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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 : [email protected]
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