BRILINTA is a registered trademark of the AstraZeneca group of companies AstraZeneca /15

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1 Notes to Speaker In the notes section of each slide, direction is provided about how to communicate the information on that slide For Talking Points that are bolded, it is mandatory that the essence of each talking point be communicated For Talking Points that are not bolded, it is expected that the essence of each talking point will be communicated Supplemental information: This content is optional. This information may be presented proactively if desired, or used in response to a question Hyperlinked slides: These slides are optional. If these slides are used, then the direction provided above will apply The slides must be used in sequence, and the presentation must be used in its entirety, with the exception of hyperlinked slides. Any changes to this slide set must be preapproved through the AstraZeneca Approval Process (AZAP) For direction on how to answer questions asked by the audience, please refer to the document titled BRILINTA (ticagrelor) Tablets Additional Information for Speakers BRILINTA is a registered trademark of the AstraZeneca group of companies AstraZeneca /15 1

2 This presentation reviews the role of BRILINTA (ticagrelor) tablets in the management of Acute Coronary Syndrome (ACS) through a hypothetical patient case study. Clinical questions relating to the patient case are included throughout the deck to help facilitate a discussion on the efficacy and safety data from the PLATelet inhibition and patient Outcomes (PLATO) study, as well as key information from BRILINTA s Prescribing Information Please refer to the full BRILINTA Prescribing Information, including Boxed WARNINGS, and Medication Guide for more information This is a promotional presentation sponsored directly by AstraZeneca and there are no continuing medical education (CME) credits associated with this activity 2

3 Note to Speaker These are rhetorical questions. Discussion/answers from the audience should not be solicited for these questions. Talking Points In patients with ACS What is the risk for a recurrent event? What is the risk of CV mortality? 3

4 The GRACE program, including the main GRACE registry and the expanded GRACE registry, has enrolled more than 100,000 patients with ACS between 1999 and An observational analysis of the expanded GRACE registry, in which nearly 40% of patients were from North America, sought to better understand the management of patients with ACS and how that correlated with clinical outcomes 2 From 2001 to 2007, 31,982 patients with suspected ACS were enrolled, of which 27,377 were diagnosed with ACS: 35% with STEMI, 36% with NSTEMI, and 29% with UA 2 Shown on this slide are hospital outcomes in these patients, specifically rates of mortality and recurrent MI 2 While rates of mortality and recurrent MI were low for patients with UA (1.7% and 1.4%, respectively), higher rates were seen in STEMI and NSTEMI patients for both outcome categories 2 Standard case report forms and definitions were used; however, cause of death was not reported and in-hospital events were not centrally adjudicated 2 1. Fox KA, Eagle KA, Gore JM, et al. The Global Registry of Acute Coronary Events, 1999 to 2009-GRACE. Heart. 2010;96: Goodman SG, Huang W, Yan AT, et al. The expanded Global Registry of Acute Coronary Events: baseline characteristics, management practices, and hospital outcomes of patients with acute coronary syndromes. Am Heart J. 2009;158:

5 Shown on this slide are results from an observational study using data from the GRACE registry which investigated the relationship between ST-segment category in ACS and complication rates, including death, in patients with ACS A total of 115 hospitals in 14 countries contributed to the data in this study From July 1999 to June 2006, 46,829 patients were enrolled in the study and followed from hospitalization to up to 6 months postdischarge. After classification by ST category, 38% had ST-segment elevation, 18% had ST-segment depression, and 44% had neither Standard case report forms and definitions were used; however, cause of death was not reported and in-hospital events were not centrally adjudicated In terms of mortality rates for patients with ST-segment elevation and ST-segment depression, cumulative incidence of mortality significantly increased relative to those without ST changes, not only in the acute period, but also continued to persist over time Reference Fox KA, Anderson FA, Goodman SG, et al. Time course of events in acute coronary syndromes: implications for clinical practice from the GRACE registry. Nat Clin Pract Cardiovasc Med. 2008;5(9):

6 In the PLATO trial, BRILINTA was studied in over 18,000 patients across a broad range of baseline characteristics. This included patients diagnosed with UA, NSTEMI, and STEMI, and patients who were managed either medically or invasively with PCI or coronary artery bypass grafting (CABG) Based on the results of the trial, BRILINTA is indicated to reduce the rate of thrombotic CV events in patients with ACS (UA, NSTEMI, or STEMI) BRILINTA reduced the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke In patients treated with PCI, it also reduces the rate of stent thrombosis BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin >100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 6

7 BRILINTA has Boxed WARNINGS that are specific to bleeding risk and aspirin dose as it relates to the effectiveness of BRILINTA In terms of bleeding risk, BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding BRILINTA should not be used in patients with active pathological bleeding or a history of intracranial hemorrhage (ICH) If a patient is to undergo urgent CABG, do not start BRILINTA Discontinue BRILINTA at least 5 days prior to any surgery, when possible Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, PCI, CABG, or other surgical procedures in the setting of BRILINTA If possible, manage bleeding without discontinuing BRILINTA because stopping BRILINTA increases the risk of subsequent cardiovascular events In terms of aspirin, maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg-100 mg per day Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 7

8 Talking Point BRILINTA is contraindicated in patients with a history of intracranial hemorrhage, active pathological bleeding, severe hepatic impairment, or hypersensitivity to ticagrelor or any component of the product Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 8

9 Note to Speaker This is a rhetorical question. Discussion/answers from the audience should not be solicited for this question. Talking Point How does the pharmacological profile of BRILINTA differ from other OAPs? 9

10 In regard to clinical pharmacology, clopidogrel and prasugrel are thienopyridines which irreversibly bind to the P2Y 12 ADP receptors on platelets. BRILINTA is a CPTP that reversibly interacts with the receptor 1-3 BRILINTA is not a prodrug. 1 Clopidogrel and prasugrel are prodrugs. After intestinal absorption, each requires cytochrome P450 (CYP)-dependent oxidation to generate its active drug 3,4 BRILINTA is active without metabolism. It does not completely depend on hepatic metabolism to inhibit platelets 4 CYP3A4 is the major enzyme responsible for BRILINTA metabolism and the formation of its major active metabolite, AR-C124910XX. The systemic exposure to the active metabolite is approximately 30%-40% of the exposure of BRILINTA BRILINTA and its active metabolite are approximately equipotent 1 The metabolism of clopidogrel is affected by CYP2C19 genotype. 2 The metabolism of prasugrel is not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5. 3 The effects of BRILINTA on thrombotic events and bleeding were not significantly affected by the CYP2C19 genotype 1 It is not known how pharmacology or chemical class correlate to clinical efficacy or safety results Note to Speaker After presenting this slide, should you wish to present a video on the mechanism of action of BRILINTA (optional), please click on V. Should you wish to present 2 slides on the mechanism of action of thienopyridines and BRILINTA (optional), please click on M. 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Plavix Prescribing Information. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Effient Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; Schömig A. Ticagrelor is there need for a new player in the antiplatelet-therapy field? N Engl J Med. 2009;361(11):

11 Mechanism of Action Video (# ) Note to Speaker If the Mechanism of Action Video is shown, it must be played with the audio turned on. After showing the video, and to resume the required presentation, click on R. Otherwise, the next slides you will present are the optional slides Mechanism of Action of Thienopyridines and Mechanism of Action of CPTPs. 11

12 The binding of ADP to P2Y 12 receptors on the platelet surface is a critical step in amplifying the structural and metabolic changes associated with platelet activation 1 The P2Y 12 receptor has proven to be an effective target for antiplatelet drugs 2 Thienopyridines bind to the P2Y 12 receptor, inhibiting ADP binding 3,4 This binding is irreversible; the P2Y 12 receptor is inhibited for the life of the platelet Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res. 2007;100: van Giezen JJJ. Optimizing platelet inhibition. Eur Heart J Suppl. 2008;10(suppl D):D23-D Plavix Prescribing Information. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; Effient Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y 12 receptor antagonist. Cardiovasc Ther. 2009;27:

13 BRILINTA, an orally active P2Y 12 receptor antagonist, belongs to a chemical class of antiplatelet agents called CPTPs 1 CPTPs have a different mechanism of action than thienopyridines 2-4 BRILINTA reversibly binds to an area on the P2Y 12 receptor that is distinct from the ADP binding site 2-4 BRILINTA does not interfere with ADP binding. Instead, it is believed that BRILINTA prevents ADP-mediated receptor activation 2-4 The receptor is functional after the dissociation of the BRILINTA molecule 2,3 The degree of receptor inhibition is dependent on the BRILINTA concentration 2,3 It is hypothesized that BRILINTA may affect cellular levels of adenosine by interfering with adenosine degradation and reuptake 5,6 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y 12 receptor antagonist. Cardiovasc Ther. 2009;27: van Giezen JJJ. Optimizing platelet inhibition. Eur Heart J Suppl. 2008;10(suppl D):D23-D van Giezen JJ, Nilsson L, Berntsson P, et al. Ticagrelor binds to human P2Y12 independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost. 2009;7: Ohman J, Kudira R, Albinsson S, et al. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Comm. 2012;418: van Giezen JJ, Sidaway J, Glaves P, et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosinemediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther. 2012;17(2):

14 In a multicenter, randomized, double-blind, Phase II (ONSET/OFFSET) study, 123 patients with stable coronary artery disease who were taking aspirin therapy (75 mg to 100 mg per day) received BRILINTA (180-mg loading dose, 90-mg twice-daily maintenance dose), clopidogrel (600-mg loading dose, 75-mg maintenance dose), or placebo for 6 weeks 1,2 BRILINTA demonstrated rapid onset and high IPA 1,3 The mean IPA of BRILINTA after a loading dose of 180 mg was about 41% at 30 minutes 1 The IPA of BRILINTA was approximately 79% at 1 hour 3 The maximum IPA effect of BRILINTA, approximately 88%, was reached at around 2 hours and was maintained for at least 8 hours 2 Looking at the IPA for clopidogrel and placebo, IPA was higher in the BRILINTA group at all time points 2 It is not known how either bleeding risk or thrombotic risk track with IPA for either BRILINTA or clopidogrel 2 Supplemental Information 90% of patients given BRILINTA had IPA greater than 70% by 2 hours postdose 1 1. 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(25): BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 3. Data on file, , AstraZeneca, LP. 14

15 The slide shows mean IPA following 6 weeks of maintenance doses of BRILINTA 90 mg twice daily, clopidogrel 75 mg once daily, and placebo 1 Time zero is the time at which the last dose was given. Mean maximum IPA after the last dose of BRILINTA was 88% and 62% for clopidogrel 1 Twenty-four hours after final dose, IPA in the BRILINTA group (58%) was similar to IPA in the clopidogrel group (52%), indicating that patients who miss a dose of BRILINTA would still maintain IPA similar to the trough IPA of patients treated with clopidogrel 1 Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery 1 Supplemental Information In the RESPOND study, it was demonstrated that transitioning from clopidogrel to BRILINTA resulted in an absolute IPA increase of 26.4% and from BRILINTA to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to BRILINTA without interruption of antiplatelet effect 1,2 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation. 2010;121:

16 To better understand the efficacy and safety outcomes with BRILINTA, it is important to review the trial design of PLATO The PLATO trial was a randomized, double-blind study comparing BRILINTA with clopidogrel both given in combination with aspirin and other standard therapy in patients with ACS 1,2 In order to target the ACS population, PLATO enrolled patients with UA/NSTEMI and STEMI who presented within 24 hours of symptom onset, were clopidogrel treated or naive, and planned for medical or invasive management 1,2 Patients were randomized to receive BRILINTA or clopidogrel 2 All patients randomized to BRILINTA received a loading dose of 180 mg followed by a maintenance dose of 90 mg BID. 2 An additional 90-mg dose was given pre-pci if >24 hours postrandomization 1 Subjects in the clopidogrel arm were treated with an initial loading dose of clopidogrel 300 mg, if previous clopidogrel therapy had not been given prior to randomization. Patients undergoing PCI could receive an additional 300 mg of clopidogrel at the investigator s discretion. Thus, the trial design supported use of high loading doses of clopidogrel 1,2 For patients not previously receiving aspirin, a loading dose of 325 mg was preferred (160 mg-500 mg allowed). A daily maintenance dose of aspirin 75 mg-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local investigator judgment 2,3 Patients were treated for at least 6 months and for up to 12 months 1,2 The study s primary end point was the composite of first occurrence of CV death, nonfatal MI (excluding silent MI), or nonfatal stroke at 12 months. The primary safety end point was Total Major Bleeding at 12 months 1,2 Supplemental Information PLATO was not designed or powered to demonstrate the efficacy of BRILINTA compared with clopidogrel in those patients who received differing doses of clopidogrel prior to randomization into the PLATO trial 3 Note to Speaker After presenting this slide, should you wish to present information on PLATO study inclusion and exclusion criteria (optional), please click on C. Please note, if you click C, you must present both slides for study inclusion and exclusion criteria. 1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 3. James SK, Akerblom A, Cannon C, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4):

17 PLATO inclusion criteria allowed for a broad spectrum of patients to be enrolled in the trial Eligible patients were those who were hospitalized for potential ST-segment elevation or non ST-segment elevation ACS, with onset during the previous 24 hours, documented by cardiac ischemic symptoms due to atherosclerosis of 10 minutes duration at rest, 18 years of age, not pregnant, and with informed consent signed Supplemental Information Patients with ACS with ST-segment elevation had to meet both of the following criteria: Persistent ST-segment elevation 1 mm (not known to be preexisting or due to a coexisting disorder) in 2 contiguous leads or new left bundle branch block Primary PCI planned Patients with ACS without ST-segment elevation had to meet at least 2 of the following 3 criteria: ST-segment changes on electrocardiogram indicating ischemia, ST-segment depression, or transient elevation 1 mm in two or more contiguous leads Positive biomarker indicating myocardial necrosis. Troponin I or T or CK-MB (myocardial fraction of creatine kinase) greater than the upper limit of normal One of the following: 60 years of age Previous MI or CABG CAD with 50% stenosis in 2 vessels Previous ischemic stroke, transient ischemic attack (TIA) (hospital-based diagnosis), carotid stenosis ( 50%), or cerebral revascularization Diabetes mellitus Peripheral artery disease Chronic renal dysfunction Reference James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4):

18 PLATO had exclusion criteria typical of ACS trials 1-3 Exclusion criteria were categorized as drug related, treatment related, medical, and general 3 Drug-related, treatment-related, and medical exclusion criteria are outlined on this slide 3 Supplemental Information General exclusion criteria, not shown on this slide, include 3 Participation in another investigational drug or device study within 30 days Pregnancy or lactation Any condition that increases the risk for noncompliance or being lost to follow-up Involvement in the planning or conduct of the study Previous enrollment or randomization in this study Examples of strong CYP3A inhibitors include ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin; and examples of strong CYP3A inducers include rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital 4 Increased risk of bradycardic events was defined as patients who had sick sinus syndrome, 2nd- or 3rddegree AV block, or bradycardic-related syncope and not protected with a pacemaker 4 1. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345: Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel vs clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357: James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4): BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 18

19 The primary outcome of the PLATO trial was a composite end point of the time to first occurrence of CV death, MI (excluding silent MI), or stroke at 12 months BRILINTA significantly reduced the rate of the primary composite end point by a relative risk reduction of 16% vs clopidogrel at 12 months. This difference was statistically significant (P=0.0003). This is an absolute risk reduction of 1.9% vs clopidogrel and event rates were 9.8% and 11.7%, respectively. The number needed to treat was 54 The difference between treatments was driven by CV death and MI with no difference in stroke Note to Speaker After presenting this slide, should you wish to present information on thrombotic CV events at 30 days (optional), please click on D. Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 19

20 The reduction in thrombotic CV events was seen as early as 30 days, with a relative risk reduction of 12% and absolute risk reduction of 0.6%, and the curves continued to diverge over 12 months 1,2 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Data on file, , AstraZeneca, LP. 20

21 BRILINTA is the first and only oral antiplatelet agent FDA approved to demonstrate superior reductions in CV death vs clopidogrel 1 CV death was a prespecified secondary efficacy end point in the PLATO trial 2 CV death occurred in 4.0% of patients in the BRILINTA group and 5.1% of patients in the clopidogrel group. This difference was statistically significant (P=0.0013) 2,3 This was a 21% relative risk reduction, 1.1% absolute risk reduction, in CV death with BRILINTA vs clopidogrel at 12 months. The number needed to treat was 91 2,3 1. Data on file, , AstraZeneca, LP. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): Supplementary appendix. 21

22 In addition to CV death, this table shows other prespecified secondary efficacy end points, which were the individual components of the composite end point 1,2 BRILINTA decreased the rate of MI (excluding silent MI) as compared with clopidogrel by 16% relative risk reduction, and 1.1% absolute risk reduction (P=0.0045) 1 In addition, there was no statistically significant difference in stroke 1 BRILINTA also reduced all-cause mortality versus clopidogrel with a 22% relative risk reduction and a 1.4% absolute risk reduction 2 However, due to the hierarchical test sequence in PLATO, all-cause mortality was an exploratory analysis and, therefore, the P value is nominal 2 Supplemental Information MI and stroke end points include patients that could have had other nonfatal events or died 1 Death from vascular causes was defined as death from cardiovascular causes or cerebrovascular causes and any death without another known cause 2 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):

23 Many trials in ACS have used TIMI bleeding definitions 1 Compared to TIMI definitions, the PLATO bleeding definitions were broad and inclusive 2,3 In the PLATO study, bleeding was characterized as 4 : Major Bleed Fatal/Life-threatening Other - The Major Bleeding category contains measures such as a drop in hemoglobin of 3-5 g/dl. As far as definitions are concerned, this is part of the criteria for TIMI minor bleeding 2,3 Minor Bleed Minimal Bleed These definitions were designed to capture laboratory and clinical bleeding in both the acute and long-term maintenance settings 2 1. Quinlan DJ, Eikelboom JN, Goodman SG, et al. Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y 12 inhibitors for acute coronary syndromes. Eur Heart J. 2011;18: James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4): Wiviott SD, Antman EM, Gibson M, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006;152: BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 23

24 In this study, the primary safety end point was Overall Total Major Bleeding. This end point is inclusive of patients who were managed with a medical or an invasive strategy, including those who underwent PCI or CABG 1 There was no significant difference for Overall Total Major Bleeding between BRILINTA and clopidogrel. The overall rates were 11.6% with BRILINTA vs 11.2% with clopidogrel at 12 months with a P value of 0.434, which is statistically nonsignificant 2 No baseline demographic factor altered the relative risk of Total Major Bleeding with BRILINTA compared with clopidogrel 2 In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures, and concomitant use of medications that increase the risk of bleeding (eg, anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDs]) 2 1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;36(11): BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 24

25 In terms of non CABG-related Bleeding, there was a somewhat greater risk of non-cabg Total Major plus Minor Bleeding with BRILINTA (8.7%) vs clopidogrel (7.0%), and of non-cabg Major Bleeding with BRILINTA (4.5%) vs clopidogrel (3.8%). The rate of non-cabg Fatal/Lifethreatening Bleeding was 2.1% with BRILINTA and 1.9% with clopidogrel. There was no increase in non-cabg Fatal Bleeding. The rate of intracranial hemorrhage with BRILINTA was 0.3% and with clopidogrel 0.2% About half of the non CABG-related Bleeding events were in the first 30 days PLATO did not show an advantage for BRILINTA compared to clopidogrel for CABG-related Bleeding CABG-related Bleeding rates were high but similar for both drugs. CABG-related Total Major Bleeding was 85.8% for BRILINTA vs 86.9% for clopidogrel These rates are high because these numbers are for the subset of 1,584 patients who underwent CABG, approximately 8.5% of the overall trial population not all study subjects When therapy was stopped 5 days prior to CABG, Major Bleeding occurred in 75% of BRILINTAtreated patients and 79% of clopidogrel-treated patients These findings support the recommendation to discontinue BRILINTA 5 days prior to surgery Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 25

26 For patients with moderate hepatic impairment, consider the risks and benefits of treatment, noting the probable increase in exposure to ticagrelor Premature discontinuation increases the risk of MI, stent thrombosis, and death Dyspnea will be discussed in further detail on a subsequent slide BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Other drug interactions with BRILINTA will be discussed in further detail in subsequent slides The most commonly observed adverse reactions associated with the use of BRILINTA vs clopidogrel were Total Major Bleeding (11.6% vs 11.2%) and dyspnea (14% vs 8%) In clinical studies, BRILINTA has been shown to increase the occurrence of Holterdetected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment Note to Speaker After presenting this slide, should you wish to present information on bradycardia-related events (optional), please click on B. Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 26

27 In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias 1 PLATO excluded patients at increased risk of bradycardia events, for example patients with sick sinus syndrome, 2nd- or 3rd-degree AV block, or bradycardic-related syncope and not protected with a pacemaker 1 There were no differences in adverse clinical consequences with BRILINTA; eg, pacemaker insertion, syncope, bradycardia, and heart block were similar between both groups 2 In a Holter substudy of about 3,000 patients, ventricular pauses 3 seconds occurred in 6.0% of BRILINTAtreated patients vs 3.5% of clopidogrel-treated patients in the acute phase, and 2.2% and 1.6% after 1 month, respectively 1 In patients with bradycardia, consider the risks and benefits of treatment before making any treatment decisions 1 Supplemental Information While the exact mechanism for the increased incidence of bradycardia seen with BRILINTA is not known, a hypothesis is that there is increased endogenous adenosine at the SA and AV nodes, resulting in bradycardic events 3,4 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): Scirica BM, Cannon CP, Emanuelsson H, et al. The incidence of bradyarrhythmias and clinical bradyarrhythmic events in patients with acute coronary syndromes treated with ticagrelor or clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) trial. J Am Coll Cardiol. 2011;57(19): Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):

28 Dyspnea was prospectively evaluated in the PLATO trial. At enrollment, PLATO investigators were asked to record whether there was a history of dyspnea and/or current dyspnea and record occurrences of dyspnea as adverse events or serious adverse events (AEs/SAEs) throughout the trial 1 The PLATO trial showed more dyspnea-related adverse events associated with BRILINTA compared with clopidogrel (13.8% vs 7.8%) 2 BRILINTA-associated dyspnea was usually mild to moderate and often resolved during continued treatment, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of patients taking clopidogrel) 2 Mild dyspnea occurred in approximately 9.6% of patients using BRILINTA and 5.5% of patients using clopidogrel 3 4.5% of BRILINTA patients had moderate dyspnea compared to 2.4% in the clopidogrel group 3 Severe dyspnea occurred in 0.4% of BRILINTA patients and 0.2% of clopidogrel patients 3 If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, rule out underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent 2 Supplemental Information Dyspnea was a potential safety concern identified in BRILINTA Phase II clinical studies; therefore, dyspnea was a prespecified safety end point in PLATO 4,5 Patients with a history of asthma, chronic obstructive pulmonary disease, and other respiratory diseases were included in PLATO 1 1. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;32: BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 3. Data on file, , AstraZeneca, LP. 4. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): James S, Åkerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4):

29 BRILINTA was added as a Class I/Grade 1B recommendation in multiple guidelines as an important part of standard of care for ACS 1-5 These guidelines include the 2014 AHA/ACC Guideline for the Management of Patients With NSTE-ACS, the 2013 ACCF/AHA Guideline for the Management of Patients With STEMI, the 2012 ACCP Guideline for Antithrombotic Therapy, the 2011 ACCF/AHA/SCAI Guideline for PCI, and the 2011 AHA/ACCF Guideline for Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease 1. Amsterdam EA, Wenger NK, Brindis RG, et al AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e O Gara PT, Kushner FG, Ascheim DD, et al ACCF/AHA guidelines for the management of STelevation myocardial infarction: Executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362- e Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):7s-47s. 4. Levine GN, Bates ER, Blankenship JC, et al ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography Interventions. Circulation. 2011;124:e574-e Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124(22):

30 This slide shows the recommendations for patients with ACS from the NSTE-ACS and STEMI Guidelines There is a Class IIa recommendation for BRILINTA over clopidogrel in NSTE-ACS patients with early invasive or ischemia-guided strategy or receiving a coronary stent 1 For the first time, BRILINTA is preferred over clopidogrel in the 2014 AHA/ACC Guideline for the Management of Patients With NSTE-ACS There is a Class I recommendation for BRILINTA as a treatment option in the management of NSTE-ACS patients 1 There is a Class I recommendation for BRILINTA as a treatment option to be given as early as possible or at time of primary PCI to patients with STEMI 2 1. Amsterdam EA, Wenger NK, Brindis RG, et al AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e O Gara PT, Kushner FG, Ascheim DD, et al ACCF/AHA guidelines for the management of STelevation myocardial infarction: Executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362- e

31 We ve discussed the efficacy and safety of BRILINTA in patients with ACS as demonstrated in PLATO. Now let s discuss how BRILINTA can be incorporated into the management of patients with ACS 31

32 This slide shows a case study of a patient who is typical of what we may see in clinical practice This is a 65-year-old female who presents with chest pain that has worsened over the past hour. On arrival to the emergency department, pain is moderate-severe in intensity Her past medical history includes hyperlipidemia and hypertension She is currently taking simvastatin 40 mg at bedtime and lisinopril 10 mg daily Her vital signs on presentation were significant for a regular HR of 100, a BP of 140/90, and RR of 20 Physical exam was significant for soft left carotid bruit and bilateral mild pitting edema of the extremities An ECG showed 1.5 mm ST elevation in inferior leads. The patient was diagnosed with STEMI While in the emergency department, the patient was given 325 mg aspirin to chew and heparin. The cath lab was activated for primary PCI. During transfer to the cath lab, symptoms began to improve with NTG SL and oxygen 32

33 Note to Speaker These questions are intended for audience interaction/discussion. Please acknowledge audience responses and reinforce the talking points below. Talking Points Would initiation of BRILINTA be restricted if this patient was loaded with clopidogrel in the ED? Could this patient be initiated on BRILINTA in the ED, without knowing coronary anatomy? Based on the study design of PLATO, patients loaded on clopidogrel in the ED were enrolled in the trial. In addition, patients could be randomized to BRILINTA prior to knowing coronary anatomy 1,2 Other important treatment considerations include contraindications, patient bleeding risk, comorbid conditions, other concomitant medications, and overall health status Let s take a closer look at the PLATO study design as well as the study designs of other ACS trials 1. James SK, Akerblom A, Cannon C, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4): Data on file, , AstraZeneca, LP. 33

34 The PLATO study was designed to mirror real world clinical practice. The study design of PLATO was also different from select studies of oral antiplatelet therapies 1-4 As discussed earlier, PLATO studied BRILINTA plus aspirin versus clopidogrel plus aspirin in 18,624 patients with ACS. CURE studied 12,562 patients randomized to either clopidogrel plus aspirin or placebo plus aspirin. TRITON TIMI-38 compared prasugrel plus aspirin to clopidogrel plus aspirin in 13,608 patients with ACS 1-3 PLATO enrolled patients with STEMI and UA/NSTEMI, similar to TRITON TIMI-38; however, CURE did not include patients with STEMI 1-4 PLATO patients could be treated invasively or medically, similar to CURE. 1,3 In the TRITON TIMI-38 trial, eligible patients were only those scheduled for PCI 2 PLATO allowed previous clopidogrel use, including in-hospital load prior to randomization. In fact, 46% of the patients in the PLATO trial had clopidogrel administered in hospital prior to randomization. 3 Therefore, if the patient in the case study received clopidogrel in the ED, BRILINTA can be initiated after weighing other important treatment considerations (i.e., contraindications, patient bleeding risk, comorbid conditions, other concomitant medications, and overall health status). In contrast, use of any thienopyridine within 5 days of enrollment was an exclusion criteria for TRITON TIMI-38 2 In terms of clopidogrel loading doses, PLATO allowed doses of 300 mg clopidogrel. 3 In contrast, patients randomized to clopidogrel in TRITON TIMI-38 received a loading dose of 300 mg clopidogrel 2 In PLATO, patients could be randomized to BRILINTA prior to knowing coronary anatomy. 3-5 However, at investigators discretion, patients could have been randomized at any point prior to PCI, including postangiography. 5 In TRITON TIMI-38, since the trial was designed to study patients with ACS undergoing PCI, coronary anatomy had to be known to be suitable for PCI before randomization in all patients except for those with STEMI presenting within 12 hours of symptom onset and primary PCI planned 2 1. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345: Wiviott SD, Antman EM, Gibson CM, et al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary syndromes: design and rationale for the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibition with prasugrel Thrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006;152: Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): James SK, Akerblom A, Cannon C, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4): Data on file, , AstraZeneca, LP. 34

35 Note to Speaker This is a rhetorical question. Discussion/answers from the audience should not be solicited for this question. Talking Point Is this patient typical of the patients studied in PLATO? 35

36 The median age of patients was 62 years, with nearly 16% over 75 years of age 1 Over 85% of patients had a positive troponin test at study entry 1 PLATO included patients with a variety of cardiovascular risk factors, such as hypertension and diabetes mellitus; and prior medical history such as previous myocardial infarction, ischemic stroke, and chronic renal disease 1 Keep in mind patients on dialysis were excluded from the trial 2 1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): James S, Akerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y 12 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(4):

37 Talking Point The patient s angiography showed left coronary system remarkable for diffuse nonobstructive CAD. The right coronary system showed a critical lesion in the distal right coronary artery 37

38 Talking Point BRILINTA plus aspirin was initiated and two drug-eluting stents were deployed in the right coronary artery Note to Speaker This is a rhetorical question. Discussion/answers from the audience should not be solicited for this question. Talking Point In the PLATO trial, what were the effects on stent thrombosis for BRILINTA? 38

39 In the PLATO trial, 11,289 patients with PCI received a stent, 5,640 in the BRILINTA-treated group and 5,649 patients in the clopidogrel-treated group 1,2 BRILINTA led to a lower rate of stent thrombosis at 12 months. The rates were 1.3% for adjudicated definite stent thrombosis with BRILINTA, compared with 1.9% with clopidogrel. This is a 33% relative risk reduction (0.6% absolute risk reduction) in stent thrombosis with BRILINTA 1,2 The results were similar for drug-eluting and bare-metal stents 1,2 Supplemental Information In terms of the specific type of stent, 3,476 patients received at least 1 drug-eluting stent and 7,813 patients received bare-metal stents 2 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):

40 Note to Speaker These questions are intended for audience interaction/discussion. Please acknowledge audience responses and reinforce the talking points below. Talking Points Could BRILINTA be used if this patient was to be An NSTEMI patient? Medically managed? Initiation of BRILINTA is not limited by ACS diagnosis or planned treatment approach. As we discussed earlier, PLATO enrolled patients with an ACS diagnosis of UA, NSTEMI, and STEMI who were planned for invasive or medical management. Let s take a look at the results in the final diagnosis subgroup and the planned treatment approach subgroup to understand the effects of BRILINTA in these patients Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded from the PLATO trial 2 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):

41 Of the overall PLATO population, nearly 38% had a final diagnosis of STEMI, 43% had NSTEMI, and 17% had UA On this slide, you can see the data in the final diagnosis subgroup which show effects consistent with the overall results for the primary end point The effect in the UA subset appeared smaller than the effect in the NSTEMI and STEMI subsets At 12 months, the rates for the composite endpoint in the STEMI subset were 8.5% for those taking BRILINTA plus aspirin vs 10.1% for those taking clopidogrel plus aspirin. This corresponds to an absolute risk reduction of 1.6%. The hazard ratio was 0.84, which is a 16% relative risk reduction Specifically looking at the NSTEMI subset, the event rates were 11.4% for BRILINTA plus aspirin and 13.9% for clopidogrel plus aspirin. This corresponds to an absolute risk reduction of 2.5%. As you can see, the hazard ratio is 0.83, which is a 17% relative risk reduction PLATO was not powered to demonstrate efficacy or safety of BRILINTA compared with clopidogrel in specific subgroups. Numerous analyses were performed to evaluate the consistency of results across subgroups; however, these must be interpreted cautiously The final diagnosis subgroups were based on postrandomized determinations Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 41

42 On this slide, you can see the data in the planned treatment approach subgroup for all patients included in PLATO which show effects consistent with the overall results for the primary end point 1,2 The intent to medically manage subgroup consisted of 5,216 patients, 28% of the overall PLATO population 1 Event rates in the planned medical management subgroup were 12.0% for BRILINTA plus aspirin and 14.3% for clopidogrel plus aspirin. BRILINTA provided an absolute risk reduction of 2.3% in this group at 12 months. As you can see, the hazard ratio is 0.85, which is a 15% relative risk reduction 1 The intent to invasively manage subgroup consisted of 13,408 patients, 72% of the overall PLATO population 2 Event rates in the planned invasive management subgroup were 9% for BRILINTA plus aspirin and 10.7% for clopidogrel plus aspirin. BRILINTA provided an absolute risk reduction of 1.7% in this group at 12 months. As you can see, the hazard ratio is 0.84, which is a 16% relative risk reduction 2 Supplemental Information In terms of actual treatment approach, 11,572 (62% of the overall PLATO population) underwent invasive management. Event rates in the invasively managed subgroup were 9.5% for BRILINTA plus aspirin and 10.7% for clopidogrel plus aspirin (HR 0.88, 95% CI ) 3 In terms of actual treatment approach, 7,052 (38%) underwent medical management. Event rates in the medically managed subgroup were 10.4% for BRILINTA plus aspirin and 13.3% for clopidogrel plus aspirin (HR 0.79, 95% CI ) 3 [If the above Supplemental Information bullet points are presented, then the below bullet point MUST be presented] The actual treatment approach subgroup was based on retrospective postrandomized determinations 3 1. James SK, Roe MT, Cannon CP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomized platelet inhibition and patient outcomes (PLATO) trial. BMJ. 2011;342: 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 randomized double-blind study. Lancet. 2010;375: BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 42

43 The data for Total Major Bleeding in the final diagnosis subgroup are shown on this slide. These data include patients who were managed with a medical or invasive strategy 1 The rates of Total Major Bleeding in the NSTEMI subset were 14.7% with BRILINTA plus aspirin and 14.3% with clopidogrel plus aspirin 1 The rates of Total Major Bleeding in the STEMI subset were 8.6% with BRILINTA plus aspirin and 8.3% with clopidogrel plus aspirin 1 The data for Total Major Bleeding by planned treatment approach subgroup for all patients included in PLATO is also shown on this slide For the planned medical management subgroup, rates of Total Major Bleeding were 11.9% in patients treated with BRILINTA plus aspirin vs 10.3% in patients treated with clopidogrel plus aspirin 2 For the planned invasive management subgroup, rates of Total Major Bleeding were 11.5% in patients treated with BRILINTA plus aspirin vs 11.6% in patients treated with clopidogrel plus aspirin 3 Within subgroups, non CABG-related Total Major Bleeding rates were higher for BRILINTA vs clopidogrel 4 1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): Supplementary appendix. 2. James SK, Roe MT, Cannon CP, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomized platelet inhibition and patient outcomes (PLATO) trial. BMJ. 2011;342: 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 randomized double-blind study. Lancet. 2010;375: Data on file, , AstraZeneca, LP. 43

44 Note to Speaker These questions are intended for audience interaction/discussion. Please acknowledge audience responses and reinforce the talking points below. Talking Points Would the initiation of BRILINTA be restricted if this patient had a history of TIA/ischemic stroke? Would you use BRILINTA if this patient had diabetes? While BRILINTA is contraindicated in patients with a history of intracranial hemorrhage, BRILINTA is not contraindicated in patients with a history of TIA/ischemic stroke In addition, if this patient had diabetes, BRILINTA can still be initiated Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 44

45 BRILINTA was studied in a broad range of patients with ACS. Several subgroup analyses were conducted to evaluate the consistency of effect of BRILINTA in different cohorts 1,2 PLATO was not powered to demonstrate efficacy or safety of BRILINTA compared with clopidogrel in specific subgroups. Numerous analyses were performed to evaluate the consistency of results across subgroups; however, these analyses must be interpreted cautiously. Some subgroups were based on postrandomization determinations 1 The effects seen with BRILINTA in select subgroup analyses of PLATO are shown here in the forest plot 1,2 The effects in the subgroups of patients with a history of TIA/ischemic stroke or diabetes were consistent with the overall results of the primary efficacy end point 1,2 Note to Speaker After presenting this slide, should you wish to present additional data on subgroup analyses (optional), please click on S. 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): Supplementary appendix. 45

46 As seen on this slide, most of the analyses showed effects consistent with the overall results of the primary efficacy end point There are 2 marked exceptions: A finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin Specifically, in the North American subgroup, there was a smaller treatment effect, driven by the US subset, in which BRILINTA was numerically inferior to clopidogrel In the US and outside the US, use of >100 mg aspirin decreased the effectiveness of BRILINTA. Overall results favored BRILINTA when used with maintenance doses of aspirin 100 mg Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 46

47 Note to Speaker This is a rhetorical question. Discussion/answers from the audience should not be solicited for this question. Talking Point When prescribing BRILINTA for this patient, what is other key information to know? 47

48 ACS patients may be started on BRILINTA whether or not they received clopidogrel previously 1 Initiate treatment with BRILINTA with a 180-mg (two 90-mg tablets) oral loading dose and 325-mg aspirin loading dose 1 Twelve hours after loading dose, continue BRILINTA treatment with a 90-mg BID maintenance dose plus aspirin 81 mg QD 1,2 A patient who misses a dose of BRILINTA should take one 90-mg tablet (the next dose) at its scheduled time 1 BRILINTA is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events 1 No dosage adjustment is needed in patients with mild hepatic impairment BRILINTA has not been studied in moderate to severe hepatic impairment. For patients with moderate hepatic impairment, consider the risks and benefits of treatment and carefully consider use For patients with severe hepatic impairment, BRILINTA is contraindicated No dosage adjustment is needed in patients with renal impairment. Patients on dialysis have not been studied 1 BRILINTA can be administered with or without food 1 Supplemental Information In a dose-finding study, the IPA was greater and more consistent over the entire dosing interval when BRILINTA was given BID vs QD. Therefore, BRILINTA was only studied using BID dosing in the PLATO trial. BRILINTA is not approved to be dosed once daily 1,3 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Data on file, , AstraZeneca, LP. 3. Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol. 2010;70:

49 Use BRILINTA with a daily maintenance dose of aspirin of 75 mg-100 mg. After the 325-mg loading dose, avoid use with aspirin over 100 mg 1 Avoid simvastatin and lovastatin doses >40 mg 1 BRILINTA is metabolized by CYP3A4/5 1 Avoid use with strong inhibitors of CYP3A Avoid use with potent inducers of CYP3A Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy 1 BRILINTA can be administered 1 With unfractionated heparin, low-molecular-weight heparin, GPIIb/IIIa inhibitors, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and proton pump inhibitors Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded from the PLATO trial 2 In general, risk factors for bleeding include concomitant use of medications that increase the risk of bleeding (eg, anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDs]) 1 Supplemental Information Strong inhibitors of CYP3A include ketoconazole, itraconazole, voriconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, atazanavir, and telithromycin 1 Potent inducers of CYP3A include rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital 1 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):

50 Loading BRILINTA is not restricted by 1,2 : Select patient characteristics Previous clopidogrel loading or maintenance dose Prior TIA/ischemic stroke Patient age or weight Management strategy Invasively managed Medically managed CYP2C19 genotype and PPI use Not affected by CYP2C19 genotype Can be administered with PPIs BRILINTA can be initiated prior to knowing coronary anatomy 3 We just talked about the drug interactions, now let's talk about some of the other important treatment considerations Other important treatment considerations include contraindications, patient bleeding risk, comorbid conditions, other concomitant medications, and overall health status 1 Do not start BRILINTA in patients planned to undergo urgent CABG. When possible, discontinue BRILINTA at least 5 days prior to any surgery 1 In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment 1 In the PLATO study, 43% of patients were 65 years of age and 15% were 75 years of age. The relative risk of bleeding was similar among treatment groups and age groups; however, greater sensitivity of some older individuals cannot be ruled out 1 Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded from PLATO 1 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11): Supplementary appendix. 3. Data on file, , AstraZeneca, LP. 50

51 Talking Point BRILINTA also has contraindications that need to be considered when prescribing Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 51

52 Note to Speaker This is a rhetorical question. Discussion/answers from the audience should not be solicited for this question. Talking Point Why is it important to take the maintenance dose of BRILINTA with 81 mg of aspirin? 52

53 As previously discussed, most of the subgroup analyses showed effects consistent with the overall results, but there are 2 marked exceptions: a finding of heterogeneity by region and a strong influence of the maintenance dose of aspirin 1 Specifically, in the North American subgroup, there was a smaller treatment effect, driven by the US subset, in which BRILINTA was numerically inferior to clopidogrel 1 There appears to be good reason to restrict aspirin maintenance dosage accompanying BRILINTA to 100 mg/day, regardless of treatment approach 1 Based on the data shown here, maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided. After any initial dose, use with aspirin 75 mg-100 mg per day 1 The PLATO protocol left the choice of aspirin maintenance dose up to the investigator and patterns of use were very different in the US and outside the US, with about 8% outside the US using aspirin doses above 100 mg and about 2% using doses above 300 mg, in contrast with US practice where 57% used doses above 100 mg and 54% used doses above 300 mg 1 The effects of aspirin dose on BRILINTA efficacy were consistent regardless of region. In the US and outside the US, use of >100 mg of aspirin decreased the effectiveness of BRILINTA. Overall results favored BRILINTA when used with maintenance doses of aspirin of 100 mg 1 Despite the need to treat such results cautiously, retrospective analyses support the possibility that this was a reliable finding and due to aspirin maintenance dose 1 The recommendation to use BRILINTA with doses 100 mg of aspirin per day is consistent with several US ACS guidelines which specify that it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance dose 2,3 Note to Speaker After presenting this slide, should you wish to present information on the thrombotic CV events by median aspirin dose (optional), please click on A. Should you wish to present a slide on guideline recommendations for aspirin maintenance dose (optional), please click G. 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. O Gara PT, Kushner FG, Ascheim DD, et al ACCF/AHA guidelines for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362-e Amsterdam EA, Wenger NK, Brindis RG, et al AHA/ACC Guideline for the Management of Patients With Non-ST Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e

54 This slide shows overall results by aspirin dose In the 15,439 patients receiving 100 mg of aspirin, rates of the primary composite end point were 7.8% with BRILINTA vs 10.1% with clopidogrel Use of >100 mg of aspirin decreased the effectiveness of BRILINTA. Overall results favored BRILINTA when used with maintenance doses of aspirin of 100 mg Despite the need to treat such results cautiously, retrospective analyses support the possibility that this was a reliable finding and due to aspirin maintenance dose Note to Speaker After showing this slide, and to resume the required presentation, click on R. Otherwise, the next slide you will present is an optional slide called Guideline Recommendations for Aspirin Dose. Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 54

55 Several guidelines state that it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses 1-4 These guidelines include the 2014 AHA/ACC Guideline for the Management of Patients With NSTE-ACS, 2013 ACCF/AHA Guideline for the Management of Patients With STEMI, 2011 ACCF/AHA/SCAI Guideline for PCI, and the 2011 AHA/ACCF Guideline for Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease 1. Amsterdam EA, Wenger NK, Brindis RG, et al AHA/ACC Guideline for the Management of Patients With Non-ST- Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e O Gara PT, Kushner FG, Ascheim DD, et al ACCF/AHA guidelines for the management of ST-elevation myocardial infarction: Executive Summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362-e Levine GN, Bates ER, Blankenship JC, et al ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography Interventions. Circulation. 2011;124:e574-e Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation. 2011;124(22):

56 BRILINTA provided superior reductions in thrombotic CV events vs clopidogrel at 12 months Difference between treatments was driven by CV death and MI with no difference in stroke BRILINTA saved more lives than clopidogrel by reducing CV death at 12 months Risk of Total Major Bleeding with BRILINTA was not significantly different vs clopidogrel There was a somewhat greater risk of non CABG-related Major and Minor Bleeding vs clopidogrel Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 56

57 BRILINTA is indicated to reduce the rate of thrombotic CV events in patients with ACS (UA, NSTEMI, or STEMI) BRILINTA reduced the rate of a combined end point of CV death, MI, or stroke compared to clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke In patients treated with PCI, it also reduces the rate of stent thrombosis BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin >100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin >100 mg daily Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 57

58 AstraZeneca is committed to conducting business with the highest standards of integrity and professionalism If you have any comments that could improve the delivery of our promotional educational programs, please contact AstraZeneca at Visit for information on the BRILINTA Savings Offer and to download BRILINTA Savings Cards for your patients 58