DIURETIC RESISTANCE IN HEART FAIL-URE:

Pathophysiology & Cases Discussion

Bambang Budi SiswantoProf MD, PhD, FIHA, FAsCC, FAPSC, FESC, FACC, FSCAI

Dept Cardiology and Vascular Medicine University IndonesiaMedical Research Unit & Medical Education Unit & Coordinator Collaboration FKUI

Email : bambbs@gmail.com

Disclosure :

• This symposium is sponsored by Ot-suka

• Speakers sponsored by Otsuka

MEDIAN TOTAL HOSPITAL LENGTH OF STAY BY COUNTRY

4.1

7.4 7.1 7.05.9

11.0

6.0

10.6

5.4

9.9

6.0 6.1

9.0

4.3

0.0

2.0

4.0

6.0

8.0

10.0

12.0

LO

S (

day

s)

* Median Total Hospital LOS in the Asia Pacific Region excludes Philippines

Median T otal Hos pital L eng th of S tay (days )

7.1 7.2

9

4.2

0123456789

10

Indones ia As ia P acific E U U S

ADHERE- Indonesia vs. AP vs. Europe vs.US (2006)

ADHERE-Indonesia 2006 : Total L.O.S.= 7.1

Siswanto BB et.al, CVD Prevention and Control (2010) 5, 35-38

University of Indonesia

IN-HOSPITAL MORTALITY BY COUNTRY (%)

2.0

5.5

6.7 6.5

7.6

5.4 5.4

0.3

8.3

7.28.2

4.8 5.0

3.03.8

Sin

gapo

re(n

=2,9

61)

Thai

land

(n=2

,045

)In

done

sia(

n=1,

687)

Aus

tralia

(n=9

09)

Mal

aysi

a(n=

907)

Phi

lippi

nes(

n=72

5)Ta

iwan

(n=5

38)

Hon

g Ko

ng(n

=394

)B

razi

l(n=6

25)

Mex

ico(

n=87

)

Latin

Am

eric

a(n=

712)

AP

(n=1

0,16

6)A

PLA

(n=1

0,87

8)U

S*

(n=1

7,38

2)U

S**

(n=

187,

565)

* 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

(Jessup M, Brozena S. N Engl J Med 2003; 348: 2007-18.)

STAGE OF HEART FAILURE & THE TREATMENT

(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 production..

• History of recurrent admission with dilated cardiomyopathy, • Poor EF complicated with right pleura effusion, ascites, swollen

ankleand left ventricle thrombus

• He was on poly pharmacies ( multiple drugs) after being dis-chargedand denied of non compliance ( before this admission )

1. furosemide 2x40mg mane2. bisoprolol fumarate 1,25 mg mane3. spironolactone 1x50mg mane4. warfarin 1x1 mg nochte5. ramipril 1x7.5mg nochte

RISK FACTORS for CAD

• Hypertension (-)• Diabetes Melitus (-)• Smoking (-)• Dyslipidemia (-)

PHYSICAL EXAMINATION20 May 2015

• Consciousness : compos mentis • Blood Pressure : 70/50mmHg, • Heart Rate : 100x/min/regular• Respiratory Rate: 24x/min, • O2 Saturation : 98%

VITAL SIGNS

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 (-)

– LungVesicular 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 normalpulmonal segment normal, downward apex, congestion (+),

infiltrate (-), right pleural effusion (+)

• ELECTROCARDIOGRAPHYST 116x/min, RAD, RVH, ST ↓in II, III, aVF, poor R wave pro-gression V1-V6

• ECHOCARDIOGRAPHYEF 18 %, TAPSE 1.3 cm, Severe Global HypokineticModerate Mitral RegurgitationModerate Tricuspid RegurgitationModerate Pulmonary hypertension Thrombus (+) at the apical LV

Hospitalized Heart Failure on NCVC

January – December 2012

Janu

ary

Febr

uary

Mar

chAp

rilMay

June Ju

ly

Augu

st

Sept

embe

r

Octob

er

Novem

ber

Decem

ber

0

50

100

150

200

250

122

89 82

130

212

133

20

70 72

122

9170

Total: 1243 patient

67.9%

32.1%

MaleFemale

Previous HF history

30.3%

35.2%

34.5%

No HF history Previous HF History (+)Prior Hospitalization in PJNHK

Etiology of Heart Failure at NCCHK 2012

Ischemic heart disease docu-

mented by coronary an-

giography; 20.2

Ischemic heart disease

not docu-mented by

coronary an-giography;

37.6 %

Dilated Car-diomyopathy;

3.4

Valve disease; 12.7

Tachycardia re-lated car-

diomyopathy; 0.2

HFPEF Syn-drome; 17.8

Other; 8.2

Precipitating Factors for hospitalization in HF

Myocardial Ischemia

Acute Coronary Syndromes

Atrial Fibrillation

Bradycardia

Ventricular Arrythmia

Infection

Hypertension

Non Compliance

Renal Dysfunction

Anemia

Diuretic as Decongestive Ther-apy

No Yes0

102030405060708090

100 No; 91.2

Yes; 8.8

IV Nitrate

No Yes0

102030405060708090

100

No; 10.5

Yes; 89.5

IV Diuretics

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

• 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

Resistance Etiology-based Strategies to Restoring DU Efficacy

► 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

35

The Cardiorenal Syndrome Development

of diureticresistance

Impairedrenal

function

Increasedmorbidity

and mortality

Neurohormonalactivation

DiminishedBloodflow

Diuretic therapyDecreased renal

perfusion

• Loop DU Pharmacology & Pharmacokinetics- Absorption - Distribution- Metabolism - Excretion

Resistance Etiology-based Strategies to Restoring DU Efficacy

- 50% inactivated by renal glucoronidation- 50% secreted as parent compound by OAT-1 sys-tem

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 = MRAVasopressine Antagonist Aquaretics . Non Diuretic Strategies = Expensive De-vices - Ultrafiltration : Neutral results

41

V2 Receptor Mediates Hyponatremia and Volume Overload:Role of Vaptans

V2RAVP

HypoNa+

Congestion,

edema

H2O

VaptansSIADH

Cirrhosis/Ascites

HeartFailure

42

Tolvaptan Site of Action

Verbalis JG, et al. Am J Med 2007;120(11 suppl 1):S1-S21. Knoers NVAM. N Engl J Med. 2005;352(18):1847-50.

44

Aquaresis is More Than Free Water Clearance

44

Aquaretic effect without increasing urinary electrolyte excretion

Potential role of Tolvaptan based on clinicaland preclinical studies

Maintains its aquaretic effect in combination with saluretic drugs

Does not affect neurohormonal factors, renal function, or hemodynamic parameters, such as blood pressure and heart rate

Hori M. Cardiovasc Drugs Ther. 2011;25(suppl 1):S1-S4.

45

Effect of Tolvaptan on Urine Volume

Udelson et al. J Am Coll Cardiol 2008;52;1540-1545.

Mean change from baseline in urine volume in the first 8 h after treatment administration

300

-2000 82 3 4 5 6 7

200

100

0

-100

1

Placebo Samsca® 15 mg Samsca® 30 mg Samsca® 60 mg

Mea

n C

hang

e F

rom

Bas

elin

e In

Urin

e V

olun

e (m

L)

Time (hrs)

A dose-dependent increase in urine output was observed among the tolvaptan-treated groups.

Bloods test results of Mr A, M, 40 yo1 Haemoglobin 13.2 g/dL

2 Leukocyte 5870 /uL

3 Hematocrit 39%

4 Thrombosis 179,000 /uL

5 GFR 36

6 Serum Blood Glucose 95 mg/dL

7 Ureum 100 mg/dL

8 BUN 47 mg/dL

9 Creatinine 2.02 mg/dL

10 Sodium 126 mEq/dL

11 Potasium 4.8 mEq/dL

12 Calcium total 2.35 mEq/dL

13 Chloride 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

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/kgof BW

25mg/kgof 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 - 56.5 kg

MANAGEMENT SUMMARY

M, 44 years

Serum sodium level was corrected, Negative Fluid balance >>>, Body

Weight <<<,, General condition was improved

Tolvaptan + furosemide drip

Post Tolvaptan Treatment Patient was

admitted in with ADHF Edema (+)

Conclusion• The initial evidence based management strategy sug-

gested that an initial “high dose” IV bolus injection con-tinued with moderate dose continuous infusion is likely to be more successful than a slower approach.

• In cases of diuretic resistance, adding a thiazide or thi-azide like diuretic or K sparring diuretic, or spironolac-tone 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 pa-tients with significant renal dysfunction.

• Low dose (renal dose) dopamine infusion can im-prove 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 Hy-ponatremia and Diuretic Resistance will lead to the risk of Osmotic Demyelination Syndrome