Stroke Prevention in Atrial Fibrillation

Stroke Prevention in Atrial Fibrillation
A Review of New Study Results and An Exploration of their Clinical Implications

-Question #1 Which of the following items are factors that determine the effectiveness of a therapy? A) Efficacy B) Penetration C) Adherence D) All of the above

-Question #2 What percentage of patients with atrial fibrillation are optimally treated with Warfarin (i.e. INR is at target) in the Primary Care setting are? A) 15% B) 25% C) 50% D) 75%

-Question #3 What percentage of patients who have a documented history of stroke secondary to atrial fibrillation, and who now present to the hospital with a second stroke, are optimally treated with Warfarin (i.e. INR is at target)? A) 10% B) 20% C) 40% D) 80%

-Question #4 True or False: Treating patients with antiarrhythmic medications to prevent recurrences of Atrial Fibrillation help to prevent subsequent strokes. A) True B) False

A Review of New Study Results and An Exploration of their Clinical Implications

-Disclosures Astra Zeneca Canada Inc. Boehringer Ingelheim Inc. Bristol Myers Squibb Canada Sanofi Aventis Pharma Inc. Servier Canada Inc.

-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 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:

Relative Risk Reduction (95% CI) Favors Placebo or Control
Stroke Prevention in Atrial Fibrillation -Efficacy of Warfarin -Meta-Analysis of Antithrombotic Therapy in A Fib New Relative Risk Reduction (95% CI) Adjusted-dose warfarin compared with placebo or control Hart.Ann Intern Med.Jun.2007/ p861/fig Study Year AFASAK I 1989; 1990 SPAF I 1991 BAATAF 1990 CAFA SPINAF 1992 EAFT 1993 All trials (n=6) N=2,900 According to the meta-analysis performed by Hart and colleagues, adjusted-dose warfarin (6 trials, 2900 participants) reduced stroke by 64% (95% CI, 49% to 74%) when compared with the control. Hart.Ann Intern Med.Jun.2007/ p861/fig 100% 50% -50% -100% Ann Intern Med 2007; 146: Favors Warfarin Favors Placebo or Control 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: 10

Relative Risk Reduction (95% CI) Favors Placebo or Control
Stroke Prevention in Atrial Fibrillation -Efficacy of Anti-Platelet Therapy -Meta-Analysis of Antithrombotic Therapy in A Fib New Antiplatelet agents compared with placebo or control Relative Risk Reduction (95% CI) Study Year AFASAK I 1989; 1990 SPAF I 1991 EAFT 1993 ESPS II 1997 LASAF Daily Alternate day UK-TIA 300 mg daily 1200 mg daily 1999 JAST 2006 Aspirin trials (n=7) SAFT 2003 Dipyridamole Combination All antiplatelet trials (n=8) Hart.Ann Intern Med.Jun.2007/ p861/fig According to the meta-analysis performed by Hart and colleagues, antiplatelet agents (8 trials, 4876 participants) reduced stroke by 22% (CI, 6% to 35%) when compared with the control. Hart.Ann Intern Med.Jun.2007/ p861/fig Ann Intern Med 2007; 146: N=4,876 100% 50% -50% -100% Favors Antiplatelet Favors Placebo or Control 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: 11

-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 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 Fuster.J Am Coll Cardiol.Aug.2006/ pe183/table 12 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] W % Hart.Ann Intern Med.Jun.2007/p857/ c1/lines A18-A19, C2/line A1 A W % van Walraven. JAMA.Nov.2002/p2441/ lines A19 A Ann Intern Med 2007; 146: Fuster.J Am Coll Cardiol.Aug.2006/ pe183/table 12 Warfarin Antiplatelets 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 12

-Anti-Thrombotic Therapy in Atrial Fibrillation -ACC/AHA/ESC Guidelines 2006 High Risk Moderate Risk Low Risk Rheumatic Valve Prior Stroke/TIA Or >2 Risk Factors: Age >75 Hypertension Diabetes Congestive Heart Failure 1 Risk Factor: Age <75 No Additional Risk Factors Warfarin INR Range 2.0 – 3.0 Aspirin mg/day Europace 2006; 8:

Effectiveness Stroke Prevention in Atrial Fibrillation Efficacy
-Effective vs. Efficacious Drug Therapy Efficacy Penetration Efficacy is a necessary but not sufficient condition for the effective prevention of cardiovascular disease and is ideally established through randomized, controlled experimental studies Adherence Effectiveness

-Limitations of Warfarin Therapy in Atrial Fibrillation Unpredictable response Slow onset/offset of action Warfarin therapy has several limitations that make it difficult to use in practice Narrow therapeutic window (INR range 2-3) Numerous food-drug interactions Numerous drug-drug interactions Routine coagulation monitoring Due to the limitations of VKAs, it has been estimated that up to 50% of patients eligible for treatment receive no anticoagulant treatment (Rowan et al. JACC. 2007) Frequent dose adjustments Risk of Bleeding Complications Warfarin was #1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse effects in therapeutic use” Warfarin caused 6% of the 702,000 ADEs treated in the ED/year; 17% required hospitalization J Thromb Thrombolysis 2008; 25:

Intracranial haemorrhage
Stroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation -Narrow Therapeutic Window Target INR ( ) Ischaemic stroke Intracranial haemorrhage 80 The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range 60 Events / 1000 patient years 40 The anticoagulant effect of VKAs are optimized when therapeutic doses are maintained within a very narrow range. Over-anticoagulation (INR >3) can lead to an increased risk of bleeding and under-anticoagulation (INR <2) can lead to increased risk of stroke. 20 N Engl J Med 2003; 349: <1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 >4.5 International Normalised Ratio (INR)

-Limitations of Warfarin Therapy in Atrial Fibrillation -Adequacy of Anticoagulation in Primary Care INR Above Target 6% No warfarin 65% INR at Target 15% Subtherapeutic INR 13% Arch Intern Med 2000; 160: 967.

-Limitations of Warfarin Therapy in Atrial Fibrillation -Preventable Strokes in Patients with Atrial Fib INR at Target 10% No warfarin 61% Subtherapeutic INR 29% Analyzed 597 patients with a first ischemic stroke who had known atrial fibrillation, were classified as high risk for stroke, and who had no known contraindications to anticoagulation Stroke 2009; 40:

-Limitations of Warfarin Therapy in Atrial Fibrillation -2o Prevention of Strokes in Patients with A Fib INR at Target 18% No warfarin 43% Subtherapeutic INR 39% Analyzed 323 patients with a second ischemic stroke who had known atrial fibrillation at the time of their first stroke, and who had no known contraindications to anticoagulation Stroke 2009; 40:

-Reasons for Coumadin Non-Adherence -The ACTIVE-A Study Bleeding Risk (23.5%) Physician Judgement (50.4%) Patient Preference (26.1%) N Engl J Med 2009; 360:

-Reasons for Coumadin Non-Adherence -The ACTIVE-A Study Low Plt (2.2%) NSAID Use (1.6%) EtOH Use (1.1%) PUD (0.7%) Bleeding Risk (23.5%) Previous Bleeding on OAC (5.8%) Physician Judgement (50.4%) Hypertension (3.2%) Fall Risk (9.8%) Patient Preference (26.1%) N Engl J Med 2009; 360:

Concerns re: Adherence
Stroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence -The ACTIVE-A Study Concerns re: Adherence (0.7%) Bleeding Risk (23.5%) Coumadin Not Indicated (28.6%) Physician Judgement (50.4%) Patient Preference (26.1%) Both (22.8%) N Engl J Med 2009; 360:

“Not Willing To Take Coumadin”
Stroke Prevention in Atrial Fibrillation -Reasons for Coumadin Non-Adherence -The ACTIVE-A Study Bleeding Risk (23.5%) Physician Judgement (50.4%) Patient Preference (26.1%) Another 22.8% of Patients “Not Willing To Take Coumadin” “Not Willing To Take Coumadin” is the sole reason in 26.1% of Patients N Engl J Med 2009; 360:

-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 W Clopidogrel+ASA vs. Warfarin ACTIVE A Clopidogrel+ASA vs. ASA 6500 patients 7500 patients 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. No Exclusion criteria for ACTIVE I ACTIVE I Irbesartan vs placebo ~9000 patients

Cumulative Hazard Rates
Stroke Prevention in Atrial Fibrillation -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

Stroke Prevention in Atrial Fibrillation -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

Percent patient months in range
Stroke Prevention in Atrial Fibrillation -INR Control in the ACTIVE-W Study -The ACTIVE-W Study INR Range Percent patient months in range <2.0 20.8 63.9 >3.0 15.4 Lancet 2006; 367:

Stroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death by INR -The ACTIVE-W Study  65% INR in Range <65% INR in Range RR = 1.83 P < RR = 1.11 P = 0.47 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 W Clopidogrel+ASA vs. Warfarin ACTIVE A Clopidogrel+ASA vs. ASA 6500 patients 7500 patients 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. No Exclusion criteria for ACTIVE I ACTIVE I Irbesartan vs placebo ~9000 patients

-Stroke, Embolism, MI and Vascular Death -The ACTIVE-A Study New 0.4 11% RRR RR=0.89 (95% CI, 0.81–0.98; P=0.01) 924 (7.6%/year) ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1A (inset) 0.3 832 (6.8%/year) Cumulative Incidence ASA 0.2 Clopidogrel + ASA 0.1 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) 0.0 ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2 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 32

28% RRR RR=0.72 (95% CI, 0.62–0.83; P=<0.001)
Stroke Prevention in Atrial Fibrillation -Stroke (All Types) -The ACTIVE-A Study New 28% RRR RR=0.72 (95% CI, 0.62–0.83; P=<0.001) 0.15 408 (3.3%/year) ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1B (inset) ASA 0.10 Cumulative Incidence 296 (2.4%/year) 0.05 Clopidogrel + 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). 0.0 ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1B 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 33

Clopidogrel + ASA vs ASA3
Stroke Prevention in Atrial Fibrillation -Risk vs. Benefit of ASA+Clopidogrel vs. Warfarin -The ACTIVE-A Study New Connolly.ACTIVE A.ACC.OrlandoFL.Mar.2009[Presentation]/slide 22 Meta-analysis ACTIVE A OAC vs ASA2 Clopidogrel + ASA vs ASA3 Benefit Relative reduction in stroke 38% 28% Risk Relative increase in major extracranial bleeding Relative increase in intracranial bleeding 70% 128% 51% 87% Hart.Ann Intern Med.Jun.2007/p864/ tab 5 ACTIVE.N Engl J Med.Mar.2009/ p8/c2/lines 23-29, p9/c1/lines 1-4 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. If 1000 patients were treated with clopidogrel plus ASA over the course of 3 years, this would prevent 28 strokes, 17 of which would be fatal or disabling as well as 6 myocardial infarctions. This would occur at a cost of 20 major (non-stroke) bleeds, including 3 fatal bleeds. [1] Adjusted dose of warfarin, when compared with ASA, reduces the risk of stroke by 38%, but increases the risk of major extracranial bleeding by 70% and the risk of intracranial bleeding by 128%.[2] In ACTIVE A, clopidogrel plus stroke reduced the risk of stroke by 28% and increased the risk of major extracranial bleeding by 51% and major intracranial bleeding by 87%.[3] Connolly.ACTIVE A.ACC.OrlandoFL.Mar.2009[Presentation]/slide 22 If 1000 patients were treated with clopidogrel plus ASA over the course of 3 years, this would prevent 28 strokes, 17 of which would be fatal or disabling as well as 6 MIs1 This would occur at a cost of 20 major (non-stroke) bleeds, including 3 fatal bleeds Hart.Ann Intern Med.Jun.2007/p864/ tab 5 ACTIVE.N Engl J Med.Mar.2009/ p8/c2/lines 23-29, p9/c1/lines 1-4 Ann Intern Med 2007; 146: N Engl J Med 2009; 360: Connolly, SJ. ACTIVE A - Effects of addition of clopidogrel to aspirin in patients with atrial fibrillation who are unsuitable for vitamin K antagonists. Presented at: ACC 58th Annual Scientific Session; March 29-31, 2009; Orlando, FL. 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: 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 34

-Pradax (dabigatran): An Oral Direct Thrombin Inhibitor Dabigatran is a reversible oral direct thrombin inhibitor (DTI) It blocks the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot (thrombus) formation 6.5% bioavailability Rapid onset of action (Peak Plasma concentration at 2 h post-dose) ~ 80% renally excreted T½ of h No known drug-drug/food-drug interactions Predictable and consistent anticoagulant effects No requirement for routine coagulation monitoring

Atrial fibrillation with ≥ 1 risk factor Absence of contraindications
Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Study Design Atrial fibrillation with ≥ 1 risk factor Absence of contraindications R Warfarin 1 mg, 3 mg, 5 mg (INR ) N=6000 Dabigatran etexilate 110 mg bid 150 mg bid 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) Primary objective: To establish the non-inferiority of dabigatran etexilate to warfarin Minimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up N Engl J Med 2009; 361 :

-The RE-LY Study -Inclusion Criteria 1) Documented atrial fibrillation and 2) One additional risk factor for stroke: a) History of previous stroke, TIA, or systemic embolism b) LVEF less than 40% c) Symptomatic Heart Failure, NYHA Class II or greater d) Age of 75 years or more e) Age of 65 years or more and one of the following additional risk factors: Diabetes mellitus, CAD or Hypertension N Engl J Med 2009; 361 :

-The RE-LY Study -Primary Outcome: Stroke or Systemic Embolism Noninferiority Superiority p-value p-value Dabigatran 110 mg vs. warfarin <0.001 0.34 Margin = 1.46 Dabigatran 150 mg vs. warfarin <0.001 <0.001 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). 0.50 0.75 1.00 1.25 1.50 HR (95% CI) N Engl J Med 2009; 361:

Cumulative hazard rates
Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Primary Outcome: Stroke or Systemic Embolism RR 0.91 (95% CI: 0.74–1.11) p<0.001 (NI) p=0.34 (Sup) 0.05 0.04 RRR 34% Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.03 Cumulative hazard rates RR 0.66 (95% CI: 0.53–0.82) p<0.001 (NI) p<0.001 (Sup) 0.02 0.01 0.0 N Engl J Med 2009; 361: 0.5 1.0 1.5 2.0 2.5 Years

Cumulative hazard rates
Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Intracranial Bleeding Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg 0.02 RRR 69% RRR 60% Cumulative hazard rates 0.01 RR 0.40 (95% CI: 0.27–0.60) p<0.001 (Sup) RR 0.31 (95% CI: 0.20–0.47) p<0.001 (Sup) 0.0 0.5 1.0 1.5 2.0 2.5 N Engl J Med 2009; 361: Years

-The RE-LY Study -Major Bleeding in the RE-LY Study Dabigatran 110 mg 150 mg Warfarin P-value 110 vs. W 150 vs. W Number of patients (n) 6015 6076 6022 Major bleeding 2.71 3.11 3.36 0.003 0.31 - Life threatening - Non-life threatening - Gastrointestinal 1.22 1.66 1.12 1.45 1.88 1.51 1.80 1.76 1.02 <0.001 0.56 0.43 0.037 0.47 Data represents %/year N Engl J Med 2009; 361:

-The RE-LY Study -Most Common Side Effects 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. N Engl J Med 2009; 361: *Occurred more commonly on dabigatran p<0.001

-Major Bleeding in the RE-LY Study -The Dabigatran Capsule Dabigatran Capsule Dabigatran Pellet Tartaric Acid Core Seal Coating Dabigatran Coat

-The Antithrombotic Therapy In Perspective Warfarin vs. Placebo Warfarin vs. ASA Warfarin vs. ASA + clopidogrel Warfarin vs. dabigatran 150 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other treatment

-The Antithrombotic Therapy In Perspective More Bleeding 1.5 ASA+Clopidogrel Warfarin Less Strokes More Strokes 0.75 1.5 2.0 2.5 3.0 0.75 Dabigatran Aspirin Placebo 0.5 Less Bleeding

-The Antithrombotic Therapy In Perspective Treatment Stroke Risk (/year) No Therapy 4.5 ASA 3.7 ASA + Clopidogrel 2.8 Warfarin 1.7 Dabigatran 110 1.5 Dabigatran 150 1.1

-The Antithrombotic Therapy In Perspective Treatment Stroke Risk (/year) No Therapy 4.5 ASA 3.7 ASA + Clopidogrel 2.8 Warfarin 1.7 Dabigatran 110 1.5 Dabigatran 150 1.1 64%

Cardiovascular Outcomes (Stroke, Death, Hospitalization)
Stroke Prevention in Atrial Fibrillation -The Natural History of Atrial Fibrillation Paroxysmal A Fib Persistent A Fib Permanent A Fib Sinus Rhythm Asymptomatic A Fib Cardiovascular Outcomes (Stroke, Death, Hospitalization) Symptomatic A Fib

-A “New” Way to Look at Atrial Fibrillation

-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 W Clopidogrel+ASA vs. Warfarin ACTIVE A Clopidogrel+ASA vs. ASA 6500 patients 7500 patients SBP>110mmHg Not on an ATII Blocker No Proven Indication for an ATII Blocker No Contraindication for an ATII Blocker 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 I Irbesartan vs placebo ~9000 patients

-Time to First Stroke, MI or Vascular Death -The ACTIVE-I Study 0.4 0.3 Cumulative Incidence 0.2 0.1 0.0 1 2 3 4 4.5 Years Presented at the European Society of Cardiology, Barcelona, 2009.

-Stroke and Other Thromboembolic Events -The ACTIVE-I Study New Irbesartan (n=4,518) Placebo (n=4,498) Hazard Ratio 95% CI p Value n %/year Stroke 380 2.1 411 2.3 0.92 0.213 TIA 130 0.7 150 0.8 0.86 0.208 Non-CNS Embolism 49 0.3 65 0.4 0.74 0.114 Stroke/TIA/Non-CNS Emb 518 2.9 585 3.4 0.87 0.024 ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1A (inset) 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) ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2 Presented at the European Society of Cardiology, Barcelona, 2009. 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 56

-Etiology of Stroke in Atrial Fibrillation -The ACTIVE-I Study ICH 10% SAH Lacunar 20% Thromboembolic Cardioembolic Other 5% Unknown 25% Ischemic 80% Hemorrhagic 20% Slide 18 Stroke 2006; 37:

-Etiology of Stroke in Atrial Fibrillation -The ACTIVE-I Study

Relative Risk Reduction (95% CI)
Stroke Prevention in Atrial Fibrillation -Prevention of A Fib with ACE-I and ATII Blockers -A Meta-Analysis Relative Risk Reduction (95% CI) ACE-I Treatment Control VanDenBerg 2/7 711 SOLVD 10/186 45/188 TRACE 22/790 42/787 Ueng 18/70 32/75 CAPP 117/5492 135/5493 STOPH2 200/2205 357/4409 GISSI 665/8865 721/8846 Subtotal 1034/17615 1339/19809 RR (95% CI) 0.45 ( ) 0.22 ( ) 0.52 ( ) 0.60 ( ) 0.87 ( ) 1.12 ( ) 0.92 ( ) 0.72 ( ) ARB Madrid 9/79 22/75 ValHeFT 116/2209 173/2200 Charm 179/2769 216/2749 LIFE 179/4417 252/4387 Subtotal 483/9474 663/9411 Total 1517/27089 2002/29220 0.39 ( ) 0.67 ( ) 0.82 ( ) 0.71 ( ) 0.71 ( ) 0.72 ( ) J Am Coll Cardiol 2005; 45: 0.1 0.2 1.0 5.0 10.0 Favors Treatment Favors Control

-Arrhythmia Outcomes -The ACTIVE-I Study There was no difference in the Number of Patients who converted to Normal Sinus Rhythm from Atrial Fibrillation There was no difference in the Number of Patients who progressed from Normal Sinus Rhythm to Atrial Fibrillation There was no difference in Hospital Admissions for Atrial Fibrillation There was no difference in Cardioversions Presented at the European Society of Cardiology, Barcelona, 2009.

-Baseline Characteristics -The ACTIVE-I Study New Irbesartan (n=4,518) Placebo (n=4,498) Age (mean) 69.5 69.6 % Female 39.2 39.3 Atrial Fibrillation -Permanent (%) -Paroxysmal (%) -Persistent (%) 66.0 19.6 14.3 64.4 20.5 14.9 Sinus Rhythm (%) 18.7 Heart Failure (%) 32.3 31.6 CHADS Risk Score 1.99 1.97 SBP/DBP (mmHg) 138/83 138/82 Heart Rate 75.3 74.9 ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1A (inset) 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) ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2 Presented at the European Society of Cardiology, Barcelona, 2009. 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 61

-Population Attributable Fraction for Hypertension -The ARIC Study % Of Patients Followed 14,448 people who were free of clinical stroke for 13.4 years Hypertension is the most powerful predictor for all stroke subtypes Stroke 2006; 37:

-Effect of BP on Stroke in Patients with A Fib -The SPORTIF Trials 4.0 3.5 3.0 2.5 Event Rate (%/Year) 2.0 1.5 1.0 0.5 100 110 120 130 140 150 160 Mean SBP (mmHg) European Heart Journal 2007; 28:

-Baseline Medications -The ACTIVE-I Study New Irbesartan (n=4,518) Placebo (n=4,498) ACE-I (%) 60.2 60.6 Beta-Blockers (%) 54.4 54.6 Diuretic (%) 54.3 54.1 Ca2+ Channel Blocker (%) 27.0 27.2 Alpha-Blocker/Vasodilator (%) 11.9 11.1 Aspirin 58.7 59.3 Warfarin 38.1 37.6 Antiarrhythmics 22.7 23.1 Digoxin 35.1 34.7 ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1A (inset) 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) ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2 Presented at the European Society of Cardiology, Barcelona, 2009. 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 67

-Baseline Medications -The ACTIVE-I Study New Irbesartan (n=4,518) Placebo (n=4,498) ACE-I (%) 60.2 60.6 Beta-Blockers (%) 54.4 54.6 Diuretic (%) 54.3 54.1 Ca2+ Channel Blocker (%) 27.0 27.2 Alpha-Blocker/Vasodilator (%) 11.9 11.1 Aspirin 58.7 59.3 Warfarin 38.1 37.6 Antiarrhythmics 22.7 23.1 Digoxin 35.1 34.7 ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2, p7/fig 1A (inset) 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) ACTIVE.N Engl J Med.Mar.2009/ p6/tab 2 Presented at the European Society of Cardiology, Barcelona, 2009. 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 68

-Wading into the Deep End

-Dronedarone: A New Antiarrhythmic Medication Dronedarone O (CH2)3CH3 CH3SO2HN (CH2)3CH3 O(CH2)3N (CH2)3CH3 O O Dronedarone is a benzofuran derivative structurally related to amiodarone but without the iodine on the benzene ring and with a sulfonamide group added to the benzofuran ring Dronedarone was originally developed with the aim of leveraging amiodarone’s antiarrhythmic efficacy and cardiac safety but with improved organ toxicity The electrophysiological properties of dronedarone are similar to those of amiodarone and their structural differences may be responsible for the unique clinical profile of dronedarone compared to amiodarone The most significant structural changes are the removal of iodine and the addition of a methane sulfonyl group. The removal of iodine should result in freedom of amiodarone’s iodine-related organ toxicity, and the second molecular change is thought to decrease lipophilicity, thus shortening the half-life and reducing tissue accumulation A consequence of this toxicity is that amiodarone administration requires dose titration to determine the minimum effective dose, as adverse effects are often dose-related. On the other hand, due to its amended profile, dronedarone is administered as a fixed dosing regimen with no loading dose or need for titration. Reference Kathofer et al. Cardiovasc Drug Rev 2005;23(3): Wegener F et al. J Cardiovasc Electrophysiol. 2006;17(S2):S17-S20 (CH2)3CH3 I CH2CH3 O(CH2)2N CH2CH3 O Amiodarone I 70

-Study Design -The ATHENA Study 4,628 patients >75 years with atrial fibrillation or years with atrial fibrillation and at least one additional cardiovascular Risk Factor* prior to randomization. Double blind. Randomized. Placebo controlled. International multicenter. Mean follow-up 21 months. R Dronedarone 400 mg BID Placebo 12-30 mos. follow-up Primary Endpoint: composite of all-cause mortality combined with cardiovascular hospitalization Secondary Endpoint: death from any cause, cardiovascular death, hospitalization for cardiovascular reasons *Risk Factor=Htn, diabetes, prior stroke/TIA, LA ≥50 mm, LVEF <40% N Engl J Med 2009; 360: 71

Cumulative Incidence (%)
Stroke Prevention in Atrial Fibrillation -Cardiovascular Hospitalization or Death -The ATHENA Study 10 20 40 50 30 Placebo on top of standard therapy* Dronedarone 400mg bid on top of standard therapy* 24% reduction in relative risk Cumulative Incidence (%) HR=0.76 Dronedarone significantly decreased the risk of cardiovascular hospitalisations or death from any cause by 24% (p<0.001), meeting the primary study endpoint Standard therapy may have included rate control agents (beta-blockers, and/or Ca-antagonist and/or digoxin) and/or anti-thrombotic therapy (Vit. K antagonists and /or aspirin and other antiplatelets therapy) and/or other cardiovascular agents such as ACEIs/ARBs and statins Reference Hohnloser SH et al. N Engl J Med 2009;360: p<0.001 Months *Standard therapy may have included anti-thrombotic therapy and/or rate control agents and/or other cardiovascular agents such as ACE-I statins N Engl J Med 2009; 360: 6 12 18 24 30 72 72

-Cardiovascular Hospitalization -The ATHENA Study Reason for first CV hospitalisation Placebo n=2327 Dronedarone n=2301 HR 95% CI p value Any reason 859 675 0.74 0.67; 0.82 <0.001 Atrial Fibrillation 510 335 0.63 0.55; 0.72 CHF 132 112 0.86 0.67; 1.10 0.22 ACS 89 62 0.70 0.51; 0.97 0.03 Syncope 32 27 0.85 0.51; 1.42 0.54 Ventricular arrhythmia or cardiac arrest 12 13 1.09 0.50; 2.39 0.83 Dronedarone reduced the incidence of all CV-related first hospitalisation by 26% (p<0.001) Post-hoc analysis examined the specific reasons for CV hospitalisation. Hospitalisations related to AF were reduced by 37% (p<0.001) Reference Hohnloser SH et al. N Engl J Med 2009;360: N Engl J Med 2009; 360: 73 73

Cumulative Incidence (%)
Stroke Prevention in Atrial Fibrillation -Effect of Dronedarone on Stroke -The ATHENA Study Placebo on top of standard therapy* 5 Dronedarone (DR) 400mg bid on top of standard therapy* 34% reduction in relative risk 4 HR=0.66 3 p=0.027 Cumulative Incidence (%) 2 Dronedarone reduced the incidence of all CV-related first hospitalisation by 26% (p<0.001) Post-hoc analysis examined the specific reasons for CV hospitalisation. Hospitalisations related to AF were reduced by 37% (p<0.001) Reference Hohnloser SH et al. N Engl J Med 2009;360: 1 12 6 18 30 24 Months HR=0.48 if CHAD>1, but no benefit if CHADS<1 60% of patients were on Warfarin Circulation 2009; 120: 74 74

-Conclusions While Warfarin has been proven to be an efficacious therapy for the prevention of stroke in atrial fibrillation, its effectiveness is limited by poor adherence as a result of both physician and patient related factors Novel strategies have been developed to potentially replace Warfarin, including combination antiplatelet therapy and oral direct thrombin inhibitors, which are both safe and effective Antiarrhythmic medications may be making a resurgence in the prevention of stroke in atrial fibrillation

-Practical Aspects to Dabigatran Administration Dosing: Currently Dabigatran is only available in the 110mg formulation and should be dosed at 110mg po bid for Stroke Prevention in Atrial Fibrillation Should not use if the CrCL<30mL/min (80% Renally Excreted) When switching from Warfarin to Dabigatran, the Warfarin should be held, and the Dabigatran should be started when the INR falls below 2 Aspirin, Plavix or Aggrenox may be used concomitantly with Dabigatran Surgical Considerations: Dabigatran should be discontinued at least 24 hours prior to elective surgical procedures Dabigatran should be resumed as soon as it is clinically feasible post procedure Bleeding: Dabigitran has a half-life of hours FFP may be used to help control bleeding Can use aPTT or Thrombin Time to monitor effect Dabigatran is dialyzable

-Etiology of Stroke in Atrial Fibrillation -The ACTIVE-I Study

-Effect of Dronedarone on Stroke -The ATHENA Study STROKE Characteristic n RR [95% CI] OAC & Antiplatelet agent 682 0.56 [0.20; 1.53] OAC alone 2105 0.58 [0.32; 1.05] Antiplatelet agent 1488 0.89 [0.49; 1.61] None of above 353 0.29 [0.06; 1.38] p=0.47 Circulation 2009; 120: 0.1 1.0 10.0 Dronedarone Better Placebo Better 78 78

-Effect of Dronedarone on Stroke -The ATHENA Study Characteristic n RR [95% CI] CHADS2 score ≤1 1639 1.29 [0.63;2.61] ≥2 2989 0.48 [0.31;0.76] CHF No 3263 0.77 [0.48;1.24] Yes 1365 0.47 [0.25;0.90] Hypertension 633 0.68 [0.22;2.09] 3995 0.64 [0.43;0.95] Age in years <75 2703 0.74 [0.45;1.19] ≥75 1925 0.53 [0.29;0.97] Diabetes mellitus 3683 0.64 [0.42;1.00] 945 0.64 [0.31;1.33] Stroke/TIA 4012 0.68 [0.45;1.05] 616 0.50 [0.23;1.09] STROKE p 0.02 0.22 0.91 0.41 0.98 0.49 Circulation 2009; 120: 0.1 Dronedarone Better 1.0 Placebo Better 10.0 79 79

Stroke Prevention in Atrial Fibrillation

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