Short Term Efficacy and Safety of Low Dose Tolvaptan in Patients With

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Original Article

Short Term Efficacy and Safety of Low Dose Tolvaptan in Patients with Acute Decompensated Heart Failure with Hyponatremia: A Prospective Observational Pilot Study from a Single Center in South India

Soumya Patra, Basant Kumar, Kaushal K. Harlalka, Apoorva Jain, H. M. Bhanuprakash, K. S. Sadananda, Harsha Basappa, K. Santhosh, K. S. Rajith, K. S. Bharathi, C. N. Manjunath Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Mysore Branch, K.R. Hospital Campus, Mysore, Karnataka, India

ABSTRACT

Background: In acute decompensated heart failure (ADHF), diuretic use, the mainstay therapy for congestion, is associated with electrolyte abnormalities and worsening renal function. Vasopressin mediates fluid retention in heart failure. In contrast to diuretics, the vasopressin antagonist tolvaptan may increase net volume loss in heart failure without adversely affecting electrolytes and renal function. Hyponatremia (serum sodium concentration, <135 mEq/L) is a predictor of death among patients with heart failure. Objective: We prospectively observed the short term efficacy and safety of low dose (15 mg) tolvaptan in admitted patients with hyponatremia and ADHF in Indian population. Methodology: A total of 40 patients with ADHF along with hyponatremia (<125 mEq/L) on standard therapy were treated with 15 mg of tolvaptan at a single oral dose for 7 days. Results: Serum sodium concentrations increased significantly after treatment with tolvaptan from baseline (P < 0.02). There was a significant improvement in symptoms and New York Heart Association (NYHA) class after starting tolvaptan (P ≤ 0.05). Total diuretic dose and mean body weight was reduced non‑significantly at th7 day from the baseline. Side‑effects associated with tolvaptan included increased thirst, dry mouth and increased urination. Few patients had worsening renal function. However, several patients developed hypernatremia. Conclusion: In this small observational study, tolvaptan initiation in patients with ADHF with hyponatremia in addition to standard therapy may hold promise in improvement in NYHA class and serum sodium. At the same time, we observed that serious adverse events such as renal function deterioration and hypernatremia developed after tolvaptan treatment, which needs to be addressed in future by randomized study with larger sample size.

Key words: Acute decompensated heart failure, hyponatremia, tolvaptan, vasopressin antagonist

How to cite this article: Patra S, Kumar B, Harlalka KK, Jain A, Bhanuprakash HM, Sadananda KS, et al. Short term efficacy and safety of low dose tolvaptan in patients with acute decompensated heart failure with hyponatremia: A prospective observational pilot study from a single center in South India. Heart Views 2014;15:1-5. © Gulf Heart Association 2014.

INTRODUCTION retention and hyponatremia are mediated thru activation of V2 - receptors.[3] In heart failure, vasopressin eart failure is a clinical state of volume overload antagonists prevent progression of left ventricular in both extra and intra vascular space. It is one dysfunction.[3] In contrast to angiotensin‑converting Hof the major public health problems and one of the leading causes of hospital admissions in the Access this article online [1] world. Arginine‑vasopressin levels are elevated in heart Quick Response Code: failure.[2,3] It results in myocardial fibrosis/hypertrophy Website: and vasoconstriction by activating V1a receptors. Water www.heartviews.org

Address for correspondence: Dr. Soumya Patra, DOI: Post Doctoral Trainee, Department of Cardiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore ‑ 560 069, Karnataka, India. 10.4103/1995-705X.132136 E‑mail: [email protected]

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enzyme inhibitors (ACEI) and beta‑blockers (BB), it clinical presentation (dyspnea, edema, etc.) and clinical may also produce an acute improvement in congestion signs. All patients received standard heart failure therapy, and hyponatremia in patients with acute heart failure.[4] including diuretics, digoxin, ACEI/angiotensin II receptor Tolvaptan is an oral, once‑daily, non‑peptide blockers (ARB), BB, aldosterone blockers, hydralazine vasopressin V2‑receptor antagonist without intrinsic agonist and/or nitrates, at the discretion of the treating physician properties.[5] In patients with heart failure, tolvaptan added to daily weight monitoring was carried in all study patients. standard diuretic therapy including potassium‑sparing and All enrolled patients according to our study protocol non‑potassium‑sparing diuretics resulted in a significant were treated with oral tolvaptan at doses of 15 mg daily decrease in body weight and edema and increase serum for maximum 7 days or until discharge if it was before sodium concentrations without adversely affecting serum 7th day of therapy. Patients were advised fluid restriction [6] electrolyte levels, vital signs or renal function. during the treatment for ADHF. In this first study on Indian population, we prospectively observed the short term efficacy and safety of low dose Investigations tolvaptan in admitted patients with hyponatremia and All patients had the following investigation performed acute decompensated heart failure (ADHF) in addition to after hospital admission. the ongoing management for heart failure. 1. Complete hemogram, fasting lipid profile, blood sugar, liver function test. METHODOLOGY 2. Renal function test (daily until 7th day or discharge). 3. Serum electrolytes (daily until 7th day or discharge). Study design 4. Chest X‑ray and electrocardiogram. It was a prospective and observational study. This study 5. Echocardiography. was conducted in a cardiac care center in South India. Outcome Study population A. The Primary outcome of this study was to observe All consecutive patients of aged more than 18 years who the changes in New York Heart Association (NYHA) met the inclusion criteria were included in this study. grade, body weight, serum sodium and serum th Eligibility criteria creatinine and blood urea at 7 day or at discharge of oral tolvaptan therapy with 15 mg from the day of Inclusion criteria enrollment. Patients of age more than 18 years admitted with a B. Secondary outcome was to observe the adverse clinical diagnosis of ADHF, evidenced by jugular venous events, which were defined as any new medical distention, rales or peripheral edema and those who problem or exacerbation of an existing medical had serum sodium of <125 mEq/L were included in problem in a patient enrolled in the study. Among this study. the adverse events, hypernatremia was defined as Exclusion criteria serum sodium of >145 mEq/L and renal dysfunction Criteria for exclusion included cardiac surgery within was defined as >25% increase in blood urea or serum 60 days of enrolment, cardiac mechanical support, creatinine from the baseline value during treatment biventricular pacemaker placement within the last with tolvaptan. 60 days, co morbid conditions with expected survival of less than 6 months, refractory end‑stage heart failure, Statistics hemofiltration or dialysis, hemoglobin level less than All data was compiled at the end of the study and the 9 g/dL, pregnancy and serum sodium >125 mEq/L. sample was analyzed with Chi‑square. The P < 0.05 Ethics will be considered as statistically significant. The study protocol was approved by the Ethics Committee of the respective authority of our institution. RESULTS Written informed consent was obtained from all patients, before inclusion in the study. Sixty‑five patients with ADHF were admitted during the study period. Among these patients, two of them had Methods expired due to heart failure and other three patients had Written proformas were filled up during inclusion of stopped taking treatment on their own within 7th days of patients, which contained epidemiological information starting tolvaptan treatment. Another 20 patients had (age, sex, occupation and place), questionnaires for risk serum sodium of >125 mEq/L. Finally, data of those factor evaluation (diabetes, drug history, malignancy, 40 patients who completed the study was compiled and comorbid condition, hypertension etc.), information of analyzed.

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Baseline demographic and clinical profile of the DISCUSSION study patients In our study group, more number of cases was male with In our study, we prospectively observed the effects the male‑female ratio of 11:9. The mean age of our study of oral once‑a‑day, V2‑receptor antagonist tolvaptan patients was 70 ± 13.6 years. The mean body weight at in patients hospitalized for symptomatic ADHF when admission was 72 ± 11.2 kg. Among the risk factors for ADHF, added to standard therapy including diuretics and 60% (24/40) patients had previous myocardial infarction or vasopressor.[7] The majority of patients hospitalized ischemic heart disease, 50% had hypertension and 40% had diabetes. Among the etiology for ADHF, 60% patients Table 1: Baseline demographic and clinical profile of had heart failure due to ischemic heart disease, followed by study patients dilated cardiomyopathy in 30% and valvular heart disease Variables Tolvaptan 15 mg in 10% of patients. 85% (34/40) of our study patients had (n=40) (%) NYHA class III/IV status at admission. Eighty percent Gender (M:F) 22:18 and 60% patients had features of pulmonary edema and Age (yrs), mean (SD) 70±13.6 years congestive heart failure, respectively. Mean ejection fraction Hypertension 20 (50) of our patients at admission had 38 ± 5%. Forty percent of Diabetes 16 (40) Previous myocardial infarction/IHD 24 (60) patient with ADHF had baseline renal dysfunction [Table 1]. ADHF etiology Ischemic 24 (60) Treatment received during the study period (other DCM 12 (30) than Tolvaptan) Valvular heart disease 04 (10) All patients in our study received loop diuretics. Sixty Ejection fraction (%), mean (SD) 38±5 percent patients received ACEI/ARB and spironolactone. Loop diuretics 40 (100) Eighty percent of patients were also received oral Beta blocker 4 (10) digoxin; 50% of our study patients received ivabradine ACE inhibitor/ARB 24 (60) for rate control, whereas, only 10% of our patients Ivabradine 20 (50) received oral BB. Sixty percent of our study patients Spironolactone 24 (60) received inotropic support during the treatment [Table 1]. Digoxin 32 (80) Intravenous inotrope 24 (60) Comparison of clinical and investigational Rales 32 (80) parameters between day of enrollment and at JVD/Edema 24 (60) 7th day or at discharge of Tolvaptan (15 mg) Baseline NYHA classification NYHA III 06 (15) therapy NYHA IV 28 (70) Among the primary outcome determined at the beginning of Body weight (kg), mean (SD) 72±11.2 kg the study, mean serum sodium was increased and normalized Baseline renal dysfunction 16 (40) after tolvaptan therapy (121 mEq/L vs. 136 mEq/L) and this Heart Rate (>100 bpm) 32 (80) result was statistically significant (P = 0.02). Interestingly, Blood pressure (systolic blood 24 (60) there was non‑statistically significant rise in mean blood pressure<90mmof Hg) urea after tolvaptan treatment (58 mg/dl vs. 86 mg/dl) though ARB: Angiotensin receptor blockers, ACE: Angiotensin-converting enzyme, SD: Standard deviation, M: Male, F: Female, ADHF: Acute decompensated heart serum creatinine was reduced non‑significantly (2.1 mg/dl vs. failure, IHD: Ischemic heart disease, DCM: Dilated cardiomyopathy, JVD: Jugular 1.9 mg/dl). Both the mean body weight and total dose venous distension, NYHA: New York Heart Association of injection Furosemide dose were reduced at 7th day of Table 2: Comparison of clinical and investigational tolvaptan therapy from the enrollment value. However, these parameters between day of enrollment and at 7th day of results were statistically insignificant. There was a statistically tolvaptan (15 mg) therapy Variable At enrollment At 7th day P value significant (P = 0.046) improvement seen in NYHA stage (n=40) (n=40) after starting tolvaptan at 7th day (85% vs. 20%) [Table 2]. Sodium (meq/L), 121±3.2 mEq/L 136±3.0 mEq/L 0.02 mean (SD) Adverse events of oral tolvaptan therapy Serum urea 58±23.9 mg/dl 86±24.6 mg/dl NS Among the observed side‑effects of Tolvaptan treatment, (mg/dl); mean (SD) dry mouth was most common (40%), followed by Serum creatinine 2.1±0.5 mg/dl 1.9±0.9 mg/dl NS nausea, vomiting (35%), thirst (30%), abdominal (mg/dl); mean (SD) Body wt. (kg); 72±11.2 kg 66.1±12 kg NS pain (20%) and muscle cramps (15%) of study patients. mean (SD) One interesting observation after starting Tolvaptan NYHA III/IV 34 (85%) 08 (20%) 0.046 treatment was that 10% (4/40) patients developed Injection frusemide 80-100 mg 40‑60 mg NS hypernatremia and 15% (6/40) patients developed dose renal dysfunction during Tolvaptan therapy [Table 3]. NS: Not significant, SD: Standard deviation, NYHA: New York Heart Association

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Table 3: Side effects of tolvaptan 15 mg demonstrated mortality benefits of tolvaptan in acute heart Side effects N=40 (%) failure.[17] Findings of our study were also similar from the Thirst 12 (30) previous studies in these aspects.[18] The mean serum Dry mouth 16 (40) sodium was significantly increased and hyponatremia was Hypernatremia 4 (10) corrected after starting oral tolvaptan. Mean body weight Renal dysfunction 6 (15) was also decreased at 7th day from the baseline, but this Nausea/vomiting 14 (35) finding was not statistically significant like previous study. Abdominal pain 8 (20) Similar to previous studies,[19] our patients significantly Muscle cramp 6 (15) became asymptomatic after starting of tolvaptan. Currently available therapeutic options in the for ADHF have signs and symptoms of pulmonary management of ADHF have several limitations in their congestion and followed by systemic congestion.[2] efficacy, safety or both.[2,3] As our patients had pulmonary Hence, removal of excess fluid from either pulmonary and systemic congestion, so we can’t use BB in all or systemic bed represents a major treatment goal. patients and that is why ivabradine was used in almost The symptomatic benefit exerted by loop diuretics 50% of study patients to control the heart rate. ACEI/ has led to their wide clinical acceptance, even in the ARB or spironolactone was used only in 60% of patients absence of efficacy and safety data from large randomized as the rest of them had renal dysfunction. Though 60% trials.[8] However, this improvement can be associated of our patients received intravenous inotropes, such as with electrolyte abnormalities, renal dysfunction, dobutamine and dopamine to improve hemodynamics; neurohormonal activation, and hypotension.[9] Hence, however, this improvement is often associated with there is a concern regarding the adverse impact of significant adverse effects that include hypotension, aggressive diuresis, particularly the impact on renal atrial and ventricular arrhythmias and possibly increased function and serum electrolytes, and this represents an post‑discharge mortality and this number was higher important contributor to the frequent inadequacy of fluid than the previous study may be due to our patients management during hospitalization.[10] presenting in decompensated NYHA class III and IV.[20] In our study, the use of tolvaptan resulted in As expected and similar with previous studies, a mean reduction from baseline in the daily use of the incidence of adverse effects associated with the furosemide at 7th day of therapy. However, it was pharmacological effects of the drug like dry mouth and statistically insignificant, which was in contrast to the thirst was seen frequently in patients after receiving previous studies on tolvaptan.[11,12] Though there was a tolvaptan.[4‑13,21] This was unusual in our study that some reduction in diuretics use, we found rising of blood urea patients had hypernatremia and worsening of renal at 7th day after therapy with tolvaptan with decrease function after starting tolvaptan treatment. serum creatinine, which was suggestive of pre renal Our study has several limitations. This was a cause with intracellular dehydration due to excess free prospective observational study with small study group, fluid dieresis with tolvaptan treatment. This finding in so results of this study cannot be generalized. We used our study was also not seen in previous studies where a fixed dose of tolvaptan for 7 days without any titration. tolvaptan treatment did not have any impact on renal We used tolvaptan only in hospitalized cases with acute function.[3‑7] Possible hypothesis for this observation heart failure who has hyponatremia. We cannot be may be due to fluid restriction, which was also advised certain whether our findings would be replicated in other and our patients may have lower body mass index than populations, including those patients with acute heart failure patients of western countries, so they have less free fluid with normal serum sodium. As we have used tolvaptan in in the body. Similar excretion of free fluid in our patients addition to diuretics, our data would not support the use may cause hypernatremia and pre renal azotemia. of an arginine vasopressin antagonist in lieu of diuretics. Inappropriate elevation of arginine vasopressin, which is seen in human with acute heart failure plays a CONCLUSION key role in mediating water retention, contributing to both congestive symptoms and electrolyte imbalance.[13,14] Though our study was a prospective observational Tolvaptan was effective most likely because of its impact on study, we found some similar results as in previous fluid balance.[14] Consistent with its mechanism of action, it studies. Tolvaptan initiation in patients with ADHF with influenced the primary end point mainly by reducing body hyponatremia has significant improvement in NYHA grade weight and maintaining serum sodium.[15] Hyponatremia and serum sodium and has non‑significant decrease in occurs in 15‑20% of hospitalized patients and constitutes body weight and diuretics doses at 7th day of therapy. At a common serum electrolyte abnormality.[16] Hyponatremia the same time, we observed that some serious adverse is reported to be an independent predictor of complications events developed after starting tolvaptan treatment such and death in patients with heart disease. So far no trial has as deterioration in renal function and hypernatremia in

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