Pharmacology for Atrial Fibrillation

Aimee Mishler, PharmD, BCPSAugust 26, 2015

Overview Pathophysiology of atrial fibrillation (AF)

Review of Rate vs Rhythm Control Recommendations

Review of Pharmacologic Treatment Options

Mechanisms of AF

Potential Causes

Definitions of AF

Term Definition

Paroxysmal AF AF that terminated spontaneously or with intervention within 7days of onset

Persistent AF AF that is sustained >7days

Long-standing Persistent AF

AF that is sustained >12months

Permanent AF When both patient and physician decide not to purse any further attempts to restore normal sinus rhythm (NSR)

Nonvalvular AF AF in the absence of rheumatic mitral stenosis, mechanical or bioprosthetic valve, or mitral valve repair

JACC Recommendation Classification

Classification Definitions

Class I

benefit >>> risk and intervention/treatment/procedure should be preformed

Class IIa

benefit >> risk – more studies needed – reasonable to preform intervention/treatment/procedure

Class IIb

benefit ≥ risk – more studies needed – intervention/treatment/procedure may be considered

Class III

no proven benefit, more costly with no proven benefit, or harmful to patients

JACC Level of Evidence

Level of Evidence (LOE) Definition

LOE A

Data from multiple populations; multiple randomized clinical trials and/or meta-analyses

LOE B

Limited population; single randomized trial or non-randomized studies

LOE C

Very limited population; expert opinions, consensus statements, or case studies

JACC Rate Control Recommendations

Class I (LOE B)o Control rate using beta blocker (BB) or non DHP calcium channel blocker (CCB)

• Paroxysmal, persistent or permanento Use IV BB or non DHP CCB to slow rate in acute settingo 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 preservedo Amiodarone may be useful for rate control when other measures are unsuccessful

Class III (LOE C, B)o Non DHP CCB should not be used in patient with decompensated heart failureo Digoxin, non DHP CCB, and IV amiodarone should not be used in pre-excitation AF

Pharmacology of Rate Control - AcuteDrug Dose Class/MOA Notes

Metoprolol

• 2.5-5mg IV q5min to max of 15mg in 15min

• IV Maintenance: 2.5-5mg q6h

B1 selective BB • IV:PO = 1:5• Caution: heart failure

Esmolol Load: 500mcg/kg IV over 1minInfusion: 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

Pharmacology of Rate Control - Maintenance

Drug Dose Class/MOA Notes

Metoprolol

Tartrate: 25-100mg po BIDSuccinate: 50-400mg po daily

B1 selective BB IV:PO = 1:5

Atenolol 25-100mg po daily B1 selective BB Crcl 15-35: max = 50mg dailyCrcl <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 dailyIR: 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 pump to inc. Ca and prolong action potential to dec. HR

• Not first line; adjunct to CCB or BB

• Often ineffective alone• Adjust with Crcl <50ml/min• Monitor levels

What should we use? Things to consider

o Fluid boluso What medication do they take at homeo Compliance of home regimeno Comorbidities

• Avoid BB in diabetes, depression, asthma, thyroid abnormalities, pheochromocytoma

• Avoid CCB left ventricular dysfunction, peripheral edemao What medication are you going to send them home with

What should we use?

What should we use?

What should we use?

Results at 3.5yo 70% rate control with BBo 54% rate control with CCB

Esmolol for AF? Short t ½ good for the critically ill patient

Evidence for post CABG AF

1989 study– Esmolol in the acute treatment of AFo HR decreased from 139 to 100bpm

Can you use BB and CCB? Controversial

o Early studies in animals resulted in asystoleo Combination used in refractory angina

Potential for serious ADEo Complete heart block/asystoleo Additive hypotensive and bradycardic effects

Potential mechanismo CCB: block inward Ca flow prolonging SA and AV nodal

conductiono BB: decrease SA automaticity and prolong AV nodal refractory

period

Rate Control and Anticoagulation

Nonvalvular AFo CHA2DS2-VASco Warfarin, dabigatran, rivaroxaban

Mechanical valveo warfarin

JACC Rhythm Control Recommendations

Class I (LOE A)o Flecaindie, dofetilide, propafenone, and ibutilide are useful for pharmacologic

cardioversion – provided contraindications are absento To maintain rhythm control consider: amiodarone, dronedarone, flecainide,

propafenone, dofetilide or sotalol Class I (LOE C)

o Risks, including proarrhythmia should be considered before initiationo 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

Pharmacology of Rhythm Control

Vaughan Williams Classification of Antiarrhythmics

Class Mechanism Medications

Class IA Sodium Channel Blocker - intermediate

Quinidine Procainamide

Class IC Sodium Channel Blocker - slow FlecainidePropafenone

Class III Potassium channel blockers• Amiodarone : also has Na, Beta, and

Calcium channel blockade• Sotalol: also has beta-blockade

AmiodaroneDofetilideDronedaoroneSotalol

Class V Multiple mechanisms Digoxin

Pharmacology of Rhythm Control - Maintenance

Drug Dose Class Notes

Amiodarone(also has Class I, II, IV properites)

400-600mg po daily in divided doses x2-wks then 100-200mg po daily

Class III

• 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 BIDQTc 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 • 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

Pharmacology of Rhythm Control - Maintenance

Drug Dose Class Notes

Stotolol 80mg po BID x3days then 120mg-160mg po BID Class III

• Administer inpatient x3days• Dose adjust at Crcl <60ml/min• CI: baseline QTc >450msec• Caution: MI, HF, asthma, DM, thyroid disorder,

bradycardia

Flecainide 50mg po q12h; inc. at 4day intervals to 300mg po daily

Class I • 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

• ADR: agranulocytosis, QRS/QTc prolongation• Caution: HF, hepatic impairment, myasthenia

gravis, renal impairment, Lupus, pulmonary disease

Rhythm Control and Anticoagulation

≥48h or unknown: o Anticoagulate x3 weeks before cardioversion and x4week after

• Regardless if electrical or chemical cardioversiono TEE + anticoagulation before cardioversion and continue x4 weeks

<48h + high risk strokeo Heparin or enoxaparin ASAP before or immediately after cardioversiono Follow with long term anticoagulation

<48h + low thromboembolic risko No anticoagulation may be considered

Rate vs RhythmStudy Population/Outcomes Results

Pharmacological Intervention in Atrial Fibrillation (PIAF)Lancet. 2000;356:1789-1794.

225 pt with persistent AF

Improvement in sx: palpitations, dyspnea, and

• 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 AFMost >65yo

Death, cardiopulmonary resuscitation, CVA, and systemic embolism

• No difference in mortality• Significantly more hospitalizations in

the rhythm-control group• CVA more common in rhythm-control

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 at 2 ½ years• Only 39% of rhythm-control in NSR• Thrombotic events greater in rhythm-

control

Rate vs 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 controlo Death: 356 (23.8%) in the rhythm-control group and 310 deaths

(21.3%) in the rate-controlo Hospitalizations: rhythm-control 80.1% vs 73% in rate control (p

<0.001)

N Engl J Med. 2002;347:1825-1833

Pharmacology Rate vs Rhythm Cons

Rhythm control

o Difficult to achieve

o More costly

o Anti-arrhythmics have more adverse effects

Rate control

o Not effective for highly symptomatic patients

o Remodeling occurs still

Summary Rate vs Rhythm

o No significant differenceo Higher hospitalization in rhythm controlo More cerebrovascular events and thrombotic events in rhythm controlo Trend toward higher mortality after two years in rhythm control

Rate control options – acuteo Diltiazem 0.25mg/kg (max 20mg) then 2.5-15mg/ho Metoprolol 2.5-5mg IV q5min to max 15mg in 15min

Rhythm control options o Amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotolol

Questions?

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