Confidence, Consensus & Continuation of Anti- Arrhythmic Drugs in ...

Confidence, Consensus
& Continuation of Anti-
Arrhythmic Drugs in
Primary and Secondary
Care
Dr Christopher Gibbs MD FRCP,
Consultant Cardiologist,
North Devon District Hospital
April 2012

Objectives
• Highlight strengths and weaknesses of the
main anti-arrhythmic drugs
• Outline appropriate patient style for each of
the anti-arrhythmic drugs
• Outline the importance of monitoring patients
who are prescribed anti-arrhythmic drugs
• Local/practical issues that may present with
the use of anti-arrhythmic drugs

‘Natural History of Atrial Fibrillation (AF) and
management Strategies Including Antiarrhythmic
Drugs (AAD’s)
et al. Eur Heart J 2010;31:2369-2429
© The European Society of Cardiology 2010. All rights reserved. For Permissions please email:
journals.permissions@oxfordjournals.org.

ESC Guidelines Recommend Comprehensive
Management of AF
Improve outcomes of AF "disease"
Prevent AF
recurrence
Rhythm control
Slow ventricular
response
Rate control
Impact
associated risks
CV effects
Treat AF "Arrhythmia"
The main selected strategy could be either rhythm or rate control, or their combination
The other components optimise the treatment effect and contribute to improve outcomes
Camm AJ, et al. Eur Heart J 2010;31:2369–2429

Principles of Antiarrhythmic Drug Therapy to
Maintain Sinus Rhythm
• Treatment is motivated by attempts to reduce AFrelated
symptoms
• Efficacy of antiarrhythmic drugs to maintain sinus
rhythm is modest
• Clinically successful antiarrhythmic drug therapy may
reduce rather than eliminate the occurrence of AF
Camm AJ, et al. Eur Heart J 2010;31:2369–2429

Principles of Antiarrhythmic Drug Therapy to
Maintain Sinus Rhythm
• If one antiarrhythmic drug ‘fails’, a clinically acceptable
response may be achieved with another agent
• Drug-induced proarrythmia and extracardiac side
effects are frequent
• Safety rather than efficacy should primarily guide choice
of antiarrhythmic agent
Camm AJ, et al. Eur Heart J 2010;31:2369–2429

Antiarrhythmic Medication for
Rhythm Control
Recommendation Class Level
The following antiarrhythmic drugs are recommended for rhythm control in patients
with AF, depending on underlying heart disease:
• amiodarone I A
• dronedarone I A
• flecainide I A
• propafenone I A
• d,l-sotalol I A
In patients without significant structural heart disease, initial antiarrhythmic therapy
should be chosen from dronedarone, flecainide, propafenone, and sotalol
If one antiarrhythmic drug fails to reduce the recurrence of AF to a clinically
acceptable level, the use of another antiarrhythmic drug should be considered
I
IIa
A
C
Camm AJ, et al. Eur Heart J 2010;31:2369–2429

Choice of Antiarrhythmic Drug According to
Underlying Pathology
Minimal or no heart disease
Significant underlying heart disease
Prevention of remodelling
ACEI/ARB/statin
β blockade where appropriate
Treatment of underlying condition and prevention/reversal of
remodelling – ACEI/ARB/statin. β blockade where appropriate
HT
CAD
CHF
No LVH LVH Stable NYHA III/IV
NYHA I/II or ‘unstable’
NYHA II
Dronedarone / Flecainide /
Propafenone / Sotalol
Dronedarone
Dronedarone
Sotalol
Dronedarone
Amiodarone
Amiodarone
Amiodarone
NYHA = New York Heart Association
‘Unstable’ = cardiac decompensation within the prior 4 weeks
= evidence for ‘upstream’ therapy for prevention of atrial remodelling still remains controversial
CAD: coronary artery disease; CHF: congestive heart failure
HT: hypertension; LVH: left ventricular hypertrophy
Adapted from: Camm AJ, et al. Eur Heart J 2010;31:2369–2429
8

Mixed treatment comparison analysis: effect of antiarrhythmic
drugs on atrial fibrillation recurrence.
Freemantle N et al. Europace 2011;13:329-345
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2011. For permissions please email: journals.permissions@oup.com.

Mixed treatment comparison analysis: effect of antiarrhythmic
drugs on all-cause mortality.
Freemantle N et al. Europace 2011;13:329-345
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2011. For permissions please email: journals.permissions@oup.com.

Mixed treatment comparison analysis: effect of antiarrhythmic
drugs on all-cause mortality in studies
involving >100 patients in either arm.
Freemantle N et al. Europace 2011;13:329-345
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2011. For permissions please email: journals.permissions@oup.com.

Mixed treatment comparison analysis: effect of antiarrhythmic
drugs on withdrawal due to adverse events.
Freemantle N et al. Europace 2011;13:329-345
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author
2011. For permissions please email: journals.permissions@oup.com.

Amiodarone
May cause severe extracardiac adverse events
Associated with drug-induced pro-arrhythmia
Usually reserved for patients with frequent, symptomatic
recurrences despite use of other antiarrhythmic drugs
Can be used in patients with structural heart disease,
including heart failure
Recommendation Class Level
Amiodarone is more effective in maintaining sinus rhythm than sotalol, propafenone,
flecainide (by analogy), or dronedarone (LOE A), but because of its toxicity profile
should generally be used when other agents have failed or are contraindicated
(LOE C)
In patients with severe heart failure, NYHA class III and IV or recently unstable
(decompensation within the prior month) NYHA class II, amiodarone should be the
drug of choice
I
I
A
B
C
Camm AJ, et al. Eur Heart J 2010;31:2369–2429
13

Amiodarone: selected adverse reactions
(far too many to list)
• ARDS
• Optic neuritis
• Ataxia
• Pancreatitis
• AV block
• Peripheral neuropathy
• Bronchiolitis obliterans • Pneumonitis
• Dyspnea
• QT prolongation
• Epididymitis
• Sinus bradycardia
• Heart failure
• Thrombocytopenia
• Hepatitis
• Torsade de pointes
• Hyper/hypothyroidism • Toxic epidermal necrolysis
• Macular degeneration • Vasculitis

Amiodarone: adverse events
• 15% of patients experience adverse events in the
first year
• 50% of patients report adverse effects with longterm
use (photosensitivity in 25-75%)
• 3.7-15% experience thyroid toxicity
(particularly hypothyroidism)
• 30% of patients may have abnormal LFT’s
• 3% of patients may develop hepatitis
• 90% corneal deposits, 5% optic neuropathy
• 1-3% risk of pulmonary toxicity

Amiodarone: monitoring
Baseline
investigations
To be undertaken by secondary care
Chest X-ray (ensure CXR within the last 12 months),
TFT ( T 3 , T 4 & TSH) LFTs, urea & electrolytes and creatinine, ECG. Consideration
could be given to lung function tests and examination of skin, eyes, and
neurological systems
Electrolyte
Every 6 months in
patients taking
diuretics
Avoid hypokalaemia
Correct the cause of
hypokalaemia
Primary
Care
Eyes Annual Opthalmological examination
recommended in data sheet
Patient should be encouraged
to attend optician annually.
Both
If blurred or
decreased vision
Arrange urgent opthalmological
assessment
Discuss urgently with Specialist Both

Amiodarone: monitoring
Monitoring Frequency Results Action &
Responsibility
Every 6 months*
Clinical adverse effects
Clinical
effectiveness
Every 6 months*
Assess for adverse effects
Assess patient remains in sinus rhythm and heart rate is
satisfactory
*Patient is assessed twice per year:
Clinical GP assessment
Alternates approximately 6 monthly with
Clinical/ ECG assessment, secondary care unless otherwise stated.
Both:
Patients who
have had
lifethreatening
arryhthmias
TFT :
T 3 ,T 4 &TSH
(i)
LFT
Every 6 months >1.5 fold rise in AST or ALT,
or signs of jaundice
T 3 , T 4 & TSH
If normal repeat
every 6 months
Normal
TSH > 4.5 TSH > 4.5,
fT 4 elevated and duration less than 3
months
Sub clinical
hypothyroidism
Hypothyroid TSH > 4.5,
fT 4 low
Thyrotoxicosis
TSH > 10,
fT 4 normal
persisting for over 6 months
TSH < 0.1mU/l
T 3 & T 4 normal
or minimally increased
TSH < 0.1mU/l
& T 4 elevated,
T 3 elevated or 50% greater than
baseline
Discuss with specialist
who may advise
amiodarone withdrawal
It is not unusual for
patients on amiodarone to
have slight elevations of
TSH and T 4
Observe
Repeat in 3 months
Consider treating with
levothyroxine or repeat in
3 months
May be treated with
levothyroxine if
amiodarone is considered
essential
Repeat in 2-4 weeks
Discuss urgently with
specialist who may advise
amiodarone withdrawal.
Arrange TSH-receptor
antibodies and TPO
antibodies
Primary Care

Sotalol: adverse events
• Beta-blocker like effects (malaise, lethargy,
wheeze, bradycardia)
• QT prolongation and proarrhythmia (female, LVH,
renal impairment)
• Effects of QT prolongation potentially exacerbated
by metabolic disturbance ( eg hypokalaemia) and
medication (QT prolonging medications,
antipsychotics, citalopram)

Flecainide: adverse events
• QT prolongation and proarrhythmia (NB coronary
disease, impaired LV function)
• Effects of QT prolongation potentially exacerbated
by metabolic disturbance (eg hypokalaemia) and
medication (QT prolonging medications,
antipsychotics, citalopram)
• Beware atrial flutter (in the absence of betablockers
or rate limiting calcium antagonists) and
AICD/pacing thresholds...

Sotalol and Flecainide: Monitoring
BNF 58
Sotalol: “with ECG monitoring and measurement of corrected
QT interval”
Flecainide: “initiated under direction of hospital consultant”
Summary of Product Characteristics: Sotalol: “caution if QTc on
treatment >500, stop if >550”.
ECG should be repeated after 2 weeks, ( 6 monthly) and after
increases in dose and advice taken if QTc >500 and stopped if
QTc >550

Flecainide: use in the wrong population……….
CAST: Cardiac Arrhythmia Suppression Trial
All-cause mortality
Survival
(%)
100
95
90
85
80
Placebo (n=725)
Encainide or flecainide (n=730)
P=0.0003
0 50 100 150 200 250 300 350 400 450 500
Days after randomization
CAST Investigators. N Engl J Med 1989; 321 :406 – 12.

Dronedarone: Updated Indications (October 2011)
• Indicated in adult clinically stable patients with
paroxysmal or persistent atrial fibrillation (AF)
for the maintenance of sinus rhythm after
successful cardioversion.
• Should only be prescribed after alternative
treatment options have been considered.
• Treatment should only be initiated and
monitored by specialists to ensure that the
benefit-risk balance is positive for patients.

Dronedarone: contraindications
As a result of the emergence of safety issues in the post
marketing period (hepatic, lung, and the negative inotropic
effect)
Now contraindicated in patients with:
Unstable haemodynamic conditions
History of, or current heart failure or left ventricular systolic
dysfunction
Permanent AF (AF duration ≥ 6 months or unknown, and
attempts to restore sinus rhythm no longer considered by the
physician)
Liver and lung toxicity related to the previous use of
amiodarone

Dronedarone: Monitoring
Liver function is tested:
‣ before initiation of treatment and after one week
‣ on a monthly basis for six months
‣ at months 9 and 12 and then
‣ periodically thereafter
If alanine transaminase (ALT) levels are elevated ≥3 (upper limit of normal levels), then
the levels should be re-measured within 48-72 hours.
If ALT levels are confirmed to be ≥3 (upper limit of normal levels), after reassessment,
dronedarone treatment should be withdrawn.
Other monitoring requirements includes:
‣ Regular cardiac examinations including an ECG at least every 6 months
‣ INR closely monitored after initiating dronedarone in patients taking vitamin K
antagonists
‣ Plasma digoxin concentration, clinical and ECG monitoring if patient on digoxin
‣ Renal monitoring with plasma creatinine values measured prior to and 7 days after
initiation of dronedarone
‣ Pulmonary monitoring as onset of dyspnoea or non productive cough may be related
to pulmonary toxicity
‣ Grapefruit juice should not be taken with dronedarone.
‣ Co–administration with potent cytochrome P 450 (CYP) 3A4 inhibitors is
contraindicated e.g. ketoconazole, itraconazole, posaconazole and clarithromycin.

Continuing antiarrhythmic drugs –
the smooth transition

The Evidence: is Amiodarone therapy
monitored appropriately longer-term
• Review/audit of prescribing and monitoring of 500 patients who had been
prescribed amiodarone – Wrexham and Flintshire
• 350, in retrospect, should not have been prescribed amiodarone
• Mean age 76 years (average duration of therapy 5.5 years)
• 70% initiated in Secondary Care
• 29% of cases documented information given regarding monitoring of noncardiac
side effects
• 28% monitored TFT’s and 29% LFT’s
• 5% monitored for pulmonary complications
• 2% monitored for opthalmic complications
• 14% documented evidence of advice/counselling given to patient re:
potential side effects of amiodarone
Khan K, Rivlin G. Cardiology News
2011 14 (2)

PROTOCOL:
AMIODARONE
This document should be read in conjunction with the current Summary of Product Characteristics
http://www.medicines.org.uk/
1. Licensed
Amiodarone is licensed for the treatment of severe cardiac rhythm disorders where other
Indications
treatments either cannot be used or have failed.
The All Wales Medicines Strategy Group recommends that shared care arrangements are
2.
suitable for patients newly initiated on amiodarone. This protocol has been endorsed by the
Therapeutic use & Welsh Cardiovascular Society (for patients with life-threatening arrythmias) and the Wales
Background
Council of the British Geriatric Society. The consultation process has included Local Medical
Committees and Welsh Drugs & Therapeutics Committees. This protocol does not cover the
use of oral amiodarone in short term treatment prior to cardioversion. Amiodarone is
commonly used to maintain sinus rhythm in patients with atrial fibrillation or who have
converted from, or relapsed into atrial fibrillation following cardioversion. It is also used before
heart surgery to help prevent atrial fibrillation. Amiodarone has been used for prevention of
ventricular arrhythmias.
Hypersensitivity to iodine or amiodarone or any excipients, evidence or history of
3. Contraindications hyperthyroidism, uncorrected hypothyroidism, sinus bradycardia and sino-atrial heart block,
combined use with drugs that may induce torsades de pointes (see Drug Interactions below),
pregnancy (except in exceptional circumstances) & breast feeding. In patients with severe
conduction disturbances or sinus node disease, amiodarone should be used only in
conjunction with a pacemaker.
A loading regimen is necessary and will be prescribed by secondary care.
4. Typical Dosage
Regimen (Adults) Loading: 200mg three times daily for one week, then 200mg twice daily for one week, then a
further reduction to 200mg daily.
Maintenance dose is usually 200mg daily; however 100mg daily may be sufficient in elderly
patients. The minimum dose to control arrhythmia is used. In rare cases a maintenance dose
of above 200mg daily may be required.
All dose adjustments will be done by secondary care unless directions have been specified in
the medical letter to the GP.
5. Drug Interactions
For a
comprehensive list
consult the
BNF(Appendix 1) or
Summary of Product
Characteristics
Amiodarone is metabolised by the cytochrome P450 system and therefore has the potential to
cause many drug interactions. The Summary of Product Characteristics or BNF (Appendix 1)
should be consulted before initiating any new drug therapy.
Amiodarone has an average plasma half life of 50 days (range 20-100 days). There is
potential for drug interactions to occur several weeks or months after stopping treatment and
the onset of drug interactions may be slow after initiating amiodarone.
Statins: Increased risk of myopathy. Simvastatin- restrict dose to 20mg daily.
Other statins: counsel patients to report any muscle pain or weakness immediately.
Anticoagulants: Amiodarone can increase anticoagulant effect. Consider warfarin dose
reduction. Patients should be monitored closely and the dose of anticoagulant altered
accordingly, remembering that amiodarone levels take several weeks to stabilise.
Antiepileptics: Amiodarone can increase plasma concentration of phenytoin, phenytoin dose
should be reduced. Note that small changes in phenytoin dose can result in large changes in
phenytoin levels. Monitor patient closely and counsel on signs of toxicity.
Beta blockers, increased risk of bradycardia, AV block and myocardial depression.
Sotalol-avoid concomitant use.
Calcium channel blockers (diltiazem and verapamil): increased risk of bradycardia, AV block
and myocardial depression.
Ciclosporin: Amiodarone increases levels of ciclosporin. Reduced dose of ciclosporin is
recommended.
Digoxin dose should be halved when amiodarone is started.
Diuretics increased risk of cardiotoxicity if hypokalaemia occurs
Drugs that prolong the QT interval: Concurrent therapy is contra-indicated due to the
increased risk of torsades de pointes,
Antiarrhythmics: e.g. quinidine, procainamide, disopyramide, sotalol.
Antipsychotics: e.g. phenothiazines, haloperidol, amisulpiride.
Antihistamines: e.g. mizolastine and terfenadine.
Antimalarials: e.g. chloroquine, hydroxychloroquine, mefloquine, quinine
Lithium and tricyclic antidepressants.
Others: co-trimoxazole IV erythromycin, moxifloxacin, pentamidine, some antivirals

AAD’s - Key Points
• Treatment is motivated by attempts to reduce AF-related symptoms
• Manage expectations - clinically successful antiarrhythmic drug therapy
may reduce rather than eliminate the occurrence of AF
• Drug-induced proarrythmia and extracardiac side effects are frequent
• Safety rather than efficacy should primarily guide choice of antiarrhythmic
agent
• Informed patient discussion and information/literature for final decision
(including copied correspondence)
• Recommending clinician has responsibility for documenting strategy for
monitoring
• Audit supports development of local Shared Care Pathways to improve
monitoring
• Easy access for advice, support and specialist review for Primary care team
and patients

Questions