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Anticoagulation – Full Curriculum

Anticoagulation – Full Curriculum. The Epidemic of Atrial Fibrillation Projected US Prevalence. 18. 16. 14. 12. Projected Number of People With AF . (millions). 10. 8. Based on Projected Incidence. 6. Based on Current Incidence. 4. 2. 0. Year. 2000. 2005. 2010. 2015. 2020.

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Anticoagulation – Full Curriculum

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  1. Anticoagulation – Full Curriculum

  2. The Epidemic of Atrial FibrillationProjected US Prevalence 18 16 14 12 Projected Number of People With AF (millions) 10 8 Based on Projected Incidence 6 Based on Current Incidence 4 2 0 Year 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Miyakasa et al. Circulation. 2006;114:119-125.

  3. Classification of AFACC/AHA/ESC Guidelines First Detected Paroxysmal(Self-terminating) Persistent(Not self-terminating) Permanent Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  4. Pharmacologic Management of Patients With Newly Discovered AFACC/AHA/ESC Guidelines Newly Discovered AF Paroxysmal Persistent No therapy needed, unless severe symptoms (eg, hypotension, HF,angina pectoris) Accept permanent AF Rate control andanticoagulation,as needed Anticoagulationand rate control,as needed Consider antiarrhythmicdrug therapy Anticoagulation, as needed Cardioversion Long-term drugprevention unnecessary Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  5. Pharmacologic Management of Patients With Recurrent Paroxysmal AF Sinus Rhythm Maintenance Recurrent Paroxysmal AF Minimal orno symptoms Disablingsymptoms in AF Anticoagulationand rate control,as needed Anticoagulationand rate control,as needed AAD therapy No drug forprevention of AF AF ablation if AAD treatment fails Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  6. Costs of Stroke in the United States • $3.4 billion paid on behalf of Medicare beneficiaries discharged from short-stay hospitals for stroke in the United States • $5692 per discharge • Initial hospital stay accounts for over 70% of costs worldwide American Heart Association. Heart Disease and Stroke Statistics–2004 Update. Caro et al. Stroke. 2000;31:582-590.

  7. Studies of Stroke in Patients With AF 8 6 4 2 0 Stroke Mortality Relative Risk Whitehall Whitehall Regional Heart Study Framingham(no heart disease) Framingham Framingham (overall) Manitoba Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  8. Stroke Rates in Placebo-Treated Patients With AFa Stroke (%) AFASAK SPAF BAATAF CAFA SPINAF EAFTb aPatients not anticoagulated; bSecondary prevention.Hart et al. Ann Intern Med.Ann Intern Med. 2007;146:857-867.

  9. Stroke Rates by Age in Patients With AF in Untreated Control Groups 9 8 7 6 5 Stroke Rate (%/year) 4 3 2 1 0 <65 65-75 >75 Age (years) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  10. Severity of Stroke With AF • 1061 patients admitted with acute ischemic stroke • 20.2% 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<.0005) Dulli et al. Neuroepidemiology. 2003;22:118-123.

  11. NO secretion by arterial endothelium and atrium reduced Due to loss of laminar flow and decreasing stretch periods Time course of recovery following SR restoration unknown Atrial abnormalities may exist independently of AF Thrombogenicity in AF: Additional Factors • Prothrombotic compounds are increased in the fibrillating atrium • Coagulation • Factor VII • Fibrinogen • D-dimer • Prothrombin fragment • Thrombin-antithrombin complex • Altered fibrinolytic balance • Increased superoxides in LAA (which degrade NO) • Platelets • P-selectin • -thromboglobulin • Platelet factor 4 Gustafsson et al. Stroke. 1990;21:47-51; Feng et al. Am J Cardiol. 2001;87:168-171; Leong et al. Am J Cardiol. 2000;86:795-797; Heppell et al. Heart. 1997;77:407-411; Mitusch et al. Thromb Haemost. 1996;75:219-223; Nagao et al. Stroke. 1995;26:1365-1368.

  12. Anticoagulation in AF: Stroke Risk Reductions Warfarin Better Control Better AFASAK Reduction ofall-cause mortality RRR 26% SPAF BAATAF CAFA SPINAFa Reduction of stroke RRR 62% EAFT Aggregate 100% 0 -50% -100% 50% aOnly SPINAF used placebo-controlled, double-blind design; no women included.Hart et al. Ann Intern Med. 1999;131:492-501.

  13. Anticoagulation in AFThe Standard of Care for Stroke Prevention WarfarinBetter ControlBetter AFASAK Unblinded SPAF Unblinded BAATAF Unblinded Terminated early CAFA SPINAFa Double-blind; men only EAFT 2o prevention; unblinded Aggregate aOnly SPINAF used placebo-controlled, double-blind design; no women included.Hart et al. Ann Intern Med. 2007;146:857-867. -100% 50% -50% 100% 0

  14. Effect of Intensity of Oral Anticoagulation on Stroke Severity N=596 patients with AF and ischemic stroke INR<2 INR2 Fatal stroke 9% 1% Severe (total dependence) 6% 4% Major (not independent) 44%38% Total 59% 43% Minor (independent) 38% 55%No neurologic sequelae 3% 2% Total 41% 57% Hylek et al. N Engl J Med. 2003;349:1019-1026.

  15. Underuse of AntithromboticTherapy in AF 597 Medicare patients with AF; Rx at hospital discharge Gage et al. Stroke. 2000;31:822-827.

  16. Use and Adequacy of Anticoagulation in AF Patients in Primary Care Practice N=660 INR above target6% No warfarin65% INR intarget range15% Subtherapeutic INR 13% Samsa et al. Arch Intern Med. 2000;160:967-973.

  17. Use and Adequacy of Anticoagulation in AF Patients on Hospital Admission SupratherapeuticINR19% No warfarin64% Therapeutic INR37% Warfarin35% Subtherapeutic INR45% Bungard et al. Pharmacotherapy. 2000;20:1060-1065.

  18. Anticoagulation With WarfarinIntensity Often Outside the Target Range International Study of Anticoagulation Management 100 INR<2 INR 2–3 INR>3 80 60 % Time in Target Range 40 20 0 US Canada France Italy Spain Ansell et al. J Thromb Thrombolysis. 2007;23:83-91.

  19. Warfarin Use in Patients With AF 100 <80 y 80 y N=5888 community residents with AF 90 80 70 60 Percentage Use 50 40 30 20 10 0 n=110 n=34 n=79 n=32 n=80 n=34 n=83 n=36 n=78 n=38 n=73 n=57 n=72 n=63 1989-1990 1990-1991 1991-1992 1992-1993 1993-1994 1994-1995 1995-1996 ExaminationYear Smith et al. Arch Intern Med. 1999;159:1574-1578.

  20. The Challenge of Nonadherence to Guidelines for AF Treatment • AF has the highest prevalence in the elderly • The elderly are at the highest risk for stroke • Thus, the elderly are most likely to benefit from anticoagulation; however, they are the least likely to receive anticoagulation

  21. Physician Questionnaire Results on AF and Warfarin • No relationship between perceived benefits of warfarin and its use • Perceived risk for hemorrhage strongly inversely associated with warfarin use (P<.001) • Estimated annual rates of warfarin-associated hemorrhage >10-fold higher than literature-based estimates • Physician attitudes reflect aversion to hemorrhagic risk that influences responses to treatment recommendations Gross et al. Clin Ther. 2003;25:1750-1764.

  22. Physician Concerns About Warfarin for Stroke Prevention in AF Risk vs benefit of warfarin • 47% benefit greatly outweigh risk • 34% risk slightly outweigh benefit • 19% risk outweigh benefit Percent History of GI Bleed Risk of Fall History ofNon-CNS Bleed History of CV Hemorrhage Frequently Cited Contraindications Monette et al. J Am Geriatr Soc. 1997;45:1060-1065.

  23. Patient Concerns About AF 91% 38% Percent 13% 9% 5% 2% Minor Side Effects Stroke Major Bleeding Cost Inconvenience Death Man-Son-Hing et al. Arch Intern Med. 1996;156:1841-1848.

  24. Patient Perceptions of AF and Anticoagulation • 61% felt that AF was not serious • 47% unaware that AF predisposed to stroke • 52% aware of reason for warfarin • 45% believed some risk associated with warfarin • 42% stated they were “careless” at times about taking warfarin Lip et al. Stroke. 2002;33:238-242.

  25. ACC/AHA/ESC Guidelines General Considerations for Anticoagulation in AF • Anticoagulation therapy is the only therapy in AF that has demonstrated mortality reduction • As a group, patients with AF are 6 times more likely to sustain stroke compared with patients in SR • Risk of stroke varies with risk factors, and decisions regarding anticoagulation should be based on stroke risk • Patients treated with rhythm control strategy are still at risk for stroke—anticoagulation cannot be discontinued indiscriminately • Anticoagulation guidelines apply to AF and atrial flutter equally Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  26. Risk vs Benefit in Anticoagulation • Estimating risk of stroke for each individual is crucial for anticoagulation decision • Risk threshold warranting anticoagulation is controversial, but most accept 2%-3% risk/year • NNT for ≤2%/year = 100 or more • NNT for ≥6%/year = 25 or less • Controversy is greatest in 3%-5% risk categories • Several risk stratification schemes exist: • AF Investigators, SPAF, Framingham, CHADS2 Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  27. Risk Factors for Stroke and Systemic Embolism Data derived from collaborative analysis of 5 untreated control groups in primary prevention trials. TIA=transient ischemic attack. Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  28. CHADS2 Risk Stratification Scheme Rockson et al. J Am Coll Cardiol. 2004;43:929-935.

  29. The CHADS2 Index Stroke Risk Score for AF van Walraven et al. Arch Intern Med. 2003;163:936-943; Nieuwlaat et al. Euro Heart Survey. Eur Heart J. 2006 (Epub).

  30. CHADS2 Risk Criteria for Stroke in Nonvalvular AF Warfarin Stroke Risk in Patients With Nonvalvular AF Not Treated With Anticoagulation According to the CHADS2 Index Patients (N=1733) CHADS2 Score (95% CI) 120 0 463 1 523 2 337 3 220 4 65 5 6 5 Adjusted Stroke Rate (%/y) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  31. Stroke Risk in New-Onset AFACP/AAFP Guidelines Warfarin a Assessment of the following comorbidities: CHF, hypertension, age ≥75, and diabetes (1 point each); history of stroke or TIA (2 points each). b Expected rate of stroke per 100 patient-years. Snow et al. Ann Intern Med. 2003;139:1009-1017.

  32. Current Recommendations for Stroke Prevention in AF American College of Chest Physicians Guidelines Will need to update when new ACCP guidelines are published in early 08 Singer et al. Chest. 2004;126(3 suppl):429S-456S.

  33. Risk-Based Approach to Antithrombotic Therapy For library only aRisk factors for thromboembolism include heart failure (HF), left ventricular ejection fraction (LVEF) less than 35%, and history of hypertension. Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  34. Risk Stratification in AF: Stroke Risk Factors • High-Risk Factors • Mitral stenosis • Prosthetic heart valve • History of stroke or TIA • Moderate-Risk Factors • Age >75 years • Hypertension • Diabetes mellitus • Heart failure or ↓ LV function Less Validated Risk Factors • Age 65-75 years • Coronary artery disease • Female gender • Thyrotoxicosis Singer et al. Chest. 2004;126:429S-456S; Fang et al. Circulation. 2005;112:1687-1691.

  35. ACC/AHA/ESC Guidelines • Warfarin (INR range 2-3) • Women age 75 years • Age 65 to 74 years with DM or CAD • LVEF <35% or fractional shortening <25%, and HTN • Age 65 years, HF • Rheumatic heart disease (mitral stenosis) • Warfarin (INR range 2-3, or higher) • Prosthetic heart valve • Prior thromboembolism • Persistent atrial thrombus on TEE • Warfarin (INR range 2-3) with optional addition of aspirin (81-325 mg) • Men age 75 years with no other risk factors For library only Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  36. ACC/AHA/ESC Guidelines • Aspirin (81-325 mg) • Age <60 years, heart disease but no risk factors • Age 60-74 years, no risk factors • Aspirin (81-325 mg) or no treatment • Age <60 years, no heart disease (lone AF) For library only Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  37. Antithrombotic Therapy for Patients With AF aIf mechanical valve, target international normalized ratio (INR) greater than 2.5. LV=left ventricular. Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  38. Special Considerations for Anticoagulation Prior to Cardioversion • For patients with AF of ≥48 hours of AF, or when duration is unknown, 3 weeks of anticoagulation with documented INR ≥ 2 are required prior to cardioversion • It may take longer than 3 weeks to achieve 3 consecutive weeks of adequate (INR ≥ 2) anticoagulation • Anticoagulation must be continued for at least 4 weeks post cardioversion • TEE can be used to assess LA for thrombus as alternative to 3-week anticoagulation (however, anticoagulation must continue for 4 weeks post cardioversion) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.

  39. Relation Between INR on the Day of Cardioversion and Risk of Thromboembolism N=1950 4 1/42 3 2/182 4/530 Confirmed Embolism (%) 2 0/779 1 0 1-1.4 1.5-1.9 2-2.4 >2.4 INR at Time of Cardioversion Gallagher et al. J Am Coll Cardiol. 2002;40:926-933.

  40. Prevalence of Atrial Thrombus With Transiently Subtherapeutic INR • 182 consecutive patients with AF and subtherapeutic INR on 2 measurements in the last 3 weeks before the scheduled cardioversion • Intra-atrial thrombus in 18 (9.9%) • None (0%) of 21 with LA dimension 4.0 cm • 11.2% with dilated LA • No difference in LVEF Shen. J Am Coll Cardiol. 2002;39(suppl):376A-377A.

  41. Anticoagulation Variability Prior to Cardioversion Time to Subtherapeutic INR After the First Therapeutic Value Number of Patients Days (midpoint) to Subtherapeutic INR Kim et al. Am J Cardiol. 2001;88:1428-1431.

  42. Achieving Adequate Anticoagulation Prior to Cardioversion Kim et al. Am J Cardiol. 2001;88:1428-1431.

  43. Warfarin Dosing and Genomics 10 9 CYP2C9 = *1/*2 GG 8 GG GG GG 7 GG GG GG GG CG GG 6 CG GG GG CG GG CG Daily Dose (mg/day) GG CG GG CG 5 CG GG GG CG CG GG CG CG CC GG CG CC 4 CG CG CC CG CC CC CG CG CC CC CG CC CC CC CC 3 CC CC CC CC CC CC CC 2 1 0 40 45 50 55 60 65 70 75 80 85 40 45 50 55 60 65 70 75 80 85 Age (years) 10 9 CYP2C9 = *1/*3 8 7 GG 6 GG Daily Dose (mg/day) GG 5 GG CG GG CG GG CG 4 GG CG GG GG CG CG CC CG CC 3 CG CC CG CC CC CC CC 2 CC CC 1 0 40 45 50 55 60 65 70 75 80 85 10 CYP2C9 = *1/*1 9 8 7 6 Daily Dose (mg/day) 5 4 3 2 1 0 Age (years) Caldwell et al.Clin Med Res. 2007;5:8-16. Age (years)

  44. Unanswered Questions About Anticoagulation in Patients Restored to SR • Does restoration of sinus rhythm prevent stroke in patients with AF? • What is the duration of anticoagulation in patients maintained in SR? • How should one determine efficacy of maintenance?

  45. Stroke Rates in AFFIRM • In AFFIRM, there were 157 ischemic strokes • At the time of stroke, only 53.5% of patients assigned to rate control and 30.8% of those assigned to rhythm control were in AF

  46. PIAF Pharmacological Intervention in Atrial Fibrillation (pilot) STAF Strategies of Treatment of Atrial Fibrillation (pilot) AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management RACE RAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Rhythm or Rate Control in AF Evidence Base 4 Randomized Trials Comparing2 Treatment Strategies The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Carlsson et al. J Am Coll Cardiol. 2003;41:1690-1696; Gronefeld. Card Electrophysiol Rev. 2003;7:113-117; Van Gelder et al. N Engl J Med. 2002;347:1834-1840.

  47. Rate Control vs Electrical Cardioversion for Persistent AF (RACE) Study • 522 patients with persistent AF/AFl 24 hours to 1 year randomized to rate vs rhythm control • Rate control to resting rate <100 bpm • Rhythm control with electrical cardioversion and serial antiarrhythmics • Follow-up 2 years • Primary end point: composite of death from cardiovascular events Van Gelder et al. N Engl J Med. 2002;347:1834-1840.

  48. RACE: Stroke Rates • Thromboembolic events in 35/522 (6.7%) • 5.5% of rate control • 7.9% of rhythm control • 6 patients had events after cessation of warfarin • 5 of these patients were in SR • 23/35 (68%) had events while taking warfarin with INR <2.0 • 17/21 (81%) bleeding episodes occurred with INR >3.0 Van Gelder et al. N Engl J Med. 2002;347:1834-1840.

  49. Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study • Long-term treatment of chronic and paroxysmal AF • Patients 65 years old or other risk factor for stroke with • AF 6 hours in last 6 months • Not continuous AF for 6 months • 1 episode documented by ECG in last 12 weeks • 1 risk factor for stroke (age 65) • Randomized to rate vs rhythm control • Both groups anticoagulated The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Waldo. Am J Cardiol. 1999; 84:698-700.

  50. AFFIRM: Stroke Rates • 74% of all strokes were ischemic • 44% occurred after warfarin discontinuation • 28% taking warfarin, but INR <2.0 • 42% occurred during AF The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833.

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