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DIURETIC RESISTANCE IN HEART FAILURE: Pathophysiology & Cases Discussion Bambang Budi Siswanto Prof MD, PhD, FIHA, FAsCC, FAPSC, FESC, FACC, FSCAI Dept Cardiology and Vascular Medicine University Indonesia Medical Research Unit & Medical Education Unit & Coordinator Collaboration FKUI Email : [email protected] Disclosure : • This symposium is sponsored by Otsuka • Speakers sponsored by Otsuka * Median Total Hospital LOS in the Asia Pacific Region excludes Philippines ng ap or Th e( n =2 ai la n d ,9 6 1) In do (n = 2, ne sia 045 ) (n Au = 16 st ra 87 l i a ) M (n al =9 ay sia 09 ) (n Ta =9 iw 07 Ho an ) (n ng Ko =53 8) ng (n = Br az 3 94 ) il( n= M La 62 ex 5) tin ic Am o( n= er ica 8 7) AP (n= 71 7* AP 2) (n LA =9 9* 44 (n =1 1) 0, 15 3) US (n EU =1 87 ,5 65 ) Si LOS (days) MEDIAN TOTAL HOSPITAL LENGTH OF STAY BY COUNTRY 12.0 6.0 11.0 8.0 7.4 7.1 5.9 10.6 10.0 6.0 9.9 5.4 9.0 7.0 6.0 4.1 6.1 4.3 4.0 2.0 0.0 ADHERE-Indonesia 2006 : Total L.O.S.= 7.1 University of Indonesia 10 9 8 7 6 5 4 3 2 1 0 Median T otal Hos pital L eng th of S tay (days ) 9 7.1 7.2 4.2 Indones ia As ia P acific E U US ADHERE- Indonesia vs. AP vs. Europe vs.US (2006) Siswanto BB et.al, CVD Prevention and Control (2010) 5, 35-38 S in ga po re( n= 2,9 Th 61 aila ) nd (n = Ind 2,0 on 45 esi ) a (n =1 ,68 Au 7) str a lia (n= 90 Ma 9) lay sia ( n= Ph 90 ilip 7) pin es (n = 72 5) Ta iwa n(n Ho =5 ng 38 ) Ko ng ( n= 39 4) Bra z il( n= 62 5) Me x ic o La ( n= tin Am 87 ) e ri ca (n= 71 AP 2) (n = 10 ,1 6 AP 6) LA (n = 10 ,87 US 8) * (n =1 7,3 US 82 ** ) ( n= 18 7,5 65 ) IN-HOSPITAL MORTALITY BY COUNTRY (% ) 8.3 7.6 6.7 5.5 6.5 5.4 5.4 8.2 7.2 4.8 5.0 3.8 3.0 2.0 0.3 * United States Most Recent 12 Months (04.01.05-03.31.06) ** United States Cumulative (01.01.01-03.31.06) Lesson learned 2006-2009 Compared to the ADHERE Registry - US ® and EuroHeart Survey II, the ADHERE ® International - APLA data suggest: 1. A younger patient population than in the US and Europe 2. More patients exhibiting severe clinical signs and symptoms. 3. Higher rates of mechanical ventilation (compared to the US) 4. More frequent use of inotropic drugs 5. Underutilization of baseline heart failure medications such as ACEI or ARB, beta blocker and low dose spironolactone 6. Higher rates of In-hospital mortality and readmission rate RISK OF DEATH RELATED WITH NYHA CLASS & GFR STAGE OF HEART FAILURE & THE TREATMENT (Jessup M, Brozena S. N Engl J Med 2003; 348: 2007-18.) (2013 ACCF/AHA Guideline for the Management of Heart Failure) Case discussion on Advanced HF • A 44 years old male was admitted to Emergency Room • increasing dyspnea at rest a week prior with edema & decreased urine pr oduction.. • • History of recurrent admission with dilated cardiomyopathy, Poor EF complicated with right pleura effusion, ascites, swollen anklean d left ventricle thrombus • He was on poly pharmacies ( multiple drugs) after being discharged and denied of non compliance ( before this admission ) 1. furosemide 2x40mg mane 2. bisoprolol fumarate 1,25 mg mane 3. spironolactone 1x50mg mane 4. warfarin 1x1 mg nochte 5. ramipril 1x7.5mg nochte RISK FACTORS for CAD • • • • Hypertension (-) Diabetes Melitus (-) Smoking (-) Dyslipidemia (-) PHYSICAL EXAMINATION 20 May 2015 VITAL SIGNS • • • • • Consciousness : compos mentis Blood Pressure : 70/50mmHg, Heart Rate : 100x/min/regular Respiratory Rate: 24x/min, O2 Saturation : 98% PHYSICAL EXAMINATION • Conjunctiva was not pale nor anemic • Jugular Venous Distended • Chest – Heart 1st and 2nd heart sound were normal, Pan Syst gr 3/6 at LSB i.c.s. 5, radiated to axilla. gallop (-) – Lung Vesicular with soft rales on the base of lung, wheezing (-) • Abdomen Liver was palpable 2 cm below processus xiphoideus, Ascites (+) • Extremities : Pitting Edema (+) on both sides Supporting diagnostic : • A-P CHEST X-RAY CTR > 55%, aorta segment normal pulmonal segment normal, downward apex, congestion (+), infiltrate (-), right pleural effusion (+) • ELECTROCARDIOGRAPHY ST 116x/min, RAD, RVH, ST ↓in II, III, aVF, poor R wave progression V 1-V6 • ECHOCARDIOGRAPHY EF 18 %, TAPSE 1.3 cm, Severe Global Hypokinetic Moderate Mitral Regurgitation Moderate Tricuspid Regurgitation Moderate Pulmonary hypertension Thrombus (+) at the apical LV Hospitalized Heart Failure on NCVC January – December 2012 250 212 200 150 133 130 122 Male 122 89 82 100 91 70 72 50 70 20 December November October September August July June May April March February January 0 Total: 1243 patient Female 67. 32. 9% 1% Previous HF history No HF history Previous HF History (+) Prior Hospitalization in PJNHK 30.3% 34.5% 35.2% Etiology of Heart Failure at NCCHK 2012 Ischemic heart Tachycardia related Other, 8.2 cardiomyopathy, 0.2 disease documented HFPEF Syndrome, by coronary 17.8 angiography, 20.2 Valve disease, 12.7 Ischemic heart disease not documented Dilated by coronary Cardiomyopathy, angiography; 3.4 37.6 % Precipitating Factors for hospitalization in HF Anemia Renal Dysfunction Non Compliance Hypertension Infection Ventricular Arrythmia Bradycardia Atrial Fibrillation Acute Coronary Syndromes Myocardial Ischemia Diuretic as Decongestive Therapy No, 100 IV Nitrate 91.2 IV Diuretics Yes, 100 80 80 60 60 40 40 Yes, 20 8.8 0 No Yes 89.5 No, 20 10.5 0 No Yes EVIDENCE BASE FOR THE USE OF DIURETICS IN ACUTE HEART FAILURE Edema of the Gut, Edema of the Kidney By Pressure Overload Diuretic Resistance • Related to Cardio-renal Syndrome or Worsening Renal Function – Often associated with renal insufficiency (acute and/or chronic) • Definitions vary – Persistent edema despite adequate diuretic doses – Diminished natriuretic response to repeated doses – Daily furosemide doses > 80mg1 • Prevalence – Chronic use of loop diuretic : 35%1 – Acute: unknown 1Neuberg GW, et al. Am Heart J 2002;144:31-8. Mechanism of DU resistance • Decrease drug bioavailability • Reduced glomerular filtration rate • Excessive sodium uptake in the proximal tubule and the loop of Henle • Renal adaptation • Excessive sodium and water retention in the distal nephron and collecting ducts • Drug interaction • Pseudoresistance Resistance Etiology-based Strategies to Restoring DU Efficacy • Loop DU Pharmacodynamics - Reduction in preload to the LV by diuresis & vasodilation - Diuretic effect of Loop DU; conc.-dependent 1) the rate of urinary excretion 2) the natriuretic response after binding to the target receptor - Loop DU’s D-R curve; sigmoidal pattern ► ADHF pts require a higher drug conc. to achieve the DU threshold and have a diminished response to ceiling doses. ⇒Administer higher dose / Increase the frequency of administration Journal of Cardiac Failure, Accepted Date: 22 May 2014 Resistance Etiology-based Strategies to Restoring DU Efficacy • Loop DU Pharmacology & Pharmacokinetics - Absorption - Metabolism - Distribution - Excretion - 50% inactivated by renal glucoronidation - 50% secreted as parent compound by OAT-1 system Journal of Cardiac Failure, Accepted Date: 22 May 2014 OVERCOMING DIURETIC RESISTANCE • Diuretic Strategies - Sequential nephron blockade/ Multiple sites of diuretic MOA - Renal Dose Dopamine - Osmotic Diuretic - Thiazides / Thiazides Like diuretic - Aldosterone antagonis = MRA Vasopressine Antagonist Aquaretics . Non Diuretic Strategies = Expensive Devices - Ultrafiltration : Neutral results Bloods test results of Mr A, M, 40 yo 1 Haemoglobin 2 Leukocyte 13.2 g/dL 5870 /uL 3 Hematocrit 4 Thrombosis 5 GFR 39% 179,000 /uL 36 6 Serum Blood Glucose 7 Ureum 95 mg/dL 100 mg/dL 8 BUN 9 Creatinine 10 Sodium 47 mg/dL 2.02 mg/dL 126 mEq/dL 11 Potasium 12 Calcium total 13 Chloride 4.8 mEq/dL 2.35 mEq/dL 94 mEq/dL Working DIAGNOSIS • Acute Decompensated Heart Failure Wet and Warm. • Recurrent admission of Dilated Cardiomio pathy with Left Ventricle Thrombus • Right Pleural Effusion • Moderate Mitral Regurgitation • Acute Kidney Injury DD/ CKD St 3 M, 44 years MANAGEMENT SUMMARY Date 6/5 7/5 8/5 9/5 10/5 Post Samsca Treatment Natrium 127 - - 137 - 141mmol/L Furosemide 10mgkg of Body Weight (BW) 10mg/kg of BW 25mg/kg of BW 25mg/kg of BW 25mg/kg Of BW per oral Tolvaptan - 15 mg 15 mg 15 mg - Input 1447 322 2244 2391 1148 - Output 1500 50 4800 5400 5300 - Fluid balance (-) -53 + 272 -2556 -3009 -4152 - Dyspnea + ++ ↓ ↓↓ ↓↓ No Dyspnea Body Weight 60kg 64 kg - Patient was admitted in with ADHF Edema (+) 56.5 kg Tolvaptan + furosemide drip Serum sodium level was corrected, Negative Fluid balance >>>, Body Weight <<<,, General condition was improved Post Tolvaptan Treatment Conclusion • The initial evidence based management strategy suggested that an initial “high dose” IV bolus injection continued with moderate dose continuous infusion is likely to be more successful than a slower approach. • In cases of diuretic resistance, adding a thiazide or thiazide like diuretic or K sparring diuretic, or spironolactone or osmotic diuresis can enhance diuresis, but no Evidence based. Close monitoring of fluid balance and Na & K is mandatory. This strategy can not done in patients with significant renal dysfunction. • Low dose (renal dose) dopamine infusion can improve the effectiveness of diuretic therapy, and help maintain renal function, or increased BP but increased HR, although the evidence base for this is limited. • Tolvaptan is a new & the only aquaretic drug with novel MOA by vasopressin antagonist pathway that appropriate to treat diuretic resistance • The infusion of Na Cl 0,3 % for correction of Hyponatremia and Diuretic Resistance will lead to the risk of Osmotic Demyelination Syndrome