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Diuretic Resistance in Heart Failure
Robert J. DiDomenico, PharmDClinical Associate Professor
Affiliate Faculty, Center for Phamacoeconomic ResearchUniversity of Illinois at Chicago
Colleges of Pharmacy & MedicineCardiovascular Clinical Pharmacist
University of Illinois Medical Center at Chicago
To Pee or Not to Pee…
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Disclosures
• Scios, Inc.– Honoraria, consulting, research support
• Sanofi-Aventis/Bristol Myers Squibb– Honoraria (c/o STRIVE™ network)
• The Medicines Company– Honoraria (c/o University
Pharmacotherapy Associates)
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Case• 54yo M• PMH:
– CHF– HTN– CAD s/p CABG– DL– DM– OSA (morbid obesity)
• Meds– Furosemide 160mg bid– Spironolactone 25mg bid– Enalapril 20mg bid– Valsartan 80mg bid– Digoxin 0.25mg daily– ECASA 325mg daily– Lovastatin 80mg qhs– Insulin– Advair– Theoplylline
• BP 113/73, HR 118, RR 40• 95% on 2L O2
• Phys exam– Wt 117kg– JVD 10cm– B crackles at bases w/wheezing– 2+ LEE to knees
• Labs 138 101 41 (baseline 20) 4.1 19 1.7 (baseline 1.2) BNP 414
• Initial Treatment (Med C)– 80mg IV furosemide in ED, then
80mg IV q12h• Response
– Urine output (18 hours) = 980ml– Increasing dyspnea
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Typical ADHF Treatment Course
0
10
20
30
40
50
60
70
80
90
% P
ati
en
ts
IV Diuretic IV vasoactive Nesiritide NTG Dobutamine Dopamine
ADHERE-3/06
Premier-12/05
Consorta-12/06
ADHERE® Q1 2006 Final Cumulative Benchmark Report. Scios, Inc.: Sunnyvale, 2006. Hauptman PJ, et al. JAMA 2006;296:1877-84.DiDomenico RJ, et al. April, 2007.
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Typical ADHF Treatment Course
0
10
20
30
40
50
60
70
80
90
% P
ati
en
ts
IV Diuretic IV vasoactive Nesiritide NTG Dobutamine Dopamine
ADHERE-3/06
Premier-12/05
Consorta-12/06
ADHERE® Q1 2006 Final Cumulative Benchmark Report. Scios, Inc.: Sunnyvale, 2006. Hauptman PJ, et al. JAMA 2006;296:1877-84.DiDomenico RJ, et al. April, 2007.
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Typical ADHF Treatment Course
0
10
20
30
40
50
60
70
80
90
% P
ati
en
ts
IV Diuretic IV vasoactive Nesiritide NTG Dobutamine Dopamine
ADHERE-3/06
Premier-12/05
Consorta-12/06
ADHERE® Q1 2006 Final Cumulative Benchmark Report. Scios, Inc.: Sunnyvale, 2006. Hauptman PJ, et al. JAMA 2006;296:1877-84.DiDomenico RJ, et al. April, 2007.
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Diuretic Resistance
• Commonly referred to as Cardiorenal Syndrome– 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: 35%1
– Acute: unknown
1Neuberg GW, et al. Am Heart J 2002;144:31-8.
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Diuretic Resistance & Mortality
Eshaghian S, et al. Am J Cardiol 2006;97:1759-64.
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Diuretic ResistanceWhat About in ADHF?
• Greenhalgh E, DiDomenico RJ– Retrospective analysis of ADHF
admissions to UIMCC in 2006– Inclusion
• >18yo, ADHF with volume overload, Tx with IV diuretic
– Exclusion• Initial Tx doesn’t include IV
diuretic• Use of IV vasoactives in 1st 24
hours• N=264
– Definition• Urine output < 500ml within 2
hours of IV furosemide• Urine output < 1000ml within 4
hours of IV furosemide
• Goals– Characterize diuretic
resistance in the acute setting– Investigate if there are any
reliable risk factors for diuretic resistance in ADHF
• Clinical characteristics– Demographics, clinical
presentation, NYHA FC– LV Fxn, renal Fxn– BP– Dose of diuretic
• Home & inpatient– Concomitant meds
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Diuretic Resistance
Diuretic Mechanism of Action
&
Mechanisms of Diuretic Resistance
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Diuretic Mechanism/Site of Action
De Bruyne LKM. Postgrad Med J 2003;79:268-71.
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Mechanisms of Diuretic Resistance
• Diminished effect in heart failure & renal failure
• Stimulation of neurohormonal axes
• Hypertrophy of distal tubules impairs natriuretic response
• Post-diuretic NaCl retention
• Venous congestion impairs renal tubular function???
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• Normal patients– Furosemide 40mg IVP
• 200 – 250mEq Na• 3 – 4 L over 3 – 4 hrs
• CHF patients natriuretic response
• Absorption & peak effect delayed
• 1/3 – 1/4 that of normal patients
• Renal insufficiency (RI)– 1/5 – 1/10 furosemide secreted
into renal tubules
– Free concentrations of diuretic may be in nephrotic syndrome due to protein binding
Diuretic PharmacodynamicsSodium & Water Excretion
Brater DC. New Engl J Med 1998;339:387-95.
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Diuretics Pharmacodynamics Sodium & Water Excretion
Ellison DH. Cardiology 2001;96:132-43.
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Diuretics & NeurohormonesDiuretic Resistance & Renal Function
Proximal TubuleAT2 increases sodium reabsorbtion
Collecting DuctHypertrophy of distal tubules. Aldosterone increases sodium reabsorbtion
GlomerulusNorepinephrine, endothelin, AT2 decrease renal blood flow and GFR
Weber KT. NEJM. 2001;345:1689-1697. Francis GS et al. Ann Intern Med. 1984;101:370-377. Dzau VJ. Kidney Int. 1987;31:1402-1415.
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600
800
1000
pg
/mL
Plasma [norepinephrine]
0102030
ng
/mL
Plasma renin activity
0
5
10
pg
/mL
Plasma [ vasopressin]
Diuretic ResistanceNeurohormonal Stimulation
Francis GS, et al. Ann Intern Med 1985;103:1-6.
Baseline
20 minutes
* p<0.01
**
*
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80
90
100
MAP HR
Vital Signs
20
25
30
mL
/min
*m2
Stroke Volume Index
010203040
mm
Hg
PCWP
1400
1600
1800
dy
ne
s*s
*cm
5
SVR
Francis GS, et al. Ann Intern Med 1985;103:1-6.
Baseline 20 minutes 3.5 hours2085+1035ml urine
* p<0.01
* * *
* * *
Diuretic ResistanceHemodynamic Effects
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Does Venous Congestion Impair Renal Function?
Doty JM et al. J Trauma 1999;47:1000-3.
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Doty JM et al. J Trauma 1999;47:1000-3.
Does Venous Congestion Impair Renal Function?
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Does Venous Congestion Impair Renal Function?
Patel KP, Carmines PK. Am J Physiol Regulatory Integrative Comp Physiol 2001;281:R239-45.
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Treatment Options for Diuretic Resistance
• Change diuretics?• Continuous infusion• Combination of Loop diuretic + thiazide• IV vasoactive drugs• Combination hypertonic saline + Loop diuretic???• Investigational therapies
– Vasopressin antagonists– Adenosine antagonists
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Treatment of Diuretic ResistanceAre All Diuretics Created Equal?
• More frequent dosing of furosemide & bumetanide may be necessary to overcome postdiuretic NaCl retention
Brater DC. New Engl J Med 1998;339:387-95.
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Treatment of Diuretic Resistance
Continuous Infusion of Diuretic
vs.
Intermittent Bolus Dosing
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Treatment of Diuretic ResistanceIV Bolus vs Continuous Infusion
Urine output (48hrs)
IV bolus: 3790ml
Cont inf: 4490ml
P<0.01
Lahav M, et al. Chest 1992;102:725-31.
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Treatment of Diuretic ResistanceIV Bolus vs Continuous Infusion
Dormans TPJ, et al. J Am Coll Cardiol 1996;28:376-82.
• Cumulative doses (area under the curve) of furosemide not significantly different
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• 39 patients with ADHF– 21 received IV bolus– 18 received continuous
infusion
• Daily urine output ~65% greater with continuous infusion vs IV bolus 0
2
4
6
8
10
12
14
Le
ng
th o
f s
tay
(d
ay
s)
IV bolus Continuousinfusion
Treatment of Diuretic ResistanceIV Bolus vs Continuous Infusion
P=0.016
Thomson MR, et al. HFSA 2007[Abstract].
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Treatment of Diuretic Resistance
Combination Diuretic Therapy
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Treatment of Diuretic ResistanceCombination Loop + Thiazide
Channer KS, et al. Br Heart J 1994;71:146-50.
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Treatment of Diuretic ResistanceCombination Loop + Thiazide
Channer KS, et al. Br Heart J 1994;71:146-50.
26/40 (65%)
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Treatment of Diuretic ResistancePractical Approach to Combination Therapy
• Start with low dose metolazone (2.5 – 5mg daily)– Long half-life negates need for more frequent dosing– May give 1st dose 30 minutes prior to IV furosemide
• Not substantiated in literature
• May consider IV chlorothiazide 250 – 500mg • Consider brief course (< 3 days) to minimize
hypovolemia & electrolyte deficiencies• Monitor volume status, electrolytes, & renal
function diligently
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Treatment of Diuretic Resistance
IV Vasoactive Therapy
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Abraham WT, et al. JACC 2005;46:57-64.
IV Vasoactive Therapy in ADHFADHERE Mortality Analysis
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IV Vasoactive Therapy in ADHFEarly Initiation May Improve Outcomes
Peacock WF, et al. HFSA 2006[Abstract].
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ASCEND-HF TrialNesiritide in Patients with ADHF
• Nesiritide + Std therapy vs Placebo + Std therapy– Minimum duration
• 24 hours
• Primary endpoint– HF rehospitalization or all-
cause mortality– Relief of dyspnea at 6 &
24hrs
• N=7000• UIMCC & JBVA are
participating sites
• Inclusion– >18yo, hospitalized for ADHF– Dyspnea at rest or minimal
activity
PLUS– Tachypnea OR pulmonary
congestion on exam
PLUS– + CXR OR BNP OR
PCWP > 20 OR EF <40%
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• Rationale– Creates an osmotic gradient, mobilizing
extracellular fluid into the intravascular space followed by immediate excretion
– Hypertonic saline may increase renal blood flow, facilitating diuretic activity
• Administration– IV furosemide 500 – 1000mg prepared together
with hypertonic saline solution 1.4 – 4.6%– Administered as 30 minute infusion q12h– Also administered IV KCl to minimize hypokalemia
Treatment of Diuretic ResistanceHypertonic Saline & IV Diuretics
Licata G, et al. Am Heart J 2003;145:459-66.
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Treatment of Diuretic ResistanceHypertonic Saline & IV Diuretics
Licata G, et al. Am Heart J 2003;145:459-66.
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Treatment of Diuretic ResistanceUltrafiltration
Costanzo MR, et al. J Am Coll Cardiol 2007;49:675-83.
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Treatment of Diuretic ResistanceUltrafiltration
Costanzo MR, et al. J Am Coll Cardiol 2007;49:675-83.
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Future Approaches for Diuretic Resistance in ADHF
New Drug Classes:Vasopressin Antagonists
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Vasopressin Receptor Antagonists
• V1a receptor
– Found in vascular smooth muscle cells
– Vasoconstriction → peripheral vascular resistance and afterload
• May induce ischemia due to coronary vasoconstriction
• V2 receptor
– Found on renal tubular cells
– Mediates free water retention through aquaporin channels
• Vasopressin Antagonists in Development– Conivaptan (Vaprisol®)
• Duel V1a & V2 antagonist
• IV form available
• PO form in development
– Tolvaptan• V2 >> V1a (30 times)
urine output without sodium loss
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Treatment of Diuretic ResistanceRole for Conivaptan?
Udelson JE, et al. Circulation 2001;104:2417-23.
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Treatment of Diuretic ResistanceRole for Conivaptan?
Udelson JE, et al. Circulation 2001;104:2417-23.
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New Drug ClassesAdenosine Receptor Antagonists
Future Approaches for Diuretic Resistance in ADHF
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Adenosine Receptors and Function
• Other receptor subtypes: A2b, A3
• Adenosine also responsible for sodium transport in proximal renal tubules (mechanism unknown)
• Adenosine levels increased in patients with heart failure
Adenosine receptor
Location Effect
A1 Kidney
(afferent arteriole)
Vasoconstriction
A2a Heart
vasculature
Vasodilation
Modlinger PS et al. Curr Opin Nephrol Hypertens. 2003; 12:497-502.
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Adenosine Antagonism in Heart FailureUrinary Output & Renal Function
-25
-20
-15
-10
-5
0
5
10
15
0 500 1000 1500 2000 2500
Urine Output (ml) 0–8 hours
GF
R (
% c
han
ge)
Placebo
IV Furosemide
n = 16 (NYHA class III HF
Gottlieb SS et al. Circulation. 2002;105:1348-1353.
BG9719
BG9719 +IV Furosemide
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PROTECT Studies:Adenosine Receptor Antagonist, KW-3902
Patients with ADHF and renal dysfunctionrequiring i.v. diuretic
IV KW-3902plus
Standard therapy
Placeboplus
Standard therapy
Primary endpoints: symptomatic relief and renal functionSecondary endpoints: safety, medical costs
Expected enrollment
n=920
http://www.clinicaltrials.gov. Identifier: NCT00354458 & NCT00328692. Accessed 10/12/06.
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Diuretic Resistance (HFSA)12.11 When congestion fails to improve in response to diuretic therapy, the following options should be considered:
– Sodium and fluid restriction– Increased doses of loop diuretic– Continuous infusion of a loop diuretic, or– Addition of a second type of diuretic orally (metolazone
or spironolactone) or intravenously (chlorothiazide)
A fifth option, ultrafiltration, may be considered (Strength of Evidence = C)
Adams KF, et al. J Card Fail 2006;12:10-38.
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Vasodilators (HFSA)
12.15 In the absence symptomatic hypotension, intravenous nitroglycerin, nitroprusside, or nesiritide may be considered as an addition to diuretic therapy for rapid improvement of congestive symptoms in patients admitted with ADHF. Frequent blood pressure monitoring is recommended with these agents.
(Strength of Evidence = B).
Adams KF, et al. J Card Fail 2006;12:10-38.
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Vasodilators (HFSA)12.16 Intravenous vasodilators (intravenous nitroglycerin or nitroprusside) and diuretics are recommended for rapid symptom relief in patients with acute pulmonary edema or severe hypertension. (Strength of Evidence = C)
12.17 Intravenous vasodilators (nitroprusside, nitroglycerin, or nesiritide) may be considered in patients with ADHF and advanced HF who have persistent severe HF despite aggressive treatment with diuretics and standard oral therapies. (Strength of Evidence = C)
Adams KF, et al. J Card Fail 2006;12:10-38.
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Inotropic Agents (HFSA)12.18 (continued) These agents may be considered in similar patients with evidence of fluid overload if they respond poorly to intravenous diuretics or manifest diminished or worsening renal function. (Strength of Evidence = C)
When adjunctive therapy is needed in other patients with ADHF, administration of vasodilators should be considered instead of intravenous inotropes (milrinone or dobutamine).
(Strength of Evidence = B)
Adams KF, et al. J Card Fail 2006;12:10-38.
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ADHF
(A) Signs & Symptoms of VOLUME OVERLOADVOLUME OVERLOAD
(E) Moderate-Severe Volume Overload
(F) IV Diuretics + IV Vasodilators
IV furosemide•If furosemide given previously, double previous IV dose (max = 360 mg)
•May also consider continuous infusion (10 – 40 mg/hr)•If no furosemide given previously & s/s of volume overload, give 40-180 mg IV as described above
PLUS
Nesiritide 2 g/kg IV push, then 0.01 g/kg/min infusion ORNitroglycerin 5-10 g/min infusion
•To achieve 30-50% decrease in PCWP, dose of 140-160 g/min may be necessary DiDomenico RJ, et al. Ann Pharmacother 2004;38:649-60.
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ADHF
(B) Signs & Symptoms of LOW CARDIAC OUTPUTLOW CARDIAC OUTPUT
DiDomenico RJ, et al. Ann Pharmacother 2004;38:649-60.
SBP > 90 mmHg?
Yes
On a -blocker chronically?
No
(H) Milrinone (I) Dobutamine
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2 4 6 8 12 24
Time (hours) from initial ED physician evaluation0
Establish ADHF diagnosis
Initiate IV ADHF therapy
Assess response to initial therapy
Reassess response to therapy
Determine patient disposition
Transfer Patient
Initial EDcontact
DiDomenico RJ, et al. Ann Pharmacother 2004;38:649-60.
Improving Treatment of ADHFTiming is Everything!
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Case Revisited• Treatment course
– Transfer Cardiology– Furosemide drip @ 10mg/hr
• Duration: 96 hours
– IV Nitroglycerin drip 20mcg/min• Duration: 24 hours
• Response– Initial response
• 1700ml urine over next 10 hours
– Developed intravascular depletion, hypotension, WRF
• D/C furosemide• IVF + milrinone x 2 days
– Renal function• Creatinine peaked at 2.0
(hospital day 2)• Creatinine returned to baseline
(1.2mg/dl) by discharge
• Discharged on hospital day 13
• BP 113/73, HR 118, RR 40• 95% on 2L O2
• Phys exam– Wt 117kg– JVD 10cm– B crackles at bases w/wheezing– 2+ LEE to knees
• Labs 138 101 41 (baseline 20) 4.1 19 1.7 (baseline 1.2) BNP 414
• Initial Treatment (Med C)– 80mg IV furosemide in ED, then
80mg IV q12h
• Response– Urine output (18 hours) = 980ml– Increasing dyspnea