ICC 16781 - 3085005 BRILINTA CV Specialty Slide … NCVH/4-26-Tue/PDFs... · This included patients...

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

Notes to Speaker

• In the notes section of each slide, direction is provided about how to communicate the information on that slide– For Talking Points that are bolded, it is mandatory that the essence of each talking point be

communicated– For Talking Points that are not bolded, it is expected that the essence of each talking point

will be communicated– Supplemental information: This content is optional. This information may be presented

proactively if desired, or used in response to a question– Hyperlinked slides: These slides are optional. If these slides are used, then the direction

provided above will apply

• The slides must be used in sequence, and the presentation must be used in its entirety, with the exception of hyperlinked slides. Any changes to this slide set must be preapproved through the AstraZeneca Approval Process (AZAP)

• For direction on how to answer questions asked by the audience, please refer to the document titled “BRILINTA® (ticagrelor) Tablets Additional Information for Speakers”

BRILINTA is a registered trademark of the AstraZeneca group of companies.©2015 AstraZeneca. 3085005 2/15

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Talking Points

• This presentation reviews the role of BRILINTA® (ticagrelor) tablets in the management of Acute Coronary Syndrome (ACS) through a hypothetical patient case study. Clinical questions relating to the patient case are included throughout the deck to help facilitate a discussion on the efficacy and safety data from the PLATelet inhibition and patient Outcomes (PLATO) study, as well as key information from BRILINTA’s Prescribing Information

• Please refer to the full BRILINTA Prescribing Information, including Boxed WARNINGS, and Medication Guide for more information

• This is a promotional presentation sponsored directly by AstraZeneca and there are no continuing medical education (CME) credits associated with this activity

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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?

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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.

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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.

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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 thromboticCV 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.

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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 aspirin75 mg-100 mg per day

Reference


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


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?

9

Speaker notes are for internal use only and are not to be shown or disseminated outside of AstraZeneca. 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, each requires cytochrome P450 (CYP)-dependent oxidation to generate its active drug3,4

• BRILINTA is active without metabolism. It does not completely depend on hepatic metabolism toinhibit 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 SpeakerAfter 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® Prescribing Information. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2013.

3. Effient® Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; 2013.

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.


Mechanism of Action Video (#1812005)

Note to Speaker

If the Mechanism of Action Video is shown, it must be played with the audio turned on.

After showing the video, and to resume the required presentation, click on “R.” Otherwise, the next slides you will present are the optional slides “Mechanism of Action of Thienopyridines” and “Mechanism of Action of CPTPs.”

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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® Prescribing Information. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2013.

4. Effient® Prescribing Information. Daiichi Sankyo, Inc. and Eli Lilly and Company. Indianapolis, IN; 2013.

5. Husted S, van Giezen JJJ. Ticagrelor: the first reversibly binding oral P2Y12 receptor antagonist. Cardiovasc Ther. 2009;27:259-274.

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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 ADPbinding 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


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 adenosine-mediated hyperemia responses in a canine model. J Cardiovasc Pharmacol Ther. 2012;17(2):164-172.

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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

• 90% 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.


3. Data on file, 1766201, AstraZeneca, LP.

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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


• 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


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.

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Talking Points

• To better understand the efficacy and safety outcomes with BRILINTA, it is important to review the trial designof 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 ACS1,2

• In order to target the ACS population, PLATO enrolled patients with UA/NSTEMI and STEMI who presented within24 hours of symptom onset, were clopidogrel treated or naive, 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 of90 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

– For patients not previously receiving aspirin, a loading dose of 325 mg was preferred (160 mg-500 mg allowed). A daily maintenance dose of aspirin 75 mg-100 mg was recommended, but higher maintenance doses of aspirin were allowed according to local investigator 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


• 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 SpeakerAfter 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 andexclusion criteria.

References1. 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.

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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 of10 minutes duration at rest, 18 years of age, not pregnant, and with informed consent signed


• 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.

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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


• 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 3rd-degree AV block, or bradycardic-related syncope and not protected with a pacemaker4

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, Braunwald E, McCabe CH, et al. Prasugrel vs clopidogrel in patients with acute coronary syndromes. N EnglJ Med. 2007;357:2001-2015.

3. 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.


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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 differencein stroke

Note to SpeakerAfter presenting this slide, should you wish to present information on thrombotic CV events at 30 days (optional), please click on “D.”

Reference


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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




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


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.


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 a 1.4% absolute risk reduction2

• However, due to the hierarchical test sequence in PLATO, all-cause mortality was an exploratory analysis and, therefore, the P value is nominal2


• 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



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 of3-5 g/dL. As far as definitions are concerned, this is part of the criteria for TIMIminor 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.


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.


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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.



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%). The rate of non-CABG Fatal/Life-threatening Bleeding was 2.1% with BRILINTA and 1.9% with clopidogrel. There was no increase in non-CABG Fatal Bleeding. The rate of intracranial hemorrhage with BRILINTA was 0.3% and with clopidogrel 0.2%

• About half of the non–CABG-related Bleeding events were in the first 30 days

• PLATO did not show an advantage for BRILINTA compared to clopidogrel forCABG-related Bleeding

• CABG-related Bleeding rates were high but similar for both drugs. CABG-related Total Major Bleeding was 85.8% for BRILINTA vs 86.9% for clopidogrel

• These rates are high because these numbers are for the subset of 1,584 patients who underwent CABG, approximately 8.5% of the overall trial population—not all study subjects

• When therapy was stopped 5 days prior to CABG, Major Bleeding occurred in 75% of BRILINTA-treated patients and 79% of clopidogrel-treated patients

• These findings support the recommendation to discontinue BRILINTA 5 days prior to surgery

Reference


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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 Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardicevents. Consider the risks and benefits of treatment

Note to SpeakerAfter presenting this slide, should you wish to present information on bradycardia-related events (optional), please click on “B.”

Reference


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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 BRILINTA-treated 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


• 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


2. Wallentin L, Becker RC, Bujah A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N EnglJ 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.

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Talking Points

• Dyspnea was prospectively evaluated in the PLATO trial. At enrollment, PLATO investigators were asked to record whether there was a history of dyspnea and/or current dyspnea and record occurrences of dyspnea as adverse events or serious adverse events (AEs/SAEs) throughout the trial1

• The PLATO trial showed more dyspnea-related adverse events associated with BRILINTA compared with clopidogrel (13.8% vs 7.8%)2

• BRILINTA-associated dyspnea was usually mild to moderate and often resolved during continued treatment, but occasionally required discontinuation (0.9% of patients taking BRILINTA versus 0.1% of patients taking clopidogrel)2

– Mild dyspnea occurred in approximately 9.6% of patients using BRILINTA and 5.5% of patients using clopidogrel3

– 4.5% of BRILINTA patients had moderate dyspnea compared to 2.4% in the clopidogrel group3

– Severe dyspnea occurred in 0.4% of BRILINTA patients and 0.2% of clopidogrel patients3

• If a patient develops new, prolonged, or worsened dyspnea during treatment with BRILINTA, rule out underlying diseases that may require treatment. If dyspnea is determined to be related to BRILINTA, no specific treatment is required; continue BRILINTA without interruption. In the case of intolerable dyspnea requiring discontinuation of BRILINTA, consider prescribing another antiplatelet agent2


• Dyspnea was a potential safety concern identified in BRILINTA Phase II clinical studies; therefore, dyspnea was a prespecified safety end point in PLATO4,5

• 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.



4. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N EnglJ Med. 2009;361(11):1045-1057.

5. James S, Åkerblom 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.

28


Talking Points

• BRILINTA was added as a Class I/Grade 1B recommendation in multiple guidelines as an important part of standard of care for ACS1-5

– These guidelines include the 2014 AHA/ACC Guideline for the Management of Patients With NSTE-ACS, the 2013 ACCF/AHA Guideline for the Management of Patients With STEMI, the 2012 ACCP Guideline for Antithrombotic Therapy, the 2011 ACCF/AHA/SCAI Guideline for PCI, and the 2011 AHA/ACCF Guideline for Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease

References

1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the AmericanCollege of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.

2. 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.

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.

29


Talking Points

• This slide shows the recommendations for patients with ACS from the NSTE-ACS and STEMI Guidelines

• There is a Class IIa recommendation for BRILINTA over clopidogrel in NSTE-ACS patients with early invasive or ischemia-guided strategy or receiving a coronary stent1

− For the first time, BRILINTA is preferred over clopidogrel in the 2014 AHA/ACC Guideline for the Management of Patients With NSTE-ACS

• There is a Class I recommendation for BRILINTA as a treatment option in the management of NSTE-ACS patients1

• There is a Class I recommendation for BRILINTA as a treatment option to be given as early as possible or at time of primary PCI to patients with STEMI2

References

1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.

2. 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.

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

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 hour. On arrival to the emergency department, pain is moderate-severe in intensity

• Her past medical history includes hyperlipidemia and hypertension

• She is currently taking simvastatin 40 mg at bedtime and lisinopril 10 mg daily

• Her vital signs on presentation were significant for a regular HR of 100, a BP of 140/90, andRR of 20

• Physical exam was significant for soft left carotid bruit and bilateral mild pitting edema of the extremities

• An ECG showed 1.5 mm ST elevation in inferior leads. The patient was diagnosed with STEMI

• While in the emergency department, the patient was given 325 mg aspirin to chew and heparin. The cath lab was activated for primary PCI. During transfer to the cath lab, symptoms began to improve with NTG SL and oxygen

32


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 enrolledin the trial. In addition, patients could be randomized to BRILINTA prior to knowingcoronary 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 otherACS 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.


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

References1. 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 prasugrelThrombolysis In Myocardial Infarction 38 (TRITON-TIMI 38). Am Heart J. 2006;152:627-635.


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.



Note to Speaker


Talking Point

• Is this patient typical of the patients studied in PLATO?

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



36


Talking Point

• The patient’s angiography showed left coronary system remarkable for diffuse nonobstructiveCAD. The right coronary system showed a critical lesion in the distal right coronary artery


Talking Point

• BRILINTA plus aspirin was initiated and two drug-eluting stents were deployed in the right coronary artery

Note to Speaker


Talking Point

• In the PLATO trial, what were the effects on stent thrombosis for BRILINTA?


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 thrombosiswith BRILINTA1,2

• The results were similar for drug-eluting and bare-metal stents1,2


• 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


2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N EnglJ Med. 2009;361(11):1045‐1057.


Note to Speaker


Talking Points

• Could BRILINTA be used if this patient was to be– An NSTEMI patient?– Medically managed?

• Initiation of BRILINTA is not limited by ACS diagnosis or planned treatment approach. As we discussed earlier, PLATO enrolled patients with an ACS diagnosis of UA, NSTEMI, and STEMI who were planned for invasive or medical management. Let’s take a look at the results in the final diagnosis subgroup and the planned treatment approach subgroup to understand the effects of BRILINTA in these patients

• Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded from the PLATO trial2

References


2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N EnglJ Med. 2009;361(11):1045‐1057.

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 andSTEMI 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% relativerisk 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 comparedwith clopidogrel in specific subgroups. Numerous analyses were performed to evaluatethe consistency of results across subgroups; however, these must beinterpreted cautiously

• The final diagnosis subgroups were based on postrandomized determinations

Reference


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 at12 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 at12 months. As you can see, the hazard ratio is 0.84, which is a 16% relative risk reduction2


• 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 postrandomized determinations3

References1. 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.


42


Talking Points

• The data for Total Major Bleeding in the final diagnosis subgroup are shown on this slide. Thesedata 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 clopidogrelplus 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 clopidogrelplus aspirin3

• Within subgroups, non–CABG-related Total Major 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.


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Note to Speaker


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


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 select 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


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.


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

• In the US and outside the US, use of >100 mg aspirin decreased the effectiveness of BRILINTA. Overall results favored BRILINTA when used with maintenance doses of aspirin ≤100 mg

Reference



Note to Speaker


Talking Point

• When prescribing BRILINTA for this patient, what is other key information to know?

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 itsscheduled 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 notbeen studied1

• BRILINTA can be administered with or without food1


• 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



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.

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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 nonsteroidalanti-inflammatory drugs [NSAIDs])1


• 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



49


Talking Points

• Loading BRILINTA is not restricted by1,2:– Select patient characteristics

• Previous clopidogrel loading or maintenance dose• Prior TIA/ischemic stroke• Patient age or weight

– Management strategy• Invasively managed• Medically managed

– CYP2C19 genotype and PPI use• Not affected by CYP2C19 genotype• Can be administered with PPIs

• BRILINTA can be initiated prior to knowing coronary anatomy3

• We just talked about the drug interactions, now let's talk about some of the other important treatment considerations

• Other important treatment considerations include contraindications, patient bleeding risk, comorbid conditions, other concomitant medications, and overall health status1

• Do not start BRILINTA in patients planned to undergo urgent CABG. When possible, discontinue BRILINTA at least 5 days prior to any surgery1

• In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias. PLATO excluded patients at increased risk of bradycardic events. Consider the risks and benefits of treatment1

• In the PLATO study, 43% of patients were ≥65 years of age and 15% were ≥75 years of age. The relative risk of bleeding was similar among treatment groups and age groups; however, greater sensitivity of some older individuals cannot be ruled out1

• Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded from PLATO1

References


2. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N EnglJ Med. 2009;361(11):1045‐1057. Supplementary appendix.



Talking Point

• BRILINTA also has contraindications that need to be considered when prescribing

Reference


51


Note to Speaker


Talking Point

• Why is it important to take the maintenance dose of BRILINTA with 81 mg of aspirin?

52


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% used 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 SpeakerAfter 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


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. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients WithNon-ST Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.

53


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 SpeakerAfter 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


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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 2014 AHA/ACC Guideline for the Management of Patients With NSTE-ACS, 2013 ACCF/AHA Guideline for the Management of Patients With STEMI, 2011 ACCF/AHA/SCAI Guideline for PCI, and the 2011 AHA/ACCF Guideline for Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic Vascular Disease

References

1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.

2. 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.

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.

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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 at 12 months

• Risk of Total Major Bleeding with BRILINTA was not significantly different vs clopidogrel

• There was a somewhat greater risk of non–CABG-related Major and Minor Bleedingvs clopidogrel

Reference


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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


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Talking Points

• AstraZeneca is committed to conducting business with the highest standards of integrityand 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 Savings Offer and to download BRILINTA Savings Cards for your patients

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ICC 16781 - 3085005 BRILINTA CV Specialty Slide … NCVH/4-26-Tue/PDFs... · This included patients...

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