Artwork by Aaron Jameson Cast of Characters n Importance n Evaluate a Case n Explain the...

Artwork by

Aaron Jameson

Cast of Characters

Importance Evaluate a Case Explain the Pathophysiology Develop the Armamentarium

– Why they work– How to monitor

Cover the important evidence for each group

Plan of Attack

CHF and Super Heroes

The Role of Rx Man

Surgeon General’s Warning This lecture will require you to

write some things down You could develop carpal tunnel

syndrome You could develop an irreversible

hand cramp You could retain something longer

than 5 minutes

A Fatal Choice You can have a cancer that:

kills 40% of people in 5 years

OR You can have your first

episode of symptomatic CHF

Did You Choose CHF?

OOPS !!

Epidemiology

CHF Kills A LOT of People CHF Makes A LOT of People’s

lives miserable CHF costs a WHOLE LOT of $

New York Heart Association

Class I Class II Class III Class IV

New Approach to the Classification of Heart Failure

Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Refractory end-stage HFD

Known structural heart disease Shortness of breath and

fatigue Reduced exercise tolerance

Symptomatic HFC

Previous MI LV systolic dysfunction Asymptomatic valvular disease

Asymptomatic HFB

Hypertension CAD Diabetes mellitus Family history of

cardiomyopathy

High risk for developing heart failure (HF)

APatient Description

Stage

Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

A At high risk for heart failure but without structural heart disease or symptoms of heart failure (eg, patients with hypertension or coronary artery disease)

Classification of HF: Comparison Between ACC/AHA HF Stage and NYHA Functional ClassACC/AHA HF Stage NYHA Functional Class

NoneNone

B Structural heart disease but without symptoms of heart failure

I Asymptomatic

C Structural heart disease with prior or current symptoms of heart failure

II Symptomatic with moderate exertion

III Symptomatic with minimal exertion

D Refractory heart failure requiring specialized interventions

IV Symptomatic at rest

2113.

Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

PenelopeA 74 year old white female 5 feet tall 160 pounds S/P CVA Hx mild CHF , HTN and DM 2

Penelope : Episode 1

Admitted to ER with Acute SOB.

Auscultation reveals crackles 1/2 way up on both sides

CXR shows mild interstitial infiltrates

BP: 150/80 2+ pitting edema


Admitted to ER with Acute SOB. Auscultation reveals crackles

1/2 way up on both sides CXR shows mild interstitial

infiltrates BP: 150/80 2+ pitting edema NYHA class?

Penelope

Drugs: Insulin Dyazide daily Zestril 5 mg daily

Penelope is tied to the railroad tracks

You can save her from floods You can give her a pillow and

make her more comfortable You can even delay the train But you can’t take her off the

tracks.

Circulation Review

PreloadPreload AfterloadAfterload

Low Low pressurepressure

High High pressurepressure

Famous Last Words

Everything that can be invented has been invented.”

--Charles H. Duell, Commissioner, U. S. Office of Patents, 1899.

Systolic vs. Diastolic Dysfunction

120 ml

Normal Heart

70ml

EF 70/120

58 %EF 70/120

58 %

CO = 70ml /beatCO = 70ml /beat

Normal Heart

120 ml

* 72/min* 72/min=5040 ml/min=5040 ml/min

Systolic Dysfunction

160 ml

40ml

Systolic Dysfunction

160 ml

CO = 40ml /beatCO = 40ml /beat * 72/min* 72/min=2880 ml/min=2880 ml/min

EF 70/120

58 %EF 40/160

25 %

57 ml

Diastolic

Dysfunction

40ml

Diastolic Dysfunction

57 ml

EF 70/120

58 %EF 40/57

70%

CO 40ml / beatCO 40ml / beat * 72/min* 72/min =2880 ml/min=2880 ml/min

Diastolic Heart Failureand Intravascular Congestion

Describe Diastolic Dysfunction

Other Neuroendocrine mediators

Arginine Vasopressin (ADH)

Stimulated by extreme low kidney perfusion, just like Aldosterone. Causes free water retention and hyponatremia

Endothelin

One of the absolute most potent vasoconstrictors. Endothelin antagonists in the works

Atrial and B-type Natriuretic peptide

Stimulated by stretch of the atria and the ventricles and cause sodium and water excretion. Sort like a counter-regulatory hormone to aldosterone

CHF: CompensationCardiac Output

Kidney Perfusion

ReninAngiotensinAldosterone

Na+ & H2O

retention

Preload

SNS

Cardiac Output

((Compensated)

CHF: CompensationCardiac Output

CHF: Compensation

Kidney Kidney PerfusionPerfusion

Cardiac Output

CHF: Compensation

Kidney Perfusion

ReninReninAngiotensinAngiotensinAldosteroneAldosterone

Cardiac Output

CHF: Compensation

Kidney Perfusion

ReninAngiotensinAldosteroneAldosterone

Na+Na+ andand H2OH2O

retentionretention

Cardiac Output

CHF: Compensation

Kidney Perfusion


PreloadPreload

Cardiac Output


retentionretention

CHF: Compensation

Kidney Perfusion


PreloadPreload

CardiacCardiacOutputOutput

(CompensatedCompensated))

Cardiac Output


retentionretention

CHF: Compensation

Kidney Kidney PerfusionPerfusion


Na+ and H2O

retention

Preload

Cardiac Output CardiacCardiacOutputOutput

(Compensated)Compensated)

CHF: Compensation

Kidney Perfusion

ReninAngiotensinAngiotensinAldosterone

Na+ and H2O

retention

SNSSNS

Cardiac Output CardiacCardiacOutputOutput

(CompensatedCompensated))

Preload

CHF: Warning: New Slide!

Cardiac Output

WHY?


Cardiac Output

WHY?

SystolicSystolic DilatedDilated CardiomyopathyCardiomyopathy CADCAD HTNHTN


Cardiac Output

WHY?

SystolicSystolic DilatedDilated CardiomyopathyCardiomyopathy CADCAD HTNHTN

Diastolic

Hypertension

CAD

Hypertrophic Cardiomyopathy

Another famous last quoteGod is Dead

Nieztsche 1885

Nieztsche is

DeadGoGod d

20072007

CHF: The Viscious CycleThe Viscious Cycle

Kidney Perfusion


Cardiac Output

CHF: The Viscious Cycle

Kidney Perfusion


VasoconstrictionVasoconstriction

SNS

Cardiac Output

CHF: The Viscious CycleCardiacCardiac OutputOutput

Kidney Perfusion


VasoconstrictionVasoconstriction

SNS

AfterloadAfterload

High Pressure

Left VentricleLeft Ventricle ArteriesArteries

High Pressure: Vasoconstriction


CHF: The Viscious Cycle

Kidney Perfusion


Cardiac Output

CHF: The Vicious Cycle

Kidney Perfusion



retentionretention

Cardiac Output

CHF: Vicious Cycle

Kidney Perfusion


PreloadPreload and and Pulmonary EdemaPulmonary Edema

Cardiac Output


retentionretention

CHF: Vicious Cycle

Kidney Perfusion



Cardiac Output


retentionretention

StrainStrain

CHF: Symptoms

Kidney Perfusion



Cardiac Output


retentionretention

StrainStrainLow PerfusionLow PerfusionLow PerfusionLow Perfusion

Fluid OverloadFluid OverloadFluid OverloadFluid Overload

CHF Pharmacotherapy

New Drugs Mechanism(s)

Monitoring for Efficacy

Monitoring for Adverse Effects

Back to Penelope: Episode 1

Admitted to ER with Acute SOB.

Auscultation reveals crackles 1/2 way up on both sides

CXR shows mild interstitial infiltrates

BP: 150/80 2+ pitting edema

This is a Job for...

Water Boy

Diuretics: Mechanism

Sodium and Water Excretion

Preload

Necessary Poison

Low perfusion Loss of Renal Function

Fluid OverloadPulmonary Edema





Diuretics: Efficacy

~1 Kg / day (short term) ~1000 mls net loss / day 700 mls insensible loss

(output) Lung Sounds / CXR Decreased Edema

Diuretics: Efficacy

Example:

Input: IV at 100ml/hour

Output: 2700 ml in 24 hours

Net:

Don’t forget 700ml insensible + 300ml = 1000ml lost

Diuretic Dosing

Long Term:Be a Sissy.

Short Term:The Nike Rule

Diuretics: Thiazides vs LoopsLoopstorsemide vs furosemideAbsorption, duration and CostOther loops

Potency vs efficacy

Diuretics: Side Effects

BUN / Cr Ratio Potassium Do Orthostatics !! Clinical Hydration Status Glucose Uric Acid Ca++

Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles


infiltrates BP: 150/80 2+ pitting edema

BP 150/80

Which rule should we use? Nike or Sissy?

Penelope : Episode 1 Admitted to ER with Acute SOB. Auscultation reveals crackles


infiltrates BP: 150/80 2+ pitting edema

BP 150/80

What about the Zestril dose?

ACE of Hearts

Angiotensin IAngiotensinogen

Renin

COW HERE

Angiotensin IAngiotensinogen

Renin

Angiotensin I

Angiotensin II

Angiotensinogen

ACE

Renin

Angiotensin I

Angiotensin II

Aldosterone

Vasoconstriction

Angiotensinogen

ACE

Renin

Na+

K+K+ Lost

Na+ Retained

Aldosterone

Angiotensin I

Angiotensin II

Vasoconstriction

ACE I

Angiotensinogen

ACE

Renin

K+K+ Retained

Aldosterone

Angiotensin I

Angiotensin II

Aldosterone

Vasoconstriction

Kinins

Breakdown

ACE I

Angiotensinogen

Renin

ACE

Kinins

OK,

So how does this benefit the fluid overloaded, under-perfused CHF patient

insert preload diagram hereinsert preload diagram here

LowLowPressurPressuree

Whew !!!

I Can Breathe !!

High Pressure: AfterloadHigh Pressure: Afterload


High Pressure: Post DilationHigh Pressure: Post Dilation


OK,

So how does this benefit the fluid overloaded, under-perfused CHF patient

Breathing and fluid

improved

Exercise capacity improved

Mental Status Improved

B. P.

Ace Inhibitors: Efficacy

BUN / Creatinine

Ace I: Adverse Effects

Potassium

Hypotension (dizziness)

Cough

AngioedemaACE & Kidneys

Ace Inhibitors:Warning Signs

Impaired Renal Perfusion Diuretic CHF

– Especially w/ Hyponatremia Ascites

Ace Inhibitors : Dosing

CHF vs HTN Caution: Hyponatremia

Ace Inhibitors : Drug Intx

Potassium Sparing Diuretics NSAIDS

What is the intx with ACE Inhibitors and NSAIDS?

V-HeFT I

Enalapril vs. Placebo Class II & III Mortality

– 34.3 vs 25.6 @ 2 years NNT 11.5– 53.6 vs 49.7 @ 4 years NNT 25.6

(benefit diminishes w/ time)

CONSENSUS I

Class IV Mortality at one year 52% vs 36% NNT 6 !!! Average dose 18.4 mg /day

SOLVD-Treatment

Class II & III Mortality at 4 years 39.7 % vs 35.2 % NNT 22 Mean daily dose of enalapril= 16.6

mg

Penelope :

Increase Zestril to 10 mg daily

Because :

Ace Inhibitors Save Lives


One month later…

Develops an intractable cough

Your questions?

Your recommendation?

Vasoconstriction

Angiotensin I

Angiotensin II

Aldosterone

Angiotensinogen

Renin

Na+

K+

Kinins

Breakdown

Chymase

Aldosterone Vasoconstriction

K+ Retained

Aldosterone

Vasoconstriction

AT1 AT1

Angiotensin IIAngiotensin II

AT2

AT3

AT4

Feedback Fetal effects Many others

ARBs

Similar to ACE inhibitors but also many differences

Highly variable half lives Highly variable AT1 receptor

affinity

RESOLVD

Candesartan vs. candesartan +enalapril vs. enalapril alone

Class II – IV Terminated early due to

candesartan groups doing worse. Difficult to interpret due to

unusually low mortality and morbidity in enalapril group

RESOLVD

Because the study wasn’t powered to show mortality, the authors conclusion didn’t mention higher mortality in the candesartan groups!

“Candesartan was as effective, safe, and tolerable as enalapril”

“The Combination… was more beneficial for preventing left ventricular remodeling”

Elite II Losartan 50mg / d vs. placebo Class III & IV Mortality: No difference

ValHeft

Valsartan Class II-IV Some benefit added to ACE OR

to a Beta Blocker INCREASED MORTALITY When added to both !!

CHARM (as in snake?)

Alternative – In ACE intolerant

patients – Improved outcomes

moderately Added

– Improved outcomes minimally

– Beta blocker would be better (opinion)

Preserved– No statistical

improvement Overall

– Statistical improvement

Penelope

Cozaar 50mg daily Continue Lasix etc.

Penelope: Episode 3

Four months later…

There has been trouble getting weights in the nursing home

Another episode of SOB, 02 saturation 85% Weight 178 pounds BUN / Cr: 40 / 1.4

Penelope

Treatment now?

Right Again! Vitamin L

Treatment: Lasix 80 mg BID

What will that do to the BUN / Cr?

Penelope:

Two weeks later…

Wt. 175 pounds Breathing improved but not good No CXR or ausculation BUN / Cr 50 / 1.5 What do you recommend ?

My Momma Always Said:

Patience is a Virtue

Penelope

Weight decreases to 158 over the next 2 months.

Breathing greatly improved in the last month.

BP: 110 / 70 Guesses on the BUN and Creat?? 90 / 2.0

Penelope: Episode 5

What next??

Decline in mental status. Sleeping 18 to 20 hours per day. Confused, wild delusions.

What do you do now?

The Hemodynamic Duo!!

Nitrates / Hydralazine: Mechanisms

Hemodynamic effects similar to Ace

Inhibitors

Nitrates decrease Preload

Hydralazine decreases afterload

Nitrates / Hydralazine PERHAPS a little:

– less mortality benefit

– more symptom benefit

Less renal impairment risk

Nitrates / Hydralazine: Efficacy

Similar to Ace Inhibitors Better in African Americans?

Nitrates / Hydralazine: Adverse Effects

P.O.S. (Pill overload syndrome)

Headache

Nausea

Hypotension

Nitrates / Hydralazine:

BIDIL®

Could we use digoxin?

Digimon

Digoxin: Mechanisms

Increased force of contraction

Decreased hospitalizations

No mortality benefit or harm

Digoxin: Efficacy

Urine Output

Mental Status

Exercise capacity improved

Digoxin: Adverse Effects

Potassium

Mental Status

Pulse / EKG

Nausea / Vomiting

Digoxin: Evidence

The Dig Trial

No difference in mortality 67.1% vs 64.3%

hospitalization 1% vs 2 % hospitalized for

suspected dig toxicity

Digoxin Pharmacology? Clinical Effect?

Meanwhile, Penelope is still on the Railroad Tracks

Increase Cozaar BUN goes to 120 (oops) Decrease Cozaar Add Hydralazine and Nitrates Titrate up to 50 mg TID and

20 mg TID

Penelope

Result?

Somnolence improves Delusions resolve BUN / Cr 80 / 1.8 Weight 158 BP: 100/60 Add a beta blocker?

Sir Blocksalot

0

10

20

30

40

50

60

70

80

Mean + SD.Adapted from Bristow M. J Am Coll Cardiol. 1993;22(4 Suppl A):61A–71A.

Normal function (n=12) Cardiomyopathy (n=54)

1

2

1*P<.05 vs normal function

Rec

epto

r d

ensi

ty (

fmo

l/mg

p

rote

in)

1: 2 80%:20% 1: 2 65%:35%

Adrenergic Receptors in Normal vs Failing Left Ventricles

*

Beta Blockers

Improve Cardiac Function ??

Decreased Mortality

Don’t Use Unless CHF is stable

Beta Blockers Block

Death

Beta Blockers: MERIT-HF

Metoprolol XL Mostly Class II & III Mortality over one year

– 11% vs. 7.2% NNT 26 Dosing

Beta Blockers:Carvedilol Trial

Mostly Class II & III Mortality over 6 months

– 3.2% vs. 7.8% NNT 21 hospitalization 14% vs 19% NNT 20 2% died or deteriorated during run in

Which beta blockers are proven in CHF?

Penelope

She does well for 3 months

Penelope died July 9, 1998

Penelope

What do we know now that we didn’t know then?

Spiro the Super Mouse

CHF: Vicious Cycle

Kidney Perfusion



Cardiac Output


retentionretention

StrainStrain

AldosteroneAldosterone

Sodium Retention Magnesium and Potassium Loss Sympathetic Activation Parasympathetic Inhibition Myocardial fibrosis Vascular Fibrosis Impairs arterial compliance

AldosteroAldosteronene

RALES

Spironolactone 25 mg / d vs. Placebo

Class III & IV Mortality at 11 months (stopped early) 46% vs 35 % NNT: 9

Newbies

Tezosentan endothelin receptor antagonist Who knows

Levosimendan Calcium sensitizer on troponin C may increase force of contraction without increasing myocardial oxygen consumption.

Nesiritide - Origin

Stretch receptors in the Atria (ANP) and the Ventricles (BNP)

Cause natriuresis and vasodilation Makes perfect sense Easy to Market Benefit??

Nesiritide This is also known as BNP and

causes diuresis and vasodilation. Studies show it superior to placebo

and equal to conventional therapy. If you don’t count mortality It costs about $1 million per dose,

may be useful in highly specific cases

Nesiritide – On the Other Hand

BNP is a good test in diagnosing CHF <100 mcg/ml NOT CHF 101 to 999 NOT normal, but

probably not CHF 1000 to 4000 CHF or related

condition >4000 almost certainly

CHF

Seven Roles for Rx Man

Sell them a scale Poke at their ankles Ensure labs (K+) Teach them to take their pulse NSAIDS Salt Police Cough Syrup patrol

Clinical Signs and Sx of CHF

Fluid Overload Shortness of Breath DOE Orthopnea / PND Pedal Edema CXR

Clinical Signs and Sx of CHF

Inadequate Perfusion Decreased Urine Output Increased BUN/Cr ratio Impaired Mental Status Cool, Clammy Skin Fatigue

Recap: AHA/ACC Heart Failure GuidelinesJ Heart Lung Transplant Feb, 2005

Class I Recommendations– Diuretics for patients with fluid retention (A)– ACEI for all patients unless contraindicated

(A)– Beta-blockers for all stable patients unless

contraindicated (A)– Digitalis for treatment of symptoms (A)– Withdrawal of drugs that may adverse the

status of heart failure patients (NSAIDs, most antiarrhythmics, most calcium channel blockers) (B)


Class I Recommendations (cont’d)• Exercise training• Implantable defibrillator if history of

arrest, V Fib or bad V. Tach• Resynchronization therapy where

indicated


Class IIa Recommendations (conflicting evidence/opinion but evidence favors)– Spironolactone for recent Class IV symptoms (B)– ARBs for patients not tolerating ACEI due to cough or

angioedema (A)– Combination of hydralazine + nitrate in patients not an

ACEI candidate due to hypotension/renal insufficiency (B)• Digitalis for treatment of symptoms (A)• Use of a CCB with negative inotropic effect may be harmful low

ejection fraction (A)

Class IIb Recommendations (conflicting evidence/opinion with less evidence to support)– Addition of an ARB to an ACEI (B)– Addition of nitrate +/- hydralazine to patients on ACEI (B)


Class III Recommendations (no data or harmful)– Intermittent IV positive inotropes (C)– ARB instead of an ACEI in patients never tried

on or could tolerate an ACEI (B)– Use of an ARB before beta-blocker in a patient

on an ACEI– Use of a CCB to treat CHF (B)– Routine use of nutritional supplements

(CoQ10, etc.) or hormones (thyroid, growth) (C)

Case #1

KK is a 71 year old male with known history of CHF admitted for hypotension and shortness of breath

Case #1 Albuterol Ipratropium Phenytoin Neurontin Levothyroxine Protonix Lasix 20mg /day Amiodarone Verapamil 240mg/day

Labs BNP 995 Troponin <0.3 x 3 LDL <100 Na 137 K 4.1 Cl 101 TCO2 29 BUN 33 Creat 1.3

Weight on admission= 84 kg BP 102/63 Heart Rate 58 TSH 2.2

#1 Monitoring Parameter? 84 Kg on admission Day 1: 83.5 Day 2: 83.3 Day 3: 83.1

Case #1

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Artwork by Aaron Jameson Cast of Characters n Importance n Evaluate a Case n Explain the...

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