2 New Frontiers in Atrial Fibrillation New Dimensions andLandmark Practice AdvancesNational Experts in Cardiovascular MedicineIlluminate and DebateNew Frontiers in Atrial FibrillationEmerging Perspectives in Thrombosis Mitigation for the Cardiovascular Specialist—Translating Evidence into ActionProgram ModeratorSamuel Z. Goldhaber, MDCardiovascular DivisionBrigham and Women’s HospitalProfessor of MedicineHarvard Medical School
3 Welcome and Program Overview CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Boehringer-Ingelheim Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program
4 Program Educational Objectives As a result of this educational activity, participants will learn about:Advances in oral anticoagulation based on new mechanisms involving inhibition of the coagulation cascade and possible implications for prophylaxis of arterial thromboembolism in the setting of atrial fibrillation.The mechanisms involved in thromboembolic prevention and the rationale for identifying agents with predictable anticoagulation, in the absence of clinical monitoring.Current ACCP, ACC, AHA, and AAN guidelines for stroke prevention in the setting of AF.Novel approaches for residual risk reduction and secondary prevention of adverse thromboembolic events (stroke) in the setting of atrial fibrillation, and related conditions.
5 Program Faculty Program Moderator Elaine M. Hylek, MD, MPH Samuel Z. Goldhaber, MDCardiovascular DivisionBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolJonathan L. Halperin, MDProfessor of Medicine (Cardiology) Mount Sinai School of MedicineDirector, Clinical Cardiology ServicesThe Zena and Michael A. WienerCardiovascular InstituteThe Marie-Josée and Henry R. KravisCenter for Cardiovascular Health Elaine M. Hylek, MD, MPHAssociate Professor of MedicineDepartment of MedicineDirector, Thrombosis Clinic andAnticoagulation ServiceBoston University Medical CenterBoston, MassachusettsJeffrey I. Weitz, MD, FRCP, FACPProfessor of Medicine and BiochemistryMcMaster UniversityDirector, Henderson Research CenterCanada Research Chair in ThrombosisHeart and Stroke FoundationJ.F. Mustard Chair in CardiovascularResearch
6 Faculty COI Disclosures Samuel Z. Goldhaber, MDResearch Support: BMS, Boehringer-Ingelheim, Eisai, Johnson and Johnson, sanofi-aventisConsultant: BMS, Boehringer-Ingelheim, Eisai, Medscape, Merck, sanofi-aventis, VortexJonathan L. Halperin, MDConsulting fees from the following companies involved in development of investigational drugs or devices: Astellas Pharma, U.S., Bayer HealthCare, Biotronik, Inc., Boehringer Ingelheim, Daiichi Sankyo Pharma, Johnson & Johnson, Portola Pharmaceuticals, and sanofi-aventisElaine M. Hylek, MD, MPHSteering Committee: Bristol-Myers Squibb Advisory Board: Astellas, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, sanofi-aventisJeffrey I. Weitz, MD, FRCP, FACPGrants/Research Support: CIHR, HSFO, CFI, ORFSpeakers Bureau: Bristol-Myers Squibb, Boehringer Ingelheim, sanofi-aventis, Daiichi-Sankyo, Bayer, Pfizer, The Medicines Company, Eisai, Takeda
7 New Frontiers in Atrial Fibrillation ATRIAL FIBRILLATION Current Challenges in Thrombosis Medicine for the Cardiovascular SpecialistSamuel Z. Goldhaber, MDCardiovascular DivisionBrigham and Women’s HospitalProfessor of MedicineHarvard Medical School
8 Atrial Fibrillation: Twice as Common as Previously Suspected Incidence increased 13% over past 20 yearsIn USA, million will be affected by 2050Increasing obesity and increasing age are risk factors that help explain rise in incidenceMiyasaka Y. Circulation 2006; 114:
9 AF Prevalence: Age and Gender Prevalence of atrial fibrillation with agePrevalence, percentAge, yearsJAMA 2001; 285: 2370
10 Mortality Rates in AFDouble the overall age and gender matched populationNo reduction in past two decadesMortality 9-fold higher during 1st 4 months after diagnosisMiyasaka Y, et al. JACC 2007; 49:
11 Risk Factors for Stroke Relative RiskOld Stroke/TIA2.5Hypertension1.6CHF1.4Increased age1.4/10 yearsDM1.7CAD1.5An increased risk of stroke is associated with multivariate predictors of stroke in control-group patients with atrial fibrillation. This is shown from several stroke-prevention trials.These risk factors must be taken into account when deciding on the appropriate course of therapy for prevention of stroke in individual patients with AF.Arch Intern Med 1994; 154:Reference:Arch Intern Med 1994; 154(13):
12 Atrial Fibrillation: A Risk Factor for Vascular Events RISK FACTORS for THROMBOSIS• Hypertension• Hyperlipidemia• Age• Diabetes Mellitus• SmokingAtherosclerosis/AtherothrombosisAtherosclerosis/AtherothrombosisAtrial fibrillation (AF) results when the atria of the heart contract and relax at different times, creating a seemingly chaotic, rapid and irregular rhythm.The condition can be caused by impulses which are transmitted to the ventricles in an irregular fashion or by some impulses failing to be transmitted. This makes the ventricles beat irregularly, which leads to an irregular (and usually fast) pulse in atrial fibrillation.Underlying causes of AF include dysfunction of the sinus node and a number of heart and lung disorders, including coronary artery disease, rheumatic heart disease, mitral valve disorders, pericarditis and others.Hyperthyroidism, hypertension and other diseases can cause arrhythmias, as can recent heavy alcohol use. Some cases of AF or flutter occur in the setting of a myocardial infarction or soon after cardiac surgery.One of the consequences of AF is stroke: about 15% of all strokes are directly attributable to AF, and in patients over 80 years AF is the single leading cause of major stroke.1,2MIAFMIAFCHFCHFStroke, MI, Vascular DeathWolf PA et al. Arch Intern Med 1987; 147:Leckey R et al. Can J Cardiol 2000; 16:References:1. Wolf PA et al. Arch Intern Med 1987; 147:2. Leckey R et al. Can J Cardiol 2000; 16:
13 Thrombus in Left Atrial Appendage Associated with Stroke Thrombus in left atrial appendage is correlated with increased thromboembolic risk in AFAbnormalities detected by transesophageal echocardiography in the left atrium (LA) and appendage showed that:impaired atrial emptying associated with atrial fibrillation (AF) leads to stasis and increases the risk of thrombus formation in the left atrium and especially the left-atrial appendage (LAA).1,2the surface of the newly formed thrombus is itself highly thrombogenic, creating a local hypercoagulable state and promoting its continued development.1,2exposure to the dynamic circulatory forces within the cardiac chambers promotes embolization of cardiogenic thrombi and subsequent ischemic events in the different arterial beds including stroke and peripheral arterial occlusion.1,2spontaneous echo contrast, LAA thrombi, LAA peak flow velocities 20 cm/s and complex aortic plaque are independently associated with increased risk of stroke in patients with AF.1,2Chimowitz. Stroke 1993; 24: 1015Zabalgoitia. J Am Coll Cardiol 1998; 31: 1622References:1. Chimowitz. Stroke 1993; 24: 1015.2. Zabalgoitia. J Am Col Cardiol 1998; 31: 1622.
14 One Sixth of all Strokes Attributable to AF %AF prevalenceStrokes attributable to AFAge Range (years)Framingham Study10203050–5960–6970–7980–89The Framingham Study examined the impact of atrial fibrillation (AF) on stroke incidence in 5,070 participants after 34 years of follow-up.Results of the study showed that the percentage of strokes attributable to AF increased dramatically with age.1The investigators of the study concluded that AF is a major cause of stroke, particularly among elderly patients. Therefore, anticoagulation therapy should be a routine part of therapy for these patients.Wolf et al. Stroke 1991; 22:Reference:Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22:14
15 Problems with Established Therapy: Warfarin Delayed onset/offsetUnpredictable dose responseNarrow therapeutic rangeDrug–drug, drug–food interactionsProblematic monitoringHigh bleeding rateSlow reversibility
16 First Month of Warfarin Therapy has High Bleeding Rate Bleeding TypeHead BleedMajor Non-Head Bleed1st Month Warfarin0.92% (annualized)1.2% (annualized)Subsequent Warfarin0.46% per year0.61% per yearFang MC. J Am Geriatr Soc 2006; 54:
17 FDA Adds “Black Box” Warning/Precaution for Warfarin October 6, 2006Warning: Bleeding RiskAugust 16, 2007Precaution: “Consider a lower initial warfarin dose for patients with certain genetic variations.”
18 Learning Objectives Warfarin dosing and genetics FDA warfarin labeling vs. NHLBI Randomized Clinical Trial
19 Warfarin: Advantages INR assesses anticoagulant level Multiple antidotes availableOmitting one or two doses usually is not clinically problematicIntroduced in Has “stood the test of time.” No liver toxicityAbility to maintain target INR is improving (Now > 60% in top facilities)No anticoagulant has demonstrated superior efficacy or safetyInexpensive
20 Warfarin: Walking a Tightrope Excessive dose precipitates hemorrhageInadequate dose predisposes to stroke and pulmonary embolismDosing nomograms are awkward, cumbersomeDosing by trial and error predominates
21 Therapeutic Range for Warfarin INR Values at Stroke or ICH 15.0StrokeIntracranial Hemorrhage10.0Odds Ratio5.01.01.02.03.04.05.06.07.08.0INRFuster et al. J Am Coll Cardiol. 2001;38:
22 Hylek, EM et al. N Engl J Med. 2003;349:1019-2614
23 “Most intracranial hemorrhages (62%) occur at INRs < 3.0” Fang MC et al. Ann Intern Med. 2004;141:745-52
24 Reduction of Stroke in AF – Warfarin Compared with Placebo Adjusted-dose warfarin compared with placeboAFASAK ISPAFBAATAFCAFASPINAFEAFTAll trials (n=6)Relative risk reduction (95% CI)Warfarin betterWarfarin worse62% (48% to 72%)10050-50-100Five randomized trials evaluated oral anticoagulation (OAC) and two of these tested ASA for primary prevention of thromboembolism in patients with non-valvular atrial fibrillation (AF). A sixth trial focused on secondary prevention among patients who had survived non-disabling stroke or transient cerebral ischemic attack.1Six trials in the meta-analysis:- Copenhagen AF, Aspirin and Anticoagulation Study (AFASAK I). Lancet 1989;1:- Stroke Prevention in AF Study (SPAF I). Circulation 1991; 84:- Boston Area Anticoagulation Trial for AF (BAATAF). N Engl J Med 1990;323:- Canadian AF Anticoagulation Study (CAFA). J Am Coll Cardiol 1991;18:- Stroke Prevention in Non-rheumatic AF (SPINAF). N Eng J Med. 1992;327:- European AF Trial (EAFT). Lancet 1993; 342:Meta-analysis according to the principle of intention to treat showed that adjusted-dose OAC is highly efficacious for prevention of stroke (both ischemic and hemorrhagic) with a risk reduction of 61% (95% CI, 47% to 71%) vs placebo. This reduction was similar for both primary and secondary prevention.1Overall, warfarin is shown to be about 60% better than placebo.1The duration of follow-up in these trials was generally between one and two years; the longest duration was 2.2 years.In clinical practice, the need for antithrombotic therapy typically extends over much longer periods.Hart et al. Ann Intern Med 1999; 131:References:1. Hart et al. Ann Intern Med 1999; 131:
25 ACTIVE W Trial OAC Clopidogrel plus ASA Standard Care (INR 2.0 – 3.0) INR at least monthlyClopidogrel plus ASAClopidogrel 75 mg once dailyASA mg once daily
27 ACTIVE W: Stroke, Non-CNS Embolism, MI and Vascular Death 5.64 %/yearRR = 1.45P =3.93 %/yearCumulative Hazard RatesYears# at RiskC+AOAC
28 ACTIVE W: Major Bleeding 2.4 %/yearRR = 1.06P = 0.672.2 %/yearCumulative Hazard Rates# at RiskC+AOACYearsLancet. 2006;367: ,
29 The Frontiers of Thrombosis: Mitigation (Stroke Reduction) in Atrial Fibrillation New oral anticoagulants, given in fixed dose without laboratory coagulation monitoring, may improve and expand on existing anticoagulation options. We will hear about these exciting development tonight.
30 New Frontiers in Atrial Fibrillation Challenges in Stroke Preventionfor Patients with Atrial FibrillationAchieving Balance BetweenPrevention of Thromboembolismand Risk of BleedingJonathan L. Halperin, MDProfessor of Medicine (Cardiology)Mount Sinai School of MedicineDirector, Clinical Cardiology ServicesThe Zena and Michael A. Wiener Cardiovascular InstituteThe Marie-Josée and Henry R. KravisCenter for Cardiovascular Health
31 Projected U.S. Prevalence of AF An Expanding Epidemic 2468101214161820002005201020152020202520302035204020452050YearProjected Number of People with AF(millions)Based on Projected IncidenceBased on Current IncidenceMiyakasa Y, et al. Circulation 2006; 114: 119.
32 Atrial Fibrillation A Substantial Threat to the Brain Affects~4% of people aged >60 years~9% of those aged >80 years5%/year stroke rate12%/year for those with prior stroke$ billions annual cost for stroke careAF-related strokes have worse outcomesWithout antithrombotic prophylaxis, atrial fibrillation (AF) carries a substantial risk of ischemic stroke, even in the absence of associated rheumatic or valvular heart disease. The expense for acute and convalescent care of stroke victims, and the inestimable cost in human terms make thromboembolism associated with nonvalvular atrial fibrillation a major public health problem. It has therefore become important for all physicians to recognize atrial fibrillation as a risk factor for preventable strokes.AF identifies millions of people with afive-fold increased risk of stroke
33 Priorities in the Management of AF The Patient Care Pathway Rhythm ControlPrevention of ThromboembolismRate Control
34 Natural History of “Lone” Atrial Fibrillation No Cardiopulmonary Disease: <60 Years Old97 PatientsMean Age = 4414.8 yearsFollow-up0.35%/yr Stroke0.40%/yr MortalityKopecky S, et al. N Engl J Med 1987; 317:669.
35 Stroke Rate (% per year) Stroke Risk in Atrial Fibrillation Untreated Control Groups of Randomized TrialsStroke Rate (% per year)To be replaced with a slide showing prevalence of AF-related stroke as a function of age (Framingham Study data or other).Age (years)Atrial Fibrillation Investigators. Arch Intern Med 1994;154:1449.
36 Anticoagulation in Atrial Fibrillation Stroke Risk Reductions WarfarinBetterControlBetterAFASAKSPAFBAATAFCAFASPINAFEAFTAggregate100%50%-50%-100%Hart R, et al. Ann Intern Med 2007;146:857.
37 Anticoagulation in Atrial Fibrillation The Standard of Care for Stroke Prevention WarfarinBetterControlBetterAFASAKUnblindedSPAFUnblindedBAATAFUnblindedCAFATerminated earlySPINAFDouble-blind; Men onlyEAFT2o prevention; UnblindedAggregate100%50%-50%-100%Hart R, et al. Ann Intern Med 2007;146:857.
38 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reduction TreatmentBetterTreatmentWorseWarfarin vs.Placebo/Control6 Trialsn = 2,900Antiplatelet drugsvs. Placebo8 Trialsn = 4,876100%50%-50%Hart R, et al. Ann Intern Med 2007;146:857.
39 Efficacy of Warfarin in Trials vs. Practice Stroke Risk Reductions TreatmentBetterTreatmentWorse6 Trialsn = 2,900Warfarin vs.Placebo/ControlWarfarin vs.No anticoagulationMedicare cohortn = 23,657100%50%-50%Hart R, et al. Ann Intern Med 2007;146:857Birman-Deych E. Stroke 2006; 37: 1070–107439
40 Intracerebral Hemorrhage The Most Feared Complication of Antithrombotic Therapy>10% of intracerebral hemorrhages (ICH) occur in patients on antithrombotic therapyAspirin increases the by ~ 40%Warfarin (INR 2–3) doubles the risk to 0.3– 0.6%/yearICH during anticoagulation is catastrophicHart RG, et al. Stroke 2005;36:158840
41 Risk Stratification in AF Stroke Risk Factors High-Risk FactorsMitral stenosisProsthetic heart valveHistory of stroke or TIAThis slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP.ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender.Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors.Singer DE, et al. Chest 2004;126:429S.Fang MC, et al. Circulation 2005; 112: 1687.
42 Risk Stratification in AF Stroke Risk Factors High-Risk FactorsMitral stenosisProsthetic heart valveHistory of stroke or TIAModerate-Risk FactorsAge >75 yearsHypertensionDiabetes mellitusHeart failure or ↓ LV functionThis slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP.ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender.Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors.Singer DE, et al. Chest 2004;126:429S.Fang MC, et al. Circulation 2005; 112: 1687.
43 Risk Stratification in AF Stroke Risk Factors High-Risk FactorsMitral stenosisProsthetic heart valveHistory of stroke or TIAModerate-Risk FactorsAge >75 yearsHypertensionDiabetes mellitusHeart failure or ↓ LV functionLess Validated Risk FactorsAge 65–75 yearsCoronary artery diseaseFemale genderThyrotoxicosisThis slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP.ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender.Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors.Singer DE, et al. Chest 2004;126:429S.Fang MC, et al. Circulation 2005; 112: 1687.
44 Risk Stratification in AF Stroke Risk Factors High-Risk FactorsMitral stenosisProsthetic heart valveHistory of stroke or TIAModerate-Risk FactorsAge >75 yearsHypertensionDiabetes mellitusHeart failure or ↓ LV functionLess Validated Risk FactorsDubious FactorsThis slide depicts risk factors for stroke from the most recent guidelines on prevention of stroke in patients with AF from the ACCP.ACCP guidelines also suggest that women with AF who are older than 75 years may be at an increased risk of stroke compared with men of the same age. The impact of gender on risk of stroke in patients with AF has not been definitively determined. Increasing age is a risk factor for stroke in patients with AF, regardless of gender.Recently, a joint committee representing the American College of Cardiology (ACC), AHA, and European Society of Cardiology (ESC) published guidelines on the management of patients with AF. This document identifies the same risk factors for stroke in patients with AF as the ACCP guidelines, with the addition of persistent thrombus on transesophageal echocardiography (TEE) and thyrotoxicosis as risk factors.Age 65–75 yearsCoronary artery diseaseFemale genderThyrotoxicosisDuration of AFPattern of AF(persistent vs. paroxysmal)Left atrial diameterSinger DE, et al. Chest 2004;126:429S.Fang MC, et al. Circulation 2005; 112: 1687.
45 Stroke Risk Score for Atrial Fibrillation The CHADS2 IndexStroke Risk Score for Atrial FibrillationScore (points)Prevalence (%)*Congestive Heart failureHypertensionAge >75 yearsDiabetes mellitusStroke or TIAModerate-High risk >Low riskVanWalraven C, et al. Arch Intern Med 2003; 163:936.* Nieuwlaat R, et al. (EuroHeart survey) Eur Heart J 2006 (E-published).
46 Nonvalvular Atrial Fibrillation Stroke Rates Without AnticoagulationAccording to Isolated Risk FactorsStroke Rate(%/year)PriorStroke/TIAAge> 75 yearsHypertensionFemaleDiabetesHeart Failure LVEFHart RG et al. Neurology 2007; 69: 546.46
47 Stroke Risk Score for Atrial Fibrillation The CHADS2 IndexStroke Risk Score for Atrial FibrillationScore(points)Risk of Stroke(%/year)ApproximateRisk threshold forAnticoagulation3%/yearVan Walraven C, et al. Arch Intern Med 2003; 163:936.Go A, et al. JAMA 2003; 290: 2685.Gage BF, et al. Circulation 2004; 110: 2287.
48 Risk Stratification and Anticoagulation Stroke Reduction with Warfarin Instead of AspirinCHADS2 Score ~Number of patients Needed-to-treatto prevent1 stroke/year134283250EAFT Study Group. Lancet 1993; 324:1255.Zabalgoitia M, et al. J Am Coll Cardiol 1998; 31:1622.
50 "Actually, it's more of a guideline than a rule.” Bill Murray in GhostbustersⒸ (1984),relaxing his rule "never to get involved with possessed people" in response to Sigourney Weaver's seductive advances.
51 Patient Selection for Anticoagulation Additional Considerations Risk of bleedingNewly anticoagulated vs. established therapyAvailability of high-quality anticoagulation management programPatient preferences
52 INR at the Time of Stroke or Bleeding Efficacy and Safety of Warfarin 2015Ischemic StrokeIntracranial bleedingOdds Ratio10511.02.03.04.05.06.07.08.0International Normalized RatioFang MC, et al. Ann Intern Med 2004; 141:745. Hylek EM, et al. N Engl J Med 1996; 335:540.
53 Warfarin for Atrial Fibrillation Limitations Lead to Inadequate Treatment Adequacy of Anticoagulation in Patients with AF in Primary Care PracticeNo warfarin 65%INR above target 6%INR in target range 15%Subtherapeutic INR 13%Samsa GP, et al. Arch Intern Med 2000;160:967.
54 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk FactorsACTIVE - WACTIVE - AAnticoagulation-eligibleOAC Contraindications or UnwillingVKA(INR 2-3)Clopidogrel+ AspirinAspirin+ PlaceboClopidogrel+ AspirinOpen-labelNon-inferiorityn = 6,706Double-blindSuperiorityn = 7,554Irbesartan, 300 mg/d vs. Placebon = 9,016ACTIVE - IRisk Factors:Age 75, hypertension, prior stroke/TIA, LVEF<45%, PAD, age CAD or diabetesPrimary outcome: Stroke, systemic embolism, MI or cardiovascular death
55 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk FactorsACTIVE – WACTIVE - AAnticoagulation-eligibleOAC Contraindications or UnwillingVKA(INR 2-3)Clopidogrel+ AspirinAspirin+ PlaceboClopidogrel+ AspirinOpen-labelNon-inferiorityn = 6,706Double-blindSuperiorityn = 7,554Irbesartan, 300 mg/d vs. Placebon = 9,016ACTIVE - I
56 Antithrombotic Therapy for Atrial Fibrillation Stroke Risk Reductions WarfarinBetterAntiplatelet RxBetterACTIVE-WAnticoagulation vs.Aspirin + Clopidogreln = 6,706Anticoagulation vs.Antiplatelet drugs7 Trialsn = 4,232100%50%-50%Connolly S, et al. Lancet 2006; 367:1903.Hart R, et al. Ann Intern Med 2007;146:857.
58 Major Hemorrhage in Relation to Prior Anticoagulant Therapy: ACTIVE-W “Starters”“Switchers”Interaction p=0.028Event Rate(%/year)NoYesAnticoagulant Therapy at EntryConnolly S, et al. Lancet 2006; 367:1903.
59 The ACTIVE Trial Clopidogrel + Aspirin Atrial Fibrillation + Risk FactorsACTIVE – WACTIVE - AAnticoagulation-eligibleOAC Contraindications or UnwillingVKA(INR 2-3)Clopidogrel+ AspirinAspirin+ PlaceboClopidogrel+ AspirinOpen-labelNon-inferiorityn = 6,706Double-blindSuperiorityn = 7,554Irbesartan, 300 mg/d vs. Placebon = 9,016ACTIVE - IConnolly SJ, et al. N Engl J Med 2009; 360:2066.
60 ACTIVE-A Reasons for Exclusion from Anticoagulation Risk factor for bleeding*23%Physician judgment against anticoagulation for patient50%Patient preference only26%Inability to comply with INR monitoringPredisposition to falling or head traumaPersistent hypertension >160/100 mmHgPrevious serious bleeding on VKASevere alcohol abuse within 2 yearsPeptic ulcer diseaseThrombocytopeniaChronic need for NSAIDConnolly SJ, et al. N Engl J Med 2009; 360:2066.
61 ACTIVE-A Total Stroke Rates ACTIVE A Medical Advisory Board Meeting_4-0928% RRR HR (95% CI, 0.62–0.83) p <0.0010.15408 (3.3%/year)AspirinACTIVE.N Engl J Med.May.2009/ p2070 /fig 1B(inset)0.10296 (2.4%/year)Cumulative Incidence0.05Clopidogrel + AspirinNote: This slide contains off-label information regarding PLAVIX, and should not be used in promotional presentations except in response to unsolicited questions from the audience.In the ACTIVE A trial, stroke was a component of the composite outcome and occurred in 3.3% of patients per year treated with ASA compared with 2.4% of patients per year treated with PLAVIX plus ASA. This represents a 28% RRR in patients treated with PLAVIX plus ASA vs ASA alone (HR 0.72; 95% CI, 0.62 to 0.83; P<0.001).0.0ACTIVE.N Engl J Med.May.2009/ p2070/table 2, p2071/fig 1B1234YearsConnolly SJ, et al. N Engl J Med 2009; 360:2066.The ACTIVE trial is sponsored by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:
62 The ACTIVE Trials Stroke Rates and Risk Reductions NewTreatmentVKAC+AAspirinACTIVE W(Annual Rate)1.42.4~ACTIVE A3.3RRRversus Aspirin-58%-28%versus C+A-42%Connolly.ACTIVE A.ACC.OrlandoFL.Mar.2009[Presentation]/slide 27Speaker will refer to slide for presentation.VKA = oral anticoagulantC+A = clopidogrel + aspirinConnolly SJ, et al. Lancet 2006; 367:1903.Connolly SJ, et al. N Engl J Med 2009; 360:2066.The ACTIVE trial is sponsored by the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.Connolly SJ. ACTIVE A: Effects of addition of clopidogrel to aspirin in patients with atrial fibrillation who are unsuitable for vitamin K antagonists. Presented at: ACC 58th Annual Scientific Session; March 29-31, 2009; Orlando, FL. Available at:
63 Warfarin Dosing and Genomics CYP2C9 – Gene encoding cytochrome P450 hepatic enzyme responsible for primary clearance of S-warfarin, the active enantiomer;variant alleles are associated with sensitivity to warfarin.VKORC1 – Gene encoding vitamin K epoxide reductase complex 1; variant alleles are associated with warfarin resistance.
64 Warfarin Dosing and Genomics Keeping Ahead of the Data
65 Dose Initiation Dose Titration 1 2 3 4, 5 6 7 8 … Intervention Period:Informed by genetic/clinical informationDose InitiationDose Titration1234, 5678…Objective: To compare the effect of pharmacogenetic & clinical warfarin dosing algorithms on initial proportion of time in therapeutic range of anticoagulation intensity
66 The Ideal Anticoagulant Wide Therapeutic Margin ThrombosisSafe Therapeutic RangeBleedingThrombosisBleedingDose, Concentration, or Intensity of Anticoagulation
67 New Anticoagulant Development The Clinical Trial Pathway DVT/VTEProphylaxisOrthopaedic SurgeryDVT/VTETreatmentArterialDiseaseOtherPotentialIndicationsAFib/StrokeProphylaxis
68 Investigational Anticoagulant Targets ORALPARENTERALTF/VIIaTFPI (tifacogin)TTP889XIXAPC (drotrecogin alfa)sTM (ART-123)IXaVIIIaRivaroxaban Apixaban LY YM150DU-176b BetrixabanTAK 42VaATXaIdraparinuxSource: Turpie State of the art presentation EFORT-08 (rivaroxaban, apixaban and dabigatran highlighted and all the others greyed out)ReferenceWeitz JI, Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853All of the drugs in the above figure are to be found in Weitz and Bates (2005) in Figure 2, apart from:Apixaban – this was called BMS in the original figureBetrixaban and YM150 – see Graham Turpie’s review paper: Turpie AGG. New oral anticoagulants in atrial fibrillation. Eur Heart J 2008;29:155–165Otamixaban – Guertin KR, Choi YM. The discovery of the Factor Xa inhibitor otamixaban: from lead identification to clinical development. Curr Med Chem 2007;14:2471–2481II (thrombin)DX-9065a OtamixabanIIaDabigatranAPC activated protein CAT antithrombinsTM soluble thrombomodulinTF tissue factorFPI tissue factor pathway inhibitorFibrinogenFibrinAdapted from Weitz JI. Thromb Haemost 2007; 5 Suppl 1:65-7.68
69 SPORTIF III and V Stroke and Systemic Embolism Ximelagatran BetterWarfarin Better-0.66SPORTIF IIIp=0.10+0.45SPORTIF Vp=0.13Pooled-0.03p=0.94-4-3-2-11234Difference in Absolute Event Rates (Ximelagatran – Warfarin)SPORTIF-V Investigators. JAMA 2005; 293:
70 SPORTIF III and V Secondary Stroke Prevention Δ = –0.44%/year95% CI –1.86, 0.98; p=0.625p=NSEvent Rate (%/year)Diener H-C, et al. Cerebrovasc Dis 2006; 21: 279
71 Major Bleeding Complications SPORTIF III and V On-treatment Analysisp=0.054Event Rate (%/year)SPORTIF IIISPORTIF VPooledDiener H-C, et al. Cerebrovasc Dis 2006; 21: 279
72 SPORTIF III and V Liver Enzyme Elevations ALT >3 x ULN100WarfarinXimelagatran80Incidence (%)60Number of patients40ALT >3x ULN20123456789101112131516182127MonthsDiener H-C, et al. Cerebrovasc Dis 2006; 21: 279
73 Emerging Anticoagulants Potential Alternatives to Warfarin Thrombin inhibitorsDirect, oralXimelagatranDabigatran(RE-LY Trial)Factor Xa inhibitorsIndirect, parenteralIdraparinuxDirect, oralRivaroxabanApixabanEdoxabanothers
74 Oral Factor Xa Inhibitors Ongoing Phase III Trials for Prevention of Stroke and Systemic Embolism in Patients with AFTrialAcronymDrugDoseComparatorNRiskfactorsROCKET-AFRivaroxaban20 mg*qdWarfarin(INR 2-3)14,000≥ 2ARISTOTLEApixaban5 mgbid15,000≥ 1ENGAGE-AFEdoxaban30 mg bid60 mg* qd16,500* Adjusted based on renal function
75 Emerging Anticoagulants Regulatory Issues Open-label vs. blinded trial designIssues related to active-control trial designHow many trials are needed?Preventing use for unapproved indicationsAssessing patient-oriented outcomes
76 Alternatives to Anticoagulation Atrial Fibrillation Current approachesRestoration and maintenance of sinus rhythmAntiarrhythmic drug therapyCatheter ablationMaze operationEmerging (investigational) approachesObliteration of the left atrial appendageTrans-catheter occluding devicesThoracoscopic epicardial plicationAmputation
77 Strokes after Conversion to NSR Rate vs. Rhythm Control Trials Rate controlRhythm controlRR (95% CI)pAFFIRM4,9175.7%7.3%1.28 ( )0.12RACE5225.5%7.9%1.44 ( )0.44STAF2661.0%3.0%3.01 ( )0.52PIAF2520.8%1.02 ( )0.49Total5,9575.0%6.5%1.28 ( )0.08Take home point:Stroke risk persists even in patients in SR.Verheugt F, et al. J Am Coll Cardiol 2003;41(suppl):130A.
78 AFFIRM Trial Stroke Rates 74% of all strokes were proven ischemic44% occurred after stopping warfarin28% in patients taking warfarin with INR <2.042% occurred during documented AFTake home point:Nearly ¾ of all strokes were related to discontinuation or inadequate anticoagulation.Background:The percentage of patients receiving warfarin therapy was not as high in the AFFIRM study compared with RACE. The use of anticoagulants remained high in the rate-control group at each assessment (85%). However, there was a decrease in warfarin use in the rhythm-control group following the first 4 months of the study. However, the overall number of patients averaged approximately 70% throughout the trial in the rhythm-control group. The majority of patients taking warfarin therapy, regardless of randomization, fell into the recommended INR range of 2.0 to 3.0.Although the rate of ischemic stroke across both groups was low, approximately 1% per year, 74% of all strokes were ischemic. However, strokes tended to occur most often in patients who had ceased to take warfarin or who had a subtherapeutic INR. As the slide illustrates, 44% of ischemic strokes occurred following termination of warfarin therapy and 28% with an INR of less than 2.0. Only 42% of ischemic strokes occurred while a patient was still in AF. There was no significant difference between the 2 groups in rate of ischemic stroke: 5.5% in the rate-control arm and 7.1% in the rhythm-control arm. There was also no significant difference in the percentage of patients with ischemic stroke, primary intracerebral hemorrhage, subdural or subarachnoid hemorrhage, or disabling anoxic encephalopathy.Wyse AG, et al. N Engl J Med 2002; 347: 1825.
79 ATHENA Trial Dronedarone vs ATHENA Trial Dronedarone vs. Placebo in Patients with AF Stroke Rates (Secondary Analysis)EventPlacebo (%/y)Dronedarone (%/y)HR(95% CI)pStroke1.791.190.660.027Stroke or TIA2.051.370.670.020Fatal stroke0.540.360.247Hohnloser SH, et al. N Engl J Med 2009; 360:
80 Percutaneous LAA Occlusion The WATCHMAN® Device Syed T, Halperin JL. Nature Clin Prac Cardiovasc Med 2007; 4:428Holmes DR, et al. Lancet 2009; 374: 534
81 Alternatives to Anticoagulation Atrial Fibrillation Current approachesRestoration and maintenance of sinus rhythmAntiarrhythmic drug therapyCatheter ablationMaze operationEmerging (investigational) approachesObliteration of the left atrial appendageTrans-catheter occluding devicesThoracoscopic epicardial plicationAmputationIs atrial fibrillation the cause of strokeor a marker of a population at risk?
82 Atrial Fibrillation and Thromboembolism The Next Challenges Better tools to stratify bleeding riskNoninvasive imaging and biomarkers of inflammation and thrombosis to predict clinical events and guide therapyConfirming successful rhythm control over timeTargeted therapy to prevent AF in patients at risk
83 From Fermented Sweet Clover to Molecular Targeting of Coagulation The Promise of New Approaches The Goal:To bring effective therapy to many more patients and prevent thousands of strokes.
84 New Frontiers in Atrial Fibrillation Stroke Prevention in High Risk Populations The Journey from Warfarin to New Options and StrategiesElaine M. Hylek, MD, MPHAssociate Professor of MedicineDepartment of MedicineDirector, Thrombosis Clinic and Anticoagulation ServiceBoston University Medical CenterBoston, Massachusetts
85 Projected Number of Persons with AF in the U.S. Between 2000 and 2050 15.915.216141210864215.913.111.710.212.18.911.7Projected Number of Personswith AF (Millions)11.17.710.36.79.45.18.104.22.168.22.214.171.124YearAssumes no further increase in age-adjusted AF incidence (blue curve) and assumes a continued increase in incidence rate as evident in 1980 to 2000 (yellow curve)Miyasaka, Y. et al. Circulation 2006;114:
86 Atrial Fibrillation Morbidity and Mortality 4- to 5-fold increased risk of strokeDoubling of the risk for dementiaTripling of risk for heart failure40 to 90% increased risk for overall mortalityRisk of stroke in AF patients by age group1.5% in 50 to 59 year age group23.5% in 80 to 89 year age groupBenjamin EJ, et al. Circulation 2009;119:86
87 Prevalence of AF by Age 20 18 16 14 12 10 8 Prevalence (%) 6 4 2 Framingham StudyCardiovascular Health StudyMayo Clinic StudyWestern Australia StudyPrevalence (%)Age (years)Feinberg WM. Arch Intern Med. 1995;155(5):469–47387
88 Prevalence of CVD* in Adults by Age and Sex (NHANES: 2005-2006) *Coronary heart disease, heart failure, stroke and hypertensionSource: NCHS and NHLBI
89 Incidence of Heart Failure Incidence of Heart Failure* by Age and Sex (Framingham Heart Study: )* MD review of medical records using strict diagnostic criteriaSource: NHLBI
90 Prevalence of Heart Failure by Age and Sex (NHANES: 2005-2006) Source: NCHS and NHLBI
91 Prevalence of Dementia North America: 6.9% prevalence; 63% increase ; 151% increase
92 “The graying population will slowly, radically transform society “The graying population will slowly, radically transform society.” Richard Suzman, NIAMore than 37 million people are ≥ age 65.By 2030, this number will exceed 70 million.By 2040, those aged ≥75 years will exceed thepopulation 65 to 74 years old.By 2050, 12%, or 1 in 8 Americans, will beage 75 or older.
93 Polypharmacy in the Elderly Elderly = 12% of population;32% of prescriptionsAverage of 6 prescription medications;1 to 3.5 over-the-counter drugsAverage nursing home patienttakes 7 medicationsAverage American senior spends$670/year for pharmaceuticals
94 Pharmacokinetic and Pharmacodynamic Changes with Aging MetabolismGenerally, lower drug doses are required to achieve the same effectReceptor numbers, affinity, or post-receptor cellular effects may changeOverall decline in metabolic capacityDecreased liver massDecreased oxidative metabolism through P450 system decreased clearance of drugs
95 Kidney Function and Age 140130120110100Standard Creatine Clearanceml/min/1.73Age (years)Andres and Tobin, 1976
96 Adverse Drug Reactions About 15% of hospitalizations in the elderly are related to adverse drug reactionsThe risk of adverse drug reactions increases with the number of prescription medications
97 Intracranial Bleed Stroke INR Adjusted Odds Ratios for Ischemic Stroke and Intracranial Bleeding in Relation to Intensity of Anticoagulation15.0Intracranial BleedStroke10.0Odds Ratio5.01.01.02.03.04.05.06.07.08.0INRFuster et al. J Am Coll Cardiol. 2001;38:
98 Polypharmacy and Non-adherence Strongest predictor of non-adherence isthe number of medicationsNon-adherence rates estimated 25-50%Intentional about 75% of the timeChanges in regimen made by patients to:- Increase convenience- Reduce adverse effects or- Decrease refill expense
99 ≥ 58% ACTIVE W Trial VKA vs dual antiplatelet Rx Minimum threshold TTR necessary torealize benefit of warfarin:≥ 58%Circulation 2008;118. Connolly SJ for Active W Investigators
100 Results From SPORTIF III and V Comparison of Outcomes Among Patients Randomized to Warfarin According to Anticoagulant ControlResults From SPORTIF III and VTTR <60% TTR 60-75% TTR >75%OutcomeTTR < 60%TTR 60-75%TTR>75%Mortality, %4.21.841.69Major Bleed, %3.851.961.58Stroke/SEE,%2.101.341.07Arch Intern Med. 2007. White HD, Gruber M, Feyzi J, Kaatz S, Tse H, Husted S, Albers G
101 Hazards of Anticoagulant Medications #1 in 2003 and 2004 in the number of mentions of “deaths for drugs causing adverse effects in therapeutic use”1Warfarin-6% of 702,000 ADEs treated in ED per year; 17% require hospitalization121 million warfarin prescriptions in 1998>>>31 million in 20042The incidence AC-related intracranial hemorrhage quintupled during this time period31 Wysowski DK, et al. Arch Intern Med. 2007;167: Budnitz DS, et al. JAMA. 2006;296: Flaherty ML, et al. Neurology. 2007;68:
102 Major Hemorrhage Rates Randomized TrialsINR TargetICHMajorAgeAFI0.31.069SPAF II0.91.470AFFIRM----2.0RE-LY0.73.472ObservationalINR TargetICHMajorAgeVan der Meer, et al. (1993)0.62.066Palareti, et al (1996)0.50.962Go, et al (2003)1.071102
103 Caveats Relating to Published Data on HemorrhageRandomized trials- Enrolled few patients ≥ 80 years- Highly selected, closely monitored- Vitamin K antagonist at entryProspective cohort studies- Predominantly non-inception cohort studies ofprevalent warfarin use (survivor bias)- Varying definitions of bleeding- Most conducted within anticoagulation clinic setting103
105 Hylek EM et al, Circulation 2007;115(21):2689-2696. Cumulative Incidence of Major Bleeding in the First Year Among Patients Newly Starting Warfarin by AgeCumulative Proportionwith Major HemorrhageDays of WarfarinAge < 80 Age >=80Hylek EM et al, Circulation 2007;115(21):
106 Risk of Stopping Therapy in the First Year Among Patients Newly Starting Warfarin by AgeRisk of Stopping WarfarinDays of WarfarinAge < 80 Age >=80Hylek EM et al, Circulation 2007;115(21):
107 Major Hemorrhagic Events and Warfarin Terminations by CHADS2 Score Major Bleed (N)Bleeding Rates%Taken Off Therapy (N)Taken Off Rates4213.17515.8412144.351617.39218132.081913.16941219.72032.84≥434623.63935.44Total4722669Hylek EM et al, Circulation 2007;115(21):
108 How Do We Reconcile These Disparate Rates? Inception versus prevalent? Burden of hemorrhagic risk factors?Post-discharge versus outpatient?Prevalence of combination therapy?Degree of initial selection bias?Observation period?
109 Optimizing Benefit and Reducing Risk HemorrhageThrombosis
110 Bleeding Risk Scores for Warfarin Therapy LowModerateHighKuijer et al. Arch Intern Med 1999;159:457-601-3>31.6 x age x sex +2.2 x cancer with 1 point for ≥60, female or malignancy and 0 if noneBeyth et al.Am J Med 1998;105:91-91-2≥3≥65 years old; GI bleed in last 2 weeks; previous stroke; comorbidities (recent MI, Hct < 30%, diabetes, Creat > 1.5) with 1 point for presence of each condition and 0 if absentGage et al.Am Heart J 2006;151:713-90-12-3≥4HEMORR2HAGES score: liver/renal disease, ETOH abuse, malignancy, >75 years old, low platelet count or function, rebleeding risk, uncontrolled HTN, anemia, genetic factors (CYP2C9) risk of fall or stroke, with 1 point for each risk factor present with 2 points for previous bleedShireman et al.Chest 2006;130:1390-6≤1.07> <2.19>2.19(0.49 x age >70) + (0.32 x female) + (0.58 x remote bleed) x recent bleed) x ETOH/drug abuse) + (0.27 x diabetes) + (0.86 x anemia) + (0.32 x antiplatelet drug use) with 1 point for presence of each and 0 if absent110
111 Maintenance Warfarin Dose by Age INR Target 2-3 Derived from two independentambulatory populations5045403530252050454035302520Warfarin Weekly Dose, mgWarfarin Weekly Dose, mgACTION on left, ATU on right< >=90< >=90AgeAgeFemale MaleFemale MaleGarcia D, et al. Chest ;127:111
112 Hylek et al, Ann Intern Med. 2001;135:393-400 In this study, outpatients were identified with an INR greater than All patients were instructed to hold two doses of warfarin and return on Day 2 for a repeat INR measurement. The Figure displays the INR decay curves of these patients over the 48-hour period. On Day 2, 63% of patients had an INR less that 4.0 and 37% of patients had an INR of 4.0 or higher. Twelve percent of patients with an index INR between 6-9 had a subtherapeutic INR (less than 2.0) after holding two doses of warfarin.Hylek et al, Ann Intern Med. 2001;135:112
113 Risk Factors for INR > 4.0 After Holding Two Doses of Warfarin Adjusted Odds RatioWarfarin dose, weekly per 10 mg0.87 ( )Age, per decade1.18 (1.01 – 1.38)Decompensated heart failure2.79 (1.30 – 5.98)Active malignancy2.48 (1.11 – 5.57)Index INR, per unit1.25 (1.14 – 1.37)Risk factors associated with prolonged return to the therapeutic range following an INR of 6.0 or greater included older age, lower warfarin dose requirements, decompensated heart failure, an actively treated malignancy, and degree of elevation of the index INR. For each decade of age, the risk of having an INR greater than 4.0 on Day 2 increased by 18%. The clinical implications of this study are that elderly patients, especially those who require lower doses of warfarin to attain an INR of , are at highest risk for prolonged exposure to risk-laden levels of anticoagulation.113
114 Causes of Elevated INRs InitiationDecreased vitamin K intakePotentiating MedicationsDecompensated heart failureChemotherapyWarfarin dosing errorBinge alcohol consumption
115 Risk of UGIB with Different Combinations of Antithrombotic Agents Mean age=72 yearsHallas J, et al. BMJ doi: /bmj AE115115
116 Strategies To Minimize Risk Of HemorrhageTHE FACTS:Incidence of UGIB and LGIB increases with age.70% of acute UGIB occur > 60 years of age.Differential mucosal effect of ASA by ageIncidence of LGIB increases 200-fold from the3rd to 9th decade of life: diverticulosis, angiodysplasias, ischemic colitis, malignancyRevised Guidelines for the Management of Patients with Atrial Fibrillation were published in August 2006.116
117 Strategies to Improve Quality of VKA-Based Anticoagulant Therapy Vigilant monitoring around all transitions in careInitiate lower doses in most susceptible patient subsetsIncrease monitoring with medication changesReinforce safety points with patients and caregiversJustify use of concomitant antiplatelet therapyPromise of novel anticoagulants117
118 Incidence of Intracranial Hemorrhage Dabigatran vs Warfarin (RE-LY) Anticoagulant/DoseICHRRPDabigatran 110 mg BID0.23%0.29<0.001Dabigatran 150 mg BID0.30%0.41Warfarin (open label)0.74%REFConnolly et al., NEJM, 2009118
120 Summary Points and Conclusions Elderly patients with AF are at the highest risk of stroke and the highest risk of hemorrhage.Rates of ischemic stroke significantly exceed rates of ICH and major extracranial hemorrhage on OAC.Intensive efforts to optimize OAC will help to decrease major bleeding.Novel anticoagulants may be safer in the elderly population due to their wider therapeutic index, shorter t1/2, lack of dietary interference, and fewer drug interactions..120
121 New Frontiers in Atrial Fibrillation The Emerging Role ofNew Oral AnticoagulantsLandmark Trials That MayAlter the Landscape of Stroke Prevention in AFJeffrey I. Weitz, MD, FRCP, FACPProfessor of Medicine and BiochemistryMcMaster UniversityDirector, Henderson Research CenterCanada Research Chair in ThrombosisHeart and Stroke FoundationJ.F. Mustard Chair in Cardiovascular Research
122 Overview of Presentation Limitations of warfarinNew oral anticoagulantsRole of new agents in AF
123 Limitations of Warfarin ConsequenceSlow onset of actionOverlap with a parenteral anticoagulantGenetic variation in metabolismVariable dose requirementsMultiple food and drug interactionsFrequent coagulation monitoringNarrow therapeutic index
124 New Oral Anticoagulants for Stroke Prevention in AF Direct Inhibitors of Factor Xa or Thrombin
125 Comparison of Features of New Oral Anticoagulants in Advanced Stages of DevelopmentFeaturesRivaroxabanApixabanDabigatran EtexilateTargetXaIIaMolecular Weight436460628ProdrugNoYesBioavailability (%)80506Time to peak (h)32Half-life (h)99-1412-17Renal excretion (%)6525AntidoteNone
126 Comparison of Features of New Anticoagulants With Those of Warfarin New AgentsOnsetSlowRapidDosingVariableFixedFood effectYesNoDrug interactionsManyFewMonitoringHalf-lifeLongShortAntidote
127 RE-LY: A Non-inferiority Trial •Atrial Fibrillation with ≥ 1 Risk Factor• Absence of Contraindications• Conducted in 951 centers in 44 countriesRRBlinded Event AdjudicationOpenOpenBlindedStatistical testing in the RE-LY Study:Primary endpoint:Non-inferiority design allowing for statistical analysis of superiority once non-inferiority is achievedAll other endpoints:Superiority testing.P < 0.05 superior (95% CI is below 1)P > 0.05 comparable (if 95% CI includes 1)WarfarinAdjustedINR 2.0 – 3.0N=6000Dabigatran etexilate mg BID N=6000Dabigatran etexilate mg BID N=6000
128 RE-LY: Baseline Characteristics Dabigatran mgDabigatran mgWarfarinRandomized601560766022Mean age (years)71.471.571.6Male (%)64.363.263.3CHADS2 score (mean)0-1 (%)(%)3+ (%)2.132.634.7126.96.36.199.230.937.032.1Prior stroke/TIA (%)19.920.319.8Prior MI (%)16.816.916.1CHF (%)31.831.9Baseline ASA (%)40.038.740.6Warfarin Naïve (%)49.949.851.4Connolly et al., NEJM, 2009
129 RE-LY: Stroke or Systemic Embolism 0.500.751.001.251.50Dabigatran 110 vs. WarfarinDabigatran 150 vs. WarfarinNon-inferiorityp-value<0.001Superiority0.34Margin = 1.46HR (95% CI)Dabigatran betterWarfarin betterConnolly et al., NEJM, 2009
130 RE-LY: Annual Rates of Bleeding Dabigatran110mg150mgWarfarinDabigatran 110mg vs. WarfarinDabigatran 150mg vs. Warfarinn601560786022RR95% CIpTotal14.6%16.4%18.2%0.78<0.0010.910.002Major2.7 %3.1 %3.4 %0.800.0030.930.31Life-Threatening1.2 %1.5 %1.8 %0.680.810.04Gastro-intestinal1.1 %1.0 %1.100.431.50Connolly et al., NEJM, 2009
132 Targeted inhibition of thrombin How can dabigatran be more effective than warfarin yet cause less bleeding?Targeted inhibition of thrombinConsistent and predictable anticoagulant effect
133 RE-LY: Secondary Efficacy Outcomes According to Treatment Group EventDabigatran 110 mgDabigatran 150 mgWarfarinMyocardial infarction0.7%0.5%Vascular death2.4%2.3%2.7%All-cause mortality3.8%3.6%4.1%Connolly, et al. N Engl J Med 2009;361:
134 RE-LY: Cumulative risk of ALT or AST >3x ULN after randomization 0.040.03WarfarinCumulative risk0.02Dabigatran 110 mgDabigatran 150 mg0.010.00.51.01.52.02.5Years of follow-upConnolly, et al. N Engl J Med 2009;361:134
135 Which Dose for Which Patient? Lower-dose regimenElderlyRenal insufficiencyLower stroke risk (CHADS2 score of 1)Higher-dose regimenHigher stroke risk (CHADS2 score ≥ 2)
136 Meta-analysis of Ischemic Stroke or Systemic Embolism W vs placeboW vs W low doseW vs ASAW vs ASA + clopidogrelW vs dabigatran 1500.30.60.91.188.8.131.52Favours warfarinFavours other treatmentCamm J.: Oral presentation at ESC on Aug 30th 2009.
137 What About Trials with Other New Oral Anticoagulants? ROCKET – RivaroxabanARISTOTLE – ApixabanENGAGE - Edoxaban
138 Is Warfarin Obsolete?New oral anticoagulants are more convenientBut, warfarin effective when time in therapeutic range is high
139 Cumulative risk of stroke, myocardial infarction, systemic embolism, or vascular death for patients treated at centers with a TTR below or above the study median (65%)1210864212108642TTR < 65%TTR >= 65%RR=0.93 ( )p=0.61RR=2.14 ( )P=0.0001Event Rate (%)Event Rate (%)C+AOACC+AOACYearsYearsConnolly, S. J. et al. Circulation 2008;118:
140 Time in Therapeutic Range (TTR) with Warfarin in the RE-LY Trial GroupRelative RiskOverall64%VKA Experienced61%VKA Naïve67%
141 Relative Risk of Stroke or Systemic Embolism with Dabigatran Versus Warfarin According to Geographical RegionHazard Ratio withDabigatran, 100mg (95% CI)P ValueforInteractionHazard Ratio withDabigatran,150 mg (95% CI)P ValueforInteractionPatientstotal no.DabigatranWarfarinSubgroup110 mg150 mgAll patients18,Long-term VKAtherapy0.720.81No9,Yes8,Region0.910.11North America6,South America1,Western Europe3,Central Europe2,South Asia1,East Asia1,Other1,0.51.01.50.51.01.5Dabigatran BetterWarfarin BetterDabigatran BetterWarfarin BetterConnolly et al., NEJM 2009
142 Who is Not a Candidate for Dabigatran? Stable on warfarinRenal impairmentSevere hepatic diseasePoor compliance
143 Unanswered QuestionsManagement of patients with severe coronary artery disease or recent GI bleeding?Will short half-life obviate need for antidotes?Will elimination of monitoring adversely impact patient care?
144 Conclusions: RE-LY and New, Oral Non-Monitored Anticoagulation Dabigatran etexilate is superior to warfarin for stroke preventionDosing of new oral anticoagulants is critical: are the doses of factor Xa inhibitors optimal?New oral anticoagulants will replace warfarin, but transition may be slow
145 New Frontiers in Atrial Fibrillation Atrial Fibrillation Current Challenges in Thrombosis Medicine for the Cardiovascular Specialist Discussion, Comments, and The Way ForwardSamuel Z. Goldhaber, MDCardiovascular DivisionBrigham and Women’s HospitalProfessor of MedicineHarvard Medical School
146 Warfarin is Not Just Sitting Around It is fighting back with:Excellent efficacy (ACTIVE)Pharmacogenetics analysisPoint-of-care testingLow costTrack Record (approved in 1954)
147 The “Red Line” in the Sand Can rapid turnaround genetic testing reduce the “Educated Guessing Game” and “Play of Chance” in warfarin dosing?
148 Warfarin Pharmacogenomics Cytochrome P450 2C9 genotyping identifies mutations associated with impaired warfarin metabolism.Vitamin K receptor polymorphism testing can identify whether patients require low, intermediate, or high doses of warfarin.Schwartz UI. NEJM 2008; 358: 999
149 Percent with Dose Estimates within 20% of Actual Dose Pharmacogenetic Algorithm versus Clinical Algorithmversus Fixed-Dose ApproachFigure 2. Percentage of Patients with Dose Estimates within 20% of the Actual Dose, as Derived with the Use of a Pharmacogenetic Algorithm, a Clinical Algorithm, and a Fixed-Dose Approach. The dose estimates are shown according to three actual-dose groups: low-dose (<=21 mg per week), intermediate-dose (>21 to <49 mg per week), and high-dose (>=49 mg per week). The fixed dose was 35 mg per week. With the fixed-dose approach, none of the estimates for the patients in the low-dose and high-dose groups were within 20% of the actual dose. Panel A shows data for the validation cohort (1009 patients), and Panel B for the derivation-plus-validation cohorts (5052 patients).Warfarin Pharmacogenetics Consortium. NEJM 2009;360:
150 Genotype vs Standard Warfarin Dosing (N=206) Couma-Gen TrialRapid turnaround CYP2C9 and VKORC1 testing vs. “empiric”Primary endpoint: TTRSmaller and fewer dosing changes with genetic testingNo difference in TTRCirculation 2007; 116:
153 Warfarin Pharmacogenetics Routine use of CYP2C9 andVKORC1 genotyping in patientswho begin warfarin therapyis not supported by evidencecurrently available.Pharmacotherapy 2008; 28:
154 Genetic Testing for Warfarin Remains Unproven: NHLBI Trial About 1,200 Patients will be randomized to:Genetic plus clinical guided nomogram, versusClinically-guided nomogramResults will be available in 2012
155 NHLBI Trial:Primary Endpoint: % Time in Therapeutic Range (TTR) Hypothesis: 60% TTR in Clinical arm versus > 72% TTR in Genetics Plus Clinical Nomogram armClinical Trials # NCT
156 Self-Monitoring INR Meta-analysis of 14 RCTS Reduced TE events (55% fewer)Reduced all-cause mortality (39% less)Reduced major bleeds (35% fewer)Benefits increase further with self-dosing73% fewer TE events63% lower all-cause mortalityHeneghan C. Lancet 2006; 367:
157 Medicare used to cover only mechanical heart valves March 19, 2008: Medicare Expanded Reimbursement for Home INR MonitoringMedicare used to cover only mechanical heart valvesNow will reimburse VTE (after 3 months of warfarin) and permanent atrial fibrillationAetna follows new Medicare guidelines (and surely others will, too)
158 Will Novel Anticoagulants Warrant Additional Costs? Does this require deconstruction, demobilization, and/or reconstruction of anticoagulation management services?Will patients require monitoring of renal/ hepatic function?
159 Novel Oral Anticoagulants Noninferiority may not suffice, but superiority findings (150 mg dose) in RE-LY are encouraging.Superiority may be necessary to alter prescribing behavior.More trials will be forthcoming.Beware of off-label use.
160 RE-LY: Stroke or Systemic Embolism 0.500.751.001.251.50Dabigatran 110 vs. WarfarinDabigatran 150 vs. WarfarinNon-inferiorityp-value<0.001Superiority0.34Margin = 1.46HR (95% CI)Dabigatran betterWarfarin betterConnolly et al., NEJM, 2009160
161 RE-LY: Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism 0.050.040.030.020.010.001.00.184.108.40.206.0WarfarinDabigatran110 mgDabigatran150 mgWarfarinDabigatran 110 mgDabigatran 150 mgConnolly, et al. N Engl J Med 2009;361:161
162 Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY Hazard Ratio withDabigatran, 110 mg(95% CI)Hazard Ratio withDabigatran, 150 mg(95% CI)Dabigatran Better Warfarin BetterDabigatran Better Warfarin BetterConnolly, et al. N Engl J Med 2009;361:162
163 Relative Risk of Stroke or Systemic Embolism with Dabigatran versus Warfarin: RE-LY Hazard Ratio withDabigatran, 110 mg(95% CI)Hazard Ratio withDabigatran, 150 mg(95% CI)Connolly, et al. N Engl J Med 2009;361:163
164 RE-LY: Analysis and Comments RE-LY participants who were randomly assigned to receive warfarin would have needed to have an INR time within the therapeutic range (TTR) approximately 79% of the time to have a stroke rate as low as that in the group receiving 150 mg of dabigatran.Even with diligent, patient self-monitoring or pharmacogenetic dosing, such tight control is unlikely in real world practice.Gage, B N Engl J Med 361;12 nejm.org September 17, 2009 Connolly SJ, Pogue J, Eikelboom J, et al. Circulation 2008;118:202937. 164
165 Time in Therapeutic Range (TTR) in Community-Based Practice: Ranges101 Community-Based Practices in 38 States (1)Mean TTR was 66.5%, but varies widely, with 37% having TTR above 75%, and 34% with TTR below 60%Mean TTR for new warfarin users (57.5%) lower than prevalent users for first six monthsTTR of patients with warfarin interruptions had TTR of 61.6%TTR rates vary widely and are affected by new warfarin use, procedural interruptions and INR target range Meta-Analysis (2)TTR was 55% Rose, AJ Thromb Haemost. 2008 Oct;6(10):Baker WL et al, J Manag Care Pharm. 2009 Apr;15(3):244-5165
166 RE-LY: Analysis and Comments To prevent one nonhemorrhagic stroke, the number of patients who would need to be treated with dabigatran at a dose of 150 mg twice daily, rather than warfarin, is approximately 357.The number of patients who would need to be treated with dabigatran (rather than warfarin) to prevent one hemorrhagic stroke is approximately 370.166
167 Discussion: Novel Oral Anticoagulants Where Do We Stand, November 12, 2009?1. “In summary although there are qualifications, we can rely on RE-LY.”Brian F. Gage, MD (NEJM, September 17, 2009, RE-LY Editorial)2. The RE-LY Trial represents the most compelling evidence to date for revising, reconsidering, and reshaping our current VKA-based paradigm for stroke prevention in AF.
168 Discussion: Novel Oral Anticoagulants Discussion, Questions, and Comments