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New Frontiers in Stroke Prevention for Atrial Fibrillation

New Paradigms in the Science and Medicine of Heart Disease. New Frontiers in Stroke Prevention for Atrial Fibrillation Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic Interventions for Stroke Prevention in Atrial Fibrillation (SPAF).

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New Frontiers in Stroke Prevention for Atrial Fibrillation

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  1. New Paradigms in the Science and Medicine of Heart Disease New Frontiers in Stroke Prevention for Atrial Fibrillation Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic Interventions for Stroke Prevention in Atrial Fibrillation (SPAF) Program Chairman Allan V. Abbott, MD Program Chair and Moderator Professor of Clinical Family Medicine Associate Dean of Continuing Medical Education Keck School of Medicine University of Southern California

  2. Program Faculty Scott Kaatz, DO, MSc, FACP Clinical Associate Professor of Medicine Associate Residency Program Director Department of Medicine Director, Anticoagulation Clinics Henry Ford Hospital Detroit, Michigan Annabelle S. Volgman, MD, FACC Associate Professor of Medicine Medical Director Heart Center for Women Rush University Medical College Chicago, Illinois Allan V. Abbott, MD Program Chair and Moderator Professor of Clinical Family Medicine Associate Dean of Continuing Medical Education Keck School of Medicine University of Southern California Los Angeles, California Alan K. Jacobson, MD, FACC Assistant Professor Loma Linda University School of Medicine Director, Anticoagulation Services Associate Chief of Staff for Research Loma Linda Veterans Affairs Medical Center Loma Linda, California

  3. New Paradigms in the Science and Medicine of Heart Disease New Frontiers in Stroke Prevention for Atrial Fibrillation Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic Interventions for Stroke Prevention in Atrial Fibrillation (SPAF) Program Chairman Allan V. Abbott, MD Program Chair and Moderator Professor of Clinical Family Medicine Associate Dean of Continuing Medical Education Keck School of Medicine University of Southern California

  4. A Brief History • 1628, William Harvey was probably the first to describe "fibrillation of the auricles" in animals. • 1785 William Withering recorded digitalis leaf brought some relief to patients with severe heart failure. • 1900, Sir Thomas Lewis in London was the first to record an electrocardiogram in a patient with atrial fibrillation. • However the exact mechanisms and importance remained controversial until the 1970s.

  5. Epidemiology of Atrial Fibrillation • Atrial fibrillation is fairly uncommon in people under 50 years but is found in 0.5% of people aged 50-59, increasing to 8-8% at age 80-89. • Atrial fibrillation may be either chronic or paroxysmal. • In the Framingham study, hypertension, cardiac failure, and rheumatic heart disease were the commonest precursors of atrial fibrillation. • About a third of patients have idiopathic or "lone" atrial fibrillation- no precipitating cause can be identified and no evidence of structural heart disease exists.

  6. Treatment, A Brief History • 1982, The epidemiological importance of atrial fibrillation as an important precursor of cardiac and cerebrovascular death was investigated by William Kannell and colleagues. • 1980s-1990s, awareness increased of the hazards of sustained atrial fibrillation and the benefits of prophylaxis against thrombosis in preventing stroke. • Early treatment was electrical or chemical cardioversion, digitalis for rate control, and warfarin or aspirin for prevention of thromboemboli.

  7. Treatment, Last Decade • Rate control with beta-blockers and/or calcium channel blockers (digoxin or amiodarone if CHF) • Cardioversion, heparin and electrical or chemical cardioversion then warfarin • Warfarin with its associated risk of bleeding and requirement for frequent monitoring remains standard today

  8. Treatment, Evolving Paradigms New treatments • End the atrial fibrillation with catheter ablation or surgical approaches • Replace warfarin with novel oral anticoagulants ablate

  9. Treatment, Evolving Paradigms Ablation Procedures

  10. Treatment, Evolving Paradigms Novel oral anticoagulants

  11. New Paradigms in the Science and Medicine of Heart Disease Epidemiology, Risk Stratification, and Individualized Therapy in Atrial FibrillationAligning Stroke-Preventing Strategies with Appropriate Patient Subgroups Annabelle S. Volgman, MD FACC Associate Professor of Medicine Medical Director, Heart Center for Women Rush University Medical Center Chicago, IL

  12. Outline • Epidemiology, risk stratification, andindividualized therapy in atrial fibrillation • Aligning stroke-preventing strategies withappropriate patient subgroup • The Role of Risk Stratification for IdentifyingAntithrombotic Strategies for Stroke Prevention: • Evidence-based options for the family medicinespecialist at the front lines of care

  13. Prevalence of AF in Adults Aged 65-84 Years (% of Total Population), 1968-1989 Pilote, L. et al. CMAJ 2007;176:S1-S44

  14. Atrial Fibrillation: Framingham Study Wolf PA et al. Stroke. 1991;22-983-8.

  15. 40 years old Men Women 80 years old Men Women 26% 23% 23% 22% Lifetime Risk of Developing AF The lifetime risk for AF was approximately 16% in the absence of a history of congestive heart failure or myocardial infarction. Lloyd-Jones DM et al. Circulation 2004.

  16. Factors that Affect Developing Primary Atrial Fibrillation 1 Aksnes TA et al. Am J Cardiol. 2008 Mar 1;101(5):634-8 2 Conen, D et al. JAMA Dec 2008, 300 (21):2489-96. 3 Faucier L et al. J Am CollCardiol, 2008; 51:828-835, 4 Healey et al. J Am Coll Card, 2005: 45:1832-1839, 5 Cheng W et al. J Altern Complement Med. 2008 Oct;14(8):965-74. 6 Ganz LI et al. Heart Rhythm 2008.

  17. Stroke Risk Increases with Age

  18. Gender Differences in the Risk of Ischemic Stroke and Peripheral Embolism in AFib The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) Study Fang,MC et al. Circulation. 2005;112:1687-1691

  19. Copenhagen City Heart Study • The independent effect of AF on stroke rate was 4.6-fold greater in women than in men: • Hazard ratio in women 7.8 (95% CI, 5.8 to 14.3) • Hazard ratio in men 1.7 (95% CI, 1.0 to 3.0) • The independent effect of AF on the cardiovascular mortality rate was 2.5-fold greater in women than in men: • Hazard ratio in women 4.4 (95% CI, 2.9 to 6.5) • Hazard ratio in men 2.2 (95% CI, 1.6 to 3.1) Friberg J et al. American Journal of Cardiology 2004; 94: 889-894

  20. Patients Older than 75 Years Less likely to Receive Therapy for CV Events • Patients older than 75 years of age • <50% chance of receiving clinically proven treatments for cardiovascular events such as MI and atrial fibrillation as compared to younger patients. • Conclusion: The study results suggest that physicians need to be more aware of and willing to use indicated treatments in the elderly.  Ganz DA et al.Journal of the American Geriatric Society 1999; 47: 145-150

  21. Risk Factors of Ischemic Stroke & Systemic Embolism in Patients with Nolvalvular Atrial Fibrillation AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

  22. Stroke Risk with Nolvalvular AF Not Treated with Anticoagulation According to the CHADS2 Index AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

  23. Risk Stratification Schemes Use to Predict Thromboembolism with Nonvalvular AF Fang MC et al. JACC 2008, 51(6):810-15.

  24. Annual TE Rates Across Risk Groups Using 5 Risk Stratification Schemes Used to Predict AF-Related TE Fang MC et al. JACC 2008, 51(6):810-15.

  25. Meta-analysis of Stroke Prevention for High Risk Atrial Fibrillation Trials • Adjusted dose warfarin • Stroke Risk Reduction – 60% • Death Risk Reduction – 25% • Antiplatelet therapy • Stroke Risk Reduction – 20% • Advantage of warfarin over antiplatelet therapy • Stroke Risk Reduction– 40% Hart R, Pearce L, Aguilar M. Annals of Internal Medicine. June 2007,146:857-67.

  26. Analysis of 5 Antithrombotic Trials • Women > 75 years were 54% less likely to receive warfarin and twice as likely to receive aspirin • Warfarin reduced stroke risk by 84% in women and 60% in men • ASA resulted in significantly decreased stroke risk in men (44%) but not in women (23%) Pilote L, CMAJ. 2007; 176(6):S1-44.

  27. Physician and Patient Reluctance • CARAF* demonstrated that women on warfarin were 3.35 times more likely to experience major bleeding. • Nine of ten women who experienced major bleeds were < 75 years old. • INRs at time of bleeding were elevated, but the levels were similar in men and women. * Canadian Registry of Atrial Fibrillation Humphries KH et al.Circulation. 2001; 103:2365-70

  28. AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

  29. SPORTIF Trial Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study Stroke Prevention in Atrial Fibrillation (SPAF) studies Women > Men (p=0.001- minor; p=NS major/minor) 1.0% for women versus 1.1% for men Annual bleeding rates were 1.5%, 1.7% and 2.1% both genders Bleeding Risks Gomberg-Maitland M, Wenger NK, Feyzi J, Lengyel M, Volgman AS, Petersen P, Frison L, Halperin JL.Eur Heart J. 2006; 27:1947-53. Fang MC, et al. Circulation. 2005; 112:1687-91. Lancet. 1996; 348:633-8.

  30. Summary • Individualize anticoagulation therapy for patients with atrial fibrillation • Low risk patients should be treated with aspirin • Intermediate to high risk patients benefit from anticoagulation but bleeding risks may offset benefit • If bleeding risk is minimized, intermediate risk patients would have improved risk/benefit ratio from anticoagulation

  31. New Paradigms in the Science and Medicine of Heart Disease The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease Mechanisms and Recent Clinical Trials Scott Kaatz, DO, MSc, FACP Clinical Associate Professor of Medicine Associate Residency Program Director Department of Medicine Director, Anticoagulation Clinics Henry Ford Hospital Detroit, Michigan

  32. The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease • Anticoagulant options in atrial fibrillation • Warfarin • Dabigatran • Apixaban • Rivaroxaban Mechanisms and Recent Clinical Trials

  33. Stroke Rate per Year with Different Antithrombotic Options in AF Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005 Connolly S. Lancet. 2006 Jun 10;367(9526):1903-12. PMID: 16765759 Connolly SJ. N Engl J Med. 2009 May 14;360(20):2066-78. PMID: 19336502 Connolly S. Hotline session at ESC 8.31.10 Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

  34. Comparative Pharmacology Courtesy of John Eikelboom

  35. The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease • Anticoagulant options in AF • Warfarin • Dabigatran • Apixaban • Rivaroxaban Mechanisms and Recent Clinical Trials

  36. Warfarin http://www.anaesthesiauk.com/images/clotting_cascade.gif

  37. Warfarin • Warfarin was launched as the ideal rat poison in 1948. Although it was thought at first to be too toxic for human use • In 1951 the failed attempted suicide of a navy recruit who had taken a large dose of rat poison led clinicians to discard dicumarol in favor of warfarin. • The first clinical study with warfarin was reported in 1955. In the same year, President Eisenhower was treated with warfarin following a heart attack Scully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdf

  38. Warfarin vs. no Treatment or Placebo Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005

  39. The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease • Anticoagulant options in AF • Warfarin • Dabigatran • Apixaban • Rivaroxaban Mechanisms and Recent Clinical Trials

  40. Direct Thrombin Inhibitors http://www.anaesthesiauk.com/images/clotting_cascade.gif

  41. Medicinal Leech(HirudoMedicinalis) • Scientific interest in leeches date back to ancient India • However, the first Western citation is credited to the Greek, Nicander of Colophon (130 BC) • This therapeutic use of leeches, the medicinal leech in particular, reached a height between 1825 and 1840. • A more contemporary use of leeches was discovered in 1957 by Markwardt • The leech secretion hirudin was isolated and subsequently its anticoagulant properties with respect to the elucidation of blood clotting mechanisms were examined. http://soma.npa.uiuc.edu/courses/physl490b/models/leech_swimming/leech_swim.html

  42. RELY Trial • Question: Is Dabigatranoral unmonitored direct thrombin inhibitor as effective and safe as warfarin for stroke prevention in AF? • Design: Randomized trial, warfarin was un-blinded • Patients: 18,113 AF patients with at least on stroke risk factor • Interventions: • Dabigatran 110 mg bid • Dabigatran 150 mg bid • Comparison: Warfarin, INR 2.0-3.0 • Primary outcome: Stoke and systemic embolism • Timeframe: Mean follow up was 2.0 years Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

  43. RELY Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

  44. RELY Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

  45. RELY Connolly SJ. N Engl J Med. 2009 Sep 17;361(12):1139-51. PMID: 19717844

  46. The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart Disease • Anticoagulant options in AF • Warfarin • Dabigatran • Apixaban • Rivaroxaban Mechanisms and Recent Clinical Trials

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