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Stroke Prevention in Atrial Fibrillation

Stroke Prevention in Atrial Fibrillation. A Review of New Study Results and An Exploration of their Clinical Implications. Stroke Prevention in Atrial Fibrillation -Question #1. Which of the following items are factors that determine the effectiveness of a therapy? A) Efficacy

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Stroke Prevention in Atrial Fibrillation

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  1. Stroke Prevention inAtrial Fibrillation A Review of New Study Results and An Exploration of their Clinical Implications

  2. Stroke Prevention in Atrial Fibrillation -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

  3. Stroke Prevention in Atrial Fibrillation -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%

  4. Stroke Prevention in Atrial Fibrillation -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%

  5. Stroke Prevention in Atrial Fibrillation -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

  6. Stroke Prevention inAtrial Fibrillation A Review of New Study Results and An Exploration of their Clinical Implications

  7. Stroke Prevention in Atrial Fibrillation -Disclosures • Astra Zeneca Canada Inc. • Boehringer Ingelheim Inc. • Bristol Myers Squibb Canada • Sanofi Aventis Pharma Inc. • Servier Canada Inc.

  8. Stroke Prevention in Atrial Fibrillation -Mortality in Rate vs. Rhythm Control Patients -The AFFIRM Study All-causemortality 30 25 Rhythm control 20 Cumulative Mortality (%) Ratecontrol 15 P=0.08 10 5 0 0 1 2 3 4 5 Years after randomization • N Engl J Med 2002; 347: 1825-33.

  9. Stroke Prevention in Atrial Fibrillation -Mortality in Rate vs. Rhythm Control Patients -The AFFIRM Study p Value <0.0001 0.0005 <0.0001 0.0005 Sinus Rhythm Antiarrhythmic Use Warfarin Use Digoxin Use 2.0 0.5 1.0 1.5 0 Risk Ratio • N Engl J Med 2002; 347: 1825-33.

  10. Stroke Prevention in Atrial Fibrillation -Efficacy of Warfarin -Meta-Analysis of Antithrombotic Therapy in A Fib Relative Risk Reduction(95% CI) Adjusted-dose warfarin comparedwith placebo or control 100% 50% 0 -50% -100% • Ann Intern Med 2007; 146: 857-67. Favors Warfarin Favors Placeboor Control

  11. Stroke Prevention in Atrial Fibrillation -Efficacy of Anti-Platelet Therapy -Meta-Analysis of Antithrombotic Therapy in A Fib Antiplatelet agents compared with placebo or control Relative Risk Reduction(95% CI) • Ann Intern Med 2007; 146: 857-67. N=4,876 100% 50% 0 -50% -100% Favors Antiplatelet Favors Placeboor Control

  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 Stroke Prevention in Atrial Fibrillation -Efficacy and Safety of Current A Fib Treatments -Meta-Analysis of Antithrombotic Therapy in A Fib W % A W % A • Ann Intern Med 2007; 146: 857-67. Warfarin Antiplatelets

  13. Stroke Prevention in Atrial Fibrillation -Anti-Thrombotic Therapy in Atrial Fibrillation -ACC/AHA/ESC Guidelines 2006 • Europace 2006; 8: 651-745.

  14. Stroke Prevention in Atrial Fibrillation -Effective vs. Efficacious Drug Therapy Penetration Efficacy • 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

  15. Stroke Prevention in Atrial Fibrillation -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 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: 52-60.

  16. Stroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation -Narrow Therapeutic Window Target INR (2.0-3.0) Ischaemicstroke 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 20 • N Engl J Med 2003; 349: 1019-26. 0 <1.5 1.5–1.9 2.0–2.5 2.6–3.0 3.1–3.5 3.6-4.0 4.1-4.5 >4.5 International Normalised Ratio (INR)

  17. Stroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation -Adequacy of Anticoagulation in Primary Care INR Above Target6% No warfarin65% INR at Target15% Subtherapeutic INR 13% • Arch Intern Med 2000; 160: 967.

  18. Stroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation -Preventable Strokes in Patients with Atrial Fib INR at Target10% No warfarin61% 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: 235-40.

  19. Stroke Prevention in Atrial Fibrillation -Limitations of Warfarin Therapy in Atrial Fibrillation -2o Prevention of Strokes in Patients with A Fib INR at Target18% No warfarin43% 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: 235-40.

  20. 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%) • N Engl J Med 2009; 360: 2066-78.

  21. Stroke Prevention in Atrial Fibrillation -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: 2066-78.

  22. 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%) • N Engl J Med 2009; 360: 2066-78.

  23. 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: 2066-78.

  24. 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%) • N Engl J Med 2009; 360: 2066-78.

  25. 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: 2066-78.

  26. Stroke Prevention in Atrial Fibrillation -The ACTIVE Program Documented AF + 1 risk factor: Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age 55-74 + 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 No Exclusion criteria for ACTIVE I ACTIVE I Irbesartan vs placebo ~9000 patients

  27. Stroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death -The ACTIVE-W Study 5.64 %/year RR = 1.45 P = 0.0002 3.93 %/year Cumulative Hazard Rates • Lancet 2006; 367: 1903-12. Years

  28. 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: 1903-12. Years

  29. Stroke Prevention in Atrial Fibrillation -INR Control in the ACTIVE-W Study -The ACTIVE-W Study • Lancet 2006; 367: 1903-12.

  30. 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 < 0.0001 RR = 1.11 P = 0.47 Cumulative Hazard Rates • Lancet 2006; 367: 1903-12. Years

  31. Stroke Prevention in Atrial Fibrillation -The ACTIVE Program Documented AF + 1 risk factor: Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age 55-74 + 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 No Exclusion criteria for ACTIVE I ACTIVE I Irbesartan vs placebo ~9000 patients

  32. Stroke Prevention in Atrial Fibrillation -Stroke, Embolism, MI and Vascular Death -The ACTIVE-A Study 0.4 11% RRR RR=0.89 (95% CI, 0.81–0.98; P=0.01) 924 (7.6%/year) 0.3 832 (6.8%/year) ASA Cumulative Incidence 0.2 Clopidogrel + ASA 0.1 0.0 0 1 2 3 4 Years • N Engl J Med 2009; 360: 2066-78.

  33. Stroke Prevention in Atrial Fibrillation -Stroke (All Types) -The ACTIVE-A Study 28% RRR RR=0.72 (95% CI, 0.62–0.83; P=<0.001) 408 (3.3%/year) 0.15 ASA 0.10 Cumulative Incidence 296 (2.4%/year) 0.05 Clopidogrel + ASA 0.0 0 1 2 3 4 Years • N Engl J Med 2009; 360: 2066-78.

  34. 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 Stroke Prevention in Atrial Fibrillation -Risk vs. Benefit of ASA+Clopidogrel vs. Warfarin -The ACTIVE-A Study • Ann Intern Med 2007; 146: 857-67. • N Engl J Med 2009; 360: 2066-78.

  35. 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 12-17 h No known drug-drug/food-drug interactions Predictable and consistent anticoagulant effects No requirement for routine coagulation monitoring Stroke Prevention in Atrial Fibrillation -Pradax (dabigatran): An Oral Direct Thrombin Inhibitor

  36. Atrial fibrillation with ≥ 1 risk factor Absence of contraindications R Dabigatran etexilate 110 mg bid N=6000 Dabigatran etexilate 150 mg bid N=6000 Warfarin 1 mg, 3 mg, 5 mg (INR 2.0-3.0) N=6000 Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Study Design • 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 : 1139-51.

  37. Stroke Prevention in Atrial Fibrillation -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 : 1139-51.

  38. Stroke Prevention in Atrial Fibrillation -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 0.50 0.75 1.00 1.25 1.50 HR (95% CI) • N Engl J Med 2009; 361: 1139-51.

  39. 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 0 0.5 1.0 1.5 2.0 2.5 • N Engl J Med 2009; 361: 1139-51. Years

  40. Warfarin Dabigatran etexilate 110 mg Dabigatran etexilate 150 mg Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Intracranial Bleeding 0.02 RRR 69% RRR 60% Cumulative hazard rates RR 0.40 (95% CI: 0.27–0.60) p<0.001 (Sup) 0.01 RR 0.31 (95% CI: 0.20–0.47) p<0.001 (Sup) 0.0 0 0.5 1.0 1.5 2.0 2.5 • N Engl J Med 2009; 361: 1139-51. Years

  41. Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Major Bleeding in the RE-LY Study Data represents %/year • N Engl J Med 2009; 361: 1139-51.

  42. Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Major Bleeding in the RE-LY Study Data represents %/year • N Engl J Med 2009; 361: 1139-51.

  43. Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Most Common Side Effects • N Engl J Med 2009; 361: 1139-51. *Occurred more commonly on dabigatran p<0.001

  44. Stroke Prevention in Atrial Fibrillation -The RE-LY Study -Most Common Side Effects • N Engl J Med 2009; 361: 1139-51. *Occurred more commonly on dabigatran p<0.001

  45. Stroke Prevention in Atrial Fibrillation -Major Bleeding in the RE-LY Study -The Dabigatran Capsule Dabigatran Capsule Dabigatran Pellet Tartaric Acid Core Seal Coating Dabigatran Coat

  46. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective Warfarin vs. Placebo Warfarin vs. ASA Warfarin vs. ASA + clopidogrel Warfarin vs. dabigatran 150 0 0.3 0.6 0.9 1.2 1.5 1.8 2.0 Favours warfarin Favours other treatment

  47. Stroke Prevention in Atrial Fibrillation -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

  48. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective

  49. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective 64%

  50. Stroke Prevention in Atrial Fibrillation -The Antithrombotic Therapy In Perspective 34%

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