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Please take this time to complete the Pre-Program Performance and Knowledge Gap Assessment Tool in your syllabus. Thank you. Thrombosis Risk Reduction: An Overview. New Frontiers in Thrombosis Reduction for Heart Disease Focus on Novel Agents Across the ACS and AF Risk Spectrum—

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  1. Please take this time to complete the Pre-Program Performance and Knowledge Gap Assessment Tool in your syllabus. Thank you.

  2. Thrombosis Risk Reduction: An Overview New Frontiers in Thrombosis Reduction for Heart Disease Focus on Novel Agents Across the ACS and AF Risk Spectrum— A Year 2010 Advanced Practice Summit for the Cardiovascular Specialist Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Program Chairman Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor of Medicine, Harvard Medical School Senior Investigator, TIMI Group

  3. CME-certified symposium jointly sponsored by the Postgraduate Institute of Medicine and CMEducation Resources, LLCCommercial Support: Sponsored by an independent educational grant from the Bristol-Myers Squibb/Pfizer PartnershipFaculty disclosures: Listed in program syllabus Welcome and Program Overview

  4. Program Faculty Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Program Chairman Chief of Cardiology, VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor, Harvard Medical School Senior Investigator, TIMI Group Boston, Massachusetts USA Gregory Y.H. Lip, MD, FRCP, FACC, FESC Consultant Cardiologist and Professor of Cardiovascular Medicine Director, Haemostasis Thrombosis & Vascular Biology Unit University of Birmingham Centre for Cardiovascular Sciences City Hospital Birmingham, England Shamir Mehta, MD, MSc, FACC, FRCPC Director, Interventional Cardiology Hamilton Health Sciences Associate Professor McMaster University Hamilton, Ontario, Canada David A. Garcia, MD Associate Professor, Division of General Internal Medicine University of New Mexico Co-Director, University of New Mexico Anticoagulation Management Service President, Anticoagulation Forum Albuquerque, New Mexico USA Richard C. Becker, MD Professor of Medicine School of Medicine Duke University Director, Duke Cardiovascular Thrombosis Center Duke Clinical Research Institute Durham, North Carolina USA

  5. Issues We Will Address • Changing landscape for AFIB with Factor II and Xa inhibitors, and how cardiologists will respond • The various risk groups for AFIB including de novo patients, patients who have failed coumadin for one reason or another (erratic TTRs or bleeding) and patients who do not want to take coumadin or are not deemed suitable candidates • Pushing the envelope on ACS prevention with triple therapy and whether non-coumadin systemic anticoagulation might offer the opportunity to more favorably balance the benefit-to-risk ratio, a possibility given the reduced ICH and major bleed rate with low-dose dabigatran

  6. Issues We Will Address • Will "milder, gentler" but non-inferior, and perhaps superior oral, non-monitored anticoagulation offer new opportunities and new challenges for risk stratifying subsets of patients with AF and ACS? • Is warfarin on the path to extinction or will it reinvent itself with the aid of pharmacogenomic guidance, algorithm-directed care, patient self-monitoring, and a host of “let's make coumadin as good as we can” maneuvers?

  7. New Dimensions and Landmark Practice Advances Atrial Fibrillation and ACS: The Changing Antithrombotic Landscape Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Chief of Cardiology,VA Boston Healthcare System Director, Integrated Interventional Cardiovascular Program,   Brigham and Women’s Hospital and the VA Boston Healthcare System Associate Professor of Medicine, Harvard Medical School Senior Investigator, TIMI Group Boston, Massachusetts

  8. Atherothrombosis:Clinical Manifestations Stroke TIA Intracranial stenosis Acute coronary syndromes • STEMI • NSTEMI • Unstable angina • Stable CAD • Atrial Fibrillation • Angioplasty • Bare metal stent • Drug eluting stent • CABG Carotid artery stenosis CEACarotid stenting Renal artery stenosis Renal artery stenting Peripheral arterial disease Acute limb ischemia Claudication Amputation Endovascular stentingPeripheral bypass Abnormal ABI Abdominal aortic aneurysm (AAA) Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

  9. Polyvascular Disease: ~15% of Patients with Stable Atherosclerosis ~25% of Patients with CAD Also Have Disease in Other Arterial Territories CAD = coronary artery disease PAD = peripheral arterial disease CVD = cerebrovascular disease CAD 8.4% CVD 1.6% 4.7% PAD Bhatt DL, Steg PG, Ohman EM, et al, on behalf of the REACH Investigators. JAMA 2006;295:180-189.

  10. One-Year CV Event Rates Increase with Number of Symptomatic Disease Locations Patients (%) CV Death Non-Fatal MI Non-Fatal Stroke CV Death/MI/Stroke CV Death/MI/Stroke/Hosp* MI=myocardial infarction; *Such as transient ischemic attack, unstable angina, worsening of peripheral arterial disease; adjusted for age and gender Steg PG, Bhatt DL, Wilson PF, et al, on behalf of the REACH Investigators. JAMA 2007;297:1197-1206.

  11. ATRIA: Prevalence of AF Increases with Age 12 10 8 Prevalence (%) 6 4 2 0 <55 55-59 60-64 65-69 70-74 75-79 80-84 ≥85 Age (years) Men (n = 10,173) Women (n = 7801) AF = atrial fibrillation Go AS et al. JAMA. 2001;285:2370-5.

  12. Atrial Fibrillation and Atherothrombosis: Risks and Management Goto S, Bhatt DL, Röther J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D’Agostino R, Ohman EM, Liau C-S, Hirsch AT, Mas J-L, Wilson PWF, Corbalán R, Aichner F, Steg Ph G, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  13. Atrial Fibrillation in CAD: Prevalencein the REACH Registry 37,724 stable outpatients with CAD AF, atrial fibrillation.Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  14. Atrial Fibrillation Rates by Patient Group Greater incidence of AF in patients with vascular disease compared with patients with risk factors only Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  15. CV Event Frequency in AF and non-AF Patients Combined event of CV death and/or nonfatal MI and/or nonfatal stroke in patients with vs without history of AF are shown after adjustment of age, gender, and classical risk factors Patients with a history of AF 10 Event rate of CV death/MI/Stroke (%) AF Non-AF 5 0 0 2 4 6 8 10 12 Time (months) Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  16. Atrial Fibrillation in CAD 37,724 patients with CAD: 12.5% prevalence of atrial fibrillation P < 0.0001 P < 0.0001 Patients (%) P < 0.0001 Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  17. Annual Rate of CV Death inAF and Non-AF Patients ** ** ** ** * *p<0.05 **p<0.01 Multivariate analysis

  18. CHADS2 Score Defined and Validated to Predict Stroke in Atrial Fibrillation Patients Sum Gage BF, JAMA 2001;285(22):2864-2870 Gage BF, Circulation2004;110;2287-2292

  19. Annual CV Event Risk in AF Patients by CHADS2 Score CHADS2 score classification was useful in predicting not only stroke but also CV death in stable outpatients with or at high-risk for atherothrombosis, but not as useful in the prediction of nonfatal MI Annual event rate (%) CHADS2 score Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  20. Annual Rate of Serious Bleeding in AF Patients with/without Anticoagulant 4,725 stable CAD outpatients with atrial fibrillation P = 0.0025 Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  21. Medication Use and Risk Factor Control in AF and Non-AF Patients Approximately 50% of patients with AF receive anticoagulation therapy. Oral anticoagulants are underused in patients who have a history of AF Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:855-863.

  22. Summary • High prevalence of AF among patients with or at high-risk of atherothrombosis • Lower use of oral anticoagulants in AF patients even though they have risk factors for ischemic stroke, probably due to the use of antiplatelet agents for the treatment of atherothrombosis • 1-year follow-up data show that the presence of AF was associated with serious and multiple CV events including a higher rate of all-cause and CV mortality, nonfatal stroke and a modest increase in the risk of nonfatal MI and unstable angina • There is a need for the optimal antithrombotic therapy among AF patients to be clarified to balance the increased risk of thrombotic events and the increased risk of bleeding associated with combined anticoagulant and antiplatelet therapy Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J2008;156:855-863.

  23. Design of ACTIVE Program Documented AF + 1 risk factor for stroke Unsuitable for VKA ACTIVE W C and ASA vs VKA ACTIVE A C and ASA vs ASA No exclusion criteria for ACTIVE ACTIVE I irbesartan vs placebo

  24. ACTIVE-W Results Stopped early because OAC was clearly superior ACTIVE Writing Group of the ACTIVE Investigators et al. Lancet. 2006;367:1903.

  25. ACTIVE A: Primary Outcome Stroke, MI, Non-CNS Systemic Embolism, Vascular Death P=0.01 Cumulative incidence Clopidogrel + ASA ASA only 0 1 2 3 4 Years ACTIVE Investigators et al. N Engl J Med. 2009;360:2066.

  26. ACTIVE A: Stroke P<0.001 Cumulative incidence ASA only Clopidogrel + ASA 0 1 2 3 4 Years ACTIVE Investigators et al. N Engl J Med. 2009;360:2066.

  27. ACTIVE A: Bleeding Rates ACTIVE Investigators et al. N Engl J Med. 2009;360:2066.

  28. Therapeutic INRs With Warfarin in Clinical Trials Connolly et al. Circulation. 2007;116:449.

  29. ACTIVE W: Benefit of OAC by Time in Therapeutic Range Stroke, MI, Non-CNS Systemic Embolism, Vascular Death Stroke Stroke TTR <65% TTR ≥65% TTR <65% TTR ≥65% RR = 0.93 (0.70-1.24)P=0.61 RR = 2.14 (1.61-2.85)P<0.0001 RR = 1.22 (0.75-1.97)P=0.42 C + ASA C + ASA RR = 2.25 (1.45-3.49)P=0.0003 C + ASA Event rate (%) Event rate (%) OAC C + ASA OAC OAC OAC Years Years Years Years Connolly et al. Circulation. 2008;118:2029.

  30. RE-LY: A Noninferiority Trial R •Atrial Fibrillation with ≥ 1 Risk Factor for Stroke • Absence of Contraindications • Conducted in 951 centers in 44 countries R Blinded Event Adjudication Open Blinded Open Warfarin Adjusted INR 2.0 – 3.0 N=6000 Dabigatran etexilate 110 mg BID N=6000 Dabigatran etexilate 150 mg BID N=6000 Connolly et al. N Engl J Med. 2009;361:1139.

  31. RE-LY: Primary Outcome Stroke or Systemic Embolism Warfarin Dabigatran 110 mga Cumulative hazard rate Dabigatran 150 mgb Months aP=0.34 vs warfarin. bP<0.001 vs warfarin. Connolly et al. N Engl J Med. 2009;361:1139.

  32. Oral Direct Factor Xa Inhibitors Currently in Development

  33. Novel Oral Direct Factor Xa Inhibitors for Stroke Prevention in AF www.clinicaltrials.gov.

  34. Thrombosis Risk Reduction in AF Need to weigh thrombotic, ischemic, and bleeding risks in atrial fibrillation patients Anticoagulation preferred if it can be done well Antiplatelet therapy has a role in some patients Novel agents likely to provide more options, perhaps even better efficacy and safety; including in patients who are not suitable candidates for VKA

  35. New Dimensions and Landmark Practice Advances Challenges and Emerging Dimensions of Stroke Prevention in the Setting ofAtrial Fibrillation (AF)Achieving Balance Between Thromboprophylaxis and Bleeding Reduction Gregory Y.H. Lip, MD FRCP FACC FESC Professor of Cardiovascular Medicine, University of Birmingham Visiting Professor of Haemostasis Thrombosis & Vascular Sciences, University of Aston Centre for Cardiovascular SciencesCity HospitalBirmingham, England UK

  36. Independent Predictors of Stroke in AF: A Systematic Review *Significant in a subgroup of AFI pooled analysis participants who underwent echocardiography The Stroke Risk in AF Working Group. Neurology 2007;69:546–554

  37. Stroke Risk Stratification in AF Past and Present Lip and Tse. Lancet 2007 August 18;370(9587):604-18

  38. EHS: Antithrombotic Drug Prescription per Risk Category ACC/AHA/ESC guidelines (A), ACCP (B), CHADS2 score (C), and Framingham score (D). Eur Heart J 2006 27, 3018–3026

  39. Potentially Preventable Strokes High-Risk Patients with AF Who Are Not Adequately Anticoagulated Preadmission medications in patients with known atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597) ‘In high-risk patients with AF admitted with a stroke …. most were either not taking warfarin or were subtherapeutic at the time of ischemic stroke. …..’ Preadmission medications in patients with known atrial fibrillation and a previous ischemic stroke/TIA who were admitted with acute ischemic stroke (very high-risk cohort, n=323) Gladstone et al Stroke 2008

  40. Published Bleeding Risk Scores Tay, Lane & Lip ThrombHaemost 2008; 100: 955–957

  41. Major Hemorrhage and Tolerability of Warfarin First Year of Therapy Among Elderly Patients With AF Distribution of Major Hemorrhagic Events and Warfarin Terminations Due to Perceived Safety Concerns by CHADS2 Score Hylek et al Circulation. 2007;115:2689-2696

  42. Risk Factors for Anticoagulation-Related Bleeding Complications in Patients with Atrial Fibrillation A Systematic Review • Systematic review for NICE guideline [www.nice.org.uk] 9 studies identified • The following patient characteristics were identified as having supporting evidence for being risk factors for anticoagulation-related bleeding complications: • Advanced age • Uncontrolled hypertension • History of myocardial infarction or ischaemic heart disease • Cerebrovascular disease • Anaemia or a history of bleeding, and • The concomitant use of other drugs such as antiplatelet agents The presence of diabetes mellitus, controlled hypertension and gender were not identified as significant risk factors. • Some of the risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patients Hughes and Lip QJM. 2007;100(10):599-607.

  43. Combining the CHADS2 and HEMORR2HAGES Scores for Guiding Antithrombotic Prophylaxis in AF Clinical Usefulness in Geriatrics Patients ‘The clinical usefulness of using the two scores seems poor since they indicated that two-thirds of the patients had a similar risk of hemorrhagic and ischemic events.’ 25 20 15 10 5 0 N=83 Mean age 89.2+/-4.9 years Events/year (%) 0 1 2 3 4 5 Score One year stroke risk for 100 patients without anticoagulation according to CHADS2 Major hemorrhage risk for 100 patients with anticoagulation according to HEMORRH2AGES Somme et al Aging Clin Exp Res. 2009 as DOI: 10.3275/6709

  44. Choosing Antithrombotic Therapy for Elderly Patients with AF Who are at Risk for Falls • A Markov decision analytic model For patients with average risks of stroke and falling … • Warfarin therapy associated with 12.90 quality-adjusted life-years per patient; • Aspirin therapy, 11.17 quality-adjusted life-years; and • No antithrombotic therapy, 10.15 quality-adjusted life-years. ‘Elderly persons who fall have a mean of 1.81 falls per year. … Given that the risk of SDH must be 535-fold or greater for the risks of warfarin therapy to outweigh the benefits, persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin to not be the optimal therapy.’ Man-Son-Hing et al Arch Intern Med. 1999;159(7):677-85

  45. Anticoagulation Control and Prediction of Adverse Events in Patients With AF A Systematic Review TTR versus adverse events (weighted by sample size) for retrospective studies. TTR versus major hemorrhage rate (n=9), correlation: r= -0.78; P=0.006; TTR versus thromboembolic rate (n=5), correlation: r= -0.88; P=0.026 8 7 6 5 4 3 2 1 0 Linear (major haemorrhage Linear (Thromboembolic) Outcome events rate (per 100 patient/years, %) 0 40 50 60 70 80 90 TTR (%) For retrospective studies, a 6.9% improvement in the TTR significantly reduced major hemorrhage by 1 event per 100 patient-years of treatment (95% CI, 0.29 to 1.71 events) Wan et al Circ Cardiovasc Qual Outcomes. 2008;1:84-91

  46. Annual Net Clinical Benefit of Warfarin Therapy Overall and by CHADS2 Score Using Different Weights for ICH The net clinical benefit of warfarin increased from essentially zero in CHADS2 stroke risk categories 0 and 1 to 2.22% per year (CI,0.58% to 3.75%) in CHADS2 categories 4 to 6. The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used. Singer et al Ann Intern Med. 2009;151:297-305.

  47. Warfarin vs Aspirin for Stroke Prevention in an Elderly Community Population with AF Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA 100 75 50 25 0 Aspirin Warfarin Participants without primary event (%) Yearly risk 1.8% vs3.8%, RR 0·48, 95% CI 0·28–0·80, p=0·003; Absolute yearly risk reduction 2%, 95% CI 0·7–3·2 0 1 2 3 4 5 6 Number at risk Warfarin 488 450 383 169 77 19 Aspirin 485 447 378 146 72 14 Years since randomization Mant et al Lancet 2007; 370: 493–503

  48. RE-LY: Time to First Stroke / SSE RR 0.91 (95% CI: 0.74–1.11) P<0.001 (NI) P=0.34 (Sup) 0.05 Warfarin Dabigatran 110 mg BID Dabigatran 150 mg BID 0.04 RRR 34% 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 0.00 0.0 0.5 1.0 1.5 2.0 2.5 Years BID = twice daily; CI = confidence interval; NI = non-inferior; RR = relative risk; RRR = relative risk reduction; Sup = superior Connolly SJ et al. N Engl J Med 2009;361:1139–51

  49. Antithrombotic Treatment and Risk of Stroke and Death in Patients with AF and CHADS2 Score=1 Combined endpoint (death or stroke) in patients with a CHADS2 score of 1 according to their antithrombotic treatment. A total of 1,012 patients, 949 ± 777 days FU, 124 events. Gorin et al ThrombHaemostat 2010 March

  50. Issues with Current AF Stroke Risk Assessment Schema Implications for the Future • All have modest predictive value for predicting high risk for thromboembolism • Low risk category needs to be truly low risk • Needs to categorise low proportion in so-called ‘moderate/ intermediate risk’ category • Recognise that risk factors are cumulative • Simple and easy to remember, yet comprehensive • Scoring system most popular • Acronym • Validated in multiple populations, ideally ‘real world’ cohorts rather than non-VKA arms of trial cohorts Risk schema need to evolve with new therapeutic information on thromboprophylaxis in AF Lip and Halperin Am J Med 2009; 10.1016/j.amjmed.2009.12.013

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