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Eduardo S. Caguioa, MD., FPCP, FPCC, FACC Asst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of Cardiology Medical Director,

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Presentation on theme: "Eduardo S. Caguioa, MD., FPCP, FPCC, FACC Asst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of Cardiology Medical Director,"— Presentation transcript:

1 Eduardo S. Caguioa, MD., FPCP, FPCC, FACC Asst. Professor, UST Faculty of Medicine and Surgery, Dept of Medicine, Section of Cardiology Medical Director, UST Hospital Acute Coronary Syndrome: Antiplatelets and Antithrombotics

2 Member of Advisory Board: Astra-ZenecaAstra-Zeneca MSDMSD PfizerPfizer ServierServier Receives honorarium for lectures or drug trials Have no financial interest in any drug company.

3 SYNERGYLMWHESSENCE CURE Clopidogrel Bleeding risk Ischemic risk GP IIb/IIIa blockers PRISM-PLUS PURSUIT ACUITY TACTICS TIMI-18 Early invasive PCI ~ 5% stents ~85% stents Drug-eluting stents ISAR-REACT 2 Milestones in ACS Management OASIS-5 [ Fondaparinux ] Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative ICTUSBivalirudin REPLACE 2 Adapted from and with the courtesy of Steven Manoukian, MD

4 Evolution of ACS Therapies Adapted from White HD et al. Lancet 2008; 372: 570–84 Aspirin Heparin Year Low molecular weight heparin IIb/IIIa receptor antagonist Early invasive management CLOPIDOGREL Atorvastatin Fondaparinux Bivalirudin Integratedstrategy DABIGATRAN

5 Proportional effects of antiplatelet therapy on Vascular events in five main high risk categories Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

6 Absolute effects of antiplatelet therapy on vascular events in five main high risk categories Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

7 Clopidogrel: Mechanism ADP = adenosine diphosphate, TXA 2 = thromboxane A 2, COX = cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101: Collagen Thrombin TXA 2 ADP Receptor (P2Y 12 ) TXA 2 ADP ADP GP IIb/IIIa receptor Activation COX Clopidogrel Ticlopidine Fibrinogen

8 Clopidogrel in NSTE ACS: CURE CURE. NEJM 2001;345: ,563 Pts, GP IIb/IIIa & early invasive approach discouraged RR 0.80, p<0.001 Clopidogrel (9.3%) Placebo (11.4%) CV Death, MI, Stroke Months of follow-up

9 Yusuf S et al. Circulation 2003;107: CURE: Very Early Efficacy of Clopidogrel in NSTE ACS Hours After Randomization P=.003 Placebo + Aspirin (n=6303) Clopidogrel + Aspirin (n=6259) 34% Relative Risk Reduction CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours Cumulative Hazard Rate

10 Fox et al. Circulation. 2004;110: Medical Rx Group Placebo Clopidogrel RR: 0.80 ( ) Clopidogrel PCI Group Placebo RR: 0.72 ( ) CABG Group Placebo Clopidogrel RR: 0.89 ( ) CURE: Benefit by Revascularization CVD/MI/Stroke

11 Clopidogrel in STEMI Fibrinolytic, ASA, Heparin Clopidogrel 300 mg + 75 mg qd Coronary Angiogram (2-8 days) Primary endpoint: Occluded artery (TIMI Flow Grade 0/1) or D/MI by time of angio randomize Placebo Double-blind, randomized, placebo-controlled trial in 3491 patients, age yrs with STEMI < 12 hours Study Drug 30-day clinical follow-up Open-label clopidogrel per MD in both groups

12 Clopidogrel in STEMI PlaceboClopidogrel 36%  P< %  P< Sabatine MS et al. NEJM 2005; 352: 1179 days CV Death, MI, or Urg Revasc (%) Placebo Clopidogrel Odds Ratio 0.80 (95% CI ) P= %

13 COMMIT: Clopidogrel (75 mg qd) in STEMI 9% relative risk reduction (P=.002) Placebo (10.1%) Clopidogrel (9.3%) Days Death, MI, Stroke (%) Mortality (%) Days Placebo (8.1%) Clopidogrel (7.5%) 7% relative risk reduction (P=.03) COMMIT Collaborative Group. Lancet. 2005;366: ,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2)

14 PCI-CLARITY Design 30-day clinical follow-up 933 underwent PCI during index hosp. 930 underwent PCI during index hosp Patients Randomized into CLARITY-TIMI assigned clopidogrel 300 mg  75 mg/d 1739assigned placebo Open-label clopidogrel w/ loading dose recommended (CLOPIDOGREL PRETREATMENT) (NO PRETREATMENT) A n g i o g r a p h y

15 CV Death, MI, or Stroke following PCI Days post PCI Percentage with outcome (%) No Pretreatment – 6.2% Clopidogrel – 3.6% Pretreatment 46% Odds Ratio 0.54 (95% CI ) P=0.008 Odds Ratio 0.54 (95% CI ) P=0.008 Sabatine MS et al. JAMA 2005;294:

16 Clopidogrel No TrialPretreatmentPretreatment PCI-CURE CREDOn/an/a PCI-CLARITY Overall ClopidogrelNo TrialPretreatmentPretreatment PCI-CURE CREDO PCI-CLARITY Overall Meta-Analysis of Clopidogrel Pretreatment OR (95% CI) CV Death or MI after PCI (%) MI before PCI (%) OR 0.67 P=0.005 P=0.005 Favors Pretreatment Favors No Pretreatment OR 0.71 P=0.004 P=0.004 Sabatine MS et al. JAMA 2005;294:

17 Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA): Study Design Double-blind treatment up to 1,040 primary efficacy events occur* Aspirin 75–162 mg once daily Clopidogrel 75 mg once daily (n=7600) Placebo 1 tab once daily (n=7600) Aspirin mg once daily Final study visit (fixed study end date) 1-month visit 3-month visit Patients 45 years or older who are at high risk of atherothrombotic events R = randomization. N=15,603 R Bhatt et al. Am Heart J. 2004;148:263 *Event-driven trial: primary efficacy outcome of vascular death, MI, stroke Visits every 6 months (12 m, 18 m…), and intermediate phone calls in between (15 m, 21m…) 6-month visit

18 Overall Population: Primary Efficacy Outcome (CV Death, MI, or Stroke) Bhatt DL et al. NEJM 2006;354: Cumulative event rate (%) Months since randomization Placebo + ASA 7.3% Clopidogrel + ASA 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22

19 Primary Endpoint (CV Death, MI, or Stroke) in Patients with Previous MI, IS, or PAD “CAPRIE-like Cohort” RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01 Primary outcome event rate (%) Months since randomization Clopidogrel + ASA 7.3% Placebo + ASA 8.8% N=9,478 Bhatt DL et al. JACC 2007;49:1982

20 20 Variable and Unpredictable Response to Clopidogrel 24 hrs after 300 mg Clopidogrel Gurbel PA et al. Circulation 2003; 107: ≤ -30 (-30,-20) (-20,-10) (-10,0) (0,10) (10,20) (20,30) (30,40) (40,50) (50,60) >60 >60  Platelet aggregation before and after Clopidogrel (%) Patients (%) Patients (%) “Resistance” = 31% N = 96 N = 96, Elective PCI “Resistance” = ≤ 10%  platelet aggregation

21 21 Clopidogrel Response Variability and Increased Risk of Ischemic Events Primary PCI for STEMI (N = 60) Matetzky S, et al. Circulation. 2004;109: Wiviott SD, Antman EM. Circulation :

22 Evolution of ACS Therapies Adapted from White HD et al. Lancet 2008; 372: 570–84 Aspirin Heparin Year Low molecular weight heparin IIb/IIIa receptor antagonist Early invasive management CLOPIDOGREL Atorvastatin Fondaparinux Bivalirudin IntegratedstrategyPRASUGREL

23 More Efficient and Less Variable Activation of Prasugrel Compared to Clopidogrel Clopidogrel CYP1A2, 2B6, 2C19 Intermediate Active Metabolite CYP3A, 2B6, 2C9, 2C19 Liver CYP2C19 variants and inhibitors affect the PK and PD of clopidogrel Liver 85% Inactive Metabolite hCE1 Prasugrel has no clinically relevant interactions with CYP2C19 variants or inhibitors Prasugrel Gut hCE2 Intermediate Active Metabolite Liver Gut and CYP3A, 2B6, 2C9, 2C19

24 Time (Hrs) Active Metabolite Concentration (ng/mL) Clopidogrel 300 mg LD Clopidogrel 600 mg LD Prasugrel 60 mg LD Higher Active Metabolite Concentrations of Prasugrel After Loading Dose C max and T max influence onset of platelet inhibition Relevant for loading dose but not maintenance dose AUC influences extent of platelet inhibition Relevant for loading and maintenance dose

25 25 Prasugrel 60 mg LD Achieves More Effective Platelet Inhibition than Clopidogrel *; p < vs. clop 300 mg/75 mg 600 mg/75 mg; † ; p < 0.05 vs. clop 300 mg/75 mg; ‡ ; p < vs. clop 300 mg/75 mg Time (Hrs) Inhibition of Platelet Aggregation (%) * * * * * * 0.0 Clopidogrel 300 mg LD Prasugrel 60 mg LD Clopidogrel 600 mg LD ‡ † ‡ ‡ ‡

26 75 mg (MD) 150 mg (MD) 225 mg (MD) 300 mg (MD) 900 mg (RD) Clopidogrel 10 mg (MD) Prasugrel % Aggregation ADP (20 µ M) 56 Time (Minutes) 80 Pena et al. Circulation 2009; 119: Platelet Aggregation in a Patient who Experienced Stent Thrombosis on Clopidogrel MD=maintenance dose, RD=reloading dose

27 Day 28 (0 hr) - Non Responders (%) Pras 60 mg Clop 300 mg Loading doseMaintenance dose 3% 52% 36% 21% 0% 45% Day 1 (4 hr) - Pras 40 mg Pras 5 mg Pras 7.5 mg Pras 10 mg Pras 15 mg Clop 75 mg Prasugrel 60 mg LD with 10 mg MD Demonstrates Superior Response Compared to Clopidogrel Jernberg et al., Eur Heart J 2006; 27:

28 TRITON-TIMI 38 Study Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint:CV death, MI, stroke 2 o endpoints:CV death, MI, stroke, rehosp-Rec Isch CV death, MI, UTVR Stent thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, life-threatening bleeds Key substudies:Pharmacokinetic, genomic Median duration of therapy - 12 months N = 13,608

29 Balance of Efficacy and Safety: All ACS Wiviott SD et al. NEJM 2007; 357: HR 1.32 ( ) P = events HR 0.81 ( ) P = Prasugrel Clopidogrel Days Endpoint (%) 12.1% 9.9% Prasugrel Clopidogrel 1.8% 2.4% 138 events CV death / MI / stroke NNT = 46 NNH = 167 TIMI major Non-CABG bleeds

30 Antiplatelet Therapy in ACS Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA ASA ASA + Clopidogrel ASA + Prasugrel - 22% - 20% - 19% + 60% + 38% + 32% Reduction in Ischemic Events Increase in Major Bleeds PlaceboAPTCCURETRITON-TIMI 38 Wiviott SD et al. NEJM 2007; 357: Ischemic events

31 Net Clinical Benefit in Subgroups: Death / MI / CVA / Major Bleed Post-Hoc Analysis OVERALL ≥ 60 kg < 60 kg < 75 yrs ≥ 75 yrs No Yes Prior TIA / stroke Age Weight Risk (%) HR P int = P int = 0.18 P int = 0.36 Wiviott SD et al. NEJM 2007; 357: Favors Prasugrel Favors Clopidogrel

32 Modified from Wiviott SD et al. NEJM 2007; 357: Balance of Efficacy and Safety in Patients < 75 Yrs, ≥ 60 kg, and without Prior TIA/Stroke Endpoint (%) Hazard Ratio, (95% CI, ) P = 0.17 Hazard Ratio, 0.75 (95% CI, ) P < Clopidogrel 11.0% Prasugrel 8.3% Clopidogrel 1.50% Prasugrel 2.0% Days CV death, NF MI, or NF stroke TIMI major bleeding

33 Kaplan-Meier estimates of the incidence of the primary composite endpoint and of non-CABG related TIMI Major bleeding for All ACS patients with diabetes Hazard Ratio, 1.06 (95% CI, ) p=0.81 All ACS Patients with Diabetes 12.2% 17.0% 2.5% 2.6% Hazard Ratio, (95% CI, ) p<0.001 Prasugrel Clopidogrel TIMI Major Bleeding Prasugrel CV Death, NF MI, or NF Stroke Days From Randomization or First Dose KM Estimates of Event Rate (%)

34 Therapeutic Considerations Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg Recommend Reduced MD Guided PK Wt 75 y 16% Avoid Prasugrel Prior CVA/TIA 4% Wiviott SD et al. NEJM 2007; 357:

35 Observed incidence and hazard ratios for primary composite endpoint (CV death, Nonfatal MI, or Nonfatal Stroke) and components of the primary and secondary endpoints for All ACS patients with diabetes. Clopidogrel % (n/N) Prasugrel % (n/N) Diabetic Population CV Death, NF MI, or NF Stroke All ACS 11.4 (180/1576) 15.8 (248/1570) UA/NSTEMI 10.8 (135/1246) 15.0 (184/1226) STEMI 13.6 (45/330) 18.6 (64/344) HR (95% CI) Subjects receiving Insulin CV Death, NF MI, or NF Stroke 13.7 (52/379) 20.2 (80/397) 10.7 (128/1197) 14.3 (168/1173) Subjects not receiving Insulin CV Death, NF MI, or NF Stroke Overall Population CV Death, NF MI, or NF Stroke Hazard RatioObserved Incidence 9.4 (643/6813) 11.5 (781/6795) ◄ Outcome Events ◄ Favors Prasugrel Favors Clopidogrel

36 Primary Endpoint Through 3 days With and Without PPI Use – TRITON-TIMI 38 UA/NSTEMI Yes No Yes No STEMI All ACS Yes No CV Death, NF MI, or NF Stroke Through 3 days Proton Pump Inhibitors HR (95% CI) Hazard Ratio Favors Prasugrel Favors Clopidogrel Clopidogrel % Prasugrel % Observed Incidence

37 High Risk Clinical Features Genetic Polymorphisms Drug-Drug Interactions ACS Managed with PCI Dual Antiplatelet Therapy 2.2% ARD in CVD/MI/Stroke (HR = 0.81; NNT = 46) 2.3% ARD in MI (HR = 0.76; NNT = 43) 1.22 % ARD in stent thrombosis (HR = 0.48; NNT = 82) Inhibition of Platelet Aggregation Faster, Greater, More Consistent

38 High Risk Clinical Features Genetic Polymorphisms Drug-Drug Interactions ACS Managed with PCI Dual Antiplatelet Therapy Inhibition of Platelet Aggregation Faster, Greater, More Consistent 0.6% ARD in non-CABG TIMI Major Bleeding (HR = 1.32; NNH = 167) Potential Mitigation of Bleeding Risk: Access site selection (radial vs femoral) Access site selection (radial vs femoral) Contraindication for prior TIA/Stroke Contraindication for prior TIA/Stroke Dose  in patients ≥75 yrs, or <60 kg Dose  in patients ≥75 yrs, or <60 kg

39 AspirinClopidogrelPrasugrel ?

40 August 30, 2009

41 TICAGRELOR: First and Only Approved CPTP  TICAGRELOR, a new chemical class, is a cyclo-pentyl-triazolo-pyrimidine (CPTP)  Ticagrelor is direct acting (not a pro- drug and does not require metabolic activation)  It binds directly to P2Y 12 receptors and reversibly interacts with the receptor, to prevent platelet activation and aggregation  Thienopyridines bind covalently to P2Y 12 ADP binding site for the life of the platelet P2Y 12 receptor on platelet Ticagrelor ADP binding site Husted S, et al. Eur Heart J. 2006;27:1038–1047. Gurbel PA, et al. Expert Opin Drug Metab Toxicol. 2009;5(8):989–1004. Van Giezen JJ, et al. J Thromb Haemost. 2009;7:

42 Inhibition of Platelet Aggregation: Onset Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) Time (Hours) Inhibition of Platelet Aggregation *P<0.0001Ticgrelor vs Clopidogrel Loading Dose Ticagrelor 180-mg loading dose in Stable CAD patients Clopidogrel 600-mg loading dose in Stable CAD patients * * * * Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585. * *

43 PLATO: Study Design Initial treatment approaches 18,624 patients with ACS (UA, NSTEMI, or STEMI*) randomized within 24 hours of symptom onset 180-mg loading dose 90 mg bid + ASA Maintenance dose Patients could be taking clopidogrel at time of randomization Medically managed (n=5,216 — 28.0%) Invasively managed (n=13,408 — 72.0%) Ticagrelor (n=9,333)Clopidogrel (n=9,293) 6–12 months of double-blind treatment 300-mg loading dose † 75 mg qd + ASA Maintenance dose Primary efficacy endpoint: Composite of CV death, MI (excluding silent MI), or stroke Primary safety endpoint: Total PLATO major bleeding ‡ *STEMI patients scheduled for primary PCI were randomized; however, they may not have received PCI. † A loading dose of 300-mg clopidogrel was permitted in patients not previously treated with clopidogrel, with an additional 300 mg allowed at the discretion of the investigator. ‡ The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients. The primary safety endpoint was the first occurrence of any major bleeding event. 1. Wallentin L, et al. N Engl J Med. 2009;361:1045– James S, et al. Am Heart J. 2009;157:599–605.

44 PLATO Main: Inclusion Criteria  Hospitalisation for STEMI or NSTEMI/UA ACS, with onset during previous 24 hours  With STEMI, the following 2 inclusion criteria were required Persistent ST elevation of at least 0.1 mV in ≥2 contiguous leads or new LBBB Primary PCI planned  With NSTEMI, at least 2 of the following 3 were required ST changes on ECG indicating ischaemia Positive biomarker indicating myocardial necrosis One of the following risk indicators  ≥60 years of age  Previous MI or CABG  CAD with ≥50% stenosis in ≥2 vessels  Previous ischaemic stroke, TIA, carotid stenosis (≥50%), or cerebral revascularisation  Diabetes mellitus  Peripheral artery disease  Chronic renal dysfunction (creatinine clearance <60 mL/min) James S, et al. Am Heart J. 2009;157:599–605.

45 PLATO Main: Key Exclusion Criteria  Contraindication to clopidogrel  Fibrinolytic therapy within 24 hours  Oral anticoagulation therapy that cannot be stopped  ACS event was a complication of previous PCI  PCI after index event (initial clinical signs and symptoms) and before first study dose  Increased risk for bradycardic events  Concomitant therapy with strong CYP3A inhibitors/inducers  Patients requiring dialysis James S, et al. Am Heart J. 2009;157:599–605.

46 PLATO: Baseline Characteristics Characteristic TICAGRELOR (n=9,333 ) Clopidogrel (n=9,291) Median age, years62.0 Age ≥75 years, n (%)1,396 (15.0)1,482 (16.0) Women, n (%)2,655 (28.4)2,633 (28.3) CV risk factors, n (%) Habitual smoker3,360 (36.0)3,318 (35.7) Hypertension6,139 (65.8)6,044 (65.1) Dyslipidemia4,347 (46.6)4,342 (46.7) Diabetes mellitus2,326 (24.9)2,336 (25.1) History, n (%) MI1,900 (20.4)1,924 (20.7) PCI1,272 (13.6)1,220 (13.1) CABG532 (5.7)574 (6.2) ECG at study entry, n (%) ST-segment elevation, persistent3,497 (37.5)3,511 (37.8) ST-depression4,730 (50.7)4,756 (51.2) T-wave inversion2,970 (31.8)2,975 (32.0) Troponin-I positive, n (%)7,965 (85.3)7,999 (86.0) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

47 Both groups included aspirin. *NNT at one year. PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) No. at risk Clopidogrel TICAGRELOR 9,291 9,333 Months After Randomization 8,521 8,628 8,362 8,460 8,1246,650 6,743 5,096 5,161 4,047 4,1478, Cumulative Incidence (%) 11.7 Clopidogrel 9.8 TICAGRELOR ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, 0.77−1.00) 0–30 Days Clopidogrel TICAGRELOR ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92) 0–12 Months

48 PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. All Patients* TICAGRELOR (n=9,333) Clopidogrel (n=9,291) HR for TICAGRELOR (95% CI) P Value ** Primary endpoint, n (%/year) Death from vascular cause + MI † + stroke 864 (9.8)1,014 (11.7)0.84 (0.77–0.92)<0.001 Secondary endpoints, n (%/yr) Death from any cause + MI † + stroke 901 (10.2)1,065 (12.3)0.84 (0.77–0.92)<0.001 Death from vascular causes + MI † + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus 1,290 (14.6)1,456 (16.7)0.88 (0.81–0.95)<0.001 MI † 504 (5.8)593 (6.9)0.84 (0.75–0.95)0.005 Death from vascular causes 353 (4.0)442 (5.1)0.79 (0.69–0.91)0.001 Stroke 125 (1.5)106 (1.3)1.17 (0.91–1.52)0.22 Death from any cause 399 (4.5)506 (5.9)0.78 (0.69–0.89) <0.001 ‡ Nominal Significance Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months. * Patients could have had more than one type of endpoint. Death from CV causes and fatal bleeding, as only traumatic fatal bleeds were excluded from the CV death category. ** By Cox regression analysis using treatment as factor; † Excluding silent MI; ‡ Death from any cause was tested after stroke, which was non-significant, so the results should be considered nominally significant.

49 Months After Randomisation Cumulative Incidence (%) Clopidogrel TICAGRELOR Clopidogrel TICAGRELOR Months After Randomisation Myocardial Infarction Cardiovascular Death Cumulative Incidence (%) PLATO: Secondary Efficacy Endpoints Rate of stroke for TICAGRELOR was not different from clopidogrel (1.3% vs 1.1% ), P= Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Supplement. BRILIQUE: Summary of Product Characteristics, ARR=1.1% RRR=16% Calculated NNT=91 P=0.005 HR: 0.84 (95% CI, 0.75–0.95) ARR=1.1% RRR=21% NNT=91 P=0.001 HR: 0.79 (95% CI, 0.69–0.91) Both groups included aspirin.

50 P=0.43 HR: 1.04 (95% CI, 0.95–1.13) PLATO: Primary Safety Endpoint PLATO-defined Total Major Bleeding (%) Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Days From First Dose Clopidogrel TICAGRELOR 11.2% 11.6% P=NS No. at risk Clopidogrel TICAGRELOR 9,186 9,235 7,305 7,246 6,930 6,826 6,6705,209 5,129 3,841 3,783 3,479 3,4336,545 Both groups included aspirin.

51 PLATO: Bleeding Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. All values presented by PLATO criteria. Both groups included aspirin. Major Bleeding Non-CABG-Major Bleeding Major and Minor Bleeding Life-threatening/ Fatal Bleeding Fatal Bleeding CABG-Major Bleeding K-M Estimated Rate (% Per Year) NS P = 0.03 P = NS

52 PLATO: Dyspnea  Ticagrelor-associated dyspnea was mostly mild to moderate in severity and did not reduce efficacy  Most events were reported as single episode occurring early after starting treatment  Not associated with new or worsening heart or lung disease  In 2.2% of patients, investigators considered dyspnoea causally related to treatment with Ticagrelor  Label precautions and warnings: use with caution in patients with history of asthma and COPD Ticagrelor: Summary of Product Characteristics, 2010.; Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. Storey R, et al. J Am Coll Cardio. 2010;55(Suppl 1):A108.E1007. Dyspnoea in the PLATO trialTicagrelorClopidogrelP Value Incidence of dyspnea adverse events (%) <0.001 Patients who discontinued treatment due to dyspnoea (%) <0.001

53 PLATO: Bradycardia-related Events All Patients Ticagrelor (n=9,235) Clopidogrel (n=9,186)P Value Bradycardia-related event, n (%) Pacemaker insertion 82 (0.9)79 (0.9)0.87 Syncope 100 (1.1)76 (0.8)0.08 Bradycardia 409 (4.4)372 (4.0)0.21 Heart Block 67 (0.7)66 (0.7)1.00 Ventricular pauses ≥3 seconds occurred in 5.8% of ticagrelor-treated patients vs 3.6% of clopidogrel-treated patients in the acute phase, and 2.1% and 1.7% after 1 month, respectively There were no differences in adverse clinical consequences (ie, pacemaker insertion, syncope, bradycardia, and heart block) Label precautions and warnings: Ticagrelor should be used with caution in patients at risk of bradycardic events Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

54 PLATO: Laboratory Parameters All Patients Ticagrelor (n=9,235) Clopidogrel (n=9,186)P Value Mean % increase (± SD) in serum creatinine from baseline At 1 month10 ± 228 ± 21<0.001 At 12 months11 ± 229 ± 22< month after end of treatment10 ± Mean % increase (± SD) in serum uric acid from baseline At 1 month14 ± 467 ± 44<0.001 At 12 months15 ± 527 ± 31< month after end of treatment7 ± 438 ± Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, Creatinine levels may increase during treatment with ticagrelor; renal function should be checked after 1 month and thereafter according to medical practice Label precautions and warnings: as a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged

55 PLATO Safety Results Summary  No increase in overall major bleeding with Ticagrelor vs clopidogrel  Non-CABG major bleeding and major + minor bleeding were more frequent with Ticagrelor vs clopidogrel  No increase in overall fatal/life-threatening bleeding with ticagrelor vs clopidogrel  There are more dyspnoea-related events associated with ticagrelor vs clopidogrel, however most events were mild to moderate in intensity and often resolved without a need for treatment  Ticagrelor should be used with caution in patients at risk of bradycardic events  Creatinine levels may increase during treatment with ticagrelor; renal function should be checked after 1 month and thereafter according to routine medical practice  Please reference the label for all precautions and warnings Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

56  Presented at ESC 2009 as an oral presentation  Subsequently published in Lancet, January 2010  A pre-specified objective of PLATO was to compare outcomes of Ticagrelol versus clopidogrel in patients with planned invasive strategy at randomization  For all patients, the intention for early invasive management had to be indicated by the investigator before patients were randomized Cannon CP, et al. Lancet. 2010;375:283−293. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study Christopher P. Cannon, Robert A. Harrington, Stefan James, et al. for the PLATelet inhibition and patient Outcomes (PLATO) investigators

57 PLATO Primary Endpoint: Initial Invasive vs Initial Non- Invasive Management Days After Randomisation James S, et al. ESC 2010; Poster #1353.; Cannon C, et al. Lancet. 2010;375:283– % 9% Clopidogrel Ticagrelor 6,676 6,732 6,129 6,236 6,034 6,134 5,8814,815 4,889 3,680 3,735 2,965 3,0485,972 Ticagrelor Clopidogrel Initial Invasive 72% of patients in PLATO P< HR: 0.84 (95% CI, 0.75–0.94) Initial Non-Invasive 28% of patients in PLATO 2,615 2,601 2,392 2,328 2,326 2,2431,835 1,854 1,416 1,426 1,109 1,0992,247 Ticagrelor Clopidogrel P<0.045 HR: 0.85 (95% CI, 0.73–1.00) 14.3% 12% Clopidogrel Ticagrelor K-M Estimated Rate Primary Composite of CV Death/MI/Stroke (%) No. at risk Days After Randomisation K-M Estimated Rate Primary Composite of CV Death/MI/Stroke (%)

58 PLATO Intent for Invasive Management: Primary Efficacy, Key Secondary Efficacy and Primary Safety Endpoints Endpoints* Ticagrelor (n=6,732) Clopidogrel (n=6,676) HR (95% CI) P Value ** Primary efficacy (%/year) CV death/MI † /stroke (0.75–0.94) Secondary efficacy (%/year) All-cause death + MI † + stroke (0.75–0.94) Death from vascular causes + MI † + stroke + severe recurrent ischaemia + recurrent ischaemia + TIA + arterial thrombus (0.77–0.93) MI † (0.69–0.92) CV death (0.68–0.98) Stroke (0.78–1.50) All-cause mortality (0.68–0.95) Primary safety (%/year) Total major bleeding (0.89–1.10) *Kaplan-Meier estimates at 360 days.**P value from univariate Cox model. † Excluding silent MI Cannon CP, et al. Lancet. 2010;375:283–293. Both groups included aspirin.

59 PLATO: Outcomes of Predefined Efficacy Endpoints A as Described in the EU Label Ticagrelor % patients with event (n=9,333) Clopidogrel % patients with event (n=9,291) ARR a (%/yr) RRR a (%) (95% CI) P Value CV Death + Mi b + stroke (8,23) Invasive intent (6, 25) Non-Invasive intent (0.3, 27) c CV death (9, 31) MI b (5, 25) Stroke (-52, 9) All-cause mortality + MI b + stroke (8, 23) CV Death + Mi b + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus (5, 19) All-cause mortality (11, 31) c Definitive stent thrombosis (8, 49) c Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months. a ARR=absolute risk reduction; RRR=relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates a relative risk increase.; b Excluding silent myocardial infarction.; c Nominal significance value; all others are formally statistically significant by pre-defined hierarchical testing. Ticagrelor: Summary of Product Characteristics, 2010.

60 Clinical Implications  In ACS patients with planned invasive management at randomisation in PLATO, compared with clopidogrel, ticagrelor significantly reduced the incidence of CV death/MI/stroke (primary efficacy endpoint)  Ticagrelol: 9.0% vs clopidogrel: 10.7% CV death  Ticagrelol: 3.4% vs clopidogrel: 4.3%  Consistent with the overall study, ticaggrelor had an increase in dyspnea in this patient population compared to clopidogrel  In PLATO, in ACS patients with a planned invasive management strategy, Ticagrelol was shown to be more effective than clopidogrel for the prevention of CV and total death without any significant increase in major bleeding*  Invasive study was consistent with the overall results from PLATO European Association for Percutaneous Cardiovascular Intervention, et al. Eur Heart J. 2010;31:2501–2555. Canadian Cardiovascular Society Anti Platelet Guidelines published online at Accessed February 12, Adapted form Cannon CP, et al. Lancet. 2010;375:283−293. * No overall increase in major bleeding in this sub-study, however there was an increase in the PLATO main non-CABG bleeding (Ticagrelor: 4.5% vs. clopidogrel 3.8%); and major and minor bleeding (Ticagrelor16.1% vs. clopidogrel 14.6%).

61 TICAGRELOR Indication  Ticagrelor, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in adult patients with acute coronary syndromes (unstable angina, non–ST-elevation myocardial infarction [NSTEMI] or ST-elevation myocardial infarction [STEMI]); including patients managed medically, and those who are managed with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) Ticagrelor: Summary of Product Characteristics, By DiagnosisBy Treatment UA/NSTEMISTEMIMedical management PCICABG   If clinically indicated, Ticagrelor should be used with caution in the following patient groups: Patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg, non-steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of ticagrelor dosing

62 Contraindications  Contraindications specific to Ticagrelor Hypersensitivity to the active substance (ticagrelor) or to any of the excipients Active pathological bleeding History of intracranial hemorrhage Moderate-to-severe hepatic impairment Combination with strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, nefazodone, ritonavir and atazanavir is contraindicated, as co- administration may lead to substantial increases in exposure to Ticagrelor Ticagrelor: Summary of Product Characteristics, 2010.

63 Special Warnings and Precautions  Precautions specific to Ticagrelor The use of Ticagrelor in patients at known increased risk for bleeding should be balanced against the benefits Ticagrelor should be discontinued 7 days prior to elective surgery Ticagrelor should be used with caution in patients with a history of asthma and/or COPD Ticagrelor should be used with caution in patients at risk of bradycardic events Ticagrelor should be used with caution in the following patient groups: patients with concomitant administration of medicinal products that may increase the risk of bleeding (eg, non- steroidal anti-inflammatory drugs (NSAIDs), oral anticoagulants and/or fibrinolytics) within 24 hours of Ticagrelor dosing Ticagrelor: Summary of Product Characteristics, 2010.

64 Special Warnings and Precautions  Precautions specific to Ticagrelor As a precautionary measure, the use of Ticagrelor in patients with uric acid nephropathy is discouraged Creatinine levels may increase during treatment with ticagrelor. Renal function should be checked after 1 month and thereafter according to routine medical practice High maintenance dose of ASA (>300 mg) is not recommended The concomitant use of Ticagrelor with doses of simvastatin >40 mg is not recommended Ticagrelor: Summary of Product Characteristics, 2010.

65 Expanding bleeding criteria to capture Minor and Minimal bleeding TIMI [Rao 1988:A] PLATO [James 2009:B] Minor Observed blood loss: clinically overt sign of hemorrhage with ↓hemoglobin 3-5 g/dL or >10% decrease in hematocrit* No observed blood loss: ↓hemoglobin ≥4 g/dL or 12% decrease in hematocrit Requires medical intervention to stop or treat bleeding Minimal Clinically overt sign of hemorrhage with ↓hemoglobin <3 g/dL or <9% decrease in hematocrit All others not requiring intervention (eg, bruising, bleeding gums, oozing from injection sites, etc) *TIMI minor bleeding resembles PLATO major bleeding by hemoglobin drop; † See Slide 8 for severe bleeding definitions Rao AK, et al. J Am Coll Cardiol.1988;11:1-11; The GUSTO Investigators. N Engl J Med.1993;329: ; Yusuf S, et al. N Engl J Med. 2001;345: ; James S, et al. Am Heart J. 2009;157:

66 Expanding the Definition of Major Bleeding Criteria in Clinical trials TIMI [Rao 1988:A] PLATO [James 2009:B] MajorMajor (fatal/life-threatening) Fatal/life-threatening (related to instrumentation, spontaneous, trauma) Fatal ICH ↓ >5 g/dL hemoglobin↓ ≥5 g/dL hemoglobin ↓ 15% absolute hematocrit≥4 unit transfusion Hypotension requiring pressors or surgery; intrapericardial with tamponade; hypovolemic shock Other Major Substantially disabling (eg, intraocular with permanent vision loss) 2-3 unit transfusion ↓ 3-5 g/dL hemoglobin ICH, intracranial hemorrhage; N/S, not specified Rao AK, et al. J Am Coll Cardiol. 1988;11:1-11;The GUSTO Investigators. N Engl J Med. 1993;329: ; Yusuf S, et al. N Engl J Med. 2001;345: ; James S, et al. Am Heart J. 2009;157:

67 Ticagrelor: important characteristics  Ticagrelor is a cyclopentyltriazolopyrimidine (CPTP): direct acting and reversibly interacts with the platelet P2Y 12 ADP-receptor [Husted 2006:A; Cannon 2007:A]  Phase 1 and 2 studies demonstrated [Husted 2006:B;C] : A rapid onset of inhibitory effect  Important for urgent management in ACS Greater and more consistent platelet inhibition than clopidogrel [Husted 2006:D; Storey 2007:A,B]  Less variability in individual response  Higher average inhibition of platelet aggregation  Reversibly binding to the P2Y 12 receptor [Husted 2006:D; Cannon 2007:A] Faster offset of platelet inhibition than clopidogrel in a pharmacodynamic (PD) and pharmacokinetic (PK) study in stable coronary artery disease (CAD) patients [Gurbel 2009:G] Recovery of platelet function does not depend on generation of new platelets Husted SE, et al. Eur Heart J. 2006;27: ; Cannon CP. J Am Coll Cardiol. 2007;50: ; Storey RF, et al. J Am Coll Cardiol. 2007;50: ; Gurbel PA, et al. Circulation. 2009;120:

68 Ticagrelor – pharmacokinetic parameters AbsorptionRapidly absorbed in the small intestine [Husted 2009:B; EMEA Label:A] Distribution~99.7% bound to human plasma protein [EMEA Label:B] Metabolism Predominantly metabolized by CYP3A4/5 in the liver, which may account for drug/drug interactions [Teng 2010:A; EMEA Label:C] Metabolized to active metabolite (AR-C124910XX) and/or inactive metabolites [Teng 2010:A; EMEA Label:A,D] Elimination Primarily eliminated via biliary secretion [EMEA Label:E] Less than 1% excreted in urine [EMEA Label:E; Husted 2009:F] Pharmacokinetics Peak plasma concentrations and steady state are dose-proportional and occur between 1.5 and 3 hours [EMEA Label:A; Butler 2008:A] Half life ~8 hours [EMEA Label: E; Teng 2010:B] Dosing with food increases the area under the curve (AUC) ~20% [EMEA Label: F; Butler 2008:B] AR-C124910XX (half-life ~10 hrs) accounts for ~30% to 40% of total activity [EMEA Label: D,E;Teng 2010:B] Husted S, et al. Cardio Ther. 2009;27: ; Butler K et al, Can J Clin Pharmacol. 2008;15:e684-e685 [Abstract 562]; Teng R. Eur J Clin Pharmacol. 2010;66: Data on File, Investigator’s Brochure.

69 Key drug interactions Data on file, Investigator’s Brochure. DrugPrimary usageEffect Warning on ticagrelor label Ketoconazole (strong CYP3A4 inhibitor) AntifungalTicagrelor C max 2.4x and AUC 7.3x a Coadministration is contraindicated Diltiazem (moderate CYP3A4 inhibitor) Vasodilation; angina; hypertension Ticagrelor C max by 69% and AUC 2.7x b Can be coadministered Rifampin (CYP3A inducer) Antibacterial Ticagrelor C max by 73% and AUC by 86% c Coadministration is discouraged Desmopressin/heparin/ enoxaparin/aspirin Alter hemostasis No effect on ticagrelor or on ADP-induced platelet aggregation Coadminister with caution Verapamil (potent P-gp inhibitor) Antihypertensive; antianginal Unknown d Coadminister with caution Simvastatin (CYP3A4 substrate) Control hypercholesterolemia Simvastatin C max by 81% and AUC by 56%; no effect on ticagrelor Coadministration with > 40 mg simvastatin is not recommended Atorvastatin (CYP3A4 substrate) Control hypercholesterolemia Atorvastatin acid C max by 23% and AUC by 36%None Levonorgesterol+ethinyl estradiolOral contraceptive Ethinyl estradiol exposure by ≈20%; no effect on levonorgesterol None Digoxin (P-gp substrate) Strengthen cardiac contractions; congestive heart failure Digoxin C max by 75% and AUC by 28%; no effect on ticagrelor Close clinical and laboratory monitoring is recommended e a Similar effects would be expected for other strong inhibitors of CYP3A4 (eg, clarithromycin, nefadozone, ritonavir, atazanavir) b Similar effects would be expected for other moderate inhibitors of CYP3A4 (eg, amprenavir, aprepitant, erythromycin, fluconazole) c Similar effects would be expected for other inducers of CYP3A (eg, dexamethasone, phenytoin, carbamazepine, phenobarbitol) d Data are also unavailable for other potent P-gp inhibitors (eg, quinidine, cyclosporine) e Appropriate monitoring is also recommended when giving other narrow therapeutic index P-gp dependent medications (eg, cyclosporine) ; AUC, area under the concentration vs time curve; C max, maximum plasma concentration; P-gp, P-glycoprotein

70 Aspirin Clopidogrel Prasugrel Ticagrelor ?

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75 1.The availability, of new treatment alternatives for stroke prevention in patients with nonvalvular atrial fibrillation is a great step forward to further improve outcomes and quality of life. 2.Compared with warfarin, these new alternatives have important advantages, with their lower risk of intracranial bleeding, no clear interactions with food, fewer interactions with medications, and no need for frequent laboratory monitoring and dose adjustments. 3.Dabigatran etexilate is a synthetic low molecular weight peptidomimetic that binds directly and reversibly to the catalytic site of thrombin. 4.Rivaroxaban, apixaban, and endoxaban are selective direct factor Xa inhibitors. 5.Based on the currently available results from the individual trials, it is clear that both the oral direct thrombin inhibitor dabigatran etexilate and the oral factor Xa inhibitors apixaban and rivaroxaban are attractive alternatives to warfarin or aspirin in patients with nonvalvular atrial fibrillation and an increased risk of stroke. New Anticoagulants in AF and ACS Perspective:

76 6.Apixaban 5 mg (with dose reduction to 2.5 mg in specific cases) BID is currently the best documented alternative to both warfarin and aspirin for stroke prevention in a broad population with atrial fibrillation and increased risk of stroke, based on two independent large-scale trials. Apixaban is awaiting Food and Drug Administration approval in the United States for atrial fibrillation. 7.Patients already on long-term vitamin K antagonist (VKA) treatment, with well- controlled international normalized ratio and handling VKA treatment and laboratory monitoring without problems, derive uncertain overall advantages from switching to the new oral anticoagulants, and the arguments for changing treatment in such patients appear weak. 8.There is also a need for more information on how to manage patients with bleeding because there are no specific antidotes for any of the new agents. 9.The cost of the drug at the patient level might be an obstacle to their use, although the cost-effectiveness at a societal level might be tolerable in comparison with other recently accepted novel treatments. 10.Additional trials are indicated to determine the utility of these agents in combination with antiplatelet treatments after myocardial infarction and percutaneous coronary intervention. New Anticoagulants in AF and ACS Perspective:

77 PCI Optimal ED Treatment: Non-ST Elevation ACS, with Cath Lab Low Molecular Weight Heparin/UFH Gp IIb/IIIa ASA + CLOPIDOGREL or PRASUGREL or TICAGRELOL

78 MM v T Optimal ED Treatment: Non-ST Elevation ACS, without Cath Lab Gp IIb/IIIa LOW MOLECULAR WEIGHT HEPARIN / UFH ASA + CLOPIDOGREL or PRASUGREL or TICAGRELOL

79 ST- ELEVATION ACS Treatment  Emergency physicians should be using optimal therapy for ACS in the ED. In the STE ACS patient, time = muscle. Whether the patient is managed interventionally or medically, the treatment imperative starts in the ED.  In thrombolytic therapy, enoxaparin with TNKase or t- PA appears to be superior to UFH.  In interventional management, enoxaparin was superior to UFH in ENTIRE / TIMI-23.

80 “Best Practice” Approach to the ACS Patient Anti-ischemic therapy Anti-thrombotic therapy Ongoing risk stratification Invasive procedures (when appropriate) ASA + antiplatelet / anticoagulant as background therapy LMWH: anticoagulant of choice Enoxaparin:- superior to UFH -  recurrent ACS -  recurrent ACS -  hospital stay -  hospital stay -  costs -  costs Therapeutic approach ASA + anticoagulant + GPIIb/IIIa in high risk patients Area of concern

81 Thank you for your attention!


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