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Flashcards in Pharmacological Management of Heart Failure Deck (24):
1

"Living Long" & Feeling Better

  • 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

2

Pathological Progression of CV Disease

  • 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

3

Heart Failure Pathophysiology

  • 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

4

Classificaiton of HF

  • ACC/AHA Stage
  • NYHA Functional Class

  • 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

5

Neurohormonal Acitvation in HF

  • 2 major pathways involved in disease progression
  • Disease progression

  • 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

6

ACE Inhibitors (ACE-Is)

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

  • 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

7

Angiotensin Receptor Blockers (ARBs)

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

  • 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

8

Aldosterone Escape

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

  • 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

9

Aldosterone Blockade

  • 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

10

Effects of NE in CV Disease

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

  • 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

11

Beta Blockers

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

  • 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

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...

  • 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

13

NO Paradigm in HF

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

  • 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

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

  • 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

15

Preventing Stroke

  • 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

16

Preventing Sudden Death

  • ~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)

17

CHF Definition

  • 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

18

Hemodynamic Interventions for Breathing Better

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

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

  • 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

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

  • 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

21

Diuretics

  • Loop diuretics
  • Thiazides
  • CHF patients are tenuous

  • 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

22

Digoxin

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

  • 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)

23

Inotropes

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

  • 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)

24

Summary

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

  • 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