Atrial Fibrillation, Causes, Treatment and What’s New

Atrial Fibrillation, Causes, Treatment and What’s New
Louann Bailey, MSN, CRNP. FAANP Northeast Ohio Cardiovascular Specialist

Objectives At the conclusion of the lectures the participant will:
Understand and apply current research and guidelines for Atrial Fibrillation management Be able to apply pharmacologic therapies to Atrial arrhythmia management and treatment Be able to verbalize non pharmacologic therapies in treatment of Atrial arrhythmia AANP 2012

Introduction Committee for documenting the evidence based medicine on Atrial Fibrillation American College of Cardiology (ACC) American Heart Association (AHA) Heart Rhythm Society (HRS) European Society Of Cardiology (ESC) European Heart Rhythm Society (EHRS) AANP 2012

Defining Atrial Fibrillation
A supraventricular Tachyarrhythmia characterized by uncoordinated atrial activation with consequent deterioration of atrial mechanical function Depends on the properties of the AV node and conducting tissues Level of vagal and sympathetic tone Presence or absence of accessory conduction pathways J AM Coll Cardiol, 2006: , ACC/AHA/ESC 2006 Guidelines for the Management of Patients with A-Fib AANP 2012

Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246
Electrocardiogram showing atrial fibrillation with a controlled rate of ventricular response Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Related Arrhythmias A flutter Atrial Tachycardia
Saw-tooth pattern of regular atrial activation called flutter Flutter waves most prominent in leads II, III, and aVF Commonly 2:1 AV block Regular or irregular May display upright P waves in II, III, aVF, but downward in V1 Heart rate is somewhere between bpm Atrial Tachycardia AANP 2012

Electrocardiogram showing typical atrial flutter with variable atrioventricular conduction Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Classification of A Fib
Lone Atrial Fibrillation There is absence of cardiac or other conditions predisposing to A Fib Acute Atrial Fibrillation AF that lasts < 48 hours in duration Paroxysmal Afib Recurrent, transient episodes, reverting to sinus rhythm, spontaneously or with treatment usually < 7 days, often < 24 hours . Persistent Afib AF that is persistent despite treatment > 7 days ” Categorize a patient by there most frequent presentation Nonvalvular Afib AF due to causes other than valvular heart disease “Hht://askdrwiki.com/meiawiki/index.php?title=Classification_of_Atrial_Fibrillation AANP 2012

Patterns of atrial fibrillation (AF)
Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Distinguishing features of Atrial arrhythmias
Atrial Tachycardia Atrial rate Atrial Tachycardia, multifocal Atrial rate > 100 Supraventricular tachycardia, paroxysmal Rate > 100, P waves not easily seen Aflutter Saw tooth pattern, flutter wave rate Atrial Fibrillation P waves absent, atrial activity totally irregular and represented by fibrillatory waves Ventricular rate The complete Guide to ECGs, 2nd ed.2002 AANP 2012

Epidemiology and Prognosis
2.2 million people in the US and 4.5 million people in Europe have Paroxysmal or persistent AF In the past 20 years, there has been a 66% increase in hospital admissions for AF Approximately 15.7 billion is spent annually in the U.S. alone AANP 2012

Prevalence AF is seen in 0.4%-1% of the general population
Increases with age Incidence is higher in men Median age is 75 years Number of men and women are about equal Approximately 60% of the patients > 75yo are women AA’s risk is about half of whites Incidence for men has doubled form the 1970’s to the 1980’s AANP 2012

Estimated age-specific prevalence of atrial fibrillation (AF) based on 4 population-based surveys Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Incidence Less then 0.1% per year for those < 40
To exceed 1.5% per year in women > 80 To exceed 2% per year in men > 80 The incidence of AF may be lower in HF patients treated with ACE I AANP 2012

Prognosis AF is associated with an increased long term risk of stroke
AF is associated with an increased risk for developing HF AF is associated with all cause mortality, especially in women AF patients have double the mortality rate as compared with those in sinus rhythm AANP 2012

Relative risk of stroke and mortality in patients with atrial fibrillation (AF) compared with patients without AF Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Prognosis The rate of ischemic stroke among patients with nonvalvular AF avg 5% per year AF is a strong independent risk factor for mortality One in six strokes occurs in patients with AF In HF studies, the annual risk due to AF was 1.5% in persons and 23.5% in ages 80-89 Avg rate of ischemic stroke is 2-7 times that of persons in sinus rhythm AANP 2012

Pathophysiological Mechanisms
Atrial Pathology Anatomical substrate Electrical Remodeling Counteracting Atrial Remodeling Other factors Inflammation Autonomic nervous system Changes associated with aging Most frequent path anatomic changes in AF are atrial fibrosis and loss of atrial muscle Histologic samples of AF have shown patchy fibrosis Apoptosis replacing atrial myocytes by interstitial fibrosis increases the potential for increased AF incidents. Atrial Fibrosis maybe caused by genetic defects Other causes maybe duet to inflammation i.e. Sarcoidosis and autoimmune disorders Atrial pathological findings may include, amyloidosis, hemochromatosis, endomyocardial fibrosis Dilatation of any type AANP 2012

Anatomical and Electrophysiological substrates
Diseases Anatomical Cellular Electrophysiological HTN A substrate Atrial Dilatation Myolysis Conduction abnormalities HF PV dilatation Apoptosis, necrosis ERP dispersion CAD Fibrosis Channel Expression Change Ectopic activity Valvular disease Focal AF B substrate Only with prolonged High rates A Flutter Atrial dilatation Ca++ channel down regulation Short ERP A substrate develops during SR, remodeling related to stretch and dilatation, Main pathway is RAAS, TGF (Transforming growth factor-beta and CTGF connective tissue growth factor B substrate due to tachycardia related remodeling and down regulation of calcium channels Aflutter also has other anatomical changes such as PV dilatation, Ag PV sleeves, Reduced contractility, fibrosis Cellular changes myolysis, connexin down regulation, adrenergic supersensitive, changed sympathetic innervations Electrophysiological changes, micro reentry, Short ERP, Slowed conduction ERP Effective refractory period PV pulmonary vein Part A substrate develops during sinus rhythm (remodeling related to stretch and dilatation, the main pathways involve the RAAS, TGF beta, and CTGF AANP 2012

Mechanisms of Atrial Fibrillation
Automatic Focus theory May be automatic focus or micro entrant circuit, rapid local activation in the LA cannot extend into the RA in an organized way Multiple Wavelet Hypothesis A large atrial mass with short refractory time and delayed conduction increases the number of wavelets, favoring sustained AF AANP 2012

Posterior view of principal electrophysiological mechanisms of atrial fibrillation Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

What Structural Changes Influences Atrial Fibrillation
Atrial size Left Ventricular size Structural changes to the Pulmonary Veins Pre-disposition of pre-excitation syndrome Loss of synchronous atrial mechanical activity AANP 2012

Etiologies and Factors Predisposing to A Fib
Electrophysiological abnormalities Enhanced automaticity (focal AF) Conduction abnormality (re-entry) Atrial pressure elevation Mitral or tricuspid valve disease Myocardial disease (systolic or diastolic disease) Semi lunar Valvular abnormalities (causing ventricular hypertrophy Systemic or pulmonary HTN (pulmonary Hypertrophy Intracardiac tumors or thrombi AANP 2012

Atrial Ischemia CAD Drugs Alcohol Caffeine Endocrine Hyperthyroidism Pheochromocytoma Inflammatory or infiltrative disease Pericarditis Amyloidosis Myocarditis Age-induced atrial fibrotic changes AANP 2012

Changes in autonomic tone  parasympathetic activity  sympathetic activity Primary or metastatic diseases in or adjacent to the atrial wall Congenital heart disease Postoperative Cardiac, pulmonary, esophageal Neurogenic SAH Nonhemorrhagic, major stroke Idiopathic (lone AF) Familial AF AANP 2012

Why is it a concern? There are myocardial and hemodynamic consequences of Atrial Fib The risk of Thromboembolism is very real The risk of Stroke is very real The risk of catastrophic debilitation is very real The risk of increased morbidity and mortality is very real AANP 2012

Pathology of Thrombus Formation
Thrombotic material associated with AF most frequently is due turbulent flow in LAA This is not seen using transthoracic echo For AF that is > 48 hours long, risk increases Virchow's triad of stasis applies Venous stasis Endothelial dysfunction Hypercoagulable state AANP 2012

Other Interesting Facts
During conversion of AF to SR, decreased velocities of flow are noted in LAA This increases risk for thromboembolic events due to stunning of the Atria Atrial stunning occurs immediately after Cardioversion and may last up till 3-4 days post Cardioversion 80% of thromboembolic strokes occur 3-10 days after Cardioversion Cardioversion can take place via DCC, Pharmacological, and spontaneously AANP 2012

Other Interesting Facts
HF, either diastolic or systolic, increases risk for stroke Strong association of stroke with AF and HTN Often see elevated C-reactive protein (CRP) in these patients with increased risk for stroke Pathophysiology of thromboembolism in patients with AF is uncertain and poorly defined AANP 2012

Other Associated Causes and Conditions that Influence AF
Catecholamine surges AF without associated HD 20-25% of AF in young adults who present Medical conditions associated with AF Obesity and and LA dilatation AF with associated HD Valvular (Mitral), HF, CAD, HTN, LVH Familial (Genetic) AF Poorly understood, ongoing research 17% increase of M&M with pts who have AF and MS AANP 2012

Impact on Quality of Life
Can be very life limiting Worry when it will reoccur Lifelong toxic meds Bad consequences for non compliance Potential bad consequences for compliance No good substitutes for treatment Best to prevent and treat underlying cause AANP 2012

Clinical Evaluation Diagnosis is based on History and clinical examination and confirmed ECG Determine cause Defining associated cardiac and extracardiac factors pertinent to the etiology, tolerability and history of prior management WU and therapy initiation can usually be done in one outpatient encounter AANP 2012

Clinical Evaluation History and physical Exam
Presence and nature of symptoms associated with AF Clinical type of AF Onset of the first symptomatic attack or date of discovery Frequency, duration, precipitating factors, modes to terminate Response to any pharmacological agents that have been tried Presence of any underlying heart disease or other reversible conditions AANP 2012

Clinical Evaluation Electrocardiogram, to identify Rhythm
LV hypertrophy P-wave duration and morphology or fibrilliatory waves Pre-excitation BBB Prior MI Other atrial arrhythmias Measure R-R, QRS, QT intervals AANP 2012

Clinical evaluation Transthoracic echocardiogram LA and RA size
LV size and function Peak RV pressure (pulmonary HTN) LV hypertrophy LA thrombus (low sensitivity) Pericardial disease AANP 2012

Clinical Evaluation Blood tests Thyroid Renal Hepatic function CBC
BNP if appropriate CRP AANP 2012

Clinical Evaluation Six minute walk test Exercise Testing
Assess for rate response Exercise Testing To reproduce exercise induced AF Evaluate for ischemia Holter monitoring or event recording If type of arrhythmia is in question Transesophageal echocardiography To ID LA thrombosis, guide DCC AANP 2012

Clinical Evaluation Electrophysiological study CXR
To clarify the mechanism of wide QRS complex tachycardia To identify a predisposing arrhythmia such as atrial flutter or paroxysmal supraventricular tachycardia CXR Lung parenchyma, Pulmonary vasculature, cardiac size AANP 2012

Management Primary goals are to meet 3 objectives Rate control
Prevention of thromboembolism Correction of the rhythm disturbance AANP 2012

Management Considerations
Type and duration of AF Severity an type of symptoms Associated CV disease Patient age Associated medical conditions Short-term and long-term treatment goals Pharmacological and nonpharmacological therapeutic options AANP 2012

Pharmacological and Nonpharmacological Therapeutic Options
Drugs and ablation are effective for both rate control and rhythm control Surgery, Maze Procedure may also be an option “ablate and pace” strategy may be an option AANP 2012

Studies and Trials that support therapy
Affirm Trial Atrial Fibrillation Follow-Up Investigation of Rhythm Management RACE Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation STAF Strategies of Treatment of Atrial Fibrillation AANP 2012

Studies that support therapy
HOT CAFE’ How to Treat Chronic Atrial Fibrillation PIAF Pharmacological Intervention I Atrial Fibrillation These studies looked at Rate control or rhythm control and found not convincing evidence that rhythm control was better than rate control regarding quality of life AANP 2012

Affirm Trial (2002) Over 4000 patients Mean age 69.7 yrs of age
F/U: 3.5 yrs Inclusion criteria: PAF, Persistent AF, 65 yrs or older, or risk of stroke or death Primary endpoint: All- cause mortality % Rate control: 25.9% % Rhythm control 26.7% P value: 0.8 Largest trial looking at rate vs. rhythm. Increase overall mortality was observed in patients treated for rhythm control compared with rate control after and average of 3.5 y Lower mortality rates with rate control arm vs. rhythm control arm AANP 2012

IV and PO Pharmacological Agents for Rate control
Acute Setting Beta blockers Esmolol, Metoprolol, Propanolol Nondihydropyridine Calcium channel blockers Diltiazem, Verapamil Amiodarone (heart rate control with accessory pathway) Digoxin (heart rate control in pts with HF without accessory pathways) AANP 2012

Non – Acute and Chronic Maintenance
Drug Class/LOE Loading Dose Onset Maintenance Dose Major SE Metoprolol I/C Main Dose 4-6 hrs 25-100mg BID  BP, HB, HR, asthma, HF Propanolol 60-90 min 80-240mg divided Diltiazem 2-4 hrs mg divided  BP, HB, HF Verapamil 1-2 hrs  BP, HB, HF, digoxin interaction Digoxin 0.5mg 2 days mg daily Digitalis toxicity, HB, HR Amiodarone IIb/C 800mg daily for 1 wk then 600mg daily for 1 wk 400mg daily for 4-6 wks 1-3 wks 200mg daily  BP, HB, pulm, thyroid, lung toxicity, Corneal deposits, optic neuropathy, warfarin interaction, SB AANP 2012

Preventing Thromboembolism Who is at Risk?
Risk Factors Relative Risk Previous Stroke or TIA 2.5 DM 1.7 H/O HTN 1.6 HF 1.4 Advanced Age AANP 2012

Stroke rates in relation to age among patients in untreated control groups of randomized trials of antithrombotic therapy Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Using the CHADS 2 Index CHADS2 Risk Criteria Score Prior Stroke or TIA
Age > 75y 1 HTN DM all types HF AANP 2012

Tools Available for Predicting Bleeding Risks
Two tools available for predicting bleeding risk HEMORR2HAGES HAS-BLED Pros/Cons Factors identified from registries or research data Yet based on warfarin only Recommendations Use info to identify those at high risk w/warfarin Stay tuned for newer predictive tools References for tools (and info/quotes on the next slide): Gage BF, Yan Y, Milligan PE, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151(3): Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in atrial fibrillation patients: the Euro Heart Survey. Chest. 2010;138: AANP 2012

Factors Associated w/Bleeding Risks
HEMORR2HAGES HAS-BLED score Prior bleed (greatest risk) Liver or kidney disease Stroke Older age (> 75 years) Uncontrolled HTN Ethanol abuse Malignancy Reduced plt count/function Anemia Genetic factors Excessive fall risk Bleeding hx or predisposition Abnormal kidney/liver function Stroke Elderly (> 65 yrs) Hypertension Drugs/alcohol concomitantly Labile INR Note to design folks (and Lou): Click on mouse and have the following become bold/new color (those that appear in both columns= the first 6 in both columns) Click a second time and have the following become bold/additional color (those that are also high risk factors for thromboembolic events – we can help identify which ones based on slide 12; this makes the point that although certain things make the pt at higher risk for bleeding; those are the very pts who are at highest risk for stroke; stroke prevention trumps bleeding risk! Talking points: Two scales have been developed to predict the risk of bleeding complications with warfarin anticoagulant therapy. The National Registry of Atrial Fibrillation (NRAF)(Gage 2006) was used to establish the HEMORR2HAGES scheme, in which 2 points are added for a prior bleed and 1 point each for the following risk factors: Hepatic or renal disease, Ethanol abuse, Malignancy, Older (age >75 years), Reduced platelet count or function, Hypertension (uncontrolled ), Anemia, Genetic factors, Excessive fall risk, and Stroke . The HAS-BLED score(Pisters 2010) is based on the Euro Heart Survey on AF and offers 1 point for the following risk factors: Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), and Drugs/alcohol concomitantly. The predictive value of either bleeding prediction score has not been validated and may not be applicable to non-warfarin oral anticoagulants. *Identified from registries/surveys using warfarin. AANP 2012

Antithrombotic Therapy for Patients with AF
Risk Category Recommended Therapy No Risk factors Aspirin 81 mg to 325 mg daily One moderate risk factor ASA 81 mg to 325 mg or warfarin (INR ) Any High Risk or more than 1 moderate-risk factor Warfarin (INR ) Mechanical valve, target INR AANP 2012

The CHADS2 Score: Stroke Risk In Atrial Fibrillation
Condition Points C Congestive heart failure 1 H Hypertension (or treated HTN) A Age > 75 years D Diabetes S Prior Stroke or TIA 2 Score Stroke Risk Therapy 0-1 Low (< 3 %/ year) ASA 1-2 Moderate (≈ 3-4%/yr) VKA or alternatives 3-5 High (≈ 6-12%/yr) 6 Very High (≈ 18%/yr) See slide 60 for alternatives to VKA AANP 2012

Antithrombotic Therapy for Patients with AF
Less validated or weaker Risk Factors Moderate Risk Factors High Risk Factors Female gender Age > to 75 Previous stroke, TIA, or embolism Age HTN Mitral Stenosis CAD HF Prosthetic Heart Valve Thyrotoxicosis LV EF 35% or less DM AANP 2012

Risk Based Approach to Antithrombotic Therapy
Patient Features Antithrombotic Therapy Class of Recommendation Age < 60 , no HD (lone AF) ASA mg or no therapy I Age < 60 , HD but no risk factors ASA mg Age 60-74, no risk factors ASA mg Age 65-74, with DM or CAD OAC INR 2-3 Age 75 or >, Women Age 75 or > Men, no risk factors OAC INR 2-3 or ASA mg Age 65 or > with HF LV EF < 35% + HTN RHD (MS) Prior Thromboembolism OAC INR 2-3 or higher Prosthetic Heart Valve Persistent Atrial Thrombus on TEE OAC INR 2-3 of higher IIa AANP 2012

Adjusted odds ratios for ischemic stroke and intracranial bleeding in relation to intensity of anticoagulation Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Effects on all stroke (ischemic and hemorrhagic) of therapies for patients with atrial fibrillation: warfarin compared with aspirin and aspirin compared with placebo Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

ACTIVE A ASA +/- Clopidogrel + vs. in Atrial Fibrillation (AF)
AF Patient Description Treatment Options Moderate high risk for stroke + No contraindication to VKA VKA e.g. warfarin (target INR 2-3) unless contraindicated* (demonstrates max stroke prevention with an acceptable major bleed risk: esp. if CHADS2 > 2, > 85 yr of age no bleed hx, or an ischemic stroke hx1) Moderate high risk for stroke cannot/will not tolerate VKA OR high-quality anticoag not achieved with VKA low risk for stroke ASA monotherapy 75mg daily + ASA mg daily Or Clopidogrel 75mg daily + ASA mg daily Choice depends on overall bleed risk & cost considerations: ASA + clopidogrel is similar to that with warfarin; therefore those who are not suitable for warfarin due to bleed risk, may also not be suitable for ASA + clopidogrel. Thus ASA + clopidogrel option really only suitable for patients who are not candidates for warfarin due to factors other than high risk of bleeding e.g. purple toe syndrome, lack of access to lab for required INR tests, likely not to be adherent to therapy/INR testing requirements, etc. High risk of bleed &low moderate stroke risk ASA (75-100mg daily) *VKA contraindications (e.g., history of falls, especially frequent, clinically significant GI bleeding, inability to obtain regular INR testing) (VKA), Vitamin K antagonist AANP 2012 1 singer De Chang Y, Fang MC, et al. The net clinical benefit of warfarin anticoagulation in atrial fibrillation . Ann Intern Med 2009: 151:

Research Trials Active A Active W
In patients with atrial fibrillation at low-moderate risk for stroke who are not suitable for warfarin therapy, the combination of ASA+ clopidogrel is associated with a decrease in vascular event risk that is equal to the increase in risk of major bleeding Drug cost per patient per year: ASA + clopidogrel = $1,260; ASA = $95 Assess risk of bleed vs. any potential benefit for individual patient If patient is on clopidogrel + a PPI, reassess need for clopidogrel &/or need for a PPI Active W Warfarin is superior to clopidogrel + ASA for prevention of vascular events in patient with AF and at least 1 stroke risk factors especially in those already taking VKA therapy Switch to H2 or misoprostol; if PPI needed, consider one with less potential for a drug interaction (pantoprazole or raberprazole. Or consider ASA monotherapy AANP 2012

Research Trials Treatment Non-Valvular Afib
RE-LY Dabigatran mg cap bid an alternative to warfarin. At the lower dose, is was as effective as warfarin with less bleeding; at the higher dose it was more effective than warfarin but with similar bleeding rates. Alter dose for GFR ROCKET AF Rivaroxaban mg daily, Direct Factor Xa inhibitor: evaluated and approved once a day dosing Down side of these meds: no reversal agent Hepatic Non-valvular Afib: Absence of rheumatic mitral valve disease or a prosthetic heart valve in any position or mitral valve repair AANP 2012 A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org

AVERROES ARISTOTLE Apixaban 5 mg twice daily or 2.5 mg twice daily (age > 80, wt < 60kg, Cr >1.5 mg/dl) Primary outcome: Stroke or systemic embolism Stopped early After one year Apixaban reduced stroke by half as compared to ASA Decrease in ischemic and hemorrhagic stroke Reduction in myocardial infarction and hospitalization Reduction in death Was an increase bleeding but not significant May be used if intolerant to VKA AANP 2012 A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org

Engage AF-TIMI 48 Looking at using Edoxaban Twice a day dosing was associated with increase in bleeding vs. Warfarin Once daily dosing was associated with similar or lower rates of bleeding of warfarin A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org AANP 2012

New Anticoagulants Direct Thrombin Inhibitors Factor Xa Inhibitors
Dabigatran Factor Xa Inhibitors Rivaroxaban Apixaban Edoxaban A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org AANP 2012

Comparison of features of New Anticoagulants with those of Warfarin
New Agents Onset Slow Rapid Dosing Variable Fixed Food Effect Yes No Monitoring Half-life Long Short Antidote A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org AANP 2012

New Oral Anticoagulants
Advantage Clinical Implications Rapid Onset No need for bridging Predictable No need for routine monitoring Specific Coagulation enzyme target Low risk for off target adverse effects Low Potential for food interaction No dietary precautions Low potential for drug interactions Few drug interactions A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org AANP 2012

Disadvantages vs. Warfarin
Features Warfarin New Agents Frequency Once Daily Twice daily Monitoring INR Uncertain Clearance Non-renal Renal 25%-80% Antidote Vitamin K, FFP, PCC Nil Familiarity Extensive Minimal Almost 60-70,000 people in these studies showing hope Showing supeiority A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org AANP 2012

Indirect Comparisons vs Warfarin
Feature Dabigatran (110 mg) (150 mg) Rivaroxaban Efficacy Non-inferior Superior Ischemic Stroke Similar Reduced Intracranial hemorrhage Reduces Major bleeding MI Increased Dyspepsia Yes No Dosing Twice Daily Once daily Time in therapeutic range 67% (median) 58%(Median) A new Era in the management of Atrial Fibrillation: An update on OAC, 2011, Heart.Org AANP 2012

Interrupting Therapies
For Surgical or diagnostic procedures Elective, off therapy for 5-7 days For Prosthetic valves, bridge with LMWH or unfractionated heparin Dental extractions May not have to stop GI bleeds Till cleared by GI, look at alternative Intra cranial bleeds Stop indefinitely AANP 2012

Non Pharmacological Approaches to Prevention of Thromboembolism
Obliteration of the LAA Surgical removal Intravascular catheters Transpericaridal approaches AANP 2012

PROTECT AF Clinical Trial Design
Prospective, randomized study of WATCHMAN LAA Device vs. Long-term Warfarin Therapy 2:1 allocation ratio device to control 800 Patients enrolled from Feb 2005 to Jun 2008 Device Group (463) Control Group (244) Roll-in Group (93) 59 Enrolling Centers (U.S. & Europe) Follow-up Requirements TEE follow-up at 45 days, 6 months and 1 year Clinical follow-up biannually up to 5 years Regular INR monitoring while taking warfarin Enrollment continues in Continued Access Registry AANP 2012

Watchman LAA Closure Technology
The WATCHMAN LAA Closure Technology is designed to prevent embolization of thrombi that may form in the LAA. The WATCHMAN® Left Atrial Appendage Closure Technology is intended as an alternative to warfarin therapy for patients with non-valvular atrial fibrillation. AANP 2012

Left Atrial Appendage Device
Watchman Device Placed in LAA AANP 2012

WATCHMAN LAA Closure Device in situ
AANP 2012

PROTEC AF Conclusion The WATCHMAN LAA Technology offers a safe and effective alternative to warfarin in patients with non-valvular atrial fibrillation at risk for stroke and who are eligible for warfarin therapy AANP 2012

Cardioversion of AF Performed electively or urgently
By means of drug or electrical shock Pharmacological Cardioversion Most effective if AF has been less than 7 days First time documented Often will spontaneously convert within hrs AANP 2012

Drugs used for DCC within 7 days of discovery
Agents with proven Efficacy Agents Less Effective/Less studied Drug Route Class LOE Dofetilide oral I A Flecainide oral/IV Ibutilide IV Propafenone Oral/IV Amiodarone IIa Drug Route Class LOE Disopyramide IV IIb B Procainamide Quinidine oral Digoxin and Sotalol should not be used at all AANP 2012

Drugs used > 7 days Agents with proven efficacy
Agents less effective/less studied Drug Route Class LOE Dofetilide oral I A Amiodarone Oral/IV IIa Ibutilide IV Drug Route Class LOE Diopyramide IV IIb B Flecanide oral Procainamide Oral/IV C Propafenone Quinidine Digoxin and Sotalol should not be used AANP 2012

Proven Drugs for Pharmacological Cardioversion
Route Dosage Potential adverse effects Amiodarone Oral IV/oral Inpatient: 1.2 to 1.8 g per day in divided doses until 10 g, then mg per day or 30mg/kg as single dose 5-7 mg/kg over min then g per day continuous IV or in divided doses until 10 g, then mg daily Hypotension Bradycardia QT prolongation Torsades GI upset Constipation Dofetlide oral Creat Clear > 60ml/min 500mcq bid 40-60ml/min mcq bid 20-40ml/min mcq bid < 20ml/min contraindicated Adjust dose for RF, body size and age Flecainide IV mg 1.5 to 3.0 mg/kg over min A flutter w RVR Ibutilide 1mg over 10 min may repeat Propafenone 600mg A flutter AANP 2012

Pharmacological management of patients with newly discovered atrial fibrillation (AF Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Pharmacological management of patients with recurrent paroxysmal atrial fibrillation (AF) Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Pharmacological management of patients with recurrent persistent or permanent atrial fibrillation (AF) Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012 Copyright ©2006 American College of Cardiology Foundation. Restrictions may apply.

Vaughan Williams Classification of Antiarrhythmic Drugs
Type IA Dispyramide Procainamide Quinidine Type IB Lidocaine Mexiletine Type IC Flecainide Propanfenone Type II Beta blockers Type III Amiodarone Bretylium Dofetilide Ibutilide Sotalol Type IV Nondihydropyridine calcium antagonists New drug dronedarone/Multag Indicated as an antiarrhythmic drug indicated to reduce the risk of CV hospitalization in patients with paroxysmal or persistent AF or Aflutter or with a recent episode of AF/AFL and assoicated CV risk factors age> 70, HTN, DM, prior CVA, LA diameter >/= 50mm or LV EF < 40% who are in sinus rhythm or will be cardioverted. Contraindicated in NYHC IV, recent decompensate (2 fold increase of mortality) 2 or 3 degree AV blk SSS except if used with PPM Otc > 500 msec or PR > 280 msec Severe Hepatic impairment Contraindicated in pregnancy Not given with ketaconazole, itaconazole or other drugs that are CYP 3A, Clarithromycin, nefazodone ritonavir or certain herbal supplements that may prolong QT May increase the risk of Torsdes if given with phenothiaine antipsycotices, tricylclic antidepressants, certain macrolide antibiotics and Class I, III Antiarrythmic AANP 2012

Other Antiarrhythmic without Iodine SE
Dronedarone Dose 400 mg twice daily, PO Cost $9.00/day, $4.50/pill Achieve steady state in 4-8 days Elimination ½ life is hours Metabolized via CYP 3A Several studies looking at reduced M&M ATHENA, EUROIDIS/ADONIS, ANDROMEDA All studies proved reduction in all cause mortality by 24% All reduced Hospitalization with Afib Non iodine drug Class III similar to Amiodarone without the same SE Contraindications in patients with NYHA Class IV HF, Class II-III HF with recent decompensated 2 and 3 degree HB SSS without PPM Bradycardia with HR <30 QTc >/= 500 msec Severe Hepatic impairment Do not give to pregnant women If given with other meds such as ketoconazole, itaconazole, voriconazole, cyclosporine, clarithromycin may increase risk of Toresades de Pointes Caution in new or worsening HF Hypokalemia, Hypomagnesemia, or with potassium depleting diuretic QT prolongation Increased Creatine Drug-Drug interactions: Class I or III Antiarrhythmic Avoid Grapefruit juice May increase Digoxin Levels GI distress AANP 2012

Dronedarone Indications for use
Antiarrhythmic drug indicated to reduce the risk of CV hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated CV risk factors (i.e., age > 70, HTN, DM, prior CVA, LAA diameter > 50mm or LVEF < 40%, who are in sinus rhythm or will be cardioverted) Go to AANP 2012

Dronedarone Contraindications In patients with NYHA Class IV failure
In patients with recent decompensated NYHA Class II-III HF, requiring hospitalization or referral to a specialist for HF or HF clinic Second and third degree heart block or SSS (exception is if they have PPM) Concomitant use of Strong CYP3A inhibitor AANP 2012

Dronedarone Contraindications continued
Concomitant use of drugs or herbals that may prolong QT interval QTc Bazett interval > 500 ms Severe hepatic impairment Pregnancy Nursing mothers AANP 2012

Dronedarone Warnings and Precautions
If HF develops or worsens, drug should be suspended Maintain normal range levels of potassium and magnesium Stop drug if QTc is > 500 ms Check renal function within 1 week of starting Teratogen: advise women of childbearing age to use contraception while on drug AANP 2012

Dronedarone in Permanent Afib
Recent findings found to affect Hepatic function Increased risk of first Coprimary outcomes (stroke, MI, Systemic Embolism, or death from CV Causes) Increased risk of second Coprimary Outcomes (Unplanned Hospitalizations for CV causes or Death) NEJM Nov 14, 2011 AANP 2012

Risk of First Copriamry Outcome
NEJM Nov 14, 2011 NEJM Nov 14, 2011 AANP 2012

Risk of Second Coprimary Outcome
NEJM Nov 14, 2011 AANP 2012

Typical Doses of Drugs used to Maintain Sinus Rhythm
Daily dosage Potential Adverse Effects Amiodarone 100 – 400 mg Photosensitivity, Pulm Toxicity, polyneuropathy, GI upset, bradycardia, Torsades de pointes (rare), Hepatic toxicity, thyroid dysfunction, eye complications Disopyramide 400 – 750 mg Torsades de pointes, HF, glaucoma, urinary retention, dry mouth Dofetilide 500 – 1000 mcq Torsades de pointes Flecainide 200 – 300 mg VT, HF conversion to AFL with RVR Profafenone 450 – 900 mg Sotalol 160 – 320 mg Torsades de pointes, HF, bradycardia, exacerbation of COPD or bronchospastic lung disease AANP 2012

Types of Proarrhythmia During Treatment
Ventricular proarrhythmia Torsades de pointes (VW IA and III drugs) Sustained monomorphic VT (VW type IC) Sustained polymorphic VT/VF without long QT (VW types IA, IC) Atrial proarrhythmia Provocation of Recurrence (Type IA, IC, and III) Conversion of AF to flutter (Type IC) Increase of defibrillation threshold (Type IC) AANP 2012

Types of Proarrhythmia During Treatment
Abnormalities of conduction or impulse formation Acceleration of ventricular rate during AF (Type IA and IC) Accelerated conduction over accessory pathway (digoxin, IV Verapamil, or Diltiazem) Sinus node Dysfunction, AV blk (almost all drugs) AANP 2012

Factors predisposing to Drug Induced Ventricular Proarrhythmia
VW types IA and III agents Long QT interval (QTc > than or = to 460ms Long QT interval syndrome Structural HD, substantial LVH Hypokalemia/Hypomagnesemia Female gender Bradycardia Maybe drug induced, sinus node disease, etc Go AANP 2012

Factors predisposing to Drug Induced Ventricular Proarrhythmia
VW type IC agents Wide QRS duration > 120 ms Concomitant VT Structural HD Depressed LV function RVR During exercise During rapid AV conduction Rapid dose increase High dose accumulation Adding Negative Inotropic drugs Excessive QRS widening (more than 150%) AANP 2012

Drugs that help with DCC
Efficacy Enhance DCC and Prevent IRAF Class LOE Suppress SRAF Known Amiodarone IIA B All drugs in Class I except ibutilide plus Beta blockers Flecanide Ibutilide Propafenone Quinidine Sotalol IRAF immediate recurrence of atrial fibrillation SRAF sub acute recurrence of atrial fibrillation AANP 2012

Drugs uncertain if help with Cardioversion
Efficacy Enhance Conversion by DCC and prevent IRAF Class LOE Suppress SRAF and Maintenance therapy Uncertain/unknown Beta blockers IIb C Diltiazem Dofetilide Disopyramide Verapamil Procainamide AANP 2012

Recommendations for Thromboembolism Prevention
AF less then 48 hrs not needed, assess risk, underlying cause AF 48 hrs or longer, non emergent, OAC with INR 2-3 for at least 3 wks or alternate OAC AF 48 hrs or longer, urgent/emergent, heparin should be given unless contraindicated, PTT should be times normal AF less than 48 hrs associated with hemodynamic instability; DCC immediately AANP 2012

Recommendations for Thromboembolism Prevention
Alternative to anticoagulation prior to DCC, perform TEE to evaluate for LAA thrombus, then give unfractionated heparin For those with positive TEE for LAA thrombus, OAC with therapeutic INR for 3-4 wks prior to DCC and 3-4 wks after AANP 2012

Maintenance of Sinus Rhythm
Look for underlying cause Pharmacological therapy can be useful to maintain SR and prevent Tachycardia induced CM Infrequent, well tolerated recurrence of AF is reasonable as a successful outcome of drug therapy Patients without structural HD can have meds started as an outpatient AANP 2012

Maintenance of Sinus Rhythm
Catheter ablation may be an alternative for patients with little or no LAE This is a procedure that requires a skilled electrophysiologist and staff Currently this is done via, percutaneously and/or also using Robotics AANP 2012

Robotic Ablation with Niobe Stereo taxis
AANP 2012

ICE: LA Appendage IAS LA LAA AANP 2012

LA LSPV LIPV AANP 2012

Transseptal TSP Needle RA LA
Importance of perfoprming the TS puncture in the plane of the LPV’s. AANP 2012

Transseptal: Needle advancement
AANP 2012

PV Angio: Identification of ostium
AANP 2012

ICE Imaging of the Esophagus
AANP 2012

“Char” formation

Pericardial Effusion Cardiac Tamponade AANP 2012

PV Antrum Isolation: Catheter Ablation ICE+Circular Mapping Catheter
AANP 2012

Treatment Algorithms for AF
RECURRENT PAROXYSMAL AF Minimal or no symptoms Disabling symptoms in AF Anticoagulation and rate control as needed Anticoagulation and rate control as needed No drug for prevention of AF Antiarrhythmic drug therapy AF ablation if Antiarrythmic drug treatment fails Fuster Vet et al. JACC. 2006, 48:e AANP 2012

Treatment Algorithms for AF (cont)
RECURRENT PERSISTENT AF Minimal or no symptoms Disabling symptoms in AF Anticoagulation and rate control as needed Anticoagulation and rate control Antiarrhythmic drug therapy Electrical cardioversion as needed Continue anticoagulation as needed and therapy to maintain sinus rhythm Consider ablation for severely symptomatic recurrent AF after failure of greater than or equal to 1 antiarrhythmic drug plus rate control Fuster Vet et al. JACC. 2006, 48:e AANP 2012

Treatment Algorithms for AF (cont)
PERMANENT AF Anticoagulation and rate control as needed Fuster Vet et al. JACC. 2006, 48:e AANP 2012

Antiarrhythmic drug therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation MAINTENANCE OF SINUS RHYTHM No (or minimal) heart disease Hypertension Coronary artery disease Heart failure Flecainide Propafenone Sotalol Substantial LVH Dofetilide Sotalol Amiodarone Dofetilide No Yes Amiodarone Dofetilide Catheter ablation Flecainide Propafenone Sotalol Amiodarone Amiodarone Catheter ablation Catheter ablation Amiodarone Dofetilide Catheter ablation Catheter ablation Fuster, V. et al. J Am Coll Cardiol 2006;48:e149-e246 AANP 2012

Atrial Fibrillation, Causes, Treatment and What’s New

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Atrial Fibrillation, Causes, Treatment and What’s New

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