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1 and Knowledge Gap Assessment Tool in your syllabus. Thank you. Please take this time to complete the Pre-Program Performanceand Knowledge Gap Assessment Tool in your syllabus. Thank you.
2 Thrombosis Reduction for Heart Disease Thrombosis Risk Reduction: An OverviewNew Frontiers inThrombosis Reduction for Heart DiseaseFocus on Novel Agents Across the ACS and AF Risk Spectrum—A Year 2010 Advanced Practice Summitfor the Cardiovascular SpecialistDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIProgram ChairmanChief of Cardiology, VA Boston Healthcare SystemDirector, Integrated Interventional Cardiovascular ProgramBrigham and Women’s Hospital and the VA Boston Healthcare SystemAssociate Professor of Medicine, Harvard Medical SchoolSenior Investigator, TIMI Group
3 Welcome and Program Overview CME-certified symposium jointly sponsored by the Postgraduate Institute of Medicine and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from the Bristol-Myers Squibb/Pfizer Partnership Faculty disclosures: Listed in program syllabus
4 Program Faculty Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI Program ChairmanChief of Cardiology, VA Boston HealthcareSystemDirector, Integrated InterventionalCardiovascular ProgramBrigham and Women’s Hospital and the VABoston Healthcare SystemAssociate Professor, Harvard Medical School Senior Investigator, TIMI GroupBoston, Massachusetts USAGregory Y.H. Lip, MD, FRCP, FACC, FESCConsultant Cardiologist and Professor ofCardiovascular MedicineDirector, Haemostasis Thrombosis &Vascular Biology UnitUniversity of Birmingham Centre forCardiovascular SciencesCity HospitalBirmingham, EnglandShamir Mehta, MD, MSc, FACC, FRCPCDirector, Interventional CardiologyHamilton Health SciencesAssociate ProfessorMcMaster UniversityHamilton, Ontario, CanadaDavid A. Garcia, MDAssociate Professor, Division of General InternalMedicineUniversity of New MexicoCo-Director, University of New Mexico Anticoagulation Management ServicePresident, Anticoagulation ForumAlbuquerque, New Mexico USARichard C. Becker, MDProfessor of MedicineSchool of MedicineDuke UniversityDirector, Duke Cardiovascular Thrombosis CenterDuke Clinical Research InstituteDurham, North Carolina USA
5 Issues We Will AddressChanging landscape for AFIB with Factor II and Xa inhibitors, and how cardiologists will respondThe various risk groups for AFIB including de novo patients, patients who have failed coumadin for one reason or another (erratic TTRs or bleeding) and patients who do not want to take coumadin or are not deemed suitable candidatesPushing the envelope on ACS prevention with triple therapy and whether non-coumadin systemic anticoagulation might offer the opportunity to more favorably balance the benefit-to-risk ratio, a possibility given the reduced ICH and major bleed rate with low-dose dabigatran
6 Issues We Will AddressWill "milder, gentler" but non-inferior, and perhaps superior oral, non-monitored anticoagulation offer new opportunities and new challenges for risk stratifying subsets of patients with AF and ACS?Is warfarin on the path to extinction or will it reinvent itself with the aid of pharmacogenomic guidance, algorithm-directed care, patient self-monitoring, and a host of “let's make coumadin as good as we can” maneuvers?
7 Atrial Fibrillation and ACS: The Changing Antithrombotic Landscape New Dimensions andLandmark Practice AdvancesAtrial Fibrillation and ACS: The Changing Antithrombotic LandscapeDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIChief of Cardiology,VA Boston Healthcare SystemDirector, Integrated Interventional Cardiovascular Program, Brigham and Women’s Hospital and the VA Boston Healthcare SystemAssociate Professor of Medicine, Harvard Medical SchoolSenior Investigator, TIMI GroupBoston, Massachusetts
9 Polyvascular Disease: ~15% of Patients with Stable Atherosclerosis ~25% of Patients with CAD Also Have Disease in Other Arterial TerritoriesCAD = coronary artery diseasePAD = peripheral arterial diseaseCVD = cerebrovascular diseaseCADThis slide shows the incidence of symptomatic disease in additional arterial beds in patients with documented coronary artery disease (CAD). Percentages shown are of total REACH population.The CAD population comprises 59.3% of the total REACH Registry population.144.6% have CAD alone8.4 % also have cerebrovascular disease (CVD)4.7% also have peripheral arterial disease (PAD)In total, 1.6% of the REACH Registry population have CAD, CVD and PAD.1Reference1. Bhatt DL et al, for the REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180–189.8.4%CVD1.6%4.7%PADBhatt DL, Steg PG, Ohman EM, et al, on behalf of the REACH Investigators. JAMA 2006;295:
10 One-Year CV Event Rates Increase with Number of Symptomatic Disease Locations Patients (%)The risk of major adverse cardiovascular event clearly increases with increased symptomatic arterial bed involvement.This provides further support for the overlap of symptomatic locations affecting and increasing event rates, rather than only initial symptomatic bed.Asymptomatic patients with ≥3 risk factors are classified as 0; even in the presence of asymptomatic carotid plaque or reduced ankle brachial index (ABI). Indeed, only considering symptomatic polyvascular disease may have resulted in an underestimation of the impact of polyvascular disease.1Percentage rates are adjusted for age, gender, smoking, diabetes, hypertension and hypercholesterolemia.1Atherothrombotic events include:transient ischemic attackunstable anginaother ischemic arterial events including worsening of peripheral arterial disease1Reference1. Steg G et al, on behalf of the REACH Registry Investigators. One Year Cardiovascular Event Rates in Outpatients with Atherothrombosis. JAMA 2007; 297 (11):CV DeathNon-Fatal MINon-Fatal StrokeCV Death/ MI/StrokeCV Death/ MI/Stroke/Hosp*MI=myocardial infarction;*Such as transient ischemic attack, unstable angina, worsening of peripheral arterial disease; adjusted for age and genderSteg PG, Bhatt DL, Wilson PF, et al, on behalf of the REACH Investigators. JAMA 2007;297:
11 ATRIA: Prevalence of AF Increases with Age 12108Prevalence (%)64The Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study was a cross-sectional analysis of 1.89 million adults aged 20 years or older enrolled in a large group-model health maintenance organization.The total prevalence of AF was 0.95%.It is estimated that there are currently 2.3 million US adults with AF.2<5555-5960-6465-6970-7475-7980-84≥85Age (years)Men (n = 10,173)Women (n = 7801)AF = atrial fibrillationGo AS et al. JAMA. 2001;285:
12 Atrial Fibrillation and Atherothrombosis: Risks and Management Goto S, Bhatt DL, Röther J, Alberts M, Hill MD, Ikeda Y, Uchiyama S, D’Agostino R, Ohman EM, Liau C-S, Hirsch AT, Mas J-L, Wilson PWF, Corbalán R, Aichner F, Steg Ph G, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
13 Atrial Fibrillation in CAD: Prevalence in the REACH Registry 37,724 stable outpatients with CADAF, atrial fibrillation. Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
14 Atrial Fibrillation Rates by Patient Group Greater incidence of AF in patients with vascular disease compared with patients with risk factors onlyGoto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
15 CV Event Frequency in AF and non-AF Patients Combined event of CV death and/or nonfatal MI and/or nonfatal stroke in patients with vs without history of AF are shown after adjustment of age, gender, and classical risk factorsPatients with a history of AF10Event rate of CV death/MI/Stroke (%)AFNon-AF524681012Time (months)Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
16 Atrial Fibrillation in CAD 37,724 patients with CAD: 12.5% prevalence of atrial fibrillationP <P <Patients (%)P <Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
17 Annual Rate of CV Death in AF and Non-AF Patients *********The rates of combined end points of CV death, non fatal myocardial infarction and non fatal stroke are two times more in AF group than non AF group and results are consistent in all symptomatic patients subgroup.*p<0.05**p<0.01Multivariate analysis
18 CHADS2 Score Defined and Validated to Predict Stroke in Atrial Fibrillation Patients 1-y Stroke rate613.7%512.3%410.9%38.6%24.5%12.2%0.8%pointsCongestive HF1HypertensionAge > 75 yrDiabetesStroke2SumGage BF, JAMA 2001;285(22):Gage BF, Circulation 2004;110;
19 Annual CV Event Risk in AF Patients by CHADS2 Score CHADS2 score classification was useful in predicting not only stroke but also CV death in stable outpatients with or at high-risk for atherothrombosis, but not as useful in the prediction of nonfatal MIAnnual event rate (%)CHADS2 scoreGoto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
20 Annual Rate of Serious Bleeding in AF Patients with/without Anticoagulant 4,725 stable CAD outpatients with atrial fibrillationP =Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
21 Medication Use and Risk Factor Control in AF and Non-AF Patients Approximately 50% of patients with AF receive anticoagulation therapy. Oral anticoagulants are underused in patients who have a history of AFVariable, %AF +(n=6,814)AF – (n=56,775)P valueAspirin49.5169.44<Any two antiplatelet agents9.6613.58Oral anticoagulants36.173.83At least one lipid lowering agent87.7489.77At least one CV agent97.5895.67At least one anti-diabetic agent81.7686.85Goto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
22 SummaryHigh prevalence of AF among patients with or at high-risk of atherothrombosisLower use of oral anticoagulants in AF patients even though they have risk factors for ischemic stroke, probably due to the use of antiplatelet agents for the treatment of atherothrombosis1-year follow-up data show that the presence of AF was associated with serious and multiple CV events including a higher rate of all-cause and CV mortality, nonfatal stroke and a modest increase in the risk of nonfatal MI and unstable anginaThere is a need for the optimal antithrombotic therapy among AF patients to be clarified to balance the increased risk of thrombotic events and the increased risk of bleeding associated with combined anticoagulant and antiplatelet therapyGoto S et al, on behalf of the REACH Registry Investigators. Am Heart J 2008;156:
23 Design of ACTIVE Program Documented AF + 1 risk factor for strokeUnsuitable for VKAACTIVE WC and ASA vs VKAACTIVE AC and ASA vs ASAACTIVE is a phase III, multicenter, multinational, parallel randomized controlled evaluation of clopidogrel plus ASA, with factorial evaluation of irbesartan, for the prevention of vascular events in patients with atrial fibrillation.Patients will be enrolled over 2 years and followed to common termination date (expected to be about 4 years after enrollment of the first patient).About 14,000 patients will be included in the ACTIVE W or ACTIVE A trials. Due to the partial factorial design, patients will only be randomized in ACTIVE I once first randomized into either ACTIVE A or ACTIVE W.Three separate but related trials are included in the ACTIVE study. These are known as ACTIVE W, ACTIVE A, and ACTIVE I.ACTIVE W (n= 6,500): A multicenter, prospective, randomized, non-inferiority trial of clopidogrel plus ASA versus standard care oral anticoagulation (open trial with blinded outcome evaluation).ACTIVE A (n= 7,500): A multicenter, randomized, double-blind, placebo-controlled superiority trial of clopidogrel plus ASA versus ASA alone.ACTIVE I (n= at least 10,000): A multicenter, partial factorial, randomized, double-blind, placebo-controlled superiority trial of irbesartan.No exclusion criteria for ACTIVEACTIVE Iirbesartan vs placebo2323
24 ACTIVE-W Results Stopped early because OAC was clearly superior Annual Event Rate, %ASA + ClopidogrelOACRRR (%)P ValuePrimary outcome5.63.9300.0003Ischemic stroke2.151.053<0.0001MI0.860.55360.09Major bleed220.127.116.11.53ACTIVE Writing Group of the ACTIVE Investigators et al. Lancet. 2006;367:1903.
25 ACTIVE A: Primary Outcome Stroke, MI, Non-CNS Systemic Embolism, Vascular DeathP=0.01Cumulative incidenceASA onlyClopidogrel + ASA1234YearsACTIVE Investigators et al. N Engl J Med. 2009;360:2066.
26 ACTIVE A: Stroke ASA only Clopidogrel + ASA Cumulative incidence Years 1234YearsACTIVE Investigators et al. N Engl J Med. 2009;360:2066.
27 ACTIVE A: Bleeding Rates ASA (%/year)Clopidogrel + ASA (%/year)P ValueMajorSevereFatal1.31.00.22.01.50.3<0.0010.07Minor1.43.5Any5.79.7ACTIVE Investigators et al. N Engl J Med. 2009;360:2066.
28 Therapeutic INRs With Warfarin in Clinical Trials Annual Event Rates in Warfarin GroupTrialYear PublishedBaseline Systolic BPINR in Therapeutic Range (%)Warfarin-Naive (%)Ischemic Stroke (%)Total Stroke (%)Hemorrhagic Stroke (%)SPAF III199614061418.104.22.168SPORTIF III200313966272.30.4SPORTIF V20051326822.214.171.124ACTIVE W200613364231.01.4Connolly et al. Circulation. 2007;116:449.
29 ACTIVE W: Benefit of OAC by Time in Therapeutic Range Stroke, MI, Non-CNS Systemic Embolism, Vascular DeathStrokeStrokeTTR <65%TTR ≥65%TTR <65%TTR ≥65%RR = 0.93 ( ) P=0.61RR = 2.14 ( ) P<0.0001RR = 1.22 ( ) P=0.42C + ASAC + ASARR = 2.25 ( ) P=0.0003C + ASAEvent rate (%)Event rate (%)OACC + ASAOACOACOACYearsYearsYearsYearsNo. at RiskC + ASA159815271156439OAC160015251152417173716251233488177116971306507159815331164441160015311156419173716351255500177117021311511Connolly et al. Circulation. 2008;118:2029.
30 RE-LY: A Noninferiority Trial •Atrial Fibrillation with ≥ 1 Risk Factor for Stroke• Absence of Contraindications• Conducted in 951 centers in 44 countriesRRBlinded Event AdjudicationOpenOpenBlindedWarfarinAdjustedINR 2.0 – 3.0N=6000Dabigatran etexilate mg BID N=6000Dabigatran etexilate mg BID N=6000Connolly et al. N Engl J Med. 2009;361:1139.
31 RE-LY: Primary Outcome Stroke or Systemic EmbolismWarfarinDabigatran110 mgaCumulative hazard rateDabigatran150 mgbMonthsaP=0.34 vs warfarin.bP<0.001 vs warfarin.Connolly et al. N Engl J Med. 2009;361:1139.
32 Oral Direct Factor Xa Inhibitors Currently in Development DrugHalf-life (Hours)BioavailabilityElimination (%)DosingRenalHepaticApixaban12502575Twice DailyBetrixaban1947100Once DailyEdoxaban6-12100%6235Rivaroxaban5-9803367YM15018-2025-82NROnce/Twice
33 Novel Oral Direct Factor Xa Inhibitors for Stroke Prevention in AF TrialNTreatment ArmsPrimary End Point(s)ROCKET-AF14,000Rivaroxaban 20 mg qd vs warfarinStroke and systemic embolismARISTOTLE18,000Apixaban 5 mg bid vs warfarinAVERROES5600Apixaban 5 mg bid vs aspirin(in patients deemed unsuitable or inappropriate for warfarin: superiority trial)ENGAGE AF – TIMI 4816,500Edoxaban 30 mg qd and 60 mg qd vs warfarin33
34 Thrombosis Risk Reduction in AF Need to weigh thrombotic, ischemic, and bleeding risks in atrial fibrillation patientsAnticoagulation preferred if it can be done wellAntiplatelet therapy has a role in some patientsNovel agents likely to provide more options, perhaps even better efficacy and safety; including in patients who are not suitable candidates for VKA
35 New Dimensions andLandmark Practice AdvancesChallenges and Emerging Dimensions of Stroke Prevention in the Setting of Atrial Fibrillation (AF) Achieving Balance Between Thromboprophylaxis and Bleeding ReductionGregory Y.H. Lip, MD FRCP FACC FESCProfessor of Cardiovascular Medicine, University of BirminghamVisiting Professor of Haemostasis Thrombosis & Vascular Sciences,University of AstonCentre for Cardiovascular Sciences City Hospital Birmingham, England UK
36 Independent Predictors of Stroke in AF: A Systematic Review Multivariately significantAdjusted relative risk (95% CI)Prior stroke or TIA5 of 5 studies2.5 (1.8–3.5)Increasing age6 of 6 studies1.5/decade (1.3–1.7)History of hypertension or systolic BP >160 mmHg2.0 (1.6–2.5)Diabetes4 of 4 studies1.8 (1.5–22)Female gender3 of 6 studies1.6 (1.4–1.9)Heart failure0 of 4 studies*Not significantCoronary artery disease0 of 4 studies*Significant in a subgroup of AFI pooled analysis participants who underwent echocardiographyThe Stroke Risk in AF Working Group. Neurology 2007;69:546–554
37 Stroke Risk Stratification in AF Past and Present Lip and Tse. Lancet 2007 August 18;370(9587):604-18
38 EHS: Antithrombotic Drug Prescription per Risk Category ACC/AHA/ESC guidelines (A), ACCP (B), CHADS2 score (C), and Framingham score (D).Eur Heart J , 3018–3026
39 Potentially Preventable Strokes High-Risk Patients with AF Who Are Not Adequately AnticoagulatedPreadmission medications in patients with known atrial fibrillation who were admitted with acute ischemic stroke (high-risk cohort, n=597)‘In high-risk patients with AF admitted with a stroke …. most were either not taking warfarin or were subtherapeutic at the time of ischemic stroke. …..’Preadmission medications in patients with known atrial fibrillation and a previous ischemic stroke/TIA who were admitted with acute ischemic stroke (very high-risk cohort, n=323)Gladstone et al Stroke 2008
40 Published Bleeding Risk Scores 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 absentTay, Lane & Lip Thromb Haemost 2008; 100: 955–957
41 Major Hemorrhage and Tolerability of Warfarin First Year of Therapy Among Elderly Patients With AFMajor BleedTaken Off TherapyCHADS2 ScoreNRate(per 100 person-years)95% CI13.120.08 to 17.38515.5944.281.17 to 10.961617.129.79 to 27.81232.040.42 to 5.961912.927.78 to 20.181219.5410.10 to 34.132032.5619.89 to 50.29>4623.428.59 to 50.97935.1216.06 to 66.68Total2669Distribution of Major Hemorrhagic Events and Warfarin Terminations Due to Perceived Safety Concerns by CHADS2 ScoreHylek et al Circulation. 2007;115:
42 Risk Factors for Anticoagulation-Related Bleeding Complications in Patients with Atrial Fibrillation A Systematic ReviewSystematic review for NICE guideline [www.nice.org.uk]9 studies identifiedThe following patient characteristics were identified as having supporting evidence for being risk factors for anticoagulation-related bleeding complications:Advanced ageUncontrolled hypertensionHistory of myocardial infarction or ischaemic heart diseaseCerebrovascular diseaseAnaemia or a history of bleeding, andThe concomitant use of other drugs such as antiplatelet agentsThe presence of diabetes mellitus, controlled hypertension and gender were not identified as significant risk factors.Some of the risk factors for anticoagulation-related bleeding are also indications for the use of anticoagulants in AF patientsHughes and Lip QJM. 2007;100(10):
43 Combining the CHADS2 and HEMORR2HAGES Scores for Guiding Antithrombotic Prophylaxis in AF Clinical Usefulness in Geriatrics Patients252015105N=83Mean age89.2+/-4.9 yearsEvents/year (%)ScoreOne year stroke risk for 100 patients without anticoagulation according to CHADS2Major hemorrhage risk for 100 patients with anticoagulation according to HEMORRH2AGES‘The clinical usefulness of using the two scores seems poor since they indicated that two-thirds of the patients had a similar risk of hemorrhagic and ischemic events.’Somme et al Aging Clin Exp Res as DOI: /6709
44 Choosing Antithrombotic Therapy for Elderly Patients with AF Who are at Risk for Falls A Markov decision analytic modelFor patients with average risks of stroke and falling …Warfarin therapy associated with quality-adjusted life-years per patient;Aspirin therapy, quality-adjusted life-years; andNo antithrombotic therapy, quality-adjusted life-years.‘Elderly persons who fall have a mean of 1.81 falls per year.… Given that the risk of SDH must be 535-fold or greater for the risks of warfarin therapy to outweigh the benefits, persons taking warfarin must fall about 295 (535/1.81) times in 1 year for warfarin to not be the optimal therapy.’Man-Son-Hing et al Arch Intern Med. 1999;159(7):677-85
45 Anticoagulation Control and Prediction of Adverse Events in Patients With AF A Systematic ReviewTTR versus adverse events (weighted by sample size) for retrospective studies.TTR versus major hemorrhage rate (n=9), correlation: r= -0.78; P=0.006;TTR versus thromboembolic rate (n=5), correlation:r= -0.88; P=0.02687654321Linear (major haemorrhageLinear (Thromboembolic)Outcome events rate (per 100 patient/years, %)TTR (%)For retrospective studies, a 6.9% improvement in the TTR significantly reduced major hemorrhage by 1 event per 100 patient-years of treatment (95% CI, 0.29 to 1.71 events)Wan et al Circ Cardiovasc Qual Outcomes. 2008;1:84-91
46 Adjusted relative risk (95% CI) Annual Net Clinical Benefit of Warfarin Therapy Overall and by CHADS2 ScoreUsing Different Weights for ICHRisk FactorNet Clinical Benefit(95% CI)Adjusted relative risk (95% CI)CHADS2 ScoreICH Weight = 1.5(Base Case)ICH Weight = 1ICH Weight = 2-0.11 (-0.44 to 0.20)-0.07 (0.38 to 0.20)-0.14 (-0.53 to 0.21)10.19 (-0.27 to 0.45)0.33 (-0.06 to 0.57)0.06 (-0.50 to 0.34)20.97 (0.43 to 1.41)1.07 (0.61 to 1.45)0.87 (0.26 to 1.35)32.07 (1.21 to 2.79)2.06 (1.26 to 2.72)2.09 (1.12 to 2.85)4-62.22 (0.58 to 3.75)2.51 (1.04 to 4.01)1.94 (0.19 to 3.52)The net clinical benefit of warfarin increased from essentially zero in CHADS2 stroke risk categories 0 and 1 to 2.22% per year (CI,0.58% to 3.75%) in CHADS2 categories 4 to 6.The patterns of results were preserved when weighting factors for intracranial hemorrhage of 1.0 and 2.0 were used.Singer et al Ann Intern Med. 2009;151:
47 Warfarin vs Aspirin for Stroke Prevention in an Elderly Community Population with AF Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA100755025AspirinWarfarinParticipants without primary event (%)Yearly risk 1.8% vs 3.8%, RR 0·48, 95% CI 0·28–0·80, p=0·003;Absolute yearly risk reduction 2%, 95% CI 0·7–3·2Number at riskWarfarinAspirinYears since randomizationMant et al Lancet 2007; 370: 493–503
48 RE-LY: Time to First Stroke / SSE RR 0.91(95% CI: 0.74–1.11)P<0.001 (NI)P=0.34 (Sup)0.05WarfarinDabigatran 110 mg BID0.04Dabigatran 150 mg BIDRRR34%0.03Cumulative hazard ratesRR 0.66(95% CI: 0.53–0.82)P<0.001 (NI)P<0.001 (Sup)0.020.010.000.00.51.01.52.02.5YearsBID = twice daily; CI = confidence interval; NI = non-inferior; RR = relative risk; RRR = relative risk reduction; Sup = superiorConnolly SJ et al. N Engl J Med 2009;361:1139–51
49 Antithrombotic Treatment and Risk of Stroke and Death in Patients with AF and CHADS2 Score=1 Combined endpoint (death or stroke) in patients with a CHADS2 score of 1 according to their antithrombotic treatment. A total of 1,012 patients, 949 ± 777 days FU, 124 events.Gorin et al Thromb Haemostat 2010 March
50 Issues with Current AF Stroke Risk Assessment Schema Implications for the FutureAll have modest predictive value for predicting high risk for thromboembolismLow risk category needs to be truly low riskNeeds to categorise low proportion in so-called ‘moderate/ intermediate risk’ categoryRecognise that risk factors are cumulativeSimple and easy to remember, yet comprehensiveScoring system most popularAcronymValidated in multiple populations, ideally ‘real world’ cohorts rather than non-VKA arms of trial cohortsRisk schema need to evolve with new therapeutic information on thromboprophylaxis in AFLip and Halperin Am J Med 2009; /j.amjmed
51 Risk for Thromboembolism (%) Comparison of Risk Stratification Schemes to Predict Thromboembolism in Nonvalvular AFAnnual Thromboembolism Rate (%)Risk for Thromboembolism (%)c-StatisticLowIntermediateHighAll patientsSubgroup*AFI13.124.762.30.560.61SPAF27.728.543.80.600.65CHADS218.8126.96.36.1990.67Framingham37.146.616.40.620.697th ACCP11.77.980.4Fang et al J Am Coll Cardiol 2008;51:810–5* Subgroup of 5,588 patients not on warfarin at baseline and with continuous follow-up off of warfarin for at least 12 months
52 Combination risk factors Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in AF Using A Novel Risk Factor-Based ApproachThe Euro Heart Survey on Atrial FibrillationDefinitive risk factorsCombination risk factorsPrevious stroke, TIAor embolismHeart failure or moderate-severeLV dysfunction [eg. LV EF ≤40%]Female genderAge ≥ 75 yHypertensionAge 65 to 74 yDiabetes mellitusVascular disease [previous MI, aortic or peripheral artery disease]CHA2DS2-VAScScoreC ongestive heart failure/ LV dysfunction1H ypertensionA ge≥752D iabetes mellitusS troke/TIA/TEV ascular disease [prior MI, PAD, or aortic plaque]A ge 65-74S ex category [Female]Lip et al Chest 2010 Feb;137(2): Epub 2009 Sep 17.
53 Risk Categorization, Incidence of Thromboembolism and Predictive Ability for Contemporary Risk Stratification Schema in the Euro Heart SurveyLowIntermediateHighc-statistic(95% CI)CHADS2 – classical% in risk categoryTE events, N (%)203 (1.4)61.916 (2.4)17.76 (3.2)0.561( )CHADS2 – revised20.434.97 (1.9)44.715 (3.1)0.586( )Framingham48.36 (1.2)41.514 (3.2)10.25 (4.6)0.638( )NICE 200613.10 (0.0)39.213 (3.1)47.712 (2.3)0.598( )ACC/AHA/ESC 200619.63 (.14)32.67 (2.0)47.815 (2.9)0.571( )ACCP 200833.447.015 (3.0)0.574( )Birmingham 20099.215.11 (0.6)75.724 (3.0)0.606( )CHA2DS2-VAScLip et al Chest 2010 Feb;137(2): Epub 2009 Sep 17.
54 Recommended antithrombotic therapy Refining Clinical Risk Stratification for Predicting Stroke and Thromboembolism in AF Using a Novel Risk Factor Based ApproachThe Euro Heart Survey on Atrial FibrillationRisk categoryCHA2DS2VAScscoreRecommended antithrombotic therapyOne definitive risk factoror ≥2 combination risk factors>1OACeg.VKA (INR 2-3, target 2.5), ?dabigatranOne combination risk factor1Antithrombotic therapy, either as OAC or aspirin mg dailyWe suggest OAC rather than aspirinNo risk factorsAspirin mg daily or no antithrombotic therapyWe suggest no antithrombotic therapyLip et al Chest 2010 Feb;137(2): Epub 2009 Sep 17.
55 Achieving Balance Between Thromboprophylaxis and Bleeding Reduction Challenges and Emerging Dimensions of Stroke Prevention in the Setting of AFAchieving Balance Between Thromboprophylaxis and Bleeding ReductionAF increases the risk of stroke and thromboembolismWe need to balance stroke prevention against bleeding riskNew risk factors and data (eg. elderly, CHADS2=1, new drugs etc) should be consideredAspirin (and antiplatelet Rx) less usefulRisk schema need to evolve with new therapeutic information on thromboprophylaxis in AFWe need a paradigm shift in stroke risk assessment guidelinesAll schema have modest value in predicting riskWe need to be better at identifying the low risk subjects, who do not need antithrombotic therapy; all others would merit anticoagulation
56 New Dimensions andLandmark Practice AdvancesThe Evolving Paradigm of Warfarin-Based Therapy: Still Relevant? And for How Long?David A. Garcia, MDAssociate Professor, Division of General Internal MedicineUniversity of New MexicoCo-Director, University of New Mexico Anticoagulation Management ServicePresident, Anticoagulation ForumAlbuquerque, New Mexico USA
57 Long-Term Oral Anticoagulation The State of the Art
58 Adjusted-dose warfarin compared with placebo AFASAK I, 1989 (2); 1990 (3)SPAF I, 1991 (5)BAATAF, 1990 (4)CAFA,1991 (6)SPINAF, 1992 (7)EAFT (8)All trials (n=6)Relative risk reduction (95% CI)Favors warfarinFavors placeboor control10050-50-100Warfarin Protects Against Stroke Adjusted-Dose Warfarin Compared With PlaceboAdjusted-dose warfarin compared with placeboHart, et al. Ann Intern Med Jun 19;146(12):
59 Timeline AC management clinics Warfarin become increasingly prevalent first usedPOC testing, PST,dosing algorithms,software programs,better understanding ofgenetics and drug interactionsWHO endorses INR1950’s199119991983Efficacy of VKAto prevent AF-related strokedemonstrated
60 Warfarin Mechanism of Action Vitamin KVIIVitamin K Utilization ImpairedIXSynthesis of Dysfunctional Coagulation FactorsXWarfarin: Mechanism of ActionThe model in this slide provides a simplified explanation for the antagonism of clotting factor biosynthesis by warfarin. The cyclic interconversion of vitamin K from its vitamin K epoxide (KO) back to its hydroquinone (KH2) form, which occurs under normal physiological and dietary conditions, is disrupted in the presence of pharmacologically effective doses of warfarin. This metabolic disruption of the cycle results in decreased availability of the active cofactor form of vitamin K, vitamin K hydroquinone (KH2). The result is decreased presence of g-carboxyglutamic acid in the vitamin K-dependent clotting factors.Warfarin inhibits the enzymatic conversion (by reductases) of KO to its active cofactor form, KH2. This inhibition decreases the amount of KH2 available to participate in the conversion of prothrombin to its biologically active form. In order for prothrombin to have normal biological activity, between 10–13 glutamic acid (glu) residues must be converted to g-carboxyglutamic acid (gla) residues. This reaction requires the addition of a second carboxyl group (–COOH) to glutamic acid residues.46. Bovill EG, Mann KG, Lawson JH, Sadowski J. Biochemistry of vitamin K: implications of warfarin therapy. In: Ezekowitz MD, editor. Systemic cardiac embolism. New York:Marcel Dekker, p47. Hirsh J, Ginsberg JS, Marder VJ. Anticoagulant therapy with coumarin agents. In: Colman RW, Hirsh J, Marder VJ, Salzman EW, editors. Hemostasis and thrombosis, 3rd ed. Philadelphia: J.B. Lippincott, pCYP450IIWarfarinSlight genetic variation can produce significant differences in dose-responserelationship
61 Warfarin Mechanism of Action Decarboxylated zymogenCarboxylated zymogenVitamin KH2Vitamin K EpoxideXVitamin KreductaseVitamin KVitamin K epoxidereductaseNADPHSlight genetic variation can produce significant differencesin dose-response relationship
62 Coagulation Pathway IIa (Thrombin) Initiation Vlla/TF X IX Propagation IXaVllIaThis is a simplified schematic representation of the coagulation cascade. Three steps are highlighted:InitiationPropagationFibrin FormationXaVaIIIIa (Thrombin)Fibrin FormationFibrinogenFibrin
63 Limitations of Warfarin (VKA) Anticoagulation ClinicsRequires frequent monitoring? Genotype testingNarrowTherapeuticIndex & Drug/DietInteractionsComplicates management of:Bleeding patientPatient with High INRLongHalf-LifeSlowOnset ofActionHeparin “overlap”often necessaryPeriprocedural Anticoagulation Difficult
64 Is VKA (warfarin) therapy getting safer and more “user-friendly”? Wisespread use of the INRAnticoagulation Management ServicesPatient Self-testingPharmacogenomicsReversal strategies
65 Events per 100 Patient-Years According to International Normalized Ratio Control Poor ControlModerate ControlGood ControlP Value(Poor vs Good)(Moderate vs Poor)(Good vs Moderate)(n = 1190)(n = 1207)Stroke or systemic embolism2.10.021.340.091.070.48Death, all cause4.2< .011.841.690.74Death, stroke, or systemic embolism5.983.012.760.67Major bleeding3.851.961.580.38We analyzed the relationship between INRcontrol and the rates of death, bleeding, MI, and strokeor SEE among 3587 patients with atrial fibrillation randomizedto receive warfarin treatment in the SPORTIF(Stroke Prevention Using an Oral Thrombin Inhibitorin Atrial Fibrillation) III and V trials. The mean±SDfollow-up was 16.6±6.3 months. Patients were dividedinto 3 equal groups (those with good control [75%],those with moderate control [60%-75%], or those withpoor control [60%]) according to the percentage timewith an INR of 2.0 to 3.0. Outcomes were comparedaccording to INR control. The main outcome measureswere death, bleeding, MI, and stroke or SEE.White H et al. Arch Intern Med :
72 Anderson et al RCT (n=200) Only published high-quality RCT Incorporated both CYP2C9 and VKORC1 genotypesPG (%)Std (%)pOut-of-range INR31330.72Therapeutic INR by Day 570680.85Serious Adverse Events450.71PG dosing: more accurate with fewer dosing changes and INR measurements (7.2 vs 8.1, p 0.06)Anderson et al, Circulation, 2007; 116:
73 Meta-analysis: % Time Therapeutic Study IDSMD 95% CIHillman (-0.3, 0.64)Caraco (0.28, 0.86)Anderson (-0.23, 0.22)Overall (I-squared = 72.5%, p= (-0.16, 0.64)Note: weights re from random effects analysisStandard dose favored Pharmacogenetics favoredKangelaris, JGIM, 2009; 24(5):
74 Pharmacogenetic Testing Promising science but…Clinical benefit still unproven
75 4-factor prothrombin complex concentrate administered Reversal Strategies13119753125 u/kg (m=20)35 u/kg (n=12)50 u/kg (n=10)Beriplex, a prothrombin complex concentrate (PCC), was administered to 42 patients requiring immediate reversal of their oral anticoagulant therapy. The dose administered was determined using the pretreatment International Normalized Ratio (INR). Blood samples were obtained before treatment and at 20, 60 and 120 min after treatment. The following investigations were performed on all samples - INR, clotting factors II, VII, IX and X, coagulation inhibitors protein C (PC) and antithrombin (AT), and other markers of disseminated intravascular coagulation, plasma fibrinogen, D-dimer and platelet count. Immediate reversal of the INR, the vitamin K-dependent clotting factors and PC was achieved in virtually all patients. Reduced AT levels were present in 18 patients before treatment. Further slight AT reductions occurred in four patients, but other associated abnormalities of haemostasis were observed in only one of the four patients. One patient with severe peripheral vascular disease, sepsis and renal and cardiac failure died of a thrombotic stroke following leg amputation, 48 h after receiving Beriplex. No other arterial and no venous thromboembolic events occurred within 7 d of treatment. Beriplex is effective in rapidly reversing the anticoagulant effects of warfarin, including PC deficiency, without inducing coagulation activation. Caution should continue to be exercised in the use of these products in patients with disseminated intravascular coagulation, sepsis or liver disease.Baseline min min min134-factor prothrombin complex concentrate administeredPreston et al. British Journal of Haematology : 619–624
76 Warfarin Reversal PO/IV vitamin K Fresh Frozen Plasma 4-factor PCC Effective but INR decrease not immediateFresh Frozen PlasmaEach unit contains limited amount of vitamin-K dependent clotting proteinsSignificant volume challenge4-factor PCCNot available in U.S.? Cost? Risk of thrombosis
77 ConclusionsAlthough warfarin treatment is safer and more practical than it was years ago, there is certainly room for further improvement.The new agents in development mayEliminate some of the challenges unique to warfarinAllow patients for whom warfarin is not feasible to receive highly effective anti-thrombotic therapy
78 Questions Regarding the New Oral Anticoagulants Do they represent a significant improvement for patients who have been taking warfarin with consistently therapeutic INR values for months/years?Will the lack of an evidence-based “reversal strategy” deter their use?How long will it take clinicians and patients to become comfortable with the lack of ability to monitor?Will the elimination of regular INR measurement reduce compliance?How will their cost compare to current costs (including INR monitoring, dose adjustment, etc.)?Which (if any) will be available to patients with significantly impaired renal function?
79 New Dimensions andLandmark Practice AdvancesEmerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Mechanism and Applications for Thrombosis Mitigation Across the Cardiovascular Disease SpectrumRichard C. Becker, MDProfessor MedicineDivisions of Cardiology and HematologyDuke University Medical CenterDuke Clinical Research Institute
80 Emerging Role of Direct Thrombin and Factor Xa Antagonists Conditions, Dynamic Substrate and Thrombus Survival in Atrial FibrillationAnticoagulants in DevelopmentPlatelet-Thrombin Interface – A Roadmap for Future PharmacotherapyRedefining Atrial Fibrillation at the Molecular and Proteomic Level
81 Increased Connective Tissue Growth Factor Expression and Fibrosis in LA of Patients with AF Adam. JACC 2010;55:
82 Rac1-induced CTGF Regulates Connexin 43 and N-Cadherin Expression in AF Adam. JACC 2010;55:
83 Stabilization of Mast Cells Infiltrating the Atrium of TAC-Operated Mice by Cromolyn Liao. JCI 2010;120:
84 Attenuation of AF and Atrial Fibrosis by Mast Cell Stabilization by Cromolyn Liao. JCI 2010;120:
85 Attenuation of Atrial Fibrosis and AF by Reconsitution with BM Cells from W/Wv Mice Liao. JCI 2010;120:
86 Extracellular Matrix Degradation and Fibrosis in Atrial Fibrillation life.nctu.edu.tw/.../image006.jpg
87 Thrombin Generation According to Factor X Concentrations Allen. J Thromb Haemost 2004;2:
88 Thrombin Generation According to Prothrombin Concentrations Allen. J Thromb Haemost 2004; 2:
89 Resupply of the Synthetic Coagulation Proteome Effect of Inhibitors Targeting fXa and fXa in the Prothrombinase ComplexResupply of the synthetic coagulation proteome: the effect of inhibitors targeting fXa and fXa in the prothrombinase complex. Time courses of thrombin generation are presented for reactions initiated with 5 pm Tf reagent (♦) and then resupplied at 20 min with an equal volume of synthetic coagulation proteome, 2 μm PCPS without Tf: control resupply (⋄); 320 nm C included in the synthetic coagulation proteome, 2 μm PCPS resupply mixture (○); 0.1 mg/ml α-bfX-2 added 2 min prior to resupply with synthetic coagulation proteome, 2 μm PCPS (□); and 0.1 mg/ml α-bfX-2 added 2 min prior to resupply with 1.4 μm fII, 3.4 μm AT, 2 μm PCPS (▵). The arrow indicates the time of α-bfX-2 addition. Thrombin generation over the initial 20 min is presented as the mean ± S.D. of four determinations. Thrombin levels at each time are expressed as total moles of active thrombin to normalize for the volume change.Orfeo T et al. J. Biol. Chem. 2008;283:
90 Resupply of the Synthetic Coagulation Proteome: Stability of the Response Resupply of the synthetic coagulation proteome: stability of the response. A 5 pm Tf-initiated reaction mixture was subdivided after 20 min (A), and the seven separate aliquots resupplied either immediately (20 min → t = 0, (♦)) or after an additional 15 (▪), 30 (▴), 45 (•), 60 (▾), 75 (), or 95 () min of incubation. Resupply was conducted with an equal volume of a solution consisting of 1.4 μm fII, 3.4 μm AT, 2 μm PCPS. Thrombin levels for the final 5 min of the Tf- initiated episode are also shown (⋄). Thrombin levels are expressed as total picomoles of active thrombin to normalize for the volume change. An arrow indicates the resupply time for each aliquot.Orfeo T et al. J. Biol. Chem. 2008;283:
91 Traditional Paradigm of Factor Xa and Thrombin Mackman. ATVB 2008;28:
94 Trials of Antithrombotic Therapy for Stroke Prevention in Atrial Fibrillation Warfarin-Control Phase IIITrialAgentBlindCHADSSizeStatusRE-LYDabigatranOL>118,113CompleteROCKETRivaroxabanDB>2-314,000ARISTOTLEApixaban15,000BOREALISBiotinylatedIdraparinux>29,600EnrollingENGAGEEdoxaban?Total71,600Historical trials: 3,763
95 Oral Direct Factor Xa Inhibitors Currently in Development DrugHalf-Life (hours)BioavailabilityElimination (%)Renal HepaticDosingApixaban12502575Twice dailyBetrixaban1947100Once dailyEndoxaban6-12100%6235Rivaroxaban5-9803367YM150intestinal18-2025-82NROnce/twice
97 (at least one high risk factor) RE-LYNon-valvular atrial fibrillation at moderate to high risk of stroke or systemic embolism(at least one high risk factor)RWarfarin1 mg, 3mg, 5 mg(INR )N=6000Dabigatran Etexilate110 mg b.i.d.N=6000Dabigatran Etexilate150 mg b.i.d.N=6000Primary objective: Noninferiority to warfarinMinimum 1 year follow-up, maximum of 3 years and mean of 2 years of follow-up.Primary end point: Stroke + systemic embolism
98 Hazard Ratio Primary Outcome of Stroke or Systemic Embolism Connolly, et al. N Engl J Med 2009;361:WarfarinDabigatran110 mg150 mgWarfarinDabigatran 110 mgDabigatran 150 mg1.00.80.60.40.20.00.050.040.030.020.010.00
99 RE-LY: Annual Rates of Bleeding 110mg150mgWarfarinD 110mg vs. WarfarinD 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 NEJM 2009;361:99
101 Oral Direct Thrombin Inhibitor AZD0837 Pharmacokinetics Lip, G. Y.H. et al. Eur Heart J : ; doi: /eurheartj/ehp318
102 Oral Direct Thrombin Inhibitor AZD0837 Dynamics Lip, G. Y.H. et al. Eur Heart J : ; doi: /eurheartj/ehp318
103 Platelet Polyphosphates and Factor XII Activation Muller. Cell 2009;139:
104 Platelet Polyphosphates and Factor XII Activation 12010080604020FXIIa [nM]TIME (MINUTES)Muller. Cell 2009;139:
105 Blood substudy program Drug administeredGenomeBlood TranscriptomeIntegrated biosignatures that predict drug response and clinical outcomesMechanistic DataMolecular basis of drug effect on clinical phenotypePlasma ProteomeBiological Phenotype(Anti-Factor Xa)Clinical Phenotype(Ischemic stroke or bleeding)Adapted from Ginsburg et al. JACC 2005;46:1615
106 Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Atrial fibrillation is the end-result of conditions characterized by inflammation, fibrosis and tissue remodeling.Thrombus formation represents a localized response to tissue injury and altered flow dynamics.Thrombin and factor Xa inhibitors can attenuate thrombus formation and possibly alter the natural history of disease.Never forget the platelet in thrombotic disorders.Defining atrial fibrillation at the molecular and proteomic level may inform clinical data.
107 Emerging Role of Direct Thrombin and Factor Xa Inhibition in Atrial Fibrillation Studies using novel anticoagulants for stroke prevention in AF are likely to change the landscape of patient management in AF.Additional trials, including those with Factor Xa inhibitors will provide a robust foundation for evaluating how the current therapeutic landscape for stroke prevention might change.Studies evaluating safety and efficacy of apixaban in patients who are not suitable candidates for VKA have the potential to identify a non-ASA strategy for a unique subset of patients.
108 New Dimensions andLandmark Practice AdvancesThe Emerging Role of Factor Xa and Direct Thrombin Inhibition for the Setting of Post-ACS Secondary PreventionShamir R. Mehta MD, MSc, FRCPC, FACCDirector, Interventional CardiologyHamilton Health SciencesAssociate Professor of MedicineMcMaster UniversityDirector, ACS Research ProgramPopulation Health Research Institute
109 CVD: A Global Epidemic 2002 World pop.: 6.12 billion Deaths: 56.6 millionCVD deaths: 16.6 millionGaziano TA. Circ 2005.
110 Troponin elevated or not ThrombosisNon-occlusivethrombosisOcclusivethrombosisCK - MB or Troponin ↑Troponin elevated or notCourtesy Dr. E Falk
111 Atherosclerotic Plaque Red Blood CellsThrombusPlatelet AggregateFibrinAtherosclerotic Plaque
112 UFH, LMWH, fondaparinux, bivalirudin Antiplatelets, Anticoagulants and their Combination in ACS: Evidence from RCT’sShort TermLong TermAntiplatelet aloneASAASA, clopidogrelAnticoagulant aloneUFHWarfarinCombinationUFH, LMWH, fondaparinux, bivalirudinUnder study
113 Randomized Trials of Aspirin in Unstable Angina: Short and Long Term Benefit ASA TreatmentLength of Follow-upRRRP valueVeterans Affairs Study (1983)325 mg/d*3 months41%0.004Canadian Study (1985)325 mg 4x daily†18 months30%0.072Montreal Heart Study (1988)650 mg first dose, 325 mg/d*6 days63%0.04RISC (1990)75 mg for 3 mon*13 months64%0.0001ATC meta-analysis (2002)Various regimens*Various46%<0.0001*comparison versus placebo, †comparison versus controlAdapted from Mehta SR, J Am Coll Cardiol. 2003;41(suppl):79SNOT APPROVED-
114 MI, stroke, CV Death: 0–30 days Benefit of Clopidogrel Therapy: Day 0-30 and Day 30-1 yearMI, stroke, CV Death: 0–30 daysProportion Event-Free3159318039294639539059544004474254815981Months0.900.920.940.960.981.0014681012MI, stroke, CV Death: 31 days - 1 yearRRR 18%95% CI 0.70–0.95 P=0.009Clopidogrel + ASAPlacebo + ASA1.00Clopidogrel + ASA0.980.96Proportion Event-FreePlacebo + ASA0.940.92RRR 21%95% CI 0.67–0.92 P=0.0030.901234WeeksNo. at RiskClopidogrel625961456070602659902418Placebo630361596048599359652388Yusuf et al. Circulation. 2003;107:966UNDERGOING REVIEW FORE-NEWSLETTER
115 Early and Long Term Clopidogrel in PCI Patients Composite of MI or cardiovascular death from randomization to end of follow-up0.1512.6%8.8%31%Relative Risk ReductionPlacebo+ ASA*0.10Cumulative Hazard RateClopidogrel+ ASA*0.05For the end point of MI or cardiovascular death from time of randomization to end of follow-up, treatment with clopidogrel in addition to aspirin and other standard therapies resulted in a 31% RRR (8.8% clopidogrel vs 12.6% placebo, P = 0.002).The curves diverged early and continued to separate over the course of 12 months.This end point included events that were prevented prior to PCI, in addition to those following the procedure.There were consistent reductions in MI or cardiovascular death in almost every subgroup examined.P = N = 26580.0100200300400Days of follow-up* In addition to other standard therapies.Mehta et al for the CURE Investigators. Lancet. 2001;358:527APPROVED-CURE-PCI-CURE
116 Initial Combination Therapy with an Anticoagulant + Antiplatelet Reduces Death/MI in UA/ NSTEMILMWH or UFH combined with ASA in ACS: Death or MIN=2,919Eikelboom J, et al. Lancet 2000
117 Combination Anticoagulant + Antiplatelet Therapy Alone Reduce Mortality and MI in the Initial Management of STEMILMWH combined with ASA in STEMI: DeathLMWH combined with ASA in STEMI: MIN=16,842Eikelboom J, et al. Circulation 2006
118 Longer Term Anticoagulant Therapy (8 days) + Antiplatelet Therapy Alone Superior to Short Term Therapy (48-72 hrs)OASIS 6 Investigators. JAMA 2006
119 Long Term Anticoagulant Therapy + ASA Reduces Death/MI/Stroke After ACS Study OR (95% CI)INR > 2.0n=5, Favors Combination Favors ASARothberg MD, et al. Ann Intern Med 2005
120 Long Term Anticoagulant Therapy + ASA May Increase Bleeding After ACS Study OR (95% CI)INR > 2.0n=5, Favors Combination Favors ASARothberg MD, et al. Ann Intern Med 2005
122 Pure Factor Xa Inhibition with Fondaparinux Reduces Bleeding and Mortality vs Enoxaparin OASIS 5 Investigators. N Engl J Med 2006;356:
123 Apixaban Characteristics Oral bioavailability: 58% No food effect Low volume distributionHalf-life: T1/2 ≈ 12 hMultiple elimination pathways: 25% renalNo CYP inhibition / inductionHighly selective for factor XaNo reactive intermediatesNo organ toxicity, LFT abnormalities, or QTc prolongationNOH2NOMeNew generic templatePinto DJ et al. J Med Chem. 2007;50:He K et al. Poster presented at: 48th Annual Meeting of the American Society of Hematology; December 2006; Orlando, FL. Poster 38-I.Frost C et al. Poster presented at: 21st Congress of the International Society of Thrombosis and Haemostasis; July 2007; Geneva, Switzerland.Lassen MR et al. J Thromb Haem. 2007;5:
124 APPRAISE Steering Committee and Investigators. Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary SyndromeResults of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) TrialAPPRAISE Steering Committee and Investigators.Circulation. 2009;119:
125 Study Design Recent (7 days) Acute Coronary Syndrome plus at least one additional risk factorRecent (7 days) Acute Coronary Syndromeplus at least one additional risk factorPhase A = 547Phase A1:1:1Phase A1:1:1Randomized, double-blind.Study drug for 6 months.Aspirin 165 mg/d.Clopidogrel per MD discretion (stratified randomization)Placebon=184Apixaban2.5 mg BIDn=179Apixaban2.5 mg BIDn=179Apixaban10 mg QDn=184Apixaban10 mg QDn=184Discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapyInterim analysis (DSMB review)Phase B = 1168Phase B3:1:1:2:2Phase B3:1:1:2:2Higher rates of total and ISTH major bleeding among the apixaban 10 mg bid and 20 mg qd arms.50% higher any bleeding and 3 x major bleedingPlacebon=427Apixaban2.5 mg BIDn=138Apixaban10 mg QDn=134Apixaban10 mg QDn=134Apixaban10 mg BIDn=248Apixaban20 mg QDn=221Total = 1715Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH)Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic strokeJohn H. Alexander, (Circulation. 2009;119: )
126 Ischemic OutcomesJohn H. Alexander, (Circulation. 2009;119: )
127 Ischemic Events by Clopidogrel Status Clopidogrel subgroup tracks with PCI subgroupNJohn H. Alexander, (Circulation. 2009;119: )
128 Bleeding ISTH and TIMI Scales John H. Alexander, (Circulation. 2009;119: )
129 Bleeding by Clopidogrel Status Clopidogrel subgroup tracks with PCI subgroupNJohn H. Alexander, (Circulation. 2009;119: )
130 APPRAISE-2 Trial Event Driven Recent Acute Coronary Syndrome (STEMI or NSTE-ACS)Randomize 1:1Stratified by Antiplatelet RegimenDouble blindAspirinOther antiplatelet at MD discretionN=10,800Apixaban 5 mg BIDPlaceboStart study drug ASAP after acute care stabilization / parenteral anticoagulationEvent DrivenPrimary: Death, MI, Ischemic StrokeSecondary: Death, MI, Severe Recurrent Ischemia, Ischemic strokeSafety: Major Bleeding
132 Primary Safety Endpoint Clinically Significant Bleeding TIMI46ATLASPrimary Safety Endpoint Clinically Significant Bleeding(= TIMI Major, TIMI Minor, Bleed Req. Med. Attn.)HR15.3%5.115Total Daily Dose:Rivaroxaban 20 mg ----Rivaroxaban 15 mg ----Rivaroxaban 10 mg ----Rivaroxaban 5 mg ----Placebo ---( )12.7%3.6( )10.9%3.410( )Clinically Significant Bleeding (%)6.1%2.25( )3.3%*p<0.01 for placebo Vs Riva 5mg. p<0.001 for Riva 10,15,20mg vs placebo306090120150180Days After Start of TreatmentKaplan-Meier estimates for cumulative events, HR(CI), for bleeding rates during the 180 day period ; HR=Hazard Ratio; CI=Confidence IntervalMega, Lancet 2009; DOI: /S (09)132
133 Safety Endpoints TIMI Major, TIMI Minor and Bleeding Req. Med. Attn. P trend<0.001Rate (%)Plac51020Plac51020Plac51020TIMI MajorTIMI MinorMed AttentionP trend<0.0001Rate (%)Plac5101520Plac5101520Plac5101520TIMI MajorTIMI MinorMed AttentionP trend=p value for dose response over actual dose values.Mega et. al, Lancet 2009; DOI: /S (09)
134 Secondary Efficacy Endpoint: Incidence of Death / MI / Stroke TIMI46ATLASSecondary Efficacy Endpoint: Incidence of Death / MI / StrokeStratum 1: ASA AloneStratum 2: ASA + Clop.HR 1.2411.94.7P trend = 0.01P trend = 0.723.8HR 0.67HR 0.79HR 0.58HR 0.70HR O.718.03.0Death / MI / Stroke (%)Death / MI / Stroke (%)7.02.72.7HR 0.374.7n=253n=154n=196n=158n=907n=154n=860n=356n=453TDDMega et. al, Lancet 2009; DOI: /S (09)
135 APPRAISE-2 Trial Event Driven Recent Acute Coronary Syndrome (STEMI or NSTE-ACS)Randomize 1:1Stratified by Antiplatelet RegimenDouble blindAspirinOther antiplatelet at MD discretionN=10,800Apixaban 5 mg BIDPlaceboStart study drug ASAP after acute care stabilization / parenteral anticoagulationEvent DrivenPrimary: Death, MI, Ischemic StrokeSecondary: Death, MI, Severe Recurrent Ischemia, Ischemic strokeSafety: Major Bleeding
136 REDEEM: Outcomes by Dabigatran Randomization Group End pointPlacebo(n=371)50 mg bid(n=369)75 mg bid(n=368)110 mg bid(n=406)150 mg bid(n=347)Primary end point188.8.131.52.97.8Major bleeding *0.50.80.32.01.2CV death, nonfatal MI, or stroke184.108.40.206.0* International Society of Thrombosis and Haemostasis criteriaOldgren J, American Heart Association 2009 Scientific Sessions; Nov. 18, 2009; Orlando, FL
137 ConclusionsShort and Long term antiplatelet alone and anticoagulant therapy alone reduce major CV events after ACSShort term combination therapy reduces major CV events in ACSLong term combination therapy with new oral anticoagulants apixaban and rivaroxaban evaluated in the context of contemporary antiplatelet therapy demonstrate a reduction in ischemic events with a dose dependent increase in bleedingThe widespread use of these agents as routine therapy after ACS will depend on the balance of ischemic event reduction vs bleeding currently being evaluated in large-scale phase III RCTs
138 Thrombosis Reduction for Heart Disease Thrombosis Risk Reduction: SummaryNew Frontiers inThrombosis Reduction for Heart DiseaseTake Home Points and ConclusionsDeepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAIProgram ChairmanChief of Cardiology, VA Boston Healthcare SystemDirector, Integrated Interventional Cardiovascular ProgramBrigham and Women’s Hospital and the VA Boston Healthcare SystemAssociate Professor of Medicine, Harvard Medical SchoolSenior Investigator, TIMI Group
139 Take Home Points: AFAF increases the risk of stroke and thromboembolismNeed to balance stroke prevention against bleeding risk: in search of the “ideal strategy”We need a paradigm shift in stroke risk assessment guidelines: current schema have modest value in predicting risk and, therefore, best prophylactic approachDefining AF at the molecular and proteomic level may helpWarfarin treatment has become safer and more practical, but limitations in achieving ideal TTR persistNewer agents inhibiting Factor Xa or thrombin offer unique opportunities in both efficacy and safety
140 Take Home Points: ACSFollowing acute coronary syndrome patients remain at high risk for:Recurrent ischemic eventsBleeding (largely secondary to antithrombotic therapy)Inhibition of Factor Xa or thrombin with oral non-monitored agents has the potential to reduce ischemic events but will probably also increase in bleedingTriple therapy with DAP plus oral, non-monitored anticoagulant may be attractive if bleeding risks can be mitigatedThe ideal level of inhibition of Factor Xa or of thrombin to improve ACS outcomes will require further study
141 Take Home Points: Novel Anticoagulants Noninferiority may not suffice to alter VKA landscape, but superiority findings and/or less bleeding observed in RE-LY are very encouragingMany more trials will be forthcomingBeware of off-label use
142 Take Home Points: Novel Anticoagulants 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 atrial fibrillationAdditional trials, including those with Factor Xa inhibitors, will provide a more robust foundation for evaluating how the current therapeutic landscape for stroke prevention might changeStudies evaluating safety and efficacy Factor Xa inhibition in patients who are not suitable candidates for VKA has the potential to identify a strategy for a unique subset of patients
143 Take Home: Conclusions Thrombosis is critical in multiple cardiovascular syndromes, including ACS and AFThrombosis risk reduction presents a significant unmet need in patients with atherothrombosisNovel pathways to prevent thrombosis likely to yield benefit based on number and quality of trials in progress across the arterial and venous risk spectrum143
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