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Aimee Mishler, PharmD, BCPS
August 26, 2015

Pathophysiology of atrial fibrillation (AF)

Review of Rate vs Rhythm Control Recommendations

Review of Pharmacologic Treatment Options
Term
Definition
Paroxysmal AF
AF that terminated spontaneously or with intervention
within 7days of onset
AF that is sustained >7days
AF that is sustained >12months
Persistent AF
Long-standing Persistent
AF
Permanent AF
Nonvalvular AF
When both patient and physician decide not to purse any
further attempts to restore normal sinus rhythm (NSR)
AF in the absence of rheumatic mitral stenosis, mechanical
or bioprosthetic valve, or mitral valve repair
Classification Definitions
Class I benefit >>> risk and intervention/treatment/procedure should be
preformed
Class benefit >> risk – more studies needed – reasonable to preform
IIa
intervention/treatment/procedure
Class
IIb
Class
III
benefit ≥ risk – more studies needed – intervention/treatment/procedure
may be considered
no proven benefit, more costly with no proven benefit, or harmful to patients
LOE A
LOE B
LOE C
Level of Evidence (LOE) Definition
Data from multiple populations; multiple randomized clinical trials and/or
meta-analyses
Limited population; single randomized trial or non-randomized studies
Very limited population; expert opinions, consensus statements, or case
studies

Class I (LOE B)
o Control rate using beta blocker (BB) or non DHP calcium channel blocker (CCB)
• Paroxysmal, persistent or permanent
o Use IV BB or non DHP CCB to slow rate in acute setting
o For hemodynamically unstable patients, electrical cardioversion is indicated

Class IIa (LOE B)
o Resting HR < 80 bpm is reasonable for symptomatic management

Class llb (LOE B, C)
o Resting HR < 110 bmp is reasonable as long as patient remains asymptomatic and systolic
function is preserved
o Amiodarone may be useful for rate control when other measures are unsuccessful
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Class III (LOE C, B)
o Non DHP CCB should not be used in patient with decompensated heart failure
o Digoxin, non DHP CCB, and IV amiodarone should not be used in pre-excitation AF
Drug
Dose
Class/MOA
Notes
Metoprolol • 2.5-5mg IV q5min to max of
B1 selective BB
15mg in 15min
• IV Maintenance: 2.5-5mg q6h
• IV:PO = 1:5
• Caution: heart failure
Esmolol
Load: 500mcg/kg IV over 1min
Infusion: 50-200mcg/kg/min
B1 selective BB
• When titrating infusion, re-bolus with
500mcg/kg every time
• Duration: 10-30min
• Caution: heart failure
Diltiazem
• Bolus: 0.25mg/kg with a
max=20mg; may repeat in
15min with 0.35mg/kg with
max = 25mg
• Infusion: 5-15mg/h
Non-DHP CCB
• Start low; 5-10mg often control rate
• Hang fluids to prevent hypotension
• Caution: left ventricular dysfunction
Digoxin
• IV: 250mcg q6h
Cardiac glycoside;
binds Na/K pump to
inc. Ca and prolong
action potential to
dec. HR
• Not first line; may be used as add
one to BB or CCB
• Often ineffective alone
• Avoid in AKI
Drug
Dose
Class/MOA
Notes
Metoprolol
Tartrate: 25-100mg po BID
Succinate: 50-400mg po daily
B1 selective BB
IV:PO = 1:5
Atenolol
25-100mg po daily
B1 selective BB
Crcl 15-35: max = 50mg daily
Crcl <15: max = 25mg daily
Bisoprolol
2.5-10mg po daily
B1 selective BB
Use caution in hepatic dysfunction
Carvedilol
6.25-25mg po BID
Non-selective BB + a-blocker
Contraindicated in severe liver failure
Diltiazem
ER: 120-360mg po daily
Non-DHP CCB
• IV to po: [(rate x 3) + 3] x 10
• Caution: lV dysfunction
Verapamil
ER: 180-480mg po daily
IR: 240-480mg divided q8h
Non-DHP CCB
• Caution in renal insufficiency
• Cirrhosis: dec. dose 50%
• Contraindicated with LV dysfunction
Digoxin
125-250mcg po daily
Cardiac glycoside; binds Na/K • Not first line; adjunct to CCB or BB
pump to inc. Ca and prolong
• Often ineffective alone
action potential to dec. HR
• Adjust with Crcl <50ml/min
• Monitor levels

Things to consider
o Fluid bolus
o What medication do they take at home
o Compliance of home regimen
o Comorbidities
• Avoid BB in diabetes, depression, asthma, thyroid abnormalities, pheochromocytoma
• Avoid CCB left ventricular dysfunction, peripheral edema
o What medication are you going to send them home with

Results at 3.5y
o 70% rate control with BB
o 54% rate control with CCB

Short t ½ good for the critically ill patient

Evidence for post CABG AF

1989 study– Esmolol in the acute treatment of AF
o HR decreased from 139 to 100bpm

Controversial
o Early studies in animals resulted in asystole
o Combination used in refractory angina

Potential for serious ADE
o Complete heart block/asystole
o Additive hypotensive and bradycardic effects

Potential mechanism
o CCB: block inward Ca flow prolonging SA and AV nodal conduction
o BB: decrease SA automaticity and prolong AV nodal refractory period

Nonvalvular AF
o CHA2DS2-VASc
o Warfarin, dabigatran, rivaroxaban

Mechanical valve
o warfarin

Class I (LOE A)
o Flecaindie, dofetilide, propafenone, and ibutilide are useful for pharmacologic
cardioversion – provided contraindications are absent
o To maintain rhythm control consider: amiodarone, dronedarone, flecainide,
propafenone, dofetilide or sotalol

Class I (LOE C)
o Risks, including proarrhythmia should be considered before initiation
o Due to toxicities, amiodarone should be used only after considertion of risks and when other
agents have failed

Class IIa (LOE A)
o Oral amiodarone is reasonable for pharmacologic cardioversion

Class III (LOE B)
o Dofetilide should not be initiated out of hospital
o Antiarrhythmics and rhythm control should not be continued when AF becomes
permanent
o Dronedarone should not be used in patients with NYHA Class III/IV HF
Class
Vaughan Williams Classification of Antiarrhythmics
Mechanism
Medications
Class IA
Sodium Channel Blocker - intermediate
Class IC
Sodium Channel Blocker - slow
Class III
Potassium channel blockers
Class V
Quinidine
Procainamide
Flecainide
Propafenone
• Amiodarone : also has Na, Beta, and
Calcium channel blockade
• Sotalol: also has beta-blockade
Amiodarone
Dofetilide
Dronedaorone
Sotalol
Multiple mechanisms
Digoxin
Drug
Dose
Class
Amiodarone
(also has
Class I, II, IV
properites)
400-600mg po daily in divided
doses x2-wks then 100-200mg po
daily
• ADR: hypotension, bradycardia, SJS, hepatotoxicity,
peripheral neuropathy, optic neurophathy, photosensitivity,
QT prolongation, pulmonary toxicity, thyroid dysfunction
• Drug interactions
• Terminal T1/2 ~55days
Dofetilide
(Tikosyn®)
500mcg po BID
QTc interval should be measured
2-3h post dose. If 15% above
baseline or >500msec dec. 50%.
If anytime after 2nd dose QTc
>500msec must discontinue.
• CI: baseline QTc >440msec, crcl <20ml/min, HTCZ,
itraconazole,ketoconazole, verapamil, bactrim
• Monitored on continuous EKG x3days
• Caution renal and hepatic impairment
• Warning: QTc prolongation; torsades
Dronedarone
(Multaq®)
400mg po BID
Class III
Notes
• CI: NYHA Class IV, permanent AF, bradycardia,
concomitant QT proloning durgs (haldol, TCA, macrolides,
antiarrhythmics), hepatic failure, baseline QTc >500msec
• ASR: increased Scr, pulmonary toxicity
• DI: CYP3A4 inhibitors
Drug
Dose
Class
Stotolol
80mg po BID x3days then 120mg160mg po BID
Class III
•
•
•
•
Flecainide
50mg po q12h; inc. at 4day
intervals to 300mg po daily
• Crcl <50ml/min dec. by 50%
• ADR: QT prolongation
• Cuation: HF, hepatic impairment
Propafenone
• ER: 225-425mg po q12h; inc.
to 325mg po q12h
• IR:150-300mg po q8h
Class I
Notes
Administer inpatient x3days
Dose adjust at Crcl <60ml/min
CI: baseline QTc >450msec
Caution: MI, HF, asthma, DM, thyroid disorder, bradycardia
• ADR: agranulocytosis, QRS/QTc prolongation
• Caution: HF, hepatic impairment, myasthenia gravis, renal
impairment, Lupus, pulmonary disease

≥48h or unknown:
o Anticoagulate x3 weeks before cardioversion and x4week after
• Regardless if electrical or chemical cardioversion
o TEE + anticoagulation before cardioversion and continue x4 weeks

<48h + high risk stroke
o Heparin or enoxaparin ASAP before or immediately after cardioversion
o Follow with long term anticoagulation

<48h + low thromboembolic risk
o No anticoagulation may be considered
Study
Population/Outcomes
Results
Pharmacological Intervention in Atrial
Fibrillation (PIAF)
Lancet. 2000;356:1789-1794.
225 pt with persistent AF
• No difference
• Exercise tolerance significantly better in the
rhythm-control
• Significantly more hospitalizations in the
rhythm-control group
Strategies of Treatment of Atrial
Fibrillation (STAF)
J Am Coll Cardiol. 2003;41:1690-96
200 pts with persistent AF
Most >65yo
Improvement in sx:
palpitations, dyspnea, and
Death, cardiopulmonary
resuscitation, CVA, and
systemic embolism
Rate vs Electrical Cardioversion for
Persistent AF (RACE)
N Engl J Med. 2002;347:1834-1840
522 pt with persistent AF
after previous electrical
cardioversion
Death, thrombotic event,
bleeding, pacemaker, ADR
• No difference in mortality
• Significantly more hospitalizations in the
rhythm-control group
• CVA more common in rhythm-control
• No difference at 2 ½ years
• Only 39% of rhythm-control in NSR
• Thrombotic events greater in rhythm-control

Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
o 4060 patients who were at least 65 years of age
• Or who had other risk factors for stroke or death and had AF that was likely to
recur
o 5 years: 63% of rhythm-control were in NSR vs 34.6%
o No clinical advantage for rhythm control over rate control
o Death: 356 (23.8%) in the rhythm-control group and 310 deaths (21.3%) in
the rate-control
o Hospitalizations: rhythm-control 80.1% vs 73% in rate control (p <0.001)
N Engl J Med. 2002;347:1825-1833
 Rhythm
control
o Difficult to achieve
 Rate
control
o Not effective for highly symptomatic
patients
o More costly
o Remodeling occurs still
o Anti-arrhythmics have more adverse
effects

Rate vs Rhythm
o No significant difference
o Higher hospitalization in rhythm control
o More cerebrovascular events and thrombotic events in rhythm control
o Trend toward higher mortality after two years in rhythm control

Rate control options – acute
o Diltiazem 0.25mg/kg (max 20mg) then 2.5-15mg/h
o Metoprolol 2.5-5mg IV q5min to max 15mg in 15min
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Rhythm control options
o Amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotolol
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