Press Release

AstraZeneca (NYSE: AZN) announced today that a combined panel of experts from the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) have updated their guidelines to include a Class I recommendation for the use of the oral antiplatelet medicine, BRILINTA® (ticagrelor) tablets in patients with Unstable Angina (UA) or Non–ST-Elevation Myocardial Infarction (NSTEMI) managed both invasively and non-invasively.

“This Guidelines update is yet another strong recommendation for BRILINTA by clinical and scientific leadership within the Cardiology community. We are pleased that the Guidelines recognize the important benefits that BRILINTA provides in the treatment of a broad range of patients with UA/NSTEMI,” said James Ferguson, MD, Executive Director, Medical Affairs and Strategic Development, US, and Vice President for Global Medical Affairs. “This expert consensus is another valued milestone illustrating how our standards of care continue to evolve, and how medications, such as BRILINTA, can very quickly become an important part of those standards.”

A Class I recommendation is the highest recommendation provided by the guidelines committee.

Specific recommendations within the guidelines relating to BRILINTA include:

Class I

Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive dual antiplatelet therapy on presentation. (Level of Evidence(LOE): A) Aspirin should be initiated on presentation. (LOE: A) The choice of a second antiplatelet therapy to be added to aspirin on presentation includes 1 of the following:

Before PCI:

• Clopidogrel (LOE: B); or
• Ticagrelor (LOE: B); or
• An IV GP IIb/IIIa inhibitor. (LOE: A)

At the time of PCI:

• Clopidogrel if not started before PCI (LOE: A); or
• Prasugrel (LOE: B); or
• Ticagrelor (LOE: B); or
• An IV GP IIb/IIIa inhibitor. (LOE: A)

For UA/NSTEMI patients in whom an initial conservative (i.e., non-invasive) strategy is selected, clopidogrel or ticagrelor should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for up to 12 months. (LOE: B)

For UA/NSTEMI patients in whom an initial conservative strategy is selected, if recurrent symptoms/ischemia, heart failure or serious arrhythmias subsequently appear, then diagnostic angiography should be performed. (LOE: A) Either an IV GP IIb/IIIa inhibitor (LOE: A), clopidogrel (loading dose followed by daily maintenance dose [LOE: B]), or ticagrelor (loading dose followed by daily maintenance dose [LOE: B]) should be added to aspirin and anticoagulant therapy before diagnostic angiography (upstream). (LOE: C)

A loading dose of P2Y12 receptor inhibitor therapy is recommended for UA/NSTEMI patients for whom PCI is planned. One of the following regimens should be used:

• Clopidogrel 600 mg should be given as early as possible before or at the time of PCI (LOE: B) or
• Prasugrel 60 mg should be given promptly and no later than 1 hour after PCI once coronary anatomy is defined and a decision is made to proceed with PCI (LOE: B) or
• Ticagrelor 180 mg should be given as early as possible before or at the time of PCI. (LOE: B)

The duration and maintenance dose of P2Y12 receptor inhibitor therapy should be as follows:

• In UA/NSTEMI patients undergoing PCI, either clopidogrel 75 mg daily, prasugrel 10 mg daily, or ticagrelor 90 mg twice daily should be given for at least 12 months. (LOE: B)
• If the risk of morbidity because of bleeding outweighs the anticipated benefits afforded by P2Y12 receptor inhibitor therapy, earlier discontinuation should be considered. (LOE: C)

Class IIa

After PCI, it is reasonable to use 81 mg per day of aspirin in preference to higher maintenance doses. (LOE: B)

NOTES TO EDITORS:

BRILINTA Indication

BRILINTA is indicated to reduce the rate of thrombotic CV events in patients with acute coronary syndrome (ACS: unstable angina [UA], non-ST-elevation myocardial infarction [NSTEMI], or ST-elevation myocardial infarction [STEMI]). BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (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 an artery-opening procedure known as percutaneous coronary intervention (PCI), BRILINTA reduces the rate of stent thrombosis.

BRILINTA has been studied in ACS in combination with aspirin. Maintenance doses of aspirin above 100 mg decreased the effectiveness of BRILINTA. Avoid maintenance doses of aspirin above 100 mg daily.

In the US, since receiving FDA approval in July 2011, BRILINTA has now been added to five established treatment guidelines. In February 2012, the American College of Chest Physicians (ACCP) updated its guidelines for Antithrombotic Therapy to include a recommendation for administering BRILINTA with low-dose aspirin to patients in the first year after ACS who have not undergone PCI or who have undergone PCI with stent placement. This was the first time that clinical treatment guidelines in the U.S. specifically suggested use of BRILINTA over clopidogrel, as a grade 2B recommendation.

In November 2011, a combined expert committee from ACCF, AHA and the Society for Cardiovascular Angiography and Interventions (SCAI) updated its guidelines for the management of patients undergoing percutaneous coronary intervention (PCI) to provide a Class I recommendation for giving BRILINTA to patients undergoing PCI. Additionally, AHA/ACCF also revised their Guidelines on Secondary Prevention and Risk Reduction Therapy to include BRILINTA, in combination with low-dose aspirin, as a Class I therapy to be taken twice daily for at least 12 months in patients receiving a bare-metal stent (BMS) or drug-eluting stent (DES) during PCI for ACS.

The ACCF/AHA guidelines for CABG, released in November 2011, include a Class I recommendation that BRILINTA should be discontinued for at least 5 days before surgery, in patients referred for elective CABG.

For patients that require BRILINTA beyond their hospital stay, a savings card program is available based on eligibility. Commercially insured and cash-paying patients may be eligible for one free 30-day prescription and can save up to $825 per year on their next 11 refills. For each refill (a 30-day supply of up to 60 tablets), savings may apply after the first $18 spent by a patient, up to a $75 savings limit. Patients covered through Medicare, Medicaid or a resident of Massachusetts may be eligible for one month free prescription. Patients can find out more at www.BRILINTAtouchpoints.com or by calling 1-888-412-7454.

AstraZeneca also offers a U.S. patient assistance program for BRILINTA through its AZ&METM Prescription Savings Program. To determine eligibility, patients can visit www.AZandMe.com or call 1-800-AZandMe (292-6363).

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA

WARNING: BLEEDING RISK

• BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding
• Do not use BRILINTA in patients with active pathological bleeding or a history of intracranial hemorrhage
• Do not start BRILINTA in patients planned to undergo urgent coronary artery bypass graft surgery (CABG). When possible, discontinue BRILINTA at least 5 days prior to any surgery
• Suspect bleeding in any patient who is hypotensive and has recently undergone coronary angiography, percutaneous coronary intervention (PCI), CABG, or other surgical procedures in the setting of BRILINTA
• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

• 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

CONTRAINDICATIONS

• BRILINTA is contraindicated in patients with a history of intracranial hemorrhage and active pathological bleeding such aspeptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with severe hepatic impairment because of a probable increase in exposure; it has not been studied in these patients. Severe hepatic impairment increases the risk of bleeding because of reduced synthesis of coagulation proteins

WARNINGS AND PRECAUTIONS

• 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 was reported in 14% of patients treated with BRILINTA and in 8% of patients taking clopidogrel. Dyspnea resulting from BRILINTA is self-limiting. Rule out other causes
• BRILINTA is metabolized by CYP3A4/5. Avoid use with strong CYP3A inhibitors and potent CYP3A inducers. Avoid simvastatin and lovastatin doses >40 mg
• Monitor digoxin levels with initiation of, or any change in, BRILINTA therapy

ADVERSE REACTIONS

• 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 bradycardic events. Consider the risks and benefits of treatment

Please read full Prescribing Information, including Boxed WARNINGS, and Medication Guide. This and additional information can also be foundat www.brilintatouchpoints.com.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

– ENDS –

About BRILINTA® (ticagrelor) tablets

BRILINTA is an oral antiplatelet treatment for ACS. BRILINTA is a direct-acting P2Y12 receptor antagonist in a new chemical class called cyclopentyltriazolopyrimidines (CPTPs). BRILINTA works by inhibiting platelet activation and has been shown to reduce the rate of thrombotic CV events, such as a heart attack or CV death, in patients with ACS.

BRILINTA is available in 90-mg tablets to be administered with a single 180-mg oral loading dose (two 90-mg tablets) followed by a twice daily, 90-mg maintenance dose. Following an initial loading dose of aspirin, BRILINTA should be used with a maintenance dose of 75 mg - 100 mg aspirin once daily, 81-mg aspirin dose in the US.

BRILINTA is a registered trademark of the AstraZeneca group of companies.

About PLATO

PLATO (PLATelet Inhibition and Patient Outcomes) was a large (18,624 patients in 43 countries), head-to-head patient outcomes study of BRILINTA versus clopidogrel, both given in combination with aspirin and other standard therapy. The study was designed to establish whether BRILINTA could achieve a clinically meaningful reduction in cardiovascular (CV) events in acute coronary syndrome (ACS) patients, above and beyond that afforded by clopidogrel. Patients were treated for at least 6 months and up to 12 months.

PLATO demonstrated that treatment with BRILINTA led to a significantly greater reduction in the primary end point – a composite of CV death, MI, or stroke – compared to patients who received clopidogrel (9.8% vs 11.7% at 12 months; 1.9% absolute risk reduction [ARR]; 16% relative risk reduction [RRR]; 95% CI, 0.77 to 0.92; P<0.001). The difference in treatments was driven by CV death and MI with no difference in stroke. In PLATO, the absolute difference in treatment benefit versus clopidogrel was seen at 30 days and the Kaplan-Meier survival curves continued to diverge throughout the 12-month treatment period.

The PLATO study also demonstrated that treatment with BRILINTA for 12 months was associated with a 21% RRR in CV death (4% vs 5.1%; 1.1% ARR; P=0.001) and a 16% RRR in MI compared to clopidogrel at 12 months (5.8% vs 6.9%; 1.1% ARR; P<0.005).

The primary safety end point in the PLATO study was Total Major Bleeding (11.6% for BRILINTA and 11.2% for clopidogrel). In PLATO, non-CABG major + minor bleeding events were more common with BRILINTA versus clopidogrel (8.7% vs 7% respectively). The rate of non–CABG-related major bleeding was higher for BRILINTA (4.5%) vs clopidogrel (3.8%).

Dyspnea was reported in 14% of patients treated with BRILINTA and in 8% of patients treated with clopidogrel. Dyspnea was usually mild to moderate in intensity and often resolved during continued treatment.

About Acute Coronary Syndrome (ACS)

ACS is an umbrella term for conditions that result from insufficient blood supply to the heart muscle. These conditions range from unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), or ST-elevation myocardial infarction (STEMI).

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialization of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.

For more information about AstraZeneca in the U.S. or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363).

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Last updated on: 17/07/2012 08:00:11