Lec – PHAR1014

MANAGING ATRIAL
FIBRILLATION AND
ANTI-ARRHYTHMIC DRUGS

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

● Introduction to arrhythmia
● What are supraventricular tachyarrhythmias?
● Atrial fibrillation –
● Presentation, symptoms, complications
● Management of rhythm
● Management of rate
● Management of embolic risk (Stroke)
● Patient selection for pharmacotherapy
● Briefly: other related arrhythmias

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

• Appreciate the impact of arrhythmias on health and quality of life

• Appreciate what affects conduction and the different types of

tachyarrhythmias and its changes on an ECG

• Be familiar with the treatment approaches and the drugs used to treat
arrhythmia, particularly AF and its thrombotic complications

• Understand the role of using tools such as CHADS2 / CHA2DS2-VA

and HAS-BLED (and other related tools and considerations)

• Know of the role of the pharmacist in the supply of antiarrhythmic

medications and in providing patient advice & education

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 The Impact of Arrhythmias
• Of the deaths due to cardiovascular disease, ~50% of those
are due to “sudden cardiac death”
• Most cases of sudden cardiac death are due to arrhythmias
• 10% of survivors of myocardial infarct die during the
subsequent year, mostly of arrhythmias
• Sudden cardiac death rather than pump failure is the cause of
50% of heart failure patients
• Most common arrhythmias are ventricular fibrillation or
ventricular tachycardia
• Atrial fibrillation is a major cause of stroke
• Atrial fibrillation prevalence increase with age (10% of those
over 70 years)
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 Arrhythmias - Introduction
• Also called “dysrrhythmia”
• Defined as “any deviation from the normal rhythm of the
heartbeat” – tachycardia, bradycardia or irregular
• Arrhythmia arise through abnormalities of impulse
formation or conduction, or both
• Defined by source and rate
• Basic consequence of arrhythmia → inefficient and ineffective
filling and ejection of blood from the heart
• Cause can be due to
➢cardiac injury (eg. myocardial infarction, ischaemia)
➢certain drugs
➢abnormal sympathetic nervous system activity

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“Supraventricular Tachyarrhythmia”
● A fast abnormal heart rhythm, beginning above
the ventricles
● Various syndromes and diseases
● Atrial Fibrillation (AF, A-fib) – most common
● Atrial Flutter
● Paroxysmal SVT

● Eg. Atrial fibrillation usually presents with an irregular

ventricular rate of around 160 to 180 beats per minute
in untreated patients

● (Ventricular arrhythmias are more lethal though!)

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Atrial Fibrillation
● The most common arrhythmia
● A disease predominantly of the elderly
• 18% >85 yrs
• Symptoms typical of tachyarrhythmias
➢ “I can feel my heart beating fast”
➢ “It feels like my heart is going to beat out of my chest”
● Can occur on its own – but usually comes with other CV
diseases (eg. HT, IHD or CHF)
● Shared risk factors

● Aetiology not completely known

● Results in stasis of blood within atria –
formation of local thrombi – risk of stroke!
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Atrial Fibrillation

● Normal Heart Rhythm

● SA node → Atria → AV node → Ventricles
● SA node drives a regular rhythm
● In AF:
● Multiple disorganised beats
from near pulmonary vein
● Atria ‘fibrillate’

● Electrical signal is passed

Randomly/sporadically through to
Ventricles
- irregular, usually fast, response
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Atrial Fibrillation – Changes to ECG

● NO P waves – continuous baseline ‘noise’

● Irregular & usually fast ventricular response

A-FIB

Normal

Image by J.Heuser, from Wikimedia. Creative Commons license

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The Spectrum of A-fib Symptoms
● Somewhere between ‘No symptoms’ and ‘Sudden Death’
● Things that can happen:
● No symptoms (90%)

● Palpitations – from a fast ventricular response

● ACS – from excess work of heart / lack of diastole (fast

response)
● HF – as above, or due to ventricles not being filled
prior to pumping (atria not doing their job)
● General dizziness, weakness etc. – due to decreased
BP or Cardiac output
● Hypotension or fainting (syncope)

● STROKE!

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Triggers for Atrial Fibrillation

● Anything that can cause tachycardia etc. can

● Trigger an episode of paroxysmal A-fib
● Turn an asymptomatic A-fib patient symptomatic
● Related: turn a slow-A-fib patient into fast-A-fib

● Examples:
● Hyperthyroidism, hypoglycaemia
● Stress/anxiety
● Stimulants
● Infection/fever?
● ACS etc.

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 Palpitations in Community Pharmacy
• Unpleasant awareness of heart beat
➢ “Racing, pounding, flopping, skipping, jumping,
thumping, fluttering”

• History
❑ Do they start suddenly?
❑ How long do they last?
❑ Chest pain or short of breath?
❑ Dizziness/faint during attack?
❑ Related to stress, anxiety, excitement?
❑ What initiates them?
❑ What medications are you taking?
❑ How much eg. tea, coffee, Coke do you drink?
❑ Do you take social/party drugs eg. cocaine or marijuana?
❑ Have you been using nasal decongestants?
❑ Do you smoke cigarettes & how many?
❑ etc.
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 As a quick aside…..What is a Stroke?
● Taught in more detail elsewhere
● An acute insult to the brain
● Different types of strokes:
● Haemorrhagic stroke
o = Bleeding in brain

● ISCHAEMIC Stroke
o Analogous to ACS/MI in the heart

o = Clot causing blockage to brain’s supply of blood, O2 etc.

● EMBOLIC Stroke
o Clot forms elsewhere – travels to brain →ischaemic stroke

o Analogous to PE for the lungs

o Main concern for AF patients!

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 Consequences of A-fib
● Short term
o Not usually very many
o If someone has ACS, Collapse, HF – this needs managing
● Longer term
o Increased risk of death (from Framingham study)
o Increased risk of heart failure
● Heart works hard for long time

o Increased risk of stroke (5 times baseline)

● Cardioembolic stroke

• Rationale for Treatment = haemodynamic stability,

symptomatic relief, prevent thromboembolism, prevent
sudden cardiac death
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Why does A-fib cause stroke?
● Inefficient contraction of atria leads to blood
pooling

● Pooled blood clots – emboli can form in atria

(usually left atrium)

● If embolus breaks or moves to left ventricle can

be expelled and block a smaller artery
Managing Atrial Fibrillation
● Short term: if patients have tachycardia causing
severe symptoms – these need management for
obvious reasons….
● Let us discuss the long term management of A-fib

● What are our (long term) therapeutic goals?

1. Manage symptoms of arrhythmia and reduce
long term complications of A-fib on the heart
2. Reduce the risk of embolic complications,
especially stroke
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Managing A-Fib
Options: Options:
● Class I or III anti- Options:
● Betablockers
arrhythmics ● Antiplatelets?
● Central-CCBs Electricity
● ● Anticoagulants
● Digoxin ● Surgical ablation

RATE ANTIEMBOLIC
RHYTHM CONTROL THERAPY
CONTROL Try and ‘reboot’ the
Try and SLOW the Prevent the
heart back to Sinus
heart (ventricular formation of clots in
Rhythm
response) the Atrium

Stop HEART-RELATED Stop Embolic

Symptoms and Complications
Complications (especially stroke)

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 Managing A-Fib
● 2 aspects:
● What does the patient require for STROKE
prophylaxis?
● Anticoagulation or Antiplatelet

● (or neither?)

● AND
● What does the patient require for their arrhythmia?

● Rhythm control or

● Rate control
Always consider the NO
TREATMENT option for
● (or neither?)
treatment of arrhythmia!!
(normally wouldn’t be our decision though..…)

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 Rate vs Rhythm Control in A-Fib
● Complicated area!!
● Large study (AFFIRM, 2002) compared (elderly patients)
● RATE control & Antithrombosis (ie patient stayed in AFib) vs.

RHYTHM control (drugs/other methods, can stop antithromb if

needed)
● No significant difference in mortality or stroke with rate or rhythm
(conclusion also supported by updated syst. reviews)
● Certain patient factors favour rate control over rhythm control,
and vice versa [Can J Cardiol 2011;27(1):47-59]
● Conclusion:
● May not matter if elderly patients stay in A-Fib

● In general, rate control is fine in asymptomatic patients

● Reverting patients to sinus rhythm has its own inherent risks

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What about younger patients?

● In practice, for patients who potentially have a

‘lifetime’ of AF ahead of them then Rhythm
control (Cardioversion) may be worthwhile
● Get them out of A-Fib, can potentially stop
anticoagulants etc. if SR can be maintained
● Strategies:
Options:
● Class I or III anti-
arrhythmics
● Electricity
● Surgical ablation

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 Cardioversion
● Surgical cardiac ablation or catheter ablation:
● Burning/removing the part of the heart where the
muscle that are malfunctioning

● Many aberrant atrial signals begin in the pulmonary

vein area

● Prevent these signals ‘beginning’ an atrial

contraction

● Newer evidence suggest catheter ablation may

be more effective than standard drug treatment
http://www.biosensewebster.com/images/patientEdCath
Ablation.jpg
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 Cardioversion
● Electrical with DC shock

● Administration of electricity under anaesthetic

● MUST rule out thrombosis in atrium first – stunning the

heart can mobilise thrombus

● Consider at least 3 weeks of anticoagulation first in

order to allow clot to dissolve

● Artificial Pacemaker & Implantable

cardiac defibrillators (ICD) also available

● ICD better than drugs but more costly

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http://mykentuckyheart.com/images/pictures/pacemaker.jpg
 Cardioversion with drug therapy
● Medications (Vaughan Williams Class I-IV & others)
● eg. Amiodarone, Sotalol, Flecainide, Disopyramide

● Flecainide probably most commonly used class I

● Amiodarone & sotalol is probably most commonly used overall
- Amiodarone has significant adverse effects

● Beta-blockers (class II) & CCB (class IV) discussed elsewhere

(previous knowledge/info applies here in context also)

● Considered for patients:

● With symptomatic A-Fib
● Where Sinus rhythm is an appropriate target

● Who are not suitable for Electrical/Surgical cardioversion

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 Flecainide (Class Ic)
• PBS-R for severe arrhythmias
• Potent class of antiarrhythmics but high risk of proarrhythmia
• Indicated for SVT, Paroxysmal AF or atrial flutter associated
with haemodynamic impairment
o or treatment of serious ventricular arrhythmias refractory
to other treatment
• Lots of serious adverse effects – high risk of bradycardia,
heart block and mild negative inotropic activity
• Therapeutic Drug Monitoring usually required to monitor
therapeutic range and to guide dosing in renal/hepatic
impairment
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 Amiodarone (Class III)
• PBS-R for severe arrhythmias
• Unusual pharmacologic effects, PK, dosing, adverse effects
- Lots of SEs that can occur within therapeutic range
• Extremely long half-life (15 to 100 days)
➢ ADRs may manifest after discontinuation - proarrhythmic
effect slow to resolve
➢ In chronic use – after initial loading for 2 weeks – lowest
effective dose should be prescribed (eg. 100-200mg/d)
• Lipophilic drug – Large volume of distribution (Vd)
• Inhibits P-glycoprotein & a lot of CYP P450 enzymes
➢ Many drug interactions – eg. grapefruit juice
• Severe multi-organ toxicities with chronic use – (lots of monitoring!)
➢ Counselling - Lengthy, complex, challenging, confronting – but essential!
• Usually well tolerated in HF (least -vely inotropic of all antiarrhythmics)
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 Other Anti-arrhythmics - Digoxin
• Commonly used in heart failure to  force of contraction
• Useful for SVT eg. AF, atrial flutter - particularly in HF patients
➢ Thus useful for preventing supraventricular
arrhythmias to becoming possibly lethal ventricular
arrhythmias
• Loading dose often used (??)
➢maintenance & LD higher doses used than for HF
• Mostly renally excreted ~70%
• Half life = ~36 hrs & steady state ~ 5 days
• Narrow therapeutic index and involved in significant DIs
• Side effects do occur, even if taking the medicine properly
• Concentration monitoring and dose changes may be required
regularly
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 Problems with Anti-arrhythmic Drugs!
• No single drug cures all arrhythmias in all people
• Lots of side effects and drug interactions
• Many are negative inotropes (decrease force of contraction)
• Anti-arrhythmic drugs are also potentially “pro-arrhythmic”
➢ Risk increase with use of >1 of these drugs
➢ Drugs that may prolong QT interval  risk of arrhythmias
➢ Drugs that have negative inotropic or chronotropic effects,
may cause heart failure or significant bradyarrhythmia
• Inconsistent mortality benefits (especially post-MI)
• Not all anti-arrhythmic drugs are suitable for all types
of arrhythmias
➢ Choice of anti-arrhythmic drug depends on the arrhythmia,
coexisting medical conditions (eg. heart failure) and the
adverse effects of the drug
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 Summary so far…..
● Generally, no significant difference between rate and rhythm
control
● Leaving patients in A-Fib, but controlling the HR (<90-100
BPM) with anticoagulation is just as safe and effective for
elderly patients
● Younger patients are often considered for cardioversion to
SR
● Electrical – make sure there is no current clot
● Pulmonary Vein Ablation/Isolation
● Medications – last line, risk vs. benefit

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Stroke Prophylaxis in AF

(Note: we are specifically talking about AF

patients here)
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Stroke Prophylaxis
● Atrial fibrillation itself rarely causes death or
serious morbidity except through
thromboembolic complications –[eTGs]
● Critical part of A-fib management
● Related to ‘blood pooling’ process –
● Anticoagulants are more effective than antiplatelets
● But carry a higher risk of bleeding
● Anticoagulants:
● Warfarin, Dabigatran (& others)
● Antiplatelets
● Aspirin, Clopidogrel (& others?)
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Stroke Prophylaxis

● Very complicated decision

● Often life-long (especially in elderly)

● Warfarin is difficult to manage in the elderly

● Risk of interactions, dose adjustments etc.

● But the elderly are at the highest risk of stroke

and highest risk of bleeds

● =Therapeutic dilemma!

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Stroke Prevention in A-fib

What tools can you use to assist?

● Work out the stroke risk and benefits of
anticoagulation
o Tool = CHADS2 for nonvalvular AF

● Work out the risks & contraindications

o Tool = HAS-BLED

Weigh up benefits and risks

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 Calculating CHADS2 score (in Afib)
Risk factor Score CHADS2 Yearly Stroke Risk
Score (with A-fib)
C Congestive Cardiac +1
Failure ( = heart failure) 0 2%

1 3%
H Hypertension (or being +1
treated for HT) 2 4%

A Age > 75 +1 3 5%

D Diabetes +1 4 9%

5 13%
S2 Stroke or TIA (previous) +2
6 18%

● Warfarin reduces risk of stroke in AF by ~70%

● Aspirin is half as effective as anti-coagulants
● Greater risk of bleeding and adverse effects with warfarin
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 Selecting antithrombotic therapy
CHADS2 score Stroke risk Drug
0 low No Tx or aspirin
1 moderate aspirin or oral anti-coag.
2 or more high Oral anti-coagulant
Oral anti-coag.
If CHA2DS2-VASc: >1 Moderate-high
(risk/benefit?)
NB: oral anti-coagulant = warfarin or NOACs

• Aspirin use is now falling out of favour (will come back to this point)
• All patients with ‘nonvalvular’ atrial fibrillation should be
anticoagulated unless they have an unacceptably high bleeding risk
or a very low risk of stroke
• Oral anticoagulant therapy can prevent the majority of ischaemic
strokes and is superior to aspirin or no therapy

You do not need to remember these tables!!

We’ll have a look at using these tables in the tutes!!
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More advanced (and preferred) = CHA2DS2-VA
Risk factor Score

C Congestive +1 ● Better discriminator

Cardiac Failure ( =
heart failure) ● Probably more widely
H Hypertension (or +1
being treated for
used now
HT)
● Same guidance
A2 Age > 75 +2
D Diabetes +1 ● >2 – consider
S2 Stroke (previous) +2
anticoagulation
● 1 – consider
V Vascular disease +1 anticoagulation?
(eg MI)
● 0 – consider no
A Age 65-74 +1
antithrombosis

NOTE: Another version of this score included an extra

point for being female – “CHA2DS2-VASc” score
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Calculate risk of bleeding
Risk factors for bleeding on warfarin therapy
Age older than 65 years
Uncontrolled hypertension
History of gastrointestinal bleeding or active peptic ulcer disease
Hepatic or renal insufficiency
Thrombocytopenia or platelet dysfunction
Malignancy
History of stroke
Cognitive or psychological impairment
Recent trauma
History of more than three falls in 12 months
Excessive alcohol intake
Pharmacotherapy with aspirin or NSAIDs

● HAS-BLED tool includes some – but not all – of

these
● Still need to think about the above risk factors
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HAS-BLED
Feature Score
● A score ≥ 3 means
H Hypertension (SBP >160) +1
exercise caution
A Abnormal renal fx +1

A Abnormal liver fx +1
with anticoagulation
A Age ≥ 65 +1 o Doesn’t mean do not
S Stroke +1 use (risk vs benefit)
B Bleeding (!!!) +1
o There are other risk
L Labile INR +1
factors not included
E Ethanol use +1

D Other drugs/meds +1 too

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Maximise benefit and minimise risk with
warfarin: INR monitoring

Intracranial
Hemorrhage

Stroke

From: http://www.ganfyd.org/index.php?title=Image:RelativeRiskINR.png

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 Alternative: What about Aspirin?
● Less effective (“modest benefit” at best)
● (Remember this is in the context of stroke prophylaxis in AF)
● Lower risk of bleeding
● What about clopidogrel?
● Alternative in patients unable to take aspirin
● Not any more beneficial compared with aspirin
● NO EVIDENCE in combination with aspirin
● Can use for other reasons (eg. MI) but AF alone is not an
indication for dual anti-platelets
● Neither aspirin nor P2Y12 inhibitors preferred anymore
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Alternative: Other newer non-vit K oral
Anticoagulants (NOACs)
● Similar benefits to warfarin
● Dabigatran (Direct Thrombin inhibitor), Rivaroxaban (Xa
inhibitor), Apixaban (Xa inhibitor)
● PBS-A (non-valvular AF + risk factors)
● Equally effective, less monitoring for anticoagulant effects
● Not for patients with prosthetic heart valves or valvular AF
● Use warfarin – more data
● Renal function important
● Long term data and safety – Not as clear?
● Studies show they are potentially safer

● Under significant review

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Dabigatran (vs. warfarin)
● Renally cleared
● Eg. avoid dabigatran CrCL <30ml/min

● ?Thus how useful is this in the elderly?

● Fewer drug interactions

● Although dabigatran interacts via P-gp

● Amiodarone & Verapamil increase Dabigatran levels

● Don’t need INR monitoring

● OR, cannot be easily monitored

● Open capsule increases bioavailability by 70% !!!

● No data for using dabigatran in valvular AF disease
● Cannot be easily reversed (Antidote not widely available)
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Recent AF/stroke guidelines (2016 European
Society of Cardiology)
• NOACs as the first line anticoagulant even for those with a
single stroke risk factor

• Warfarin to be used only in patients not eligible for NOACs,

such as those with moderate-severe mitral stenosis,
mechanical heart valves and severe chronic kidney disease

• Aspirin and other antiplatelets have no role in stroke

prevention (unless there is a clear indication)

• Catheter ablation as the first-line treatment for patients with

symptomatic recurrences of AF on arrhythmic drug therapy

• Keep watching this space!!

[Eur Heart J (2016) 37 (38): 2893-2962]

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 Summary
● Most patients with AF require treatment with an
antithrombotic agent
● Effective at preventing stroke
● Anti-coagulation is more effective, but riskier than
anti-platelets
● We can mitigate risks of warfarin by appropriate patient
selection, counselling, monitoring etc.
● Newer anticoagulants: still finding their place in therapy but
could be the future of anticoagulation post- AF
● Current view is that NOACs or warfarin should be used
for stroke prophylaxis post AF – not antiplatelets!

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Just a few other arrhythmias to
note….

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 Drug-induced Prolonged QT interval
• Prolonged QT = predispose patients to potentially fatal type of
ventricular arrhythmia eg. Torsades de pointes

• Drugs can prolong QT interval directly or indirectly

➢ Degree of prolongation depends on dose & route of admin

• Some patients have normal QT interval under normal conditions

➢ But may develop a prolonged QT & associated arrhythmia with
certain drugs – due to genetics?

• Drug can have a direct effect – see next slide

➢ Website www.QTdrugs.org - has updated drug list

• Drug can decrease metabolism & increase concentration of drugs

known to increase QT interval
➢ Amount of increase is associated with drug concentration
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Drugs that may prolong QT interval

Ref: AMH

Avoid combinations of drugs that may prolong QT interval

as this  risk of arrhythmias
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Other Supraventricular Tachycardias

● Atrial Flutter
● Similar to A-fib, lots of impulses in atria
● Caused by re-entry – usually more regular than A-fib
● Not as ‘disorganised’

● Often degenerates into A-fib

● Management:
● As for A-Fib
● DC shock or pace cardioversion also useful
● Others
● Paroxysmal SVTs, many different kinds
● Verapamil, -blocker, mechanical
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 What about Bradyarrhythmias?
• Mild (HR of 50-59 bpm) to severe (HR of 30-45 bpm)
• Signs: Pale skin, cold & clammy, weak pulse, dizziness, SOB
etc. – can be due to drugs, hypothyroid, node dysfunction etc.
• Pacemaker - Preferred treatment for persistent bradycardia
• If haemodynamic compromise present – use
atropine/isoprenaline for management of acute bradyarrhyth.
o Atropine IV – short acting anti-cholinergic; increases HR;
safe but may not be effective
o Isoprenaline IV – -agonist; prolonged infusion for a
longer duration of action (are they -blocked?)
o Adrenaline IV is preferred if systolic blood pressure is
very low
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 General Treatment Considerations
• Are drugs underlying cause of arrhythmia?
• Alcohol? Lifestyle? Electrolyte imbalance?
• Type of arrhythmia?
• Comorbidities? (eg. HF & -ve inotropic/chronotropic, renal/liver dis.)
• ADR causing arrhythmia? Worsening of arrhythmia causing
more arrhythmias? → Making sure patient familiar with
symptoms of arrhythmia
• Tx likely to be long-term? Short term? (eg. post CABG)
• Fitting Tx into patient’s lifestyle -doable? Timing practical? SEs?
• Regular check-ups
• Ensuring patient knows how to self-monitor both worsening
of condition & possible ADRs
• Ensuring patient knows how to act/what to do when necessary
• ALL antiarrhythmics can be pro-arrhythmic
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