HEART FAILURE

By Getachew Alemkere (MSc in clinical pharmacy)

School of Pharmacy, Addis Ababa University, Addis Ababa,
Ethiopia

1
 Introduction
 Heart failure is a progressive clinical syndrome that can
result from
 any disorder that impairs the ability of the ventricle to fill
with or eject blood,
Thus rendering the heart unable to pump blood at a rate
sufficient to meet the metabolic demands of the body.
Heart failure can result from any disorder that
affects the ability of the heart to contract (systolic
function) and/or relax (diastolic dysfunction)

2
What is Right Heart Failure?

– Usually occurs as a result of left heart failure

– The right ventricle pumps blood to the lungs
for oxygen
– Occasionally isolated right heart failure can
occur due to lung disease or blood clots to the
lung (pulmonary embolism)

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What is Left Heart Failure?
 Involves the left ventricle (lower chamber) of the heart
 Systolic failure
• The heart looses it’s ability to contract or pump blood into
the circulation
 Diastolic failure
• The heart looses it’s ability to relax because it becomes
stiff
• Heart cannot fill properly between each beat
 Systolic and diastolic heart failure are treated with
different types of medications ???
 In both types, blood may “back up” in the lungs causing
fluid to leak into the lungs (pulmonary edema)
 Fluid may also build up in tissues throughout the body
(edema)
 Epidemiology

 ~6 million Americans had HF

 670,000 more cases diagnosed each year
 Incidence, prevalence, & hospitalization rates of heart
failure are increasing
 Annual hospital discharges > 1 million
 Direct & indirect costs for 2009 ~$37.2 billion

Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics—2009 update: A report from the American Heart 5
Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009;117:e21–e181.
 HF Causes …
 Systolic dysfunction (decreased contractility)
 reduction in muscle mass (e.g. myocardial infarction)
• CAD most common cause of SHF, 70% of cases.
 dilated cardiomyopathies
 ventricular hypertrophy
• pressure overload (e.g. systemic or pulmonary
hypertension, aortic or pulmonic valve stenosis)
• volume overload (e.g. valvular regurgitation)
 Diastolic dysfunction
 restricted ventricular filling, increased ventricular stiffness
• ventricular hypertrophy, hypertrophic cardiomyopathy
6
• infiltrative myocardial diseases: amyloidosis, sarcoidosis,
Pathophysiology
 CO: volume of blood ejected per unit time (L/min)
 CO = HR x SV
 MAP = CO x SVR
 In normal LV function, increasing SVR has little effect on
SV
 As LV dysfunction increases, the negative inverse
relationship between SV & SVR becomes more
important

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8
Compensatory Mechanisms in HF

 The heart’s decrease in pumping capacity results in

compensatory responses to maintain CO
 Responses are intended to be short term after acute
reductions in BP or renal perfusion
 Persistent decline in CO in HF results in long term
activation of compensatory responses leading to
functional, structural, biochemical, molecular changes

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 Compensatory Responses in HF
Compensatory Beneficial Effects of Detrimental Effects of
Response Compensation Compensation
↑ed preload Optimize stroke-volume via Frank- Pulmonary and systemic congestion
(through Na+ & Starling mechanism and edema formation
water retention) ↑ed MVO2
Vasoconstriction Maintain BP in face of reduced CO ↑ed MVO2
Shunt blood from nonessential ↑ed afterload ↓s stroke volume &
organs to brain and heart further activates the compensatory
responses
Tachycardia and Helps maintain CO ↑ed MVO2
↑ed contractility Shortened diastolic filling time
(because of SNS β1-receptor downregulation, ↓ed
activation) receptor sensitivity
Precipitation of ventricular arrhythmias
↑ed risk of myocardial cell death
Ventricular Helps maintain CO Diastolic dysfunction
hypertrophy and Reduces myocardial wall stress Systolic dysfunction
remodeling Decreases MVO2 ↑ risk of myocardial cell death
↑ risk of myocardial ischemia
↑ arrhythmia risk
Fibrosis
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: 10
http://www.accesspharmacy.com, …. MVO2: myocardial oxygen demand
11
Compensatory Responses in HF

 Tachycardia & increased contractility

 primarily results from NE release
 CO increases until diastolic filling is compromised (HR 170
to 200 bpm)
 Fluid retention & increased preload
 decreased CO leads to reduced perfusion of other organs
including the kidneys
 activation of renal-angiotensin-aldosterone system (RAAS)
 Na+ & H2O retention increase preload to increase CO
 in chronic HF, increases in preload have smaller effects on
SV than in normal hearts
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13
Compensatory Responses in HF
 Vasoconstriction & increased afterload
 helps redistribute blood flow away from nonessential
organs to coronary & cerebral blood vessels; increases
afterload
 increased afterload leads to decreased CO
 Ventricular hypertrophy & remodeling
 key component of pathology progression
 remodeling affects the heart at molecular & cellular levels
 major focus for therapeutic interventions
• therapies that reverse modeling, decrease mortality, slow
disease progression
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15
 NYHA Functional Classification
Functional Class
I Patients with cardiac disease but without limitation of physical activity.
Ordinary activity does not cause undue fatigue, dyspnea, or palpitation.
II Patients with cardiac disease that results in slight limitations of physical
activity. Ordinary physical activity results in fatigue, palpitation,
dyspnea, or angina.
III Patients with cardiac disease that results in marked limitation of physical
activity. Although patients are comfortable at rest, less-than-ordinary
activity will lead to symptoms.
IV Patients with cardiac disease that results in an inability to carry or
physical activity without discomfort. Symptoms of congestive HF are
present even at rest. With any physical activity, ↑ed discomfort is
experienced.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: 16
http://www.accesspharmacy.com
Signs and symptoms of HF

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HF Symptoms
 Range from asymptomatic to cardiogenic shock

 dyspnea, particularly on exertion  nocturia

 orthopnea  hemoptysis
 paroxysmal nocturnal dyspnea  abdominal pain
 exercise intolerance  anorexia
 tachypnea  nausea, bloating
 cough  poor appetite
 fatigue  early satiety
 ascites
 mental status changes
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Signs of HF

 Pulmonary rales  Tachycardia

 Pulmonary edema  Cardiomegaly
 S3 gallop  Peripheral edema
 Cool extremities  Jugular venous distension
 Pleural effusion  Hepatojugular reflux
 Cheyne-Stokes  Hepatomegaly
respiration

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Diagnosis

 No single test is available to confirm the diagnosis of

HF—it is a clinical syndrome associated with specific
signs and symptoms.
 Perform history & physical to identify disorders or
behaviors that may cause/worsen HF
 Medication history
 focus on ethanol, tobacco, illicit drugs, dietary/herbal
supplements, NSAIDs, antineoplastic agents

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Laboratory tests

 BNP >100 pg/mL (>29 pmol/L)

 ECG: may be normal or it could show numerous
abnormalities including acute ST-T wave changes from
myocardial ischemia, atrial fibrillation, bradycardia, LVH
 SrCr: may be ↑ed due to hypoperfusion. Preexisting renal
dysfunction can contribute to volume overload
 CBC: useful to determine if heart failure due to reduced
oxygen-carrying capacity

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Laboratory tests…

 Chest x-ray: useful for detection of cardiac enlargement,

pulmonary edema, and pleural effusions
 Echocardiogram: used to assess LV size, valve function,
pericardial effusion, wall motion abnormalities, and
ejection fraction
 Hyponatremia: serum sodium <130 mEq/L (<130
mmol/L) is associated with ↓ed survival and may indicate
worsening volume overload and/or disease progression

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 TREATMENT
Chronic Heart Failure
DESIRED OUTCOMES
 Improve the patient’s quality of life;

 Relieve or reduce symptoms;

 Prevent or minimize hospitalizations for exacerbations

of HF;

 Slow progression of the disease process; and

 prolong survival.
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Lifestyle changes

 Stop smoking
 Loose weight
 Avoid alcohol
 Avoid or limit caffeine
 Eat a low-fat, low-sodium diet
• Restrict sodium intake to < 2gms a day
 Exercise: Structured aerobic exercise,
• improved quality of life
• Also may reduce risk of death and hospitalization

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Lifestyle changes

 Reduce stress
 Keep track of symptoms and weight and report
any changes or concern to the doctor
 Limit fluid intake
 See the doctor more frequently

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Staging

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Treatment Algorism

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Drugs Used in Heart Failure
Drug Therapies for Routine Use

 Diuretic therapy is initiated in low doses in the

outpatient setting, with dosage adjustments based on
symptom assessment and daily body weight.

 Change in body weight is a sensitive marker of fluid

retention or loss,
 and it is recommended that patients monitor their status by
taking daily morning body weights.

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 Thiazide Diuretics.
 Block sodium & chloride reabsorption in the DCT
(approximately 5% to 8% of filtered sodium).
 Relatively weak diuretics & infrequently used alone in HF.

 For Diuretic Resistance, thiazides or the thiazide-like diuretic

metolazone used in combination with loop diuretics to
promote a very effective diuresis.
 In addition, preferred in patients with only mild fluid
retention & elevated BP
 because of their more persistent antihypertensive effects
compared to loop diuretics. 31
Loop Diuretics

 Loop diuretics are usually necessary to restore and

maintain euvolemia in heart failure.
 They act by inhibiting a Na-K-2Cl transporter in the
thick ascending limb of the LH, where 20% to 25% of
filtered sodium normally is reabsorbed.
 loop diuretics are highly bound to plasma proteins,
they are not highly filtered at the glomerulus.

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Loop Diuretics

 They reach the tubular lumen by active transport via

the organic acid transport pathway.
 Competitors for this pathway (probenecid or organic by-
products of uremia) can inhibit delivery to their site of
action and decrease effectiveness.

 Loop diuretics also induce a prostaglandin-mediated

increase in renal blood flow, which contributes to their
natriuretic effect.
 Co-administration of NSAIDs blocks this PG-mediated
effect and can diminish diuretic efficacy.
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 Loop Diuretics

 HF Vs reduced maximal response to loop diuretics.

 decrease in the rate of diuretic absorption and/or increased
proximal or distal tubule reabsorption of sodium, possibly
due to ↑ed activity of the Na-K-2Cl transporter.

 For such case, once the ceiling dose is reached, it is

recommended to give the diuretic more frequently for
additional effect rather than to give progressively
higher doses

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Loop Diuretics

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 Diuretics side effects
 Variety of metabolic abnormalities, severity related to potency of diuretic
 Hypokalemia
 Most common disturbances with thiazide & loop diuretics, which
 In patients with HF may be exacerbated by hyperaldosteronism
 ↑ risk of ventricular arrhythmias in HF & is worrisome in patients with digoxin
 Often accompanied by hypomagnesemia.
 (adequate Mg is necessary for entry of K into the cell, cosupplementation
with both Mg & K may be necessary to correct the hypokalemia)
 Concomitant ACEI (or ARB) and/or AA may help to minimize effect
 Serum potassium concentration should be monitored closely in patients with HF
& supplemented appropriately when needed.

 chronic diuretic use was associated with increased risk of mortality and
hospitalization.

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 ACE Inhibitors

 ACEI therapy prevent RAAS-mediated progressive

worsening of myocardial function.
 ↓ in angiotensin II & aldosterone attenuates many of the
deleterious effects of these neurohormones, including
ventricular remodeling, myocardial fibrosis, myocyte
apoptosis, cardiac hypertrophy,
norepinephrine release, vasoconstriction, and
sodium and water retention.

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 ACE Inhibitors

 The endogenous vasodilator bradykinin, which is

inactivated by ACE, is also ↑ed by ACEIs, along with
the release of vasodilatory prostaglandins & histamine.
 persistence of clinical benefits with ACEIs despite angiotensin II
& aldosterone levels return to pretreatment levels in some
patients suggests this is a potentially important effect

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ACE Inhibitors

 In addition to improving survival, ACEIs also reduce

the combined risk of death or hospitalization, slow the
progression of heart failure, and reduce the rates of
reinfarction

 ACEIs benefit post-MI patients, whether they are initiated

early (within 36 hours) and continued for 4 to 6 weeks or
started later and administered for several years.

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 ACE Inhibitors
 The benefits of ACEI is independent of the etiology of HF
(ischemic vs nonischemic) and are observed in patients with
mild, moderate, or severe symptoms.
 ACEIs also are effective for preventing the development of
HF & reducing cardiovascular risk.

 In summary, ACE inhibitors improve symptoms, slow disease

progression, and decrease mortality in patients with HF
and reduced LVEF (stage C) is unequivocal.
 Current guidelines indicate these patients should receive ACEIs,
unless contraindications are present.
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 ACE Inhibitors

 Despite the overwhelming benefit demonstrated with

these agents, there is substantial evidence that they
are underused & underdosed
 Significant numbers of HF patients do not receive ACEIs, and
of those who are receiving these agents, many are taking
lower-than recommended doses
 common reasons for underuse or underdosing are
concerns about safety and adverse reactions to ACEIs,
especially in patients with underlying renal dysfunction
or hypotension.
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 ACE Inhibitors

 renal dysfunction should not be an absolute CI to ACEI use in

patients with left ventricular dysfunction

 only small differences in mortality outcomes between the

high and low doses.

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 ACEI adverse effects

 The primary adverse effects of ACEIs are secondary to

suppressing angiotensin II (hypotension & functional
renal insufficiency) and ↑ing bradykinin (Cough &
Angioedema).

 ACEIs reduced BP in nearly all patients with

hypotension, (symptoms: dizziness, lightheadedness,
blurred vision, presyncope, and syncope).

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 ACEI adverse effects…. Hypotension
 at any time, Mostly early in Rx or after ↑ in dose
 Risk factors: hyponatremia (serum sodium <130 mEq/L),
hypovolemia, and overdiuresis
 Many patients experiancing symptomatic hypotension
early in therapy are still good candidates for long-term
treatment if risk factors for low BP are addressed.
Management
 initiating with lower ACEIs doses and/or temporarily withholding
or reducing the dose of diuretic and liberalizing salt & fluid intake
 space administration times of vasoactive medications (e.g., diuretics & BBs)
(Often-overlooked solution) 44
ACEI adverse effects…Functional renal insufficiency

Functional RI(characterised by ↑in SrCr & BUN).

 Reversible…carful monitoring
 Patients most sensitive are with:
severe HF,
hypotension,
hyponatremia (2ndry to diuretic therapy, is most important),
volume depletion,
bilateral renal artery stenosis, and
concomitant use of NSAIDs
Management
 ↓ of diuretic dosage or liberalization of sodium intake
45
 ACEI adverse effects
 Careful dose titration can minimize the risks of
hypotension and transient worsening of renal function.
 Thus, usual initial doses should be about ¼ the final target dose,
with slow upward dose titration based on BP and SrCr.
 In certain patients, especially those hospitalized patients
who seem at high risk for hypotension or worsening of
renal function, it may be advisable to initiate therapy with
a short-acting agent such as captopril.
 Once stabilized, switched to an ACEI given once daily.

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 ACEI adverse effects…. cough

 (adverse effects related to bradykinin accumulation)

 (1) A dry, nonproductive, hacking cough
Occurs (5–15% of patients) with all the agents
In the first few months of therapy, resolves within 1 to 2
weeks of discontinuation, and reappears with rechallenge.
Replacement of ACEI with an ARB is reasonable

Cough of HF Vs ACEI use; rule out other potential

causes of cough, such as pulmonary congestion.

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 ACEI adverse effects… Angioedema

(2) Angioedema
rare but potentially life-threatening
more frequent in African Americans than others.
ARBs as alternative - caution, rare cross-reactivity
reported.

Use of ACEIs is CI in
 patients with a history of angioedema.
 1st , 2nd , & 3rd TM of pregnancy
o ↑ed risk of fetal renal failure, intrauterine growth retardation,
and other congenital defects.

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 ARBs
 ARBs have a low incidence of adverse effects.
 The incidence and risk factors for developing hypotension,
↓ in renal function, and hyperkalemia are similar to that
of ACEIs.
 Thus, not alternatives in these complications for ACEIs.
 Careful monitoring when used with another inhibitor of the RAAS
(e.g., ACEIs or AA)..↑ (combined) side effect
 Neither candesartan nor valsartan is metabolized by the
cytochrome P450 system, so no pharmacokinetic drug—
drug interactions with these agents are expected.

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β-Blockers

 it is not essential that ACEI doses be optimized before

a βB is started because the addition of a βB is likely
to be of greater benefit than an ↑in ACEI dose.
 the benefits of β-blockade occur regardless of HF
etiology or disease severity
 Prior to initiation of therapy, the patient
 should have no or minimal evidence of fluid retention &
 should not have required recent IV inotropic therapy.

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 β-Blockers

 Potential mechanisms to explain the favorable effects of β-

blockers in heart failure include
 antiarrhythmic effects,
 attenuating or reversing ventricular remodeling,
 ↓ing myocyte death from catecholamine induced necrosis or
apoptosis,
 improving LV systolic function, ↓ing HR and ventricular wall
stress thereby reducing myocardial oxygen demand, and
 inhibiting plasma renin release

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 β-Blockers

In summary BBs slow disease progression,

↓hospitalizations, and improve survival in HF.
BB have also been shown to improve QOL in many patients with
heart failure, although this is not a universal finding.

Therefore, BBs are recommended as standard therapy for all

patients with systolic dysfunction, regardless of the severity
of their symptoms.

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Β-Blockers

 βBs should be initiated in stable patients who have no

or minimal evidence of fluid overload.
 βB s are contraindicated in people with
 acute heart failure ,
 hypotension,
 cardiogenic shock and
 atrioventricular heart block,
 hospitalized in the intensive care unit or
 recently required intravenous inotropic support
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54
 β-Blockers

 Initiation of a βB at normal doses in patients with HF

may lead to symptomatic worsening or acute
decompensation owing to the drug’s negative inotropic
effect.

 To minimize the likelihood for acute decompensation, βBs

should be started in very low doses with slow upward
dose titration.

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 β-Blockers

 βB doses should be doubled no more often than every 2

weeks, as tolerated, until the target or maximally tolerated
dose is reached.

 Make every effort to titrate doses up to target whenever

possible in order to provide maximal survival benefits.
 response to βBs is dose dependent, with greater ↓in
hospitalization rates and improvements in LVEF at higher doses.
 As well, Greater magnitude of HR reduction was significantly
associated with greater improvement in survival.

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 β-Blockers
 Beta blockers have a variety of potential beneficial
effects in patients with DHF.
 slowing the HR, ↑the time available for both LV
filling and coronary flow, particularly during exercise
 reducing myocardial oxygen demand
 lowering the BP, causing regression of LVH

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Table: Initial & Target Doses for BBs Used in Treatment of HF
Drug Initial Doseb Target Dose
Bisoprolola 1.25 mg once daily ?? 10 mg once daily
Carvedilola 3.125 mg bid 25 mg bidc
Carvedilol CR 10 mg once daily 80 mg once daily
Metoprolol succinate CR/Xla 12.5–25 mg once dailyd 200 mg once daily
aRegimens proven in large trials to reduce mortality.
bDoses should be doubled approximately every 2 weeks, or as tolerated by the patient,

until the highest tolerated or target dose is reached.

cTarget dose for patients >85 kg is 50 mg bid.

dIn MERIT-HF, the majority of NYHA class II patients were given 25 mg once daily,

while the majority of class III were given 12.5 mg once daily as their starting dose.

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 BB Adverse Effects
 Bradycardia or heart block, hypotension, fatigue, impaired
glycemic control in diabetic patients, bronchospasm in
patients with asthma, and worsening HF.
Management
 Monitor vital signs and Carefully assess for signs &
symptoms of worsening HF during BB initiation & up titration.
 Up titration should be avoided if signs of worsening HF,
including volume overload (Weight) and poor
perfusion…Continue titration after stabilization
 continuing BB therapy during hospitalization for acute heart
failure whenever possible. 59
 BB Contraindications
 Absolute contraindications to BB use includes:
 Uncontrolled bronchospastic disease,
 Symptomatic bradycardia,
 Advanced heart block without a pacemaker, and
 Acute decompensated heart failure.
 With caution in patients with
 asymptomatic bradycardia or
 Well-controlled asthma
 Particular caution in marked bradycardia (<55 bpm) or
hypotension (systolic BP <80 mm Hg).
60
 Diabetes & recurrent hypoglycemia
Drug Therapies to Consider for Select
Patients

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 Aldosterone Antagonists (AAs)
 Spironolactone and eplerenone are AAs, work by
blocking the mineralocorticoid receptor, the target site
for aldosterone.
 In the heart, AAs inhibit cardiac extracellular matrix
and collagen deposition, thereby attenuating cardiac
fibrosis and ventricular remodeling.

 attenuate the systemic pro-inflammatory state and oxidative

stress caused by aldosterone

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Aldosterone Antagonists

Randomized Clinical trial of more than 1,600 patients

 Spironolactone reduced mortality as a consequence
of both progressive HF and sudden cardiac death.

 Spironolactone also produced a 35% reduction in

hospitalizations for worsening HF and significant
symptomatic improvement, as assessed by changes in
NYHA functional class.

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 Aldosterone Antagonists

 Spironolactone as a diuretic contribute little to its benefits

in HF.
 Which requires higher dose at which Hyperkalemia (>5 mEq/L)
is problematic

Potential factors contributing to Hyperkalemia

 the initiation of AAs in patients with impaired renal function or high
potassium concentrations and
 failure to ↓ or stop potassium supplements when starting AA.
 Other risk factors: diabetes, inadequate laboratory monitoring,
and concomitant use of both ACEI and ARBs or NSAIDs
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Aldosterone Antagonists

 Chief among recommendations by ACC/AHA is to avoid

AAs in patients with renal dysfunction.

 The risk for hyperkalemia is dose dependent, and the

morbidity and mortality reductions with AAs in clinical trials
occurred at low doses (i.e., spironolactone 25 mg/day and
eplerenone 50 mg/ day).

 The doses of AA should be limited to those associated with beneficial

effects so as to ↓ the risk for hyperkalemia.

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Table: Recommended Strategies for Reducing Risk of Hyperkalemia with AAs
1. Avoid starting AAs in patients with any of the following:
 SrCr >2 mg/dL in women or >2.5 mg/dL in men or a CrCl <30 mL/min,
 Recent worsening of renal function
 Serum K concentration >5 mEq/L,
 History of severe hyperkalemia
1. Start with low doses (12.5 mg/d for spironolactone and 25 mg/d for eplerenone), especially in
the elderly and in those with diabetes or a CrCl <50 mL/min.
2. Decrease or discontinue potassium supplements when starting AA.
3. Avoid concomitant use of NSAIDs or COX-2 inhibitors or high-dose ACEI or ARBs
4. Avoid triple therapy with an ACEI, ARB, and AA.
5. Monitor serum K concentrations and renal function within 3 days and 1 week after the
initiation or dose titration of AA or any other medication that could affect K homeostasis.
Thereafter, K concentrations and renal function should be monitored monthly for the first 3
months, then every 3 months.
1. If K exceeds 5.5 mg/dL* at any point during therapy, discontinue any K supplementation, or,
in the absence of potassium supplements, reduce or stop AA therapy.
2. Counsel patients to:
 Limit intake of high potassium-containing foods and salt substitutes.
 Avoid use of nonprescription NSAIDs. 66

 Temporarily discontinue AA if diarrhea develops or diuretic therapy is interrupted.

 AA Side effect

 K sparing

 Spironolactone also interacts with androgen and

progesterone receptors, which may lead to gynecomastia
and other sexual side effects in some patients.
 Such adverse effects are less frequent with eplerenone owing to
its low affinity for the progesterone and androgen receptors.

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 Nitrates & Hydralazine

 Nitrates: nitric oxide donors lead to venodilation &

decreased preload
 Hydralazine: direct vasodilator leads to decreased
SVR, increased SV, CO
 antioxidant properties, prevents nitrate tolerance
 Combination particularly effective in African
Americans
 43% decrease in all cause mortality
 possibly due to decreased nitric oxide; may benefit from
therapy that enhances nitric oxide bioavailability
Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. 68
N Engl J Med 2004;351:2049–2057.
 Nitrates & Hydralazine
 Current guidelines: add to standard therapy in African
Americans with moderate-severe to severe HF or other
ethnicities who have symptoms despite standard therapy
 1st line if unable to tolerate ACEIs/ARBs due to renal
insufficiency, hyperkalemia, hypotension
 Require frequent dosing
 Combination marketed as BiDil, which contains hydralazine
37.5 mg and ISDN 20 mg.
 Adverse effects:
 headache
 dizziness
 GI distress
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Acute Decompensated Heart Failure
(ADHF)
 The terms decompensated heart failure or exacerbation of
heart failure refer to those patients with new or worsening
signs or symptoms,
 which are usually caused by volume overload and/or
hypoperfusion and lead to additional medical care, such
as emergency room visits and hospitalizations.

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ADHF…

 ADHF characterized by the development of dyspnea

 associated with rapid accumulation of fluid within the
lung's interstitial and alveolar spaces
 As a result of acutely elevated cardiac filling
pressures

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ADHF…

Causes of Decompensation
 Mild insult (e.g. dietary indiscretion)
 Medical noncompliance
 Concurrent noncardiac illness (e.g. infection)
 New cardiac event
 MI
 atrial fibrillation
 myocarditis
 acute valvular insufficiency

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ADHF…

 Clinical syndromes within decompensated heart failure

include:
 systemic volume overload,
 low output, and
 acute pulmonary edema.

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TREATMENT

 The overall goals of therapy in the patient with

decompensated heart failure are:
 to relieve congestive symptoms or optimize volume status,
 treat symptoms of low cardiac output, so that the patient
can be discharged in a compensated state on oral drug
therapy.
• Although diuretic, vasodilator, and positive inotrope therapy
can be very effective at achieving these goals, their efficacy
must be balanced against the potential for serious toxicity.
 Thus, another important goal is to minimize the risks of
pharmacologic therapy.
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Diuretics

 IV loop diuretics (furosemide, bumetanide, torsemide)

used in decompensated HF
 Bolus doses decrease preload: improve pulmonary
congestion
 excess decrease in preload with diuretics leads to
decreased CO
 dose-dependent association with increased mortality
 high dose associated with decreased renal function in
decompensated HF
 Improve congestion symptoms
75
Diuretics

 HF most common setting where diuretic resistance is

observed; can overcome resistance
 add a 2nd diuretic such as a thiazide
 increase dose
 increase dosing frequency
 use a continuous infusion

76
Diuretic Resistance

 heart failure is the most common clinical setting in

which diuretic resistance is observed
Mechanisms responsible
For furosemide absorption is prolonged
approximately twofold, and peak concentrations
are about half of normal.
High concentrations of sodium reaching the distal
tubule as a result of the blockade of sodium
reabsorption in the loop of Henle.

77
Diuretic Resistance

 low cardiac output

reduced renal perfusion, subsequent decreased
delivery of drug to the kidney
 Excessive salt intake may override the diuretics
capacity of diuretics
 Drugs like NSAIDs may inhibit the synthesis of local
PGs
 Proteinuria

78
Diuretic Resistance

Maneuvers
 Continuous IV infusion than intermittent dosing
 Using ceiling dose of loop diuretics
 Using positive ionotropic agents, increase CO and
renal perfusion
 Combining loop diuretics with thiazide ones

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80
Positive Inotropic Agents

 Dobutamine, milrinone, dopamine

 Digoxin not routinely used
 delayed effect
 limited inotropic effect
 long duration of action
 potential toxicity

81
Digoxin

 The efficacy of digoxin in patients with HF and

supraventricular tachyarrhythmias such as atrial
fibrillation is well established and widely accepted.
 Digoxin improves LVEF, quality of life, exercise
tolerance, and heart failure symptoms.
 The DIG trial was a double-blind, randomized, placebo-
controlled trial with the primary end point of all-cause
mortality. Patients (n = 6,800) with HF symptoms and an EF of
45% or less were eligible and were followed for a mean of
37 months.

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Digoxin

 Most patients received background therapy with

diuretics and ACE inhibitors.
 The mean serum digoxin concentration achieved was
0.8 ng/mL after 12 months of therapy.

 No significant difference in all-cause mortality was

found between patients receiving digoxin and
placebo (34.8% and 35.1%, respectively).

83
Digoxin

 Hospitalizations for worsening heart failure were

reduced 28% by digoxin compared to placebo (P <
0.001),
 hospitalizations for other cardiovascular causes were
increased in the digoxin group.
 Digoxin withdrawal increased the risk of treatment
failure and deterioration of exercise capacity and
ejection fraction

84
Digoxin

 Digoxin should not be used in patients with a normal

LVEF, sinus rhythm, and no history of HF symptoms.

 Beneficial effect of digoxin was evident at serum

concentrations from 0.5 to 0.9 ng/mL, whereas serum
concentrations greater than or equal to 1.2 ng/mL
were harmful

85
Digoxin

 In most patients with normal renal function, this

plasma concentration range can be achieved with a
daily dose of 0.125 mg.

 In the DIG trial, patients had a LVEF greater than

45%; digoxin had no effect on mortality or
hospitalization in these patients.

86
Digoxin

 Digoxin is generally NOT used in patients with DHF

because contractility is intact.
 The DIG ancillary trial, a parallel study to the DIG
trial, evaluated the role of digoxin in patients with HF
and an LVEF >45 percent
 Digoxin had no effect on all-cause or cause-specific
mortality, or all-cause or cardiovascular
hospitalization

87
 Adverse Effects

 Cardiac
 AV block
 Bradycardia
 Ventricular extrasystole
 Arrhythmias
 CNS toxicity
 Delirium
 Confusion and somnolence
 GI: Anorexia ,nausea and vomitting
 Blurred vision
 Tendency to yellow-green vision
 Photophobia

Therapeutic index is ~ 2! 11/14/2018

88
Serum Electrolytes Affect Toxicity
 K+
 Digitalis competes for K binding at Na/K ATPase
 Hypokalemia: increase toxicity
 Hyperkalemia: decrease toxicity
 Mg2+
 Hypomagnesemia: increases toxicity
 Ca2+
 Hypercalcemia: increases toxicity

11/14/2018
89
Treatment of Digitalis Toxicity

 Bile resins or activated charcoal

 Atropine: advanced heart block
 KCl: increased automaticity
 Antiarrythmics: ventricular arrhythmias
 Fab antibodies (Digibind): toxic serum
concentration; acute toxicity

11/14/2018
90
 Positive Inotropic Agents

Dopamine
 Stimulates adrenergic receptors, causes release of
NE from adrenergic nerve terminals.
 produces dose dependent hemodynamic effects
because of its relative affinity for α 1-, β 1-, β 2-,
and D1

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Positive Inotropic Agents

1. The low dose Dopamine (2 to 5 mcg/kg/min)

Predominantly acts on β 1 and D1receptors
 Increase in cardiac out put and renal perfusion with variable
effect on heart rate
2. Medium dose Dopamine (5 and 10 mcg/kg/min)
Predominantly acts on β 1 and β 2 receptors
 Increase cardiac out put and Decrease in TPR
3. High dose Dopamine ( > 10 mcg/kg/min)
Predominantly acts on α 1 receptors
 Increase in TPR
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Positive Inotropic Agents

Dobutamine
β1- and β2-receptor agonist with some α1-agonist
effects.
dobutamine does not cause release of NE from nerve
terminals.
β2-receptor-mediated vasodilation will tend to offset
some of the α1-receptor-mediated vasoconstriction

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Positive Inotropic Agents

 Cardiac β1- stimulation by dobutamine causes an

increase in contractility but generally no significant
change in heart rate
 Dobutamine increase in stroke volume, cardiac
output, and modest decreases in systemic vascular
resistance
 started at 2.5 mcg/kg per min and, if tolerated and
needed, can be gradually increased to 15 mcg/kg
per min

94
Positive Inotropic Agents

 Milrinone
 phosphodiesterase III inhibitor, inodilator
 adverse events: arrhythmias, hypotension,
thrombocytopenia
 use in patients on chronic β-blocker therapy

95
Vasodilators

 Nitroprusside, nitroglycerin, nesiritide

 Described by 1˚site of action
 venous vs arterial
 arterial vasodilation decreases afterload, increases CO
 venous dilation decreases preload
 mixed dilation works on resistance & capacitance vessels

96
Vasodilators

 Nitroprusside
 Sodium nitroprusside, a mixed arterial–venous vasodilator,
acts on vascular smooth muscle, increasing synthesis of nitric
oxide to produce its balanced vasodilating action.
 decreases PAOP, SV, BP
 dose limiting factor: hypotension
 used primarily in patients with increased SVR
 administered as continuous infusion
 rebound phenomenon after abrupt withdrawal due to
reflex neurohormonal activation; taper the dose

97
Vasodilators

 Nitroprusside
 can compromise renal perfusion pressure in patients with
chronic HTN, baseline azotemia, or when therapy
augmentation for CO is minimal
 monitor for cyanide & thiocyanate toxicity at high doses >
3 days or renal dysfunction
 Nitroprusside should be avoided in the presence of
elevated intracranial pressure because it may worsen
cerebral edema in this setting.

98
Vasodilators

 Nitroglycerin
 IV nitroglycerin is often the preferred agent for preload
reduction in patients with ADHF, especially those with
evidence of pulmonary congestion.
 decreases preload, PAOP, arterial vasodilation
 beneficial effects on myocardial O2 demand & supply
 dose limiting effects: hypotension, excess PAOP decrease
 tolerance may develop over 12 to 72 hours
 may worsen cerebral edema in presence of increased
intracranial pressure

99
 Vasodilators
 Nesiritide
 Nesiritide is a recombinant form of BNP, which is secreted by
the ventricular myocardium in response to volume overload.
 Exogenous administration of nesiritide mimics the vasodilatory
and natriuretic actions of BNP by stimulating natriuretic peptide
receptor A.
 dose dependent vasodilation, increases CO, natriuresis, diuresis;
decreases cardiac filling pressures, SNS, RAAS activity
 role in pharmacotherapy controversial
• marginal lack of improvement compared to nitroglycerin versus
cost
• risk of worsening renal function
100
Beta blockers in ADHF

 For patients on chronic beta blocker therapy, if the

degree of decompensation is mild without
hypotension or evidence of hypoperfusion
 Withdrawal of beta blocker therapy was associated
with increased mortality as compared to continuation of
such therapy.
For patients on chronic beta blocker therapy with
moderate-to-severe decompensation or hypotension,
 decrease or withhold beta blocker therapy during the
early phase of treatment.
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Beta blockers in ADHF

 In patients requiring inotropic support or those with

severe volume overload
withhold therapy
For patients who are not treated with beta blocker
therapy chronically
do not initiate a beta blocker in the early mgmt of
acute HF
However, initiation prior to discharge is
recommended in stable patients.
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Non-Pharmacologic Interventions

 Intraaortic Balloon Pump

 is a type of mechanical circulatory assistance device
occasionally employed in patients with advanced heart failure
who do not respond adequately to drug therapy, such as those
with intractable myocardial ischemia or cardiogenic shock.
 balloon inserted in thoracic aorta & synchronized to increase
aortic diastolic pressure & coronary perfusion
 useful short term in patients with decompensated HF in MI &
unstable patients unresponsive to inotropic therapy
 use with IV vasodilators & inotropic agents

103
Non-Pharmacologic Interventions

 Ventricular Assist Devices

 assists or replaces right or left ventricle pumping function
 left ventricular assist device (LVAD): short term use to
stabilize patients waiting for intervention to correct
underlying cardiac function or bridge heart transplantation
• permanent device implantation considered for patients who
are not transplant candidates
 complications: bleeding, air embolism, right ventricular
failure, surgical complications, hemolysis, thrombosis, renal &
hepatic dysfunction, arrhythmias

104
Non-Pharmacologic Interventions

 Ultrafiltration
 fluid removal for renal replacement therapy
 decreases PAOP, increases CO & diuresis
 no effect on BP, HR, or renal function
 potential candidates: patients with diuretic resistance, renal
impairment with diuretic administration or inotropic therapy
 complications: infection, rapid volume removal, intravascular
depletion
 monitor for electrolyte depletion

105
Non-Pharmacologic Interventions

 Cardiac resynchronization therapy

 implantation of specialized biventricular pacemaker to
restore synchronous activation of the ventricles
 indicated in NYHA class III & IV patients with QRS duration ≥
120 msec, LVEF ≤ 35%
 improves
• ventricular contraction • NYHA classification
• hemodynamic function • mortality
• quality of life • hospitalizations
• exercise capacity

106
Surgical Therapy

 Orthotopic cardiac transplantation: best therapeutic

option for well-selected patients with chronic,
irreversible NYHA class IV HF & 10-year survival
~50%
 many patients rejected for age, concurrent illness,
psychosocial factors
 Shortage of donors: alternative surgical techniques for
patients who are not candidates for cardiac transplant
 ventricular aneurysm resection, mitral valve repair,
myocardial cell transplantation

107
Hospital Discharge

 Patients close to optimal fluid status

 Optimize chronic oral drug therapy
 Educate patient & family
 Clinic follow up 7 to 10 days after discharge
 Integration of palliative care may be necessary
 Consider end-of-life care for patients with persistent
symptoms at rest despite multiple attempts to optimize
therapy

108