New Frontiers in Stroke Prevention for Atrial Fibrillation Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic

New Frontiers New Frontiers inin Stroke Prevention Stroke Prevention forfor

Atrial FibrillationAtrial Fibrillation

Focus on Evolving Strategies for Initial Assessment, Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic Risk Stratification, Monitoring, and Pharmacologic

Interventions for Stroke Prevention in Atrial Interventions for Stroke Prevention in Atrial Fibrillation (SPAF)Fibrillation (SPAF)

New Paradigms in the New Paradigms in the Science and Medicine of Heart DiseaseScience and Medicine of Heart Disease

Program ChairmanProgram ChairmanAllan V. Abbott, MDAllan V. Abbott, MD

Program Chair and ModeratorProgram Chair and ModeratorProfessor of Clinical Family MedicineProfessor of Clinical Family Medicine

Associate Dean of Continuing Medical EducationAssociate Dean of Continuing Medical EducationKeck School of MedicineKeck School of Medicine

University of Southern CaliforniaUniversity of Southern California

Program FacultyProgram Faculty

Allan V. Abbott, MDAllan V. Abbott, MDProgram Chair and ModeratorProgram Chair and ModeratorProfessor of Clinical Family MedicineProfessor of Clinical Family MedicineAssociate Dean of Continuing Medical Associate Dean of Continuing Medical EducationEducationKeck School of MedicineKeck School of MedicineUniversity of Southern CaliforniaUniversity of Southern CaliforniaLos Angeles, CaliforniaLos Angeles, California Alan K. Jacobson, MD, FACCAlan K. Jacobson, MD, FACCAssistant ProfessorAssistant ProfessorLoma Linda University School of Loma Linda University School of MedicineMedicineDirector, Anticoagulation ServicesDirector, Anticoagulation ServicesAssociate Chief of Staff for ResearchAssociate Chief of Staff for ResearchLoma Linda Veterans Affairs MedicalLoma Linda Veterans Affairs Medical CenterCenterLoma Linda, CaliforniaLoma Linda, California

Scott Kaatz, DO, MSc, FACPScott Kaatz, DO, MSc, FACPClinical Associate Professor of MedicineClinical Associate Professor of MedicineAssociate Residency Program DirectorAssociate Residency Program DirectorDepartment of MedicineDepartment of MedicineDirector, Anticoagulation ClinicsDirector, Anticoagulation ClinicsHenry Ford Hospital Henry Ford Hospital Detroit, Michigan Detroit, Michigan

Annabelle S. Volgman, MD, Annabelle S. Volgman, MD, FACCFACCAssociate Professor of MedicineAssociate Professor of MedicineMedical DirectorMedical DirectorHeart Center for WomenHeart Center for WomenRush University Medical CollegeRush University Medical CollegeChicago, IllinoisChicago, Illinois

New Frontiers New Frontiers inin Stroke Prevention Stroke Prevention forfor


Focus on Evolving Strategies for Initial Assessment, Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic Risk Stratification, Monitoring, and Pharmacologic

Interventions for Stroke Prevention in Atrial Interventions for Stroke Prevention in Atrial Fibrillation (SPAF)Fibrillation (SPAF)


Program ChairmanProgram ChairmanAllan V. Abbott, MDAllan V. Abbott, MD

Program Chair and ModeratorProgram Chair and ModeratorProfessor of Clinical Family MedicineProfessor of Clinical Family Medicine

Associate Dean of Continuing Medical EducationAssociate Dean of Continuing Medical EducationKeck School of MedicineKeck School of Medicine

University of Southern CaliforniaUniversity of Southern California

A Brief HistoryA Brief History

► 1628, William Harvey was probably the 1628, William Harvey was probably the first to describe "fibrillation of the first to describe "fibrillation of the auricles" in animals.auricles" in animals.

► 1785 William Withering recorded digitalis 1785 William Withering recorded digitalis leaf brought some relief to patients with leaf brought some relief to patients with severe heart failure.severe heart failure.

► 1900, Sir Thomas Lewis in London was the 1900, Sir Thomas Lewis in London was the first to record an electrocardiogram in a first to record an electrocardiogram in a patient with atrial fibrillation.patient with atrial fibrillation.

► However the exact mechanisms and However the exact mechanisms and importance remained controversial until importance remained controversial until the 1970s.the 1970s.

Epidemiology of Atrial FibrillationEpidemiology of Atrial Fibrillation

► Atrial fibrillation is fairly uncommon in Atrial fibrillation is fairly uncommon in people under 50 years but is found in people under 50 years but is found in 0.5% of people aged 50-59, increasing to 0.5% of people aged 50-59, increasing to 8-8% at age 80-89.8-8% at age 80-89.

► Atrial fibrillation may be either chronic or Atrial fibrillation may be either chronic or paroxysmal. paroxysmal.

► In the Framingham study, hypertension, In the Framingham study, hypertension, cardiac failure, and rheumatic heart cardiac failure, and rheumatic heart disease were the commonest precursors disease were the commonest precursors of atrial fibrillation.of atrial fibrillation.

► About a third of patients have idiopathic About a third of patients have idiopathic or "lone" atrial fibrillation - no or "lone" atrial fibrillation - no precipitating cause can be identified and precipitating cause can be identified and no evidence of structural heart disease no evidence of structural heart disease exists.exists.

Treatment, A Brief HistoryTreatment, A Brief History

► 1982, The epidemiological importance of 1982, The epidemiological importance of atrial fibrillation as an important precursor atrial fibrillation as an important precursor of cardiac and cerebrovascular death was of cardiac and cerebrovascular death was investigated by William Kannell and investigated by William Kannell and colleagues.colleagues.

► 1980s-1990s, awareness increased of the 1980s-1990s, awareness increased of the hazards of sustained atrial fibrillation and hazards of sustained atrial fibrillation and the benefits of prophylaxis against the benefits of prophylaxis against thrombosis in preventing stroke.thrombosis in preventing stroke.

► Early treatment was electrical or chemical Early treatment was electrical or chemical cardioversion, digitalis for rate control, and cardioversion, digitalis for rate control, and warfarin or aspirin for prevention of warfarin or aspirin for prevention of thromboemboli.thromboemboli.

Treatment, Last DecadeTreatment, Last Decade

► Rate control with beta-blockers and/or Rate control with beta-blockers and/or calcium channel blockers (digoxin or calcium channel blockers (digoxin or amiodarone if CHF)amiodarone if CHF)

► Cardioversion, heparin and electrical or Cardioversion, heparin and electrical or chemical cardioversion then warfarinchemical cardioversion then warfarin

► Warfarin with its associated risk of Warfarin with its associated risk of bleeding and requirement for frequent bleeding and requirement for frequent monitoring remains standard today monitoring remains standard today

Treatment, Evolving ParadigmsTreatment, Evolving Paradigms

New treatmentsNew treatments

►End the atrial fibrillation with catheter End the atrial fibrillation with catheter ablation or surgical approachesablation or surgical approaches

►Replace warfarin with novel oral Replace warfarin with novel oral anticoagulants ablateanticoagulants ablate


Ablation Ablation ProceduresProcedures


Novel oral anticoagulantsNovel oral anticoagulants

Epidemiology, Risk Stratification, Epidemiology, Risk Stratification, and Individualized Therapy in and Individualized Therapy in


Aligning Stroke-Preventing Strategies with Aligning Stroke-Preventing Strategies with Appropriate Patient Subgroups Appropriate Patient Subgroups

Annabelle S. Volgman, MD FACCAnnabelle S. Volgman, MD FACCAssociate Professor of MedicineAssociate Professor of Medicine

Medical Director, Heart Center for WomenMedical Director, Heart Center for WomenRush University Medical CenterRush University Medical Center

Chicago, ILChicago, IL


OutlineOutline

► Epidemiology, risk stratification, andEpidemiology, risk stratification, andindividualized therapy in atrial fibrillationindividualized therapy in atrial fibrillation● Aligning stroke-preventing strategies withAligning stroke-preventing strategies with

appropriate patient subgroupappropriate patient subgroup

► The Role of Risk Stratification for The Role of Risk Stratification for IdentifyingIdentifyingAntithrombotic Strategies for Stroke Antithrombotic Strategies for Stroke Prevention:Prevention:● Evidence-based options for the family Evidence-based options for the family

medicinemedicinespecialist at the front lines of carespecialist at the front lines of care

ATRIA: Prevalence of atrial fibrillation increases with age

<55 55-59 60-64 65-69 70-74 75-79 80-84 ≥85

Prevalence (%)

Age (years)

Go AS et al. JAMA. 2001;285:2370-5.

Men (n = 10,173)Women (n = 7801)

0

2

4

6

8

10

12

Pilote, L. et al. CMAJ 2007;176:S1-S44Pilote, L. et al. CMAJ 2007;176:S1-S44

Prevalence of AF in Adults Aged 65-84 Prevalence of AF in Adults Aged 65-84 Years (% of Total Population), 1968-1989Years (% of Total Population), 1968-1989

AdultsAdults 1968-1968-19701970

1971-1971-19731973

1975-1975-19771977

1979-1979-19811981

1983-1983-19851985

1987-1987-19891989

Men 3.23.2 5.35.3 6.56.5 7.87.8 7.57.5 9.19.1

Women 2.82.8 3.33.3 4.34.3 4.34.3 3.93.9 4.74.7

Atrial Fibrillation: Framingham Atrial Fibrillation: Framingham StudyStudy

Wolf PA et al. Stroke. 1991;22-983-8.Wolf PA et al. Stroke. 1991;22-983-8.

AgeAge AF Prevalence AF Prevalence (%)(%)

Strokes Strokes Attributable to Attributable to

AF (%)AF (%)

50-59 0.50.5 6.56.5

60-69 1.81.8 8.58.5

70-79 4.84.8 18.818.8

80-89 8.88.8 30.730.7

Lifetime Risk of Developing AFLifetime Risk of Developing AF

► 40 years old40 years old● MenMen● WomenWomen

► 80 years old80 years old● Men Men ● WomenWomen

● 26%26%● 23%23%

● 23%23%● 22%22%

The lifetime risk for AF was approximately 16% in the absenceThe lifetime risk for AF was approximately 16% in the absence of a history of congestive heart failure or myocardial infarction. of a history of congestive heart failure or myocardial infarction.

Lloyd-Jones DM et al. Circulation 2004.

Factors that Affect Developing Factors that Affect Developing Primary Atrial FibrillationPrimary Atrial Fibrillation

FactorFactor Study Study EffectEffect

Obesity/MS/DM VALUE VALUE 11 IncreaseIncrease

Alcohol WHS WHS 22 Increase Increase

Statins Multiple Multiple 33 DecreaseDecrease

ACE-I/ARBs Multiple Multiple 44 DecreaseDecrease

Fish/Fish oils Multiple Multiple 55 Decrease (post-Decrease (post-op)op)

Vitamin E WHS WHS 66 No effectNo effect

1 1 Aksnes TA et al. Am J Cardiol. 2008 Mar 1;101(5):634-8 Aksnes TA et al. Am J Cardiol. 2008 Mar 1;101(5):634-8 2 2 Conen, D et al. JAMA Dec 2008, 300 (21):2489-96.Conen, D et al. JAMA Dec 2008, 300 (21):2489-96. 3 3 Faucier L et al. J Am Coll Cardiol, 2008; 51:828-835, Faucier L et al. J Am Coll Cardiol, 2008; 51:828-835, 44 Healey et al. Healey et al. J Am Coll Card, 2005: J Am Coll Card, 2005: 45:1832-1839, 45:1832-1839, 5 5 Cheng W et al. J Altern Complement Med. 2008 Oct;14(8):965-74. Cheng W et al. J Altern Complement Med. 2008 Oct;14(8):965-74. 6 6 Ganz LI et al. Heart Rhythm 2008.Ganz LI et al. Heart Rhythm 2008.

Stroke Risk Increases with AgeStroke Risk Increases with Age

Gender Differences in the Risk of Ischemic Gender Differences in the Risk of Ischemic Stroke and Peripheral Embolism in AFibStroke and Peripheral Embolism in AFib

Fang,MC et al. Fang,MC et al. Circulation.Circulation. 2005;112:1687-1691 2005;112:1687-1691

The AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) StudyThe AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) Study

Copenhagen City Heart Study Copenhagen City Heart Study

Friberg J et al. Friberg J et al. American Journal of Cardiology 2004; 94: 889-894American Journal of Cardiology 2004; 94: 889-894

► The independent effect of AF on stroke The independent effect of AF on stroke rate was 4.6-fold greater in women than in rate was 4.6-fold greater in women than in men: men: ● Hazard ratio in women 7.8 (95% CI, 5.8 to Hazard ratio in women 7.8 (95% CI, 5.8 to

14.3) 14.3) ● Hazard ratio in men 1.7 (95% CI, 1.0 to 3.0) Hazard ratio in men 1.7 (95% CI, 1.0 to 3.0)

► The independent effect of AF on the The independent effect of AF on the cardiovascular mortality rate was 2.5-fold cardiovascular mortality rate was 2.5-fold greater in women than in men: greater in women than in men: ● Hazard ratio in women 4.4 (95% CI, 2.9 to 6.5) 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) Hazard ratio in men 2.2 (95% CI, 1.6 to 3.1)

Patients Older than 75 Years Less Patients Older than 75 Years Less likely to Receive Therapy for CV likely to Receive Therapy for CV

EventsEvents► Patients older than 75 years of age Patients older than 75 years of age

● <50% chance of receiving clinically <50% chance of receiving clinically proven treatments for cardiovascular proven treatments for cardiovascular events such as MI and atrial events such as MI and atrial fibrillation as compared to younger fibrillation as compared to younger patients. patients.

► Conclusion: Conclusion: The study results suggest The study results suggest that physicians need to be more that physicians need to be more aware of and willing to use indicated aware of and willing to use indicated treatments in the elderly. treatments in the elderly.

Ganz DA et al.Journal of the American Geriatric Society 1999; 47: 145-150

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

Risk Factors of Ischemic Stroke & Systemic Risk Factors of Ischemic Stroke & Systemic Embolism in Patients with Nolvalvular Atrial Embolism in Patients with Nolvalvular Atrial

FibrillationFibrillation

Risk FactorsRisk Factors Relative RiskRelative Risk

Previous stroke or TIA 2.52.5

Diabetes mellitus 1.71.7

History of hypertension 1.61.6

Heart failure 1.41.4

Advanced age (continuous, per decade)

1.41.4


Stroke Risk with Nolvalvular AF Not Treated Stroke Risk with Nolvalvular AF Not Treated with Anticoagulation According to the CHADS2 with Anticoagulation According to the CHADS2

IndexIndex

CHADSCHADS22 Risk Criteria Risk Criteria ScoreScorePrevious stroke or TIA 22

Age > 75 years 11

Hypertension 11

Diabetes mellitus 11

Heart failure 11

Patients Patients (N = (N = 1733)1733)

Adjusted Stroke Rate (%/y) Adjusted Stroke Rate (%/y) (95% (95% CI)CI)

CHADSCHADS22 Score Score

120 1.9 (1.2 to 3.0)1.9 (1.2 to 3.0) 00

463 2.8 (2.0 to 3.8)2.8 (2.0 to 3.8) 11

523 4.0 (3.1 to 5.1)4.0 (3.1 to 5.1) 22

337 5.9 (4.6 to 7.3)5.9 (4.6 to 7.3) 33

220 8.5 (6.3 to 11.1)8.5 (6.3 to 11.1) 44

65 12.5 (8.2 to 17.5)12.5 (8.2 to 17.5) 55

5 18.2 (10.5 to 27.4)18.2 (10.5 to 27.4) 66

Fang MC et al. JACC 2008, 51(6):810-15.

Risk Stratification Schemes Use to Predict Risk Stratification Schemes Use to Predict Thromboembolism with Nonvalvular AFThromboembolism with Nonvalvular AF

Fang MC et al. JACC 2008, 51(6):810-15.

Annual TE Rates Across Risk Groups Using 5 Risk Annual TE Rates Across Risk Groups Using 5 Risk Stratification Schemes Used to Predict AF-Related Stratification Schemes Used to Predict AF-Related

TETE

New Frontiers for S troke Prevention in Atrial Fibrillation

Annabelle S . Volgm an, M D FAC CAssociate P rofessor of M edicine

M edica l D irector, H eart C enter for W om enR ush U niversity M e dica l C enter

C hicago, IL

C H A 2 D S 2C H A 2 D S 2 -- V A S cV A S c

Lip GYH , e t a l, C hest 2010:137(2) :263-272.

•S lig h tly b e tte r p re d ictive va lu e fo r stro ke a n d th ro m b o e m b o lism•C le a rly id e n tifie s lo w risk p a tie n ts a n d fe we r in to in te rm e d ia terisk

Meta-analysis of Stroke Prevention for Meta-analysis of Stroke Prevention for High Risk Atrial Fibrillation TrialsHigh Risk Atrial Fibrillation Trials

► Adjusted dose warfarinAdjusted dose warfarin● Stroke Risk Reduction – 60%Stroke Risk Reduction – 60%● Death Risk Reduction – 25%Death Risk Reduction – 25%

► Antiplatelet therapyAntiplatelet therapy● Stroke Risk Reduction – 20%Stroke Risk Reduction – 20%

► Advantage of warfarin over antiplatelet Advantage of warfarin over antiplatelet therapy therapy ● Stroke Risk Reduction– 40%Stroke Risk Reduction– 40%

Hart R, Pearce L, Aguilar M. Hart R, Pearce L, Aguilar M. Annals of Internal Medicine.Annals of Internal Medicine. June 2007,146:857-67. June 2007,146:857-67.

► Women > 75 years were 54% less likely to Women > 75 years were 54% less likely to receive warfarin and twice as likely to receive warfarin and twice as likely to receive aspirin receive aspirin

► Warfarin reduced stroke risk by 84% in Warfarin reduced stroke risk by 84% in women and 60% in menwomen and 60% in men

► ASA resulted in significantly decreased ASA resulted in significantly decreased stroke risk in men (44%) but not in women stroke risk in men (44%) but not in women (23%)(23%)

Analysis of 5 Antithrombotic TrialsAnalysis of 5 Antithrombotic Trials

Pilote L, CMAJ. 2007; 176(6):S1-44.

Physician and Patient ReluctancePhysician and Patient Reluctance

► CARAF* demonstrated that women CARAF* demonstrated that women on warfarin were 3.35 times more on warfarin were 3.35 times more likely to experience major bleeding. likely to experience major bleeding.

► Nine of ten women who experienced Nine of ten women who experienced major bleeds were < 75 years old. major bleeds were < 75 years old.

► INRs at time of bleeding were INRs at time of bleeding were elevated, but the levels were similar elevated, but the levels were similar in men and women.in men and women.

* * Canadian Registry of Atrial Fibrillation

Humphries KH et al.Humphries KH et al. CirculationCirculation. 2001; 103:2365-70. 2001; 103:2365-70


Bleeding RisksBleeding Risks

► SPORTIF TrialSPORTIF Trial

► Anticoagulation and Anticoagulation and Risk Factors in Atrial Risk Factors in Atrial Fibrillation (ATRIA) Fibrillation (ATRIA) StudyStudy

► Stroke Prevention in Stroke Prevention in Atrial Fibrillation Atrial Fibrillation (SPAF) studies(SPAF) studies

► Women > Men Women > Men (p=0.001- minor; (p=0.001- minor; p=NS major/minor)p=NS major/minor)

► 1.0% for women 1.0% for women versus 1.1% for menversus 1.1% for men

► Annual bleeding rates Annual bleeding rates were 1.5%, 1.7% and were 1.5%, 1.7% and 2.1% both genders2.1% both genders

Gomberg-Maitland M, Wenger NK, Feyzi J, Lengyel M, Volgman AS, Petersen P, Frison L, Halperin JL. Eur Heart J. 2006; 27:1947-53. Fang MC, et al. Circulation. 2005; 112:1687-91. Lancet. 1996; 348:633-8.

SummarySummary

► Individualize anticoagulation therapy for Individualize anticoagulation therapy for patients with atrial fibrillationpatients with atrial fibrillation

► Low risk patients should be treated with Low risk patients should be treated with aspirinaspirin

► Intermediate to high risk patients benefit Intermediate to high risk patients benefit from anticoagulation but bleeding risks from anticoagulation but bleeding risks may offset benefitmay offset benefit

► If bleeding risk is If bleeding risk is minimizedminimized, intermediate , intermediate risk patients would have improved risk patients would have improved risk/benefit ratio from anticoagulationrisk/benefit ratio from anticoagulation

The Emerging Role of Direct The Emerging Role of Direct Thrombin and Factor Xa Inhibition Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart for Thrombosis Reduction in Heart

Disease Disease

Mechanisms and Recent Clinical TrialsMechanisms and Recent Clinical TrialsScott Kaatz, DO, MSc, FACPScott Kaatz, DO, MSc, FACP

Clinical Associate Professor of MedicineClinical Associate Professor of MedicineAssociate Residency Program DirectorAssociate Residency Program Director

Department of MedicineDepartment of MedicineDirector, Anticoagulation ClinicsDirector, Anticoagulation Clinics

Henry Ford Hospital Henry Ford Hospital Detroit, Michigan Detroit, Michigan


► Anticoagulant options in atrial fibrillationAnticoagulant options in atrial fibrillation

► WarfarinWarfarin

► DabigatranDabigatran

► ApixabanApixaban

► RivaroxabanRivaroxaban

The Emerging Role of Direct Thrombin and Factor Xa The Emerging Role of Direct Thrombin and Factor Xa Inhibition for Thrombosis Reduction in Heart DiseaseInhibition for Thrombosis Reduction in Heart Disease

Mechanisms and Recent Clinical TrialsMechanisms and Recent Clinical Trials

Stroke Rate per Year with Different Stroke Rate per Year with Different Antithrombotic Options in AFAntithrombotic Options in AF

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

OptionOption ApproximatApproximate Rate/Yeare Rate/Year HartHart ACTIVE WACTIVE W ACTIVE ACTIVE

AAAVERROEAVERROE

SSRELYRELY

No treatment 4.5%4.5% 4.5%4.5% ThrombinThrombin

ASA 3.5%3.5% 3.2%3.2% YesYes 3.3%3.3% 3.3%3.3%

ASA + Clopidogrel 2.5%2.5% 2.4%2.4% 2.4%2.4%

Warfarin 1.5%1.5% 1.8%1.8% 1.4%1.4% 1.6%1.6%

Apixaban 1.5%1.5% 1.5%1.5%

Dabigatran 110 1.5%1.5% 1.4%1.4%

Dabigatran 150 1.0%1.0% 1.0%1.0%

Comparative Pharmacology Comparative Pharmacology

CharacteristicCharacteristic ApixabanApixaban RivaroxabanRivaroxaban Dabigatran Dabigatran

Target Factor XaFactor Xa Factor Xa Factor Xa ThrombinThrombin

Prodrug NoNo NoNo YesYes

Bioavailability 60%60% 80%80% 6%6%

Dosing Fixed, b.i.d.Fixed, b.i.d. Fixed, o.d.Fixed, o.d. Fixed, o.d./bid Fixed, o.d./bid

Half life 12 hours12 hours 7 to 11 hours7 to 11 hours 12-17 hours12-17 hours

Renal clearance 25%25% 35%35% 80%80%Routine coag.

monitoring NoNo NoNo NoNo

Drug interactions

Potent CYP3A4 Potent CYP3A4 & P-gp & P-gp

inhibitorsinhibitors

Potent CYP3A4 Potent CYP3A4 & P-gp & P-gp

inhibitors inhibitors

Potent P-gp Potent P-gp inhibitors inhibitors

Courtesy of John Eikelboom

► Anticoagulant options in AFAnticoagulant options in AF► WarfarinWarfarin► DabigatranDabigatran► ApixabanApixaban► RivaroxabanRivaroxaban



WarfarinWarfarin

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

► In 1951 the failed attempted suicide In 1951 the failed attempted suicide of a navy recruit who had taken a of a navy recruit who had taken a large dose of rat poison led clinicians large dose of rat poison led clinicians to discard dicumarol in favor of to discard dicumarol in favor of warfarin.warfarin.

► The first clinical study with warfarin The first clinical study with warfarin was reported in 1955. In the same was reported in 1955. In the same year, President Eisenhower was year, President Eisenhower was treated with warfarin following a treated with warfarin following a heart attackheart attack

WarfarinWarfarin

Scully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdfScully. The Biochemist, Feb 2002 http://www.biochemist.org/bio/02401/0015/024010015.pdf

• Warfarin was launched as the ideal rat poison Warfarin was launched as the ideal rat poison in 1948. Although it was thought at first to be in 1948. Although it was thought at first to be too toxic for human usetoo toxic for human use

Warfarin vs. no Treatment Warfarin vs. no Treatment or Placeboor Placebo

Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005Hart RG. Ann Intern Med. 2007 Jun 19;146(12):857-67. PMID: 17577005




Direct Direct Thrombin Thrombin InhibitorsInhibitors

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

•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 hirudinhirudin 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

Medicinal LeechMedicinal Leech(Hirudo Medicinalis) (Hirudo Medicinalis)

RELY TrialRELY Trial

► Question: Is Dabigatran oral unmonitored direct Question: Is Dabigatran oral unmonitored direct thrombin inhibitor as effective and safe as warfarin thrombin inhibitor as effective and safe as warfarin for stroke prevention in AF?for stroke prevention in AF?

► Design: Randomized trial, warfarin was un-blindedDesign: Randomized trial, warfarin was un-blinded► Patients: 18,113 AF patients with at least on stroke Patients: 18,113 AF patients with at least on stroke

risk factorrisk factor► Interventions:Interventions:

● Dabigatran 110 mg bidDabigatran 110 mg bid● Dabigatran 150 mg bidDabigatran 150 mg bid

► Comparison: Warfarin, INR 2.0-3.0Comparison: Warfarin, INR 2.0-3.0► Primary outcome: Stoke and systemic embolismPrimary outcome: Stoke and systemic embolism► Timeframe: Mean follow up was 2.0 yearsTimeframe: Mean follow up was 2.0 years

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

RELYRELY


RELYRELY


RELYRELY





AVERROESAVERROES

► Question: Is apixaban superior to ASA in Question: Is apixaban superior to ASA in patients with AF who are not candidates patients with AF who are not candidates for warfarin?for warfarin?

► Design: RCT, double blindedDesign: RCT, double blinded► Patients: AF patients not candidates for Patients: AF patients not candidates for

warfarinwarfarin► Intervention: apixaban 5 mg (2.5 mg) bidIntervention: apixaban 5 mg (2.5 mg) bid► Comparison: ASA 81-325 mg qdComparison: ASA 81-325 mg qd► Outcome: stroke or systemic embolismOutcome: stroke or systemic embolism

Connolly S. Hotline, ESC, 8.31.10Connolly S. Hotline, ESC, 8.31.10







ROCKETROCKET

► Question: is rivaroxaban non-inferior to warfarin Question: is rivaroxaban non-inferior to warfarin for stroke prevention in AFfor stroke prevention in AF

► Design: RCT, double blindedDesign: RCT, double blinded► Patients: AF and CHADSPatients: AF and CHADS22 >> 2 2► Intervention: rivaroxaban 20 mg qdIntervention: rivaroxaban 20 mg qd► Comparison: warfarinComparison: warfarin► Outcome:Outcome:

● Stroke and systemic embolismStroke and systemic embolism● Major and non-major clinically relevant bleedingMajor and non-major clinically relevant bleeding

► Result expected to be presented at AHA, Result expected to be presented at AHA, November 2010November 2010www.clinicaltrials.gov NCT00403767www.clinicaltrials.gov NCT00403767




Optimizing Stroke Prevention in Optimizing Stroke Prevention in AF with Established and AF with Established and

Currently Available TherapiesCurrently Available Therapies

The Role of Vitamin K Antagonists – The Role of Vitamin K Antagonists – What Works? What Doesn’t?What Works? What Doesn’t?

Alan K. Jacobson, MDAlan K. Jacobson, MDDirector, Anticoagulation ServicesDirector, Anticoagulation Services

Loma Linda VA Medical CenterLoma Linda VA Medical CenterLoma Linda, CaliforniaLoma Linda, California


Why do we need another warfarin Why do we need another warfarin management lecture?management lecture?

► Warfarin therapy is:Warfarin therapy is:● Highly effectiveHighly effective● Complex to manageComplex to manage● UnderutilizedUnderutilized● When utilized, managed poorlyWhen utilized, managed poorly

… … but effective solutions have but effective solutions have evolved. evolved.

Disturbed FlowDisturbed Flow

(left atrium)(left atrium)

Stroke RiskStroke Risk

Blood Flow in Atrial FibrillationBlood Flow in Atrial Fibrillation

1.91.92.32.3

2.12.1

0.90.9

Warfarin in Prospective AF TrialsWarfarin in Prospective AF TrialsIntention-to-treat analysisIntention-to-treat analysis

ControlControlWarfarinWarfarin

AFASAKAFASAK SPAFSPAF BAATAFBAATAF CAFACAFASPINAFSPINAF 825825 504504 922922 490490 896896 p=0.03p=0.03 p=0.01 p=0.002 p=0.01 p=0.002 p>0.2p>0.2p=0.001p=0.001

88

66

44

22

00

Stro

ke R

ate

(%/y

ear)

Stro

ke R

ate

(%/y

ear)

Adapted from Atwood, Albers, Herz 1993;18:27-38

4.64.6

3.03.03.63.6

4.34.3

person-yearsperson-yearsp valuep value

7.07.0

0.40.4

Loma Linda VA Medical Center, 2010

RR 79% 83% 83% 73% 79% 83%

Anticoagulant Therapy is EffectiveAnticoagulant Therapy is Effective

Anticoagulation of AFAnticoagulation of AFRisk — BenefitRisk — Benefit

XOR vs.

Oral Anticoagulation - ChallengesOral Anticoagulation - Challenges

► Narrow therapeutic dosing rangeNarrow therapeutic dosing range● 10-15% dosing window10-15% dosing window

► Variable dosage requirement Variable dosage requirement ● Effect of medicationsEffect of medications● Effect of dietEffect of diet● Effect of liver functionEffect of liver function

► Serious consequences if dosing Serious consequences if dosing wrong wrong

Burdens of AnticoagulationBurdens of Anticoagulation

► Restricted diets - Restricted diets - NOTHINGNOTHING green, green, NONO Vitamin KVitamin K

► Restricted medications - Restricted medications - NONO aspirin, aspirin, NONO NSAIDS NSAIDS

► Ongoing need for blood tests to check Ongoing need for blood tests to check PT/INRPT/INR

► Burdens affect patients and providersBurdens affect patients and providers► Clinical practice has often been driven Clinical practice has often been driven

more by tradition than sciencemore by tradition than science

Burdens of AnticoagulationBurdens of Anticoagulation

► Solutions:Solutions:● Diet - Diet - CONSISTENTCONSISTENT Vitamin K intake Vitamin K intake● Drug interactions - Drug interactions - CONSISTENT if CONSISTENT if

NECESSARYNECESSARY

● Minimal need for restrictions, in fact, some Minimal need for restrictions, in fact, some may benefit from supplementationmay benefit from supplementation

● Prothrombin time testing and Prothrombin time testing and management…. ??management…. ??

Ongoing Patient EducationOngoing QI

Direct Active Managementby Qualified Health Care Provider

Patient Schedulingand Tracking

Accessible, Accurate, and Frequent PT/INR

Testing

Patient-specificDecision Supportand Interaction

Systematic Anticoagulation Systematic Anticoagulation ManagementManagement

Enabling Technologies: POC testing, computerizationEnabling Technologies: POC testing, computerization

Quality QuestionQuality Question

Are you able to identify, on an Are you able to identify, on an ongoing basis, which patients ongoing basis, which patients

are overdue for testing?are overdue for testing?

Active vs. Passive Active vs. Passive ManagementManagement

Patients Assigned to Warfarin in AF Patients Assigned to Warfarin in AF TrialsTrials

Intensity of Anticoagulation When Stroke OccurredIntensity of Anticoagulation When Stroke Occurred

Petersen et al. Lancet 1989:171–75Petersen et al. Lancet 1989:171–75SPAF. Circ 1991;84:527–39SPAF. Circ 1991;84:527–39BAATAF. N Engl J Med 1990; 323:1505–11BAATAF. N Engl J Med 1990; 323:1505–11

Connolly et al. J Am Coll Cardiol 1991;18:349–55Connolly et al. J Am Coll Cardiol 1991;18:349–55Ezekowitz et al. N Engl J Med 1992;327:1406–12Ezekowitz et al. N Engl J Med 1992;327:1406–12Hirsh, Dalen, Deykin, Poller. CHEST 1992;312S–326SHirsh, Dalen, Deykin, Poller. CHEST 1992;312S–326S

AFASAKAFASAK SPAF ISPAF I BAATAFBAATAF SPINAFSPINAFCAFACAFA

1.01.0

2.02.0

3.03.0

4.04.0

1.71.7

1.61.6

1.51.5

1.41.4

1.31.31.21.21.11.11.01.0

INRINR

RatioRatio

PTPT

RatioRatio

(ISI 2.4)(ISI 2.4)

ACCP recommendations: INR 2.0–ACCP recommendations: INR 2.0–3.03.0

1.81.8

Target range for individual studyTarget range for individual study

Bleed Bleed RiskRisk

INR Intensity

1 2 3 4 5 67

PERCEIVEDPERCEIVED INR Therapeutic Range INR Therapeutic Range

Clot Clot RiskRisk

00

2020

4040

6060

8080

100100

4.0-

4.4

4.0-

4.4

1.5-

1.9

1.5-

1.9

1.0-

1.4

1.0-

1.4

2.0-

2.4

2.0-

2.4

2.5-

2.9

2.5-

2.9

3.0-

3.4

3.0-

3.4

3.5-

3.9

3.5-

3.9

4.5-

4.9

4.5-

4.9

5.0-

5.4

5.0-

5.4

5.5-

5.9

5.5-

5.9

6.0-

6.4

6.0-

6.46.

56.5

INRINR

Inci

den

ce p

er 1

00 P

atie

nt-Y

ear

sIn

cide

nce

per

100

Pat

ient

-Ye

ars

INR-Specific Incidence of All Adverse Events (All Episodes ofINR-Specific Incidence of All Adverse Events (All Episodes ofThromboembolism, All Major Bleeding Episodes, and Unclassified Stroke).Thromboembolism, All Major Bleeding Episodes, and Unclassified Stroke).

The dotted lines indicate the 95 percent confidence interval.The dotted lines indicate the 95 percent confidence interval.Cannegeiter et al

ACTUALACTUAL INR therapeutic rangeINR therapeutic range

Incidence Rates of Ischemic Stroke Incidence Rates of Ischemic Stroke and Intracranial Hemorrhageand Intracranial Hemorrhage

Adapted from Hylek EM, et al. Adapted from Hylek EM, et al. N Engl J Med.N Engl J Med. 2003;349:1019-1026. 2003;349:1019-1026.

Recommended Range for Warfarin Recommended Range for Warfarin Therapy Therapy For Patients in Atrial FibrillationFor Patients in Atrial Fibrillation

► Target: INR 2.5Target: INR 2.5► Range: INR 2.0–Range: INR 2.0–

3.03.0

CHEST 1998;114:579s-589sCHEST 1998;114:579s-589s

Methods of Monitoring - OptionsMethods of Monitoring - Options

► Central Laboratory Testing with Central Laboratory Testing with Professional Management of ResultsProfessional Management of Results

► Point-of-Care Testing Point-of-Care Testing (Professional)(Professional) with with Professional Management of ResultsProfessional Management of Results

► Point-of-Care Testing Point-of-Care Testing (Patient)(Patient) with with Patient or Professional ManagementPatient or Professional Management

Which is best???Which is best???Different solutions for different patients in Different solutions for different patients in different settingsdifferent settings

Why do we need another warfarin Why do we need another warfarin management lecture?management lecture?

► Warfarin therapy is:Warfarin therapy is:● Highly effectiveHighly effective● Complex to manageComplex to manage● UnderutilizedUnderutilized● When utilized, managed poorlyWhen utilized, managed poorly

… … but effective solutions have but effective solutions have evolved. evolved.

Progress of MedicineProgress of Medicine

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

(Lancet 1899, Dr. F. Roberts).(Lancet 1899, Dr. F. Roberts).

Progress of MedicineProgress of Medicine

► Out of the enormous number of medicinal agents brought Out of the enormous number of medicinal agents brought under our notice by puffing advertisements in the press, under our notice by puffing advertisements in the press, medical as well as lay, by pamphlets or even large books medical as well as lay, by pamphlets or even large books delivered by post, or by actual 'specimens for trial' which delivered by post, or by actual 'specimens for trial' which are nowadays so liberally delivered at our residences, are nowadays so liberally delivered at our residences, comparatively few hold their ground, or stand a fair and comparatively few hold their ground, or stand a fair and candid criticism and investigation of their vaunted merits. candid criticism and investigation of their vaunted merits. Still a certain proportion do and I see every reason to Still a certain proportion do and I see every reason to anticipate that, as the result of the systematic researches, anticipate that, as the result of the systematic researches, scientific and practical, now carried on in so many scientific and practical, now carried on in so many laboratories, valuable additions will be made from time to laboratories, valuable additions will be made from time to time to the medicinal agents at our disposal for the help time to the medicinal agents at our disposal for the help and comfort of our patients. and comfort of our patients.

► I only hope that in our love for the new I only hope that in our love for the new we will not entirely throw out old friends we will not entirely throw out old friends which have done real and effective which have done real and effective service in the past and are today as service in the past and are today as deserving of our regard as ever.deserving of our regard as ever.

(Lancet 1899, Dr. F. Roberts).(Lancet 1899, Dr. F. Roberts).

The FutureThe Future

► Refined management of the old drug – Refined management of the old drug – warfarinwarfarin

► Variety of new agents with predictable Variety of new agents with predictable therapeutic ranges and improved risk therapeutic ranges and improved risk benefit but with continued need for benefit but with continued need for education, hemorrhagic risk assessment, education, hemorrhagic risk assessment, and monitoringand monitoring

► Improved range of options to facilitate Improved range of options to facilitate stroke prevention in patients with atrial stroke prevention in patients with atrial fibrillationfibrillation

Documents

New Frontiers in Stroke Prevention for Atrial Fibrillation Focus on Evolving Strategies for Initial Assessment, Risk Stratification, Monitoring, and Pharmacologic