PREVENTING Atrial Fibrillation Related STROKES with Anticoagulants

PREVENTING Atrial Fibrillation Related STROKES with Anticoagulants
September June 2013

Disclosure of Commercial Support
PREVENTING Atrial Fibrillation Related STROKES with Anticoagulants Disclosure of Commercial Support This activity is supported by educational grants from Boehringer Ingelheim Pharmaceuticals, Inc. and Bristol-Myers Squibb and Pfizer Inc. This slide presentation and artwork was independently developed by Boston University School of Medicine’s Powerpoint designer. Boston University School of Medicine’s Disclosure Policy Boston University School of Medicine asks all individuals involved in the development and presentation of Continuing Medical Education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve any apparent conflicts of interest. In addition, faculty members are asked to disclose when any unapproved use of pharmaceuticals and devices is being discussed. Speaker notes: Read off commercial support statement and mention slides independently developed.

Accreditation Information
PREVENTING Atrial Fibrillation Related STROKES with Anticoagulants Accreditation Information This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Boston University School of Medicine and Anticoagulation Forum. Boston University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Boston University School of Medicine designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Continuing Nursing Education Provider Unit, Boston University School of Medicine is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. CNE Contact Hours: 1.00 Nurses will receive contact hours for those sessions attended, after completion of an evaluation and claim for credit form. Speaker Note: Do not need to read this through- again in syllabus and just supplied here as backup. Continuing Pharmacy Education Credits The University of Rhode Island College of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Attendance and completion of program evaluations at the conclusion of the program are required for a statement of credit. This knowledge-based activity is approved for 1.0 Contact Hours (0.1 CEUs). UAN: L01-P. Expiration date: September 5, 2013.

Learning Objectives At the conclusion of this activity participants will be able to: Describe benefits of oral anticoagulants for stroke prevention in atrial fibrillation Identify the population of patients who would be at risk of stroke with atrial fibrillation Compare current and new oral anticoagulants with regards to safety, efficacy, pharmacology, cost and convenience Compare the benefits and risks of oral anticoagulant therapy for reducing the risk of stroke in atrial fibrillation patients Utilize available decision making tools to stratify the risks and benefits of anticoagulation therapy in patients with atrial fibrillation : Speaker Notes: Do not need to read through these- in syllabus.

Highlights Prevalence and incidence of AF Risk stratification for stroke and bleeding New oral anticoagulants Guidelines Practical considerations for choosing an anticoagulant

Question #1 An 82 year old man is in your office for an annual Medicare physical. What is the chance he has atrial fibrillation? 1% 5% 10% 25%

Prevalence of Diagnosed AF
Stratified by Age and Sex Men surpass women in every age range x-axis = % y-axis = # of men/women JAMA. 2001 May 9;285(18): Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Source Division of Research, Kaiser Permanente of Northern California, 3505 Broadway, 12th Floor, Oakland, CA 94611, USA. CONTEXT: Atrial fibrillation is the most common arrhythmia in elderly persons and a potent risk factor for stroke. However, recent prevalence and projected future numbers of persons with atrial fibrillation are not well described. OBJECTIVE: To estimate prevalence of atrial fibrillation and US national projections of the numbers of persons with atrial fibrillation through the year 2050. DESIGN, SETTING, AND PATIENTS: Cross-sectional study of adults aged 20 years or older who were enrolled in a large health maintenance organization in California and who had atrial fibrillation diagnosed between July 1, 1996, and December 31, 1997. MAIN OUTCOME MEASURES: Prevalence of atrial fibrillation in the study population of 1.89 million; projected number of persons in the United States with atrial fibrillation between RESULTS: A total of adults with diagnosed atrial fibrillation were identified during the study period; 45% were aged 75 years or older. The prevalence of atrial fibrillation was 0.95% (95% confidence interval, 0.94%-0.96%). Atrial fibrillation was more common in men than in women (1.1% vs 0.8%; P<.001). Prevalence increased from 0.1% among adults younger than 55 years to 9.0% in persons aged 80 years or older. Among persons aged 50 years or older, prevalence of atrial fibrillation was higher in whites than in blacks (2.2% vs 1.5%; P<.001). We estimate approximately 2.3 million US adults currently have atrial fibrillation. We project that this will increase to more than 5.6 million (lower bound, 5.0; upper bound, 6.3) by the year 2050, with more than 50% of affected individuals aged 80 years or older. CONCLUSIONS: Our study confirms that atrial fibrillation is common among older adults and provides a contemporary basis for estimates of prevalence in the United States. The number of patients with atrial fibrillation is likely to increase 2.5-fold during the next 50 years, reflecting the growing proportion of elderly individuals. Coordinated efforts are needed to face the increasing challenge of optimal stroke prevention and rhythm management in patients with atrial fibrillation. PMID: # Women 530 310 566 896 1498 1572 1291 1132 # Men 1529 634 934 1426 1907 1886 1374 759 Go AS, JAMA May 9;285(18): Pub Med PMID:

Question #2 A 46 year old male patient is in for an annual physical exam. What is his lifetime risk of developing AF? 1% 5% 10% 25%

1 in 4 Incidence of AF Men & women >40 Years will develop AF
Lifetime Risk for AF at Selected Index Ages by Sex Index Age, yrs Men Women 40 26.0% (24.0 – 27.0) 23.0% (21.0 – 24.0) 50 25.9% (23.9 – 27.0) 23.2% (21.3 – 24.3) 60 25.8% (23.7 – 26.9) 23.4% (21.4 – 24.4) 70 24.3% (22.1 – 25.5) 23.0% (20.9 – 24.1) 80 22.7% (20.1 – 24.1) 21.6% (19.3 – 22.7) Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Circulation Aug 31;110(9): Epub 2004 Aug 16. PMID: Circulation. 2004 Aug 31;110(9): Epub 2004 Aug 16. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Source Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University Feinberg School of Medicine, 680 N Lake Shore Drive, Suite 1102, Chicago, IL, 60611, USA. BACKGROUND: Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated. METHODS AND RESULTS: We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 ( person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%. CONCLUSIONS: Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies. 1 in 4 Men & women >40 Years will develop AF Lifetime risk if currently free of AF Lloyd-Jones DM, et al. Circulation Aug 31;110(9): Pub Med PMID:

Question #3 68 year old female with atrial fibrillation and no other co-morbidities. How would you classify her stroke risk? Low Moderate High

Scoring Systems in Atrial Fibrillation
Given that anticoagulant therapy has both risks (principally bleeding) and benefits (a reduced risk of thrombosis) many authors have attempted to produce scoring systems which estimate the risks of these outcomes No one scoring system is universally accepted or highly predictive (in individual patients)

Scoring Systems in Stroke Risk
A variety of systems have been published Outlined on next slide All use selected clinical characteristics to predict the risk of stroke Most widely used is the CHADS2 score All scores provide a rough estimate of risk of thrombosis in a population at similar risk as patient being reviewed

Atrial Fibrillation Risk Stratification
12 Schemes applied to 1000 patients from SPAF III study High Moderate Low Figure. Relative distribution of patients predicted to have high (black), moderate (gray), and low (white) stroke risk by applying different risk stratification schemes to a representative cohort of atrial fibrillation patients. The mean age was 72 years and the frequencies of female sex, hypertension, diabetes, heart failure, systolic blood pressure >160 mm Hg, coronary artery disease, and previous stroke/TIA were 40%, 56%, 15%, 29%, 12%, 24%, and 10%, respectively. For the Framingham Heart Study criteria,15 high risk was considered ≥14 points, moderate risk was 8 to 13 points, and low risk was ≤7 points. For Van Walraven et al,14 there are only 2 risk strata: low risk and combined moderate and high risk. Because the European Atrial Fibrillation Trial criteria were intended to apply to patients with recent previous stroke/TIA, it is not included.8 See Table 2⇑⇑ for study abbreviations. Stroke. 2008 Jun;39(6): Epub 2008 Apr 17. Comparison of 12 risk stratification schemes to predict stroke in patients with nonvalvular atrial fibrillation. Stroke Risk in Atrial Fibrillation Working Group. Collaborators (16) BACKGROUND AND PURPOSE: More than a dozen schemes for stratifying stroke risk in patients with nonvalvular atrial fibrillation have been published. Differences among these schemes lead to inconsistent stroke risk estimates for many atrial fibrillation patients, resulting in confusion among clinicians and nonuniform use of anticoagulation. METHODS: Twelve published schemes stratifying stroke risk in patients with nonvalvular atrial fibrillation are analyzed, and observed stroke rates in independent test cohorts are compared with predicted risk status. RESULTS: Seven schemes were based directly on event-rate analyses, whereas 5 resulted from expert consensus. Four considered only clinical features, whereas 7 schemes included echocardiographic variables. The number of variables per scheme ranged from 4 to 8 (median, 6). The most frequently included features were previous stroke/TIA (100% of schemes), patient age (83%), hypertension (83%), and diabetes (83%), and 8 additional variables were included in >/=1 schemes. Based on published test cohorts, all 8 tested schemes stratified stroke risk, but the absolute stroke rates varied widely. Observed rates for those categorized as low risk ranged from 0% to 2.3% per year and those categorized as high risk ranged from 2.5% to 7.9% per year. When applied to the same cohorts, the fractions of patients categorized by the different schemes as low risk varied from 9% to 49% and those categorized by the different schemes as high-risk varied from 11% to 77%. CONCLUSIONS: There are substantial, clinically relevant differences among published schemes designed to stratify stroke risk in patients with atrial fibrillation. Additional research to identify an optimum scheme for primary prevention and subsequent standardization of recommendations may lead to more uniform selection of patients for anticoagulant prophylaxsis. Stroke Risk in Atrial Fibrillation Working Group. Stroke Jun;39(6): Pub Med PMID:

NRAF Crude Stroke Rate per 100 Patient-yrs
CHADS2: Risk of Stroke National Registry of Atrial Fibrillation Participants (NRAF) CHADS2 Score # Patients (n = 1733) # Strokes (n = 94) NRAF Crude Stroke Rate per 100 Patient-yrs NRAF Adjusted Stroke Rate (95% CI)† 120 2 1.2 1.9 ( ) 1 463 17 2.8 2.8 ( ) 523 23 3.6 4.0 ( ) 3 337 25 6.4 5.9 ( ) 4 220 19 8.0 8.5 ( ) 5 65 6 7.7 12.5 ( ) 44.0 18.2 ( ) Adjusted stroke rate is the expected stroke rate per 100 patient-years from the exponential survival model, assuming that aspirin was not taken. JAMA. 2001 Jun 13;285(22): Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Source Division of General Medical Sciences, Washington University School of Medicine Campus, Box 8005, 660 S Euclid Ave, St Louis, MO 63110, USA. CONTEXT: Patients who have atrial fibrillation (AF) have an increased risk of stroke, but their absolute rate of stroke depends on age and comorbid conditions. OBJECTIVE: To assess the predictive value of classification schemes that estimate stroke risk in patients with AF. DESIGN, SETTING, AND PATIENTS:Two existing classification schemes were combined into a new stroke-risk scheme, the CHADS( 2) index, and all 3 classification schemes were validated. The CHADS( 2) was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack. Data from peer review organizations representing 7 states were used to assemble a National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge. MAIN OUTCOME MEASURE:Hospitalization for ischemic stroke, determined by Medicare claims data. RESULTS:During 2121 patient-years of follow-up, 94 patients were readmitted to the hospital for ischemic stroke (stroke rate, 4.4 per 100 patient-years). As indicated by a c statistic greater than 0.5, the 2 existing classification schemes predicted stroke better than chance: c of 0.68 (95% confidence interval [CI], ) for the scheme developed by the Atrial Fibrillation Investigators (AFI) and c of 0.74 (95% CI, ) for the Stroke Prevention in Atrial Fibrillation (SPAF) III scheme. However, with a c statistic of 0.82 (95% CI, ), the CHADS( 2) index was the most accurate predictor of stroke. The stroke rate per 100 patient-years without antithrombotic therapy increased by a factor of 1.5 (95% CI, ) for each 1-point increase in the CHADS( 2) score: 1.9 (95% CI, ) for a score of 0; 2.8 (95% CI, ) for 1; 4.0 (95% CI, ) for 2; 5.9 (95% CI, ) for 3; 8.5 (95% CI, ) for 4; 12.5 (95% CI, ) for 5; and 18.2 (95% CI, ) for 6. CONCLUSION:The 2 existing classification schemes and especially a new stroke risk index, CHADS( 2), can quantify risk of stroke for patients who have AF and may aid in selection of antithrombotic therapy. PMID: [PubMed - indexed for MEDLINE] Scoring: 1 point: Congestive heart failure, HTN, < 75 years, and DM 2 points: Stroke history or transient ischemic attack † Expected stroke rate per 100 pt-yrs from the exponential survival model, assuming aspirin not taken Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. JAMA Jun 13;285(22): Pub Med PMID:

CHA2DS2-VASc 2009 Birmingham Schema Expressed as a Point-Based Scoring System Risk Factor Score Congestive heart failure/LV dysfunction 1 Hypertension Age ≥ 75 y 2 Diabetes mellitus Stroke/TIA/TE Vascular disease (prior myocardial infarction, peripheral artery disease, or aortic plaque) Age y Sex category (i.e. female gender) Chest. 2010 Feb;137(2): Epub 2009 Sep 17. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Source University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK. BACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included. METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF. RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003). CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. This schema could improve our approach to stroke risk stratification in patients with AF. Comment in CHA2DS2-VASc risk scheme: not ready for clinical use. [Chest. 2010] Obstructive sleep apnea is a risk factor for stroke and atrial fibrillation. [Chest. 2010] LV = left ventricular; TE = thromboembolism Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest Feb;137(2): Pub Med PMID:

TE Rate During 1 yr, Adjusted for
CHA2DS2-VASc Stroke or Other TE at One Year CHA2DS2-VASc Score # #TE Events TE Rate During 1 yr (95% CI) TE Rate During 1 yr, Adjusted for Aspirin RX 103 0% (0-0) 0% 1 162 0.6% ( ) 0.7% 2 184 3 1.6% ( ) 1.9% 203 8 3.9% ( ) 4.7% 4 208 1.9% ( ) 2.3% 5 95 3.2% ( ) 3.9% 6 57 3.6% ( ) 4.5% 7 25 8.0% ( ) 10.1% 9 11.1% ( ) 14.2% 100% ( ) 100% Total 1,084 P Value for trend 0.003 Table 6—Stroke or Other TE at 1 Year Based on the 2009 Birmingham (CHA2DS2-VASc) Scoring System See Tables 1 and 2 for expansion of abbreviations. Theoretical TE rates without therapy: corrected for the % of patients receiving aspirin within each group, assuming that aspirin provides a 22% reduction in TE risk, based on Hart et al Chest. 2010 Feb;137(2): Epub 2009 Sep 17. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Source University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK. BACKGROUND: Contemporary clinical risk stratification schemata for predicting stroke and thromboembolism (TE) in patients with atrial fibrillation (AF) are largely derived from risk factors identified from trial cohorts. Thus, many potential risk factors have not been included. METHODS: We refined the 2006 Birmingham/National Institute for Health and Clinical Excellence (NICE) stroke risk stratification schema into a risk factor-based approach by reclassifying and/or incorporating additional new risk factors where relevant. This schema was then compared with existing stroke risk stratification schema in a real-world cohort of patients with AF (n = 1,084) from the Euro Heart Survey for AF. RESULTS: Risk categorization differed widely between the different schemes compared. Patients classified as high risk ranged from 10.2% with the Framingham schema to 75.7% with the Birmingham 2009 schema. The classic CHADS(2) (Congestive heart failure, Hypertension, Age > 75, Diabetes, prior Stroke/transient ischemic attack) schema categorized the largest proportion (61.9%) into the intermediate-risk strata, whereas the Birmingham 2009 schema classified 15.1% into this category. The Birmingham 2009 schema classified only 9.2% as low risk, whereas the Framingham scheme categorized 48.3% as low risk. Calculated C-statistics suggested modest predictive value of all schema for TE. The Birmingham 2009 schema fared marginally better (C-statistic, 0.606) than CHADS(2). However, those classified as low risk by the Birmingham 2009 and NICE schema were truly low risk with no TE events recorded, whereas TE events occurred in 1.4% of low-risk CHADS(2) subjects. When expressed as a scoring system, the Birmingham 2009 schema (CHA(2)DS(2)-VASc acronym) showed an increase in TE rate with increasing scores (P value for trend = .003). CONCLUSIONS: Our novel, simple stroke risk stratification schema, based on a risk factor approach, provides some improvement in predictive value for TE over the CHADS(2) schema, with low event rates in low-risk subjects and the classification of only a small proportion of subjects into the intermediate-risk category. This schema could improve our approach to stroke risk stratification in patients with AF. Comment in CHA2DS2-VASc risk scheme: not ready for clinical use. [Chest. 2010] Obstructive sleep apnea is a risk factor for stroke and atrial fibrillation. [Chest. 2010] Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Chest Feb;137(2): Pub Med PMID:

CHA2DS2-VASc and CHADS2 Score 0–1
Refines stroke risk stratification in AF patients: nationwide cohort 1 Year Follow-up 12 Years Follow-up Person Yrs Events Stroke rate (95%CI) CHADS2 score 0–1 40,272 1,405 3.49 (3.31–3.68) 187,200 4,599 2.46 (2.39–2.53) CHA2DS2-VASc = 0 6,919 58 0.84 (0.65–1.08) 39,500 299 0.76 (0.68–0.85) CHA2DS2-VASc = 1 8,880 159 1.79 (1.53–2.09) 45,926 662 1.44 (1.34–1.56) CHA2DS2-VASc = 2 11,863 435 3.67 (3.34–4.03) 51,595 1,489 2.89 (2.74–3.04) CHA2DS2-VASc = 3 11,473 660 5.75 (5.33–6.21) 45,799 1,933 4.22 (4.04–4.41) CHA2DS2-VASc = 4 1,137 93 8.18 (6.68–10.02) 4,380 216 4.93 (4.32–5.64) CHADS2 score = 0 17,327 275 1.59 (1.41–1.79) 92,531 1182 1.28 (1.21–1.35) 6,811 119 1.75 (1.46–2.09) 35,079 504 1.44 (1.32–1.57) CHA2DS2-VASc = 2 3,347 90 2.69 (2.19–3.31) 16,710 353 2.11 (1.90–2.34) 250 8 3.20 (1.60–6.40) 1,242 26 2.09 (1.43–3.07) CHADS2 Score = 1 22,945 1,130 4.92 (4.65–5.22) 94,669 3417 3.61 (3.49–3.73) 2,069 40 1.93 (1.42–2.64) 10,847 158 1.46 (1.25–1.70) 8,516 345 4.05 (3.65–4.50) 34,885 1136 3.26 (3.07–3.45) 11,223 652 5.81 (5.38–6.27) 44,557 1907 4.28 (4.09–4.48) Incorrect date on ref of original slide: Olesen JB. Thromb Haemost May 31;107(6): PMID: – should be June Table 2: Event rate of stroke/thromboembolism per 100 person years in atrial fibrillation patients. 1 year follow-up 12 years follow-up Thromb Haemost. 2012 Jun;107(6): Epub 2012 Apr 3. The value of the CHA2DS2-VASc score for refining stroke risk stratification in patients with atrial fibrillation with a CHADS2 score 0-1: a nationwide cohort study. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. Source Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark. Abstract North American and European guidelines on atrial fibrillation (AF) are conflicting regarding the classification of patients at low/intermediate risk of stroke. We aimed to investigate if the CHA2DS2-VASc score improved risk stratification of AF patients with a CHADS2 score of 0-1. Using individual-level-linkage of nationwide Danish registries , we identified patients discharged with AF having a CHADS2 score of 0-1 and not treated with vitamin K antagonist or heparin. In patients with a CHADS2 score of 0, 1, and 0-1, rates of stroke/ thromboembolism were determined according to CHA2DS2-VASc score, and the risk associated with increasing CHA2DS2-VASc score was estimated in Cox regression models adjusted for year of inclusion and antiplatelet therapy. The value of adding the extra CHA2DS2-VASc risk factors to the CHADS2 score was evaluated by c-statistics, Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI). We included 47,576 patients with a CHADS2 score of 0-1, from these 7,536 (15.8%) were CHA2DS2-VASc score=0, 10,062 (21.2%) were CHA2DS2-VASc score=1, 14,310 (30.1%) were CHA2DS2-VASc score=2, 14,188 (29.8%) were CHA2DS2-VASc score=3, and 1,480 (3.1%) were CHA2DS2-VASc score=4. Of the cohort with a CHADS2 score of 0-1, the stroke/thromboembolism rate per 100 person-years increased with increasing CHA2DS2-VASc score (95% confidence interval): 0.84 ( ), 1.79 ( ), 3.67 ( ), 5.75 ( ), and 8.18 ( ) at one year follow-up with CHA2DS2-VASc scores of 0, 1, 2, 3, and 4, respectively. Patients with a CHADS2 score=0 were not all 'low risk', with one-year event rates ranging from 0.84 (CHA2DS2-VASc score=0) to 3.2 (CHA2DS2-VASc score=3). Results from Cox regression analyses, NRI, and IDI confirmed the improved predictive ability of the CHA2DS2-VASc score in the AF patients who have a CHADS2 score of 0-1. In conclusion, the CHA2DS2-VASc provides critical information on risk of stroke in AF patients with a CHADS2 score of 0-1 that can aid a decision of using anticoagulation. Even in patients categorised as 'low risk' using a CHADS2 score=0, the CHA2DS2-VASc score significantly improved the predictive value of the CHADS2 score alone and a CHA2DS2-VASc score=0 could clearly identify 'truly low risk' subjects. Use of the CHA2DS2-VASc score would significantly improve classification of AF patients at low and intermediate risk of stroke, compared to the commonly used CHADS2 score. PMID: Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. Thromb Haemost. 2012 Jun;107(6): Pub Med PMID:

Question #4 78 year old male with atrial fibrillation and hypertension (CHADS2 score = 2 [4% stroke rate per year]). What is his annual major bleeding rate? 1% 2% 3% 5% 10%

Bleeding Risk Scores Variety of scoring systems developed to predict risk of bleeding in patients initiating anticoagulants, as with stroke risk Less predictive than stroke risk scores, in general Each score incorporates clinical characteristics and provides estimate of risk of bleeding in a population similar to patients being considered Unclear whether to include risk scores in decision making for individual patients

Bleeding Risk Scores Widely Used in AF
HAEMORRHAGES1 HASBLED2 ATRIA Score3 We classified our patients for bleeding risk using previously published risk stratification models: HAEMORR2HAGES [10], HASBLED [12], ATRIA score [13], 10 Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, Radford MJ. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151:713-19 12 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest ;138: 13 Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, Singer DE. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58: Gage BF, et al. Am Heart J Mar;151(3): PMID: Pub Med PMID: Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. Chest Nov;138(5): PMID: Fang MC, et al. J Am Coll Cardiol Jul 19;58(4): Pub Med PMID:

Bleeding Risk Scores in AF
ATRIA HAS-BLED HEMORR2HAGES Anemia1 3 Hypertension4 1 Hepatic10 or Renal disease2 Severe renal disease2 Abnormal Renal5 or Liver function6 Ethanol abuse Age ≥75 yrs 2 Stroke Malignancy Any prior hemorrhage Bleeding Older Age (>75 yrs) Hypertension3 Labile INR8 Reduced platelet number or function11 Elderly (>65 yrs) Rebleeding12 Drugs9 or Alcohol Anemia13 Genetic factors14 Excessive fall risk15 SOURCE GIVEN IN ORIGINAL SLIDE SET: Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol Jul 24. [Epub ahead of print] PMID: Am Coll Cardiol. 2012 Jul 24. [Epub ahead of print] Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED Bleeding Risk-Prediction Scores in Patients With Atrial Fibrillation Undergoing Anticoagulation: The AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) Study. Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Source University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom. OBJECTIVES:The objective of this study was to compare the predictive performance of bleeding risk-estimation tools in a cohort of patients with atrial fibrillation (AF) undergoing anticoagulation. BACKGROUND:Three bleeding risk-prediction schemes have been derived for and validated in patients with AF: HEMORR(2)HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol). Τhe relative predictive values of these bleeding scores have not previously been compared. METHODS:We analyzed the dataset from the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial, a multicenter, randomized, open-label noninferiority study that compared fixed-dose idraparinux with adjustable-dose oral vitamin K antagonist therapy in patients with AF. The principal safety outcome was any clinically relevant bleeding event, which was a composite of major bleeding plus clinically relevant nonmajor bleeding. RESULTS:The HAS-BLED score performed best in predicting any clinically relevant bleeding, reflected both in net reclassification improvement (10.3% and 13% improvement compared with HEMORR(2)HAGES and ATRIA, respectively) and receiver-operating characteristic (ROC) analyses (c-indexes: 0.60 vs and 0.50 for HAS-BLED vs. HEMORR(2)AGES and ATRIA, respectively). Using decision-curve analysis, the HAS-BLED score demonstrated superior performance compared with ATRIA and HEMORR(2)HAGES at any threshold probability for clinically relevant bleeding. HAS-BLED was the only score that demonstrated a significant predictive performance for intracranial hemorrhage (c-index: 0.75; p = 0.03). An ATRIA score >3 was not significantly associated with the risk for any clinically relevant bleeding on Cox regression or on ROC analysis (c-index: 0.50; p = 0.87). CONCLUSIONS: All 3 tested bleeding risk-prediction scores demonstrated only modest performance in predicting any clinically relevant bleeding, although the HAS-BLED score performed better than the HEMORR(2)HAGES and ATRIA scores, as reflected by ROC analysis, reclassification analysis, and decision-curve analysis. Only HAS-BLED demonstrated a significant predictive performance for intracranial hemorrhage. Given its simplicity, the HAS-BLED score may be an attractive method for the estimation of oral anticoagulant-related bleeding risk for use in clinical practice, supporting recommendations in international guidelines. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. Hemoglobin <13 g/dl men; <12 g/dl women Estimated glomerular filtration rate <30 ml/min or dialysis-dependent Diagnosed hypertension Systolic blood pressure >160 mmHg Presence of chronic dialysis or renal transplantation or serum creatinine ≥200 mmol/L Chronic hepatic disease (eg cirrhosis) or biochemical evidence of significant hepatic derangement (eg bilirubin 2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.) Unstable/high INRs or poor time in therapeutic range (eg <60%) Concomitant use of drugs, such as antiplatelet agents, non-steroidal anti-inflammatory drugs, or alcohol abuse etc. Cirrhosis, two-fold or greater elevation of AST or APT, or albumin <3.6 g/dl Platelets <75,000, use of antiplatelet therapy (eg daily aspirin) or NSAID therapy; or blood dyscrasia Prior hospitalization for bleeding Most recent hematocrit <30 or hemoglobin <10 g/dl CYP2C9*2 and/or CYP2C9*3 Alzheimer's dementia, Parkinson's disease, schizophrenia, or any condition predisposing to repeated falls Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000– Jul 24. [Epub ahead of print] Online Appendix. PMID:

Clinically Relevant Bleeding
AMADEUS Cohort Stratified by the HEMORR2HAGES, HAS-BLED, and ATRIA Schemes Scheme All Patients Clinically Relevant Bleeding Major Bleeding HEMORR2HAGES Low (≤1) Risk 1,738 (76.6) 182 (10.5) 25 (1.4) Intermediate Risk (2–3) 517 (22.8) 63 (12.2) 13 (2.5) High Risk (>3) 13 (0.5) 3 (23.1) 1 (7.7) TOTAL 2,268 248 (10.9) 39 (1.7) HAS-BLED Low Risk (<3) 1,739 (75.9) 159 (9.1) 22 (1.3) High Risk (≥3) 553 (24.1) 92 (16.6) 17 (3.1) TOTAL 2,292 251 (11.0) ATRIA Low Risk (<4) 2,038 (90) 220 (10.8) 31 (1.5) Intermediate Risk (4) 102 (4.4) 13 (12.7) 3 (2.9) High Risk (>4) 128 (5.6) 18 (14.1) 5 (3.9) TOTAL Table 2. AMADEUS Cohort Stratified by the HEMORR2HAGES, HAS-BLED, and ATRIA Schemes J Am Coll Cardiol. 2012 Jul 24. [Epub ahead of print] Performance of the HEMORR(2)HAGES, ATRIA, and HAS-BLED Bleeding Risk-Prediction Scores in Patients With Atrial Fibrillation Undergoing Anticoagulation: The AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) Study. Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. Source University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, United Kingdom. OBJECTIVES:The objective of this study was to compare the predictive performance of bleeding risk-estimation tools in a cohort of patients with atrial fibrillation (AF) undergoing anticoagulation. BACKGROUND:Three bleeding risk-prediction schemes have been derived for and validated in patients with AF: HEMORR(2)HAGES (Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk and Stroke), ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, Drugs/Alcohol). Τhe relative predictive values of these bleeding scores have not previously been compared. METHODS:We analyzed the dataset from the AMADEUS (Evaluating the Use of SR34006 Compared to Warfarin or Acenocoumarol in Patients With Atrial Fibrillation) trial, a multicenter, randomized, open-label noninferiority study that compared fixed-dose idraparinux with adjustable-dose oral vitamin K antagonist therapy in patients with AF. The principal safety outcome was any clinically relevant bleeding event, which was a composite of major bleeding plus clinically relevant nonmajor bleeding. RESULTS:The HAS-BLED score performed best in predicting any clinically relevant bleeding, reflected both in net reclassification improvement (10.3% and 13% improvement compared with HEMORR(2)HAGES and ATRIA, respectively) and receiver-operating characteristic (ROC) analyses (c-indexes: 0.60 vs and 0.50 for HAS-BLED vs. HEMORR(2)AGES and ATRIA, respectively). Using decision-curve analysis, the HAS-BLED score demonstrated superior performance compared with ATRIA and HEMORR(2)HAGES at any threshold probability for clinically relevant bleeding. HAS-BLED was the only score that demonstrated a significant predictive performance for intracranial hemorrhage (c-index: 0.75; p = 0.03). An ATRIA score >3 was not significantly associated with the risk for any clinically relevant bleeding on Cox regression or on ROC analysis (c-index: 0.50; p = 0.87). CONCLUSIONS:All 3 tested bleeding risk-prediction scores demonstrated only modest performance in predicting any clinically relevant bleeding, although the HAS-BLED score performed better than the HEMORR(2)HAGES and ATRIA scores, as reflected by ROC analysis, reclassification analysis, and decision-curve analysis. Only HAS-BLED demonstrated a significant predictive performance for intracranial hemorrhage. Given its simplicity, the HAS-BLED score may be an attractive method for the estimation of oral anticoagulant-related bleeding risk for use in clinical practice, supporting recommendations in international guidelines. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. Apostolakis S, Lane DA, Guo Y, Buller H, Lip GY. J Am Coll Cardiol 2012;60:000– Jul 24. [Epub ahead of print] Online Appendix. PMID: 24

Risks of Bleeding with Warfarin or Dabigatran in AF
Speaker Note: Red circle= highlighted because it is the score of the case patient Figure 1 Annual rates of stroke or SE and vascular mortality in relation to CHADS2 risk scores Ann Intern Med. 2011 Nov 15;155(10):660-7, W204. Risks for stroke, bleeding, and death in patients with atrial fibrillation receiving dabigatran or warfarin in relation to the CHADS2 score: a subgroup analysis of the RE-LY trial. Oldgren J, Alings M, Darius H, Diener HC, Eikelboom J, Ezekowitz MD, Kamensky G, Reilly PA, Yang S, Yusuf S, Wallentin L, Connolly SJ;RE-LY Investigators. Source Uppsala Clinical Research Centre and Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Abstract BACKGROUND: CHADS(2) is a simple, validated risk score for predicting the risk for stroke in patients with atrial fibrillation not treated with anticoagulants. There are sparse data on the risk for thrombotic and bleeding complications according to the CHADS(2) score in patients receiving anticoagulant therapy. OBJECTIVE: To evaluate the prognostic importance of CHADS(2) risk score in patients with atrial fibrillation receiving oral anticoagulants, including the vitamin K antagonist warfarin and the direct thrombin inhibitor dabigatran. DESIGN: Subgroup analysis of a randomized, controlled trial. (ClinicalTrials.gov registration number: NCT ) SETTING: Multinational study setting. PATIENTS: patients with atrial fibrillation who were receiving oral anticoagulants. MEASUREMENTS: Baseline CHADS(2) score, which assigns 1 point each for congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and 2 points for stroke. RESULTS: Distribution of CHADS(2) scores were as follows: 0 to patients; patients; and 3 to patients. Annual rates of the primary outcome of stroke or systemic embolism among all participants were 0.93% in patients with a CHADS(2) score of 0 to 1, 1.22% in those with a score of 2, and 2.24% in those with a score of 3 to 6. Annual rates of other outcomes among all participants with CHADS(2) scores of 0 to 1, 2, and 3 to 6, respectively, were the following: major bleeding, 2.26%, 3.11%, and 4.42%; intracranial bleeding, 0.31%, 0.40%, and 0.61%; and vascular mortality, 1.35%, 2.39%, and 3.68% (P < for all comparisons). Rates of stroke or systemic embolism, major and intracranial bleeding, and vascular and total mortality each increased in the warfarin and dabigatran groups as CHADS(2) score increased. The rates of stroke or systemic embolism with dabigatran, 150 mg twice daily, and of intracranial bleeding with dabigatran, 150 mg or 110 mg twice daily, were lower than those with warfarin; there was no significant heterogeneity in subgroups defined by CHADS(2) scores. LIMITATION: These analyses were not prespecified and should be deemed exploratory. CONCLUSION: Higher CHADS(2) scores were associated with increased risks for stroke or systemic embolism, bleeding, and death in patients with atrial fibrillation receiving oral anticoagulants. Primary Funding Source: Boehringer Ingelheim. Comment in ACP Journal Club. CHADS2 score predicted bleeding and death in atrial fibrillation treated with anticoagulants. [Ann Intern Med. 2012] Learning the respective roles of warfarin and dabigatran to prevent stroke in patients with nonvalvular atrial fibrillation. [Ann Intern Med. 2011] PMID: Oldgren J, et al. Ann Intern Med Nov 15;155(10):660-7, W204. Pub Med PMID: 25

Adjusted HR for Death After Stroke, MI, or Major Hemorrhage
In Patients Who Received Antiplatelet Therapy in the ACTIVE Trials Event Pts With Event, n Subsequent Deaths, n (Adjusted Rate) HR for Death (95% CI)† Relative Weights‡ Ischemic stroke 785 362 (36.4) (5.10 – 6.47) 1.00 (reference) Hemorrhage stroke 59 48 (81.4) 17.67 (13.15 – 23.75) 3.08 Subdural hemorrhage 42 15 (32.4) 3.44 (2.06 – 5.74) 0.60 Major extracranial bleeding event 435 162 (31.6) 3.82 (3.24 – 4.51) 0.67 Myocardial infarction 260 120 (38.9) 5.44 (4.51 – 6.56) 0.95 Ann Intern Med. 2011 Nov 1;155(9): Net clinical benefit of adding clopidogrel to aspirin therapy in patients with atrial fibrillation for whom vitamin K antagonists are unsuitable. Connolly SJ, Eikelboom JW, Ng J, Hirsh J, Yusuf S, Pogue J, de Caterina R, Hohnloser S, Hart RG; ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) Steering Committee and Investigators. Source McMaster University, Hamilton, Ontario, Canada. Abstract BACKGROUND: Adding clopidogrel to aspirin therapy reduces stroke in patients with atrial fibrillation (AF) but increases hemorrhage. OBJECTIVE: To quantify the net benefit of adding clopidogrel to aspirin therapy, accounting for differences in clinical significance between ischemic and hemorrhagic events. DESIGN: Observational cohort study to assign the relative weighting of events and post hoc analysis of randomized trial data to assess net benefit of dual antiplatelet therapy in the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) clinical trials. SETTING: Global randomized clinical trial. PATIENTS: 10,041 patients with AF, 7554 of whom were not candidates for warfarin therapy. MEASUREMENTS: Ischemic events (ischemic stroke or myocardial infarction) and hemorrhagic events (hemorrhagic stroke or subdural or extracranial bleeding), weighted by the hazard ratio for death (or death or disability) after an event relative to death (or death or disability) after ischemic stroke. The net clinical benefit of dual antiplatelet therapy in the ACTIVE A trial participants was defined as the sum of weighted event incidence with dual antiplatelet therapy subtracted from the sum of weighted event incidence on control treatment, expressed as ischemic stroke equivalents prevented per 100 patients years. RESULTS: Adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalent (95% CI, to 1.24) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage and 0.67 ischemic stroke equivalent (CI, to 1.18) when weighted by death or disability after ischemia or hemorrhage. LIMITATION: No attempt was made to relate deaths used for weighting to events; disability data were missing for more than one half of patients. CONCLUSION: Adding clopidogrel to aspirin therapy resulted in a modest net benefit among patients with AF for whom warfarin was unsuitable. The benefit would probably be clinically relevant for some patients, but estimates could not exclude the possibility of either no benefit or very small harm in this population. PRIMARY FUNDING SOURCE: Bristol-Myers Squibb and sanofi-aventis. † Compared to no event ‡ ratio of hazard ratios Connolly SJ, et al. Ann Intern Med Nov 1;155(9): Pub Med PMID:

Pharmacokinetics of NOACs
Apixaban Dabigatran Rivaroxaban Direct factor inhibition Xa IIa Bioavailability (Frel) 80% 6% Peak action (tmax) 1–3 hr Protein binding 84% 35% 92–95% Renal clearance 25% 33% Elimination half life with creatinine clearance > 80 ml/min 15.1 hr 13.8 hr 8.3 hr Elimination half life with creatinine clearance 50–79 ml/min 14.6 hr 16.6 hr 8.7 hr Elimination half life with creatinine clearance 30–49 ml/min 17.6 hr 18.7 hr 9.0 hr Elimination half life with creatinine clearance < 30 ml/min 17.3 hr 27.5 hr 9.5 hr Am J Hematol. 2012 May;87 Suppl 1:S doi: /ajh Epub 2012 Apr 4. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Source Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. Abstract The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Copyright © 2012 Wiley Periodicals, Inc. PMID: Kaatz S, et al. Am J Hematol May;87 Suppl 1:S Pub Med PMID:

Measuring the Effect of NOACs
Coagulation Assays Apixaban Rivaroxaban Dabigatran PT -dilute PT -modified PT Not useful Data n/a Qualitative Data n/a aPTT TT -dTT/HEMOCLOT No effect No effect Qualitative Quantitative Chromogenic Assays -Anti-Xa -Anti-Iia No Effect Table 3: A summary of different assays and their utility with apixaban, rivaroxaban and dabigatran. aPTT, activated partial thromboplastin time; dPT, dilute prothrombin time; dTT, dilute thrombin time; INR, international normalized ratio; mPT, modified prothrombin time; NOAC, novel oral anticoagulants; PT, prothrombin time; TT, thrombin. NB: any assay intended for quantitative assessment must be calibrated for the specific drug measured (e.g. a chromogenic anti-Xa assay calibrated for enoxaparin cannot be used – without calibration - interchangeably to measure rivaroxaban). Most assays used for “qualitative” assessment exclude the presence of clinically important drug effect when COMPLETELY NORMAL – when abnormal, these assays can be interpreted only as showing that anticoagulant effect is present. n/a = not available Garcia DA, et al. In review. 29

Human volunteers and rat model
Reversal of NOACs Types of Studies Evaluating Reversal of New Oral Anticoagulants Apixaban Dabigatran Rivaroxaban Oral activated charcoal No data In vitro Hemodialysis Human volunteers Hemoperfusion with activated charcoal Fresh frozen plasma Mouse model Activated factor VIIa Rat model Rat and baboon model 3-factor PCC 4-factor PCC Human volunteers and rat model Table II. Types of Studies Evaluating Reversal of New Oral Anticoagulants Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Am J Hematol May;87 Suppl 1:S doi: /ajh Epub 2012 Apr 4. Review. PMID: Am J Hematol. 2012 May;87 Suppl 1:S doi: /ajh Epub 2012 Apr 4. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Source Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. Abstract The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Copyright © 2012 Wiley Periodicals, Inc. Kaatz S, et al. Am J Hematol May;87 Suppl 1:S Pub Med PMID:

Reversal of NOACs Suggestions for Reversal of New Oral Anticoagulants
Apixaban Dabigatran Rivaroxaban Oral activated charcoal Yes Hemodialysis No Hemoperfusion with activated charcoal Possible Fresh frozen plasma Activated factor VIIa Unclear 3-factor PCC 4-factor PCC Table III. Suggestions for Reversal of New Oral Anticoagulants Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Am J Hematol May;87 Suppl 1:S doi: /ajh Epub 2012 Apr 4. Review. PMID: Am J Hematol. 2012 May;87 Suppl 1:S doi: /ajh Epub 2012 Apr 4. Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors. Kaatz S, Kouides PA, Garcia DA, Spyropolous AC, Crowther M, Douketis JD, Chan AK, James A, Moll S, Ortel TL, Van Cott EM, Ansell J. Source Department of Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA. Abstract The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug-drug interactions and less food-drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Copyright © 2012 Wiley Periodicals, Inc. Kaatz S, et al. Am J Hematol May;87 Suppl 1:S Pub Med PMID:

Meta-analysis of Efficacy and Safety of New Oral Anticoagulants
Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients All cause stroke/SEE Ischemic and unspecified stroke Am J Cardiol. 2012 Aug 1;110(3): Epub 2012 Apr 24. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Source Division of Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Abstract New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin. Copyright © 2012 Elsevier Inc. All rights reserved. Hemorrhagic stroke Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3): Pub Med PMID:

Meta-analysis of Efficacy and Safety of New Oral Anticoagulants
Dabigatran, Rivaroxaban, Apixaban vs. Warfarin in AF patients Major bleeding Intracranial bleeding Figure 3. Forest plot for (A) major bleeding, (B) intracranial bleeding, and (C) gastrointestinal bleeding, new oral anticoagulants (NOA) versus warfarin in patients with AF. Am J Cardiol. 2012 Aug 1;110(3): Epub 2012 Apr 24. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Source Division of Clinical Epidemiology, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada; Faculty of Medicine, McGill University, Montreal, Quebec, Canada. Abstract New oral anticoagulants, including apixaban, dabigatran, and rivaroxaban, have been developed as alternatives to warfarin, the standard oral anticoagulation therapy for patients with atrial fibrillation (AF). A systematic review and meta-analysis of randomized controlled trials was performed to compare the efficacy and safety of new oral anticoagulants to those of warfarin in patients with AF. The published research was systematically searched for randomized controlled trials of >1 year in duration that compared new oral anticoagulants to warfarin in patients with AF. Random-effects models were used to pool efficacy and safety data across randomized controlled trials. Three studies, including 44,563 patients, were identified. Patients randomized to new oral anticoagulants had a decreased risk for all-cause stroke and systemic embolism (relative risk [RR] 0.78, 95% confidence interval [CI] 0.67 to 0.92), ischemic and unidentified stroke (RR 0.87, 95% CI 0.77 to 0.99), hemorrhagic stroke (RR 0.45, 95% CI 0.31 to 0.68), all-cause mortality (RR 0.88, 95% CI 0.82 to 0.95), and vascular mortality (RR 0.87, 95% CI 0.77 to 0.98). Randomization to a new oral anticoagulant was associated with a lower risk for intracranial bleeding (RR 0.49, 95% CI 0.36 to 0.66). Data regarding the risks for major bleeding (RR 0.88, 95% CI 0.71 to 1.09) and gastrointestinal bleeding (RR 1.25, 95% CI 0.91 to 1.72) were inconclusive. In conclusion, the new oral anticoagulants are more efficacious than warfarin for the prevention of stroke and systemic embolism in patients with AF. With a decreased risk for intracranial bleeding, they appear to have a favorable safety profile, making them promising alternatives to warfarin. Copyright © 2012 Elsevier Inc. All rights reserved. GI Bleeding Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Am J Cardiol. 2012 Aug 1;110(3): Pub Med PMID:

Question #5 78 year old female with atrial fibrillation, hypertension and CHF. CHADS2 = 3 CHA2DS2-VASc = 5 HAS-BLED = 2 What would you use for stroke prevention? No anti-thrombotics Aspirin Aspirin + clopidogrel VKA antagonist Dabigatran or Rivaroxaban

European Society of Cardiology Guidelines
CHA2DS2-VASc and Stroke Rate Risk Factors For Stroke and Thrombo-embolism in Non-valvular AF Risk Factor Score Congestive heart failure/LV dysfunction* 1 Hypertension* Age >75** 2 Diabetes Mellitus* Stroke / TIA / Thrombo-embolism** Vascular Disease* Age 65-74* Sex category (i.e. female sex)* Maximum Score 9 Note: maximum score is 9 since age may contribute 0,1, or 2 points * ‘Clinically relevant non-major’ risk factor ** “Major” risk factor ESC = European Society of Cardiology Risk factor scoring system-based approach expressed as a point based scoring system, with CHA2DS2-VASc acronym Europace Oct;12(10): Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH; ESC Committee for Practice Guidelines, Vahanian A, Auricchio A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P; Document Reviewers, Vardas PE, Agladze V, Aliot E, Balabanski T, Blomstrom-Lundqvist C, Capucci A, Crijns H, Dahlöf B, Folliguet T, Glikson M, Goethals M, Gulba DC, Ho SY, Klautz RJ, Kose S, McMurray J, Perrone Filardi P, Raatikainen P, Salvador MJ, Schalij MJ, Shpektor A, Sousa J, Stepinska J, Uuetoa H, Zamorano JL, Zupan I. Collaborators (43) Erratum in Europace Jul;13(7):1058. Dosage error in article text. PMID: Camm AJ. Europace Oct;12(10): Pub Med PMID:

European Society of Cardiology Guidelines
Approach to Thromboprophylaxis in Patients with AF Risk Category CHA2DS2-VASc Score Recommended Antithrombotic Therapy1 One ‘major’ risk factor or > 2 ‘clinically relevant non-major’ risk factors > 2 OAC One ‘clinically relevant non-major’ risk factor’ 1 Either OAC or aspirin mg daily Preferred: OAC rather than aspirin No risk factors Either aspirin mg daily or no antithrombotic therapy Preferred: no antithrombotic therapy rather than aspirin Connolly ref from ESC Guidelines, page 2384: Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151. AF = atrial fibrillation; CHA2DS2-VASc = cardiac failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled)-vascular disease, age 65–74 and sexcategory (female); INR = international normalized ratio; OAC ¼ oralanticoagulation, such as a vitamin K antagonist (VKA) adjusted to an intensity range of INR 2.0–3.0 (target 2.5). A OAC, such as a VKA, adjusted to an intensity range of INR 2.0–3.0 (target 2.5). New OAC drugs, which may be viable alternatives to a VKA, may ultimately be considered. For example, should both doses of dabigatran etexilate receive regulatory approval for stroke prevention in AF, the recommendations for thromboprophylaxis could evolve as follows considering stroke and bleeding risk stratification: (a) Where oral anticoagulation is appropriate therapy, dabigatran may be considered, as an alternative to adjusted dose VKA therapy. (i) If a patient is at low risk of bleeding (e.g. HAS-BLED score of 0–2; see Table 10 for HAS-BLED score definition), dabigatran 150 mg b.i.d. may be considered, in view of the improved efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and similar rates of major bleeding events, when compared with warfarin); and (ii) If a patient has a measurable risk of bleeding (e.g. HAS-BLED score of ≥3), dabigatran etexilate 110 mg b.i.d. may be considered, in view of a similar efficacy in the prevention of stroke and systemic embolism (but lower rates of intracranial haemorrhage and of major bleeding compared with VKA). (b) In patients with one ‘clinically relevant non-major’ stroke risk factor, dabigatran 110 mg b.i.d. may be considered, in view of a similar efficacy with VKA in the prevention of stroke and systemic embolism but lower rates of intracranial haemorrhage and major bleeding compared with the VKA and (probably) aspirin. (c) Patients with no stroke risk factors (e.g. CHA2DS2-VASc =0) are clearly at so low risk, either aspirin 75–325 mg daily or no antithrombotic therapy is recommended. Where possible, no antithrombotic therapy should be considered for such patients, rather than aspirin, given the limited data on the benefits of aspirin in this patient group (i.e., lone AF) and the potential for adverse effects, especially bleeding. N Engl J Med Sep 17;361(12): Epub 2009 Aug 30. Dabigatran versus warfarin in patients with atrial fibrillation. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. Collaborators (1725) Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. Erratum in N Engl J Med Nov 4;363(19):1877.Abstract BACKGROUND: Warfarin reduces the risk of stroke in patients with atrial fibrillation but increases the risk of hemorrhage and is difficult to use. Dabigatran is a new oral direct thrombin inhibitor. METHODS: In this noninferiority trial, we randomly assigned 18,113 patients who had atrial fibrillation and a risk of stroke to receive, in a blinded fashion, fixed doses of dabigatran--110 mg or 150 mg twice daily--or, in an unblinded fashion, adjusted-dose warfarin. The median duration of the follow-up period was 2.0 years. The primary outcome was stroke or systemic embolism. RESULTS: Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). The rate of major bleeding was 3.36% per year in the warfarin group, as compared with 2.71% per year in the group receiving 110 mg of dabigatran (P=0.003) and 3.11% per year in the group receiving 150 mg of dabigatran (P=0.31). The rate of hemorrhagic stroke was 0.38% per year in the warfarin group, as compared with 0.12% per year with 110 mg of dabigatran (P<0.001) and 0.10% per year with 150 mg of dabigatran (P<0.001). The mortality rate was 4.13% per year in the warfarin group, as compared with 3.75% per year with 110 mg of dabigatran (P=0.13) and 3.64% per year with 150 mg of dabigatran (P=0.051). CONCLUSIONS: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage. (ClinicalTrials.gov number, NCT ) 2009 Massachusetts Medical Society Risk of Bleeding HAS-BLED Score Dabigatran Dosage2 Low risk 0–2 150 mg b.i.d. Measurable risk, or 1 clinically-relevant non-major risk factor ≥3 110 mg b.i.d. Camm AJ. Europace Oct;12(10): Pub Med PMID: Connolly SJ, et al. N Engl J Med 2009;361:1139–1151. PMID:

2011 ACCF/AHA/HRS Guidelines
Antithrombotic Therapy for Patients with Atrial Fibrillation Risk Category1 Recommended Therapy No risk factors Aspirin, 81 to 325 mg daily One moderate risk factor Aspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5) Any high risk factor or > 1 moderate-risk factor Warfarin (INR 2.0 to 3.0, target 2.5)* Less Validated / Weaker Risk Factors1 Moderate Risk Factors High Risk Factors Female gender Age >75 years Previous stroke, TIA or embolism Age 65 to 74 years Hypertension Mitral stenosis Coronary artery disease Heart failure Prosthetic heart valve* * If mechanical valve, target international normalized ratio (INR) > 2.5 Thyrotoxicosis LV ejection fraction <35% Diabetes mellitus Speaker Note: This slide is set up as an “animated slide” where each of the three sections appear by each mouse click. TABLE 13. Antithrombotic Therapy for Patients With Atrial Fibrillation INR indicates international normalized ratio; LV, left ventricular; and TIA, transient ischemic attack. ⁎ If mechanical valve, target international normalized ratio (INR) greater than 2.5. Circulation. 2011 Mar 15;123(10):e Epub 2011 Mar 7. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Kay GN, Le Huezey JY, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann LS, Smith SC Jr, Priori SG, Estes NA 3rd, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS,Kushner FG, Ohman EM, Stevenson WG, Tarkington LG, Yancy CW; American College of Cardiology Foundation/American Heart Association Task Force. Collaborators (13) PMID: J Am Coll Cardiol. 2011 Mar 15;57(11): Epub 2011 Feb ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Wann LS, Curtis AB, Ellenbogen KA, Estes NA 3rd, Ezekowitz MD, Jackman WM, January CT, Lowe JE, Page RL, Slotwiner DJ, Stevenson WG, Tracy CM. Comment in Dabigatran in patients with nonvalvular atrial fibrillation. [J Am Coll Cardiol. 2011] PMID: Original text in 2011 Update had footnote to Connolly SJ, below: N Engl J Med. 2009 Sep 17;361(12): Epub 2009 Aug 30. Dabigatran versus warfarin in patients with atrial fibrillation. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; RE-LY Steering Committee and Investigators. PMID: 2011 Focused Update Recommendation Class I2 Comments 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) New Recommendation Fuster V. Circulation Mar 15;123(10): Pub Med PMID: Wann LS, et al. J Am Coll Cardiol. 2011 Mar 15;57(11): Pub Med PMID:

ACCP Guidelines For patients with Nonrheumatic AF, including those with Paroxysmal AF Level of Risk ACCP Recommendation Alternative* Not Recommended Low Risk (CHADS2 = 0) No Therapy Aspirin Oral anticoagulation or combination therapy with aspirin and clopidogrel Intermediate Risk (CHADS2 = 1) Oral anticoagulation Aspirin with clopidogrel High Risk (CHADS2 = 2) (dabigatran 150 mg b.i.d. vs. VKA**) Section Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. - You JJ - Chest - 01-FEB-2012; 141(2 Suppl): e531S-75S (MEDLINE® is the source for the citation and abstract of this record ) BACKGROUND: The risk of stroke varies considerably across different groups of patients with atrial fibrillation (AF). Antithrombotic prophylaxis for stroke is associated with an increased risk of bleeding. We provide recommendations for antithrombotic treatment based on net clinical benefit for patients with AF at varying levels of stroke risk and in a number of common clinical scenarios. METHODS: We used the methods described in the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines article of this supplement. RESULTS: For patients with nonrheumatic AF, including those with paroxysmal AF, who are (1) at low risk of stroke (eg, CHADS(2) [congestive heart failure, hypertension, age â‰¥ 75 years, diabetes mellitus, prior stroke or transient ischemic attack] score of 0), we suggest no therapy rather than antithrombotic therapy, and for patients choosing antithrombotic therapy, we suggest aspirin rather than oral anticoagulation or combination therapy with aspirin and clopidogrel; (2) at intermediate risk of stroke (eg, CHADS(2) score of 1), we recommend oral anticoagulation rather than no therapy, and we suggest oral anticoagulation rather than aspirin or combination therapy with aspirin and clopidogrel; and (3) at high risk of stroke (eg, CHADS(2) score of â‰¥ 2), we recommend oral anticoagulation rather than no therapy, aspirin, or combination therapy with aspirin and clopidogrel. Where we recommend or suggest in favor of oral anticoagulation, we suggest dabigatran 150 mg bid rather than adjusted-dose vitamin K antagonist therapy. CONCLUSIONS: Oral anticoagulation is the optimal choice of antithrombotic therapy for patients with AF at high risk of stroke (CHADS(2) score of 2). At lower levels of stroke risk, antithrombotic treatment decisions will require a more individualized approach. Citation: Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. You JJ - Chest - 01-FEB-2012; 141(2 Suppl): e531S-75S MEDLINE® is the source for the citation and abstract of this record *For patients with AF unsuitable for, or who refuse, oral anticoagulant (for reasons other than concerns about major bleeding) **VKA = adjusted-dose vitamin K antagonist You JJ, et al. Chest Feb;141(2 Suppl):e531S-75S. Pub Med PMID:

Canadian Cardiovascular Society Guidelines
Assess Thromboembolic Risk (CHADS2) OAC* CHADS2 = 1 *ASA is a reasonable alternative for some as indicated by risk/benefit No anti-thrombotic ASA OAC* No additional risk factors for stroke Either female sex or vascular disease Age > 65 yrs or combination female sex and vascular disease CHADS2 = 0 When OAC therapy is indicated, most patients receive: Dabigatran, rivaroxaban, or apixaban (after Health Canada approval) In preference to warfarin Conditional Recommendation, High-Quality Evidence *ASA is a reasonable alternative for some as indicated by risk/benefit No anti-thrombotic ASA OAC* No additional risk factors for stroke Either female sex or vascular disease Age > 65 yrs or combination female sex and vascular disease CHADS2 = 0 OAC CHADS2 = 2 Increasing stroke risk Speaker note: This slide is also set up as an animated slide requiring you to scroll through for each section. Figure 1 Summary of recommendations for antithrombotic agent use based on Congestive Heart Failure, Hypertension, Age > 75, Diabetes Mellitus, and Prior Stroke or Transient Ischemic Attack (CHADS2) score. Additional risk factors of age > 65, vascular disease, and female sex are integrated to increase granularity at low CHADS2 score (CHADS2 = 0). ASA, acetylsalicylic acid (aspirin); OAC, oral anticoagulant. Can J Cardiol. 2012 Mar-Apr;28(2): Focused 2012 update of the Canadian Cardiovascular Society atrial fibrillation guidelines: recommendations for stroke prevention and rate/rhythm control. Skanes AC, Healey JS, Cairns JA, Dorian P, Gillis AM, McMurtry MS, Mitchell LB, Verma A, Nattel S; Canadian Cardiovascular Society Atrial Fibrillation Guidelines Committee. Source Arrhythmia Service, University Hospital, University of Western Ontario, London, Ontario, Canada. Erratum in Can J Cardiol May;28(3):396. Abstract The Canadian Cardiovascular Society (CCS) published the complete set of 2010 Atrial Fibrillation (AF) Guidelines in the January, 2011 issue of the Canadian Journal of Cardiology. During its deliberations, the CCS Guidelines Committee engaged to a timely review of future evidence, with periodic composition of focused updates to address clinically important advances. In 2011, results were published from 3 pivotal AF trials: the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, and the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS), comparing dronedarone with placebo in patients with permanent AF and additional cardiovascular disease risk-factor burden. Each of these large randomized trials provided clear results with major implications for AF management. Other important evidence that has emerged since the 2010 Guidelines includes findings about prediction instruments for AF-associated stroke and bleeding risk, stroke risk in paroxysmal-AF patients, risk-benefit considerations related to oral anticoagulation in patients with chronic kidney disease, and risk/benefit considerations in the use of antiplatelet agents, alone and in combination with each other or with oral anticoagulants, in AF patients. The Guidelines Committee judged that this extensive and important new evidence required focused updating of the 2010 Guidelines with respect to stroke prevention and rate/rhythm control. This report presents the details of the new recommendations, along with the background and rationale. Copyright Â© 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. Skanes AC, et al. Can J Cardiol Mar-Apr;28(2): Pub Med PMID:

Optimal Candidates for New Drugs
Patients who: Find INR testing burdensome Despite adherence to provider recommendations, have low ‘time-in-range’ Can afford (or arrange to get) the new drugs Have normal renal function

Optimal Candidates for Warfarin
Patients who: Have (borderline) renal insufficiency Are taking stable dose of warfarin and do not find INR testing burdensome Have access to self-testing machine Are concerned about the lack of an evidence-based reversal strategy

TTR per Country in RELY USA: Improvement Needed
Speaker note: highlight USA rate to show we could be doing better. Per Kaatz- we are on level with Bulgaria. When comparing the populations within the different cTTR quartiles there were several significant differences in baseline characteristics (table 1). However, because random allocation to the investigational treatment groups was stratified by centre, these were well balanced between the treatment groups within each of the cTTR quartiles. Lancet. 2010 Sep 18;376(9745): Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S,Connolly SJ; RE-LY investigators. Source Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden. Abstract BACKGROUND: Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. METHODS: In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT FINDINGS: The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0·036 and p=0·0006, respectively) and total mortality (interaction p=0·066 and p=0·052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. INTERPRETATION: The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. FUNDING: Boehringer Ingelheim. Copyright © 2010 Elsevier Ltd. All rights reserved. USA: Improvement Needed Wallentin L, et al. Lancet Sep 18;376(9745): PMID:

Stroke and Systemic Embolism
By Center TTR in RELY Figure 2. Time to primary outcome in each quartile of centre's mean time in therapeutic rangecTTR=centre's mean time in therapeutic range. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ; RE-LY investigators. Lancet Sep 18;376(9745): PMID: Lancet. 2010 Sep 18;376(9745): Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S,Connolly SJ; RE-LY investigators. Source Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden. BACKGROUND: Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. METHODS: In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT FINDINGS: The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0·036 and p=0·0006, respectively) and total mortality (interaction p=0·066 and p=0·052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. INTERPRETATION: The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. FUNDING: Boehringer Ingelheim. Copyright © 2010 Elsevier Ltd. All rights reserved. TTR=optimum therapeutic range cTTR=center's mean TTR Wallentin L, et al. Lancet Sep 18;376(9745): Pub Med PMID:

Major Bleeding By Center TTR in RELY
Figure 3. Time to major bleeding event in each quartile of centre's mean time in therapeutic rangecTTR=centre's mean time in therapeutic range. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S, Connolly SJ; RE-LY investigators. Lancet Sep 18;376(9745): PMID: Lancet. 2010 Sep 18;376(9745): Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, Pais P, Dans A, Eikelboom J, Oldgren J, Pogue J, Reilly PA, Yang S,Connolly SJ; RE-LY investigators. Source Uppsala Clinical Research Centre, Uppsala University, Uppsala, Sweden. BACKGROUND: Effectiveness and safety of warfarin is associated with the time in therapeutic range (TTR) with an international normalised ratio (INR) of 2·0-3·0. In the Randomised Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial, dabigatran versus warfarin reduced both stroke and haemorrhage. We aimed to investigate the primary and secondary outcomes of the RE-LY trial in relation to each centre's mean TTR (cTTR) in the warfarin population. METHODS: In the RE-LY trial, 18 113 patients at 951 sites were randomly assigned to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR 2·0-3·0. Median follow-up was 2·0 years. For 18 024 patients at 906 sites, the cTTR was estimated by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method. We compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. RE-LY is registered with ClinicalTrials.gov, number NCT FINDINGS: The quartiles of cTTR for patients in the warfarin group were: less than 57·1%, 57·1-65·5%, 65·5-72·6%, and greater than 72·6%. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0·89) or 150 mg dabigatran (interaction p=0·20) versus warfarin. Neither were any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0·71) or 150 mg dabigatran (interaction p=0·89) versus warfarin. There was a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0·03), with less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR. There were significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0·036 and p=0·0006, respectively) and total mortality (interaction p=0·066 and p=0·052, respectively) with reduced event rates at low cTTR, and similar rates at high cTTR. INTERPRETATION: The benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding, and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centres' quality of INR control. For all vascular events, non-haemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control. Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives. FUNDING: Boehringer Ingelheim. Copyright © 2010 Elsevier Ltd. All rights reserved. TTR=optimum therapeutic range cTTR=center's mean TTR Wallentin L, et al. Lancet Sep 18;376(9745): PMID:

Rivaroxaban vs. Warfarin
Stroke and Systemic Embolization by Center Proportion of INR in Therapeutic Range in ROCKET AF Rivaroxaban Warfarin Rivaroxaban vs. Warfarin Center TTR‡ Total Event Rate (100 Pt Yrs)§ Hazard Ratio (95% CI)II % 45/1735 (2.59) 1.77 62/1689 (3.67) 2.53 0.70 (0.48, 1.03) 50.7%-58.5% 53/1746 (3.04) 1.94 63/1807 (3.49) 2.18 0.89 (0.62, 1.29) % 54/1734 (3.11) 1.90 62/1758 (3.53) 2.14 0.89 (0.62, 1.28) % 37/1676 (2.21) 1.33 55/1826 (3.01) 1.80 0.74 (0.49, 1.12) Table 5 N Engl J Med. 2011 Sep 8;365(10): Epub 2011 Aug 10. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC,Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Collaborators (1236) Source Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27705, USA. BACKGROUND: The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin. METHODS: In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism. RESULTS: In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group. CONCLUSIONS: In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT ). Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. N Engl J Med Sep 8;365(10): Epub 2011 Aug 10. PMID: N=7061 rivaroxaban N=7082 warfarin P value for interaction=0.736 Time in therapeutic range-2-3 inclusive ‡Center TTR calculated using total INR values in target range from all warfarin subjects within center, divided by total INR values from all warfarin subjects within center §Number of events per 100 patient-years of follow-up II Hazard ratio from Cox proportional hazard model with treatment as a covariate Patel MR, et al. N Engl J Med. 2011 Sep 8;365(10): Pub Med PMID:

Summary Prevalence and incidence of AF Risk stratification for stroke and bleeding New oral anticoagulants Guidelines Practical considerations for choosing an anticoagulant

PREVENTING Atrial Fibrillation Related STROKES with Anticoagulants

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PREVENTING Atrial Fibrillation Related STROKES with Anticoagulants

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