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Pharmacology for Atrial Fibrillation
Aimee Mishler, PharmD, BCPS August 26, 2015
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Overview Pathophysiology of atrial fibrillation (AF)
Review of Rate vs Rhythm Control Recommendations Review of Pharmacologic Treatment Options
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Mechanisms of AF Multifactorial – all lead to structural and electrical abnormalites Abnormalities alter tissue to promote abnormal impulse formation or propagation
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Potential Causes
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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
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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
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Level of Evidence (LOE) Definition
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
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JACC Rate Control Recommendations
Class I (LOE B) Control rate using beta blocker (BB) or non DHP calcium channel blocker (CCB) Paroxysmal, persistent or permanent Use IV BB or non DHP CCB to slow rate in acute setting For hemodynamically unstable patients, electrical cardioversion is indicated Class IIa (LOE B) Resting HR < 80 bpm is reasonable for symptomatic management Class llb (LOE B, C) Resting HR < 110 bmp is reasonable as long as patient remains asymptomatic and systolic function is preserved Amiodarone may be useful for rate control when other measures are unsuccessful Class III (LOE C, B) Non DHP CCB should not be used in patient with decompensated heart failure Digoxin, non DHP CCB, and IV amiodarone should not be used in pre-excitation AF
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Pharmacology of Rate Control - Acute
Drug 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 1min Infusion: mcg/kg/min When titrating infusion, re-bolus with 500mcg/kg every time Duration: 10-30min 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
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Pharmacology of Rate Control - Maintenance
Drug Dose Class/MOA Notes Metoprolol Tartrate: mg po BID Succinate: mg po daily B1 selective BB IV:PO = 1:5 Atenolol 25-100mg po daily Crcl 15-35: max = 50mg daily Crcl <15: max = 25mg daily Bisoprolol 2.5-10mg po daily Use caution in hepatic dysfunction Carvedilol mg po BID Non-selective BB + a-blocker Contraindicated in severe liver failure Diltiazem ER: mg po daily Non-DHP CCB IV to po: [(rate x 3) + 3] x 10 Caution: lV dysfunction Verapamil ER: mg po daily IR: mg divided q8h Caution in renal insufficiency Cirrhosis: dec. dose 50% Contraindicated with LV dysfunction Digoxin mcg 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 Digoxin – adjust to 25-75% normal dose at crcl 50 and 10-25% at crcl 10 Verap: no dose adj recommendations but case reports of ADR with renal insuff. And study show reduced renal cl of metabolite DI with verap and dig = inc. dig level
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What should we use? Things to consider Fluid bolus
What medication do they take at home Compliance of home regimen Comorbidities Avoid BB in diabetes, depression, asthma, thyroid abnormalities, pheochromocytoma Avoid CCB left ventricular dysfunction, peripheral edema What medication are you going to send them home with Up-regulation of receptors --- may just need higher dose of what they have not to change meds
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What should we use? From Tur Prospective, randomized
Patients: ≥ 120bmp + SBP ≥95mmHg Intervention: diltiazem 0.25mg/kg (max 25mg) VS metoprolol 0.15mg/kg (max 10mg) Outcome: HR ≤ 100 or ↓ rate by 20% 20 in each group
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What should we use? Retrospective cohort
Pt with underlying medical condition or those with startegies other than rate control were excluded BB= CCB= Primary outcome: hospital admission Secondary: LOS,ADE, returning within 30days, stroke in 30days
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What should we use? Results at 3.5y 70% rate control with BB
54% rate control with CCB Follow up 3.5y later Initial tx: bb = 24%, ccb =17, dig = 16%, ccb+dig 14, bb + dig 14 Both +/- Dig Overall only 58% control with first drug
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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 AF HR decreased from 139 to 100bpm 45 patients with atrial fibrillation or atrial flutter, in a randomized, parallel, open-label study. Patients with either new onset (<48 hours, n = 31) or old onset (> 48 hours, n = 14) of atrial fibrillation or flutter with rapid ventricular rate were stratified to receive esmolol (n = 21) or verapamil (n = 24). The heart rate declined with esmolol from 139 to 100 beats/min (p < 0.001)
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Can you use BB and CCB? Controversial Potential for serious ADE
Early studies in animals resulted in asystole Combination used in refractory angina Potential for serious ADE Complete heart block/asystole Additive hypotensive and bradycardic effects Potential mechanism CCB: block inward Ca flow prolonging SA and AV nodal conduction BB: decrease SA automaticity and prolong AV nodal refractory period Early studies in 1980s using animals given verap after propranolol resulted in ventricular asystole Beta-blockers bind to beta-adrenoceptors located in cardiac nodal tissue, the conducting system, and contracting myocytes. The heart has both β1 and β2 adrenoceptors, although the predominant receptor type in number and function is β1. These receptors primarily bind norepinephrine that is released from sympathetic adrenergic nerves. Additionally, they bind norepinephrine and epinephrine that circulate in the blood. Beta-blockers prevent the normal ligand (norepinephrine or epinephrine) from binding to the beta-adrenoceptor by competing for the binding site.
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Rate Control and Anticoagulation
Nonvalvular AF CHA2DS2-VASc Warfarin, dabigatran, rivaroxaban Mechanical valve warfarin CHADS VASC CHF HTN Age >75 DM Stroke/TIA Vascular dx Age 65-74 Sex F
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JACC Rhythm Control Recommendations
Class I (LOE A) Flecaindie, dofetilide, propafenone, and ibutilide are useful for pharmacologic cardioversion – provided contraindications are absent To maintain rhythm control consider: amiodarone, dronedarone, flecainide, propafenone, dofetilide or sotalol Class I (LOE C) Risks, including proarrhythmia should be considered before initiation Due to toxicities, amiodarone should be used only after considertion of risks and when other agents have failed Class IIa (LOE A) Oral amiodarone is reasonable for pharmacologic cardioversion Class III (LOE B) Dofetilide should not be initiated out of hospital Antiarrhythmics and rhythm control should not be continued when AF becomes permanent Dronedarone should not be used in patients with NYHA Class III/IV HF
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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 Flecainide Propafenone Class III Potassium channel blockers Amiodarone : also has Na, Beta, and Calcium channel blockade Sotalol: also has beta-blockade Amiodarone Dofetilide Dronedaorone Sotalol Class V Multiple mechanisms Digoxin Class II = beta blockers Class IV = ccb Class Ib = lido, phenytoin Dig: Direct suppression of the AV node conduction to increase effective refractory period and decrease conduction velocity; Inhibition of the sodium/potassium ATPase pump in myocardial cells results in a transient increase of intracellular sodium, which in turn promotes calcium influx via the sodium-calcium exchange pump leading to increased contractility
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Pharmacology of Rhythm Control - Maintenance
Drug Dose Class Notes Amiodarone (also has Class I, II, IV properites) mg po daily in divided doses x2-wks then mg 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 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 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 Dofetilide: Potassium-depleting diuretics: Risk of hypokalemia and/or hypomagnesemia may be increased by potassium-depleting diuretics, increasing the risk of malignant arrhythmias such as TdP. Dronedarone: CYP3A4 inhibitors (eg, ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir
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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: mg po q12h; inc. to 325mg po q12h IR: mg po q8h ADR: agranulocytosis, QRS/QTc prolongation Caution: HF, hepatic impairment, myasthenia gravis, renal impairment, Lupus, pulmonary disease
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Rhythm Control and Anticoagulation
≥48h or unknown: Anticoagulate x3 weeks before cardioversion and x4week after Regardless if electrical or chemical cardioversion TEE + anticoagulation before cardioversion and continue x4 weeks <48h + high risk stroke Heparin or enoxaparin ASAP before or immediately after cardioversion Follow with long term anticoagulation <48h + low thromboembolic risk No anticoagulation may be considered
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Rate vs Rhythm Study Population/Outcomes Results
Pharmacological Intervention in Atrial Fibrillation (PIAF) Lancet. 2000;356: 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: 200 pts with persistent AF Most >65yo Death, cardiopulmonary resuscitation, CVA, and systemic embolism No difference in mortality CVA more common in rhythm-control Rate vs Electrical Cardioversion for Persistent AF (RACE) N Engl J Med. 2002;347: 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 PIAF: randomized, multicenter in Germany– compared rate vs rhythm STAF: open, randomized, controlled pilot; Total mortality was not significantly different between the 2 groups, but showed a tendency toward greater mortality in the rate-control group (2.5% vs 4.9%). Cerebrovascular events were more common with rhythm-control (3.1% vs. 0.6% per year) RACE: randomized
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Rate vs Rhythm Control Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) 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 5 years: 63% of rhythm-control were in NSR vs 34.6% No clinical advantage for rhythm control over rate control Death: 356 (23.8%) in the rhythm-control group and 310 deaths (21.3%) in the rate-control Hospitalizations: rhythm-control 80.1% vs 73% in rate control (p <0.001) mean follow-up time of 3.5 years Mortality: trend toward higher in rhythm but not sig. Of note, this trend did not begin to emerge until after the second year of follow-up, suggesting that long-term use of antiarrhythmic drugs may be associated with additional, serious adverse effects. N Engl J Med. 2002;347:
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Pharmacology Rate vs Rhythm Cons
Rhythm control Difficult to achieve More costly Anti-arrhythmics have more adverse effects Rate control Not effective for highly symptomatic patients Remodeling occurs still Neither has been conclusively shown to improve survival vs the other
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Summary Rate vs Rhythm Rate control options – acute
No significant difference Higher hospitalization in rhythm control More cerebrovascular events and thrombotic events in rhythm control Trend toward higher mortality after two years in rhythm control Rate control options – acute Diltiazem 0.25mg/kg (max 20mg) then mg/h Metoprolol 2.5-5mg IV q5min to max 15mg in 15min Rhythm control options Amiodarone, dofetilide, dronedarone, flecainide, propafenone, sotolol
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Questions?
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References 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation: executive summary. J Am Col Cardiol. 2014;64(21): Demircan C, Cikriklar H, Engindeniz Z, et. Al. Comparison of the effectivness of intravenous diltiazem and metoprolol in management of rapid ventricular rate in atrial fibrillation. Emerg Med J. 2005;22: Scheuermeyer F, Grafstein E, Stenstrom R, et. Al. Safety and efficacy of calcium channel blockers versus beta-blockers for rate control in patients with atrial fibrillation and no acute underlying medical illness. Academic Emerg Med. 2013;20: Olshanskky B, Rosenfeld L, Warner A, et. al. The atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study. J Am Col Cardiol. 2004;43(7): Packer M, Meller J, Medina N, et. Al. Hemodynamic consequences of combined beta-adrenergic and slow calcium channel blockade in man. 1982;65(4): Leon M, Rosing D, Bonow R, et. Al. Combination therapy with calcium channel blockers and beta blockers for chronic stable angina pectoris. Am J Cardiol. 1985;55(3):69B-80B. Prystowsky E. The effects of slow channel blockers and beta blockers on atrioventricular nodal conduciton. J Clin Pharmacol. 1988;28(1):6-21. O’Brien K, Alesander E, and Patel L. Efficacy and safety of Pharmacological options for rate control in atrial fibrillation. ACCN Advanced Crit Care. 2012;23(2): Hohnloser S, Kuck KH, Lilienthal J. Pharmacological Intervention in Atrial Fibrillation (PIAF). Lancet. 2000;356: Van Gelder IC, Hagens VE, Bosker HA, et al. Strategies of Treatment of Atrial Fibrillation (STAF). J Am Coll Cardiol. 2003;41: Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med. 2002;347: Platia E, Michelson E, Porterfield J, et. al. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. The American Journal of Cardiology. 1989;63(13):25–929. Mooss A, Wurdeman R, Mohiuddin S, et. Al. Esmolol versus diltiazem in the treatment of postoperative atrial fibrillation/atrial flutter after open heart surgery. American Heart Journal. 2000;140(1):176–180. Hilleman D, Reyes A, Mooss A, et. Al. Esmolol versus diltiazem in atrial fibrillation following coronary artery bypass graft surgery. Curr Med Research and Opp. 2003;19:
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