DRO-062811000 Approved: 6-30-11 Atrial Fibrillation Guideline Update Focus on Pharmacotherapy and New Paradigms of Therapy Dennis J. Jacobsen, Ph.D. FAHA, FACSM Medical Affairs, sanofi
Background/Disclosures • UNK (Chemistry/Biology) • University of MN (MS, Physiology) • Texas A&M (Ph.D., Physiology) • Faculty/Research • UNK • KU • Medical Affairs – sanofi
DRO-062811000 Atrial Fibrillation Disease State Awareness Objectives • Describe prevalence and epidemiology • Define clinical presentation and evaluate the risk factors for developing AF • Discuss the mechanisms and pathophysiology of AF • Atrial remodeling • Classification of AF • Review ACC/AHA/ESC 2011 Guidelines for the Management of Patients With AF • Stroke prevention • Update on rate control • Rhythm management • Review new consideration in AF management
DRO-062811000 Epidemiology of Atrial Fibrillation in the US: Rising Prevalence of the Disease • As of 2010, 2.66 million Americans are estimated to have AF1 • Lifetime risk for developing AF is high2 • 1 in 4 for men and women aged 40 years • Prevalence increases rapidly with age3 • 3.8% for persons aged 60 years • 9% for persons aged 80 years AF affects 1 in 25 adults aged >60 years and 1 in 10 adults >80 years3 1. Lloyd-Jones D et al. Circulation. 2010;121:e46-e215. 2. Lloyd-Jones DM et al. Circulation. 2004;110:1042-1046. 3. Go AS et al. JAMA. 2001;285:2370-2375.
16 14 12 10 8 6 4 2 0 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 DRO-062811000 Projected Prevalence of AF Through 2050 15.9 15.2 14.3 13.1 11.7 10.2 12.1 11.7 8.9 11.1 7.7 10.3 Projected Number of Persons With AF (millions) 9.4 6.7 8.4 5.9 7.5 5.1 6.8 6.1 5.6 Current age-adjusted AF incidence 5.1 Increased age-adjusted AF incidence Year Miyasaka Y et al. Circulation. 2006;114:119-125.
AF Disease Progression Can Lead to Cardiac Remodeling DRO-052611000 Electrical1 • Shortening of atrial refractory periods2 • Loss of normal adaptation of atrial refractoriness to heart rate3 Contractile1 Structural1 • Histologic changes4 • Left atrium and LA appendage enlargement5 • Decrease in cardiac output6 • Reduced atrial contractility4 1. Allessie M, et al. Cardiovasc Res. 2002;54:230-246; 2. Prystowsky EN, et al. Circulation. 1996;93:1262-1277; 3. Hobbs WJC, et al. Circulation. 2000;101:1145-1151; 4. Thijssen VLJL, et al. Cardiovasc Pathol. 2000;9:17-28; 5. Sanfilippo AJ, et al. Circulation. 1990;82:792-797; 6. Fuster V, et al. Circulation. 2006;114:e257-e354.
DRO-062811000 The Chronic Progressive Nature of Untreated AF May Explain the Need for Early Intervention The AF Continuum of Disease Diagnosis AF episode Sinus rhythm (SR) Kirchhof P et al. Europace. 2007;9:1006-1023.
AF induces electrophysiologic changes that promote further AF and both cause and are a consequence of electrical, contractile, and structural atrial remodeling DRO-062811000 Atrial Remodeling and Persistent Atrial Fibrillation Wijffels MC et al. Circulation. 1995;92:1954-1968.
Patients Converted to SR Within 3 Months of AF Onset are More Likely to Remain in SR DRO-062811000 P<0.02 82% 36% Dittrich HC et al. Am J Cardiol. 1989;63:193-197.
DRO-062811000 Goals of Therapy
DRO-062811000 Classification and Patterns of Atrial FibrillationACC/AHA/ESC Guidelines First detected* >7 d 7 d May be recurrent† Paroxysmal (self-terminating) Persistent (not self-terminating) Permanent Cardioversion failed or not attempted Cardioversion failed or not attempted *Lone AF generally applies to younger individuals (<60 years) without clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension; †Recurrent AF defined as 2 episodes; termination with pharmacologic or direct-current cardioversion does not change designation. Adapted from Fuster V et al. Circulation. 2006;114:e257-e354.
DRO-062811000 Clinical Presentation of Atrial Fibrillation • AF presents with a wide range of symptoms1 • May also be asymptomatic • Impact of asymptomatic AF2 • Potential for underlying electrical and structural damage to atrial myocardium • While AF symptoms alone may not always be severe, untreated disease can result in significant morbidity and mortality3 LIGHT-HEADEDNESS PALPITATIONS DYSPNEA SYNCOPE CHEST PAIN FATIGUE THROMBO-EMBOLISM DEATH 1. Fuster V et al. Circulation. 2006;114:e257-e354. 2.Page RL et al. Circulation. 2003;107:1141-1145. 3. Stewart S et al. Am J Med. 2002;113:359-364.
DRO-062811000 The ALFA StudyPrevalence of Symptoms Total Population(N=756) ALFA = Étude en Activité Libérale de la Fibrillation Auriculaire. Lévy S et al. Circulation. 1999;99:3028-3035.
P <0.0005 DRO-062811000 Severity of Stroke with AF • 1061 patients admitted with acute ischemic stroke • 20.3% had AF • Bedridden state • With AF 41.2% • Without AF 23.7% • Odds ratio for bedridden state following stroke due to AF, 2.23 (95% CI, 1.87-2.59; P<0.0005) CI = confidence interval. Dulli DA et al. Neuroepidemiology 2003;22:118-123.
DRO-062811000 CHADS2 Stroke Risk Stratification Scheme for Patients With Nonvalvular AFib Relationship between CHADS2 score and annual risk of stroke Adapted from Hersi A et al. Curr Probl Cardiol. 2005;30:175-234.
Vaughan-Williams Classification • AADs have distinct characteristics based on which ionic currents they block • Vaughan-Williams classification based on their dominant electrophysiological effect: • There are 3 Class I subtypes: 1a, 1b, and 1c AADs = antiarrhythmic drugs. Adapted from: http://www.cvpharmacology.com/antiarrhy/sodium-blockers.htm.
DRO-113010000 Vaughan Williams Classification1 • Multiple mechanisms contribute to the occurrence of AF2 • Balance between safety and efficacy is critical to choosing an appropriate AAD3 • Agent selection should consider severity of AF Burden, safety, CV comorbidities, and dosing convenience to improve compliance with therapy3,4 1. Vaughan Williams EM. J Clin Pharmacol.1984;24129-147.2. Nattel S, et al. Circ Arrhythm Electrophysiol.2008;1:62-73.3. Fuster V, et al. Circulation. 2006;114:e257-e354. 4. Naccarelli GV, et al. US Cardiology.2004:1-5.
DRO-113010000 Class III AgentsPrimary effect on K+ channel, most have additional drug-specific effects on other ion channels
DRO-062811000 AF Guideline Focus Update Stroke Prevention Rate Control Update Anti-Arrhythmic Update
DRO-062811000 Recommendation for Combining Anticoagulant with Antiplatelet Therapy • Multiple studies have shown that oral anticoagulation with warfarin is effective for prevention of thromboembolism in AF1 • Aspirin offers only modest protection against stroke in AF and is less efficacious than adjusted-dose oral anticoagulation1 • The ACTIVE-W trial showed that oral anticoagulation with warfarin was superior to the combination of clopidogrel plus aspirin for prevention of vascular events in AF with similar bleeding risks2 1. Wann LS et al. Circulation. 2011;123:104-123. 2. Connolly S et al. Lancet. 2006;367:1903-1912.
DRO-062811000 ACTIVE A: Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events Patient Population • Afib (Afib at enrollment or at least 2 episodes of intermittent Afib in the prior 6 months) and at least 1 predetermined risk factor for stroke • Cannot take VKA (eg, warfarin) n=3,772 Clopidogrel 75 mg + ASA (75–100 mg) Placebo + ASA (75–100 mg) n=3,782 Median follow up 3.6 years Primary Endpoint • First occurrence of a composite of stroke, non-CNS systemic embolism, MI, or vascular death Safety Endpoints • Major and minor bleeding Connolly SJ et al. N Engl J Med. 2009; 360: 2066-2078.
DRO-062811000 ACTIVE A: Primary Endpoint: Stroke, MI, Non-CNS-embolism or Vascular Death 0.4 924 (7.6%/year) RR=0.89 (0.81-0.98) P=0.01 832 (6.8%/year) 0.3 Aspirin 0.2 Cumulative Incidence Clopidogrel + Aspirin 0.1 0.0 0 1 2 3 4 Years Connolly SJ et al. N Engl J Med. 2009;360:2066-2078.
DRO-062811000 ACTIVE A: Bleeding Connolly SJ et al. N Engl J Med. 2009;360:2066-2078.
DRO-062811000 Recommendation for Combining Anticoagulant With Antiplatelet Therapy Class IIb • The addition of clopidogrel to aspirin (ASA) to reduce the risk of major vascular events, including stroke, might be considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient preference or the physician’s assessment of the patient’s ability to safely sustain anticoagulation. (Level of Evidence: B) Comments: New Recommendation Wann LS et al. Circulation. 2011;123:104-123.
DRO-062811000 RE-LY: A Noninferiority Trial Atrial fibrillation 1 Risk Factor Absence of contra-indications 951 centers in 44 countries Blinded Event Adjudication R Open Blinded Blinded Warfarin adjusted (INR 2.0-3.0) N=6022 Dabigatran Etexilate 110 mg BID N=6015 Dabigatran Etexilate 150 mg BID N=6076 Connolly SJ et al. N Engl J Med. 2009;361:1139-1151.
DRO-062811000 RE-LY—Stroke or Systemic Embolism Noninferiority P Value Superiority P Value Dabigatran 110 vs Warfarin <0.001 0.34 Dabigatran 150 vs Warfarin <0.001 <0.001 Margin = 1.46 Dabigatran better Warfarin better 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Connolly SJ et al. N Engl J Med. 2009;361:1139-1151.
DRO-062811000 RE-LY—Bleeding Results Connolly SJ et al. N Engl J Med. 2009;361:1139-1151.
DRO-062811000 Recommendations for Emerging Antithrombotic Agents Class I • Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 mL/min), or advanced liver disease (impaired baseline clotting function). Level of evidence: B) Comments: New Recommendation Wann LS et al. Circulation. 2011;123:104-123.
DRO-062811000 Current Trials of Anticoagulant Treatments in the Prevention of Stroke in Patients With AF Medi C et al. Stroke. 2010;41:2705-2713.
DRO-062811000 Rate Control During Atrial Fibrillation • Rate control usually targets heart rate of 60-80 bpm resting and 90-115 bpm during moderate exercise1 • AFFIRM definition of adequate rate control2: • Up to 80 bpm at rest • Average of up to 100 bpm over 18 hours of ambulatory Holter monitoring with no rate greater than 100% of maximum age-predicted exercise heart rate or • Maximum of 110 bpm during 6 minute walk test 1. Wann LS et al. Circulation. 2011;123:104-123. 2. Olshansky B et al. J Am Coll Cardiol 2004;43:1201-1208.
DRO-062811000 RACE II: RAte Control Efficacy in Permanent Atrial Fibrillation Permanent AF >80 bpm Lenient Rate Control n=311 Strict Rate Control n=303 HR <110 bpm (12 lead ECG) HR < 80 bpm (12 lead ECG) and HR <110 bpm (at 25% duration of maximal exercise time) Van Gelder IC et al. N Engl J Med. 2010;362:1363-1373.
DRO-062811000 RACE II: RAte Control Efficacy in Permanent Atrial Fibrillation Cumulative Incidence of Primary Composite Endpoint 20 Strict 14.9% 15 Cumulative Incidence (%) 10 Lenient 12.9% 5 0 0 6 12 18 24 30 36 months No. At Risk Strict 303 282 273 262 246 212 131 Lenient 311 298 290 285 255 218 138 Van Gelder IC et al. N Engl J Med. 2010;362:1363-1373.
DRO-062811000 Recommendations for Rate Control During Atrial Fibrillation • Class III – No Benefit Treatment to achieve strict rate control of heart rate (<80 bpm at rest or <110 bpm during a 6-minute walk) is not beneficial compared to achieving a resting heart rate of <110 bpm in patients with persistent AF who have stable ventricular function (left ventricular ejection fraction >0.40) and no or acceptable symptoms related to the arrhythmia, though uncontrolled tachycardia may over time be associated with a reversible decline in ventricular performance. (Level of Evidence: B) Comments: New recommendation Wann LS et al. Circulation. 2011;123:104-123.
DRO-062811000 ATHENAStudy Design • Randomization was stratified to center, and by the presence or absence of AF (or AFL) at the time of randomization R Dronedarone Placebo 400 mg BID Minimum treatment and follow-up of 12 months Hohnloser SH et al. J Cardiovasc Electrophysiol. 2008;19:69-73.
ATHENAPrimary Outcome: Time to First Cardiovascular Hospitalization or Death DRO-062811000 100 75 50 25 0 Hazard ratio: 0.76 (0.69-0.84) P<0.001 Cumulative Incidence (%) Placebo Dronedarone 0 6 12 18 24 30 Months No. at Risk Placebo 2327 1858 1625 1072 385 3 Dronedarone 2301 1963 1776 1177 403 2 Hohnloser SH et al. N Engl J Med. 2009;360:668-678.
DRO-062811000 ATHENASelected AEs and Laboratory Abnormalities in Patients Who Received the Study Drug TEAE = treatment-emergent adverse event, defined as an AE occurring between first dose of study drug and 10 days after the last dose. Hohnloser SH et al. N Engl J Med. 2009;360:668-678.
DRO-062811000 Recommendations for Use of Dronedarone in Atrial Fibrillation Class IIa • Dronedarone is reasonable to decrease the need for hospitalization for cardiovascular events in patients with paroxysmal AF or after conversion of persistent AF. Dronedarone can be initiated during outpatient therapy. (Level of Evidence: B) Comment: New Recommendation Wann LS et al. Circulation. 2011;123:104-123.
R DRO-062811000 ANDROMEDAStudy Design and Inclusion Criteria Dronedarone 400 mg BID Treatment for minimumof 12 months Placebo • Patients hospitalized with new or worsening heart failure* and • At least 1 episode of shortness of breath on minimal exertion or at rest (NYHA class III or IV) or paroxysmal nocturnal dyspnea within the month before admission and • Wall-motion index of no more than 1.2 (approximating an ejection fraction of no more than 35%) *Patients were assigned no later than day 7 after hospital admission. Inclusion could be postponed if the patient was on a respirator. NYHA = New York Heart Association. Køber L et al. N Engl J Med. 2008;358:2678-2687.
ANDROMEDAPrimary Endpoint: Time to Death or Hospitalization for Worsening Heart Failure Prematurely terminated due to imbalance in death between the 2 arms DRO-062811000 CI = confidence interval. Køber L et al. N Engl J Med. 2008;358:2678-2687.
DRO-040611006 Recommendations for Use of Dronedarone in Atrial Fibrillation Class III—Harm • Dronedarone should not be administered to patients with class IV heart failure or patients who have had an episode of decompensated heart failure in the past 4 weeks, especially if they have depressed left ventricular function (left ventricular ejection fraction 35%) (Level of evidence: B) • Comment: New Recommendation Wann LS et al. Circulation. 2011;123:104-123.
Dronedarone Flecainide Propafenone Sotalol Amiodarone Dofetilide Catheter ablation DRO-062811000 2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation Maintenance of Sinus Rhythm No (or minimal)heart disease Hypertension Coronary Artery Disease Heart Failure Dronedarone Flecainide Propafenone Sotalol Substantial LVH Dofetilide Dronedarone Sotalol Amiodarone Dofetilide No Yes Amiodarone Dofetilide Catheter ablation Amiodarone Catheter ablation Catheter ablation Amiodarone Catheter ablation Drugs are listed alphabetically and not in order of suggested use. The seriousness of heart disease progresses from left to right, and selection of therapy in patients with multiple conditions depends on the most serious condition present. LVH indicates left ventricular hypertrophy. Wann LS et al. Circulation. 2011;123:104-123.
DRO-062811000 New Approaches toAtrial Fibrillation Management Considerations Beyond Being Just a Rhythm
Rate vs rhythm control Binary outcome: SR or AF First recurrence of AF = failure of therapy Focus on the ECG result Rate and rhythm control Flexible outcome: mostly SR Recurrence pattern over time Focus on the patient’s symptoms and well-being DRO-062811000 Changing the Paradigm of Goals of AF Therapy Old Paradigm New Paradigm Pinter A et al. Cardiovasc Ther. 2010;28:302-310.
DRO-062811000 Atrial Fibrillation Treatment Options Rate Control1 Maintenance of SR1 Stroke Prevention1 Pharmacologic Nonpharmacologic • Pharmacologic • Warfarin • Thrombin inhibitor • Aspirin • Nonpharmacologic • Removal/isolation • LA appendectomy • Pharmacologic • Ca2+ blockers • β-blockers • Digitalis • Amiodarone • Nonpharmacologic • Ablate and pace Class IA Class IC Class III New AADs Catheter ablation Pacing Surgery (maze procedure, pulmonary veinisolation) Implantable atrial defibrillator Ca2+ blockers2 ACE-I2 ARB2 PUFA2 Statins2 Prevent remodeling2 • AAD = antiarrhythmic drug; ACE-1 = angiotensin-converting enzyme inhibitors; ARB = angiotensin-receptor blocker; LA = left ventricle; PUFA = polyunsaturated fatty acids (fish oils); SR = sinus rhythm. • Adapted from Prystowsky EN. Am J Cardiol. 2000;85:3D-11D. • Benjamin EJ et al. Circulation. 2009;119:606-618.
DRO-062811000 Utilizing a Comprehensive Approach Quality of Life AF on Electrogram Symptoms Potential overlap between ECG-documented presence of AF, symptoms, and quality of life. Quality of life may be impaired in the absence of symptoms or by symptoms related to concomitant disorders rather than AF. Adapted from Grönefeld GC et al. Eur Heart J Suppl. 2003;5(suppl H):H25-H33. Camm AJ et al. Eur Heart J Suppl. 2008;10(suppl H):H55-H78.
DRO-062811000 Defining Success With Management of Atrial Fibrillation • Current common measures of success1,2 • Any AF recurrence • Time to first recurrence of AF • Reduction of AF burden • Redefining the best measure of success: reduction in AF burden and symptoms • Mortality1,2 • Cardiovascular hospitalization3 • Quality of life4 Symptomsduringepisodes Duration ofepisodes Frequency ofepisodes 1. Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10. 2. Fuster V et al. Circulation. 2006;114:e257-e354.3. Wyse DG et al. Heart Rhythm. 2004;1:531-537. 4. Dorian P et al. J Am Coll Cardiol. 2000;36:1303-1309.
DRO-062811000 Summary • Nonvalvular atrial fibrillation is managed with: • Rate agents • Rhythm agents • Stroke prevention • Recent focus updates incorporate new therapies into existing guidelines • Management of nonvalvular AF should include outcomes other than just rhythm management (eg, hospitalization, QOL, etc)