Vasopressin Antagonism: A Novel Therapeutic Strategy in Hyponatremia with HF, Liver Cirrhosis and SIADH

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1 Vasopressin Antagonism: A Novel Therapeutic Strategy in Hyponatremia with HF, Liver Cirrhosis and SIADH 張凱崴台灣大塚製藥股份有限公司

2 Contents 1. AVP and body fluid balance 2. AVP disorder and hyponatremia 3. Prevalence, morbidity and mortality 4. Current treatment strategy 5. AVP antagonists- Samsca (tolvaptan) 6. Indication and warning AVP: Arginine Vasopressin

3 Body Fluid Compartments water is the largest component of our body; since the major determinant of body water is AVP-regulated water excretion by the kidneys, it follows logically that AVP must be the most important hormone in the body

4 AVP Stimulation and Effects hyperosmolality hypovolemia angiotensin II + baroreceptors natriuretic peptides AVP V1a Receptors V2 Receptors vasoconstriction renal H 2 O reabsorption

5 Vasa recta AVP Regulation of Water Reabsorption from Renal Tubular Cells AVP AQP3 AVP V 2 Receptor GTP (Gs) Collecting Duct Cell ATP camp PKA AQP2 Exocytic Insertion H 2 O AQP2 H 2 O Collecting duct AQP4 Recycling vesicle Endocytic Retrieval basolateral membrane apical membrane

6 Plasma vasopressin (pg/ml) Plasma AVP Levels are Inappropriately Elevated in Most Patients with SIADH Normal Range Plasma osmolality (mosm/kg) Robertson et al. Am J Med 72: , 1982

7 Vasopressin (pmol/l) Plasma Vasopressin According to HF Severity ** * 13.4 Aged-Matched NYHA NYHA NYHA NYHA Control Class I Class II Class III Class IV (n=10) (n=10) (n=19) (n=23) (n=20) *P<0.05 vs control; **P<0.001 vs control. Data from 72 subjects with CHF admitted to Omiya Medical Center in Japan. Nakamura T et al. Int J Card. 2006;106(2):

8 Endocrinological Diseases too little hormone just right hormone too much hormone DI SIADH, CHF, cirrhosis

9 Hyponatremia Classification Dilutional hyponatremia 1 Total body sodium near normal Total body water increased Depletional hyponatremia 2 Hypovolemic Sodium lost Total body water reduced Hypervolemic 1 (edema) Heart failure Cirrhosis Nephrotic syndrome Euvolemic 1 (no edema) SIADH Hypothyroidism Secondary adrenal insufficiency Diarrhea Vomiting Burns Trauma Pancreatitis Diuretic excess Renal salt wasting Primary adrenal insufficiency 1. Douglas I. Cleve Clin J Med. 2006;73:S4-S Kumar S. et al. Lancet. 1998;352:

10 Percent Prevalence of Hyponatremia in Singapore N= Hospitalized Outpatient Community Na<136 meq/l Na<126 meq/l Na<116 meq/l Hawkins RC et al. Clin Chim Acta Nov;337(1-2):

11 Patients (%) Prevalence of Hyponatremia in Patients Hospitalized With HF 40 Hyponatremia Is a Relatively Common Electrolyte Disturbance in Patients Hospitalized With HF Serum [Na + ]: OPTIME meq/l ACTIV 2 <136 meq/l ESCAPE 3 <134 meq/l EVEREST 4 <135 meq/l OPTIMIZE-HF 5 <135 meq/l 1. Klein L et al. Circulation. 2005;111(19): ; 2. Gheorghiade M et al. JAMA. 2004;291(16): ; 3. Gheorghiade M et al. Arch Intern Med. 2007;167(18): ; 4. Data on file: Protocol ; 5. Gheorghiade M et al. Eur Heart J. 2007;28(8):

12 Patients (%) Distribution of Serum Sodium in Patients With Cirrhosis-Related Ascites meq/l Serum [Na + ] distribution in 997 patients hospitalized or attending outpatient clinics (5% Asian) Serum [Na + ] 135 meq/l : 49.4% meq/l meq/l meq/l meq/l meq/l >145 meq/l Hyponatremia was reported in approximately 57% of hospitalized patients with chronic liver disease and in 40% of outpatients with liver disease 21.6% patients had serum [Na + ] 130 meq/l Angeli P et al. Hepatology. 2006;44(6):

13 Symptomatic Hyponatremia: Neurological Manifestations headache irritability nausea / vomiting mental slowing confusion / delerium disorientation symptomatic but less impaired; usually chronic stupor / coma convulsions respiratory arrest life-threatening, usually acute

14 Mortality (%) Mortality Rates are Uniformly Higher in Hyponatremic Patients with a Variety of Different Illnesses Normonatremic Hyponatremic Heart failure Pulmonary tuberculosis Child diarrhea Myocardial infarction n = 397 n = 169 n = 1,330 n = 153 (Flear) (Westwater) (Samadi) (Flear) Kidney International, Vol. 29 (1986), pp

15 Survival (%) Cumulative Survival Rates in HF Patients Based on Serum Sodium Concentration Na >130 meq/l (n=163) Na 130 meq/l (n=40) 60 p < Months Lee & Packer, Circulation 73: , 1986

16 Clinical Pathway of Hyponatremia?

Fluid Restriction is the Most Common Treatment of Hyponatremia fluid restriction in patients with SIADH corrects hyponatremia by only 1 2 meq/l/d, even when severe

17 Fluid Restriction is the Most Common Treatment of Hyponatremia fluid restriction in patients with SIADH corrects hyponatremia by only 1 2 meq/l/d, even when severe (<500 ml/d) in addition, fluid restriction is poorly tolerated because of increased thirst, with subsequent poor compliance Schwartz et al, Am J Med 23: , 1957

18 Therapy isotonic saline hypertonic saline fluid restriction demeclocycline mineralocorticoid urea AVP antagonist Targets pathophysiology limitations ineffective in dilutional hyponatremias; can t be used in edema-forming disorders; no controlled safety database no consensus re appropriate infusion rates; overcorrection can cause osmotic demyelination; can t be used in edema-forming disorders; no controlled safety database slow to correct over many days; poorly tolerated due to thirst; can t be used with high AVP levels and urine osmolalities inconsistent responses; slow to correct; nephrotoxic in cirrhosis and CHF only one report in elderly patients with SIADH; no safety database; can t be used in edemaforming disorders no USP formulation; not FDA approved for hyponatremia; poor palatability conivaptan approved only for in-hospital use; infusion-site reactions with iv use Tolvaptan approved oral use for in-hospital and out-hospital

19 Non-peptide AVP Receptor Antagonists Conivaptan Lixivaptan Satavaptan Tolvaptan Receptor V 1a /V 2 V 2 V 2 V 2 Route of administration IV Oral Oral Oral Urine volume Urine osmolality Na + excretion/ 24 hrs low dose high dose Company Astellas Cardiokine Sanofi Otsuka Status USA launch? Stopped? Global launch

20 Pharmacokinetics Cmax 2-3 h. Half life 6-8 hours Protein binding: above 98% (in vitro) TOLVAPTAN is primarily metabolized by CYP3A4,coadminstration of ketoconazole increased C max and the area under the plasma concentration versus time curve of tovaptan by 248% and 440%, but not affect amiodarone and warfarin. Renal effect: do not effect with minor to moderate renal failure,but there is no safety for severe renal failure patients(clcr<10ml/min or Serum creatine>3.5mg/dl )

22 Treatment of Hyponatremia: Natriutesis vs Aquaresis Serum Sodium Dilutional Hyponatremia (HF, Cirrhosis, SIADH) < 135 meq/l < 135 meq/l Normalization 100% Furosemide Tolvaptan H 2 0 NA H 2 0 NA H 2 0 NA 0% H 2 0 NA H 2 0 Natriutesis Aquaresis 23 /2

23 利尿劑的種類及作用部位最新人體藥理學 Referenc General parmacology

24 Problem with the Existing Diuretics Careful observation for development of a variety of side effects is recommend in patients treated with diuretics, especially when used at high doses and in combination. We should care: 1.Renal dysfunction 2.Electrolyte abnormalities: k +, Ca + 3.Symtomatic hypotension 4.gout Reference: HFSA 2010 Practice Guideline

25 Tolvaptan SALT Trial Study Design (Study of Ascending Levels of Tolvaptan in Hyponatremia) Day mg 30mg 60mg Maintenance Off Therapy Tolvaptan (n=225) Screening Placebo (n=223) Randomization & Titration started* Treatment End Follow-up INCLUDED: Patients with euvolemic or hypervolemic hyponatremia associated with HF, cirrhosis, SIADH EXCLUDED: Patients likely to require saline therapy during the study; Acute and transient hyponatremia associated with head trauma or post-operative states; Hyponatremia due to primary polydipsia, adrenal insufficiency, or hypothyroidism Schrier RW et al. N Engl J Med. 2006;355: *Daily titration based on serum sodium levels.

26 Mean Serum Sodium ± SD (meq/l) Tolvaptan SALT Trial Improved and Maintained Serum [Na+] (Baseline Serum [Na+] <135 meq/l) Tolvaptan mg (n=213) Placebo (n=203) * * * * * * * * *P< vs placebo. 0 Base- 8h line Day 1 Treatment Day 7-day Follow -up Schrier et al. NEJM 355: , 2006

27 Average Daily AUC Change from Baseline (meq/l +/- SE) Tolvaptan SALT Trial Demonstrated Superiority with All Etiologies Tolvaptan Placebo Day 4 Day p<0.001 p< p< p< p<0.001 p< Cirrhosis CHF SIADH/other Hyponatremia Etiology 0 Cirrhosis CHF SIADH/other Hyponatremia Etiology Tolvaptan N Placebo N Schrier et al. NEJM 355: , 2006

28 Percent of Patients Percentage of Subjects with Normalized Serum Sodium Concentration ( 135 meq/l) 100 Tolvaptan SALT Trial Samsca (tolvaptan) Placebo Day 1, hour 8 Day 2 Day 4 Day 30 P< for all visits during tolvaptan treatment compared to placebo DATA on File: Protocols and

29 Tolvaptan SALT Trial changes in SF-12 general health survey scores after 30 days of oral administration 7.5 Placebo p= Tolvaptan p= Physical Component Score (physical function, body pain, general health, physically limited accomplishment) Mental Component Score (vitality, social function, calmness, sadness, emotionally limited accomplishment) Schrier et al. NEJM 355: , 2006

30 treatment of hyponatremia results in an improvement of the MCS to the mean of average U.S. adults Depression Cutpoint hyponat before rx treatment hyponat after rx Adult Mean Adult Median SF-12 Mental Component Summary (MCS)

31 Adverse Reactions Adverse Reactions (>2% more than placebo) in Samsca-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term Gastrointestinal Disorders Tolvaptan mg/day (n = 223) n (%) Placebo (n = 220) n (%) Dry mouth 28 (13) 9 (4) Constipation 16 (7) 4 (2) General disorders and administration site conditions Thirst a 35 (16) 11 (5) Asthenia 19 (9) 9 (4) Pyrexia 9 (4) 2 (1) Metabolism and nutrition disorders Hyperglycemia b 14 (6) 2 (1) Anorexia c 8 (4) 2 (1) Renal and urinary disorders Tolvaptan SALT Trial Pollakiuria or polyuria d 25 (11) 7 (3) The following terms are subsumed under the referenced ADR: a polydipsia; b diabetes mellitus; c decreased appetite; d urine output increased, micturition urgency, nocturia.

32 Serum Sodium Concentration (meql) Tolvaptan Maintained Improved Serum Sodium for Over Two Years in Open Label Extension of SALT Placebo-controlled SALT Studies Follow up (7 days post- termination of drug) Tolvaptan mg Open-label SALT-WATER Study Placebo p< Follow up (7 days post- discontinuation at any visit) FU Day Washout Months Tolvaptan n=213 Placebo n= J Am Soc Nephrol 21: , 2010

33 Adjusted* Mean Days Adjusted* Mean Days Effect of Tolvaptan on Length of Stay Among SIADH Patients With Hyponatremia a SALT study subgroup analysis Samsca (n=52) P= Placebo (n=58) Samsca (n=32) 8.00 Placebo (n=48) P=.576 Serum [Na + ] <135 meq/l Serum [Na + ] <130 meq/l Joseph G Verbalis. European J Endocrinology. 2011;164:

34 HYPONATREMIA TREATMENT ALGORITHM EUVOLEMIC HYPONATREMIA (SIADH) LEVEL 3 - SEVERE SYMPTOMS: vomiting, seizures, obtundation, respiratory distress, coma hypertonic NaCl administration, followed by fluid restriction ± vaptan LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion, disorientation, altered mental status LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression vaptan or hypertonic NaCl administration, followed by fluid restriction fluid restriction, but vaptan under select circumstances: inability to tolerate fluid restriction or failure of fluid restriction very low sodium level (<125 meq/l) with increased risk of developing symptomatic hyponatremia need to correct serum [Na + ] to safer levels for surgery or procedures, or for ICU/hospital discharge unstable gait and/or high fracture risk prevention of worsened hyponatremia with increased fluid administration therapeutic trial for symptom relief

35 EVEREST Outcomes Trial Design Randomization 48 hours Treatment Period (Median 9.9 months) 60 days Safety Follow-up 14 days Hospitalization for Worsening HF Tolvaptan 30 mg QD + Standard Therapy (n=2072) Placebo QD+ Standard Therapy (n=2061) 1065 Deaths Short-term Endpoints: Composite of change in weight and VAS between baseline and Day 7 or discharge Long-term Endpoints: All-cause mortality CV death or HF hospitalization Konstam MA et al, EVEREST Investigators. JAMA. 2007;297(12):

36 Body Weight (kg) EVEREST changes in body weight and [Na] Inpatient Outpatient TLV PLC Serum Na + (meq/l) (baseline <134 meq/l) Day Day 1 Day 7 or Discharge Day 7 or Discharge Inpatient After Discharge (wk) TLV PLC Tolvaptan Placebo

37 Proportion Remaining in Study EVEREST adjudicated CV mortality/morbidity Subjects with Baseline Sodium 130 meq/l (ITT Population) Subjects with Baseline Sodium <130 meq/l (ITT Population) Tolvaptan Placebo Hazard Ratio: % CI Limits: 0.973,1.165) PLC p<0.05 Hazard Ratio: % CI Limits: 0.372, PLC TLV TLV Months in Study Months in Study Overall CV Mortality/Morbidity (ITT) HR 1.04; 95%CI ( )

38 Tolvaptan Adverse Reactions Associated With Changes in Renal Function of HF Patients 8 Inpatient Outpatient 6 BUN (mg/dl) Day Day 7 or Discharge TLV PLC Tolvaptan Placebo Serum Cr (mg/dl) Day Day 7 or Discharge Inpatient Konstam MA, et al. JAMA. 2007;297: After Discharge (wk) 525 TLV 537 PLC

39 2013 ACCF Guideline describes Tolvaptan could Significantly improve in-patient HF Syndrome Reference:2013 ACCF/AHA Heart Failure Guideline 93-

40 Volume amount Taiwan Phase III Study A Multicenter, Double-blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Tolvaptan in the Treatment of Cardiac-Induced Edema in Patients with Heart Failure The Recovery Phase from Acute Stage (Including CHF patients who are hospitalized with an acute exacerbation) Samsca s Target Patients 1.Heart Failure 2.In Hospital 3.With oral diuretics 4.Plan to add other diuretics Ideal Weights Time

Tolvaptan reduces the risk of worsening renal function in patients with acute decompensated heart failure in high risk population The incidence of WRF

46 Tolvaptan reduces the risk of worsening renal function in patients with acute decompensated heart failure in high risk population The incidence of WRF was significantly lower In the tolvaptan group compared to the conventional group (22.7%and 41.4%,respectively:p-0.045) Reference: journal of cardiology 2012

47 Effects of Hyponatremia on the Brain with Adaptive Response Adrogué HJ. N Engl J Med 2000;342:1581

48 SAMSCA 衛署核准適應症

49 警語警語 : 應在醫院中開始或重新開始用藥並監視血清鈉濃度 SAMSCA 只有在可嚴密監視血清鈉濃度的醫院中才可開始或重新開始使用低血鈉症矯正速度過快 ( 如 >12 meq/l/24 小時 ) 會引起滲透壓去髓鞘症候群, 繼而導致發音困難失語吞嚥困難嗜睡情緒改變痙攣性四肢麻痺癲癇發作昏迷及死亡對容易發生的患者, 包括嚴重營養不良酒精中毒或晚期肝病的患者, 應以較緩慢的速度進行矯正

50 SAMSCA Contraindication Reference: SAMSCA label

51 How to monitor the overcorrect hyponatremia When using SAMSCA SAMSCA Should be initiated and reinitiated in patients only in a hospital where serum sodium can be monitored closely. should continue ingestion of fluid in response of thirst During initiation and titration, frequently monitor for changes in serum electrolytes and volume. Reference: SAMSCA label

52 Summary Hyponatremia is common and associated with significant morbidity and mortality Treatment depends upon the underlying cause Rate of correction must be tailored to duration and severity of symptoms Rapid correction for acute hyponatremia with symptoms Slow correction for chronic hyponatremia to avoid ODS Samsca (tolvaptan) suitable, safe, and effective for chronic euvolemic or hypervolemic hyponatremia

53 Thank you and your comments!

Italy: Samsca already included in The Lung Cancer Guidelines (July 2012) Guidelines Guidelines for the management of Lung Cancer Patient Recommendations The restriction of fluid intake to 500 ml and

54 Italy: Samsca already included in The Lung Cancer Guidelines (July 2012) Guidelines Guidelines for the management of Lung Cancer Patient Recommendations The restriction of fluid intake to 500 ml and a urinary output of more than 500 ml is an option for patients with symptomatic Hyponatremia and SIADH LEVEL OF EVIDENCE III AND GRADE OF RECOMMENDATION B In patients with symptomatic Hyponatremia lasted for more than 48 hours, the correction of serum sodium levels should be done slowly (1.5 up to 2) and must not exceed 10-12mEq/l in the first 24 hours, in order to avoid the risk of a syndrome by osmotic demyelization LEVEL OF EVIDENCE III AND GRADE OF RECOMMENDATION A If the patient is asymptomatic, the correction should take place more slowly (0.5) and should not exceed meq/l in the first 24 hours LEVEL OF EVIDENCE III AND GRADE OF RECOMMENDATION A The Demociclina (not approved in Italy for Hyponatremia) was recommended in the past as second line therapy of Hyponatremia LEVEL OF EVIDENCE III AND GRADE OF RECOMMENDATION D The Conivaptan, was approved for use in patients hospitalized with Hyponatremia. its administration is intravenous LEVEL OF EVIDENCE III AND GRADE OF RECOMMENDATION B Tolvaptan, indicated in SIADH, is administered orally and has proven effective in normalizing serum sodium concentration in various pathological conditions. LEVEL OF EVIDENCE I AND GRADE OF RECOMMENDATION A

55 Story 1 Idiopathic SIADH with Relapse Hyponatremia

Apply SAMSCA to Hyponatremia Caused by Idiopathic SIADH Could Significantly Increase SSL The SSL of patients various during in/out patient. 1.

56 Apply SAMSCA to Hyponatremia Caused by Idiopathic SIADH Could Significantly Increase SSL The SSL of patients various during in/out patient. 1.Accept conventional therapy for hyponatremia in-patient but did not improve SSL obviously 2.After taking 15mg SAMSA, Patient s SSL become normal and hyponatremia release 3.After discharge and routine checking SSL, it was maintaining on 140mmol/L Reference :Adapted from Taiwan Medical Journal vol 55 No11,2012

57 Urine output 24 小時小便量 (ml) 體重 (kgw) Body Weight Apply SAMSCA to Hyponatremia Caused by Idiopathic SIADH, Also Significantly Effect Urine Output and Body Weight 尿量體重 Tolvaptan (15mg/d) 5/26 5/27 5/28 5/29 5/30 5/31 6/1 6/2 6/3 6/4 6/5 6/6 6/7 Date Tolvaptan (15mg/d) Urine output(the blue line) increase and body weight decrease (the orange line) obviously when using SAMSCA, If stop drug without water restriction,urine output decrease, and body weight increase. After adding on SAMSCA, the patient s condition recovered. Reference :Adapted from Taiwan Medical Journal vol 55 No11,2012

58 Half Dosage Efficacy of SAMSCA

59 Conclusion SAMSCA,with its unique aquaresis effect,could significantly increase SSL, no matter in idiopathic SIADH, secondary SIADH or HF SAMSCA could become standard prescription to benefit to treat underlying disease in good condition.

62 Case Report 40 y/o man; no past medical hx Repeated ER visits due to dyspnea, orthopnea and leg edema Echocardiography showed concentric LVH with dilated atria and EF 47% EKG: low voltage CXR: large bil. pleural effusion Na meq/l; Creatinine 2.0 mg/dl

63 CXR

64 EKG

65 Echocardiography

66 Case Report Cardiac amyloidosis was suspected Abdominal fat biopsy confirmed amyloidosis Congestive symptoms partially relieved by pleural effusion tapping; not responsive to fluid restriction and IV loop diuretics/oral spironolactone Start samsca 15 mg QD

67 meq/l Serum Sodium Level during Tolvaptan hours after 1st dose 72 hours after 2nd dose 血鈉值 Before treatment 24 hours after 1st dose

68 Treatment Course Total body weight loss of 4 kg Dyspnea and orthopnea improved greatly Still leg edema Creatinine level 1.9 mg/dl Discharged without further use of samsca Repeated pleural effusion tapping in OPD.

69 Case 2

70 Case Presentation A 90-year-old man with history of hypertension and heart failure for a couple of years. Rx: Co-diovan 1# qd, bisoprolol 1.25mg qd, furosemide 40 mg qd Presented with worsening dyspnea, ++ edema, and poor appetite /nausea for 1 week. BP 134/78 mmhg; Resp rate 18 breaths/min Pulse rate 84 bpm, body temp 36.5 Pulse oximetry 94% (RA) (PaO2 83 mmhg)

71 Lab findings BUN/Cr 42.3/ 1.6 mg/dl ALT (GPT): 27 IU/l; Alb: 3.4 mg/dl Na: 111 mmol/l ( ); K/Ca/Mg: 4.4/9.3/2.0 mg/dl Blood OSMO: 230 mosm ( ) ; Urine OSMO: 376 mosm ( ); Urine Na: 108 mmol/l Hgb 10.1g/dl (12.1) Glucose 126 mg/dl Thyroid function test: WNL

72 12-lead ECG

73 Trans-thoracic Echocardiography Degenerative changes and calcification of AV/MV with moderate AR/MR Mild global hypokinesis with LVEF: 41%

74 Portable Chest X-ray at Admission Poor response to Fluid restriction (< 1.2 l/d) Salt restriction (< 2 g/d)and Furosemide IV

75 In-hospital Changes in Serum Na and Body Weight Samsca 15 mg qd for toal 5 doses BW: Kg 111

76 In-hospital Changes of Biochemistry Data BUN/Cr 42.3/ 1.6 mg/dl BUN/Cr 22.4/1.2 mg/dl ALT (GPT): 27 IU/l; Alb: 3.4 mg/dl ALT (GPT): 32 IU/l; Alb: 3.6 mg/dl Na: 111 mmol/l ( ) Na: 135 mmol/l K: 4.4 mg/dl K: 3.9 mg/dl

77 19 Apr, Apr, 2013 NYHA Fc III-IV NYHA Fc II

78 Story 2 :Secondary SIADH with Relapse Hyponatremia

79 Patient Background Age:82-year-old woman Underlying diseases Left renal cell carcinoma post radical nephrectomy(cancer) Chronic kidney disease with edema Depression Chief complaint: Progressively generalized weakness for 3 weeks during chemo therapy Adapted from SAMSCA Expert Meeting Presented by Professor Wu TMUH

80 Na (mmoe/l) Apply SAMSCA Significantly Improvement Patient s SSL 血鈉值 SSL /20 11/21 11/22 11/23 11/24 11/25 11/26 11/27 11/28 Discontinuing Furosemide(diuretics) Date SAMSCA QD for 2 days Adapted from SAMSCA Expert meeting Presented by Professor Wu TMUH

81 Back up

82 Listed hospital 花慈 (MC) 台中榮總 (MC) 馬偕 (MC) 三總 (MC) 市南 (RH) 彰化秀傳 (RH) 嘉義聖馬爾定 (RH) 北醫附醫 (RH) 新竹馬偕 (RH) 彰濱秀傳 (RH) 新樓醫院 (RH) 員榮 (AH) 嘉義陽明 (AH) 宏恩醫院 (AH)

83 Patient s Serum Sodium Level After Serum sodium change SAMSCA Very good responses Without any SAE Liver Cirrhosis cirrhosis(1) cirrhosis(2) 曹心怡黃啟宏周柏青陳鉞忠陳益祥 HF(2) 林彥宏吳允升張博淵嚴建榮劉秉彥蔡明松梁興禮郝繼隆許志揚 Using day Stop SAMSCA without fluid restriction

84 Samsca 在美國的使用經驗 Item Administration after hospitalization/ 住院後起始用日 In-patient length of Samsca therapy/ 住院使用天數 Percentage of patients discharged with outpatient prescriptions/ 出院持續處方使用率 ( 使用期間 ) Samsca use in patients with Na <125 meq/l/ 使用於 Na<125 病患占比 Use in the ICU,CCU / Telemetry Step Down unit 使用於 ICU,CCU 等急性病房占比 Result 2.4 天 4.2 天 29% ( 平均 1~3 週 ) 80% 36% Starting Dose with 15mg/ 起使劑量使用 15mg 占比 70% Titration (up or down)/ 劑量需調整者占比 ( 上或下 ) 40% Change in Na and LoS/ 血鈉變化 / 住院日數變化 +12.3/-3.2 Ref.: Report of SAMSCA chart registry-ii

86 病例 - 心臟衰竭低血鈉 68 歲男性呼吸困難惡化入院, 體重增加, furosemide 劑量增加仍然下肢水腫疾病史 : 心臟衰竭, 冠心病, 冠狀動脈繞道手術, 主動脈瓣置換術, 心房顫動處方 : β-blocker, ARB, warfarin, furosemide Na + 118, BUN 31 mg/dl, Cr 1.8 mg/dl, BNP 473, serum osmolality 262 超音波 : LVEF 25%-30%, 中度二尖瓣血逆流 (MR), 右心室收縮壓 (RVSP) 40 mm Hg 關心 : 血鈉惡化 / 腎功能惡化 EDD = end diastolic diameter, EF = ejection fraction, MR = mitral regurgitation, WRF = worsening renal function.

87 mmol/l m m m m o o l l / / m m o l / L m m o l / L 血鈉和體液對治療的反應 Sodium/Fluid Response to Therapy S o d i u m ( m m o l / L ) S o d i u m ( m m o l / L ) Sodium (mmol/l) S S o o d d i ui u m m Sodium T h u S e p T h u S e p S o d i u m ( m m o l / L ) S o d i u m ( m m o l / L ) H L L L S o d i u m S o d i u m 1 O c t 2 S a t 3 S u n 4 M o n 5 T u e T h e l o w v a l u e f o r t h e s e l e c t e d n o r m a l r a n g e i s g r e a t e r t h a n o r e q u a l 1 O c t 2 S a t 3 S u n 4 M o n 5 T h e l o w v a l u e f o r t h e s e l e c t e d n o r m a l r a n g e i s g r e a t e r t h a n o 3 0 T h u 3 0 T h u S e p S e p O c t 2 S a t 3 S u n 4 M o n 5 T u e 6 W e d 7 T h u 8 F r i 1 O c t 2 S a t 3 S u n 4 M o n 5 T u e 6 W e d 7 T h u 8 F r i T h e l o w v a l u e f o r t h e s e l e c t e d n o r m a l r a n g e i s g r e a t e r t h a n o r e q u a l t o T h e l o w v a l u e f o r t h e s e l e c t e d n o r m a l r a n g e i s g r e a t e r t h a n o r e q u a l t o Thu 1 Oct 2 Sat 3 Sun 4 Mon 5 Tue 6 Wed 7 Thu 8 Fri Sep 2010 The low value for the selected normal range is greater than or equal to 利尿劑增量 Oral diuretics increased 15 mg Samsca tolvaptan initiated 體液排出 3 公升 3 liters negative fluid balance

88 病例 - 心臟衰竭低血鈉 ( 台灣 ) 80 歲男性低血鈉伴隨神經學症狀 ( 四肢抖動, 有抽筋現象和昏眩問題 ) 疾病史 : 心臟衰竭, 冠狀動脈繞道手術, 中風 Na meq/l 關心 : 低血鈉的神經學症狀

89 meq/l 病患血鈉值對 Samsca 治療的反應 ( 台灣 ) hours after 1st dose 8 hours after 2nd dose 血鈉值 Before treatment May 14 May 19 May 19 May 20

90 台大醫院使用 SAMSCA 治療 SIADH 及低血鈉症的結果

91 台大醫院使用 SAMSCA 治療 SIADH 及低血鈉症的結果

92 病例肝硬化低血鈉 (B 肝 ) 58 歲, 女性, 急診, 處理水滯留 ; 腫脹問題逐漸加劇, 下肢水腫, 輕度運動即呼吸困難, 過去 3 個月腹圍加大 B 型肝炎, 甲狀腺功能低下處方 :Furosemide 40 mg bid, [Na+] 122 meq/l,[k+] 3.8 meq/l,bun 23 mg/dl,creatinine 1.6 mg/dl 每日限制鈉 2 g 水分 1.2 公升

Serum Sodium and Fluid Response to Initial Therapy 情況更糟, 腹部腫脹不適持續, 利尿劑加量治療水腫 (Furosemide 60 mg IV bid 及 spironolactone 50 mg po qd) 懷疑限水限鈉順從性低肝硬化, 門脈高壓,

93 Serum Sodium and Fluid Response to Initial Therapy 情況更糟, 腹部腫脹不適持續, 利尿劑加量治療水腫 (Furosemide 60 mg IV bid 及 spironolactone 50 mg po qd) 懷疑限水限鈉順從性低肝硬化, 門脈高壓, 食道靜脈曲張, 穿刺引流 3 公升腹水 Fluid restriction 1200 ml/d Cr 1.6 mg/dl Cr 1.4 mg/dl Cr 1.2 mg/dl Cr 1.3 mg/dl Admission HD 2 HD 3 HD 4 Cr = creatinine; HD = hospital day.

94 Samsca 投予後的血鈉值變化 Samsca 15 mg/d Samsca 30 mg/d Furosemide 60 mg bid, spironolactone 50 mg qd Day Net Fluid Balance 1800 ml 1600 ml 2400 ml

95 Comparison of Two Dose and Dosing regimens of Tolvaptan in congestive Heart failure 7 days 7 days 48 hours Discontinue diuretics Tolvaptan 30 mg QD washout Placebo (n=223) Tolvaptan 15 mg BID Follow up period Results:2 dosing regimens were evaluated in patients with CHF show That the pharmacodynamics and the pharmacokinetics of the drug were comparable. Reference: J Cardiovasc Pharmacol. Volume 46,Number 5 November 2005

96 Are there differences in renal function and hemodynamics when weight is reduced to the same extent by a loop diuretic as compared to a V 2 receptor antagonists?

98 Diuretic Effects of Tolvaptan and Furosemide in Conscious Dogs Control Cardiovasc Drug Rev 25: 1-13, 2007 Urine volume (0-6 hr) ** ** ** Urine osmolality (0-6 hr) Tolvaptan (mg/kg, p.o.) ** * * ** ** ** ** ** ** ** ** ** ** Free water clearance (0-6 hr) Furosemide (mg/kg, p.o.) ## ## ## Mean+SEM, n=6 * p<0.05, ** p<0.01 vs. control ## p<0.01 vs. Furo 1 mg/kg Furo (1 mg/kg) + TLV (3 mg/kg)

99 Urine Electrolytes Excretion of Tolvaptan and Furosemide in Conscious Dogs Control Urine volume (6 hr) ** ** ** Urinary Na excretion (6hr) Urinary K excretion (6hr) * * ** ** Tolvaptan (mg/kg, p.o.) ** ** ** ** ** ** ** ** Furosemide (mg/kg, p.o.) Furosemide Tolvaptan Urine volume (ml/kg/6 hr) Mean+SEM, n=6, * p<0.05, ** p<0.01 vs control Cardiovasc Drug Rev (2007) 25, 1-13

100 (ng/ml/hr) (ng/ml) (pg/ml) (pg/ml) Neurohormonal Effects of Tolvaptan and Furosemide in Conscious Dogs Differences between pre-dosing and 6-hr post-dosing D AVP D PRA ** ** ** ** Aldosterone (at 6 hr post-dosing) D Epinephrine ** Tolvaptan (mg/kg, p.o.) Furosemide (mg/kg, p.o.) 0 Furo 1 mg/kg + TLV 3 mg/kg Tolvaptan (mg/kg, p.o.) Furosemide (mg/kg, p.o.) Furo 1 mg/kg + TLV 3 mg/kg n=6, Mean +SEM * p<0.05, ** p<0.01 vs. control, ## p<0.01 vs. Furo 1 mg/kg Cardiovasc Drug Rev 25, 1-13, 2007

101 Change from Baseline (kg) Change in Body Weight 2 1 Placebo (n=57) Tolvaptan (n=53) Treatment Period Day Follow-Up Mean±S.D. Cardiovasc Drugs Ther 25: (Suppl 1) S33-S45, 2011

102 Change from Baseline (kg) Change from Baseline (cm) Change from Baseline (cm) Improvement Rates (%) Efficacy of Tolvaptan Placebo Tolvaptan BW (n=57)(n=53) P< (t test) JVD * (n=19)(n=27) P=0.03 (t test) At the End of Treatment (LOCF) Mean±S.D. Hepatomegaly * (n=17)(n=18) P=0.03 (t test) Edema * (n=38)(n=36) P=0.07 (Fisher s exact test) * Number of symptomatic patients Cardiovasc Drugs Ther 25: (Suppl 1) S33-S45, 2011

103 Serum Osmolality (mosm/kg H 2 O) Plasma Renin Activity (ng/ml/h) Plasma AVP (pg/ml) Plasma BNP (pg/ml) Endocrinological Parameters Plasma AVP Treatment Follow-Up Placebo (n=57) Tolvaptan (n=53) (Observed Case) 1, Plasma BNP Treatment Placebo (n=56) Tolvaptan (n=53) Serum Osmolality Plasma Renin Activity Treatment Follow-Up Placebo (n=57) Tolvaptan (n=53) (Observed Case) Day Cardiovasc Drugs Ther 25: (Suppl 1) S33-S45, Treatment Day Placebo (n=49) Tolvaptan (n=49) Mean±S.D.

104 Serum K (meq/l) Serum Na (meq/l) Serum Electrolytes (Observed Cases) Na Placebo (n=57) Tolvaptan (n=53) K 4 3 Treatment 時間 Period Follow-Up Baseline 4-8h 24h 2-3day 7day +2day +7day Time Mean±S.D. Cardiovasc Drugs Ther 25: (Suppl 1) S33-S45, 2011

Hyponatremia as a Cardiovascular Biomarker

Hyponatremia as a Cardiovascular Biomarker Uri Elkayam, MD Professor of Medicine University of Southern California Keck School of Medicine elkayam@usc.edu Disclosure Research grant from Otsuka for the