Lec – PHAR1014

MANAGING HEART
FAILURE

Dr Vincent Chan
Discipline of Pharmacy
School of Health and Biomedical Sciences
RMIT University
Email: vincent.chan@rmit.edu.au
1
Lecture Overview

• Impact of heart failure

• Classification and Diagnosis
• Symptoms and physiology
• Non-pharmacological treatment
• Pharmacotherapy

2
 Learning Objectives
After this lecture, you should be able to:

• Discuss the impact and pathophysiology of heart failure

• Describe some causes and symptoms of heart failure

• Demonstrate knowledge of the rationale and implementation of

drugs used for the management of systolic heart failure

• Develop awareness of the role of the pharmacist in the

management of heart failure & associated comorbidities and
non-drug strategies as applicable

• Assist patients in optimising treatment of heart failure through

appropriate education & advice
3
 What is Heart Failure

• Literally: failure of heart to ‘do its job’

– That is, pump blood around the body

• AKA “Congestive Heart/Cardiac Failure”

– CCF/CHF http://www.mc.edu/campus/users/kelley00/ChronicHeartFailure.jpeg

• Is the result of a cardiac abnormality or insult

• Symptoms will classically involve: Hypoxia!
– Predictable!
– Discuss later

4
 Heart Failure: Impact
• Affects about 2% of Australian and incidence & prevalence
increase with age
➢ ~1% in people aged 50-59; >50% in people aged 85
• More females than males die of heart failure because they
generally live longer (males higher if age-standardised)
• High mortality rate (although falling)
➢ In Australia: ~61,000 HF related deaths/yr
➢ Mild heart failure → ~50% mortality at 5 years
➢ Severe heart failure → ~50% mortality at 1 year
• High hospitalisation and readmission rates → Major cost!!
• Major disease burden because of high cost of care (expected
to ), symptomatic, low quality of life and premature death
• National Heart Foundation
• Australian Institute of Health and Welfare 2012. Australia’s health 2012; Chen et al. 2017 5
Heart Failure Classification
• New York Heart Association (NYHA) Classes
Class Definition Terminology

No limitation to physical Asymptomatic left

I
activity ventricular dysfunction

Slight limitations to physical

II activity (mild fatigue, Mild heart failure
dyspnoea, angina etc.)

Marked limitations to
III Moderate heart failure
physical activity

Symptoms at rest (unable

IV to carry out physical activity Severe heart failure
without discomfort)
6
Causes of HF
• Typically, the heart is either damaged, strained,
or enlarged (makes it less efficient to pump –
cardiomegaly)
– MI/IHD – most common cause (scarring,
remodelling)
– Long term hypertension – heart ‘pumping’ against
resistance
– Smoking, excessive alcohol, obesity
– Atrial fibrillation
– Heart valve diseases
– Genetic abnormalities/Congenital heart defects
– Drugs
– etc. etc.
7
 HF – Signs and Symptoms
• Symptoms vary according to type of HF & heart compartment
• Oedema – lungs, liver, gut, ankles etc.
➢ “Pitting oedema”; “Pedal oedema”
➢ Ascites, swollen ankles
• Cough or wheeze
• Breathlessness, dyspnoea
• Tachycardia
• Reduced exercise tolerance
• Fatigue/tiredness
• Low blood pressure
• Raised jugular venous pressure (JVP)
• Increase serum Cr and urea
8
HF Pathophysiology: A Vicious Cycle

Heart is damaged &

cannot output
effectively to body

This makes it WORSE

• Pumping into high pressure =
harder
• Pumping more fluid = harder Body (e.g. kidneys)
• Pumping harder = harder wants to correct
this lower perfusion
• Pumping faster = harder

This leads to
• FLUID RETENTION To maintain
• VASOCONSTRICTION perfusion, body
• INCREASED VENOUS compensates
RETURN • Renin/Angiotensin/Aldost
• INCREASED FORCE of erone
CONTRACTION • Sympathetic drive
• INCREASED RATE OF (including centrally)
CONTRACTION • + others

9
Vicious Cycle / Tightrope
• Setting off this cycle leads to an acute worsening in the
condition
– Acute exacerbation of HF
– Patient becomes worse over hours – weeks

• Lots of things will trigger:

– Illnesses
– Change in BP/HR
– Exercise
– Dehydration (leads to decreasing volume)
– Excess fluid intake (often restricted to 1.5L)
– Excessive salt intake
– Medications (which kinds?)
– Etc.

10
Classification of HF

• Two ways:

1. The SIDE of the heart affected, or

2. Whether the ejection fraction (EF) is

diminished

11
HF: 1) Classification by SIDE
• Predominantly LEFT vs RIGHT sided
• Right sided:
– Hepatic congestion
– Peripheral oedema
– Elevated venous pressure

• Left sided
– Pulmonary congestion
– Shortness of breath

• Commonly: Both sided and both can overlap

12
 HF: 2) Classification by Ejection Fraction
• Usually: HF is a disease of systolic dysfunction due to myocardial
damage
– Leading to decreased left ventricular ejection fraction (majority)
– “Left Ventricular Systolic Dysfunction Heart Failure” (LVSD-HF)
– “HF with reduced left ventricular ejection fraction” (HFrEF)

• Some patients have:

– “Preserved Left Ventricular Ejection Fraction”-HFpEF (minority)
– Due to inadequate ventricular filling
– Less filling -> less blood being pumped out
– Less common, treated differently
– Causes and symptoms are pretty much the same
• These used to be known as systolic and diastolic HF
13
Diagnosis

• Clinical (ie. Sx/Hx etc.)

• Echocardiogram
Images in public domain, from wikimedia

– 2D imaging of heart
– Can show you thickening, ejection fraction etc.

• Blood test:
– Brain Natriuretic Peptide
– Secreted by ventricles when they are overstretched

• Clinical signs include:

– Jugular Venous Pressure (JVP)

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Heart Failure - management

• (We will be talking mostly about patients with

HFrEF)
– What used to be called ‘systolic’ HF

– Treatment can be different for patients with preserved

ejection fraction – will cover later

15
HF Pathophysiology: Targets for
Pharmacotherapy?
Heart is damaged &
cannot output
effectively to body

This makes it WORSE

• Pumping into high pressure =
harder
• Pumping more fluid = harder Body (e.g. kidneys)
• Pumping harder = harder wants to correct
this lower perfusion
• Pumping faster = harder

This leads to
• FLUID RETENTION To maintain
• VASOCONSTRICTION perfusion, body
• INCREASED VENOUS compensates
RETURN • Renin/Angiotensin/Aldost
• INCREASED FORCE of erone
CONTRACTION • Sympathetic drive
• INCREASED RATE OF (including centrally)
CONTRACTION • + others

16
 Heart Failure - management
Aim to:
• Improve symptoms
• Improve exercise tolerance
• Reverse disease progression & deterioration in
ventricular function
• Reduce hospital admissions
• Live longer (reduce mortality)

Pharmacological treatment aims to either:

• Improve the ability of the heart muscle to contract (positive
inotropic agents)
• Or to decrease the workload of the heart (vasodilators,
diuretics)
• The most successful treatments, defined as an improved
survival, all reduce workload
17
 Non-Pharmacological management
• HEART FAILURE MANAGEMENT PROGRAM
• OPTIMISE doses (eg. ACE-I and -blocker)
• Sodium and fluid restriction
• Weight loss, no smoking, cut down alcohol (preferably none)
• Regular tolerable/low intensity physical activity is recommended
➢ Aerobic exercise improved health status, quality of life and clinical
outcomes (all-cause mortality & hospitalisation) [HF-ACTION]
• Medication management advice
• Set of scales!
– Good for detecting short term fluid changes
– Patients should have a ‘plan of action’ which might involve
PRN diuretics / temporary inc. dose
18
 Pharmacological management
Start ACE inhibitor and titrate
to maximally tolerated dose
(consider Angiotensin receptor
antagonist if ACE inhibitor not
tolerated)

Add diuretic

Add -blocker and titrate to

Add digoxin maximally tolerated dose

+ other Inotropes??

Add Aldosterone Antagonists

• Influenza and pneumonia immunisation

19
Reduced Ejection Fraction HF - Therapy

• ACE-I/ARB Save Lives and

• Beta-blockers (some) Improve symptoms

• Aldosterone antagonists

• Digoxin
Improve symptoms
• Diuretics only
• Inotropes
+ non-pharmacological measures
20
Medicines for Reduced Ejection Fraction HF
• ACE-inhibitors
– Probably the front-runner/clear winner
• Should be started ASAP after diagnosis of HF
• Evidence & recommended for all grades of HF
• Class effect – variation in duration of action
• Improves symptoms, prognosis, hospitalizations and
deaths
• In all patients with HFrEF, for all classes of the disease,
at all times
• The higher the dose of the ACE-I, the better the patient
does
21
Medicines for Reduced Ejection Fraction HF
• Dosing:
– Start low, go slow
– titrate up dose every 2 weeks to maximally
tolerated dose
– Do not want to drop patient’s BP too suddenly
– Monitor: GFR and electrolytes (K+ especially)
– Can tolerate a small decrease in GFR, BP or a small
rise in K+
– HF patients are more likely to get these problems,
as they have worsened physiological capacity to
tolerate ‘insults’ to the system
• Symptomatic improvements may not be seen for weeks-
months after initiation of an ACE inhibitor
22
Angiotensin Receptor Blockers (sartans/ATRAs)

• ARBs Not as much evidence as ACE-I

– Most evidence exists for valsartan and candesartan

• Improve symptoms and hospitalisations &

mortality
• Similar efficacy but not superior to ACE inhibitors
• Used when patients have cough secondary to
ACE-I
– NB: Risks with kidney and angioedema still exist

• Same dosing strategy and monitoring as ACE-I

23
What if patient cannot have ACE-I OR ARB?

• Situations might include:

– Angioedema
– Bilateral renal artery stenosis

• Vasodilation is the only modality with most evidence

– Potent vasodilation using vasodilators
– a combination of hydralazine and nitrates
– This is very poorly tolerated and can produce significant
drops in BP
– Done very rarely and only under expert supervision

24
 Medicines for Reduced Ejection Fraction HF
• Beta-Blockers
– Used to be contraindicated….now standard Tx!
– Belief was: decreasing force of contraction would make
heart failure worse
– There is now unequivocal evidence that in patients with HF,
beta-blockers:
– Decrease mortality
– Decrease hospitalisations
– Improve symptoms
– However….. Caution is required!
• Not a class effect
• Evidence: combined -blocker/ACEI is better than ACEI alone
25
Beta blockers for HF

• Beta blockers DO decrease force of contraction

at the start!
• This can significantly worsen heart failure at the
start of therapy
– Especially if a patient is already decompensated
– Especially if initial dosing is too aggressive

• Recommendation:
– Add a Beta blocker to ACE-I therapy
– For patients with HF
– With STABLE disease without recent exacerbations

26
Beta blockers in HF – Dosing Strategy
• ABSOLUTELY
CRITICAL to start low
and go slow
• Like ACE-I, aim for
target doses as high as
possible
o BUT DO NOT be
overly aggressive • Taken from NPS News 75 – Systolic Heart Failure: Improving
Treatment

• Monitor patients for http://www.nps.org.au/health_professionals/publications/nps_news/cu

rrent/improving_treatment_of_systolic_heart_failure

signs of worsening HF
• Dose increase every 2-
4 weeks if patient stable
27
Beta Blockers in HF
• Which beta-blockers to use?
– Not all have evidence (some no improvement, some
worst)
– Only four currently have evidence:
▪ Metoprolol Slow/Extended Release
– (Normal release metoprolol is commonly used for
HT & for other things, but effectiveness in HF ??)
▪ Carvedilol (also an alpha blocker)
▪ Bisoprolol
▪ Nebivolol (newest of the four – thus least evidence)
– All PBS-Restricted
• Benefits not immediately apparent (Persevere!! -
Symptomatic improvements may not be seen for months)
28
Carvedilol

• Non-specific
– 1-blocker What might you expect with
– 1-blocker the additional 1-blockade??
– 2-blocker
– “Antioxidant” effects

• COMET study showed it more effective than

other beta blockers
➢ HOWEVER generated controversy as many believed
formulation and dose not optimised for both drugs
??More effective – we do not really know
Poole-Wilson PA, Swedberg K, Cleland JGF, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients
with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet
2003;362:7-13

29
Medicines for Reduced Ejection Fraction HF
• Aldosterone antagonists
• eg. Spironolactone & Eplerenone
• Improve symptoms and mortality when added to 1st
line therapy in patients with ongoing symptoms
• Add in to patients who still have symptoms on ACE-I & β-
blocker
• Significant risks: Hyperkalaemia!!
– eg. ACE-I + K+-sparing diuretic in combination
• EVIDENCE: Significant benefit in decreasing
hospitalisations, mortality and morbidity
• Eplerenone is PBS-A (HF after acute MI)
30
Aldosterone antagonists

• Their efficacy is related to aldosterone

antagonism – NOT diuresis
– Doses of spironolactone are lower – eg. 25mg daily for
HF vs. up to ~200mg daily for oedema

• Eplerenone only marketed for HFrEF post-MI

• MONITORING IS CRUCIAL
– Life-threatening K+ occurs in patients with
– ACE-I or ARB
– Aldosterone antagonist
– Renal failure

31
Three other drugs for HF….

32
Newer Drug…. (“ARNI”)
• Entresto®
• Combines the moieties of an ARB (valsartan) and a
neprilysin inhibitor (sacubitril)
• New ACE inhibitor alternative; PBS-A listed mid 2017
– More effective than enalapril [PARADIGM-HF trial]
– Better for kidneys
• Evidence currently insufficient to recommend as first-line
• Seems to have similar risks and adverse effects as ACE
inhibitors (probably less)
– Hypotension, hyperkalaemia and angiodema
• Need to cease ACEI or sartan before commencing
• Valsartan dose in this fixed dose combo NOT equivalent
to valsartan dose in other products
• Keep watching this space!!
33
Ivabradine
• Coralan® ; PBS-A for HF only
• Inhibits cardiac pacemaker (If) current to  HR
• SHIFT trial showed decreased HF hospitalisation and CV
death
• Added to therapy if HR remains high despite maximal
beta-blocker therapy, and:
– Patient must have sinus rhythm and a resting heart rate 77 bpm
at the time ivabradine treatment is initiated
– Patient must receive concomitant optimal standard chronic heart
failure treatment, which must include the maximum tolerated dose
of a beta-blocker, unless contraindicated or not tolerated

• Will ‘-blocker + ivabradine’ be added to guidelines as

standard practice?
34
 A diabetes drug for HF?
• Empagliflozin (Jardiance®); PBS-A for diabetes
• SGLT2 inhibitor (reducing renal glucose
reabsorption)
• EMPA-REG Outcome trial showed it decreased HF
hospitalisation and CV death
• Useful both patients with both HF and diabetes
• Leads to more glucose in urine - some predictable
adverse effects
• Also evidence for canagliflozin
• Not currently in our HF guidelines - Watch this
space??
35
Summary so far…..
• Patients with HFrEF should take:
– ACE-I/ARBs
– Beta-blocker (selected ones only)
• And if symptoms get worse
– Aldosterone antagonists

• These three agents improve:

– Symptoms
– Hospitalisations
– Survival
36
Heart Failure - Therapy

• ACE-I/ARB Save Lives and

• Beta blockers Improve symptoms

• Aldosterone antagonists

• Digoxin
Improve symptoms
• Diuretics only
• Inotropes
+ non-pharmacological measures
37
Symptomatic Management - Diuretics
• In HF diuretics are used to remove fluid
• They are for symptomatic relief (oedema)
• Loop diuretics are most effective diuretics (eg. Furosemide)
• Not used as monotherapy but combined with standard
therapy
• High doses are sometimes needed (eg. renal impairment)
• Patients with severe acute HF may require intravenous
diuretics
• Monitor: Creatinine – will probably worsen renal function
(can tolerate a bit of worsening)

38
 Loop diuretics – patient counselling/issues
• Produce rapid & intense diuresis (Onset within 1 hour (oral);
4-6 hour duration of action)
• Take in the morning – can keep patients up at night going to
toilet
– BD doses often given at 0800 and 1200 for this reason

• In HF, use lowest effective dose (usually together with ACE

inhibitor). Must balance/adjust dose for individual

• Monitor weight and electrolyte (~1 kg/day) & renal function

• EVIDENCE: diuretics improve symptoms but do NOT reduce

mortality or hospital admissions due to worsening heart
failure
39
Thiazide diuretics
• Do not remove enough fluid to cause significant diuresis
in “regular” doses
• BUT – when added to a loop diuretic – significant
synergistic diuresis
• This is because:
– Body reabsorbs most water @ Loop of Henle
– In presence of ‘Full’ loop diuretic dose – increased retention of
water at other parts eg. distal tubule
– Hence, added thiazide in leads to a diuresis that is greater than
both added together (synergy)

• In practice:
– STOP thiazides if patient commences loop diuretic
– Occasionally combo used intentionally with difficult to treat
oedema
40
Digoxin
• Digoxin’s actions are:
– POSITIVE inotrope
– Increase FORCE of contraction
– NEGATIVE chronotrope
– Decrease RATE of contraction
– Decrease sympathetic tone?

• Second-line in severe HF and Heart failure patients who

remain symptomatic despite optimal HF treatment with other
drugs (eg. ACEI & -blocker)
• Also have a role in heart failure patients with atrial fibrillation
• In HF, the actions improve symptoms, QoL and
hospitalisations – but NO EFFECT on mortality
41
Digoxin dosing & features
• Also used in arrhythmia
• HF doses (and therapeutic range) are generally lower
• Narrow therapeutic index and involved in significant drug
interactions – thus role in HF controversial!
• Side effects do occur, even if taking the medicine
properly (monitor for digoxin toxicity)
• High normal digoxin levels are associated with increased
mortality in HF
– Logical conclusion of increasing the force of
contraction:
→ Symptoms improve, but heart lifespan reduced,
may increase myocardial oxygen demand
42
Inotropes (catecholamines) – “sympathomimetics”
• May be required in:
– end-stage disease (palliation)
– Severe acute episodes (ICU)

• By injection
• Dobutamine IV infusion is most common
• These will increase the force of contraction, and improve
symptoms in the short term
• In the long term, will shorten the lifespan of the heart
• Hence, use is for:
– End of life symptomatic management
– Short term use in patients who are severely ill or awaiting transplant

• Reduce or stop beta-blocker dose first

43
Heart Failure – other medicines
• Nitrates
– Vasodilators, will reduce preload and hence take
‘strain’ off heart – can be used as add-on therapy in
certain instances

• Antithrombotics – eg. Oral anticoagulants

– With severe Systolic dysfunction, risk of thrombus is
elevated
– These patients may have another reason to be on
antithrombotics, otherwise may be considered

44
Heart Failure: Contraindicated drugs
• NSAIDs (including COX-2 selective)
• Will cause constriction of afferent arteriole in
kidney
– Decrease perfusion to kidney
– Fluid retention, RAAS activation, hypertension etc.
etc. etc.

• Will worsen heart failure and can tip patients into

an acute exacerbation of heart failure
• No!!!

45
Heart Failure: Contraindicated drugs
• Verapamil or Diltiazem
• These will depress cardiac contractility (like
beta-blockers)
– Therefore they can worsen heart failure

• They do not provide the benefits in terms of

decreasing the sympathetic drive
• Contraindicated

• Also anti-arrhythmic drugs

– cardiodepressant and proarrhythmic effects
46
Finally, What about HF with Preserved
Ejection Fraction??
• Less evidence – less is known
• Need to treat the underlying cause if known
• Need to treat comorbidities
• If diastolic filling is main problem: may benefit from drugs
that slow heart rate (and allow ventricles to fill)
– INCLUDING beta-blockers, verapamil or diltiazem ??
– Area of research
– Blocking RAAS useful
– Drugs that are beneficial seem to address the
underlying causes such as myocardial remodelling

47