Understanding Stroke Prevention in Atrial Fibrillation

Understanding Stroke Prevention in Atrial Fibrillation
Michel D’Astous Cardiologist Centre hospitalier universitaire Dr Georges-L Dumont University Hospital Center

Atrial Fibrillation Atrial fibrillation (AF) is the most common heart rhythm disturbance It is estimated that 1 in 4 individuals aged 40 will develop AF Atrial fibrillation (AF) is the most common heart rhythm disturbance. The lifetime risk of developing Atrial fibrillation in individuals aged 40 is 25%. Reference Lloyd-Jones DM, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.Circulation 2004;110: Atrial fibrillation image Avalable at fibrillation.html. Accessed January 18, Normal rhythm AF AF=atrial fibrillation Lloyd-Jones DM, et al. Circulation 2004;110:

ECG Showing Atrial Fibrillation
This shows the main findings of ECG in atrial fibrillation: absence of P waves, irregularly irregular R-R intervals, and irregular fluctuations in baseline (notably in leads III and VI). Reference Key findings: Absence of P waves Irregularly irregular R-R intervals Irregular fluctuations in the baseline (most noticeable in leads III and V1)

Classification of Atrial Fibrillation
Terminology Clinical features Pattern Initial event (first detected episode) Symptomatic or Asymptomatic Onset unknown May or may not re-occur Paroxysmal Spontaneous termination <7 days and most often <48 hours Recurrent Persistent Not self-terminating: Lasting >7 days or prior cardioversion Permanent (‘accepted’) Not terminated, terminated but relapsed, no cardioversion attempt Established Atrial fibrillation (AF) is considered recurrent when a patient develops two or more episodes. These episodes may be paroxysmal if they terminate spontaneously, defined by consensus as terminating within seven days, or persistent if the arrhythmia requires electrical or pharmacological cardioversion for termination. Successful termination of AF does not alter the classification of persistent AF in these patients. Longstanding AF (defined as over 1 year) not successfully terminated by cardioversion, or when cardioversion is not pursued, is classified as permanent. Without treatment, AF can result in some degree of disruption to the circulation of blood around the body. In some cases of AF, the degree of haemodynamic instability can represent a critical condition that requires immediate intervention. Reference Fuster v, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48: Fuster V, et al. ACC/AHA/ESC 2006 guidelines. J Am Coll Cardiol 2006;48:

AF is a Progressive Disease
AF Duration Reference Khan I.A. Int J Card 2003;87: Paroxysmal Trigger dependent (Initiation) Permanent Substrate dependent (Maintenance) Relative Importance Persistent 8 8 8 8 Khan I.A. Int J Card 2003;87: 8

Treatment of AF 1: Find a cause 2:Heart rate control
3:Rhythm vs Rate control 4:ASA vs Anticoagulation

Etiologies of AF Numerous causes: Think of: Hypertension
Coronary heart disease Valvular heart disease Cardiomyopathies Any trauma, infection of lungs or heart R/o Hyperthyroidism Lone AF

Investigation of AF CBC, renal analysis, liver function tests
ECG (LVH, Q waves, QT) Do not forget: TSH Echocardiogram Sometimes: Stress test, holter, Chest Xray, TEE

Stroke Prevention in Atrial Fibrillation
-Mortality in Rate vs. Rhythm Control Patients -The AFFIRM Study All-cause mortality 30 25 20 Rhythm control Cumulative Mortality (%) Rate control 15 P=0.08 10 5 1 2 3 4 5 Years after randomization Randomized patients with atrial fibrillation and a high risk of stroke to either cardioversion and treatment with antiarrhythmic drugs to maintain sinus rhythm or the use of rate-controlling drugs The use of anticoagulant drugs was recommended but not mandated N Engl J Med 2002; 347:

-Mortality in Rate vs. Rhythm Control Patients -The AFFIRM Study p Value <0.0001 0.0005 Sinus Rhythm Antiarrhythmic Use Warfarin Use Digoxin Use A recent meta-analysis, which combined the results from the FASTER, CHARISMA, CARESS and MATCH studies add weight to the hypothesis that early treatment of patients with acute TIA or minor stroke with combination therapy will reduce the incidence of major adverse events. Again, these results would be considered hypothesis generating and need to be confirmed in a in a larger study. 0.5 1.0 1.5 2.0 Risk Ratio N Engl J Med 2002; 347:

Atrial Fibrillation Major Risk Factor for Stroke
Independent risk factor for stroke - increases the risk of stroke by 5-fold1,2,3 Accounts for approximately 15-20% of all strokes nationally1,4 Risk of stroke in AF patients increases with age 1.5% in 50–59 year olds 23.5% in 80–89 year olds Risk of stroke is the same in AF patients regardless of whether they have paroxysmal or sustained AF Atrial fibrillation is a major risk factor for stroke. It increases the risk of stroke by 5- fold and accounts for approximately 15-20% of all strokes nationally. It is associated with a 50-90% increase in mortality risk after adjustment for coexisting cardiovascular conditions. The risk of stroke in AF patients who do not receive anticoagulation averages ~5% per year. The risk of stroke in AF patients increases with age: 1.5% in 50–59 year olds 23.5% in 80–89 year olds References 1. Atrial Fibrillation Investigation Group. Arch Intern Med 2. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22(8):983-8. 3. Savelieva I, Bajpai A, Camm AJ . Stroke in atrial fibrillation: update on pathophysiology, new antithrombotic therapies, and evolution of procedures and devices. Ann Med 2007;39(5): 4. Singer DE, Albers GW, Dalen JE, Fang MC, Go AS, Halperin JL, Lip GY, Manning WJ; American College of Chest Physicians. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133(6 Suppl):546S-592S. 1. Atrial Fibrillation Investigation Group. Arch Intern Med. 1994 2. Wolf PA, et al. Stroke 1991 3. Savelieva I, et al. Ann Med 2007 4. Singer DE, et al. Chest 2008 AF=atrial fibrillation

Stroke Risk is Independent of Type of Atrial Fibrillation
Reference Neuwfaat R, et al. Eur Heart J 2008. Neuwfaat R, et al. Eur Heart J 2008

Stroke Severity in Patients with AF
Effect of first ischemic stroke in patients with AF (n=597) 60% 40% 0% 50% 30% 20% 10% In a recent study by Gladstone and colleagues of nearly 600 patients who were admitted to the hospital with a first ischemic stroke from AF, 60% were disabling and 20% were fatal.1 Note that the rate if disability for these strokes is considerably higher than for stroke overall reported by Thom et al where 22% of men and 25% of women who have an initial stroke die within a year. This percentage is higher among people aged 65 and older, and 51% of men and 53% of women under the age of 65 who have a stroke die within 8 years. The length of time to recover from a stroke depends on its severity where 50–70% of stroke survivors regain functional independence, but 15–30% are permanently disabled, and 20% require institutional care at 3 months after onset.2 References Gladstone DJ, et al. Potentially preventable strokes in high-risk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 2009; 40: Thom T, et al. Heart disease and stroke statistics update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee.Circulation 2006; 113: e85–e151. % of patients Disabling Fatal AF=atrial fibrillation Gladstone DJ et al. Stroke 2009; 40:

Age- and Sex-Adjusted Incidence of AF in 1995-2000
Incidence of Atrial Fibrillation Expected to Increase as Population Ages Age- and Sex-Adjusted Incidence of AF in Projected Number of Persons With AF in the United States Between 2000 and 2050 Atrial fibrillation is more common in men than in women at all ages and increases significantly with age. Demographic projections suggest a tripling of the frequency over the next 40 years. The age- and sex-adjusted incidence of AF in 1995 to 2000, in Olmstead County, Minnesota, US, is shown in the graph on the left. Age was clearly an important risk factor for AF, with virtually no cases among individuals aged <55 years. The incidence per 1000 patient years increased to over 40 and almost 29 among men and women, respectively, aged ≥85 years. The graph on the right shows the projected number of persons with AF in the US between 2000 and Miyasaka and colleagues project that, by year 2050, nearly 15.9 million people will have AF, assuming a continued increase in incidence rate similar to that in All of these patients are at increased risk for stroke. Reference Miyasaka Y, Barnes ME, Gersh BJ et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114: Millions Year AF=atrial fibrillation Miyasaka Y et al. Circulation. 2006;114:

Diabetes and Atrial Fibrillation
Incidence of new onset AF AF is 44% more prevalent in DM AF is 38% more likely to develop in DM DM is a highly significant independent predictor of AF in women Reference Diabetes Care 2009;32: AF = Atrial fibrillation DM = Diabetes mellitus Diabetes Care 2009;32:

Blood Pressure in AF Patients Risk of CVA/Systemic Embolus
100 110 120 130 140 150 160 SBP Event rate (%/year) 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Mean SBP (mmHg) Hypertension contributes to increased stroke and systemic embolus in AF. This graph emanates from a cross-sectional, longitudinal analysis of data from the SPORTIF III and V trials. It showed an increasing rate of stroke and SEE with increasing quartiles of systolic blood pressure. In the combined SPORTIF III and V cohort, the event rate for stroke/SEE increased markedly at mean SBP above 140 mmHg, as shown by the blue arrow. When the top quartile of SBP was compared with the lowest quartile, the hazard ratio for stroke and SEE was 1.83 (95% CI: ), whereas mortality was lower in the top quartile (HR 0.64; 95% CI: ). There was no relationship between bleeding and quartiles of BP. The proportion of subjects with mean systolic BP at least 140 mmHg was 35.8% (1220/3407) in SPORTIF III and 20.6% (807/3922) in SPORTIF V (p<0.0001). There was a higher stroke rate observed in SPORTIF III which may be related to the greater proportion of subjects with SBP of at least 140 mmHg during the trial. Reference Lip GY et al; for the SPORTIF Investigators. Effect of hypertension on anticoagulated patients with atrial fibrillation. Eur Heart J 2007;28:752-9. SBP = Systolic blood pressure Lip GY et al; for the SPORTIF Investigators. Eur Heart J 2007;28:752-9. 27

Dec, 2003 issue

AF EPIDEMIC!

Pathophysiology of AF-Associated Ischemic Stroke
About 16% of ischemic strokes are associated with AF, and 10% are likely due to embolism of left atrial appendage thrombus Embolism of left atrial appendage thrombi accounts for most strokes in AF patients, particularly the larger and more disabling strokes. Based on the best available clinical estimates, about two thirds of strokes in AF patients are due to atrial thrombi; however, this does vary according to the distribution of additional risk factors and antithrombotic therapy; high-risk AF patients have a particularly high proportion of cardioembolic strokes. Overall, approximately 10% of all ischemic strokes in population-based cohorts are due to embolism of left atrial appendage thrombi in AF patients. Reference Hart, R. G. et al. Atrial fibrillation and stroke : concepts and controversies. Stroke 2001;32: AF=atrial fibrillation Hart RG & Halperin JL. Stroke 2001;32:

Left Atrial Appendage (LAA)
Left atrial appendage (LAA) is the most common site for thrombus formation in patients with AF Left atrial appendage is the most common site for thrombus formation in patients with AF Reference Image courtesy of Albers G, Stanford Stroke Center, Stanford School of Medicine AF=atrial fibrillation Image courtesy of Albers G, Stanford Stroke Center, Stanford School of Medicine

-Efficacy and Safety of Current A Fib Treatments -Meta-Analysis of Antithrombotic Therapy in A Fib New Hart.Ann Intern Med.Jun.2007/ p857/ c1/lines A18-A19, C2/line A1 van Walraven. JAMA.Nov.2002/ p2441/ lines A19 Fuster.J Am Coll Cardiol.Aug.2006/ pe183/table 12 Adjusted dose warfarin and antiplatelet agents have been shown to reduce the risk of stroke compared with control by 64% and 22%, respectively, with an increase in bleeding Warfarin has been shown to be more effective than aspirin, in reducing stroke by 45%, but increasing the risk of bleeding Based on these results, warfarin and other oral anticoagulants (OAC) are recommended for patients at increased risk of stroke; and aspirin is recommended for patients at lower risk Hart.Ann Intern Med.Jun.2007/p857/ c1/lines A18-A19, C2/line A1 Hart.Ann Intern Med.Jun.2007/ p864/ table 5 Note: This slide contains off-label information regarding PLAVIX, and should not be used in promotional presentations except in response to unsolicited questions from the audience. Adjusted-dose warfarin and antiplatelet agents have been shown to reduce the risk of stroke compared with control by 64% and 22%, respectively, with an increase in the number of bleeding events including intracranial hemorrhage and major extracranial hemorrhage.[1] Warfarin has been shown to be more effective than aspirin, in reducing stroke by 45%, but increasing the risk of bleeding.[2] Based on these results, warfarin and other oral anticoagulants (OAC) are recommended for patients at increased risk of stroke; and aspirin is recommended for patients at lower risk.[3] Hart.Ann Intern Med.Jun.2007/p857/ c1/lines A18-A19, C2/line A1 van Walraven. JAMA.Nov.2002/p2441/ lines A19 Fuster.J Am Coll Cardiol.Aug.2006/ pe183/table 12 W % Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146: van Walraven C, Hart RG, Singer DE, Laupacis A, Connolly S, Petersen P, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA. 2002;288: Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation; A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation); Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. J Am Coll Cardiol. 2006;48:e A W % A Ann Intern Med 2007; 146: Warfarin Antiplatelets 37

Warfarin Challenges: Narrow Therapeutic Window
Relationship between clinical events and INR intensity Warfarin—while highly effective in reducing the risk for stroke—is associated with a number of important limitations. Of these, the fact that warfarin has a narrow therapeutic window is among the most important. The data shown on this slide comes from 2 case-controlled studies that evaluated the relationship of INR to intracranial bleeding and ischemic stroke. The 1994 study included 121 adult patients who were hospitalized for intracranial hemorrhage while taking warfarin.1 In this study, the INR was the dominant risk factor for intracranial bleeding. In the second study, the risk of stroke in 74 patients with AF rose steeply at INRs below 2.2 It is clear from this graph that warfarin has a narrow therapeutic window, with an increased risk of ischemic stroke when the INR is <2, and an increased risk of bleeding when the INR >3. References 1. Hylek EM, Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med. 1994;120: 2. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med. 1996;335: ICH=intracranial hemorrhage INR=international normalized ratio 1. Hylek EM et al. Ann Intern Med. 1994;120: ; 2. Hylek EM et al. N Engl J Med. 1996;335:

Limitations of Warfarin Therapy
Unpredictable response Frequent dose adjustments Warfarin therapy has several limitations that make it difficult to use in practice Narrow therapeutic window (INR range 2-3) Numerous food-drug interactions Due to the limitations of warfarin, it has been estimated that up to 50% of patients eligible for treatment receive no anticoagulant treatment.1 References Rowan SB, et al. Trends in Anticoagulation for Atrial Fibrillation in the U.S. An Analysis of the National Ambulatory Medical Care Survey Database. J Am Coll Cardiol 2007;49:1561–5. 2. Ansell J, et al. Pharmacology and Management of the Vitamin K Antagonists. ACCP Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:160S-198S. 3. Umer Ushman MH, et al. Advancement in antithrombotics for stroke prevention in atrial fibrillation.J Interv Card Electrophysiol 2008; 22: 4. Nutescu EA, et al. New anticoagulant agents: direct thrombin inhibitors.Cardiol Clin 2008; 26: Routine coagulation monitoring Numerous drug-drug interactions Slow onset/offset of action Warfarin resistance Ansell J, et al. Chest 2008;133:160S-198S; Umer Ushman MH, et al. J Interv Card Electrophysiol 2008; 22: ; Nutescu EA, et al. Cardiol Clin 2008; 26:

INR Control Clinical Trials Versus Clinical Practice
INR* control in clinical trial versus clinical practice (TTR**) 66% Clinical trial1 Clinical practice2 Time in Therapeutic Range (TTR) of with warfarin tends to be highest (60– 70%) in well-controlled environments, e.g. clinical trials1 INR control tends to be much lower in clinical practice.2 In a retrospective review in clinical practice setting: relative risk reduction of stroke was only 38%.3 References Kalra L, et al. Prospective cohort study to determine if trial efficacy of anticoagulation for stroke prevention in atrial fibrillation translates into clinical effectiveness. BMJ 2000;320: Matchar DB, et al. Improving the quality of anticoagulation of patients with atrial fibrillation in managed care organizations: results of the managing anticoagulation services trial. Am J Med 2002; 113:42-51. 3. Rietbrock S, et al. How effective are dose-adjusted warfarin and aspirin for the prevention of stroke in patients with chronic atrial fibrillation? An analysis of the UK General Practice Research Database. Thromb Haemost. 2009; 101: 44% 38% % of eligible patients receiving warfarin 25% 18% 9% <2.0 2.0 – 3.0 >3.0 INR *INR = International normalized ratio; ** TTR = Time in Therapeutic Range (INR 1. Kalra L, et al. BMJ 2000;320: ; 2. Matchar DB, et al. Am J Med 2002; 113:42-51 * Pooled data: up to 83% to 71% in individualized trials

-The ACTIVE Program Documented AF + 1 risk factor: Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age CAD or diabetes Contra-indications to Warfarin or Unwilling ACTIVE is a phase III, multicenter, multinational, parallel randomized controlled evaluation of clopidogrel plus ASA, with factorial evaluation of irbesartan, for the prevention of vascular events in patients with atrial fibrillation. Patients will be enrolled over 2 years and followed to common termination date (expected to be about 4 years after enrollment of the first patient). About 14,000 patients will be included in the ACTIVE W or ACTIVE A trials. Due to the partial factorial design, patients will only be randomized in ACTIVE I once first randomized into either ACTIVE A or ACTIVE W. Three separate but related trials are included in the ACTIVE study. These are known as ACTIVE W, ACTIVE A, and ACTIVE I. ACTIVE W (n= 6,500): A multicenter, prospective, randomized, non-inferiority trial of clopidogrel plus ASA versus standard care oral anticoagulation (open trial with blinded outcome evaluation). ACTIVE A (n= 7,500): A multicenter, randomized, double-blind, placebo-controlled superiority trial of clopidogrel plus ASA versus ASA alone. ACTIVE I (n= at least 10,000): A multicenter, partial factorial, randomized, double-blind, placebo-controlled superiority trial of irbesartan. ACTIVE W Clopidogrel+ASA vs. Warfarin ACTIVE A Clopidogrel+ASA vs. ASA 6500 patients 7500 patients No Exclusion criteria for ACTIVE I ACTIVE I Irbesartan vs placebo ~9000 patients

-Stroke, Embolism, MI and Vascular Death -The ACTIVE-W Study 5.64 %/year RR = 1.45 P = Cumulative Hazard Rates 3.93 %/year Lancet 2006; 367: Years

-Major Bleeding -The ACTIVE-W Study 2.4 %/year RR = 1.06 P = 0.67 2.2 %/year Cumulative Hazard Rates Lancet 2006; 367: Years

-The ACTIVE Program Documented AF + 1 risk factor: Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age CAD or diabetes Contra-indications to Warfarin or Unwilling ACTIVE is a phase III, multicenter, multinational, parallel randomized controlled evaluation of clopidogrel plus ASA, with factorial evaluation of irbesartan, for the prevention of vascular events in patients with atrial fibrillation. Patients will be enrolled over 2 years and followed to common termination date (expected to be about 4 years after enrollment of the first patient). About 14,000 patients will be included in the ACTIVE W or ACTIVE A trials. Due to the partial factorial design, patients will only be randomized in ACTIVE I once first randomized into either ACTIVE A or ACTIVE W. Three separate but related trials are included in the ACTIVE study. These are known as ACTIVE W, ACTIVE A, and ACTIVE I. ACTIVE W (n= 6,500): A multicenter, prospective, randomized, non-inferiority trial of clopidogrel plus ASA versus standard care oral anticoagulation (open trial with blinded outcome evaluation). ACTIVE A (n= 7,500): A multicenter, randomized, double-blind, placebo-controlled superiority trial of clopidogrel plus ASA versus ASA alone. ACTIVE I (n= at least 10,000): A multicenter, partial factorial, randomized, double-blind, placebo-controlled superiority trial of irbesartan. ACTIVE W Clopidogrel+ASA vs. Warfarin ACTIVE A Clopidogrel+ASA vs. ASA 6500 patients 7500 patients No Exclusion criteria for ACTIVE I ACTIVE I Irbesartan vs placebo ~9000 patients

-Stroke, Embolism, MI and Vascular Death -The ACTIVE-A Study New ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1A (inset) 0.4 11% RRR RR=0.89 (95% CI, 0.81–0.98; P=0.01) 924 (7.6%/year) 0.3 Note: This slide contains off-label information regarding PLAVIX, and should not be used in promotional presentations except in response to unsolicited questions from the audience. In the ACTIVE A trial, the primary endpoint occurred in 7.6% of patients per year treated with ASA compared with 6.8% of patients per year treated with clopidogrel + ASA. This represented an 11% relative risk reduction (RRR) in patients treated with clopidogrel + ASA vs ASA alone (RR=0.89; 95% CI, 0.81 to 0.98; P=0.01). Reduction in the primary endpoint was driven by a significant RRR in stroke of 28% (RR=0.72; 95% CI, 0.62 to 0.83; P<0.001) ASA 832 (6.8%/year) Cumulative Incidence 0.2 ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2 Clopidogrel + ASA 0.1 0.0 1 2 3 4 Years N Engl J Med 2009; 360: ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation [published online ahead of print March 31, 2009]. N Engl J Med. doi: /NEJMoa 45

-Stroke (All Types) -The ACTIVE-A Study New ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1B (inset) 28% RRR RR=0.72 (95% CI, 0.62–0.83; P=<0.001) 0.15 408 (3.3%/year) ASA Note: This slide contains off-label information regarding PLAVIX, and should not be used in promotional presentations except in response to unsolicited questions from the audience. In the ACTIVE A trial, stroke was a component of the primary endpoint and occurred in 3.3% of patients per year treated with ASA compared with 2.4% of patients per year treated with clopidogrel + ASA. This represents a 28% RRR in patients treated with clopidogrel + ASA vs ASA alone (RR=0.72; 95% CI, 0.62 to 0.83; P<0.001). 0.10 Cumulative Incidence 296 (2.4%/year) ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1B 0.05 Clopidogrel + ASA 0.0 1 2 3 4 Years N Engl J Med 2009; 360: ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation [published online ahead of print March 31, 2009]. N Engl J Med. doi: /NEJMoa 46

Congestive heart failure
CHADS2 Score 1 point for Congestive Heart Failure 1 point for Hypertension 1 point for Age ≥ 75 years 1 point for Diabetes Mellitus 2 points for Prior Stroke or TIA CHADS2 Score* Stroke rate 1.9 ( ) 1 2.8 ( ) 2 4.0 ( ) 3 5.9 ( ) 4 8.5 ( ) 5 12.5 ( ) 6 18.2 ( ) *Score 0: Patients can be administered aspirin *Score 1: Patients can be on aspirin and anticoagulant therapy *Score ≥2: Patients should be on anticoagulant therapy CHADS2 is an easy-to use classification scheme that estimates the risk of stroke in elderly patients with AF. Physicians and patients should use CHADS2 to make decisions about antithrombotic therapy based on patient-specific risk of stroke. The CHADS2 index is calculated by assigning 1 point each for the presence of congestive heart failure, history of hypertension, age ≥ 75 years, and diabetes mellitus by assigning 2 points for a history of transient ischemic attack or ischemic stroke. The CHADS2 score for the patient case (Alice), is 3, calculated as follows: 0 points – Alice does not have congestive heart failure 1 point – Alice is being treated for hypertension 0 points – Alice is less than 75 years old 0 points – Alice does not have diabetes mellitus 2 points – Alice has just suffered her first transient ischemic attack 3 points - Total Reference Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285: Patient Case - Alice Condition Points Congestive heart failure Hypertension 1 Age, 74 yr Diabetes mellitus Prior stroke/TIA 2 Total Points 3 Gage BF, et al. JAMA. 2001;285:

CHA2DS2VASc Risk Factors Points C CHF H Hypertension A Age > 75
D Diabetes S Stroke/TIA/TE V Vascular disease (MI, PVD, Aortic) A Age 65-75 Sc Sex category ( female gender) 1 2

CHA2DS2-VASc CHA2DS2-VASc score TE Rate during 1 year % 1 2 3 4 5 6 7
1 2 3 4 5 6 7 8 0,7 1,9 4,7 2,3 3,9 4,5 10,1 14,2

Risk Factors for Bleeding
Age ≥ 65 Previous Stroke Previous peptic ulcer disease Previous gastrointestinal bleeding Renal impairment Anemia Thrombocytopenia Liver disease Diabetes mellitus Use of antiplatelet drugs Higher rate of bleeding for patients ≥ 65 yr versus younger patients (hazard ratio 2.6, 95% confidence interval ). Bleeding rates increased with the number of risk factors present, hazard ratio associated with each additional risk factor, 1.7 (95% confidence interval, ). This information regarding risk factors for bleeding is derived from a randomized, double-blind study, was conducted in which 738 patients who had completed three or more months of warfarin therapy for unprovoked venous thromboembolism were randomly assigned to continue warfarin therapy with a target international normalized ratio (INR) of 2.0 to 3.0 (conventional intensity) or a target INR of 1.5 to 1.9 (low intensity). There was a higher rate of major bleeding episodes among patients 65 years of age or older than among those younger than 65 years (hazard ratio, 2.6 [95 percent confidence interval, 1.0 to 6.9]), and the rate increased with the number of predefined risk factors for bleeding that were present at enrollment (risk factors included an age of 65 years or more, previous stroke, previous peptic ulcer disease, previous gastrointestinal bleeding, renal impairment, anemia, thrombocytopenia, liver disease, diabetes, and use of antiplatelet therapy; hazard ratio associated with each additional risk factor, 1.7 [95 percent confidence interval, 1.1 to 2.6]). Reference Kearon C, et al. Extended Low-Intensity Anticoagulation for Thrombo-Embolism Investigators. Comparison of low-intensity warfarin therapy with conventional- intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism.N Engl J Med. 2003;349:631-9. Kearon C, et al. N Engl J Med 2003;349:

Anticoagulation Contraindications
Pregnancy Associated with developmental abnormalities Threatened abortion, eclampsia and pre-eclampsia Recent surgery CNS; eye; traumatic surgery, resulting in large open surfaces Bleeding tendencies associated with active ulceration or overt bleeding GI, GU or RT Cerebrovascular haemorrhage aneurysms– cerebral, dissecting aorta Pericarditis and pericardial effusions Bacterial endocarditis Unsupervised patients with Alcoholism Psychosis Other lack of patient co-operation Spinal puncture Any diagnostic or therapeutic procedures with potential for uncontrollable bleeding Miscellaneous Major regional Lumbar block anaesthesia Malignant hypertension Known warfarin hypersensitivity This slide reviews warfarin contraindications. Reference RxList. Coumadin: Overdosage & Contraindications. Available at Accessed March 31, 2010. CNS = central nervous system; GI = gastrointestinal; GU = genitourinary; RT = reproductive tract

Warfarin and Stroke Prevention in Patients with Atrial Fibrillation
AFSAK I SPAF I BAATAF CAFA SPINAF EAFT All trials (n = 6) Adjusted dose warfarin compared with placebo or control This is data from a meta-analysis of trials characterizingthe efficacy and safety of antithrombotic agents for stroke prevention in patients who have atrial fibrillation. Twenty-nine randomized trials with 28,044 participants (mean age, 71 years; mean follow-up, 1.5 years) were included. The chart shows that compared with the control, adjusted-dose warfarin (6 trials, participants) reduced stroke by 64% (95% CI, 49% to 74%). Additional data demonstrated when only ischemic strokes were considered, adjusted-dose warfarin was associated with a 67% (95% CI, 54% to 77%) relative risk reduction. The analysis also showed that antiplatelet agents reduced stroke by 22% (95% CI, 6% to 35%). Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (relative risk reduction, 39% [95% CI, 22% to 52%]) (12 trials, participants). Absolute increases in major extracranial hemorrhage were small (0.3% per year) and all- cause mortality was substantially reduced (26% [95% CI, 3% to 43%) by adjusted-dose warfarin versus control. Reference Hart RG, Pearce LA, and Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146: AFSAK I = Copenhagen Atrial Fibrillation, Aspirin and Anticoagualtion Study SPAF I = Stroke Prevention in Atrial Fibrillation Study BAATAF = Boston Area Anticoagulation Trial doe Atrial Fibrillation CAFA = Canadian Atrial Fibrillation Anticoagulation SPINAF = Stroke Prevention in Nonrheumatic Atrial Fibrillation EAFT = European Atrial Fibrillation Trial Hart RG et al. Ann Intern Med 2007;146:

Underutilization of Warfarin in Atrial Fibrillation*
Approximately half of high-risk patients with atrial fibrillation receive warfarin therapy 13 community hospitals 21 academic hospitals Warfarin therapy No warfarin therapy This is data from a retrospective cohort study of inpatients was performed at 21 teaching, 13 community, and 4 Veterans Administration hospitals in the US. Among the 945 patients studied, the mean age was 71.5 (± 13.5) years; 43% were >75 years of age, 54.5% were men, and 67% had a history of hypertension. Most (86%) had factors that stratified them as at high risk of stroke, and only 55% of those received warfarin. Neither warfarin nor aspirin were prescribed in 21% of high-risk patients, including 18% of those with a previous stroke, transient ischemic attack, or systemic embolic event. Age >80 years (p = 0.008) and perceived bleeding risk (p = ) were negative predictors of warfarin use. Persistent/permanent AF (p < ) and history of stroke, transient ischemic attack, or systemic embolus (p = ) were positive predictors of warfarin use, whereas high-risk stratification was not. This study confirms the under-use of warfarin, but also adds to published reports in several regards. It showed that risk stratification, the guidepost for treatment in international guidelines, had little effect on warfarin use, and that age >80 years and AF classification (permanent/persistent) are factors that influence warfarin use. Reference Waldo AL et al. Hospitalized patients with atrial fibrillation and a high risk of stroke are not being provided with adequate anticoagulation. J Am Coll Cardiol 2005;46:1729–1736. *US population January–December 2002 Waldo AL, et al. J Am Coll Cardiol 2005

Stroke: Under Treatment
Sub-optimal Primary Prevention of Stroke in Patients with AF in Canada Secondary Stroke Prevention Patients only Marginally Better Primary prevention in Canadian Stroke Registry (n=597*) Secondary prevention in Canadian Stroke Registry (n=323*†) Data from the Canadian Stroke Registry looking at 12 Stroke Centers. People with Afib, at CHADS2 of 2+ indicated for Warfarin treatment who showed up at the stroke center with a stroke. 29% on Warfarin but not in range, 29% on nothing, 29% on Aspirin despite being indicated for Warfarin, 2% on Plavix plus Aspirin despite being indicated for Warfarin. Of the 597 (pie chart on left) Outcomes 20% Dead, 20% survived with no lasting effects, 60% with disability Pie chart on right, these are people with previous stroke…only 18% therapeutic. We Must Do Better. AF: atrial fibrillation; TIA: transient ischemic attack. *history of AF, classified high risk for systemic emboli according to published guidelines, no contraindications to anticoagulation. †Patients with acute ischemic stroke/TIA Gladstone et al. Stroke 2009;40:235-40

Update in Antiplatelets and Anticoagulants
-Newer Antithrombotic Agents Intrinsic pathway Extrinsic pathway Xll Xl lX TF Fondaparinux VIII VII Coumadin X LMWH V II Heparin XIII Fibrin Clot 55

-New Agents for the Prevention of Stroke Intrinsic pathway Extrinsic pathway Xll Xl lX TF VIII VII X Direct Factor Xa Inhibitors -apixaban -rivaroxaban V II Direct Thrombin Inhibitors -dabigatran XIII Fibrin Clot

Dabigatran Etexilate (Direct Thrombin Inhibitor) in Atrial Fibrillation
Reversible direct thrombin inhibitor (DTI) Oral prodrug that is converted to dabigatran, Rapid onset of action Half life of h Renal excretion ~ 80% Low potential for drug-drug interactions, no drug-food interactions No requirement for routine coagulation monitoring Dabigatran etexilate is a new oral direct thrombin inhibitor (DTI). It is the prodrug of the active compound, dabigatran, which binds directly to thrombin with a high affinity and specificity. It has a rapid onset of action, with a half-life of between 12 to 17 hours. The majority of the drug (approximately 80%) is renally excreted. Dabigatran has low potential for drug-drug interactions and does not possess drug-food interactions. It has a predictable anticoagulant effect, is adminstered at a fixed dose, and does not require monitoring. Reference Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008;47: Stangier J. Clin Pharmacokinet 2008;47:

RE-LY®: Randomised Evaluation of Long Term Anticoagulant Therapy
18,113 patients who had atrial fibrillation and at least one risk factor for stroke 50% of enrolled patients were naïve to previous oral AC Median treatment duration: 2 years Primary outcome: stroke or systemic embolism References Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med ;361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ, et al. N Engl J Med 2009;361:

RE-LY®: Inclusion Criteria
Documented atrial fibrillation, and One additional risk factor for stroke: History of previous stroke, TIA, or systemic embolism LVEF less than 40% Symptomatic Heart Failure, NYHA Class II or greater Age of 75 years or more Age of 65 years or more and one of the following additional risk factors: Diabetes mellitus, CAD or Hypertension Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ, et al. N Engl J Med 2009;361:

Baseline characteristics
Dabigatran 110 mg Dabigatran 150 mg Warfarin Randomized 6015 6076 6022 Mean age (years) 71.4 71.5 71.6 Male (%) 64.3 63.2 63.3 CHADS2 score (mean) 0-1 (%) (%) 3+ (%) 2.1 32.6 34.7 32.7 2.2 32.2 35.2 30.9 37.0 32.1 Prior stroke/TIA (%) 19.9 20.3 19.8 Prior MI (%) 16.8 16.9 16.1 CHF (%) 31.8 31.9 Baseline ASA (%) 40.0 38.7 40.6 VKA naïve (%) 50.1 50.2 48.6 Patients were well distributed between the three arm of the trial. There were no significant differences in baseline characteristics between the dabigatran etexilate arms and the warfarin arm. Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ., et al. N Engl J Med 2009; 361:

Stroke or systemic embolism (SSE)
Noninferiority Superiority p-value p-value Dabigatran 110 mg vs. warfarin <0.001 0.30 Both dosages of dabigatran etexilate met the non-inferiority criteria (p value < 0.001). The upper limit of the confidence intervals for dabigatran etexilate 110 mg BID was far below the non-inferiority margin of Dabigatran 150 mg BID demonstrated superiority with the point of estimate and 95% CI well below the line of unity and a p-value of < (superiority). Dabigatran 150 mg vs. warfarin <0.001 <0.001 Margin = 1.46 0.50 0.75 1.00 1.25 1.50 HR (95% CI) Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ., et al. N Engl J Med 2009; 361:

Time to first stroke / SSE
RR 0.90 (95% CI: 0.74–1.10) p<0.001 (NI) p=0.30 (Sup) 0.05 0.04 RRR 35% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.03 Cumulative hazard rates RR 0.65 (95% CI: 0.52–0.81) p<0.001 (NI) p<0.001 (Sup) 0.02 0.01 0.0 0.5 1.0 1.5 2.0 2.5 Years RR, relative risk; CI, confidence interval; NI, non-inferior; Sup, superior Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ., et al. N Engl J Med 2009; 361:

All cause mortality RR 0.91 (95% CI: 0.80–1.03) p=0.13 (sup)
% per year 446 / 6,015 438 / 6,076 487 / 6,022 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ., et al. N Engl J Med 2009; 361:

Major bleeding rates RR 0.80 (95% CI: 0.70–0.93) p=0.003 (sup)
RRR 20% % per year 342 / 6,015 399 / 6,076 421 / 6,022 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ., et al. N Engl J Med 2009; 361:

Hemorrhagic stroke 50 45 40 30 20 14 10 12 D110 mg BID D150 mg BID
RR 0.31 (95% CI: 0.17–0.56) p<0.001 (sup) RR 0.26 (95% CI: 0.14–0.49) p<0.001 (sup) 50 Number of events 45 40 RRR 69% RRR 74% 0.38% Both dosages of dabigatran etexilate significantly reduced the incidence of hemorrhagic stroke (one element of the primary efficacy endpoint including stroke and systemic embolism) compared to warfarin: The relative risk reduction (RRR) for dabigatran etexilate 110mg BID compared to warfarin was 69%, RRR for dabigatran etexilate 150mg was 74%. 30 20 14 10 12 0.12% 0.10% D110 mg BID D150 mg BID Warfarin 6,015 6,076 6,022 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ., et al. N Engl J Med 2009; 361:

RE-LY®: Rates of MI Characteristic Myocardial Infarction (%/year) 0.82
Dabigatran 110 mg (N=6015) Dabigatran 150 mg (N=6076) Warfarin (N=6022) P-value Dabigatran 110 mg vs. Warfarin P-value Dabigatran 150 mg vs. Warfarin Myocardial Infarction (%/year) 0.82 0.81 0.64 0.09 0.12 The rate of myocardial infarction was 0.64% per year with warfarin and was higher with dabigatran: 0.82% per year in the 110-mg group (P = 0.09) and 0.81% per year in the 150-mg group (P = 0.12). References Connolly SJ, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Connolly SJ, et al. N Engl J Med 2009;361:

Time to first intra-cranial bleed
Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.02 RRR 59% RRR 70% Cumulative hazard rates 0.01 RR 0.41 (95% CI: 0.28–0.60) p<0.001 (Sup) RR 0.30 (95% CI: 0.19–0.45) p<0.001 (Sup) 0.0 0.5 1.0 1.5 2.0 2.5 Years RR, Relative risk; CI, confidence interval; Sup, superior Connolly SJ., et al. N Engl J Med 2009; 361: Adapted from Camm J.: Oral presentation at ESC on Aug. 30, Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

Vascular mortality 2.69 2.43 2.28 RR 0.90 (95% CI: 0.77–1.06)
p=0.21 (sup) RR 0.85 (95% CI: 0.72–0.99) p=0.04 (sup) % per year 2.69 RRR 15% 2.43 2.28 Regarding vascular mortality, dabigatran etexilate 150mg BID was superior to warfarin with p=0.038. Dabigatran etexilate 110mg BID was statistically comparable to warfarin regarding vascular mortality. However, numerically there were fewer deaths with dabigatran etexilate 110mg BID compared to warfarin. Definition of vascular mortality: Vascular mortality includes both cardiovascular death and other types of vascular death: Cardiovascular death : - Sudden / arrhythmic death (e.g. documented asystole, documented ventricular flutter/fibrillation, recent myocardial infarction, other) - Pump failure death (e.g. cardiac heart failure/cardiac shock, cardiac tamponade, recent myocardial infarction, other) Other vascular death: resulting from stroke, pulmonary embolus, peripheral embolus, haemorrhage, unknown cause (but still classifiable as "vascular"), other 289/ 6,015 274 / 6,076 317 / 6,022 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ., et al. N Engl J Med 2009; 361:

RE-LY®: Most Common Adverse Events
Dabigatran 110 mg (%) Dabigatran 150 mg (%) Warfarin (%) Dyspepsia* 11.8 11.3 5.8 Dyspnea 9.3 9.5 9.7 Dizziness 8.1 8.3 9.4 Peripheral edema 7.9 7.8 Fatigue 6.6 6.2 Cough 5.7 6.0 Chest pain 5.2 5.9 Arthralgia 4.5 5.5 Back pain 5.3 5.6 Nasopharyngitis 5.4 Diarrhea 6.3 6.5 Urinary tract infection 4.8 Upper respiratory tract infection 4.7 Overall rates of adverse events were low and similar between the treatment arms. The increase in dyspepsia, or related symptoms, could be related to the dabigatran capsules. To enhance absorption of dabigatran, a low pH is required. Therefore dabigatran capsules contain dabigatran-coated pellets with a tartaric acid core. This acidity may explain the increased incidence of dyspeptic symptoms with dabigatran. Elevations in the serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level of more than 3 times the upper limit of the normal range did not occur more frequently with dabigatran, at either dose, than with warfarin. References Connolly SJ., et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: *Occurred more commonly on dabigatran p<0.001 Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ, et al. N Engl J Med 2009;361:

RE-LY®: Summary Results
110 mg dose versus warfarin Comparable rates of stroke/systemic embolism Statistically significant reduction in hemorrhagic stroke Statistically significant reduction in major bleeding rates Significant reduction in total bleeds, life threatening bleeds and intracranial bleeds 150 mg dose versus warfarin Statistically significant reduction in stroke/systemic embolism Statistically significant reduction in vascular mortality Comparable rates of major bleeding rates Significant reduction in total bleeds, life threatening bleeds and intracranial bleeds References Connolly SJ., et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Connolly SJ, et al. N Engl J Med 2009;361:

Key Points The following guidelines were reviewed:
Antithrombotic use in atrial fibrillation Prevention of thromboembolism in patients with AF undergoing cardioversion Perioperative management of patients receiving vitamin K antagonists (VKA) Management of AF patients with special considerations – myocardial infarction, hyperthyroidism, pregnancy, hypertrophic cardiomyopathy Management of patients with newly discovered AF, with recurrent paroxysmal AF, and with recurrent persistent or permanent AF

Key Points Atrial fibrillation worsens prognosis of patients with comorbidities Atrial fibrillation increases risk along the cardiovascular continuum Hypertension is one of the strongest predictors for stroke in patients with atrial fibrillation A potential management strategy for switching patients from warfarin to dabigatran is outlined

Management of Weekend Patients
Management of the patient presenting on a Friday afternoon E.g. initiation of warfarin upon admission and check INR on Sunday or Monday according to the potential drugs interaction with other medications, or underlying condition if this is an issue How often to monitor symptoms, time in therapeutic range, anticoagulation clinic vs office management For warfarin, initial frequency should be biweekly until therapeutic range obtain, subsequently to be checked weekly for up to two consecutives in the therapeutic range, followed by every 4 to 6 weeks time interval (CHEST 2008)

Renal Impairment Reference Stangier J. Clinical Pharmacokinetics and Pharmacodynamics of the Oral Direct Thrombin Inhibitor Dabigatran Etexilate. Clin Pharmacokinet 2008; 47: Exposure to dabigatran is increased by renal impairment and correlates with the severity of renal dysfunction. Dabigatran can be partly (62-68%) removed from plasma by haemodialysis. Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation Stangier Clin Pharmacokinet 2010; 49(4):

-Apixaban: An Oral Direct Factor Xa Inhibitor Apixaban is a reversible oral direct Factor Xa Inhibitor Apixaban binds directly to the active site on Factor Xa, and does not require Antithrombin in order exert its pharmacological effect 50% bioavailability Peak Plasma concentration achieved at 3-4 h post-dose Multiple excretion pathways, ~ 27% renally excreted T½ of 12 h No known drug-drug/food-drug interactions Predictable and consistent anticoagulant effects No requirement for routine coagulation monitoring

-The AVERROES Study -Study Design Apixaban 5 mg BID AF and ≥1 risk factor, and demonstrated or expected unsuitable for VKA 2.5 mg BID in selected patients Statistical testing in the RE-LY Study: Primary endpoint: Non-inferiority design allowing for statistical analysis of superiority once non-inferiority is achieved All other endpoints: Superiority testing. P < 0.05  superior (95% CI is below 1) P > 0.05  comparable (if 95% CI includes 1) R 5,600 patients Double-Blind ASA ( mg/d) Primary objective: To establish the non-inferiority of apixaban 5mg bid to ASA mg od Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up Presented at the European Society Cardiology, Stockholm September 2010. 76

-The AVEROES Study -Primary Outcome: Stroke or Systemic Embolism 0.06 ASA mg od Apixaban 5 mg bid 0.03 0.05 RRR 54% 0.04 Cumulative Risk 0.03 0.02 RR 0.46 (95% CI: 0.33–0.64) p<0.001 0.01 0.0 3 6 9 12 15 18 21 Months No. at Risk Presented at the European Society Cardiology, Stockholm September 2010. ASA 2791 2720 2541 2124 1541 626 329 Apix 2809 2761 2567 2127 1523 617 353

Rivaroxaban (Factor Xa inhibitor) in Atrial Fibrillation: ROCKET
Patients with atrial fibrillation + ≥2 risk factors: CHF, hypertension, age ≥75, diabetes or stroke, TIA or systemic embolus n ~14,000 Rivaroxaban Warfarin 20 mg daily 15 mg for CrCl 30–49 INR target 2.5 (2.0–3.0 inclusive) Monthly monitoring and adherence to standard of care guidelines Primary endpoint: stroke or non-CNS systemic embolism over 4 years (Estimated study completion: May 2010) TIA, transient ischaemic attack; CrCl, creatine clearance

ROCKET AF Presented AHA Nov 15th, 2010
Rivaroxaban non-inferior but not superior in intention-to-treat ( vs Warfarin) Comparable major and non-major bleeds Less fatal and intracerebral bleeds with Rivaroxaban 90% CHADS2 score of 3 or higher

New Oral Anticoagulants
1- Who will pay? 2-Assessing compliance? 3-Treating bleeding complications?

Compliance? With Apixaban: RNI With Dabigatran: Thrombin Clotting time aPTT

Bleeding often controlled with supportive measures Dabigatran dialysable Specific agents for reversal of anticoagulant effects: Recombinant activated Factor VII PCCs ( Prothrombin complexe concentrates)

Overdose and Reversal Strategies Scientific evidence from in vitro / animal data
Recommendations for management of dabigatran overdose Maintain or increase diuresis Early charcoal administration Hemoperfusion over charcoal filter / hemodialysis Recommendations for management of severe bleeding Specific agents for the reversal of anticoagulant effects: Recombinant activated factor VII Prothrombin complex concentrates (PCCs) Hemodialysis and hemofiltration In vivo confirmation of suggested reversal strategies is ongoing Van Ryn J., et al. Thromb & Haemost 2010;103: doi: /TH Dabigatran etexilate is in clinical development and not licensed for clinical use in stroke prevention for patients with atrial fibrillation

Atrial Fibrillation Guidelines Update Introduction
Anne M Gillis MD, FRCPC, FHRS Professor of Medicine Department of Cardiac Sciences University of Calgary Libin Cardiovascular Institute of Alberta

Recommendations - Antithrombotic
2. We recommend that patients at very low risk of stroke (CHADS2 = 0) should receive aspirin ( mg/day). (Strong recommendation, High Quality Evidence). We suggest that some young persons with no standard risk factors for stroke may not require ay antithrombotic therapy. (Conditional recommendation, Moderate Quality Evidence).

3. We recommend that patients at low risk of stroke (CHADS2 = 1) should receive OAC therapy (either warfarin [INR 2 – 3] or dabigatran). (Strong recommendation, High Quality Evidence). We suggest, based on individual risk/benefit considerations, that aspirin is a reasonable alternative for some. (Conditional recommendation, Moderate Quality Evidence). 4. We recommend that patients at moderate risk of stroke (CHADS2 ≥ 2) should receive OAC therapy (either warfarin [INR 2 – 3] or dabigatran). (Strong recommendation, High Quality Evidence)

5. We suggest, that when OAC therapy is indicated, most patients should receive dabigatran in preference to warfarin. In general, the dose of dabigatran 150 mg po bid is preferable to a dose of 110 mg po (exceptions discussed in text). (Conditional recommendation. High Quality Evidence).

Recommendations – Stable CAD
10. We suggest that patients with AF or AFL who have stable CAD should receive antithrombotic therapy selected based upon their risk of stroke (aspirin for CHADS2 = 0 and OAC for CHADS2 ≥ 1). Warfarin is preferred over dabigatran for those at high risk of coronary events. (Conditional Recommendation, Moderate Quality Evidence)

THANK YOU!

QUESTIONS?

Understanding Stroke Prevention in Atrial Fibrillation

Similar presentations

Presentation on theme: "Understanding Stroke Prevention in Atrial Fibrillation"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Understanding Stroke Prevention in Atrial Fibrillation

Similar presentations

Presentation on theme: "Understanding Stroke Prevention in Atrial Fibrillation"— Presentation transcript:

Similar presentations

About project

Feedback