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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 the talking points 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 the slide is 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.
© 2013 AstraZeneca.
2639100

6/13

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

1
Talking Points
• This presentation reviews the role of BRILINTA 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

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

2
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?

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

3
Talking Points
• 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 20091
• 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 outcomes2
• 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 UA2
• Shown on this slide are hospital outcomes in these patients, specifically rates of mortality and
recurrent MI2
• 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
categories2
• Standard case report forms and definitions were used; however, cause of death was not reported
and in-hospital events were not centrally adjudicated2

References
1. Fox KA, Eagle KA, Gore JM, et al. The Global Registry of Acute Coronary Events, 1999 to 2009-GRACE. Heart.
2010;96:1095-1101.
2. 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;158:193-201.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

4
Talking Points

• 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):580-589.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

5
Talking Points
• 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

6
Talking Points
• 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

7
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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

8
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?

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

9
Talking Points
• In regard to clinical pharmacology, clopidogrel and prasugrel are thienopyridines which irreversibly bind to
the P2Y12 ADP receptors on platelets. BRILINTA is a CPTP that reversibly interacts with the receptor1-3
• BRILINTA is not a prodrug.1 Clopidogrel and prasugrel are prodrugs. After intestinal absorption, both
require cytochrome P450 (CYP)-dependent oxidation to generate its active drug3,4
• BRILINTA is active without metabolism. It does not completely depend on hepatic metabolism to
inhibit platelets4
– 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 equipotent1
• 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 genotype1
• 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.”

References
1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
2. Plavix® [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011.
3. Effient® Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; 2012.
4. Schömig A. Ticagrelor—is there need for a new player in the antiplatelet-therapy field? N Engl J Med.
2009;361(11):1108-1111.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

10
Mechanism of Action Video (#1812005)
Note to Speaker
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”.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

11
Talking Points
• The binding of ADP to P2Y12 receptors on the platelet surface is a critical step in amplifying the
structural and metabolic changes associated with platelet activation1
• The P2Y12 receptor has proven to be an effective target for antiplatelet drugs2
• Thienopyridines bind to the P2Y12 receptor, inhibiting ADP binding3,4
• This binding is irreversible; the P2Y12 receptor is inhibited for the life of the platelet2-5

References
1. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res. 2007;100:1261-1275.
2. van Giezen JJJ. Optimizing platelet inhibition. Eur Heart J Suppl. 2008;10(suppl D):D23-D29.
3. Plavix® [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011.
4. Effient® Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; 2012.
5. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther.
2009;27:259-274.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

12
Talking Points
• BRILINTA, an orally active P2Y12 receptor antagonist, belongs to a chemical class of antiplatelet
agents called CPTPs1
• CPTPs have a different mechanism of action than thienopyridines2-4
• BRILINTA reversibly binds to an area on the P2Y12 receptor that is distinct from the ADP
binding site2-4
• BRILINTA does not interfere with ADP binding. Instead, it is believed that BRILINTA prevents
ADP-mediated receptor activation2-4
• The receptor is functional after the dissociation of the BRILINTA molecule2,3
• The degree of receptor inhibition is dependent on the BRILINTA concentration2,3
• It is hypothesized that BRILINTA may affect cellular levels of adenosine by interfering with
adenosine degradation and reuptake5,6

References
1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
2. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther.
2009;27:259-274.
3. van Giezen JJJ. Optimizing platelet inhibition. Eur Heart J Suppl. 2008;10(suppl D):D23-D29.
4. 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;7:1556-1565.
5. Ohman J, Kudira R, Albinsson S, et al. Ticagrelor induces adenosine triphosphate release from human red blood cells.
Biochem Biophys Res Comm. 2012;418:754-758.
6. 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):164-172.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

13
Talking Points
• 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 weeks1,2
• BRILINTA demonstrated rapid onset and high IPA1,3
• The mean IPA of BRILINTA after a loading dose of 180 mg was about 41% at 30 minutes1
• The IPA of BRILINTA was approximately 79% at 1 hour3
• The maximum IPA effect of BRILINTA, approximately 88%, was reached at around 2 hours and
was maintained for at least 8 hours2
• Looking at the IPA for clopidogrel and placebo, IPA was higher in the BRILINTA group at all
time points2
• It is not known how either bleeding risk or thrombotic risk track with IPA for either
BRILINTA or clopidogrel2
Supplemental Information
• Ninety percent of patients given BRILINTA had IPA greater than 70% by 2 hours postdose1

References
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):2577-2585.
2. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
3. Data on file, 1766201, AstraZeneca, LP.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

14
Talking Points
• The slide shows mean IPA following 6 weeks of maintenance doses of BRILINTA 90 mg twice
daily, clopidogrel 75 mg once daily, and placebo1
• 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 clopidogrel1
• 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 clopidogrel1
• 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
surgery1
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 effect1,2

References
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;121:1188-1199.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

15
Talking Points
• 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 ACS1
• In order to target the ACS population, PLATO enrolled patients with UA/NSTEMI and STEMI who presented within 24
hours of symptom onset and planned for medical or invasive management1,2
• Patients were randomized to receive BRILINTA or clopidogrel2
– 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 postrandomization1
– 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 clopidogrel1,2
– Concomitant aspirin was recommended at a loading dose of 160 mg - 500 mg. A daily maintenance dose of aspirin
75 mg - 100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local
investigator judgment2,3
• Patients were treated for at least 6 months and for up to 12 months1,2
• 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 months1,2
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 trial3
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.
References
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):1045‐1057.
2. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
3. James SK, Akerblom A, Cannon C, 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(4):599-605.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

16
Talking Points
• 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 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(4):599-605.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

17
Talking Points
• PLATO had exclusion criteria typical of ACS trials1-3
• Exclusion criteria were categorized as drug related, treatment related, medical, and general3
• Drug-related, treatment-related, and medical exclusion criteria are outlined on this slide3

Supplemental Information
• General exclusion criteria, not shown on this slide, include3
– 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 phenobarbital4
• 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 pacemaker4

References
1. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to
aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502.
2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel vs clopidogrel in patients with acute coronary syndromes. N Engl
J Med. 2007;357:2001-2015.
3. 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):599-605.
4. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

18
Talking Points
• 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

19
Talking Points
• 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 months1,2

References
1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
2. Data on file, 1755503, AstraZeneca, LP.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

20
Talking Points
• BRILINTA is the first and only oral antiplatelet agent FDA-approved to demonstrate superior
reductions in CV death vs clopidogrel1
• CV death was a prespecified secondary efficacy end point in the PLATO trial2
• 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 912,3

References
1. Data on file, 1795500, 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):1045‐1057.
3. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl
J Med. 2009;361(11):1045-1057. Supplementary appendix.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

21
Talking Points
• In addition to CV death, this table shows other prespecified secondary efficacy end points, which
were the individual components of the composite end point1,2
• 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 stroke1
• BRILINTA also reduced all cause mortality versus clopidogrel with a 22% relative risk reduction
and an absolute risk reduction 1.4%2
• However, due to the hierarchical test sequence in PLATO, all-cause mortality was an
exploratory analysis and, therefore, the P value is nominal2
Supplemental Information
• MI and stroke end points include patients that could have had other nonfatal events or died1
• Death from vascular causes was defined as death from cardiovascular causes or cerebrovascular
causes and any death without another known cause2

References
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):1045‐1057.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

22
Talking Points
• Many trials in ACS have used TIMI bleeding definitions1
• Compared to TIMI definitions, the PLATO bleeding definitions were broad and inclusive2,3
• In the PLATO study, bleeding was characterized as4:
– 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 bleeding2,3
– Minor Bleed
– Minimal Bleed
• These definitions were designed to capture laboratory and clinical bleeding in both the acute and
long-term maintenance settings2

References
1. Quinlan DJ, Eikelboom JN, Goodman SG, et al. Implications of variability in definition and reporting of major bleeding in
randomized trials of oral P2Y12 inhibitors for acute coronary syndromes. Eur Heart J. 2011;18:2256-2265.
2. 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):599-605.
3. 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;152:627-635.
4. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

23
Talking Points
• 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 CABG1
• 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 nonsignificant2
• No baseline demographic factor altered the relative risk of Total Major Bleeding with BRILINTA
compared with clopidogrel2
• 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

References
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):1045-1057.
2. BRILINTA prescribing information. AstraZeneca, LP. Wilmington, DE.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

24
Talking Points
• 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%). There was no increase in Fatal/Lifethreatening or 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, with 85.5% 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

25
Talking Points
• 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

26
Talking Points
• In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected
bradyarrhythmias1
• 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
pacemaker1
• There were no differences in adverse clinical consequences with BRILINTA; eg, pacemaker insertion,
syncope, bradycardia, and heart block were similar between both groups2
• 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, respectively1
• In patients with bradycardia, consider the risks and benefits of treatment before making any treatment
decisions1
Optional 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 events3,4
References
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):1045-1057.
3. 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):1908‐1916.
4. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther.
2009;27(4):259‐274.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

27
Talking Points
• In PLATO, investigators in the trial were requested to record occurrence of dyspnea as an adverse event1
• 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 mostly 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
• If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, rule out underlying
causes 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 agent2
• In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported
dyspnea. There was no effect on pulmonary function after one month or after at least 6 months of chronic treatment2
• While the exact mechanism for the increased incidence of dyspnea associated with BRILINTA is not known, a
hypothesis is that BRILINTA may interfere with adenosine degradation and reuptake, resulting in excess endogenous
adenosine, causing dyspnea3-5
Supplemental Information
• Dyspnea was a potential safety concern identified in BRILINTA phase II clinical studies, therefore dyspnea was a
prespecified safety end point in PLATO6,7
• Patients with a history of asthma, chronic obstructive pulmonary disease, and other respiratory diseases were included
in PLATO1
References
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;32:2945-2953.
2. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
3. Storey RF, Bliden KP, Patil SB, et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable
coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185-193.
4. Ohman J, Kudira R, Albinsson S, et al. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys
Res Comm. 2012;418:754-758.
5. van Giezen JJ, Sidaway J, Glaves P, et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia
responses in a canine model. J Cardiovasc Pharmacol Ther. 2012;17(2):164-172.
6. Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med.
2009;361(11):1045-1057.
7. 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):599-605.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

28
Talking Points
• BRILINTA was added as a Class I/Grade 1 recommendation in multiple guidelines as an
important part of standard of care for ACS1-5
– These guidelines include the 2013 ACCF/AHA Guideline for the Management of Patients with
STEMI, the 2012 ACCF/AHA Guideline for the Management of Patients with UA/NSTEMI, 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

References
1. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 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-e425.
2. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007
guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the
American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation.
2013;127:e663-e828.
3. 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. 2011 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-e651.
5. 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):2458-2473.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

29
Talking Points
• 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

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

30
Talking Points
• 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 few
hours. On arrival to the emergency department, the patient is pain free; however, she
subsequently experiences recurring chest pain
• Her past medical history includes hyperlipidemia and hypertension
• She is currently taking simvastatin 40 mg at bedtime and lisinopril 10 mg daily
• Her vitals are stable and physical examination was unremarkable
• An ECG showed 1.5 mm ST depression in inferior leads, and blood work showed an abnormal
troponin level. The patient was diagnosed with NSTEMI
• While in the emergency department, the patient was given sublingual nitroglycerin, 325 mg
aspirin to chew, and heparin. Cardiology was consulted and the patient was transferred to the
cath lab

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

31
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 anatomy1,2
• 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

References
1. James SK, Akerblom A, Cannon C, 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(4):599-605.
2. Data on file, 2379807, AstraZeneca, LP.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

32
Talking Points
• 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 therapies1-4
• 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 ACS1-3
• PLATO enrolled patients with STEMI and UA/NSTEMI, similar to TRITON TIMI-38; however, CURE did not include
patients with STEMI1-4
• 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 PCI2
• 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-382
• 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 clopidogrel2
• 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 planned2
References
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;345:494-502.
2. 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;152:627-635.
3. 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.
4. James SK, Akerblom A, Cannon C, 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(4):599-605.
5. Data on file, 2379807, AstraZeneca, LP.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

33
Note to Speaker
This is a rhetorical question. Discussion/answers from the audience should not be solicited for
this question.
Talking Point
• Is this troponin-positive patient typical of the patients studied in PLATO?

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

34
Talking Points
• The median age of patients was 62 years, with nearly 16% over 75 years of age1
• Over 85% of patients had a positive troponin test at study entry1
• 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 disease1
• Keep in mind patients on dialysis were excluded from the trial2

References
1. 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.
2. 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):599-605.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

35
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

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

36
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?

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

37
Talking Points
• 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 group1,2
• 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 BRILINTA1-3
• The results were similar for drug-eluting and bare-metal stents1,2
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 stents2

References
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):1045‐1057.
3. Cutlip DE, Windecker S, Mekram R, et al; on behalf of the Academic Research Consortium. Clinical end points in
coronary stent trials. Circulation. 2007;105:2344-2351.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

38
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
– Noninvasively managed?
– a STEMI patient?
• 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 trial2

References
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):1045‐1057.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

39
Talking Points
• 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 post-randomized determinations

Reference
BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

40
Talking Points
• 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 point1,2
• The intent to medically manage subgroup consisted of 5,216 patients, 28% of the overall PLATO
population1
• 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 reduction1
• The intent to invasively manage subgroup consisted of 13,408 patients, 72% of the overall PLATO
population2
• 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 reduction2
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 0.78-0.99)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 0.69-0.91)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 post-randomized determinations3
References
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;342:1-11.
2. 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;375:283-293.
3. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

41
Talking Points
• 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 strategy1
• The rates of Total Major Bleeding in the NSTEMI subset were 14.7% with BRILINTA plus aspirin
and 14.3% with clopidogrel plus aspirin1
• The rates of Total Major Bleeding in the STEMI subset were 8.6% with BRILINTA plus aspirin
and 8.3% with clopidogrel plus aspirin1
• 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 aspirin2
• 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 aspirin3
• Within subgroups, non–CABG-related Bleeding rates were higher for BRILINTA
vs clopidogrel4
References
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):1045‐1057. 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;342:1-11.
3. 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;375:283-293.
4. Data on file, 1344601, AstraZeneca, LP.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

42
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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

43
Talking Points
• 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 cohorts1,2
• 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 determinations1
• The effects seen with BRILINTA in the subgroup analyses of PLATO are shown here in the forest
plot1,2
• 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 point1,2
Note to Speaker
After presenting this slide, should you wish to present additional data on subgroup analyses
(optional), please click on “S.”

References
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):1045‐1057. Supplementary appendix.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

44
Talking Points
• 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

Reference
BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

45
Note to Speaker
This is a rhetorical question. Discussion/answers from the audience should not be solicited for
this question.
Talking Points
• When prescribing BRILINTA for this patient, what is other key information to know?

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

46
Talking Points
• ACS patients may be started on BRILINTA whether or not they received clopidogrel previously1
• Initiate treatment with BRILINTA with a 180-mg (two 90-mg tablets) oral loading dose and 325-mg aspirin
loading dose1
• Twelve hours after loading dose, continue BRILINTA treatment with a 90-mg BID maintenance dose plus
aspirin 81 mg QD1,2
• A patient who misses a dose of BRILINTA should take one 90-mg tablet (the next dose) at its
scheduled time1
• BRILINTA is metabolized by the liver and impaired hepatic function can increase risks for bleeding and
other adverse events1
– 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 studied1
• BRILINTA can be administered with or without food1
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 daily1,3
References
1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
2. Data on file, 1397901, 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;70:65-77.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

47
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?

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

48
Talking Points
• 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 aspirin1
• Specifically, in the North American subgroup, there was a smaller treatment effect, driven by the US subset, in which
BRILINTA was numerically inferior to clopidogrel1
• There appears to be good reason to restrict aspirin maintenance dosage accompanying BRILINTA to ≤100 mg/day,
regardless of treatment approach1
• 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 day1
• 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% received doses
above 300 mg1
• 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 mg1
• Despite the need to treat such results cautiously, retrospective analyses support the possibility that this was a reliable
finding and due to aspirin maintenance dose1
• 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
dose2,3
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.”
References
1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE.
2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 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-e425.
3. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007
guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the
American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation.
2013;127:e663-e828.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

49
Talking Points
• 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

50
Talking Points
• Several guidelines state that it is reasonable to use 81 mg of aspirin per day in preference to
higher maintenance doses1-4
– These guidelines include the 2013 ACCF/AHA Guideline for the Management of STEMI after
PCI, 2012 ACCF/AHA Guideline for the Management of Patients with UA/NSTEMI after PCI,
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 after PCI

References
1. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 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-e425.
2. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007
guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the
American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation.
2013;127:e663-e828.
3. Levine GN, Bates ER, Blankenship JC, et al. 2011 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-e651.
4. 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):2458-2473.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

51
Talking Points
• 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 mg1
• Avoid simvastatin and lovastatin doses >40 mg1
• BRILINTA is metabolized by CYP3A4/51
– 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 therapy1
• BRILINTA can be administered1
– 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 trial2
• 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 telithromycin1
• Potent inducers of CYP3A include rifampin, dexamethasone, phenytoin, carbamazepine,
and phenobarbital1
References
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):1045‐1057.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

52
Talking Points
BRILINTA provides important attributes at initiation1,2
‒ BRILINTA initiation is not restricted by:
• Patient age, weight, or CYP2C19 genotype
• Prior TIA/ischemic stroke
• Planned treatment approach
• BRILINTA can be initiated:
‒ Prior to knowing coronary anatomy
‒ Regardless of previous clopidogrel loading or maintenance dose
•

• Other important treatment considerations include contraindications, patient bleeding risk,
comorbid conditions, other concomitant medications, and overall health status

References
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):1045‐1057. Supplementary appendix.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

53
Talking Points
• 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
• 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

54
Talking Points
• 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.

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

55
Talking Points
• 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 1.800.236.9933
• Visit www.brilintatouchpoints.com for information on the BRILINTA Cost Savings Program, and to
download BRILINTA Savings Cards for your patients

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca.

56

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2639100

  • 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 the talking points 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 the slide is 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. © 2013 AstraZeneca. 2639100 6/13 Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 1
  • 2. Talking Points • This presentation reviews the role of BRILINTA 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 Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 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? Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 3
  • 4. Talking Points • 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 20091 • 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 outcomes2 • 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 UA2 • Shown on this slide are hospital outcomes in these patients, specifically rates of mortality and recurrent MI2 • 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 categories2 • Standard case report forms and definitions were used; however, cause of death was not reported and in-hospital events were not centrally adjudicated2 References 1. Fox KA, Eagle KA, Gore JM, et al. The Global Registry of Acute Coronary Events, 1999 to 2009-GRACE. Heart. 2010;96:1095-1101. 2. 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;158:193-201. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 4
  • 5. Talking Points • 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):580-589. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 5
  • 6. Talking Points • 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 6
  • 7. Talking Points • 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 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? Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 9
  • 10. Talking Points • In regard to clinical pharmacology, clopidogrel and prasugrel are thienopyridines which irreversibly bind to the P2Y12 ADP receptors on platelets. BRILINTA is a CPTP that reversibly interacts with the receptor1-3 • BRILINTA is not a prodrug.1 Clopidogrel and prasugrel are prodrugs. After intestinal absorption, both require cytochrome P450 (CYP)-dependent oxidation to generate its active drug3,4 • BRILINTA is active without metabolism. It does not completely depend on hepatic metabolism to inhibit platelets4 – 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 equipotent1 • 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 genotype1 • 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.” References 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Plavix® [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011. 3. Effient® Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; 2012. 4. Schömig A. Ticagrelor—is there need for a new player in the antiplatelet-therapy field? N Engl J Med. 2009;361(11):1108-1111. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 10
  • 11. Mechanism of Action Video (#1812005) Note to Speaker 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”. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 11
  • 12. Talking Points • The binding of ADP to P2Y12 receptors on the platelet surface is a critical step in amplifying the structural and metabolic changes associated with platelet activation1 • The P2Y12 receptor has proven to be an effective target for antiplatelet drugs2 • Thienopyridines bind to the P2Y12 receptor, inhibiting ADP binding3,4 • This binding is irreversible; the P2Y12 receptor is inhibited for the life of the platelet2-5 References 1. Meadows TA, Bhatt DL. Clinical aspects of platelet inhibitors and thrombus formation. Circ Res. 2007;100:1261-1275. 2. van Giezen JJJ. Optimizing platelet inhibition. Eur Heart J Suppl. 2008;10(suppl D):D23-D29. 3. Plavix® [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011. 4. Effient® Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; 2012. 5. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27:259-274. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 12
  • 13. Talking Points • BRILINTA, an orally active P2Y12 receptor antagonist, belongs to a chemical class of antiplatelet agents called CPTPs1 • CPTPs have a different mechanism of action than thienopyridines2-4 • BRILINTA reversibly binds to an area on the P2Y12 receptor that is distinct from the ADP binding site2-4 • BRILINTA does not interfere with ADP binding. Instead, it is believed that BRILINTA prevents ADP-mediated receptor activation2-4 • The receptor is functional after the dissociation of the BRILINTA molecule2,3 • The degree of receptor inhibition is dependent on the BRILINTA concentration2,3 • It is hypothesized that BRILINTA may affect cellular levels of adenosine by interfering with adenosine degradation and reuptake5,6 References 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27:259-274. 3. van Giezen JJJ. Optimizing platelet inhibition. Eur Heart J Suppl. 2008;10(suppl D):D23-D29. 4. 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;7:1556-1565. 5. Ohman J, Kudira R, Albinsson S, et al. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Comm. 2012;418:754-758. 6. 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):164-172. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 13
  • 14. Talking Points • 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 weeks1,2 • BRILINTA demonstrated rapid onset and high IPA1,3 • The mean IPA of BRILINTA after a loading dose of 180 mg was about 41% at 30 minutes1 • The IPA of BRILINTA was approximately 79% at 1 hour3 • The maximum IPA effect of BRILINTA, approximately 88%, was reached at around 2 hours and was maintained for at least 8 hours2 • Looking at the IPA for clopidogrel and placebo, IPA was higher in the BRILINTA group at all time points2 • It is not known how either bleeding risk or thrombotic risk track with IPA for either BRILINTA or clopidogrel2 Supplemental Information • Ninety percent of patients given BRILINTA had IPA greater than 70% by 2 hours postdose1 References 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):2577-2585. 2. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 3. Data on file, 1766201, AstraZeneca, LP. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 14
  • 15. Talking Points • The slide shows mean IPA following 6 weeks of maintenance doses of BRILINTA 90 mg twice daily, clopidogrel 75 mg once daily, and placebo1 • 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 clopidogrel1 • 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 clopidogrel1 • 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 surgery1 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 effect1,2 References 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;121:1188-1199. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 15
  • 16. Talking Points • 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 ACS1 • In order to target the ACS population, PLATO enrolled patients with UA/NSTEMI and STEMI who presented within 24 hours of symptom onset and planned for medical or invasive management1,2 • Patients were randomized to receive BRILINTA or clopidogrel2 – 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 postrandomization1 – 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 clopidogrel1,2 – Concomitant aspirin was recommended at a loading dose of 160 mg - 500 mg. A daily maintenance dose of aspirin 75 mg - 100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local investigator judgment2,3 • Patients were treated for at least 6 months and for up to 12 months1,2 • 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 months1,2 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 trial3 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. References 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):1045‐1057. 2. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 3. James SK, Akerblom A, Cannon C, 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(4):599-605. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 16
  • 17. Talking Points • 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 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(4):599-605. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 17
  • 18. Talking Points • PLATO had exclusion criteria typical of ACS trials1-3 • Exclusion criteria were categorized as drug related, treatment related, medical, and general3 • Drug-related, treatment-related, and medical exclusion criteria are outlined on this slide3 Supplemental Information • General exclusion criteria, not shown on this slide, include3 – 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 phenobarbital4 • 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 pacemaker4 References 1. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502. 2. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel vs clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015. 3. 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):599-605. 4. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 18
  • 19. Talking Points • 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 19
  • 20. Talking Points • 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 months1,2 References 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Data on file, 1755503, AstraZeneca, LP. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 20
  • 21. Talking Points • BRILINTA is the first and only oral antiplatelet agent FDA-approved to demonstrate superior reductions in CV death vs clopidogrel1 • CV death was a prespecified secondary efficacy end point in the PLATO trial2 • 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 912,3 References 1. Data on file, 1795500, 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):1045‐1057. 3. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. Supplementary appendix. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 21
  • 22. Talking Points • In addition to CV death, this table shows other prespecified secondary efficacy end points, which were the individual components of the composite end point1,2 • 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 stroke1 • BRILINTA also reduced all cause mortality versus clopidogrel with a 22% relative risk reduction and an absolute risk reduction 1.4%2 • However, due to the hierarchical test sequence in PLATO, all-cause mortality was an exploratory analysis and, therefore, the P value is nominal2 Supplemental Information • MI and stroke end points include patients that could have had other nonfatal events or died1 • Death from vascular causes was defined as death from cardiovascular causes or cerebrovascular causes and any death without another known cause2 References 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):1045‐1057. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 22
  • 23. Talking Points • Many trials in ACS have used TIMI bleeding definitions1 • Compared to TIMI definitions, the PLATO bleeding definitions were broad and inclusive2,3 • In the PLATO study, bleeding was characterized as4: – 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 bleeding2,3 – Minor Bleed – Minimal Bleed • These definitions were designed to capture laboratory and clinical bleeding in both the acute and long-term maintenance settings2 References 1. Quinlan DJ, Eikelboom JN, Goodman SG, et al. Implications of variability in definition and reporting of major bleeding in randomized trials of oral P2Y12 inhibitors for acute coronary syndromes. Eur Heart J. 2011;18:2256-2265. 2. 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):599-605. 3. 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;152:627-635. 4. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 23
  • 24. Talking Points • 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 CABG1 • 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 nonsignificant2 • No baseline demographic factor altered the relative risk of Total Major Bleeding with BRILINTA compared with clopidogrel2 • 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 References 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):1045-1057. 2. BRILINTA prescribing information. AstraZeneca, LP. Wilmington, DE. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 24
  • 25. Talking Points • 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%). There was no increase in Fatal/Lifethreatening or 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, with 85.5% 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 25
  • 26. Talking Points • 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 26
  • 27. Talking Points • In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias1 • 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 pacemaker1 • There were no differences in adverse clinical consequences with BRILINTA; eg, pacemaker insertion, syncope, bradycardia, and heart block were similar between both groups2 • 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, respectively1 • In patients with bradycardia, consider the risks and benefits of treatment before making any treatment decisions1 Optional 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 events3,4 References 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):1045-1057. 3. 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):1908‐1916. 4. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27(4):259‐274. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 27
  • 28. Talking Points • In PLATO, investigators in the trial were requested to record occurrence of dyspnea as an adverse event1 • 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 mostly 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 • If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, rule out underlying causes 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 agent2 • In a substudy, 199 patients from PLATO underwent pulmonary function testing irrespective of whether they reported dyspnea. There was no effect on pulmonary function after one month or after at least 6 months of chronic treatment2 • While the exact mechanism for the increased incidence of dyspnea associated with BRILINTA is not known, a hypothesis is that BRILINTA may interfere with adenosine degradation and reuptake, resulting in excess endogenous adenosine, causing dyspnea3-5 Supplemental Information • Dyspnea was a potential safety concern identified in BRILINTA phase II clinical studies, therefore dyspnea was a prespecified safety end point in PLATO6,7 • Patients with a history of asthma, chronic obstructive pulmonary disease, and other respiratory diseases were included in PLATO1 References 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;32:2945-2953. 2. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 3. Storey RF, Bliden KP, Patil SB, et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185-193. 4. Ohman J, Kudira R, Albinsson S, et al. Ticagrelor induces adenosine triphosphate release from human red blood cells. Biochem Biophys Res Comm. 2012;418:754-758. 5. van Giezen JJ, Sidaway J, Glaves P, et al. Ticagrelor inhibits adenosine uptake in vitro and enhances adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther. 2012;17(2):164-172. 6. Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057. 7. 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):599-605. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 28
  • 29. Talking Points • BRILINTA was added as a Class I/Grade 1 recommendation in multiple guidelines as an important part of standard of care for ACS1-5 – These guidelines include the 2013 ACCF/AHA Guideline for the Management of Patients with STEMI, the 2012 ACCF/AHA Guideline for the Management of Patients with UA/NSTEMI, 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 References 1. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 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-e425. 2. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e663-e828. 3. 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. 2011 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-e651. 5. 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):2458-2473. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 29
  • 30. Talking Points • 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 Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 30
  • 31. Talking Points • 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 few hours. On arrival to the emergency department, the patient is pain free; however, she subsequently experiences recurring chest pain • Her past medical history includes hyperlipidemia and hypertension • She is currently taking simvastatin 40 mg at bedtime and lisinopril 10 mg daily • Her vitals are stable and physical examination was unremarkable • An ECG showed 1.5 mm ST depression in inferior leads, and blood work showed an abnormal troponin level. The patient was diagnosed with NSTEMI • While in the emergency department, the patient was given sublingual nitroglycerin, 325 mg aspirin to chew, and heparin. Cardiology was consulted and the patient was transferred to the cath lab Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 31
  • 32. 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 anatomy1,2 • 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 References 1. James SK, Akerblom A, Cannon C, 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(4):599-605. 2. Data on file, 2379807, AstraZeneca, LP. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 32
  • 33. Talking Points • 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 therapies1-4 • 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 ACS1-3 • PLATO enrolled patients with STEMI and UA/NSTEMI, similar to TRITON TIMI-38; however, CURE did not include patients with STEMI1-4 • 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 PCI2 • 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-382 • 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 clopidogrel2 • 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 planned2 References 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;345:494-502. 2. 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;152:627-635. 3. 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. 4. James SK, Akerblom A, Cannon C, 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(4):599-605. 5. Data on file, 2379807, AstraZeneca, LP. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 33
  • 34. Note to Speaker This is a rhetorical question. Discussion/answers from the audience should not be solicited for this question. Talking Point • Is this troponin-positive patient typical of the patients studied in PLATO? Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 34
  • 35. Talking Points • The median age of patients was 62 years, with nearly 16% over 75 years of age1 • Over 85% of patients had a positive troponin test at study entry1 • 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 disease1 • Keep in mind patients on dialysis were excluded from the trial2 References 1. 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. 2. 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):599-605. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 35
  • 36. 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 Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 36
  • 37. 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? Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 37
  • 38. Talking Points • 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 group1,2 • 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 BRILINTA1-3 • The results were similar for drug-eluting and bare-metal stents1,2 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 stents2 References 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):1045‐1057. 3. Cutlip DE, Windecker S, Mekram R, et al; on behalf of the Academic Research Consortium. Clinical end points in coronary stent trials. Circulation. 2007;105:2344-2351. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 38
  • 39. 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 – Noninvasively managed? – a STEMI patient? • 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 trial2 References 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):1045‐1057. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 39
  • 40. Talking Points • 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 post-randomized determinations Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 40
  • 41. Talking Points • 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 point1,2 • The intent to medically manage subgroup consisted of 5,216 patients, 28% of the overall PLATO population1 • 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 reduction1 • The intent to invasively manage subgroup consisted of 13,408 patients, 72% of the overall PLATO population2 • 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 reduction2 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 0.78-0.99)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 0.69-0.91)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 post-randomized determinations3 References 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;342:1-11. 2. 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;375:283-293. 3. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 41
  • 42. Talking Points • 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 strategy1 • The rates of Total Major Bleeding in the NSTEMI subset were 14.7% with BRILINTA plus aspirin and 14.3% with clopidogrel plus aspirin1 • The rates of Total Major Bleeding in the STEMI subset were 8.6% with BRILINTA plus aspirin and 8.3% with clopidogrel plus aspirin1 • 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 aspirin2 • 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 aspirin3 • Within subgroups, non–CABG-related Bleeding rates were higher for BRILINTA vs clopidogrel4 References 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):1045‐1057. 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;342:1-11. 3. 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;375:283-293. 4. Data on file, 1344601, AstraZeneca, LP. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 42
  • 43. 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 43
  • 44. Talking Points • 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 cohorts1,2 • 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 determinations1 • The effects seen with BRILINTA in the subgroup analyses of PLATO are shown here in the forest plot1,2 • 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 point1,2 Note to Speaker After presenting this slide, should you wish to present additional data on subgroup analyses (optional), please click on “S.” References 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):1045‐1057. Supplementary appendix. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 44
  • 45. Talking Points • 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 Reference BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 45
  • 46. Note to Speaker This is a rhetorical question. Discussion/answers from the audience should not be solicited for this question. Talking Points • When prescribing BRILINTA for this patient, what is other key information to know? Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 46
  • 47. Talking Points • ACS patients may be started on BRILINTA whether or not they received clopidogrel previously1 • Initiate treatment with BRILINTA with a 180-mg (two 90-mg tablets) oral loading dose and 325-mg aspirin loading dose1 • Twelve hours after loading dose, continue BRILINTA treatment with a 90-mg BID maintenance dose plus aspirin 81 mg QD1,2 • A patient who misses a dose of BRILINTA should take one 90-mg tablet (the next dose) at its scheduled time1 • BRILINTA is metabolized by the liver and impaired hepatic function can increase risks for bleeding and other adverse events1 – 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 studied1 • BRILINTA can be administered with or without food1 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 daily1,3 References 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. Data on file, 1397901, 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;70:65-77. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 47
  • 48. 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? Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 48
  • 49. Talking Points • 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 aspirin1 • Specifically, in the North American subgroup, there was a smaller treatment effect, driven by the US subset, in which BRILINTA was numerically inferior to clopidogrel1 • There appears to be good reason to restrict aspirin maintenance dosage accompanying BRILINTA to ≤100 mg/day, regardless of treatment approach1 • 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 day1 • 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% received doses above 300 mg1 • 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 mg1 • Despite the need to treat such results cautiously, retrospective analyses support the possibility that this was a reliable finding and due to aspirin maintenance dose1 • 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 dose2,3 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.” References 1. BRILINTA Prescribing Information. AstraZeneca, LP. Wilmington, DE. 2. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 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-e425. 3. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e663-e828. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 49
  • 50. Talking Points • 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 50
  • 51. Talking Points • Several guidelines state that it is reasonable to use 81 mg of aspirin per day in preference to higher maintenance doses1-4 – These guidelines include the 2013 ACCF/AHA Guideline for the Management of STEMI after PCI, 2012 ACCF/AHA Guideline for the Management of Patients with UA/NSTEMI after PCI, 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 after PCI References 1. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 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-e425. 2. Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e663-e828. 3. Levine GN, Bates ER, Blankenship JC, et al. 2011 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-e651. 4. 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):2458-2473. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 51
  • 52. Talking Points • 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 mg1 • Avoid simvastatin and lovastatin doses >40 mg1 • BRILINTA is metabolized by CYP3A4/51 – 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 therapy1 • BRILINTA can be administered1 – 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 trial2 • 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 telithromycin1 • Potent inducers of CYP3A include rifampin, dexamethasone, phenytoin, carbamazepine, and phenobarbital1 References 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):1045‐1057. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 52
  • 53. Talking Points BRILINTA provides important attributes at initiation1,2 ‒ BRILINTA initiation is not restricted by: • Patient age, weight, or CYP2C19 genotype • Prior TIA/ischemic stroke • Planned treatment approach • BRILINTA can be initiated: ‒ Prior to knowing coronary anatomy ‒ Regardless of previous clopidogrel loading or maintenance dose • • Other important treatment considerations include contraindications, patient bleeding risk, comorbid conditions, other concomitant medications, and overall health status References 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):1045‐1057. Supplementary appendix. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 53
  • 54. Talking Points • 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 • 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 54
  • 55. Talking Points • 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. Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 55
  • 56. Talking Points • 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 1.800.236.9933 • Visit www.brilintatouchpoints.com for information on the BRILINTA Cost Savings Program, and to download BRILINTA Savings Cards for your patients Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 56