Atrial Fibrillation New Frontiers in Stroke Prevention for

Atrial Fibrillation New Frontiers in Stroke Prevention for
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

Program Faculty Scott Kaatz, DO, MSc, FACP
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 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

Atrial Fibrillation New Frontiers in Stroke Prevention for
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

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. Atrial fibrillation has been recognized and described for 3 centuries, but not well understood until the last few decades.

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 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. Brief overview of who gets a fib, its varied presentation, and the Framingham findings.

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. Overview of changes that have occurred over the last 3 decades (older physicians in the audience will appreciate this and find the next part of the discussion more relevant)

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 Overview of current standard approaches to managing a fib Fam Physician’s role

Treatment, Evolving Paradigms
New treatments End the atrial fibrillation with catheter ablation or surgical approaches Replace warfarin with novel oral anticoagulants ablate Discussion of newer appoaches to stop the fibrillation And intro to the use of newer anticoagulants Evolving role of the family physician in decision-making

Ablation Procedures Overview of catheter ablation and surgical approaches

Novel oral anticoagulants

New Paradigms in the Science and Medicine of Heart Disease Epidemiology, Risk Stratification, and Individualized Therapy in Atrial Fibrillation Aligning 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

Outline Epidemiology, risk stratification, and individualized therapy in atrial fibrillation Aligning stroke-preventing strategies with appropriate patient subgroup The Role of Risk Stratification for Identifying Antithrombotic Strategies for Stroke Prevention: Evidence-based options for the family medicine specialist at the front lines of care

ATRIA: Prevalence of atrial fibrillation increases with age
The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study was a cross-sectional analysis of 1.89 million adults aged 20 years or older enrolled in a large group-model health maintenance organization. The total prevalence of AF was 0.95%. It is estimated that there are currently 2.3 million US adults with AF.

Prevalence of AF in Adults Aged 65-84 Years (% of Total Population), 1968-1989
Men 3.2 5.3 6.5 7.8 7.5 9.1 Women 2.8 3.3 4.3 3.9 4.7 Pilote, L. et al. CMAJ 2007;176:S1-S44

Atrial Fibrillation: Framingham Study
Age AF Prevalence (%) Strokes Attributable to AF (%) 50-59 0.5 6.5 60-69 1.8 8.5 70-79 4.8 18.8 80-89 8.8 30.7 Atrial fibrillation: Framingham study The impact of AF on stroke was examined in 5070 participants in the Framingham Study. After 34 years of follow-up, there was a near five-fold increase in the incidence of stroke in patients with AF. In patients aged years, there was an excess risk of stroke with the presence of AF and the attributable risk of stroke from AF increased significantly with age. Wolf PA et al. Stroke. 1991;

Lifetime Risk of Developing AF
40 years old Men Women 80 years old 26% 23% 22% 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.

Factors that Affect Developing Primary Atrial Fibrillation
Study Effect Obesity/MS/DM VALUE 1 Increase Alcohol WHS 2 Statins Multiple 3 Decrease ACE-I/ARBs Multiple 4 Fish/Fish oils Multiple 5 Decrease (post-op) Vitamin E WHS 6 No effect 1 Aksnes TA et al. Am J Cardiol Mar 1;101(5): Conen, D et al. JAMA Dec 2008, 300 (21): 3 Faucier L et al. J Am Coll Cardiol, 2008; 51: , 4 Healey et al. J Am Coll Card, 2005: 45: , 5 Cheng W et al. J Altern Complement Med Oct;14(8): Ganz LI et al. Heart Rhythm 2008.

Stroke Risk Increases with Age

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:

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) 1976 and 1994 from 29,310 subjects. The average follow-up was 5 years. Friberg J et al. American Journal of Cardiology 2004; 94:

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. A study by the Pacemaker Selection in the Elderly Investigators Ganz DA et al.Journal of the American Geriatric Society 1999; 47:

Risk Factors Relative Risk
Risk Factors of Ischemic Stroke & Systemic Embolism in Patients with Nolvalvular Atrial Fibrillation Risk Factors Relative Risk Previous stroke or TIA 2.5 Diabetes mellitus 1.7 History of hypertension 1.6 Heart failure 1.4 Advanced age (continuous, per decade) AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

Adjusted Stroke Rate (%/y) (95% CI)
Stroke Risk with Nolvalvular AF Not Treated with Anticoagulation According to the CHADS2 Index CHADS2 Risk Criteria Score Previous stroke or TIA 2 Age > 75 years 1 Hypertension Diabetes mellitus Heart failure Patients (N = 1733) Adjusted Stroke Rate (%/y) (95% CI) CHADS2 Score 120 1.9 (1.2 to 3.0) 463 2.8 (2.0 to 3.8) 1 523 4.0 (3.1 to 5.1) 2 337 5.9 (4.6 to 7.3) 3 220 8.5 (6.3 to 11.1) 4 65 12.5 (8.2 to 17.5) 5 18.2 (10.5 to 27.4) 6 AHA/ACC/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation. Circulation, JACC and Europace, 2006.

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

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):

Adjusted dose warfarin
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:

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.

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:

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

Bleeding Risks SPORTIF Trial
Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study Stroke Prevention in Atrial Fibrillation (SPAF) studies Women > Men (p= 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 Gomberg-Maitland M, Wenger NK, Feyzi J, Lengyel M, Volgman AS, Petersen P, Frison L, Halperin JL. Eur Heart J. 2006; 27: Fang MC, et al. Circulation. 2005; 112: Lancet. 1996; 348:633-8.

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

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

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

Stroke Rate per Year with Different Antithrombotic Options in AF
Approximate Rate/Year Hart ACTIVE W ACTIVE A AVERROES RELY No treatment 4.5% Thrombin ASA 3.5% 3.2% Yes 3.3% ASA + Clopidogrel 2.5% 2.4% Warfarin 1.5% 1.8% 1.4% 1.6% Apixaban Dabigatran 110 Dabigatran 150 1.0% Hart RG. Ann Intern Med Jun 19;146(12): PMID: Connolly S. Lancet Jun 10;367(9526): PMID: Connolly SJ. N Engl J Med May 14;360(20): PMID: Connolly S. Hotline session at ESC Connolly SJ. N Engl J Med Sep 17;361(12): PMID:

Comparative Pharmacology
Characteristic Apixaban Rivaroxaban Dabigatran Target Factor Xa Thrombin Prodrug No Yes Bioavailability 60% 80% 6% Dosing Fixed, b.i.d. Fixed, o.d. Fixed, o.d./bid Half life 12 hours 7 to 11 hours 12-17 hours Renal clearance 25% 35% Routine coag. monitoring Drug interactions Potent CYP3A4 & P-gp inhibitors Potent P-gp inhibitors Courtesy of John Eikelboom 38

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

Warfarin

Warfarin Warfarin was launched as the ideal rat poison in 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 In the same year, President Eisenhower was treated with warfarin following a heart attack Scully. The Biochemist, Feb

Warfarin vs. no Treatment or Placebo
Hart RG. Ann Intern Med Jun 19;146(12): PMID:

Direct Thrombin Inhibitors

Medicinal Leech (Hirudo Medicinalis)
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.

RELY Trial Question: Is Dabigatran oral 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 Primary outcome: Stoke and systemic embolism Timeframe: Mean follow up was 2.0 years Connolly SJ. N Engl J Med Sep 17;361(12): PMID:

RELY Connolly SJ. N Engl J Med Sep 17;361(12): PMID:

AVERROES Question: Is apixaban superior to ASA in patients with AF who are not candidates for warfarin? Design: RCT, double blinded Patients: AF patients not candidates for warfarin Intervention: apixaban 5 mg (2.5 mg) bid Comparison: ASA mg qd Outcome: stroke or systemic embolism Connolly S. Hotline, ESC,

Connolly S. Hotline, ESC,

ROCKET Question: is rivaroxaban non-inferior to warfarin for stroke prevention in AF Design: RCT, double blinded Patients: AF and CHADS2 > 2 Intervention: rivaroxaban 20 mg qd Comparison: warfarin Outcome: Stroke and systemic embolism Major and non-major clinically relevant bleeding Result expected to be presented at AHA, November 2010 NCT

New Paradigms in the Science and Medicine of Heart Disease Optimizing Stroke Prevention in AF with Established and Currently Available Therapies The Role of Vitamin K Antagonists – What Works? What Doesn’t? Alan K. Jacobson, MD Director, Anticoagulation Services Loma Linda VA Medical Center Loma Linda, California

Why do we need another warfarin management lecture?
Warfarin therapy is: Highly effective Complex to manage Underutilized When utilized, managed poorly … but effective solutions have evolved.

Blood Flow in Atrial Fibrillation
Disturbed Flow (left atrium) Stroke Risk Because of the irregular, rapid rhythm in atrial fibrillation the blood does not circulate properly in the atria. Because of this disturbed flow, blood clots will form in the atria. These blood clots can be pumped out of the atria into the ventricle and then on to the brain where they can cause a stroke. These clots can also flow to other parts of the body such as the kidneys, intestines, etc. where they can also cause problems. The brain is very important in the total functioning of the body, therefore, a large percentage of the blood flow from the heart goes to the brain first and then to other parts of the body. For this reason, the clots have a greater chance of going to the brain and causing a stroke.

Warfarin in Prospective AF Trials Intention-to-treat analysis
8 6 4 2 Control Warfarin 7.0 Stroke Rate (%/year) 4.6 4.3 3.6 3.0 2.3 2.1 1.9 0.4 0.9 person-years p value AFASAK SPAF BAATAF CAFA SPINAF p= p= p=0.002 p>0.2 p=0.001 Adapted from Atwood, Albers, Herz 1993;18:27-38

Anticoagulant Therapy is Effective
RR 79% 83% 83% 73% 79% 83% Loma Linda VA Medical Center, 2010

Anticoagulation of AF Risk — Benefit
X vs. OR

Oral Anticoagulation - Challenges
Narrow therapeutic dosing range 10-15% dosing window Variable dosage requirement Effect of medications Effect of diet Effect of liver function Serious consequences if dosing wrong

Burdens of Anticoagulation
Restricted diets - NOTHING green, NO Vitamin K Restricted medications - NO aspirin, NO NSAIDS Ongoing need for blood tests to check PT/INR Burdens affect patients and providers Clinical practice has often been driven more by tradition than science

Burdens of Anticoagulation
Solutions: Diet - CONSISTENT Vitamin K intake Drug interactions - CONSISTENT if NECESSARY Minimal need for restrictions, in fact, some may benefit from supplementation Prothrombin time testing and management…. ??

Systematic Anticoagulation Management
Ongoing Patient Education Ongoing QI Direct Active Management by Qualified Health Care Provider Patient Scheduling and Tracking Accessible, Accurate, and Frequent PT/INR Testing Patient-specific Decision Support and Interaction Enabling Technologies: POC testing, computerization

Quality Question Are you able to identify, on an ongoing basis, which patients are overdue for testing?

Active vs. Passive Management

Patients Assigned to Warfarin in AF Trials Intensity of Anticoagulation When Stroke Occurred
1.8 4.0 1.7 1.6 3.0 PT INR 1.5 Ratio Ratio 1.4 (ISI 2.4) 2.0 1.3 1.2 1.1 1.0 1.0 Slide 25 The intensity of anticoagulation at the time of stroke in AF patients assigned to warfarin is illustrated. The majority of strokes that were documented in the “warfarin groups” of the original five trials occurred in patients who were not taking anticoagulant therapy at the time of the event The shaded area illustrates the ACCP recommended range of INR 2.0–3.019. AFASAK CAFA SPAF I BAATAF SPINAF ACCP recommendations: INR 2.0–3.0 Target range for individual study Petersen et al. Lancet 1989:171–75 SPAF. Circ 1991;84:527–39 BAATAF. N Engl J Med 1990; 323:1505–11 Connolly et al. J Am Coll Cardiol 1991;18:349–55 Ezekowitz et al. N Engl J Med 1992;327:1406–12 Hirsh, Dalen, Deykin, Poller. CHEST 1992;312S–326S

PERCEIVED INR Therapeutic Range
Bleed Risk Clot Risk INR Intensity

ACTUAL INR therapeutic range
20 40 60 80 100 ³6.5 INR Incidence per 100 Patient-Years INR-Specific Incidence of All Adverse Events (All Episodes of Thromboembolism, All Major Bleeding Episodes, and Unclassified Stroke). The dotted lines indicate the 95 percent confidence interval. Cannegeiter et al

Incidence Rates of Ischemic Stroke and Intracranial Hemorrhage
(Review graph) Adapted from Hylek EM, et al. N Engl J Med. 2003;349:

Target: INR 2.5 Range: INR 2.0–3.0
Recommended Range for Warfarin Therapy For Patients in Atrial Fibrillation Target: INR 2.5 Range: INR 2.0–3.0 Change from just a range, to including a target value in a subtle attempt to get physicians to move away from an effective target of 2.0 which was resulting in many patients spending much of their time below 2.0 The Fifth American College of Chest Physicians (ACCP) Consensus Conference on Antithrombotic Therapy recommended that an INR of 2.0 to 3.0 be used in patients with atrial fibrillation for stroke prevention.12 The Consensus Panel also recommended a target INR of 2.5. This is largely due to the data from numerous clinical trials, and recent case-control studies showing the adverse consequences of exceeding or failing to achieve a therapeutic intensity of anticoagulation. CHEST 1998;114:579s-589s

Methods of Monitoring - Options
Central Laboratory Testing with Professional Management of Results Point-of-Care Testing (Professional) with Professional Management of Results Point-of-Care Testing (Patient) with Patient or Professional Management Which is best??? Different solutions for different patients in different settings

Why do we need another warfarin management lecture?
Warfarin therapy is: Highly effective Complex to manage Underutilized When utilized, managed poorly … but effective solutions have evolved.

Progress of Medicine Out of the enormous number of medicinal agents brought under our notice by puffing advertisements in the press, medical as well as lay, by pamphlets or even large books delivered by post, or by actual 'specimens for trial' which are nowadays so liberally delivered at our residences, comparatively few hold their ground, or stand a fair and candid criticism and investigation of their vaunted merits. Still a certain proportion do and I see every reason to anticipate that, as the result of the systematic researches, scientific and practical, now carried on in so many laboratories, valuable additions will be made from time to time to the medicinal agents at our disposal for the help and comfort of our patients. I only hope that in our love for the new we will not entirely throw out old friends which have done real and effective service in the past and are today as deserving of our regard as ever (Lancet 1899, Dr. F. Roberts).

The Future Refined management of the old drug – warfarin
Variety of new agents with predictable therapeutic ranges and improved risk benefit but with continued need for education, hemorrhagic risk assessment, and monitoring Improved range of options to facilitate stroke prevention in patients with atrial fibrillation

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