Acute Coronary Syndrome:

Acute Coronary Syndrome:
Antiplatelets and Antithrombotics 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

Disclosures Member of Advisory Board: Astra-Zeneca MSD Pfizer Servier
Receives honorarium for lectures or drug trials Have no financial interest in any drug company. Disclosures

Milestones in ACS Management
Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative LMWH ESSENCE Bivalirudin REPLACE 2 OASIS-5 [ Fondaparinux ] GP IIb/IIIa blockers PRISM-PLUS PURSUIT CURE Clopidogrel TACTICS TIMI-18 Early invasive ICTUS The treatment of UA/NSTEMI has evolved considerably over the last decade. In the early 1990s, the “standard” of care was aspirin, unfractionated heparin, a conservative management strategy, and, if done, PCI involved primarily balloon angioplasty. Subsequently a number of management options (upper portion of the slide) as well as major trials (middle portion of the slide) have come forward. The clinical availability of GP IIb/IIIa blockers (green) in 1995, with trials such as PRISM-PLUS and PURSUIT (also in green) showing their efficacy in UA/NSTEMI patients, particularly those undergoing coronary intervention. The LMWH enoxaparin was studied in the mid-1990s in ESSENCE (in dark blue), and was released for use in unstable angina in Clopidogrel (in orange) released in 1998, was a mainstay of therapy for coronary intervention (particularly the rapidly-growing world of stents). It’s utility in UA/NSTEMI was confirmed in the large scale CURE trial. Bivalirudin also was approved (based on the REPLACE 2 trial) for use as procedural anticoagulation for PCI in about Finally, on the basis of trials such as TACTICS, the rapid invasive management strategy began to predominate, particularly in the US, in the late 1990s. Newer data (gray boxes) have come forward (the trial names are color-coded to correspond to the agent and prior trials) that need to be assimilated into modern-day practice. Trials such as SYNERGY ( enoxaparin vs UFH in high-risk ACS patients managed with a rapid invasive management strategy), OASIS 5 (fondaparinux vs enoxaparin in higher-risk ACS), ICTUS (testing a rapid invasive strategy versus a selective invasive strategy in troponin (+) patients). ISAR-REACT 2 (assessing the utility of abciximab in ACS patients already pre-loaded with high doses of clopidogrel), and ACUITY(evaluating bivalirudin in rapidly invasively managed UA/NSTEMI) are going to help define the practice standards for the future. In the bottom of the slide are schematic graphs of the general trends in bleeding and thrombotic (ischemic) events over this same period. The arrival of GP IIb/IIIa antagonists brought with it substantial increases in bleeding. Thienopyridines both reduced this rate (by substituting for IIb/IIIa antagonists in lower-risk patients) and worsened it (by further adding to the antithrombotic milieu. Enoxaparin had some issues in that it did not fit well with anticoagulation management (traditionally done with ACTs and UFH in the cath lab). The emerging early invasive strategy served to further highlight the importance of the transition to the cath lab. The arrival of bivalirudin brought with it an option for reducing the risk of bleeding complications. With time, better technologies, and better adjunctive therapies the clinical events rates have continued to fall, but this is to a large extent somewhat balanced by the emerging use of more sensitive markers for myocardial damage (such as troponin). ISAR-REACT 2 SYNERGY ACUITY 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 PCI ~ 5% stents ~85% stents Drug-eluting stents Ischemic risk Bleeding risk Adapted from and with the courtesy of Steven Manoukian, MD

Evolution of ACS Therapies
IIb/IIIa receptor antagonist CLOPIDOGREL Atorvastatin Low molecular weight heparin Fondaparinux DABIGATRAN Bivalirudin Aspirin Oral antiplatelet agents have been the cornerstone of therapy for preventing adverse vascular events in a spectrum of patients with atherothrombotic disease. While evidence from large outcome trials has demonstrated unequivocal clinical benefit, data from registries have indicated that atherothrombotic patients are undertreated with antiplatelet agents. This gap in treatment places patients with atherothrombotic disease at increased risk for additional cardiovascular events. Despite this abundance of recent information on oral antiplatelet therapy for atherosclerotic cardiovascular disease, unresolved issues remain about its optimal use. And because of these reasons, we welcome a new antiplatelt therapy –Prasugrel (Effient) with its net clinical benefit to promising to improve individual patient outcome.. Heparin Integrated strategy Early invasive management 1990 1996 1997 2000 2001 2005 2007 2008 Year Adapted from White HD et al. Lancet 2008; 372: 570–84

Proportional effects of antiplatelet therapy on Vascular events in five main high risk categories
A metaanalysis was done on antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk patients by the Antithrombotic trialist collaboration. Information about serious vascular events (nonfatal myocardial infarction, nonfatal stroke, or vascular death) was available from 287 trials of antiplatelet treatment versus control among a total of 135,000 patients at high risk of occlusive arterial disease. When we subdivided the trials into five main Meta-analyses have demonstrated clear reductions in the combined outcome of any serious vascular event by one quarter among high risk patients (those with prior myocardial infarction, acute myocardial infarction, previous stroke or transient ischemic attack,acute stroke, stable angina,peripheral arterial disease and atrial fibrillation). Overall, Aspirin produced a 34% reduction in non-fatal myocardial infarction with a P < Aspirin produced a 25% proportional reduction in non-fatal stroke with no significant heterogeneity between the proportional reductions in the five high risk categories of the patient. Aspirin produced a highly significant 15% proportional reduction in vascular deaths. Hence, treatment with aspirin has been proven to beneficial in patients with cardiovascular disease. Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71–86.

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

Clopidogrel: Mechanism
ADP Receptor (P2Y12) Clopidogrel Ticlopidine ADP ADP GP IIb/IIIa receptor Collagen Thrombin TXA2 Activation Fibrinogen COX TXA2 ADP = adenosine diphosphate, TXA2 = thromboxane A2, COX = cyclooxygenase. Adapted from Schafer AI. Am J Med. 1996;101:

Clopidogrel in NSTE ACS: CURE
12,563 Pts, GP IIb/IIIa & early invasive approach discouraged 0.14 Placebo (11.4%) 0.12 0.10 Clopidogrel (9.3%) 0.08 CV Death, MI, Stroke 0.06 RR 0.80, p<0.001 0.04 0.02 0.0 3 6 9 12 Months of follow-up CURE. NEJM 2001;345:

CURE: Very Early Efficacy of Clopidogrel in NSTE ACS
CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours 0.025 34% Relative Risk Reduction 0.020 Placebo + Aspirin (n=6303) 0.015 Cumulative Hazard Rate 0.010 P=.003 Clopidogrel + Aspirin (n=6259) 0.005 0.0 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Randomization Yusuf S et al. Circulation 2003;107:

CURE: Benefit by Revascularization
Medical Rx Group Placebo Clopidogrel RR: 0.80 ( ) 0.20 4 0.15 0.10 0.05 0.0 100 200 300 0.20 4 0.15 0.10 0.05 0.0 100 200 300 PCI Group Placebo RR: 0.72 ( ) CVD/MI/Stroke CVD/MI/Stroke Clopidogrel 0.20 4 0.15 0.10 0.05 0.0 100 200 300 CABG Group Placebo Clopidogrel RR: 0.89 ( ) CVD/MI/Stroke Fox et al. Circulation. 2004;110:

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

Clopidogrel in STEMI 36%  P<0.0001 Placebo 20% Clopidogrel
15 36%  P<0.0001 Placebo 20% 10 Clopidogrel CV Death, MI, or Urg Revasc (%) 5 Odds Ratio 0.80 (95% CI ) P=0.026 Clopidogrel Placebo 5 10 15 20 25 30 days Sabatine MS et al. NEJM 2005; 352: 1179

COMMIT: Clopidogrel (75 mg qd) in STEMI
45,851 Patients p/w STEMI w/in 24 hrs; ASA; lytic therapy (~1/2) Placebo (10.1%) Placebo (8.1%) 9 8 7 6 5 4 3 2 1 7 6 5 4 3 2 1 Clopidogrel (9.3%) Clopidogrel (7.5%) Death, MI, Stroke (%) Mortality (%) The COMMIT trial demonstrated that clopidogrel reduces the relative risk of the primary endpoint of death by 7% (p=0.03). Thus, it can be concluded that clopidogrel (75 mg once daily) is beneficial, on a background of standard treatment including ASA, in a wide range of acute STEMI patients1 The results of the metoprolol arm of COMMIT are to be presented separately from the clopidogrel results. There is no significant interaction between the two active treatments in the trial. Therefore, all comparisons will be conducted separately (clopidogrel versus placebo and metoprolol versus placebo) Reference 1. Chen ZM et al. ACC 2005. 9% relative risk reduction (P=.002) 7% relative risk reduction (P=.03) 7 14 21 28 7 14 21 28 Days Days COMMIT Collaborative Group. Lancet. 2005;366:1607.

PCI-CLARITY Design 3491 Patients Randomized into CLARITY-TIMI 28
1739 assigned placebo 1752 assigned clopidogrel 300 mg  75 mg/d (NO PRETREATMENT) (CLOPIDOGREL PRETREATMENT) Open-label clopidogrel w/ loading dose recommended A n g i o g r a p h y 933 underwent PCI during index hosp. 930 underwent PCI during index hosp. 30-day clinical follow-up

CV Death, MI, or Stroke following PCI
8 Odds Ratio 0.54 (95% CI ) P=0.008 No Pretreatment – 6.2% 6 46% Percentage with outcome (%) 4 Clopidogrel – 3.6% Pretreatment 2 Sabatine MS et al. JAMA 2005;294: 10 20 30 Days post PCI

Meta-Analysis of Clopidogrel Pretreatment
MI before PCI (%) Clopidogrel No Trial Pretreatment Pretreatment PCI-CURE CREDO n/a n/a PCI-CLARITY Overall Clopidogrel No PCI-CURE CREDO PCI-CLARITY Overall Favors Pretreatment Favors No Pretreatment OR 0.67 P=0.005 CV Death or MI after PCI (%) 0.25 0.5 1.0 2.0 OR (95% CI) OR 0.71 P=0.004 0.25 0.5 1.0 2.0 Sabatine MS et al. JAMA 2005;294: OR (95% CI)

Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA): Study Design N=15,603 Clopidogrel 75 mg once daily (n=7600) Patients 45 years or older who are at high risk of atherothrombotic events Aspirin mg once daily Clopidogrel has been shown to reduce the incidence of recurrent ischemic events in patients with acute coronary syndromes or in those undergoing coronary stenting, but a substantial number of CV episodes continue to occur. A prospective study by Matetzky, et al was initiated in 60 consecutive patients with STEMI who underwent PCI with stenting to determine whether clinical outcomes are affected by variability in response to clopidogrel. All patients received aspirin on admission and throughout the study period. Patients were stratified into quartiles according to change in ADP-induced platelet aggregation in response to clopidogrel treatment from day 1 (baseline) to day 6; those in the first quartile exhibited the least change, while those in the fourth quartile exhibited the most. This slide shows study patients stratified into quartiles according to degree of platelet activity inhibition in response to clopidogrel treatment. Patients in 4 quartiles were compared with regard to (a) changes in ADP-induced platelet aggregation expressed as percentage of baseline activity; (b) percentage reduction in aggregate size at day 6 compared with baseline values; and (c) incidence of recurrent major adverse cardiovascular events during a 6-month follow-up. This study suggests that up to 25% of STEMI patients undergoing primary PCI with stenting are clopidogrel-resistant and may be at increased risk for recurrent events. R Double-blind treatment up to 1,040 primary efficacy events occur* Aspirin 75–162 mg once daily Placebo 1 tab once daily (n=7600) Final study visit (fixed study end date) *Event-driven trial: primary efficacy outcome of vascular death, MI, stroke 1-month visit 3-month visit Visits every 6 months (12 m, 18 m…), and intermediate phone calls in between (15 m, 21m…) 6-month visit R = randomization. Bhatt et al. Am Heart J. 2004;148:263 Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004;109:

Overall Population: Primary Efficacy Outcome (CV Death, MI, or Stroke)
Cumulative event rate (%) 2 4 6 8 Months since randomization 12 18 24 30 Placebo + ASA 7.3% Clopidogrel + ASA 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22 The primary efficacy endpoint in CHARISMA was a cluster of the first occurrence of fatal or nonfatal MI, or fatal or nonfatal stroke (of any cause), or cardiovascular death (including haemorrhagic death) With a median of 28 months of follow-up, the primary event rate was 6.8% in the clopidogrel plus aspirin arm and 7.3% in the placebo plus aspirin arm (p=0.22, relative risk [RR] 0.93, 95% confidence interval [CI] 0.83, 1.05) (Figure 1). This reduction was not statistically significant (p=0.217) 1 The yearly primary outcome events rates were 3.12% and 3.36% for clopidogrel plus ASA vs. placebo plus ASA, respectively Clopidogrel plus ASA prevented 39 primary events overall during the study follow-up1 The Kaplan-Meier curve of the primary endpoint shows that the curves separate very early after randomization, and continue diverging over time, which indicates a continuous trend in favor of the clopidogrel and ASA treatment arm. 1 Bhatt DL, Fox KA, Hacke W, et al. 2006, in press. Bhatt DL et al. NEJM 2006;354:

Primary outcome event rate (%) Months since randomization
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 (%) 2 4 6 8 10 Months since randomization 12 18 24 30 Clopidogrel + ASA 7.3% Placebo + ASA 8.8% N=9,478 A post-hoc analysis of patients (n=9478) with a previous MI, stroke, or PAD (similar to the entry criteria for the CAPRIE trial) showed a significant 17.1% RRR in favor of clopidogrel plus ASA over ASA alone Bhatt DL et al. JACC 2007;49:1982

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

Clopidogrel Response Variability and Increased Risk of Ischemic Events Primary PCI for STEMI (N = 60) 20 40 60 80 100 120 10 30 5 µM ADP induced plt agg Death/ACS/CVA by 6 m Days 1 2 3 4 5 6 Baseline (%) Quartiles of response Q1 Q2 Q3 Q4 Clop resist 6.7 Percent P = 0.007 Matetzky S, et al. Circulation ;109: Wiviott SD, Antman EM. Circulation :

Evolution of ACS Therapies
IIb/IIIa receptor antagonist CLOPIDOGREL Atorvastatin Low molecular weight heparin PRASUGREL Fondaparinux Bivalirudin Aspirin Heparin Integrated strategy Early invasive management 1990 1996 1997 2000 2001 2005 2007 2008 Year Adapted from White HD et al. Lancet 2008; 372: 570–84

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

Active Metabolite Concentration
Higher Active Metabolite Concentrations of Prasugrel After Loading Dose 600 Cmax and Tmax 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 500 400 Active Metabolite Concentration (ng/mL) 300 Prasugrel 60 mg LD Clopidogrel 600 mg LD Clopidogrel 300 mg LD 100 2 4 6 8 Time (Hrs)

Platelet Aggregation (%)
Prasugrel 60 mg LD Achieves More Effective Platelet Inhibition than Clopidogrel 100 * * * * * 80 Clopidogrel 600 mg LD ‡ † * 60 Platelet Aggregation (%) Inhibition of Clopidogrel 300 mg LD 40 20 Prasugrel 60 mg LD -10 0.0 0.25 0.5 1 2 4 6 24 Time (Hrs) *; 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

Platelet Aggregation in a Patient who Experienced Stent Thrombosis on Clopidogrel
1 2 3 4 -20 20 40 60 % Aggregation ADP (20 µ M) 5 6 Time (Minutes) 80 75 mg (MD) 150 mg (MD) 225 mg (MD) 300 mg (MD) 900 mg (RD) Clopidogrel 10 mg (MD) Prasugrel MD=maintenance dose, RD=reloading dose Pena et al. Circulation 2009; 119:

Jernberg et al., Eur Heart J 2006; 27:1166-1173
Prasugrel 60 mg LD with 10 mg MD Demonstrates Superior Response Compared to Clopidogrel 60 52% 50 Loading dose Maintenance dose 45% 40 36% Non Responders (%) 30 - - 21% 20 10 3% 3% 0% 0% Pras 40 mg Pras 60 mg Clop 300 mg Pras 5 mg Pras 7.5 mg Pras 10 mg Pras 15 mg Clop 75 mg Day 1 (4 hr) Day 28 (0 hr) Jernberg et al., Eur Heart J 2006; 27:

TRITON-TIMI 38 Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI ASA N = 13,608 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 60 mg LD/ 10 mg MD Median duration of therapy - 12 months 1o endpoint: CV death, MI, stroke 2o 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 28

Balance of Efficacy and Safety: All ACS
15 138 events Clopidogrel 12.1% CV death / MI / stroke HR 0.81 ( ) P = 10 9.9% Prasugrel NNT = 46 Endpoint (%) 5 35 events TIMI major Non-CABG bleeds Prasugrel 2.4% HR 1.32 ( ) P = 0.03 1.8% Clopidogrel NNH = 167 30 60 90 180 270 360 450 Days Wiviott SD et al. NEJM 2007; 357: 29

Antiplatelet Therapy in ACS
ASA ASA + Clopidogrel 100 ASA + Prasugrel - 22% Reduction in Ischemic Events - 20% - 19% Ischemic events Increase in Major Bleeds + 60% + 38% + 32% Placebo APTC CURE TRITON-TIMI 38 Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA Wiviott SD et al. NEJM 2007; 357: 30

Net Clinical Benefit in Subgroups: Death / MI / CVA / Major Bleed Post-Hoc Analysis
Risk (%) + 54 Yes Prior TIA / stroke -16 No Pint = 0.006 ≥ 75 yrs -1 Age < 75 yrs Pint = 0.18 -16 < 60 kg +3 Weight ≥ 60 kg Pint = 0.36 -14 -13 OVERALL 0.5 Favors Prasugrel 1 Favors Clopidogrel 2 HR Wiviott SD et al. NEJM 2007; 357: 31

CV death, NF MI, or NF stroke
Balance of Efficacy and Safety in Patients < 75 Yrs, ≥ 60 kg, and without Prior TIA/Stroke 16 CV death, NF MI, or NF stroke 14 Clopidogrel 11.0% 12 Hazard Ratio, 0.75 (95% CI, ) P < 0.001 10 Endpoint (%) 8 Prasugrel 8.3% 6 TIMI major bleeding 4 Hazard Ratio, 1.240 (95% CI, ) P = 0.17 Prasugrel 2.0% 2 Clopidogrel 1.50% 30 90 180 270 360 450 Days Modified from Wiviott SD et al. NEJM 2007; 357:

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. All ACS Patients with Diabetes 20 Clopidogrel 17.0% CV Death, NF MI , or NF Stroke Hazard Ratio, 0.705 (95% CI, ) p<0.001 15 S Prasugrel 12.2% KM Estimates of Event Rate (%) 10 5 Prasugrel 2.6% Hazard Ratio, 1.06 (95% CI, ) p=0.81 TIMI Major Bleeding Clopidogrel 2.5% 30 90 180 270 360 450 Days From Randomization or First Dose

Therapeutic Considerations
Recommend Reduced MD Guided PK Wt < 60 kg Age > 75 y Avoid Prasugrel Prior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg Wiviott SD et al. NEJM 2007; 357: 34 34

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. Observed Incidence Hazard Ratio Prasugrel % (n/N) Clopidogrel % (n/N) Outcome Events Overall Population CV Death, NF MI, or NF Stroke 9.4 (643/6813) 11.5 (781/6795) Diabetic Population CV Death, NF MI, or NF Stroke 11.4 (180/1576) 15.8 (248/1570) All ACS 10.8 (135/1246) 15.0 (184/1226) UA/NSTEMI 13.6 (45/330) 18.6 (64/344) STEMI ◄ Subjects receiving Insulin CV Death, NF MI, or NF Stroke 13.7 (52/379) 20.2 (80/397) ◄ Subjects not receiving Insulin CV Death, NF MI, or NF Stroke 10.7 (128/1197) 14.3 (168/1173) 0.5 Favors Prasugrel 1.0 Favors Clopidogrel 2.0 HR (95% CI)

CV Death, NF MI, or NF Stroke Proton Pump Inhibitors
Primary Endpoint Through 3 days With and Without PPI Use – TRITON-TIMI 38 Observed Incidence CV Death, NF MI, or NF Stroke Through 3 days Hazard Ratio Prasugrel % Clopidogrel % Proton Pump Inhibitors All ACS 4.9 6.1 Yes 4.5 5.3 No UA/NSTEMI 4.7 5.7 Yes 4.4 5.2 No STEMI 5.3 7.3 Yes No 4.9 5.7 Favors Prasugrel Favors Clopidogrel 0.5 1.0 2.0 HR (95% CI)

Inhibition of Platelet Aggregation Faster, Greater, More Consistent
ACS Managed with PCI Dual Antiplatelet Therapy High Risk Clinical Features Genetic Polymorphisms Drug-Drug Interactions Inhibition of Platelet Aggregation Faster, Greater, More Consistent 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
ACS Managed with PCI Dual Antiplatelet Therapy High Risk Clinical Features Genetic Polymorphisms Drug-Drug Interactions 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) Contraindication for prior TIA/Stroke Dose  in patients ≥75 yrs, or <60 kg

Aspirin Clopidogrel Prasugrel ?

August 30, 2009

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 P2Y12 receptors and reversibly interacts with the receptor, to prevent platelet activation and aggregation Thienopyridines bind covalently to P2Y12 ADP binding site for the life of the platelet ADP binding site Title: TICAGRELOR: First and Only CPTP Key Points: Ticagrelor is the first in a new chemical class, the cyclo-pentyl-triazolo-pyrimidines (CPTPs), which are selective ADP-receptor antagonists that act on the P2Y12 ADP-receptor It is orally active and does not require hepatic metabolism for activity Ticagrelor binds directly to P2Y12 receptors to reversibly inhibit platelet activation and aggregation This is different from thienopyridines as they bind covalently to the ADP binding site for the life of the platelet Additional Information: Ticagrelor contains ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is a selective adenosine diphosphate (ADP) receptor antagonist acting on the P2Y12 ADP-receptor that can prevent ADP-mediated platelet activation and aggregation. Ticagrelor is orally active, and reversibly interacts with the platelet P2Y12 ADP-receptor. Ticagrelor does not interact with the ADP binding site itself, but interacts with platelet P2Y12 ADP-receptor to prevent signal transduction References: Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038–1047. Gurbel PA, Antonino MJ, Tantry US. Recent developments in clopidogrel pharmacology and their relation to clinical outcomes. Expert Opin Drug Metab Toxicol. 2009;5(8):989–1004. Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120:2577–2585. Ticagrelor: Summary of Product Characteristics, 2010. Ticagrelor P2Y12 receptor on platelet 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:

Inhibition of Platelet Aggregation: Onset
* * * Ticagrelor (n=54) * * Clopidogrel (n=50) Inhibition of Platelet Aggregation * Title: Inhibition of Platelet Aggregation: Onset Key Point: Ticagrelor demonstrated a more rapid onset of IPA as compared with clopidogrel in patients with stable coronary artery disease on ASA, The mean IPA of ticagrelor after a loading dose of 180 mg was about 41% at 30 minutes as compared to a mean IPA of 8% for clopidogrel after a loading dose of 600 mg at 30 A high degree of IPA with ticagrelor was maintained for 2–8 hours (89%) Additional Information: IPA at 2 hours after loading was greater for ticagrelor than for clopidogrel (89% versus 38%, P<0.0001) 90% of patients given ticagrelor had final extent IPA greater than 70% by 2 hours post dose Patients can be switched from clopidogrel to ticagrelor without interruption of antiplatelet effect References: Gurbel PA, Bliden KP, Butler K, et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation. 2009;120:2577–2585. Ticagrelor: Summary of Product Characteristics, 2010. Placebo (n=12) Time (Hours) Loading Dose Ticagrelor 180-mg loading dose in Stable CAD patients Clopidogrel 600-mg loading dose in Stable CAD patients *P<0.0001Ticgrelor vs Clopidogrel Adapted from Gurbel PA, et al. Circulation. 2009;120:2577–2585.

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. Title: PLATO: Study Design Key Points: Ticagrelor was investigated in the landmark PLATO study that recruited 18,624 patients from 862 centers in 43 countries from October 2006 through July 20081 PLATO was designed to reflect clinical practice in ACS by2 Including a broad spectrum of ACS patients and treatment plans and following them for up to 1 year Allowing prior clopidogrel use1 Including both intent for invasive management (72%) and intent for medical management (28%)3 Allowing up to a 600-mg clopidogrel loading dose pre-PCI3 The primary efficacy endpoint was a composite of CV death, MI (excluding silent MI), and stroke The primary safety endpoint was Total PLATO major bleeding The PLATO study expanded the definition of major bleeding to be more inclusive compared with previous studies in ACS patients Additional Information: A total of 18,624 patients were included who presented within 24 hours of onset of UA, NSTEMI, or STEMI symptoms and were randomized prior to available laboratory or coronary anatomy results1 Patients could be treated non-invasively or invasively with PCI or CABG, and were randomized at the time of treatment planning1 Patients treated with clopidogrel prior to enrollment were included, and a clopidogrel loading dose of 300 mg was permitted in patients not previously treated with clopidogrel, with an additional 300 mg permitted at the discretion of the investigator3 References Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605. Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375:283–293. 1. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057. 2. James S, et al. Am Heart J. 2009;157:599–605.

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) Title: PLATO Main: Inclusion Criteria Key Points: The inclusion criteria were chosen to be reflective of clinical practice and similar to the CURE study The short time window for inclusion (within 24 hours) and the requirement of additional risk factors for inclusion if a patient did not have both ST-segment deviation and cardiac biomarker elevation excluded patients with the lowest risk of recurrent events from the population. Therefore, the study included those patients most likely to benefit from antiplatelet therapy Additional Information: N/A Reference: James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605. James S, et al. Am Heart J. 2009;157:599–605.

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 Title: PLATO Main: Key Exclusion Criteria Key Points: The PLATO study exclusion criteria sought to enroll a typical ACS population Patients with ST-segment elevation ACS treated with fibrinolysis were excluded because of the lack of safety data with this combination of treatments As a result of data seen in a phase II trial (DISPERSE2), patients with increased risk for bradycardic events due to sinus pauses were excluded Due to drug-drug interaction (DDI) data from clinical pharmacology studies, patients requiring concomitant therapy with strong CYP3A inhibitors/inducers were excluded Patients requiring dialysis were excluded because of the lack of clinical data in this patient population Additional Information: N/A Reference: James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605. James S, et al. Am Heart J. 2009;157:599–605.

PLATO: Baseline Characteristics
TICAGRELOR (n=9,333) Clopidogrel (n=9,291) Median age, years 62.0 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 smoker 3,360 (36.0) 3,318 (35.7) Hypertension 6,139 (65.8) 6,044 (65.1) Dyslipidemia 4,347 (46.6) 4,342 (46.7) Diabetes mellitus 2,326 (24.9) 2,336 (25.1) History, n (%) MI 1,900 (20.4) 1,924 (20.7) PCI 1,272 (13.6) 1,220 (13.1) CABG 532 (5.7) 574 (6.2) ECG at study entry, n (%) ST-segment elevation, persistent 3,497 (37.5) 3,511 (37.8) ST-depression 4,730 (50.7) 4,756 (51.2) T-wave inversion 2,970 (31.8) 2,975 (32.0) Troponin-I positive, n (%) 7,965 (85.3) 7,999 (86.0) Title: PLATO: Baseline Characteristics Key Points: The 2 treatment groups were well balanced with regard to all baseline characteristics including age, gender, CV risk factors, history, ECG at study entry and Troponin-I results Additional Information: Approximately 15% of the study population was age ≥75 years Approximately 25% of the study population had diabetes mellitus Reference: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke)
0–30 Days 0–12 Months 13 12 11.7 Clopidogrel 11 10 9.8 TICAGRELOR 9 Clopidogrel 8 5.4 7 Cumulative Incidence (%) 6 Title: PLATO: Primary Efficacy Endpoint (Composite of CV Death, MI, or Stroke) Key Points: BRILINTA significantly reduces the combined risk of CV death, MI, or stroke vs clopidogrel in patients with ACS The absolute risk reduction of BRILINTA over clopidogrel starts early and continues to build over the full 1-year treatment regimen BRILINTA provided benefits in the critical early period of risk. Importantly, the benefits were consistent over time The Kaplan-Meier curves continued to diverge up to 12 months, demonstrating a benefit beyond the acute phase Additional Information: In the PLATO study, BRILINTA significantly decreased the rate of the combined endpoint of CV death, MI, and stroke in ACS patients with UA, NSTEMI, or STEMI who were medically or invasively managed1,2 The difference in treatments was driven by reduced risk of CV death and MI, with no significant difference in the rate of stroke3 In the first 30 days, an absolute risk reduction of 0.6% (P=0.045) was seen with BRILINTA as compared to clopidogrel, with a hazard ratio of 0.88 (95% CI, 0.77–1.00) Improvement in the absolute risk reduction continued over the full 12 months (ARR: 1.9%, P<0.001) and was seen with BRILINTA as compared to clopidogrel (HR: 0.84 [95% CI, 0.77–0.92]) In the PLATO trial, for every 54 ACS patients treated with BRILINTA instead of clopidogrel one atherothrombotic event (NNT=54) was prevented References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. Supplement to: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. BRILIQUE: Summary of Product Characteristics, 2010. 5 ARR=0.6% RRR=12% P=0.045 HR: 0.88 (95% CI, 0.77−1.00) ARR=1.9% RRR=16% NNT=54* P<0.001 HR: 0.84 (95% CI, 0.77–0.92) 4 4.8 3 TICAGRELOR 2 1 2 4 6 8 10 12 Months After Randomization No. at risk Clopidogrel TICAGRELOR 9,291 9,333 8,521 8,628 8,362 8,460 8,124 6,650 6,743 5,096 5,161 4,047 4,147 8,219 Both groups included aspirin. *NNT at one year. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints
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) 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) 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 Title: PLATO: Predefined Testing of Primary and Major Secondary Efficacy Endpoints Key Points: BRILINTA significantly decreased the rate of the primary efficacy endpoint of CV death, MI, and stroke in ACS patients with UA, NSTEMI, or STEMI who were medically or invasively managed1,2 The difference in treatments was driven by reduced risk of CV death and MI, with no significant difference in the rate of stroke1 Similar to the primary efficacy endpoint, BRILINTA also significantly decreased the rate of the following secondary efficacy endpoints1: Death from any cause + MI (excluding silent MI) + stroke Death from vascular causes + MI (excluding silent MI) + stroke + severe recurrent ischaemia + recurrent ischaemia + TIA + arterial thrombus MI (excluding silent MI) Death from vascular causes There was no significant difference in the rate of stroke between BRILINTA and clopidogrel1 Due to statistical hierarchical testing, which is defined as, formal statistical testing performed in sequence until first nonsignificant result was observed; the P-value for the secondary endpoint of “Death from any cause” has only nominal significance1 Additional Information: To address the issue of multiple testing, a hierarchical test sequence was conducted in which the secondary composite efficacy endpoints were tested individually, in the order in which they are listed on the slide, until the first nonsignificant difference was found between the 2 treatment groups1 References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. BRILIQUE: Summary of Product Characteristics, 2010. Plavix® (clopidogrel bisulfate) Prescribing Information. Sanofi-aventis U.S. LLC. Revised March 2010. * 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. Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO: Secondary Efficacy Endpoints
Myocardial Infarction Cardiovascular Death 7 6.9 Clopidogrel 7 6 5.8 6 Clopidogrel 5.1 5 TICAGRELOR 5 4.0 4 4 Cumulative Incidence (%) Cumulative Incidence (%) TICAGRELOR Title: PLATO: Secondary Efficacy Endpoints Key Points: BRILINTA significantly reduced the risk of MI (excluding silent MI) vs clopidogrel1 BRILINTA is the first oral antiplatelet to reduce CV death vs clopidogrel in a broad ACS patient population (UA, NSTEMI, STEMI) for up to 52 weeks1 Rate of stroke for BRILINTA was not different from clopidogrel (1.3% vs 1.1% ), P=0.225 Additional Information: In the PLATO trial, for every 91 ACS patients treated with BRILINTA instead of clopidogrel, 1 CV death was prevented; NNT=913 In the PLATO trial, for every 91 ACS patients treated with BRILINTA instead of clopidogrel, 1 MI was prevented; calculated NNT=91 NNT = 1/ARR References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. Plavix® (clopidogrel bisulfate) Prescribing Information. Sanofi-aventis U.S. LLC. Revised March 2010. BRILIQUE: Summary of Product Characteristics, 2010. 3 3 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) 2 2 1 1 2 4 6 8 10 12 2 4 6 8 10 12 Months After Randomisation Months After Randomisation Rate of stroke for TICAGRELOR was not different from clopidogrel (1.3% vs 1.1% ), P=0.225. Both groups included aspirin. 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, 2010.

PLATO: Primary Safety Endpoint
15 TICAGRELOR 11.6% P=NS 11.2% 10 Clopidogrel PLATO-defined Total Major Bleeding (%) Title: PLATO: Primary Safety Endpoint Key Points: There was no significant difference in the rates of PLATO-defined Total Major Bleeding, despite the increased efficacy of BRILINTA vs clopidogrel1 Additional Information: The PLATO study expanded bleeding definitions from previous trials in patients with ACS. In the PLATO study, total major bleeding was more inclusive than in previous studies of ACS patients because it included bleeding that led to clinically significant disability (eg, intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in hemoglobin levels of ≥3 g/dL or requiring transfusion of 2 to 3 units of red cells1,2 References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157:599–605. 5 P=0.43 HR: 1.04 (95% CI, 0.95–1.13) 60 120 180 240 300 360 Days From First Dose No. at risk Clopidogrel TICAGRELOR 9,186 9,235 7,305 7,246 6,930 6,826 6,670 5,209 5,129 3,841 3,783 3,479 3,433 6,545 Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO: Bleeding P = 0.008 NS K-M Estimated Rate (% Per Year) NS NS
Title: PLATO: Bleeding Key Points: There were no significant differences in Major Bleeding, Life-threatening/Fatal bleeding, Fatal Bleeding or CABG-Major Bleeding events with BRILINTA vs clopidogrel in the PLATO trial1 However, there was a significant increase in risk of non-CABG Major bleeding with BRILINTA vs clopidogrel1 There was also a significant increase in Major and Minor Bleeding with BRILINTA vs clopidogrel1 Minor bleeding was defined as: requires medical intervention to stop or treat bleeding Additional Information: The PLATO study expanded bleeding definitions from previous trials in patients with ACS. In the PLATO study, total major bleeding was more inclusive than in previous studies of ACS patients because it included bleeding that led to clinically significant disability (eg, intraocular bleeding with permanent vision loss) or bleeding either associated with a drop in hemoglobin levels of ≥3 g/dL or requiring transfusion of 2 to 3 units of red cells2 References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. BRILIQUE: Summary of Product Characteristics, 2010. K-M Estimated Rate (% Per Year) NS P = 0.03 NS Major Bleeding Life-threatening/ Fatal Bleeding Fatal Bleeding Major and Minor Bleeding Non-CABG-Major Bleeding CABG-Major Bleeding All values presented by PLATO criteria. Both groups included aspirin. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.

PLATO: Dyspnea Dyspnoea in the PLATO trial Ticagrelor Clopidogrel P Value Incidence of dyspnea adverse events (%) 13.8 7.8 <0.001 Patients who discontinued treatment due to dyspnoea (%) 0.9 0.1 Title: PLATO: Dyspnea Key Points: The PLATO trial showed more dyspnoea-related adverse events associated with ticagrelor compared with clopidogrel1,2 There were more dyspnea-related drug discontinuations in patients taking ticagrelor (0.9%) than in those taking clopidogrel (0.1%)1,2 Most of the dyspnea-related adverse events (AEs) were mild to moderate in intensity and resolved without a need for treatment1,2 Most events were reported as a single episode occurring early after starting treatment1 The data from PLATO do not suggest that the higher frequency of dyspnoea with ticagrelor is due to new or worsening heart or lung disease1 Additional Information: In 2.2% of patients taking ticagrelor and in 0.6% taking clopidogrel, investigators considered the dyspnoea causally related to treatment in the PLATO study and few were serious (0.14% ticagrelor; 0.02% clopidogrel)1 The mechanism for the increased incidence of dyspnoea has not yet been determined1 References: Ticagrelor: Summary of Product Characteristics, 2010. Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. 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.

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 Title: PLATO: Bradycardia-related Events Key Points: There were no differences in adverse clinical consequences, ie, pacemaker insertion, syncope, bradycardia and heart block between ticagrelor and clopidogrel in the PLATO trial1 Additional Information: Due to observations of mostly asymptomatic ventricular pauses in an earlier clinical study, patients with an increased risk of bradycardic events (eg, patients without a pacemaker who have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) were excluded from the main PLATO study evaluating the safety and efficacy of ticagrelor. Therefore, due to the limited clinical experience, ticagrelor should be used with caution in these patients2 References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. Ticagrelor: Summary of Product Characteristics, 2010. 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.

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 month 10 ± 22 8 ± 21 <0.001 At 12 months 11 ± 22 9 ± 22 1 month after end of treatment 0.59 Mean % increase (± SD) in serum uric acid from baseline 14 ± 46 7 ± 44 15 ± 52 7 ± 31 7 ± 43 8 ± 48 0.56 Title: PLATO: Laboratory Parameters Key Points: Serum creatinine increases reversed after treatment was stopped and there was no difference in frequency of AEs and clinical sequelae1,2 The same was true with the serum uric acid increases, as they reversed after treatment was stopped and there was no difference in frequency of AEs and clinical sequelae1,2 Renal function should be checked after 1 month and thereafter according to medical practice2 Additional Information: Creatinine levels may increase during treatment with BRILINTA. The mechanism has not been elucidated. Renal function should be checked after 1 month and thereafter according to routine medical practice, paying special attention to patients ≥75 years, patients with moderate/severe renal impairment and those receiving concomitant treatment with an ARB2 In the PLATO study, patients on ticagrelor had a higher risk of hyperuricaemia than those patients receiving clopidogrel. Caution should be exercised when administering ticagrelor to patients with history of hyperuricaemia or gouty arthritis. As a precautionary measure, the use of ticagrelor in patients with uric acid nephropathy is discouraged2 References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. Ticagrelor: Summary of Product Characteristics, 2010. 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 Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

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 Title: PLATO Safety Results Key Points: To summarize the PLATO safety data presented1,2 No increase in overall major bleeding with BRILINTA 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 ticagrleor 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 BRILINTA; renal function should be checked after 1 month and thereafter according to routine medical practice Additional Information: N/A References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. Ticagrelor: Summary of Product Characteristics, 2010. Wallentin L, et al. N Engl J Med. 2009;361:1045–1057.; Ticagrelor: Summary of Product Characteristics, 2010.

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 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.

PLATO Primary Endpoint: Initial Invasive vs Initial Non-Invasive Management
Initial Invasive 72% of patients in PLATO Initial Non-Invasive 28% of patients in PLATO 14.3% Clopidogrel 12% 10.7% Clopidogrel Title: PLATO Primary Endpoint: Initial Invasive vs Initial Non-Invasive Management Key Points: Ticagrelor provides a consistent benefit vs clopidogrel regardless of treatment approach, whether invasive or non-invasive The primary endpoints of both the initial invasive and initial non-invasive management are similar and consistent with the primary efficacy endpoint of the main PLATO trial Additional Information: The initial invasive management patient population consisted of 72% of the total PLATO population with a statistically significant HR: 0.84 (95% CI, 0.75–0.94, P<0.0025) The initial non-invasive management patient population consisted of 28% of the total PLATO population with a statistically significant HR: 0.85 (95% CI, 0.73–1.00, P<0.045) References: James S, Roe M, Cannon CP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for a non-invasive management in the PLATO trial. Presented at the European Society of Cardiology, Stockholm, Sweden, 28 August–1 September Poster #1353. Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375:283–293. Ticagrelor 9% K-M Estimated Rate Primary Composite of CV Death/MI/Stroke (%) K-M Estimated Rate Primary Composite of CV Death/MI/Stroke (%) Ticagrelor P<0.0025 HR: 0.84 (95% CI, 0.75–0.94) P<0.045 HR: 0.85 (95% CI, 0.73–1.00) Days After Randomisation Days After Randomisation No. at risk 6,676 6,732 6,129 6,236 6,034 6,134 5,881 4,815 4,889 3,680 3,735 2,965 3,048 5,972 Ticagrelor Clopidogrel Ticagrelor 2,601 2,392 2,326 2,247 1,854 1,426 1,099 Clopidogrel 2,615 2,392 2,328 2,243 1,835 1,416 1,109 James S, et al. ESC 2010; Poster #1353.; Cannon C, et al. Lancet. 2010;375:283–293.

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 9.0 10.7 0.84 (0.75–0.94) 0.0025 Secondary efficacy (%/year) All-cause death + MI† + stroke 9.4 11.2 0.0016 Death from vascular causes + MI† + stroke + severe recurrent ischaemia + recurrent ischaemia + TIA + arterial thrombus 13.1 15.3 0.85 (0.77–0.93) 0.0005 MI† 5.3 6.6 0.80 (0.69–0.92) 0.0023 CV death 3.4 4.3 0.82 (0.68–0.98) 0.0250 Stroke 1.2 1.1 1.08 (0.78–1.50) 0.6460 All-cause mortality 3.9 5.0 0.81 (0.68–0.95) 0.0103 Primary safety (%/year) Total major bleeding 11.5 11.6 0.99 (0.89–1.10) 0.8803 Title: PLATO Intent for Invasive Management: Primary Efficacy, Key Secondary Efficacy and Primary Safety Endpoints Key Points: The treatment effect of ticagrelor over clopidogrel appears consistent across multiple patient subgroups including those with initial invasive treatment pathway intended at randomisation There was no significant difference in total major bleeding with BRILINTA vs clopidogrel Additional Information: Similar to the primary efficacy endpoint, ticagrelor also significantly decreased the rate of the following secondary efficacy endpoints: All-cause death + MI (excluding silent MI) + stroke Death from vascular causes + MI (excluding silent MI) + stroke + severe recurrent ischaemia + recurrent ischaemia + TIA + arterial thrombus MI (excluding silent MI) CV Death There was no significant difference in the rate of stroke between ticagrelor and clopidogrel1 Due to statistical hierarchical testing (the formal statistical testing performed in sequence until first non-significant result was observed), the P-value for the secondary endpoint of “All-cause mortality” has only nominal significance Reference: Cannon CP, Harrington RA, James S, et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet. 2010;375:283–293. *Kaplan-Meier estimates at 360 days.**P value from univariate Cox model.† Excluding silent MI Both groups included aspirin. Cannon CP, et al. Lancet. 2010;375:283–293.

PLATO: Outcomes of Predefined Efficacy Endpoints A as Described in the EU Label
Ticagrelor % patients with event (n=9,333) Clopidogrel (n=9,291) ARRa (%/yr) RRRa (%) (95% CI) P Value CV Death + Mib + stroke 9.3 10.9 1.9 16 (8,23) 0.0003 Invasive intent 8.5 10.0 1.7 16 (6, 25) 0.0025 Non-Invasive intent 11.3 13.2 2.3 15 (0.3, 27) 0.0444c CV death 3.8 4.8 1.1 21 (9, 31) 0.0013 MIb 5.4 6.4 16 (5, 25) 0.0045 Stroke 1.3 -0.2 -17 (-52, 9) 0.2249 All-cause mortality + MIb + stroke 9.7 11.5 2.1 16 (8, 23) 0.0001 CV Death + Mib + stroke + severe recurrent ischemia + recurrent ischemia + TIA + arterial thrombus 13.8 15.7 12 (5, 19) 0.0006 All-cause mortality 4.3 1.4 22 (11, 31) 0.0003c Definitive stent thrombosis 1.2 0.6 32 (8, 49) 0.0123c Title: PLATO: Outcomes of Predefined Efficacy Endpoints as Described in the EU Label Key Points: Ticagrelor significantly decreased the rate of the primary efficacy endpoint of CV death, MI, and stroke in ACS patients with UA, NSTEMI, or STEMI who were medically or invasively managed1,2 The difference in treatments was driven by reduced risk of CV death and MI, with no significant difference in the rate of stroke1 Similar to the primary efficacy endpoint, ticagrelor also significantly decreased the rate of the following secondary efficacy endpoints1: Death from any cause + MI (excluding silent MI) + stroke Death from vascular causes + MI (excluding silent MI) + stroke + severe recurrent ischaemia + recurrent ischaemia + TIA + arterial thrombus MI (excluding silent MI) Death from vascular causes There was no significant difference in the rate of stroke between ticagrelor and clopidogrel1 Due to statistical hierarchical testing (the formal statistical testing performed in sequence until first non-significant result was observed), the P-value for the secondary endpoint of “Death from any cause” has only nominal significance1 Additional Information: To address the issue of multiple testing, a hierarchical test sequence was conducted in which the secondary composite efficacy endpoints were tested individually, in the order in which they are listed on the slide, until the first non-significant difference was found between the 2 treatment groups1 References: Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–1057. Ticagrelor: Summary of Product Characteristics, 2010. Plavix® (clopidogrel bisulfate) Prescribing Information. Sanofi-aventis U.S. LLC. Revised March 2010. NOTE: This is an alternative slide for markets that cannot use slide #17 aARR=absolute risk reduction; RRR=relative risk reduction = (1-Hazard ratio) x 100%. A negative RRR indicates a relative risk increase.; bExcluding silent myocardial infarction.; cNominal significance value; all others are formally statistically significant by pre-defined hierarchical testing. Both groups included aspirin. The percentages presented are Kaplan-Meier estimates of the rate of the endpoint at 12 months. Ticagrelor: Summary of Product Characteristics, 2010.

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 * 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%). 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, 2011. Adapted form Cannon CP, et al. Lancet. 2010;375:283−293.

TICAGRELOR Indication
By Diagnosis By Treatment UA/NSTEMI STEMI Medical management PCI CABG  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) Title: Ticagrelor Indication Key Points: Ticagrelor is indicated for the prevention of atherothrombotic events (CV death, MI, and stroke) in adult ACS patients Ticagrelor can be taken by a broad range of ACS patients, including those managed medically or those managed with PCI and/or CABG Additional Information: 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) 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 Reference: Ticagrelor: Summary of Product Characteristics, 2010. 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 Ticagrelor: Summary of Product Characteristics, 2010.

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 Title: Contraindications Key Points: The following are contraindications for Ticagrelor Hypersensitivity to the active substance or to any of the excipients Active pathological bleeding History of intracranial haemorrhage 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 Additional Information: N/A References: Ticagrelor: Summary of Product Characteristics, 2010. Ticagrelor: Summary of Product Characteristics, 2010.

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 Title: Special Warnings and Precautions Key Points: The following are 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 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 Additional Information: N/A Reference: Ticagrelor: Summary of Product Characteristics, 2010. Ticagrelor: Summary of Product Characteristics, 2010.

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 Title: Special Warnings and Precautions Key Points: The following are 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 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 Additional Information: N/A Reference: Ticagrelor: Summary of Product Characteristics, 2010. Ticagrelor: Summary of Product Characteristics, 2010.

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) The PLATO study, expanding further on TIMI and CURE criteria, defined minor and minimal bleeding events. This facilitated the capture of bleeding events that occur in ACS patients in both the acute and chronic setting[James 2009:A] PLATO Minor was defined as any event requiring medical intervention (ie, nose bleed w/packing)[James 2009:B] PLATO Minimal includes any other reported bleed that does not require intervention or treatment (ie, bruising)[James 2009:B] Note the differences in criteria across all 4 definitions of minor and minimal. In CURE, there were no definitions for minimal bleeding Also note that the hemoglobin drop in TIMI Minor resembles the PLATO Major criteria, as noted in slide 8 (Major bleeding definitions) James S, et al. Am Heart J. 2009;157: *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:

Expanding the Definition of Major Bleeding Criteria in Clinical trials
TIMI [Rao 1988:A] PLATO [James 2009:B] Major Major (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 Recent trials have used elements from both the TIMI and GUSTO criteria for major bleeding, with additions, combinations, elaborations, or modifications[Steinhubl 2007:C] The CURE study split the GUSTO and TIMI major bleeding categories into “Major (fatal/life-threatening)” and “Other Major” categories, and incorporated additional clinical measures[Yusuf 2001:A] The PLATO study further increased inclusivity beyond TIMI and CURE, with both Major (fatal/life-threatening) and Other Major categories containing additional clinical and laboratory measures[James 2009:B] TIMI-Major is less inclusive than PLATO-”Major Fatal/Life-threatening”; TIMI-Major does not include intrapericardial bleeding with tamponade CURE does not include decrease in hemoglobin of 3-5 g/dL as an other major bleed, while PLATO does Yusuf S, et al. N Engl J Med. 2001;345: James S, et al. Am Heart J. 2009;157: Notes reference: Steinhubl SR, et al. Am Heart J. 2007;154:3-11. 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:

Ticagrelor: important characteristics
Ticagrelor is a cyclopentyltriazolopyrimidine (CPTP): direct acting and reversibly interacts with the platelet P2Y12 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 P2Y12 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 Ticagrelor is the first in a new chemical class, the CPTPs, and is chemically distinct from the thienopyridines, prasugrel and clopidogrel[Husted 2006:A] Ticagrelor has a rapid onset of inhibitory effect on the receptor[Husted 2006:B,C] Ticagrelor does not require metabolic activation[Husted 2006:A] Studies have demonstrated that ticagrelor has a greater and more consistent inhibition of platelet aggregation compared with clopidogrel[Storey 2007:A,B; Husted 2006:E] Ticagrelor’s reversible binding of the P2Y12 receptor also plays an integral role in its favorable PK and PD[Husted 2006:D] These data do not necessarily translate to the clinical outcomes seen in the PLATO phase 3 clinical trial Husted SE, et al. Eur Heart J. 2006;27: Storey RF, et al. J Am Coll Cardiol. 2007;50: 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:

Ticagrelor – pharmacokinetic parameters
Absorption Rapidly 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] Ticagrelor is rapidly absorbed following oral administration[Husted 2009:B; EMEA Label:A] Ticagrelor is metabolized primarily via cytochrome P450 3A enzymes and has one known active metabolite, ARC124910XX, that is present in blood at approximately one-third of the concentration of the parent drug[Teng 2010:A; EMEA Label:B] Although this metabolite has potency in inhibiting the P2Y12 receptor equivalent to that of the parent compound, metabolic activation is not a requirement for IPA to occur In 6 subjects receiving a single oral dose of 14Cticagrelor, average total recovery of radioactive dose was 84.3%, consisting of 26.5% in urine and 57.8% in feces[Husted 2009:F] Ticagrelor and its active metabolite, AR-C124910XX, constituted the major components identified in feces, plasma, and less than 1% of components in urine Absorption of ticagrelor is rapid (median time to peak plasma concentration [tmax] of hours), as is the formation of its main (active) metabolite, AR-C124910XX (tmax hours)[Teng 2010:B] The mean terminal-phase half-life is approximately 7 to 8.5 hours for ticagrelor and 8.5 to 10 hours for AR-C124910XX[Teng 2010:B,C; EMEA Label D,E] AR-C124910XX exposure is approximately one-third that of ticagrelor Exposure to ticagrelor is slightly higher (approximately 1.25-fold) following administration with food, with exposure to AR-C124910XX not appearing to be affected, suggesting it can be administered with or without food[Butler 2008:B; EMEA Label:E] 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: 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.

Warning on ticagrelor label
Key drug interactions Drug Primary usage Effect Warning on ticagrelor label Ketoconazole (strong CYP3A4 inhibitor) Antifungal Ticagrelor Cmax 2.4x and AUC 7.3xa Coadministration is contraindicated Diltiazem (moderate CYP3A4 inhibitor) Vasodilation; angina; hypertension Ticagrelor Cmax by 69% and AUC 2.7xb Can be coadministered Rifampin (CYP3A inducer) Antibacterial Ticagrelor Cmax 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 Unknownd Simvastatin (CYP3A4 substrate) Control hypercholesterolemia Simvastatin Cmax by 81% and AUC by 56%; no effect on ticagrelor Coadministration with > 40 mg simvastatin is not recommended Atorvastatin (CYP3A4 substrate) Atorvastatin acid Cmax by 23% and AUC by 36% None Levonorgesterol+ethinyl estradiol Oral contraceptive Ethinyl estradiol exposure by ≈20%; no effect on levonorgesterol Digoxin (P-gp substrate) Strengthen cardiac contractions; congestive heart failure Digoxin Cmax by 75% and AUC by 28%; Close clinical and laboratory monitoring is recommendede CYP3A4 is the major enzyme responsible for ticagrelor metabolism[EMEA Label:C] Ticagrelor is primarily a CYP3A4 substrate and a mild inhibitor of CYP3A4. It is also a P-gp substrate and a weak inhibitor of P-gp[EMEA Label:P] Coadministration of ticagrelor with strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, nefazodone, ritonavir, atazanavir) is contraindicated as it may lead to a substantial increase in ticagrelor exposure[EMEA Label:H,I] Moderate CYP3A4 inhibitors (eg, amprenavir, aprepitant, erythromycin, fluconazole) can be coadministered with ticagrelor[EMEA Label:J] Coadministration of ticagrelor with strong CYP3A4 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, phenobarbital) is discouraged as it may lead to a decrease in exposure and efficacy of ticagrelor[EMEA Label:H] Coadministration of ticagrelor with heparin, enoxaparin, aspirin, or desmopressin did not have any effect on the pharmacokinetics of ticagrelor or ADP-induced platelet aggregation. If clinically indicated, such agents should be used with caution in combination with ticagrelor[EMEA Label:L] No data are available on concomitant use of ticagrelor with potent P-gp inhibitors (eg, verapamil, quinidine, cyclosporine). As these medications may increase ticagrelor exposure, concomitant use with ticagrelor should be made with caution[EMEA Label:L] Ticagrelor is a mild CYP3A4 inhibitor. Coadministration of ticagrelor and CYP3A4 substrates with narrow therapeutic indices (eg, cisapride, ergot alkaloids) is not recommended, as ticagrelor may increase the exposure to these agents[EMEA Label:Q] Coadministration of ticagrelor with doses of simvastatin exceeding 40 mg daily could cause simvastatin-associated adverse effects. Similar effects may be associated with lovastatin. As such, concomitant use of ticagrelor with greater than 40 mg doses of either simvastatin or lovastatin is not recommended[EMEA Label:M] Coadministration of atorvastatin and ticagrelor increased atorvastatin acid Cmax by 23% and AUC by 36%. These increases are not considered clinically significant[EMEA Label:M] Data suggests ticagrelor is not a CYP2C9 inhibitor and therefore is unlikely to alter the CYP2C9 mediated metabolism of medications such as warfarin and tolbutamide[EMEA Label:R] No clinically relevant effect on oral contraceptive efficacy is expected when levonorgestrel and ethinyl estradiol are coadministered with ticagrelor[EMEA Label:N] Coadministration of ticagrelor and digoxin increased the digoxin Cmax by 75% and AUC by 28%. Mean trough digoxin levels were increased by approximately 30% though individual maximum increases up to 2-fold were observed. Exposure to ticagrelor and its active metabolite were not affected. Appropriate clinical and/or laboratory monitoring is recommended when giving narrow therapeutic index P-gp dependent medications, such as digoxin or cyclosporine, with ticagrelor[EMEA Label:O] Data on File, Investigator’s Brochure. aSimilar effects would be expected for other strong inhibitors of CYP3A4 (eg, clarithromycin, nefadozone, ritonavir, atazanavir) bSimilar effects would be expected for other moderate inhibitors of CYP3A4 (eg, amprenavir, aprepitant, erythromycin, fluconazole) cSimilar effects would be expected for other inducers of CYP3A (eg, dexamethasone, phenytoin, carbamazepine, phenobarbitol) dData are also unavailable for other potent P-gp inhibitors (eg, quinidine, cyclosporine) eAppropriate monitoring is also recommended when giving other narrow therapeutic index P-gp dependent medications (eg, cyclosporine) ; AUC, area under the concentration vs time curve; Cmax, maximum plasma concentration; P-gp, P-glycoprotein Data on file, Investigator’s Brochure.

Aspirin Clopidogrel Prasugrel Ticagrelor ?

The ARISTOTLE trial randomized 18 201 AF patients to apixaban (5 mg orally twice daily) or warfarin (target INR of 2.0 to 3.0). After a median follow-up of 1.8 years, results showed that apixaban was associated with a 21% reduction in the risk of stroke or systemic embolism, a 31% reduction in bleeding, and an 11% reduction in all-cause mortality.

Stroke or systemic embolism occurred in 182 patients receiving 110 mg of dabigatran (1.53% per year), 134 patients receiving 150 mg of dabigatran (1.11% per year), and 199 patients receiving warfarin (1.69% per year) (Table 2 and Fig. 1). Both doses of dabigatran were noninferior to warfarin (P<0.001). The 150-mg dose of dabigatran was also superior to warfarin (relative risk, 0.66; 95% confidence interval [CI], 0.53 to 0.82; P<0.001), but the 110-mg dose was not (relative risk, 0.91; 95% CI, 0.74 to 1.11; P = 0.34). Rates of hemorrhagic stroke were 0.38% per year in the warfarin group, as compared with 0.12% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.31; 95% CI, 0.17 to 0.56; P<0.001) and 0.10% per year in the group that received 150 mg of dabigatran (relative risk, 0.26; 95% CI, 0.14 to 0.49; P<0.001).

Primary Outcome In the per-protocol population (the patients included in the primary efficacy analysis), stroke or systemic embolism occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 patients in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority) (Table 2 and Fig. 1A). In the as-treated safety population, primary events occurred in 189 patients in the rivaroxaban group (1.7% per year) and in 243 patients in the warfaringroup (2.2% per year) (hazard ratio, 0.79; 95% CI, 0.65 to 0.95; P = 0.01 for superiority). Among all randomized patients in the intention-to-treat analysis, primary events occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority) (Fig. 1B). During treatment in the intention-to-treat population, patients in the rivaroxaban group had a lower rate of stroke or systemic embolism (188 events, 1.7% per year) than those in the warfarin group (240 events, 2.2% per year) (P = 0.02) (Ta- ble 2 and Fig. 2). Among patients who stopped taking the assigned study drug before the end of the study, during a median of 117 days of follow- up after discontinuation, primary events occurred in 81 patients in the rivaroxaban group (4.7% per year) and in 66 patients in the warfarin group (4.3% per year) (P = 0.58).

New Anticoagulants in AF and ACS Perspective:
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. 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. Dabigatran etexilate is a synthetic low molecular weight peptidomimetic that binds directly and reversibly to the catalytic site of thrombin. Rivaroxaban, apixaban, and endoxaban are selective direct factor Xa inhibitors. 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:
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. 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. 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. 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. Additional trials are indicated to determine the utility of these agents in combination with antiplatelet treatments after myocardial infarction and percutaneous coronary intervention.

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

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

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.

“Best Practice” Approach to the ACS Patient
Area of concern Therapeutic approach Anti-ischemic therapy Ongoing risk stratification Invasive procedures (when appropriate) According to the ACC/AHA guidelines for the management of UA/NSTEMI, the optimal therapeutic approach to ACS patients includes anti-ischemic, antiplatelet and antithrombotic therapy, ongoing risk stratification, and the use of invasive procedures when appropriate. The most effective antithrombotic therapy would include aspirin (ASA) and an anticoagulant agent as background therapy. The addition of GPIIb/IIIa inhibitors to ASA plus anticoagulant agent is recommended for high-risk patients. LMWH is the anticoagulant of choice, given the compelling evidence of its clinical and practical advantages over UFH. In addition, it is known that a large proportion of ACS patients are susceptible to recurrent clinical events. As treatment with LMWH, particularly enoxaparin, has been shown to significantly reduce the rate of recurrent UA and MI, as well as the need for revascularization procedures (providing important hospital cost-savings). Anti-thrombotic therapy ASA + antiplatelet / anticoagulant as background therapy LMWH: anticoagulant of choice Enoxaparin:- superior to UFH -  recurrent ACS -  hospital stay -  costs ASA + anticoagulant + GPIIb/IIIa in high risk patients

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