www.HRSonline.org The Epidemic of Atrial Fibrillation Projected US Prevalence 0 2 4 6 8 10 12 14 16 18 20002005201020152020202520302035204020452050 Year Projected Number of People With AF (millions) Based on Projected Incidence Based on Current Incidence
www.HRSonline.org Classification of AF ACC/AHA/ESC Guidelines Fuster et al. J Am Coll Cardiol. 2006;48:854-906. Persistent (Not self-terminating) Paroxysmal (Self-terminating) First Detected Permanent
www.HRSonline.org Pharmacologic Management of Patients With Newly Discovered AF ACC/AHA/ESC Guidelines Fuster et al. J Am Coll Cardiol. 2006;48:854-906. Newly Discovered AF Paroxysmal No therapy needed, unless severe symptoms (eg, hypotension, HF, angina pectoris) Persistent Accept permanent AF Anticoagulation and rate control, as needed Rate control and anticoagulation, as needed Consider antiarrhythmic drug therapy Long-term drug prevention unnecessary Anticoagulation, as needed Cardioversion
www.HRSonline.org Pharmacologic Management of Patients With Recurrent Paroxysmal AF Sinus Rhythm Maintenance Recurrent Paroxysmal AF Minimal or no symptoms Anticoagulation and rate control, as needed Disabling symptoms in AF Anticoagulation and rate control, as needed AAD therapy No drug for prevention of AF AF ablation if AAD treatment fails Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org 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.
www.HRSonline.org Studies of Stroke in Patients With AF0 6 4 28MortalityStroke Framingham (overall) Framingham (no heart disease) Whitehall Manitoba Whitehall Regional Heart Study Framingham Relative Risk Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Stroke Rates in Placebo-Treated Patients With AF a. a Patients not anticoagulated; b Secondary prevention. Hart et al. Ann Intern Med. Ann Intern Med. 2007;146:857-867. Stroke (%) AFASAKSPAFBAATAFCAFASPINAF EAFT b
www.HRSonline.org Stroke Rates by Age in Patients With AF in Untreated Control Groups Stroke Rate (%/year) 9 8 7 5 4 3 1 0 <6565-75>75 Age (years) 6 2 Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Severity of Stroke With AF 1061 patients admitted with acute ischemic stroke 20.2% had AF Bedridden state With AF41.2% Without AF23.7% 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.
www.HRSonline.org 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 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 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.
www.HRSonline.org Anticoagulation in AF: Stroke Risk Reductions a Only SPINAF used placebo-controlled, double-blind design; no women included. Hart et al. Ann Intern Med. 1999;131:492-501. Warfarin BetterControl Better AFASAK SPAF BAATAF CAFA SPINAF a EAFT 100% 50% 0-50% -100% Aggregate Reduction of stroke RRR 62% Reduction of all-cause mortality RRR 26%
www.HRSonline.org Anticoagulation in AF The Standard of Care for Stroke Prevention Warfarin Better Control BetterAFASAK SPAF BAATAF CAFA SPINAF a EAFT 100% 50% 0 -50% -100% Aggregate Terminated early Double-blind; men only Unblinded 2 o prevention; unblinded a Only SPINAF used placebo-controlled, double-blind design; no women included. Hart et al. Ann Intern Med. 2007;146:857-867.
www.HRSonline.org Hylek et al. N Engl J Med. 2003;349:1019-1026. N=596 patients with AF and ischemic stroke Fatal stroke9%1% Severe (total dependence)6%4% Major (not independent)44%38% Total59%43% Minor (independent)38%55% No neurologic sequelae 3% 2% Total41%57% Effect of Intensity of Oral Anticoagulation on Stroke Severity INR<2INR 2
www.HRSonline.org Gage et al. Stroke. 2000;31:822-827. 597 Medicare patients with AF; Rx at hospital discharge Underuse of Antithrombotic Therapy in AF WarfarinAspirinNeither Age (years) 65-75 >75 42% 29% 23% 21% 36% 53% Sex Male Female 38% 29% 22% 21% 42% 51% Location Urban Rural 36% 30% 23% 17% 42% 54%
www.HRSonline.org Samsa et al. Arch Intern Med. 2000;160:967-973. Use and Adequacy of Anticoagulation in AF Patients in Primary Care Practice INR above target 6% Subtherapeutic INR 13% INR in target range 15% No warfarin 65% N=660
www.HRSonline.org Bungard et al. Pharmacotherapy. 2000;20:1060-1065. Use and Adequacy of Anticoagulation in AF Patients on Hospital Admission Therapeutic INR 37% Subtherapeutic INR 45% No warfarin 64% Supratherapeutic INR 19% Warfarin 35%
www.HRSonline.org Anticoagulation With Warfarin Intensity Often Outside the Target Range Ansell et al. J Thromb Thrombolysis. 2007;23:83-91. % Time in Target Range 0 20 40 60 80 100 USCanadaFranceItalySpain INR<2INR 2–3INR>3 International Study of Anticoagulation Management
www.HRSonline.org Smith et al. Arch Intern Med. 1999;159:1574-1578. Warfarin Use in Patients With AF N=5888 community residents with AF Percentage Use 100 90 80 70 60 50 40 30 20 10 0 <80 y 80 y Examination Year n=110n=34n=79n=32n=80n=34n=83n=36n=78n=38n=73n=57n=72n=63 1989-19901990-19911991-19921992-19931993-19941994-19951995-1996
www.HRSonline.org 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
www.HRSonline.org 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.
www.HRSonline.org Physician Concerns About Warfarin for Stroke Prevention in AF Risk of Fall History of GI Bleed History of Non-CNS Bleed History of CV Hemorrhage Risk vs benefit of warfarin 47% benefit greatly outweigh risk 34% risk slightly outweigh benefit 19% risk outweigh benefit Frequently Cited Contraindications Percent Monette et al. J Am Geriatr Soc. 1997;45:1060-1065.
www.HRSonline.org Patient Concerns About AF Stroke Death Major Bleeding Inconvenience Minor Side Effects Cost Man-Son-Hing et al. Arch Intern Med. 1996;156:1841-1848. Percent 91% 38% 13% 9% 2% 5%
www.HRSonline.org Lip et al. Stroke. 2002;33:238-242. 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
www.HRSonline.org 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.
www.HRSonline.org 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.
www.HRSonline.org Risk Factors for Stroke and Systemic Embolism Risk FactorsRelative Risk Previous stroke or TIA2.5 Diabetes mellitus1.7 History of hypertension1.6 Heart failure1.4 Advanced age (continuous, per decade)1.4 Fuster et al. J Am Coll Cardiol. 2006;48:854-906. Data derived from collaborative analysis of 5 untreated control groups in primary prevention trials. TIA=transient ischemic attack.
www.HRSonline.org CHADS2 Risk Stratification Scheme Risk Factors Score CRecent congestive heart failure1 HHypertension1 A Age 75 years 1 DDiabetes mellitus1 S 2 History of stroke or transient ischemic attack 2 Rockson et al. J Am Coll Cardiol. 2004;43:929-935.
www.HRSonline.org The CHADS2 Index Stroke Risk Score for AF Score (points)Prevalence (%) Prior stroke or TIA210 Age >75 years128 Hypertension165 Diabetes mellitus118 Heart failure132 High risk 33 22 Moderate risk1-233-50 Low risk0-118-51 van Walraven et al. Arch Intern Med. 2003;163:936-943; Nieuwlaat et al. Euro Heart Survey. Eur Heart J. 2006 (Epub).
www.HRSonline.org Fuster et al. J Am Coll Cardiol. 2006;48:854-906. CHADS2 Risk Criteria for Stroke in Nonvalvular AF Warfarin Stroke Risk in Patients With Nonvalvular AF Not Treated With Anticoagulation According to the CHADS 2 Index 5 65 220 337 523 463 120 Patients (N=1733) (95% CI) 6 5 4 3 2 1 0 CHADS 2 Score Adjusted Stroke Rate (%/y)
www.HRSonline.org Stroke Risk in New-Onset AF ACP/AAFP Guidelines CHADS 2 a Score Adjusted Stroke Rate b (95% CI) CHADS 2 Risk Level 0 1.9 (1.2-3.0)Low 1 2.8 (2.0-3.8)Low 2 4.0 (3.1-5.1)Moderate 3 5.9 (4.6-7.3)Moderate 4 8.5 (6.3-11.1)High 512.5 (8.2-17.5)High 618.2 (10.5-27.4)High 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. Warfarin
www.HRSonline.org Singer et al. Chest. 2004;126(3 suppl):429S-456S. Current Recommendations for Stroke Prevention in AF American College of Chest Physicians Guidelines Risk CategoryGoal INRComment Age <65 years, no other risk factors None Aspirin 325 mg qd Age 65-75 years, no other risk factors 2.5 (2.0-3.0) Warfarin or aspirin 325 mg qd Any high-risk factor2.5 (2.0-3.0)Warfarin High-risk factors: previous TIA, systemic embolism, or stroke; HTN, LV dysfunction, and/or recent CHF; age >75 years; DM; rheumatic heart disease (mitral stenosis); and prosthetic heart valve Will need to update when new ACCP guidelines are published in early 08
www.HRSonline.org Risk-Based Approach to Antithrombotic Therapy Patient FeaturesAntithrombotic Therapy Class of Recommendation Age <60 y, no HD (lone AF) ASA (81-325 mg/d) or no therapy I Age <60 y, HD but no risk factors a ASA (81 to 325 mg/d)I Age 60-74 y, no risk factors a ASA (81 to 325 mg per day)I Age 65-74 y with DM or CADOAC (INR 2.0 to 3.0)I Age ≥75 y, womenOAC (INR 2.0 to 3.0)I Age ≥75 y, men, no other risk factors OAC (INR 2.0-3.0) or ASA (81-325 mg/d) I Age ≥65, HFOAC (INR 2.0-3.0)I LVEF <35% or fractional shortening <25%, and hypertension OAC (INR 2.0-3.0)I Rheumatic HD (mitral stenosis)OAC (INR 2.0-3.0)I Prosthetic heart valveOAC (INR 2.0-3.0 or higher)I Prior thromboembolismOAC (INR 2.0-3.0 or higher)I Persistent atrial thrombus on TEEOAC (INR 2.0-3.0 or higher)IIa a Risk 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. For library only
www.HRSonline.org Risk Stratification in AF: Stroke Risk Factors Singer et al. Chest. 2004;126:429S-456S; Fang et al. Circulation. 2005;112:1687-1691. High-Risk Factors Mitral stenosis Prosthetic heart valve History of stroke or TIA 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 Less Validated Risk Factors Age 65-75 years Coronary artery disease Female gender Thyrotoxicosis
www.HRSonline.org 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 Fuster et al. J Am Coll Cardiol. 2006;48:854-906. For library only
www.HRSonline.org 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) Fuster et al. J Am Coll Cardiol. 2006;48:854-906. For library only
www.HRSonline.org a If 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. Antithrombotic Therapy for Patients With AF Risk CategoryRecommended Therapy No risk factorsAspirin, 81 to 325 mg daily One moderate-risk factorAspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5) Any high-risk factor or more than 1 moderate-risk factor Warfarin (INR 2.0 to 3.0, target 2.5) a Less Validated or Weaker Risk FactorsModerate-Risk FactorsHigh-Risk Factors Female sex Age 65 to 74 years Coronary artery disease Thyrotoxicosis Age 75 years Hypertension Heart failure LV ejection fraction 35% or less Diabetes mellitus Previous stroke, TIA, or embolism Mitral stenosis Prosthetic heart valve a
www.HRSonline.org 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.
www.HRSonline.org Relation Between INR on the Day of Cardioversion and Risk of Thromboembolism Gallagher et al. J Am Coll Cardiol. 2002;40:926-933. Confirmed Embolism (%) 4 3 2 1 0 1-1.41.5-1.92-2.4>2.4 0/779 4/530 2/182 1/42 INR at Time of Cardioversion N=1950
www.HRSonline.org 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.
www.HRSonline.org Anticoagulation Variability Prior to Cardioversion Number of Patients Days (midpoint) to Subtherapeutic INR Kim et al. Am J Cardiol. 2001;88:1428-1431. Time to Subtherapeutic INR After the First Therapeutic Value
www.HRSonline.org Achieving Adequate Anticoagulation Prior to Cardioversion n (interquartile range) INR checks 9 (6-11) Days to 1st therapeutic INR 7 (4-15) Days to 3 weeks therapeutic INR35 (27-47) Days to cardioversion58 (41-78) Kim et al. Am J Cardiol. 2001;88:1428-1431.
www.HRSonline.org Warfarin Dosing and Genomics Caldwell et al. Clin Med Res. 2007;5:8-16. Age (years) CYP2C9 = *1/*1 Age (years) Daily Dose (mg/day) 0 2 4 6 8 10 1 3 5 7 9 404550556065707580 85 CG GG CG CC CYP2C9 = *1/*3 Daily Dose (mg/day) 0 2 4 6 8 10 1 3 5 7 9 404550556065707580 85 CG GG CG CC CYP2C9 = *1/*2 Daily Dose (mg/day) 0 2 4 6 8 10 1 3 5 7 9 404550556065707580 85 Age (years) CG GG CG CC
www.HRSonline.org 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?
www.HRSonline.org 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
www.HRSonline.org Rhythm or Rate Control in AF Evidence Base PIAFPharmacological Intervention in Atrial Fibrillation (pilot) STAFStrategies of Treatment of Atrial Fibrillation (pilot) AFFIRMAtrial Fibrillation Follow-up Investigation of Rhythm Management RACERAte Control versus Electrical Cardioversion for Persistent Atrial Fibrillation 4 Randomized Trials Comparing 2 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.
www.HRSonline.org 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.
www.HRSonline.org Van Gelder et al. N Engl J Med. 2002;347:1834-1840. 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
www.HRSonline.org The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Waldo. Am J Cardiol. 1999; 84:698-700. 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
www.HRSonline.org 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.
www.HRSonline.org AFFIRM Results CovariateP ValueHazard Ratio99% CI Sinus rhythm<.00010.530.39-0.72 Warfarin use<.00010.500.37-0.69 Digoxin use.00071.421.09-1.86 AAD use.00051.491.11-2.01 Time-Dependent Covariates Associated With Survival Epstein. Presented at the American Heart Association’s Scientific Sessions 2003. November 2003; Orlando, FL. HR <1.00: decreased risk of death. HR >1.00: increased risk of death.
www.HRSonline.org AFFIRM and RACE Conclusions Trials were to compare end points in rate control vs rhythm control One hypothesis was that sinus rhythm will reduce the stroke rate Critical finding was that rhythm control did not protect from stroke, even though patients were thought to be in SR Patients may have paroxysms of AF that go undetected The AFFIRM Investigators. N Engl J Med. 2002;347:1825-1833; Van Gelder et al. N Engl J Med. 2002;347:1834-1840.
www.HRSonline.org Strokes in Patients Converted to SR n Rate control Rhythm control RR (95% CI)P AFFIRM49175.7%7.3%1.28 (0.95-1.72).12 RACE5225.5%7.9%1.44 (0.75-2.78).44 STAF2661.0%3.0%3.01 (0.35-25.30).52 PIAF2520.8% 1.02 (0.73-2.16).49 Total59575.0%6.5%1.28 (0.98-1.66).08 Verheugt et al. J Am Coll Cardiol. 2003;41(suppl):130A.
www.HRSonline.org Page et al. Circulation. 2003;107:1141-1145. Azimilide (382) Proportion Free of Asymptomatic Event Placebo (233) Placebo 100 mg or 125 mg azimilide 0.5 0.6 0.7 0.8 0.9 1.0 02468101214161820222426 Prevalence of Asymptomatic AF in Drug Trials Patients Studied for 30 Seconds Every 2 Weeks Time (weeks)
www.HRSonline.org Detection of Recurrent AF: ECG vs Implanted Device Recording FU=follow-up. Israel et al. J Am Coll Cardiol. 2004;43:47-52. Number of Patients 100 80 60 40 20 BaselineFU1FU2FU3FU4FU5FU10FU9FU8FU7FU6 n=110110 85731525394860 P<.0001 Implanted device ECG
www.HRSonline.org Prevalence of Recurrent AF During Follow-up Israel et al. J Am Coll Cardiol. 2004;43:47-52. Patients (%) 70 60 50 40 30 20 10 0 AF >72 hAF >48 hAF >24 hAF >12 hAF <12 h
www.HRSonline.org Intracranial Hemorrhage: The Most-Feared Complication of Antithrombotic Therapy >10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapy Aspirin increases the risk of ICH by ~40% Warfarin (INR 2-3) doubles the risk of ICH to 0.3%-0.6% per year ICH during anticoagulation is usually catastrophic Hart et al. Stroke. 2005;36:1588-1593.
www.HRSonline.org Absolute Rates of Primary ICH General population, age ~70 y0.15%/y Aspirin (any dosage) Atrial fibrillation0.2%/y Cerebrovascular disease0.3%/y Aspirin plus clopidogrel Atrial fibrillation0.3%/y Cerebrovascular disease0.4%/y Warfarin (INR 2.5) Atrial fibrillation0.3-0.6%/y Cerebrovascular disease0.4-1.0%/y Warfarin (INR 2.5) plus aspirin0.5-1.0%/y Hart et al. Stroke. 2005;36:1588-1593. Estimated Absolute Rates of Primary Intracerebral Hemorrhage
www.HRSonline.org CNS Bleeding and Anticoagulation Hart et al. Stroke. 2005;36:1588-1593. Intracranial Hemorrhage vs Anticoagulation Intensity in AF Patients: 2 Recent Studies For library only Absolute rateRelative risk Reference point INR INR Case Control Study mean age: cases=78 y; controls 75 y Longitudinal Cohort Study mean age =71 years
www.HRSonline.org CNS Bleeding and Anticoagulation Hart et al. Stroke. 2005;36:1588-1593. Intracranial Hemorrhage vs Anticoagulation Intensity in AF Patients: 2 Recent Studies Longitudinal Cohort StudyCase Control Study Absolute RateRelative Risk Mean age, 71 years Mean age, cases=78 years, controls=75 years INR Rate per 100 Person-YearsINRRelative Risk <1.50.5<1.51.4 1.5-188.8.131.52-1.91.2 2.0-184.108.40.206-3.01.0 (reference) 2.6-3.00.5—— 3.1-220.127.116.11-3.41.4 3.6-18.104.22.168-3.94.6 4.0-4.52.7>4.08.8 >4.59.4—— For library only
www.HRSonline.org INR at the Time of Stroke or Bleeding Efficacy and Safety of Warfarin5.06.08.01.02.03.04.07.0 5 15 10 Ischemic stroke Intracranial bleeding 1 20 Odds Ratio INR Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org ICH During Long-term Anticoagulation With Warfarin Meta-analysis a PV=prosthetic valves. Levine et al. Chest. 2001;119:108S-121S. ICH (%/year) Fihn (AF) INR <3.0 Fihn (>75) Turpie (PV a ) SPAF- 2 ( 75) SPAF (AF) Pengo (PV a ) SPAF- 2 ( 75) SPAF- 3 (AF) INR 2.0-4.5 INR 2.0-3.0 INR 2.5-3.5 INR 3.0-4.5 INR 2.0-4.5
www.HRSonline.org Antithrombotic Therapy for AF ACC/AHA/ESC Guidelines 2006 Risk CategoryRecommended Therapy No risk factors CHADS 2 = 0 Aspirin, 81-325 mg qd One moderate-risk factor CHADS 2 = 1 Aspirin, 81-325 mg/d or warfarin (INR 2.0-3.0, target 2.5) Any high-risk factor or >1 moderate-risk factor CHADS 2 2 or mitral stenosis Warfarin (INR 2.0-3.0, target 2.5) Prosthetic valve Warfarin (INR 2.5-3.5, target 3.0) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class I Recommendations: Preventing Thromboembolism Antithrombotic therapy for all patients with AF, except those with lone AF or contraindications. (Level of Evidence: A) Antithrombotic agent should be based on absolute risk of stroke and bleeding and RR and benefit for patient. (Level of Evidence: A) For patients without mechanical heart valves at high risk of stroke, warfarin is recommended in a dose adjusted to achieve INR of 2.0 to 3.0, unless contraindicated. (Level of Evidence: A) Anticoagulation with a VKA for patients with >1 moderate-risk factor (eg, ≥75 y, HTN, HF, impaired LV systolic function, and DM). (Level of Evidence: A) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class I Recommendations (cont’d) INR determined at least weekly during initiation of therapy and monthly when anticoagulation is stable. (Level of Evidence: A) Aspirin, 81-325 mg daily, as an alternative to VKA in low-risk patients or those with contraindications to oral anticoagulation. (Level of Evidence: A) For patients with AF who have mechanical heart valves, target intensity of anticoagulation should be based on type of prosthesis, maintaining an INR of at least 2.5. (Level of Evidence: B) Antithrombotic therapy is recommended for patients with AFl as for those with AF. (Level of Evidence: C) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class IIa Recommendations: Preventing Thromboembolism For patients with nonvalvular AF and 1 of the following risk factors, treatment with aspirin or a VKA is reasonable, based on risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences: age ≥75 y (especially in women), HTN, HF, impaired LV function, or DM. (Level of Evidence: A) For patients with nonvalvular AF with ≥1 of the following risk factors, antithrombotic therapy with aspirin or a VKA is reasonable: age 65 to 74 y, female gender, or CAD. Agent choice should be based upon the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences. (Level of Evidence: B) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class IIa Recommendations (cont’d) Select antithrombotic therapy using the same criteria irrespective of the pattern (ie, paroxysmal, persistent, or permanent) of AF. (Level of Evidence: B) In patients with AF w/o mechanical prosthetic heart valves, it is reasonable to interrupt anticoagulation for up to 1 wk without substituting heparin for surgical or diagnostic procedures that carry a risk of bleeding. (Level of Evidence: C) It is reasonable to re-evaluate the need for anticoagulation at regular intervals. (Level of Evidence: C) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class IIb Recommendations: Preventing Thromboembolism In patients ≥75 y at risk of bleeding but w/o contraindications to oral anticoagulant therapy, and patients with moderate-risk factors who can’t tolerate anticoagulation at INR 2.0 to 3.0, an INR of 2.0 (range 1.6 to 2.5) may be considered for primary prevention of ischemic stroke and systemic embolism. (Level of Evidence: C) When surgical procedures interrupt oral anticoagulant therapy for longer than 1 wk in high-risk patients, unfractionated heparin (UH) may be administered or low-molecular-weight heparin (LMWH) given by SC injection. (Level of Evidence: C) Following PCI or revascularization in patients with AF, low-dose aspirin (less than 100 mg daily) and/or clopidogrel (75 mg daily) may be given concurrently with anticoagulation to prevent myocardial ischemic events. (Level of Evidence: C) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class IIb Recommendations (cont’d) During PCI, anticoagulation may be interrupted, but VKA should be resumed soon after PCI and the dose adjusted to an INR in the therapeutic range. Aspirin may be given temporarily, but maintenance should consist of combination of clopidogrel, 75 mg daily, plus warfarin (INR 2.0 to 3.0). Clopidogrel should be given for ≥1 mo after implantation of a bare metal stent, ≥3 mo for a sirolimus-eluting stent, ≥6 mo for a paclitaxel-eluting stent, and ≥12 mo in selected patients, after which warfarin may be given as monotherapy in the absence of a subsequent coronary event. (Level of Evidence: C) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class IIb Recommendations (cont’d) In patients with AF younger than 60 y without heart disease or risk factors for thromboembolism (lone AF), the risk of thromboembolism is low without treatment and the effectiveness of aspirin for primary prevention of stroke relative to the risk of bleeding has not been established. (Level of Evidence: C) In patients with AF who sustain ischemic stroke or systemic embolism during treatment with low-intensity anticoagulation (INR 2.0 to 3.0), rather than add an antiplatelet agent, it may be reasonable to raise the intensity of anticoagulation to a maximum target INR of 3.0 to 3.5. (Level of Evidence: C) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Class III Recommendations Preventing Thromboembolism Long-term anticoagulation with a VKA is not recommended for primary prevention of stroke in patients <60 y w/o heart disease (lone AF) or any risk factors for thromboembolism. (Level of Evidence: C) Fuster et al. J Am Coll Cardiol. 2006;48:854-906.
www.HRSonline.org Patient Selection for Anticoagulation: Additional Considerations Risk of bleeding Newly anticoagulated vs established therapy Availability of high-quality anticoagulation management program Patient preferences
www.HRSonline.org CMS Physician Quality Reporting Initiative Measure #33 – Stroke and stroke rehabilitation: anticoagulant therapy at discharge for AF Percent of patients ≥18 years with ischemic stroke/TIA and permanent, persistent, or paroxysmal AF given A/C at D/C: Report for patients with ischemic stroke/TIA with documented AF at discharge Patients given anticoagulant at D/C All patients ≥18 years with ischemic stroke or TIA and permanent, persistent, or paroxysmal AF US Department of Health and Human Services. http://www.cms.hhs.gov/PQRI/Downloads/ PQRIMeasuresList.pdf. Accessed on November 14, 2007.
www.HRSonline.org CMS Physician Quality Reporting Initiative Clinical recommendation statements Antithrombotic therapy (oral A/C or ASA) to all patients with AF, except lone AF (ACC/AHA/ESC, 2001) (Class I, Level of Evidence: A) Long-term oral A/C (target INR 2.5; range 2.0-3.0) in AF patients with recent stroke/TIA (Albers, ACCP, 2001) (Grade 1A) Oral A/C also beneficial in patients with several other high-risk factors (Albers, ACCP, 2001) (Grade 1A) Oral A/C (target INR, 2.5; range 2.0-3.0) for patients with ischemic stroke/TIA with permanent, persistent, or paroxysmal AF (Sacco, ASA, 2006) (Class I, Level of Evidence: A) US Department of Health and Human Services. http://www.cms.hhs.gov/PQRI/Downloads/ PQRIMeasuresList.pdf. Accessed on November 14, 2007.