Pharmacological Management of Heart Failure

Question 1

“Living Long” & Feeling Better

Answer 1

• Reducing progression
  
  • Neurohormonal interventions
  • Introduce disease modifying therapies that alter disease course
• Preventing complications
  
  • Not directly related to heart failure as a pump
  • Stroke & arrhythmias
• Hemodynamic interventions
  
  • Reduce volume overload &/or increase amount of blood pumped by the heart

Question 2

Pathological Progression of CV Disease

Answer 2

• Heart failure continues to progress even after the initial insult is over
• Ex. a patient has a large anterior wall MI that she survives, & she never has an MI again
  
  • Initially, she will get better b/c once-stunned (not dead) myocardium recovers
  • However, her LV function, LV size, & clinical status will continue to deteriorate due to progressive LV remodeling

Question 3

Heart Failure Pathophysiology

Answer 3

• Heart failure is progressive
• There are several pathwayts playing roles in CHF
• Activation of these pathways causes CHF to worsen –> vicious cycle
• This is what you have to interrupt to treat heart failure

Question 4

Classificaiton of HF

• ACC/AHA Stage
• NYHA Functional Class

Answer 4

• ACC/AHA Stage (cannot go back a stage)
  
  • A: at high risk for HF w/o structural heart disease or symptoms
    
    • HTN, atherosclerotic disease, diabetes mellitus, CAD, FH, cardiotoxic drugs
    • 1 year mortality = 2-3%
  • B: structural heart disease (LV dysfunction) w/o HF symtpoms
    
    • LVH, MI, low LVEF, dilation, valvular disease
    • 1 year mortality = 5-10%
  • C: structural heart disease (LV dysfunction) w/ prior or current HF symptoms
    
    • 1 year mortality = 15-30%
  • D: refractory HF requiring specialized interventions (severe CHF)
    
    • Many symptoms, recurrent hospitalizations
    • 1 year mortality > 50%
• NYHA Functional Class (can go back a stage)
  
  • 0: none
  • I: asymptomatic
  • II: symptomatic w/ moderate exertion
    III: symptomatic w/ minimal exertion
  • IV: symptomatic at rest

Question 5

Neurohormonal Acitvation in HF

• 2 major pathways involved in disease progression
• Disease progression

Answer 5

• 2 major pathways involved in disease progression
  
  • Angiotensin II
    
    • Angiontensin pathway:
    • Angiontensin II binds to AT1
    • Cascade –> increased hypertorphy, vasoconstriction, & NA/water retention in the periphery
  • Norepinephrine
• DIsease progression
  
  • Hypertrophy
  • Apoptosis
  • Ischemia
  • Arrhythmias
  • Remodeling
  • Fibrosis

Question 6

ACE Inhibitors (ACE-Is)

• Effects
• Clinical effects
• ACE-I continuum
• Side effects

Answer 6

• Effects
  
  • Block conversion of angiotensin I to angiotensin II
  • Decrease afterload
  • Lower angiotensin II 9transiently)
  • Lower neurohormones
  • Decrease fibrosis
  • Prevent progressive remodeling
• Clinical effects
  
  • Improve symptoms & quality of life
  • Improve exercise tolerance
  • Improve ejection fraction
  • Reduce hospitalization
  • Reduce mortality
• ACE-I continuum
  
  • ACE-Is are indicated across the entire spectrum of CHF
    
    • (1) at risk
    • (2) asymptomatic LV dysfunction
    • (3) symptomatic LV dysfunction
    • (4) severe CHF
  • Ex. captopril (short acting) & enalapril (long acting)
• Side effects
  
  • Cough
    
    • Most common reason why ACE-Is are stopped
    • Mediated by bradykinin
    • Most common cause of cough: CHF itself
    • Ensure the patient isn’t volume overloaded & doesn’t have a URI
  • Worsening renal function (usually only w/ significant renovascular disease)
    
    • Another mage cause of stopping ACE-Is
    • Ensure there’s not another cause of renal failure (ex. dehydration)
    • Important cause of worsening renal function: NSAID use
  • Hyperkalemia
    
    • Ensure the cause isn’t K supplementation
  • Angioedema
    
    • Absolute contraindication
  • Overall: there are major benefits of ACE-Is in CHF, so make sure they’re not stopped for the wrong reason

Question 7

Angiotensin Receptor Blockers (ARBs)

• Effects of adding candesartan or valsartan
• ARBs vs. ACE-Is

Answer 7

• Effects of adding candesartan or valsartan
  
  • Reduce death or hospitalizations
  • Possibly reduce deaths
  • Can increase risk of nephrotoxicity & hypotension
• ARBs vs. ACE-Is
  
  • ARBs are equivalent (but not superior to & more expensive than ACE-Is
  • Primarily used in ACE-I intolerant patients
    
    • Used in patients w/ current or prior CHF symptoms as a result of LV
    • Used in patients w/ ACE-I related cough since ARBs don’t upregulate bradykinins
  • ARBs also cause renal failure, hyperkalemia & angioedema
    
    • ​ARBs aren’t indicated when ACE-Is cause renal failure or hyperkalemia

Question 8

Aldosterone Escape

• Aldosterone escape
• Effect of eplerenone immediately after MI
• Effect of spironolactone in moderate & severe CHF
• Aldosterone antagonists

Answer 8

• Aldosterone escape
  
  • Aldosterone levels may fall initially in response to ACE inhibition or angiotensin II receptor blockade
  • But they return to normal (“escape”) by 12 weeks
• Effect of eplerenone immediately after MI
  
  • Reduces mortality
• Effect of spironolactone in moderate & severe CHF
  
  • Substantial benefit
• Aldosterone antagonists
  
  • Should be part of routine CHF management for anything more than “at risk” patients

Question 9

Aldosterone Blockade

Answer 9

• Clearly indicated in class 3 to 4 heart failure
• 12.5 to 25 mg QD spironolactone
  
  • Spironolactone is cheaper & should be the first choice
• Need to watch K closely
  
  • Particularly on ACE-Is or K supplementations
  • Generally cut K supplements in half when initiating
• Gynecomastia / mastalgia may occur w/ spironolactone switch to eplerenone
• Consider use when K requiremetns are high

Question 10

Effects of NE in CV Disease

• Sympathetics
• NE vs. mortality in patients w/ CHF

Answer 10

• Sympathetics
  
  • Essential in maintaining cardiac output when this drops acutely
  • Good b/c the most common cause of an acute drop in CO is traumatic blood loss
    
    • The heart pumps more, blood vessels constrict to divert blood to vital organs, & kidneys retain more fluid & water
  • Sympathetic overdrive may keep you going for some time, but over time will lead to bad things
• NE vs. mortality in patients w/ CHF
  
  • More sympathetically “hyper” patient –> worse patient will do w/ high NE levels
  • Damage caused by sympathetic activation is persistent: effect increases w/ time

Question 11

Beta Blockers

• Continuum (class effect)
• Clinical effects
• Contraindications
• Effect of ACE-Is & beta blockers on ventricular remodeling

Answer 11

• Continuum (class effect)
  
  • Carvedilol: only bet ablocker that benefits severe CHF b/c it’s a non-selective beta blocker that also has some alpha blocking activity
  • Use carvedilol in severe CHF or in CHF w/ HTN b/c it’s a better antihypertensive agent than selective beta blockers
• Clinical effects
  
  • Improve symptoms & quality of life
  • Improve ejection fraction
  • Prevent progressive remodeling
  • Reduce hospitalizations
  • Prlong survival & reduce sudden death
  • May transiently worsen symptoms
    
    • Worsening LV function & cardiac output
    • Fatigue (gets better in 1-2 weeks)
    • Fluid retention (may require temporary increase in water pills)
• Contraindications
  
  • Active volume overload
    
    • This will get worse, so wait until they’re dry before starting or increasing
  • Hypotension
  • Bronchospasm
  • Asthma & COPD (use iwth caution)
  • Bradycardia
    
    • Particularly symptomatic or high degree AV block
    • Less of an issue since most patients get ICDs
• Effect of ACE-Is & beta blockers on ventricular remodeling
  
  • ACE-Is stop the progressive LV dilation of CHF
  • Beta blockers stop & might reverse adverse remodeling

Question 12

Beta Blockade

• Beta blockers paradox
• Beta blockade in patients w/ CHF & post-MI LVD
• Beta blockade can be used safely in the majority of CHF patients who…

Answer 12

• Beta blockers paradox
  
  • Initial negative inotropy is balanced by enhanced myocardial recovery
  • Blocking sympathetic overdrive w/ beta blockers in subjects w/ CHF could initially reduce cardiac output, but over time, the heart would perform better w/ beta blockers
• Beta blockade in patients w/ CHF & post-MI LVD
  
  • Beta blockers reduce mortality in CHF by mechanisms other than stopping remodeling (ex. reducing deaths from arrhythmias)
• Beta blockade can be used safely in the majority of CHF patients who…
  
  • Are free of volume overload when beta blockade is started
  • Have a systolic BP > 90 mmHg & HR > 60
  • Don’t have bronchospasm

Question 13

NO Paradigm in HF

• Vasoconstricting & growth promoting systems
• Vasodilating & growth inhibiting systems

Answer 13

• Vasoconstricting & growth promoting systems: worsen hemodynamics & progress remodeling
  
  • NE
  • Angiotensin II
  • Endothelins
  • Arginine vasopressin
• Vasodilating & growth inhibiting systems: improve hemodynamics & prevent remodeling
  
  • Natriuretic peptides
  • Bradykinin
  • NO

Question 14

Consequences of Nitric Oxide & Super Oxide Balance Disruption in Heart Failure Patients

• Effects of NO in CHF
• Effects of free radicals in CHF
• Effects of nitrates + hydralazine in CHF

Answer 14

• Effects of NO in CHF: beneficial
  
  • Direct effects on contractility
  • Inhibits apoptosis
  • Promotes vasodilation
• Effects of free radicals in CHF: detrimental
  
  • Damage DNA
• Effects of nitrates + hydralazine in CHF: beneficial
  
  • Nitrates stimulate the production of NO
  • Hydralazine inhibits the oxidase (free radical) pathway
    
    • Can induce lupus via anti-histone antibodies
  • Primary use: ACE/ARB intolerant patients w/ renal dysfunction
  • Both decrease BP, so use w/ caution

Question 15

Preventing Stroke

Answer 15

• Risks
  
  • Patients w/ LV dysfunction (particularly w/ large anterior wall MIs) are at risk for LV thrombus formation
  • CHF patients are also at risk for atrial fibrillation
• Anticoagulation
  
  • Consider anticoagulation w/ warfarin in all patients w/ anterior wall MIs or w/ EF < 20% (contraversial)
  • Treat afib w/ warfarin unless contraindicated

Question 16

Preventing Sudden Death

Answer 16

• ~40% of deaths in patients w/ CHF is due to arrhythmias
• Beta blockers
  
  • Reduce some arrhythmias & reduce sudden death
• ICDs
  
  • Consider ICDs in all patients w/ EF < 35%
• Antiarrhythmics
  
  • For palliation only
  • Don’t reduce sudden death & may increase it
  • Exception: amiodarone doesn’t increase mortality
  • Use is restricted to patients who get shocks w/ an ICD to reduce the number of shocks (palliation)

Question 17

CHF Definition

Answer 17

• A condition in which the heart either can’t maintain adequate systemic perfusion or can do so only at the expense of increased filling pressures

Question 18

Hemodynamic Interventions for Breathing Better

Answer 18

• Mechanism: improving volume status (mostly) & cardiac output (when needed)
• Diuretics
• Digoxin
• Positive inotropic agents
• Mechanical interventions that improve hemodynamics (e.g., CRT, LVADs)

Question 19

Compensatory Mechanisms: Frank-Starling Law

• X-axis: LVEDP = filling pressure
• Y-axis: cardiac index (cardiac output / body surface area)
• Curved lines: how the cardiac index behaves as filling pressure increases
• This plot classifies the hemodynamic problem in each patient w/ CHF

Answer 19

• X-axis: LVEDP = filling pressure
  
  • Normal < 12
  • Patients start feeling short of breath as LVEDP increases
  • Back pressure in the pulmonary capillaries –> fluid leakage & edema
  • This starts happening at different pressures depending on various factors
    
    • Most common factor: how long the patient has had high pressure
    • Most common pressure when patient starts feeling it: 18 mmHg
• Y-axis: cardiac index (cardiac output / body surface area)
  
  • Normal > 2.2 lt/min/m2
• Curved lines: how the cardiac index behaves as filling pressure increases
  
  • All of this gets worse with exertion
  • Severe cases: patients have high enough pressures to cause pulmonary edema to get close to a normal resting cardiac index
  • For the same cardiac output, a patient w/ LV dysfunction has to have a higher filling pressure
  • For the same pressure, patients w/ LV dysfunction generate a lower cardiac output
• This plot classifies the hemodynamic problem in each patient w/ CHF
  
  • Class I: normal output & normal pressures
  • Class IV: can’t get a normal cardiac index despite high filling pressures

Question 20

Forrester Hemodynamic Subsets

• For each subset:
  
  • I: Warm Dry
  • II: Warm Wet
  • III: Cold Dry
  • IV: Cold Wet
• Characteristics
  
  • LVEDP
  • Cardiac index
  • BP
  • JVP
  • Lungs
  • Extremities
  • Creatinine
  • Cardiac output
  • Filling pressures
  • Therapy

Answer 20

• Criteria
  
  • Wet = filling pressures are high from fluid overload
  • Cold = cardiac output is reduced & patients look & feel cold
• I :Warm Dry
  
  • LVEDP: low
  • Cardiac index: high
  • BP: normal
  • JVP < 5cm
  • Lungs: clear
  • Extremities: no/trace edema
  • Creatinine: normal
  • Cardiac output: normal
  • Filling pressures: normal
  • Therapy: none
• II: Warm Wet
  
  • LVEDP: high
  • Cardiac index: high
  • BP: normal
  • JVP > 5cm
  • Lungs: crackles
  • Extremities: ++ edema
  • Creatinine: normal
  • Cardiac output: normal
  • Filling pressures: high
  • Therapy: diuretics
• III: Cold Dry
  
  • LVEDP: low
  • Cardiac index: low
  • BP: low
  • JVP ~ 5cm
  • Lungs: minimal crackles
  • Extremities: no/trace edema
  • Creatinine: increased
  • Cardiac output: low
  • Filling pressures: normal
  • Therapy: adjust medical tehrapy
• IV: Cold Wet
  
  • LVEDP: high
  • Cardiac index: low
  • BP: low
  • JVP >> 5cm
  • Lungs: ++ crackles
  • Extremities: ++ edema
  • Creatinine: increased
  • Cardiac output: low
  • Filling pressures: high
  • Therapy: inotropes, IABP, VAD/transplant

Question 21

Diuretics

• Loop diuretics
• Thiazides
• CHF patients are tenuous

Answer 21

• Loop diuretics
  
  • Primary agents used in CHF
  • Potent agents that can cause profound diuresis
• Thiazides
  
  • Added for synergy when loop diuretics aren’t enough
  • Aldosterone antagonists: potassium sparing thiazides
• CHF patients are tenuous
  
  • When a person w/ a normal cardiac function has a lot of volume “room” to play with before becoming dehydrated or volume overloaded, it takes much less for a patient w/ CHF to “get into trouble”
  • Frequent monitoring of renal function & electrolytes is essential

Question 22

Digoxin

• General
• General effects
• Parasympathetic effects
• Electrophysiological effects
• Clinical effects & use
• Side effects
  
  • Cardiac
  • CNS
  • GI
  • EKG abnormalities

Answer 22

• General
  
  • One of the oldest drugs
  • Inhibits of Na/K ATPase
  • Increases intracellular Ca2+ to increase contractility
    
    • Blunts Ca2+ extrusion
    • Increases Ca2+i
  • Enhances sarcomere shortening
• General effects
  
  • Increase cardiac output
  • Improve cardiac efficiency
  • Decrease heart rate
  • Decrease cardiac size
  • Restore baroreceptor sensitivity
  • Reduce sympathetic activity
  • Increase renal perfusion
• Parasympathetic effects
  
  • Decreases conduction velocity in the AV node
  • Increases effective refractory period in the AV
  • Heart block (toxic concentrations)
• Electrophysiological effects
  
  • Less negative membrane potential –> decreased conduction velocity
    
    • –> increased chance of ectopic beats & other arrhythmias
  • Decreased action potential duration –> decreased refractory period in ventricles
  • Enhanced automaticity due to steeper phase 4 & after-depolarizations
• Clinical effects & use
  
  • Improves symptoms only
  • Reduces hospitalizations
  • Used in CHF & atrial fibrillation
  • Narrow therapeutic window (esp in elderly & paitents w/ renal impairment)
  • Doesn’t reduce & may increase mortality (esp in elderly)
• Side effects
  
  • Cardiac
    
    • Atrial tachycardias
    • AV block
      Bradycardia
    • Ventricular extrasystole
    • Arrhythmias
  • CNS
    
    • Visual halo
    • Yellow vision
  • GI
    
    • Nausea
  • EKG abnormalities
    
    • T wave inversion
    • Decrease RT interval
    • Uncoupled P waves (toxic concentrations)
    • Bigeminy (toxic concentrations)

Question 23

Inotropes

• Use
• Effects
• Classes
• Indications
  
  • Signs of severely decreased cardiac output
  • Signs of refractory volume overload
• Complications

Answer 23

• Use
  
  • Patients must exhibit both cold (decreased cardiac output) & wet (volume overload) symptoms to justify use
• Effects
  
  • Blunt response to increased filling pressure –> increased volume isn’t enough to maintain adequate response
  • Inotropes increase contractility to maintain adequate response
• Classes
  
  • Direct beta agonists (vasodilators, stop beta blockers before using)
    
    • Dobutamine
    • Epinephrine
  • Phosphodiesterase inhibitors (increase intracellular Ca2+)
    
    • Milrinone
    • Enoximone
• Indications: palliation
  
  • Signs of severely decreased cardiac output
    
    • Hypotension
    • Increasing renal insufficiency
    • Mental status changes
    • Severe fatigue
  • Signs of refractory volume overload
    
    • Lung congestion
    • Peripheral edema
    • JVP
• Complications
  
  • Hypotension
  • Sinus tachycardia
  • Atrial fibrillation
  • Ventricular ectopy / tachycardia
  • Worsening ischemia (by increasing myocardial work / O2 demand)
  • Death (all agents increase mortality)

Question 24

Summary

• ACE-Is
• Beta blockers
• Spironolactone
• Digoxin
• Inotropes

Answer 24

• ACE-Is
  
  • Improve survival across the board
• Beta blockers
  
  • Improve survival in mild to moderate CHF
  • May be benificial in class I & some class IV patients
• Spironolactone
  
  • aka aldactone, aldosterone antagonist
  • Improves survival in class III & IV
• Digoxin
  
  • Diuretic that improves symptoms but not survival
• Inotropes
  
  • All positive inotropes improve function but worsen survival