Diuretic Resistance in Heart Failure Robert J. DiDomenico, PharmD Clinical Associate Professor...

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…

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)

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

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.

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.

Diuretic Resistance & Mortality

Eshaghian S, et al. Am J Cardiol 2006;97:1759-64.

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

Diuretic Resistance

Diuretic Mechanism of Action

&

Mechanisms of Diuretic Resistance

Diuretic Mechanism/Site of Action

De Bruyne LKM. Postgrad Med J 2003;79:268-71.

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???

• 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.

Diuretics Pharmacodynamics Sodium & Water Excretion

Ellison DH. Cardiology 2001;96:132-43.

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.

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

**

*

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

Does Venous Congestion Impair Renal Function?

Doty JM et al. J Trauma 1999;47:1000-3.

Doty JM et al. J Trauma 1999;47:1000-3.



Patel KP, Carmines PK. Am J Physiol Regulatory Integrative Comp Physiol 2001;281:R239-45.

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

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.

Treatment of Diuretic Resistance

Continuous Infusion of Diuretic

vs.

Intermittent Bolus Dosing

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.


Dormans TPJ, et al. J Am Coll Cardiol 1996;28:376-82.

• Cumulative doses (area under the curve) of furosemide not significantly different

• 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


P=0.016

Thomson MR, et al. HFSA 2007[Abstract].


Combination Diuretic Therapy

Treatment of Diuretic ResistanceCombination Loop + Thiazide

Channer KS, et al. Br Heart J 1994;71:146-50.

Treatment of Diuretic ResistanceCombination Loop + Thiazide

Channer KS, et al. Br Heart J 1994;71:146-50.

26/40 (65%)

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


IV Vasoactive Therapy

Abraham WT, et al. JACC 2005;46:57-64.

IV Vasoactive Therapy in ADHFADHERE Mortality Analysis

IV Vasoactive Therapy in ADHFEarly Initiation May Improve Outcomes

Peacock WF, et al. HFSA 2006[Abstract].

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%

• 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.

Treatment of Diuretic ResistanceHypertonic Saline & IV Diuretics

Licata G, et al. Am Heart J 2003;145:459-66.

Treatment of Diuretic ResistanceUltrafiltration

Costanzo MR, et al. J Am Coll Cardiol 2007;49:675-83.

Future Approaches for Diuretic Resistance in ADHF

New Drug Classes:Vasopressin Antagonists

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

Treatment of Diuretic ResistanceRole for Conivaptan?

Udelson JE, et al. Circulation 2001;104:2417-23.

New Drug ClassesAdenosine Receptor Antagonists

Future Approaches for Diuretic Resistance in ADHF

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.

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

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.

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.

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).


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)


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)


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.

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

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!

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

Diuretic Resistance in Heart Failure Robert J. DiDomenico, PharmD Clinical Associate Professor...

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