Atrial Fibrillation

Marina Shenouda, Pharm.D. Candidate

Erika Zwachte, PGY-1 Pharmacy Resident

Preceptors: Drs. Genevieve Hale and Kajal Jain

February 25, 2021

Objectives

- Review the pathophysiology of Atrial Fibrillation (AFib)

- Discuss pharmacological and nonpharmacological approaches to
AFib
- Differentiate between rate control and rhythm control therapies
- List treatment options for special populations

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 Background
- Supraventricular tachyarrhythmia with uncoordinated atrial activation
- Ineffective atrial contraction → irregular heartbeat

- Lifetime risk of AFib estimated at 1 in 4 people in the U.S.

- Prevalence increases with age

- Most common arrhythmia in primary care

- Further CV complications → cardiomyopathies, heart failure and stroke

Circulation. 2019;139(10) 3
Pathophysiology

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Action Potentials

5
Electrocardiogram (ECG)

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 Mechanisms of AFib

Circulation. 2014;130(23) 7
Types of AFib
Type of AFib Definition
Paroxysmal AFib that terminates spontaneously or with intervention within 7 days of onset;
episodes may recur with variable frequency

Persistent Continuous AFib that is sustained >7 days

Long-standing persistent Continuous AFib of > 12 months

Permanent Term used when a joint decision has been made by the clinician and patient to
cease further attempts to restore and/or maintain NSR

Valvular AFib with moderate to severe mitral stenosis or with a mechanical heart valve;
long-term anticoagulation with warfarin is indicated

Non-valvular AFib without moderate to severe mitral stenosis or a mechanical heart valve
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Clinical Presentation

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Risk Factors
- Advanced age
- Heart Failure
- High blood pressure
- Diabetes
- Chronic kidney disease
- Ischemic heart disease
- Obesity

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Diagnosis of AFib

- Medical history
- Physical examination
- ECG
- Holter monitor
- Implantable loop recorders
- Pacemakers

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Goals of Therapy
HR Goals
- Control symptoms
Symptomatic &/or LVEF <40%
- Improve quality of life 80 bpm resting, 100 bpm exercising

- Prevent thromboembolism Persistent AF & LVEF >40%

110 bpm
- Restore and maintain NSR

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Non-Pharmacological Interventions
- Electrical cardioversion

- AV node ablation

- Left atrial appendage occlusion ( LAAO)

- WATCHMAN Device (stroke prevention)

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Rate Control vs. Rhythm Control
Rate Control Rhythm Control

Advantages Disadvantages Advantages Disadvantages

Easy to achieve and Electrical and structural Reduce symptoms of Adverse drug effects
maintain remodeling due to fatigue & exercise
Cost of meds & monitoring
continued AF intolerance
Outpatient therapy Potential inpatient stay
Minimal structural atrial
changes Recurrence of AF

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Pharmacological Interventions

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Roadmap of AFib Treatment
AFib Therapies

Maintenance Urgent

Rate Control Rhythm Control Cardioversion IV Medications

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 Rate Control
- Beta Blockers
- Non-dihydropyridine Calcium Channel Blockers
- Digoxin ( not 1st line agent)

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 Class II: Beta Adrenergic Blockers
MOA: blocking sympathetic tone, control ventricular rate
Adverse Effects Contraindications Clinical Pearls

Hypotension Cardiogenic shock Do not stop abruptly

Bradycardia 2nd and 3rd degree AV block Use with caution in diabetic patients

Fatigue/dizziness WPW

Impotence

Monitoring Parameters: BP, HR ( monitor closely if CCB are used )

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Class II: Beta Adrenergic Blockers
Drug Name Dose
Oral: 25-100 mg BID
Metoprolol tartrate IV:2.5-5.0 mg IV bolus over 2 min, up to 3 doses

Metoprolol succinate XL Oral:50-400 mg QD

Atenolol Oral:25-100 mg QD

Oral: N/A
Esmolol IV: 500 mcg/kg IV bolus over 1 min, then 50-300
mcg/kg/min IV

Oral: 10-40 mg TID or QID

Propranolol IV: 1 mg over 1 min, up to 3 doses at 2-min interval

Nadolol Oral: 10-240 mg QD

Carvedilol Oral: 3.125-25 mg BID

Bisoprolol 2.5-10 mg QD 19
Class IV: Nondihydropyridine Calcium Channel
Blockers
MOA: block calcium channels, negative inotropic effects ( ↓ contractility)

Monitoring
Drug & Dose Adverse Effects Contraindications Clinical Pearls
Parameters

Cardizem, ECG Edema Severe hypotension Considered over

Cardizem CD, BBs in asthma and
BP Arrhythmias 2nd /3rd degree
Cardizem LA, COPD
heart block/sick
Cartia XT, HR Constipation ( verapamil) sinus syndrome Avoid grapefruit
(diltiazem)
120-360 mg daily Electrolytes Gingival hyperplasia juice
Cardiogenic shock

Calan SR LFTs Headache HFrEF

(verapamil) Dizziness WPW
180-480 mg daily

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Digoxin
MOA: inhibits Na+/K+ ATPase pump, resulting in (+) inotrope ( ↑force of contraction )

Monitoring Therapeutic
Adverse Effects CI Dose
Parameters Levels

HR Visual changes (yellow halos) Heart HF: 0.5-0.9 IV: 0.25 mg IV with
Block mg/mL repeat dosing to a
[Serum Digoxin] ↓ K+, ↓ Mg
maximum of 1.5 mg
Acute AFib: 0.8-2
Electrolytes ↑ Ca++ over 24 h
renal ng/mL
failure PO: 0.125-0.25 mg
daily
VFib

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Roadmap of AFib Treatment
AFib Therapies

Maintenance Urgent

Rate Control Rhythm Control Cardioversion IV Medications

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Rhythm Control
- Restores and maintains sinus rhythm
to improve QOL
- Can include medications,
cardioversion, or ablation
- Must consider comorbid heart
disease (CAD or HF)
- High risk for adverse events and
strict monitoring requirements
Circulation. 2014;130(23) 23
 Class Ia
MOA: Na+ channel blockers with negative inotropic effects and anticholinergic activity

Norpace (disopyramide)
Monitoring
Dose Adverse Effects Contraindications Clinical Pearls
Parameters

IR: 100-200 mg HR (pro-arrh.) Anti-SLUD Hypersensitivity Least anticholinergic

every 6 hours
QT interval Myasthenia gravis Cardiogenic shock Potential hypotension
CR: 200-400 mg beginning tx
QT prolongation 2-3 degree block
every 12 hours Take on empty
Congenital QT syndrome
stomach
(hep/renal adj.)

Circulation. 2014;130(23) 24
 Class Ia
Quinidine
Monitoring
Dose Adverse Effects Contraindications Clinical Pearls
Parameters

324-648 mg every HR (pro-arrh.) BBW: ↑mortality in tx Thrombocytopenia Avoid in HF pts

8 hours of AFib or flutter
QT interval 2-3 degree heart block Take w/ food
267 mg gluconate ↑QTc
TTP Can cause (+) coombs
= 200 mg sulfate Diarrhea, stomach test
Myasthenia gravis
cramps
(renally adjusted) Combo w/ quinolones
CNS toxicity (tinnitus,
blurry vision, delirium)

Circulation. 2014;130(23) 25
 Class Ia
Procainamide
Monitoring
Dose Adverse Effects Contraindications Clinical Pearls
Parameters

IV LD: up to 17 HR (pro-arrh.) BBW: blood Hypersensitivity Reserved for pts w/

mg/kg - rate: dyscrasias tachyarrh.
Therapeutic levels: Complete heart block
20-50 mg/min) (agranulocytosis),
(+) ANA w/ Least GI side effects
Procainamide: 4-10 2-3 degree AV block
(hep./renal adj.) mcg/mL long-term (leads
to DILE) Torsades
NAPA: 15-25 mcg/mL
Hypotension
Both: 10-30 mcg/mL
Rash

Circulation. 2014;130(23) 26
 Class Ib
MOA: Na+ channel blockers - used ONLY in ventricular arrhythmias (no efficacy in AFib)

Drug & Dose Contraindications Clinical Pearls

Xylocaine 2-3 degree heart block (unless functional PPM) Caution in elderly, hepatic imp., & HF pts
(lidocaine)
WPW syndrome, Adam-Stokes syndrome
Allergy to corn or amide anesthetics

Mexiletine BBW: abnormal LFTs in CHF/ischemic pts Blood dyscrasias

200 mg every 8
2-3 degree heart block (unless functional PPM) Severe skin reactions (DRESS)
hours (max: 1.2
g/day) Cardiogenic shock Take with food

Note:
Lidocaine → used for refractory VT/cardiac arrest (alternative to amiodarone)
Mexiletine → reserved for life threatening ventricular arrhythmias due to BBW
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Circulation. 2014;130(23)
 Class Ic
MOA: most potent Na+ channel blockers, slowing conduction
Monitoring
Drug & Dose Parameter Adverse Effects Contraindications
s

Tambocor (flecainide) HR BBW: when treating Aflutter, 1:1 AV Hypersensitivity, HF, CAD, MI,
50-100 mg every 12 conduction may occur 2-3 degree heart block
hours (max 400 mg/day) QT interval
CNS depr. (dizziness, visual dist.) Warnings: severe hepatic imp.

Rythmol SR HR BBW: mortality (recent MI pts) Hypersensitivity

(propafenone)
Renal/hep. Metallic taste, GI, dizziness HF, bradycardia, marked ↓BP,
function bronchospastic disorders
Note:
Flecainide → use with life threatening ventricular arrhythmias
Propafenone → use with life threatening ventricular arrhythmias due to BBW, β-blocker properties at high doses
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Circulation. 2014;130(23)
 Class III
MOA: primarily block K+ channels (also block α, β, Na+, and Ca++)
Nexterone / Pacerone (amiodarone)
Monitoring
Dose Adverse Effects Contraindications Clinical Pearls
Parameters

Cardioversion: ECG Pulmonary toxicity Iodine hypersensitivity Blue skin

600-800 mg /day for a discoloration
BP Hepatotoxicity 2-3 degree heart block
10 g LD, then 200 mg (sunscreen)
daily HR Hypotension, Severe sinus node
Optic neuritis
Bradycardia dysfunction
Maintenance of NSR: Electrolytes Max doses of
400-600 mg/day for Ataxia Bradycardia causing
LFTs syncope simvastatin 20
2-4 weeks, then mg/day or lovastatin
100-200 mg daily Corneal
TSH, free T4 Cardiogenic shock 40 mg/day
microdeposits

Circulation. 2014;130(23) Photosensitivity 29

 Class III
Multaq (dronedarone)
Monitoring
Dose Adverse Effects Contraindications Clinical Pearls
Parameters

400 mg HR BBW: ↑risk of death, Pregnancy/breastfeeding Reserved for pts w/

every 12 stroke, and HF in NYHA tachyarrh.
QT & PR 2-3 degree AV block unless
hours IV pts, permanent AFib
intervals + pacemaker Least GI side effects
(w/food) Pulmonary disease
Renal function Sx HF, HR < 50 bpm, QTc ≥ < ADRs/efficacy than
500 msec, PR interval > 280 amiodarone
Electrolytes msec
Hepatic imp.
Prev. lung or liver tox.

Circulation. 2014;130(23) 30
 Class III
Betapace AF / Betapace / Sotylize / Sorine (sotalol) → non-selective β-blocker
Dose Adverse Effects Contraindications Clinical Pearls
PO: 80-160 mg BID Bradycardia/fatigue Hypersensitivity Betapace AF distributed with
informational material
Chest pain/palpitations Bronchial asthma,
IV: 75 mg over 5
bronchospasm Not effective for conversion
hours HA/dizziness of AFib to NSR
2-3 degree AV block, long
QT syndromes (> 450 msec)
Cardiogenic shock
K+ < 4 mEq/L
CrCl < 40 mL/min

Circulation. 2014;130(23) 31
Sotalol Monitoring

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 Class III
Covert (ibutilide)
Monitoring
Dose Adverse Effects Contraindications
Parameters
IV: QT interval BBW: proarrhythmic Hypersensitivity
<60kg: 0.01mg/kg over 10
mins HR Ventricular
tachycardias (TdP)
Electrolytes
≥60kg: 1mg/kg over 10 mins HA, hypotension, QT
*confirm benefits>risks* prolongation
Note:
Administered with continuous ECG monitoring, by personnel trained in ID & tx of acute ventricular arrhythmias

Circulation. 2014;130(23) 33
 Class III
Tikosyn (dofetilide)
Monitoring
Dose Adverse Effects Contraindications Clinical Pearls
Parameters
500 mcg BID Renal function BBW: pts must remain in CrCl <20 mL/min Use ABW for CrCl
the facility for min. of 3 estimation
QT interval Long QT syndromes (>
CrCl <60 mL/min: days when starting
440 msec)
↓dose SCr dofetilide (monitor SCr,
ECG, cardiac Hypersensitivity
CrCl <20 mL/min: ECG resuscitation)
contraindicated Various DDI (including
Torsades de Pointes verapamil and HCTZ)
(TdP)

Headache

Circulation. 2014;130(23) 34
Dofetilide Monitoring

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Drug Drug Interactions
Medication Mechanism Common Medications
Amiodarone CYP3A4 metabolism, Qt prolonging agents Clopidogrel, warfarin, trazodone, atorvastatin

Sotalol Qt prolonging agents Citalopram, levofloxacin

Propafenone P-gp transport, Qt prolonging agents Colchicine, sirolimus

Dofetilide Qt prolonging agents HCTZ, -azoles, trimethoprim, thorazine, verapamil

Dronedarone Inhibits CYP2D6/3A4 & P-gp, Qt prolongation Quetiapine, levofloxacin

Diltiazem CYP3A4 metabolism Atorvastatin, colchicine, macrolides

Verapamil CYP3A4 metabolism, P-gp transport Colchicine, lovastatin, macrolides

Digoxin Absorption, P-gp transport Sucralfate, atorvastatin, amiodarone, dronedarone

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Pharmacological cardioversion
- Flecainide,dofetilide, propafenone, IV ibutilide
- Amiodarone
- Propafenone or flecainide
- Dofetilide

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Direct-current cardioversion
- No response to pharmacological therapy
- Tachycardia with hemodynamic instability
- Persistent AF

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Stroke Prevention
 CHA₂DS₂VASc Score

Circulation. 2014;130(23) 40
 Interpreting CHA₂DS₂VASc Score

Circulation. 2014;130(23) 41
 HAS-BLED Score ⩾3: high risk

Can J Cardiol. 2011; 27:74-90 42

Non-Vitamin K Oral Anticoagulants

Direct Factor Xa Inhibitors Direct Thrombin Inhibitor

1. Rivaroxaban (Xarelto) 1. Dabigatran (Pradaxa)
2. Apixaban (Eliquis)
3. Edoxaban (Savaysa)

No need to monitor efficacy

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 Xarelto (rivaroxaban)
- Evaluated in the ROCKET-AF trial compared with warfarin
- Bioavailability:
- Without food → 66%
- With food → 80 - 100%

Standard Dose Dose Adjustment Clinical Pearls

20 mg PO daily 15 mg PO daily with evening meal - Avoid use in liver
with evening meal dysfunction (Child-Pugh
- CrCl 15–50 mL/min
- Dialysis Class B or C)
- Tablets can be crushed
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Patel et al. N Engl J Med. 2011. 365(10):883-91.
 Eliquis (apixaban)
Evaluated in the ARISTOTLE trial compared with warfarin
- Significantly safer than warfarin in causing major bleeding

Standard Dose Dose Adjustment Clinical Pearls

5 mg PO twice daily 2.5 mg PO twice daily
- If 2 of 3 criteria met:
- Age ≥ 80 years
- Weight ≤ 60 kg
- Scr ≥ 1.5 mg/dL
Lopes et al. Am Heart J. 2010. 159(3):331-9.
- Avoid use in liver dysfunction
(Child-Pugh Class C)
- May increase LFTs
- Preferred DOAC in ESRD
- Tablets can be crushed
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 Savaysa (edoxaban)
- Evaluated in the ENGAGE-AF TIMI 48 trial compared with
warfarin
- Significantly safer than warfarin in causing major bleeding

Standard Dose Dose Adjustment Clinical Pearls

60 mg PO daily 30 mg PO daily - Avoid use in liver dysfunction
(Child-Pugh Class B or C)
(CrCl 15–50 mL/min)
- Contraindications:
- CrCl < 15 mL/min
- CrCl > 95 mL/min
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Patel et al. N Engl J Med. 2011. 365(10):883-91.
 Pradaxa (dabigatran)
- Evaluated in the RE-LY trial compared with warfarin
- BEERS list recommends against use in patients ≥75 years
- Bleeding risk greatly increased in RE-LY trial

- Antidote: Praxbind

Standard Dose Dose Adjustment Clinical Pearls

150 mg BID CrCl 15–30 mL/min (75 mg BID) Avoid with CrCl < 15 mL/min
CrCl 30–50 mL/min (dronedarone) Can increase aPTT, PT, INR
AE: dyspepsia (10%)

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Connolly et al. N Engl J Med. 2009. 361(12):1139-51.
Warfarin
MOA: Inhibits the C1 subunit of the of the multi-unit VKORC1 enzyme,depletion of factors
II,VII,IX,X, protein C and S

Monitoring
Drug & Dose Adverse Effects Contraindications Clinical Pearls
Parameters

Coumadin, INR (2-3) Bleeding /bruising Pregnancy Take at the same

Jantoven time every day
Hct Skin necrosis HIT
( Warfarin)
10 mg QD,adjust Vitamin K in diet
Hgb Purple toe syndrome Tissue
dose per INR necrosis/gangrene DOC in patients
Signs of bleeding with mechanical
≤ 5 mg ( special heart valve
cases)

DDI: CYP2C9 inducers↓INR ,CYP2C9 inhibitors ↑INR,oral antibiotics 48

Unfractionated Heparin
MOA: binds to antithrombin,inactivates factors IIa, Xa,prevents conversion of fibrinogen
to fibrin
Monitoring
Drug & Dose Adverse Effects Contraindications Clinical Pearls
Parameters

Unfractionated aPTT Bleeding /bruising Uncontrolled bleeding Serious internal

Heparin Injection bleeding
Platelets Thrombocytopenia Severe
Prophylaxis of
thrombocytopenia
VTE: 5000 units Hgb HIT
SC Q8-12 H History of HIT
Treatment of VTE: Hct Alopecia
80 units/kg IV
bolus;18 Hyperkalemia
units/kg/hr Osteoporosis
infusion

DDI: NSAIDs, SSRIs, SNRIS, antiplatelet drugs, thrombolytics 49

Low Molecular Weight Heparin
MOA: bind to antithrombin, which inactivates factor Xa,IIa
Monitoring
Drug & Dose Adverse Effects Contraindications Clinical Pearls
Parameters

Lovenox Scr Bleeding /bruising Uncontrolled Serious internal

(enoxaparin) bleeding bleeding
Prophylaxis of Platelets Thrombocytopenia
Severe
VTE: 30 mg SC Hgb HIT thrombocytopenia
Q12H or 40 mg SC
QD Hct Anemia History of HIT
Crcl<30:30 mg/kg
SC QD Anti Xa-level Injection site reactions

Treatment of VTE:
1 mg/kg SC Q12H

Crcl<30:1 mg/kg
SC QD

DDI: NSAIDs, SSRIs, SNRIS, antiplatelet drugs, thrombolytics 50

Special Populations
HFrEF Pregnancy Athletes
Often occurs with AFib Most frequent arrhythmia during Intense sports activity increases AFib
pregnancy risk
Urgent:
- Cardioversion Urgent: Beta blockers:
- Cardioversion - Useful for HR control with
Rate control: - Ibutilide or flecainide exertion
- Beta blockers - Increase exercise intolerance
- Digoxin Rate control:
- Beta blockers (not atenolol) “Pill in pocket” for episodic control or
Rhythm control: - Digoxin ablation
- Amiodarone - Verapamil
- Dofetilide Stop sport activity for 40 hours
- Ablation Rhythm control: (flecainide) or 20 hours (propafenone)
- Flecainide & until AFib resolution
- Propafenone
- Sotalol
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Conclusions
- Heart disease is a common condition to have with AFib and greatly
complicates pharmacotherapy options
- Rate control is generally well tolerated compared to rhythm control
therapy
- Rhythm control may have additional long term benefits by
preventing disease progression
- Benefits of using rhythm control agents should always outweigh
risks of medications safety/side effect profile
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References
• January CT, Wann LS, Alpert JS, et al. ACC/AHA Task Force Members. 2014 AHA/ACC/HRS guideline for the
management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart
Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014. 130:e199–e267.
• January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the
Management of Patients With Atrial Fibrillation. Circulation. 2019. 140:e125–e151.
• Connolly SJ, Ezekowitz MD, Yusuf S, et al. RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in
patients with atrial fibrillation. N Engl J Med. 2009. 361(12):1139-51.
• Patel MR, Mahaffey KW, Garg J, et al. ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial
fibrillation. N Engl J Med. 2011. 365(10):883-91.
• Lopes RD, Alexander JH, Al-Khatib SM, et al. ARISTOTLE Investigators. Apixaban for reduction in stroke and other
Thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010. 159(3):331-9.
• Giugliano RP, Ruff CT, Braunwald E, et al. ENGAGE AF-TIMI 48 Investigators. Edoxaban versus Warfarin in Patients
with Atrial Fibrillation. N Engl J Med, 2013. 369:2093-2104.
• Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M, CCS Atrial Fibrillation Guidelines Committee. Canadian
cardiovascular society atrial fibrillation guidelines 2010: Prevention of stroke and systemic thromboembolism in
atrial fibrillation and flutter. Can J Cardiol. 2011; 27:74-90
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Questions
Atrial Fibrillation
Marina Shenouda, Pharm.D. Candidate
Erika Zwachte, PGY-1 Pharmacy Resident

Preceptors: Drs. Genevieve Hale and Kajal Jain

February 25, 2021