blood pressure and circulating blood volume.Decrease in blood volume or blood pressure of approximately 8% to 10% - stimulates vasopressin secretion.The underloading of arterial baroreceptors is responsible for the stimulation of vasopressin secretion.Vasopressin increases the passive reabsorption of electrolyte-free water in the kidney in an attempt to restore perfusion pressure- may result in hypervolemic hyponatremia.
19Receptor subtypes that mediate the actions of vasopressin
20Factors stimulating the release of vasopressin The 2 key mechanisms regulating fluid/electrolyte balance areRenal water reabsorption, due to vasopressin, andDrinking behavior driven by thirst perception.Vasopressin increases passive water reabsorption in the kidney and results in more concentrated urine, which is reflected by increased urine osmolality.Hyponatremia may result from sodium loss, excessive fluid intake, or, more frequently, water retention.
21Factors stimulating the release of vasopressin Osmotic stimuliNonosmotic stimuli of vasopressin release: These stimuli include decreased effective arterial blood volume or blood pressure, pain, nausea, stress, and a variety of drugs.Decreases of approximately 8% to 10% in arterial blood pressure and circulating blood volume may activate baroreceptors in the carotid sinus, aortic arch, cardiac atria, and pulmonary venous system, which stimulate the release of vasopressin.Vasopressin release due to nonosmotic stimuli is responsible for the predominance of euvolemic and hypervolemic hyponatremia (e.g., SIADH, HF, or Cirrhosis).
22Why recognising and treating hyponatremia is important ?
24Hyponatremia - HFThe Organized Program to Initiate Life Saving Treatment in Patients Hospitalized for Heart Failure (OPTIMIZE-HF) registry recorded that 25.3% of 47,647 heart failure patients had hyponatremia on admission.In this registry, patients with hyponatremia had increased in-hospital and postdischarge mortality and longer median hospital stay compared with those with higher sodium levels..OPTIMIZE-HF registry, Eur Heart J, 2007;28(8):980–88.
25Hyponatremia Is Associated with Higher Mortality Lancet. 1982;2(8289):101-2.Clin Sci. 1939;4:73-7.Br Med J. 1983;286(6366):671-3.Br Med J. 1979;1(6173):
26Hyponatremia - HFCurrently, there are no guidelines for the appropriate way to deal with low serum sodium levels in heart failure patients;Treatment generally consists of fluid restriction, which has not been clinically examined in this setting.Vasopressin receptor antagonists that selectively increase solute-free water excretion by the kidneys are showing evidence of being effective for the treatment of hyponatremia in heart failure.
27Rationale of present therapies Increase the amount of sodium in the bodyDecrease intake of waterPrevent water reabsorption into the body and prevent dilution
28Current therapies of hyponatremia Isotonic and hypertonic saline for short-term use, and fluid restriction, demeclocycline, salt tablets, and rarely mineralocorticoids and urea for long-term use.All of these therapies work in specific circumstances, but none are ideal and all have limitations for a variety of different reasons, including variable efficacy, slow responses, intolerable side effects such as thirst, and dangerous toxicities such as ODS.
29Current therapies of hyponatremia Fluid restrictionIs that fluid restriction usually cannot be sustainedBecause it produces intolerable dehydration and thirst.Secondly, fluid restriction works very slowly—generally 1 to 2 mEq/L per day even under a severe fluid restriction of <500 mL/d.Consequently, this method can take many days to correct a low serum [Na+].Fluid restriction, long the mainstay of treating chronic hyponatremia, is arguably the least expensive and potentially the safest treatment. But its major drawback, reported as early as in the initial description of SIADH in 1957, is that fluid restriction usually cannot be sustainedbecause it produces intolerable dehydration and thirst. Secondly, fluid restriction works very slowly—generally 1 to 2 mEq/L per day even under a severe fluid restriction of <500 mL/d. Consequently, this method can take many days to correct a low serum [Na+].Am J Med. 1957;23(4):
30Current therapies of hyponatremia All treatments other than demeclocycline and the vaptans fail to attack the mechanistic cause of dilutional hyponatremia, which is inappropriately elevated plasma AVP levels.
31Treatments for Hyponatremia TherapyLimitationsIsotonic salineIneffective in dilutional hyponatremias; can’t be used in edema-forming disorders; no controlled safety databaseHypertonic salineNo consensus re appropriate infusion rates; overcorrection can cause osmotic demyelination; can’t be used in edema-forming disorders; no controlled safety databaseFluid restrictionSlow to correct over many days; poorly tolerated due to thirst; unsuccessful with high AVP levels and urine osmolalitiesDemeclocyclineNot FDA approved for hyponatremia; slow to correct;nephrotoxic in cirrhosis and CHF
32Treatments for Hyponatremia TherapyLimitationsMineralocorticoidOnly one report in elderly patients with SIADH; no safety database; can’t be used in edema-forming disordersUreaNo USP formulation; not FDA approved for hyponatremia; poor palatability
33Aquaretic therapiesThe newest addition in hyponatremia treatment
34rationale for aquaretic therapies The appropriate method of treating hyponatremia in HF is by removing excess total body waterThat is the objective of fluid restriction that decreases body water via insensible losses of water, but very inefficiently and very slowly.A better therapy would be blocking the process of urinary concentration, which originates from AVP binding to the V2 receptor in the kidney and would prevent all the downstream intracellular consequences of V2 receptor activation including the insertion of the aquaporin water channels into the apical membrane of the collecting duct cells.
38Was approved by US FDA in february 19,2009 Tolvaptan (INN), also known as OPC-41061, is a selective, Competitive vasopressin receptor 2 antagonist used to treat hyponatremia (low blood sodium levels) associated with congestive heart failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone (SIADH).
39TolvaptanMechanism of action of the Tolvaptan: stimulate increased water excretion from the kidney.Importantly, blocking the V2 receptor has no effect on sodium or potassium excretion; it simply causes increased excretion of water without increased solute.Therefore, vaptans are electrolyte-sparing, and it is more appropriate to call their effect “aquaresis” or increased urinary water excretion rather than diuresis, which classically has been defined as increased urinary water and solute (particularly sodium and potassium) excretion.
40Mechanism of actionTolvaptan is a selective vasopressin V2-receptor antagonist with an affinity for the human V2-receptor 1.8 times that of native vasopressin.Tolvaptan affinity for the V2-receptors is approximately 29 times that for the V1a-receptor.Urinary excretion of sodium and potassium, and plasma potassium concentrations are not significantly changed.When taken orally, 15- to 60-mg doses of tolvaptan antagonize the effect of vasopressin and cause an increase in urine water excretion that results in an increase in free water clearance (aquaresis), a decrease in urine osmolality, and a resulting increase in serum sodium.Am J Med. 2007;120(suppl 11A):S1-S21
42Targeted MOA: Vasopressin V2-receptor antagonism Binding of a V2-receptor antagonist, such as tolvaptan, blocks the activation of the receptor by endogenous vasopressin.The resulting increase in urine output produced by a V2-receptor antagonist is quantitatively similar to diuretics such as loop diuretics, but qualitatively different in that electrolyte-free water is excreted without a significant increase in urine solute excretion, including sodium and potassium.For this reason, the renal effects produced by V2-receptor antagonists are termed aquaresis, to distinguish them from the renal effects produced by some diuretic agents, which include not only increased water excretion but also natriuresis and kaliuresis
43Dosing and titrationThe usual starting dose for (tolvaptan) is 15 mg administered once daily without regard to meals.The dose of Tolvaptan may be increased to 30 mg once daily, after at least 24 hours, to a maximum of 60 mg once daily, as needed to achieve the desired level of serum sodium.During initiation and titration, frequently monitor for changes in serum electrolytes and volume to prevent overcorrection of serum sodium
44Dosage and administration Route of administration: OralInitial dose (hospitalization: mgrequired)Dose range (titrated to : –60 mgresponse)Frequency of administration Once daily
45Pharmacokinetic profile Peak plasma concentration:(mean) [ng/mL]Time to achieve peak plasma:concentration (median) [h]Area under the plasmaconcentration-time curve overthe 24-hour dosage interval(mean) [ng • h/mL]Elimination half-life (mean) [h]
46Tolvaptan is contraindicated in the following conditions: Urgent need to raise serum sodium acutelyInability of the patient to sense or appropriately respond to thirstHypovolemic hyponatremiaConcomitant use of strong CYP 3A inhibitorsAnuric patients
47Adverse effectsProblems with speech or muscle control, trouble swallowing, trouble moving your arms and legs, mood changes, and seizure (convulsions) – may be osmotic demyelination syndrome due to rapid correction of sodiumweakness or fainting;melaena;Hemoptysis,hemetemesis;Less serious side effects may include:dry mouth;increased thirstabnormal frequent urination (pollakiuria)constipation; orloss of appetite, fruity breath odor, drowsiness, dry skin, nausea, vomiting.
49Study of Ascending Levels of Tolvaptan in Hyponatremia SALT 1 & 2Study of Ascending Levels of Tolvaptan in Hyponatremia
50SALT-1 and SALT-2Multicenter, randomized, double-blind, placebo-controlled trials, the efficacy of tolvaptan was evaluated in patients with euvolemic and hypervolemic hyponatremia.N= 448 patientsHypervolemic or euvolemic hyponatremia resulting from (HF, cirrhosis, or SIADH)Oral placebo (n=223) orOral Tolvaptan (n=225) in a titrated regimen of 15 to 60 mg once daily.N Engl J Med 2006;355:
52Inclusion/exclusion criteria Inclusion criteria:Exclusion criteria:18 years of age or olderHad hypervolemic or euvolemic hyponatremia (serum sodium <135 mEq/L) associated with HF, cirrhosis, or SIADHPsychogenic polydipsiaHead traumaPostoperative conditionsUncontrolled hypothyroidism or adrenal insufficiencyHyponatremic conditions associated with the use of medications that could have been safely withdrawnClinically evident hypovolemic hyponatremia
53Study Assessments Patients were evaluated at baseline, 8 hours after the first administration of the study drug (tolvaptanor placebo), and on days 2, 3, 4, 11, 18, 25, 30, and 37.Study drugs were withheld after day 30,and the effect of discontinuation of the study drug was assessed on day 37
54Primary end pointsThe change in the average daily area under the curve (AUC) for the serum sodium concentrationfrom baseline to day 4from baseline to day 30
55Secondary end pointsthe change in the AUC for the serum sodium concentration in patients with marked hyponatremia,the absolute serum sodium concentration at each visit,the time to normalization of the serum sodium concentration,the percentages of patients with serum sodium concentrations that had normalized at day 4 and day 30, and the categorical serum sodium concentration on day 4 and day 30 (normal value >135 mmol per liter; mild hyponatremia, 130 to 135 mmol per liter as conservatively extended for the analysis of categorical change; or marked hyponatremia <130 mmol per liter) for patients with mild or marked hyponatremia at baseline.Other secondary end points were fluid intake and output on day 1,change in body weight in patients with hypervolemic hyponatremia on day 1, fluid restriction or use of intravenous saline as rescue therapy,
60Subjects with serum sodium <135 mEq/L (ITT population) ResultsTolvaptan15–60 mg/dayPlaceboEstimated effectSubjects with serum sodium <135 mEq/L (ITT population)Change in average daily serum [Na+] AUC: baseline to day 4 (mEq/L) mean (SD)(n)4.0 (2.8)(213)0.4 (2.4)(203)3.7 ( )P<0.0001Change in average daily serum [Na+] AUC:baseline to day 30 (mEq/L) mean (SD)6.2 (4.0)1.8 (3.7)4.6 ( )
61Subgroup with serum sodium <130 mEq/L ResultsTolvaptan15–60 mg/dayPlaceboEstimated effectSubgroup with serum sodium <130 mEq/LChange in average daily serum [Na+] AUC:baseline to day 4 (mEq/L) mean (SD)(n)4.8 (3.0)(110)0.7 (2.5)(105)4.2 ( )P<0.0001Change in average daily serum [Na+] AUC: baseline to day 30 (mEq/L) mean (SD)7.9 (4.1)2.6 (4.2)5.5 ( )
62Subgroup with serum sodium <125 mEq/L ResultsTolvaptan15–60 mg/dayPlaceboEstimated effectSubgroup with serum sodium <125 mEq/LChange in average daily serum [Na+] AUC: baseline to day 4 (mEq/L) mean (SD)(n)5.7 (3.8)(26)1.0 (1.8)(30)5.3 ( )P<0.0001Change in average daily serum [Na+] AUC:baseline to day 30 (mEq/L) mean (SD)10.0 (4.8)4.1 (4.5)5.7 ( )
68Summary – SALT 1 and SALT -2 A total of 424 patients with euvolemic and hypervolemic hyponatremia (serum sodium <135 mEq/L) were treated for 30 days with tolvaptan or oral placebo, then followed for an additional 7 days after withdrawal.The primary end point for these studies was the average daily AUC for change in serum sodium from baseline to day 4 (tolvaptan, 4.0 mEq/L vs placebo, 0.4 mEq/L) and baseline to day 30 (tolvaptan, 6.2 mEq/L vs placebo, 1.8 mEq/L) in patients with a serum sodium <135 mEq/L.
69Summary – SALT 1 & 2Patients received either tolvaptan or placebo, at a starting dose of 15 mg. The dosage of tolvaptan or placebo was increased to 30 mg or 60 mg, if necessary. During the 7-day discontinuation/follow-up period, serum sodium concentrations in patients treated with tolvaptan declined to placebo-like levels.In patients with euvolemic or hypervolemic hyponatremia, tolvaptan, an oral vasopressin V2-receptor antagonist, was effective in increasing serum sodium concentrations at day 4 and day 30.
70Extension study of the SALT trials SALTWATERExtension study of the SALT trials
71SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2J Am Soc Nephrol 2010, 21(4):
80Results & conclusion- SALTWATER Mean serum sodium increased from mmol/L at baseline to 135 mmol/L throughout the observation period (P versus baseline at most points).Conclusion: Prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety.
81EVERESTEfficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan
83Inclusion criteria Patients 18 years of age or older with reduced left ventricular ejection fraction (40%), signs of volume expansion,New York Heart Association class III/IV symptoms, andHospitalization for exacerbation of chronic HF no more than 48 hours earlier were eligible for the study.
84Exclusion criteria Cardiac surgery within 60 days of enrollment, cardiac mechanical support, biventricular pacemaker placement within the last 60 days,comorbid conditions with an expected survival of less than 6 months,acute myocardial infarction at the time of hospitalization,hemodynamically significant uncorrected primary cardiac valvular disease,refractory end-stage HF,hemofiltration or dialysis,supine systolic arterial blood pressure less than 90 mm Hg,serum creatinine level greater than 3.5 mg/dL (309 μmol/L),serum potassium level greater than 5.5 mEq/L, andhemoglobin level less than 9 g/dL.
85STUDY POPULATIONA total of 2072 patients in tolvaptan group and patients in placebo group hospitalized with heart failure
86InterventionPatients were randomized to receive either tolvaptan (30 mg/d) or matching placebo, within 48 hours of admission
87Primary end points The outcome study had 2 primary end points: all-cause mortality andthe composite of cardiovascular death or hospitalization for HF
88Secondary end pointsthe composite of cardiovascular mortality or cardiovascular hospitalization;incidence of cardiovascular mortality;and incidence of clinical worsening of HF (death, hospitalization for HF, or unscheduled visit for HF)
89Additional secondary end points included changes from baseline in body weight at day 1,serum sodium level at day 7 or discharge in patients with a baseline serum sodium level of less than 134 mEq/L,edema score at day 7 or discharge for those with edema at baseline,patient-assessed dyspnea at day 1 for those with dyspnea at baseline,
97Conclusion : EVERESTTolvaptan modestly improves dyspnoea compared with standard therapy alone, regardless if given early or relatively late after hospitalization, and also across major pre-specified subgroups
98ECLIPSE: EffeCt of toLvaptan on hemodynamIc Parameters in Subjects with hEart failure
109End pointsThe primary endpoint of the current study was body weight change from the baseline at the end of treatment.The secondary endpoints were changes in congestive symptoms,including lower limb edema, pulmonary congestion, jugularvenous distention hepatomegaly, pulmonary rales and thirdheart sound induced with fluid retention
119serum osmolality (c) and plasma renin activity (d)
120Time-course of serum Na+ levels in patients with serum Na+ ≥135 mEq/L (a) or <135 mEq/L (b) at baseline
121Quest StudyResults: Compared with placebo, tolvaptan administered for 7 days significantly reduced body weight and improved symptoms associated with volume overload. The safety profile of tolvaptan was considered acceptable for clinical use with minimal adverse effects.Conclusion: Tolvaptan reduced volume overload and improved congestive symptoms associated with HF by a potent water diuresis (aquaresis).
122ACTIV in CHF trial:Effects of Tolvaptan, Vasopressin Antagonist, in Patients Hospitalized With Worsening Heart Failure delete
124End points The study had 2 primary end points designed to assess the acute (in-hospital) and the intermediate-term (outpatient ,after hospital discharge) effects of the study drug.The in-hospital end point was change in body weight at 24 hours after the administration of the first dose of study drugThe outpatient end point was worsening heart failure at 60 days after randomization
125Secondary end points Secondary end points included changes in dyspnea, JVD, rales, edema,body weight (at discharge and in the outpatient setting)urine output (in patient)serum electrolyte levelslength of hospital stay after randomizationuse of diureticspatient and physician-assessed symptom scales
131Signs and Symptoms of Heart Failure at Day 1 and at Hospital Discharge P>0.05 for all comparisons of tolvaptan vs placebo except for dyspnea at discharge, for which P=.04. JVD indicates jugular venous distention.