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  1. 1. Atrial Fibrillation Mechanisms and Management: Integrating Care for Better Outcomes
  2. 2. Contents • The Cardiologist’s Perspective on AF Management • The Electrophysiologist’s Perspective on AF Management • Case Presentation I: 65-Year-Old Man with Hypertension and LVH • Case Presentation II: 72-Year-Old Woman with Paroxysmal AF
  3. 3. The Cardiologist’s Perspective on AF Management
  4. 4. Managing patients with AF: The cardiologist’s perspective AF is a complex disorder that is increasing in frequency AF can be present with, be affected by, and serve as a contributing factor in a wide range of CV conditions As a marker of adverse outcomes, AF supports the need for prompt, aggressive management of all coexisting CV risk factors Treatments directed at CV risk factors may also have beneficial effects on AF recurrence
  5. 5. ATRIA: Prevalence of atrial fibrillation increases with age 12 10 8 Prevalence 6 (%) 4 2 0 <55 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 Age (years) Women (n = 7801) Men (n = 10,173) Go AS et al. JAMA. 2001;285:2370-5.
  6. 6. Hospital admissions for AF have increased 400,000 380,000 Increased ~34% over 6 years 360,000 Total admissions/ 340,000 year 320,000 300,000 280,000 1996 1997 1998 1999 2000 2001 Khairallah F et al. Am J Cardiol. 2004;94:500-4.
  7. 7. ATRIA: AF projected to continue increasing Projected numbers of adults with AF in the US, 1995 to 2050 7.0 6.0 5.4 5.6 5.0 5.2 4.8 4.0 4.3 Adults with 3.8 AF (millions) 3.0 3.3 2.9 2.4 2.7 2.0 2.3 2.1 1.0 0 1990 2000 2010 2020 2030 2040 2050 Year Go AS et al. JAMA. 2001;285:2370-5.
  8. 8. CV conditions frequently associated with nonvalvular AF • Hypertension • Obesity/metabolic syndrome/diabetes • Ischemic heart disease • Heart failure/diastolic dysfunction • Obstructive sleep apnea • Physical inactivity • Thyroid disease • Inflammation? Wattigney WA et al. Circulation. 2003. Gersh BJ et al. Eur Heart J Suppl. 2005. Fuster V et al. J Am Coll Cardiol. 2006. Mozaffarian D et al. Circulation. 2008.
  9. 9. Pathophysiology of AF and comorbidities Inflammation? • HTN and/or vascular disease ↓Compliance • Mitral regurgitation • Left ventricular hypertrophy Atrial stretch • Diastolic dysfunction ↑Stretch-activated channels Inflammation? ↑Dispersion of refractoriness ↑Pulmonary vein focal/discharges? Increased vulnerability to AF? Adapted from Gersh BJ et al. Eur Heart J Suppl. 2005;7(suppl C):C5-11.
  10. 10. VALUE: Impact of new-onset diabetes on development of AF N = 15,245 with hypertension at high risk New-onset 0.04 diabetes 0.03 Proportion of Diabetes patients with 0.02 at baseline 1st event No diabetes 0.01 0 0 500 1000 1500 2000 Time to persistent new-onset AF (days) n = 5250 with DM at baseline Aksnes TA et al. Am J Cardiol. n = 1298 initially nondiabetic patients developed DM during follow-up 2008;101:634-8.
  11. 11. Obstructive sleep apnea: Marker of incident AF N = 3542 undergoing diagnostic polysomnogram; mean follow-up 4.7 years 20 15 Cumulative OSA frequency 10 of AF (%) 5 No OSA 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time (years) OSA = obstructive sleep apnea Gami AS et al. J Am Coll Cardiol. 2007;49:565-71.
  12. 12. High healthcare burden of AF Each year . . . • 5 million office visits • 234,000 outpatient department visits • 276,000 emergency department visits • 350,000 hospitalizations • $6.65 billion in treatment costs Coyne KS et al. Value Health. 2006;9:348-56.
  13. 13. Impact on QoL: AF vs other CV illness 100 AF AF AF AF 80 AF AF SF-36 60 scale* 40 20 0 y n ng lth e th lit ol tio al ni ea ta lr he nc tio Vi lh na fu l nc ra io ta al en e ot fu en ic Em M al ys G ci Ph So General pop Recent MI AF HF *Higher numbers indicate higher QoL SF-36 = Medical Outcomes Study Short Form 36 Adapted from Dorian P et al. J Am Coll Cardiol. 2000;36:1303-9.
  14. 14. Summary: AF burden ↑Prevalence ↑Hospitalizations ↑CV comorbidities ↑Economic costs ↓QoL All contribute to ↑burden of disease
  15. 15. Possible “upstream” treatments and mechanisms for AF prevention ACEIs/ARBs Statins Glucocorticoids Omega-3 fatty acids Physical activity ↓Inflammation ↓Oxidative stress ↓RAAS activity ↑Endothelial function ↓Autonomic nervous system activity ↑Vascular stability ↓Atrial remodeling Stabilize left atrial endocardium ↓Atrial fibrillation Courtesy of CJ Pepine, MD.
  16. 16. Trials of RAAS inhibition in AF prevention Favors treatment Favors control ACEIs CAPP Captopril GISSI Lisinopril HOPE Ramipril SOLVD Enalapril STOP-H2 Enalapril TRACE Trandolapril Ueng Enalapril Van den Berg Lisinopril Subtotal ARBs CHARM Candesartan LIFE Losartan Madrid Irbesartan ValHeFT Valsartan Subtotal Subtotal Total Total 0.1 0.2 0.5 1.0 2.0 5.0 RR* (95% CI) Salehian O et al. Am Heart J. 2007;154:448-53. *Random-effects model Healey JS et al. J Am Coll Cardiol. 2005;45:1832-9.
  17. 17. AF prevention with ACEI or ARB plus antiarrhythmic drug N = 177 with lone paroxysmal AF 1.0 0.9 Group 2 Amiodarone + 0.8 losartan Group 3 Amiodarone + 0.7 perindopril 0.6 Amiodarone AF recurrence- Group 1 0.5 free survival 0.4 0.3 0.2 Group 1 vs 2: P = 0.006 Group 1 vs 3: P = 0.04 0.1 Group 2 vs 3: P = 0.47 0.0 0 90 180 270 360 450 540 630 720 810 Time after randomization (days) Yin Y et al. Eur Heart J. 2006;27:1841-6.
  18. 18. Statins in prevention of AF (1st episode or AF recurrence) Study Statin Control or subcategory n/N n/M Favors treatment Favors control MIRACL 93/1539 96/1548 Tveit 18/51 17/51 Dernellis 14/40 36/40 ARMYDA 3 35/101 56/99 Chello 2/20 5/20 Ozaydin 3/24 11/24 Total (95% CI) 1775 1782 Total events: 165 (Statin), 221 (Control) Test for heterogeneity: Chi2 = 29.47, df = 5 (P < 0.0001), I2 = 83.0% 0.1 0.2 0.5 1 2 5 10 Test for overall effect: Z = 2.35 (P = 0.02) OR (random) 95% CI Not assessed in this meta-analysis: • Degree of ↓LDL-C • Statin dose Fauchier L et al. J Am Coll Cardiol. 2008;51:828-35.
  19. 19. Inflammation and AF: Methylprednisolone to prevent AF recurrence Primary endpoint Expanded endpoint hsCRP Glucocorticoid 1.0 Glucocorticoid 1.0 10 0 Change from baseline (%) 0.8 Free of permanent AF 0.8 -10 Placebo Free of recurrent AF P = NS Placebo 0.6 0.6 -30 Placebo 0.4 0.4 -50 P < 0.001 P < 0.001 Glucocorticoid 0.2 0.2 -70 P < 0.001 0.0 0.0 -90 0 8 16 24 32 0 8 16 24 32 40 0 8 16 24 32 40 Time (months) Dorian P, Singh BN. Eur Heart J Suppl. 2008;10(suppl H):H11-31.
  20. 20. Omega-3 fatty acids in AF prevention: Conflicting results in clinical trials Study, year Design Patients Intervention Main findings Cardiovascular Population-based N = 4815 Fish consumption AF risk: Health Study, 2004 Prospective ≥65 yo 1. 1-4x per week ↓28% (1 vs 3) cohort 2. ≥5x per week P = 0.005 12-y FU 3. <1x per month ↓31% (2 vs 3) P = 0.008 Calo et al, 2005 Randomized N = 160 PUFAs ≥5 days Postop AF risk ↓65% Open-label CABG P = 0.013 Mean age 65 yo Nodari et al, 2005 Placebo-controlled N = 70 PUFAs 1 g/d x 6 mos AF recurrence: Persistent AF 13.3% (PUFA) vs 40% Cardioversion (placebo), P < 0.0001 Mean age 70 yo Danish Diet, Population-based N = 47,949 Fish consumption No effect Cancer and Health Prospective Mean age 56 yo ?↑Risk for AF as Study, 2005 cohort age and HTN 5.7-y mean FU increased Rotterdam Study, Population-based N = 5184 Fish/PUFA No effect 2006 Prospective Mean age 67 yo consumption cohort 6.4-y mean FU Adapted from Dorian P, Singh BN. Eur Heart J Suppl. 2008;10(suppl H):H11-31; Nodari S et al. Eur Heart J. 2006;27(suppl 1):887.
  21. 21. Cardiovascular Health Study: Risk of incident AF during 12-year follow-up 1.2 N = 5446 age ≥65 years 1 0.8 Multivariable- adjusted RR of new-onset AF 0.6 0.4 P trend < 0.001 0.2 Q1 Q2 Q3 Q4 Combined distance and pace of usual walking (quartiles) Adjusted for age, gender, race, site, education, smoking (status Mozaffarian D et al. and pack-yrs), CHD, COPD, diabetes, alcohol use, beta-blocker use Circulation. 2008;118:800-7.
  22. 22. Summary and conclusions • Complex disorder, increasing in frequency • Cardiac functional/structural alterations related to AF may reflect “end stages” of CV diseases in general • Early and aggressive pursuit of sinus rhythm may prevent clinical consequences of AF while improving QoL • Therapies without primary antiarrhythmic properties seem to modify risk for and recurrence of AF
  23. 23. The Electrophysiologist’s Perspective on AF Management
  24. 24. Prognostic impact of AF Sudden cardiac death (SCD) Heart failure • AF is independent risk factor • Those with AF had significantly for SCD among patients with ↑mortality from HF progression structural heart disease vs those without AF (RR 1.20, P = 0.02) (AVID)1,2 (RR 1.95, P < 0.001) (SOLVD)4 Post-myocardial infarction mortality • Those with AF had ↑post-MI mortality vs those without AF (RR 1.50, P < 0.001) (TRACE)3 1. AVID Investigators. N Engl J Med. 1997. 2. Wyse G et al. J Interv Card Electrophysiol. 2001. 3. Pedersen OD et al. Eur Heart J. 1999. 4. Dries DL et al. J Am Coll Cardiol. 1998.
  25. 25. Atrial fibrillation: Framingham study Strokes Age AF prevalence attributable (years) (%) to AF (%) 50-59 0.5 6.5 60-69 1.8 8.5 70-79 4.8 18.8 80-89 8.8 30.7 Wolf PA et al. Stroke. 1991;22:983-8.
  26. 26. Severity of stroke with AF • N = 1061 admitted with acute ischemic stroke – 20.2% had AF • Bedridden state – With AF 41.2% P < 0.0005 – 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) Dulli DA et al. Neuroepidemiology. 2003;22:118-23.
  27. 27. AF: The more you look, the more you find Estimated correlation between follow-up technique and AF recurrence following catheter ablation 100% Implanted Daily Tele-ECG device† 7-day-ECG* Detection 24-day-ECG* of AF Tele-ECG* recurrences ECG* *During 3-month follow-up †As the theoretical gold standard Tele = transtelephonic Arya A et al. Pacing Clin Electrophysiol. 2007;30:458-62.
  28. 28. Detection of recurrent AF Electrocardiographic vs implanted device recording 100 80 Device: AF detected in 88% of patients P < 0.0001 ECG: AF detected in 46% of patients Cumulative 60 incidence (%) 40 Implanted device 20 ECG Baseline 1 3 6 12 18 24 30 36 42 48 Time (months) n = 110 110 110 110 85 73 60 48 39 25 15 Israel CW et al. J Am Coll Cardiol. 2004;43:47-52.
  29. 29. Cumulative incidence of asymptomatic AF recurrence >48 hours* 110 20 Cumulative 15 incidence (%) 10 38% of patients with AF >48 hours were asymptomatic 5 Baseline 1 3 6 12 18 24 30 36 42 48 54 60 66 Time (months) *Not detected by serial ECG recordings during follow-up Israel CW et al. J Am Coll Cardiol. 2004;43:47-52.
  30. 30. Anticoagulation for nonvalvular AF Pooled data from AFASAK, SPAF, and BAATAF For every 1000 patients with nonvalvular AF in clinical trials treated with warfarin for 1 year: Benefit Risk 31 fewer thromboembolic events* 1 more intracranial or major bleed* *Compared with control 35 more minor bleeds occurred with warfarin Intention-to-treat analysis Adapted from Albers GW et al. Ann Neurol. 1991;30:511-8.
  31. 31. Bleeding risk and age N = 2376 receiving warfarin; Combined & retrospective cohort studies Minor bleeding • Categories <50 50-59 Referent category – Minor: No costs or 60-69 70-79 consequences >80 – Serious: Require testing Serious bleeding or treatment Age group <50 50-59 Referent category – Life-threatening/fatal (years) 60-69 70-79 >80 • Events (812) Life-threatening or fatal bleeding – 553 minor <50 Referent category – 222 serious 50-59 60-69 – 33 life-threatening 70-79 >80 – 4 fatal 0 1 2 3 4 5 6 7 8 9 18 Adjusted relative risk (95% CI) Age not determinant of risk except possibly ≥80 years Fihn SD et al. Ann Internal Med. 1996;124:970-9.
  32. 32. Survival following ischemic stroke: Warfarin vs aspirin* 1.0 Warfarin, INR ≥2 Aspirin 0.9 Warfarin, INR <2 0.8 Probability of survival None 0.7 0.6 P = 0.002† 0.0 0 5 10 15 20 25 30 Time after admission (days) *Warfarin/aspirin therapy administered before or during stroke †Overall difference among groups Hylek EM et al. N Engl J Med. 2003;349:1019-26.
  33. 33. Catheter ablation vs antiarrhythmic drug therapy for AF N = 432 with AF; Meta-analysis of 4 randomized clinical trials ADT more CPVA more Risk ratio Source effective effective (95% CI) % Weight Pappone et al, 2006 3.86 (2.65-5.63) 37.5 Stabile et al, 2006 6.43 (2.91-14.21) 18.1 Wazni et al, 2005 4.22 (2.14-8.32) 22.0 Krittayaphong et al, 2003 2.00 (1.02-3.91) 22.4 Overall (95% CI) 3.73 (2.47-5.63) 0.04 0.20 1.00 5.00 25.00 Risk ratio ADT = antiarrhythmic drug therapy CPVA = circumferential pulmonary vein ablation Noheria A et al. Arch Intern Med. 2008;168:581-6.
  34. 34. A4 study: Catheter ablation vs antiarrhythmic drug therapy for AF N = 112 with paroxysmal AF resistant to ≥1 AAD 100.0 80.0 Freedom 60.0 from recurrent AF (%) 40.0 20.0 Logrank P < 0.0001 0.0 0 50 100 150 200 250 300 350 400 Follow-up (days) RF ADT RF = radiofrequency catheter ablation Jaïs P et al. Circulation. 2008;118:2498-505.
  35. 35. Worldwide survey of catheter ablation N = 8745 with AF treated at 90 centers • 12,830 procedures, with 27% of patients undergoing >1 procedure • 6% major complication rate – 4 deaths (0.05%) – 107 tamponade (1.22%) – 20 strokes (0.28%) – 47 TIA (0.66%) – 94 PV stenosis (1.3%) Cappato R et al. Circulation. 2005;111:1100-5.
  36. 36. US experience with catheter ablation N = 517 with AF undergoing catheter ablation treated at 1 US institution • 641 procedures • 32 major complications (5%) – 7 CVA (1.1%) – 8 cardiac tamponade (1.2%) – 1 PV occlusion (0.16%) – 11 vascular injury (1.7%) – No deaths or esophageal injury • Complication rate 9% 1st 100 patients, 4% thereafter • Predictors of complications – Female gender – Age >70 years Spragg DD et al. J Cardiovasc Electrophysiol. 2008;19:627-31.
  37. 37. ACC/AHA/ESC 2006 AF rhythm-control guidelines Maintenance of SR No (or minimal) Hypertension CAD HF heart disease Flecainide Substantial LVH Dofetilide Amiodarone Propafenone Sotalol Dofetilide Sotalol No Yes Amiodarone Catheter Catheter Amiodarone Dofetilide ablation ablation Flecainide Catheter Amiodarone ablation Propafenone Sotalol Catheter ablation Amiodarone Catheter Dofetilide ablation Fuster V et al. Circulation. 2006;114:e257-e354.
  38. 38. HRS/EHRA/ECAS Expert Consensus Statement: Indications for catheter ablation of AF • Indications – Symptomatic AF refractory or intolerant to ≥1 Class 1 or 3 antiarrhythmic drug – Selected symptomatic patients with HF and/or ↓EF • Should not be considered as 1st line therapy, except in rare clinical situations • Repeat procedures should be delayed for ≥3 months, if symptoms can be controlled with medical therapy Calkins H et al. Heart Rhythm. 2007;4:816-61.
  39. 39. Morbidity with AF following CABG MultiCenter Study of Perioperative Ischemia; Prospective, observational study With AF Without AF P N 617 1648 Post-op LOS (days) 12.8 10.2 <0.01 CHF (%) 10 7 0.01 Renal failure (%) 8 5 0.04 Neurologic injury Major (%) 7 2 <0.01 Minor (%) 6 2 <0.01 LOS = length of stay Mathew JP et al. JAMA 1996;276:300-6.
  40. 40. Summary and conclusions • AF is not benign • Assess treatment efficacy by reduction in arrhythmia burden, not merely reduction in symptoms • Anticoagulation may be considered in the elderly • Ablation should generally be considered only after a trial of antiarrhythmic drug therapy • Postoperative AF should be treated
  41. 41. Case Presentation: 65-Year-Old-Man with Hypertension and LVH Are rate and rhythm control mutually exclusive?
  42. 42. 65-Year-old man • History of hypertension for 23 years • Negative history for dyslipidemia or diabetes • Develops AF with severe symptoms despite treatment with beta-blockers • Referred by PCP for further management of his AF and assessment of CV risk • BMI: 27 kg/m2 • BP: 155/98 mm Hg both arms • Peripheral pulses – R: DP and PT 2+ – L: DP1 and PT 0 • ECG: AF at ~98/min • Cr: 1.3 mg/dL; eGFR: 48 mL/min per 1.73 m2
  43. 43. 65-Year-old man: Echocardiography Courtesy of AP Selwyn, MD.
  44. 44. 65-Year-old man: Doppler imaging E’ A’ Courtesy of AP Selwyn, MD.
  45. 45. Primary care preferences: Rate vs rhythm control as optimal strategy for AF N = 148 PCPs from 36 US states 80 60 60 Respondents 40 (%) 22 18 20 0 Rate control* Rhythm control† Strategies are equal *With anticoagulation †With or without anticoagulation McCabe JM et al. Am J Cardiol. 2009;103:535-9.
  46. 46. AFFIRM: Primary outcome Cumulative mortality (%) 30 P = 0.08 • N = 4060 with AF 25 – Age ≥65 years or ≥1 risk Rhythm control 20 factor for stroke or death – 1st AF episode: 36% 15 10 Rate control – No contraindications for warfarin 5 • Follow-up 3.5 years 0 0 1 2 3 4 5 • Predominant diagnosis Time (years) Hypertension 51%, CAD 26% • n = 2033 rhythm control • n = 2027 rate control AFFIRM Investigators. N Engl J Med. 2002;347:1825-33.
  47. 47. ACC/AHA/ESC 2006 AF guidelines Newly discovered AF Paroxysmal Persistent Rate control and Accept No therapy anticoagulation permanent AF needed unless as needed significant symptoms Rate control and Consider anticoagulation antiarrhythmic as needed therapy Anticoagulation as needed Cardioversion Long-term antiarrhythmic drug therapy unnecessary Fuster V et al. Circulation. 2006;114:e257-e354.
  48. 48. Antiarrhythmic medical therapies Amiodarone Propafenone Class Class III Antiarrhythmic drugs IC Sotalol New and old Flecainide New Upstream Novel drugs Class III agents therapies SAC Connexin blockers modulators Dofetilide Azimilide 5-HT4 Na+/H+ antagonist inhibitor Tedisamil Dronedarone Adenosine Na+/Ca2+ Multi-channel inhibitor agonist blockers Celivarone ARDAs Courtesy of J Camm, MD.
  49. 49. Dronedarone • Amiodarone-like compound lacking the iodine moiety • Similar electrophysiologic properties to amiodarone • Side effects are minor, generally GI, and infrequent • No evidence of thyroid or pulmonary toxicity • 24-hour half-life • Treatment may be initiated in outpatient setting Wegener FT et al. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S17-S20.
  50. 50. EURIDIS, ADONIS: Primary endpoint First recurrence of AF/AFL EURIDIS ADONIS 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 Cumulative 0.4 0.4 incidence P = 0.01 0.3 0.3 P = 0.002 0.2 0.2 0.1 0.1 0.0 0.0 0 60 120 180 240 300 360 0 60 120 180 240 300 360 Time (days) Placebo Dronedarone 400 mg bid Singh BN et al. N Engl J Med. 2007;357:987-99.
  51. 51. ERATO: Dronedarone added to rate-lowering drugs Mean 24-hour Holter heart rate Calcium All patients Beta-blockers Digoxin antagonists 0 -4 -5.1 Mean change P = 0.10 -8 (bpm) -12 -11.5 -11.7 P < 0.0001 P < 0.0001 -16 -14.9 P < 0.0001 Davy J-M et al. Am Heart J. 2008;156:527.e1-9.
  52. 52. ATHENA: Time to primary outcome N = 4628 ≥75 yrs with AF or 70-74 yrs with AF + ≥1 CV risk factor 100 HR 0.76 (0.69-0.84) P < 0.001 75 Cumulative 50 incidence (%) 25 0 0 6 12 18 24 30 Time (months) Placebo Dronedarone Primary outcome: First hospitalization due to CV events or death; Mean follow-up 21 ± 5 months Hohnloser SH et al. N Engl J Med. 2009;360:668-78.
  53. 53. ATHENA: All-cause mortality 10.0 HR 0.84 (0.66-1.08) 100 7.5 P = 0.18 Placebo 5.0 75 2.5 Dronedarone Cumulative 50 0.0 incidence (%) 0 6 12 18 24 30 24 0 0 6 12 18 24 30 Time (months) Placebo Dronedarone Hohnloser SH et al. N Engl J Med. 2009;360:668-78.
  54. 54. ATHENA: CV mortality 7.5 Placebo 100 HR 0.71 (0.51-0.98) P = 0.03 5.0 75 2.5 Dronedarone Cumulative 0.0 50 incidence (%) 0 6 12 18 24 30 24 0 0 6 12 18 24 30 Time (months) Placebo Dronedarone Hohnloser SH et al. N Engl J Med. 2009;360:668-678.
  55. 55. ATHENA: CV hospitalization HR 0.74 (0.67-0.82) 100 P < 0.001 75 Cumulative 50 incidence (%) 24 0 0 6 12 18 24 30 Time (months) Placebo Dronedarone Hohnloser SH et al. N Engl J Med. 2009;360:668-78.
  56. 56. ATHENA: Primary outcome according to selected baseline characteristics Patients Dronedarone Placebo Characteristic* (no./total no.) better better Age <75 yr 942/2703 ≥75 yr 709/1925 Gender Male 850/2459 Female 801/2169 Presence of atrial fibrillation or flutter Yes 396/1155 No 1255/3473 Structural heart disease Yes 1115/2732 No 524/1853 Any congestive HF Yes 603/1365 No 1048/3263 LVEF <35% 86/179 35 to <45% 145/361 ≥45% 1387/4004 Use of ACEI or ARB Yes 1175/3216 No 476/1412 Use of beta-blocker Yes 1226/3269 No 425/1359 0.1 1.0 10.0 Hazard ratio (95% CI) *Not prespecified Hohnloser SH et al. N Engl J Med. 2009;360:668-78.
  57. 57. ATHENA post hoc analysis: Stroke reduction 5 HR 0.66 (95% CI 0.46-0.96) P = 0.027 Placebo 4 (n = 70, annual rate = 1.8%) 3 Dronedarone Cumulative (n = 46, annual rate = 1.2%) incidence (%) 2 1 0 0 6 12 18 24 30 Months Connolly SJ. Circulation. 2009;120:1174-80.
  58. 58. ATHENA post hoc analysis: Reduction in stroke, ACS, or CV death 15 HR 0.68 (95% CI 0.55-0.84) P < 0.001 Placebo (n = 216, annual rate = 5.5%) 10 Cumulative Dronedarone incidence (%) (n = 147, annual rate = 3.8%) 5 0 0 6 12 18 24 30 Months Connolly SJ. Circulation. 2009;120:1174-80.
  59. 59. Atrial-selective drugs • Effect on IKur (KV 1.5) or INa currents • Theoretical selective atrial effect • Will likely see ventricular effects at highest concentrations Savelieva I, Camm J. Europace. 2008;10:647-65.
  60. 60. Vernakalant (RSD1235) • Unique ion channel-blocking profile – Frequency- and voltage-dependent INa block – Early activating K+ channel block – Blocks IKACh • Rate-enhanced activity on conduction • Atrial-selective APD/ERP prolongation • Activity confirmed in several species • No adverse hemodynamic effects • Novel aminocyclohexyl ether drug Beatch GN et al. Circulation. 2003;108(suppl IV):IV-85.
  61. 61. Conversion to sinus rhythm with IV vernakalant in patients who experienced AF for <7 days 60 50 40 Patients 30 (%) 20 10 0 ACT I ACT II ACT III ACT IV† (n = 220)* (N = 150) (n = 170)* (n = 170)* Placebo Vernakalant *Subgroup analysis; †Not placebo-controlled Savelieva I, Camm J. Europace. 2008;10:647-65.
  62. 62. AF treatment strategies AF DC or chemical cardioversion to reestablish SR as Rate control Rhythm control needed Antiarrhythmic Catheter Atrial Beta-blocker Surgery + Digoxin drugs ablation defibrillator Ca channel blocker + Digoxin Propafenone Maze Pulmonary veins AV node ablation Flecainide procedure LA linear lesions + Pacer Sotalol RA linear lesions Amiodarone Focal lesions Dofetilide Anticoagulation Disopyramide for all patients Quinidine with risk factors Procainamide Anticoagulation for all patients with risk for stroke New drugs factors for stroke Courtesy of KA Ellenbogen, MD.
  63. 63. Clinical pearls • Rate and rhythm control are not mutually exclusive strategies • Rhythm control has a role in highly symptomatic patients • Since many AF episodes are asymptomatic, symptom-guided treatment will result in suboptimal control of the arrhythmia • Therapy should be directed at reducing AF burden – New agents with potentially improved safety profiles are under investigation • Attention should also be paid to reducing global cardiovascular risk Courtesy of AE Epstein, MD and AP Selwyn, MD.
  64. 64. Case Presentation: 72-Year-Old Woman with Paroxysmal AF Meeting the challenge of effective anticoagulation
  65. 65. 72-Year-old woman • Paroxysmal AF for 5 years – Events have lasted 8-23 hours and have occurred every 3-5 months – Episodes are minimally symptomatic and tolerable on rate-control therapy • History of hypertension, controlled on diet and medications • No history of diabetes, heart failure, or embolic events • No history of heart murmur or bleeding disorder
  66. 66. Diagnostic studies ECG rhythm strip during an episode • Echocardiogram – Normal LV and RV size and function; normal LA and RA size; no significant valvular disorders. LV wall thickness 1.0 cm • Chest x-ray – Normal heart size, clear lung fields • Blood studies – CBC, chemistry profile, lipid profile, TSH, Mg all within normal limits Courtesy of JA Reiffel, MD.
  67. 67. CHADS2 risk stratification scheme CHADS2 risk criteria Score C Congestive heart failure 1 H Hypertension 1 A Age ≥75 years 1 D Diabetes mellitus 1 S2 Prior stroke or TIA 2 Fuster V et al. Circulation. 2006;114:e257-e354.
  68. 68. Warfarin risk/benefit balance 20 15 Odds ratio 10 5 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 International normalized ratio Ischemic stroke Intracranial bleeding Fuster V et al. Circulation. 2006;114:e257-e354.
  69. 69. Misconceptions about rhythm-control strategy N = 148 PCPs from 36 US states 80 73 64 60 55 Respondents 40 (%) 20 0 Helps avoid Decreases Decreases long-term mortality stroke anticoagulation McCabe JM et al. Am J Cardiol. 2009;103:535-9.
  70. 70. AFFIRM: Incidence of stroke and anticoagulation status at time of stroke N = 4060 with AF and ≥65 years or with additional stroke risk factors Rate control Rhythm control n (%) n (%) Ischemic stroke 77 (5.5)* 80 (7.1)* INR 2.0 25 19 INR <2.0 27 17 Not taking warfarin 25 44 AF at time of event 42 25 Regardless of treatment strategy, majority of strokes occurred in patients with subtherapeutic INR or not taking warfarin However, some strokes occurred despite therapeutic INR and sinus rhythm *Percentages derived from Kaplan-Meier analysis AFFIRM Investigators. N Engl J Med. 2002;347:1825-33.
  71. 71. Inadequate warfarin treatment in patients with AF N = 660 with AF in primary care practices 4%: INR above target 26%: INR within target 5%: INR below target 65%: No warfarin Samsa GP et al. Arch Intern Med. 2000;160:967-73.
  72. 72. Adequacy of anticoagulation • Even with intentions to follow the guidelines, and with patient cooperation, effective anticoagulation is erratic at best • INR often deviates outside of the therapeutic range – Dietary fluctuations – Changes in bowel flora – Interactions – Formulation substitution – Lab errors – Other • Time that INR is in therapeutic range is variable … even when patients are managed carefully Courtesy of JA Reiffel, MD.
  73. 73. Why patients do not like warfarin • Concerns about bleeding • Inconvenience and costs of prothrombin time testing – Home check units not yet in widespread use – Physicians still have doubts about accuracy of home testing methods, which are conveyed to patients • Dietary interactions • Drug interactions (including OTCs and herbals) • Concerns about travel • Concerns about procedures (eg, dental) Courtesy of JA Reiffel, MD.
  74. 74. Proposed algorithm for warfarin initiation in elderly patients INR value at 10 AM Warfarin dose (mg)* Day 0 Do not measure 4 Day 1 Do not measure 4 Day 2 Do not measure 4 Day 3 <1.3 5† 1.3 ≤ INR < 1.5 4† 1.5 ≤ INR < 1.7 3† 1.7 ≤ INR < 1.9 2† 1.9 ≤ INR < 2.5 1† INR ≥2.5 Measure INR daily and omit dose until INR <2.5, then give 1 mg *Given at 6 PM †Predicted maintenance dose Elderly: ≥70 years Siguret V et al. Am J Med. 2005;118:137-42.
  75. 75. Make the regimen as easy as possible for your patients and yourself • Try to use 1 size tablet • Try to link varying doses to days of week (ie, MWF, TTSS) or to odd/even days on calendar • Remember drug interactions and their time course when you change any other therapy • Remember to tell patient to contact you if there are any changes in concomitant medications by another physician, OTC agents, or GI status (eg, bowel prep, gastroenteritis) • Give patient list of Vit K-containing foods and instruct to keep diet constant • Give patient Vit K Rx to keep for emergencies Courtesy of JA Reiffel, MD.
  76. 76. Other important considerations with warfarin • What dose should be used to initiate it? • Do you use genetic pattern testing? • When might you need to cover the period of initiation with LMWH or ASA? • What regimen do you use when warfarin has to be held for a procedure and how do you reinitiate it? • How often do you check the INR? • Do you use home INR monitoring? • What do you do if the patient is also taking ASA and clopidogrel? Courtesy of JA Reiffel, MD.
  77. 77. Coagulation cascade Intrinsic system Extrinsic system XII XIIa XII VIIa + Tissue factor XI XIa rs ibito XI XIa + VIIIa nh a I X rs c tor bi to Fa i X Xa + Va n Inh m bi r o Th Prothrombin Thrombin Fibrinogen Fibrin XIII XIIIa Brass LF. Chest. 2003;124(suppl):18S-25S. Stable fibrin clot Mann KG. Chest. 2003;124(suppl):4S-10S. Nesheim M. Chest. 2003;124(suppl):33S-39S.
  78. 78. Future directions in anticoagulant therapy • Indirect Factor Xa inhibitors – Idraparinux (BOREALIS-AF) • Direct Factor Xa inhibitors – YM150 (ONYX-2) – Apixaban (ARISTOTLE) – Betrixaban (EXPERT) – Rivaroxaban (ROCKET AF) • Alternative DTIs – Dabigatran (RE-LY) • Indirect thrombin inhibitors (eg, odiparcil) Courtesy of JA Reiffel, MD and PR Kowey, MD.
  79. 79. Rivaroxaban • Factor Xa inhibitor with once-daily dosing • Superior to enoxaparin in preventing VTE after knee replacement surgery and THA (Phase III studies–the RECORD trials) and effective in preventing DVT and PE after other orthopedic surgery (Phase IIb trials) • No “liver signal” in VTE trials • No significant drug interactions • Excess bleeding in early trials with doses ≥30 mg/d • Approved for marketing for VTE in the European Union in 2008 • Being studied for stroke prevention in AF and for ACS Courtesy of JA Reiffel, MD.
  80. 80. Apixaban • Direct Xa inhibitor (follow-up to razaxaban, halted due to excess bleeding) • BID dosing • Under development for VTE prevention, VTE treatment, and stroke prevention in AF – AVERROES being conducted in patients who failed or are unsuitable for vitamin K therapy • ACS trial (APPRAISE-1) showed increased risk of bleeding and only a trend towards increased efficacy when added to ASA or clopidogrel Courtesy of JA Reiffel, MD.
  81. 81. Dabigatran • Direct thrombin inhibitor • Active moiety of the prodrug dabigatran etexilate • Onset of action <1 hr; T ½ 12-15 hrs; no food interaction • Renally excreted (80%), the rest biliary • Dialyzable • Increases aPTT, PT, TT, ECT but these are not used to monitor therapy – ECT and TT are sensitive to dabigatran effect • Being developed for VTE prevention, VTE treatment, and AF Courtesy of JA Reiffel, MD.
  82. 82. PETRO: Dabigatran in AF phase II clinical trial N = 502 with AF, treatment duration 12 weeks Dabigatran dose Major Relevant (mg, twice daily) n ASA (mg) bleed bleed TE events 50 59 0 0 0 1 (1.7%) 50 21 81 0 1 (4.8%) 1 (4.8%) 50 27 325 0 1 (3.7%) 0 150 100 0 0 9 (9%) 0 150 36 81 0 2 (5.6%) 0 150 33 325 0 2 (6.1%) 0 300 105 0 0 6 (5.7%) 0 300 34 81 1 (2.9%) 5 (14.7%) 0 300 30 325 3 (10%) 6 (20%) 0 Warfarin (INR 2-3) 70 0 0 4 (5.7%) 0 ALT >3x ULN in 0.9% of patients Ezekowitz MD et al. Am J Cardiol. 2007;100:1419-26.
  83. 83. Design of RE-LY: A non-inferiority trial Randomized Evaluation of Long-Term Anticoagulation Therapy Atrial fibrillation 1 Stroke risk factors Absence of contraindications Primary outcome: Blinded event adjudication R Stroke or systemic embolism Open Blinded Warfarin Dabigatran Dabigatran (Adjusted INR etexilate etexilate 2.0-3.0) 110 mg bid 150 mg bid n = 6022 n = 6015 n = 6076 Follow up: 1-yr minimum, 2-yr median, 3-yr maximum Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
  84. 84. RE-LY: Stroke or systemic embolism Primary outcome Dabigatran Warfarin better better P for non- P for inferiority superiority Dabigatran 110 vs warfarin <0.001 0.34 Dabigatran 150 vs warfarin <0.001 <0.001 Non-inferiority margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
  85. 85. RE-LY: Stroke or systemic embolism 1.0 0.05 0.04 ↓34% 0.8 P < 0.001 0.03 0.6 0.02 Cumulative hazard rate 0.01 0.4 0.00 0 6 12 18 24 30 0.2 0.0 0 6 12 18 24 30 Months Warfarin Dabigatran 110 Dabigatran 150 Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
  86. 86. RE-LY: MI, hospitalization, death Dabigatran Dabigatran Dabigatran 110 Dabigatran 150 110 150 Warfarin vs warfarin vs warfarin Annual Annual Annual RR RR rate (%) rate (%) rate (%) (95% CI) P (95% CI) P Myocardial 0.72 0.74 0.53 1.35 0.07 1.38 0.048 infarction (0.98-1.87) (1.00-1.91) Hospitalization 19.4 20.2 20.8 0.92 0.003 0.97 0.34 (0.87-0.97) (0.92-1.03) Death 3.75 3.64 4.13 0.91 0.13 0.88 0.051 (0.80-1.03) (0.77-1.00) Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
  87. 87. RE-LY: Bleeding and net clinical benefit Dabigatran Dabigatran Dabigatran 110 Dabigatran 150 110 150 Warfarin vs warfarin vs warfarin Annual Annual Annual RR RR rate (%) rate (%) rate (%) (95% CI) P (95% CI) P Major 2.71 3.11 3.36 0.80 0.003 0.93 0.31 bleeding (0.69-0.93) (0.81-1.07) Minor 13.16 14.84 16.37 0.79 <0.001 0.91 0.005 bleeding (0.74-0.84) (0.85-0.97) Net clinical 7.09 6.91 7.64 0.92 0.10 0.91 0.04 benefit* (0.84-1.02) (0.82-1.00) *Composite of stroke, systemic embolism, pulmonary embolism, MI, death, or major bleeding Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
  88. 88. RE-LY: Liver function test abnormalities Dabigatran 110 Dabigatran 150 Warfarin n (%) n (%) n (%) ALT or AST >3x ULN 124 (2.1) 117 (1.9) 132 (2.2) ALT or AST >3x ULN with 13 (0.2) 13 (0.2) 21 (0.3) concurrent bilirubin >2x ULN (Potential Hy’s Law case) ALT = alanine aminotransferase AST = aspartate aminotransferase ULN = upper limit of normal Connolly SJ et al. N Engl J Med. 2009;361:1139-51.
  89. 89. Clinical pearls • Minimum burden of AF that can promote atrial clot is uncertain • AF patients with high-risk markers for thromboembolism should receive anticoagulation, in the absence of a clear contraindication • Based on recent clinical trials, anticoagulation in such patients should be continued regardless of whether (and how) sinus rhythm is restored • Improved physician and patient education and compliance is required to maximize efficacy and safety of anticoagulation • New alternatives to warfarin appear to be on the horizon; they appear likely to be easier to use and are eagerly awaited Courtesy of JA Reiffel, MD.

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