New Data Suggest Patient Smoking Habits Had No Impact on PLATO Study Findings of a Greater Reduction in Thrombotic Cardiovascular Events with BRILINTA (ticagrelor) Compared to Clopidogrel

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca (NYSE: AZN) today announced results from a PLATO sub-analysis that evaluated the effect of smoking status on clinical outcomes in patients with acute coronary syndrome (ACS). This analysis suggests the overall findings from the PLATO study of greater reduction in thrombotic CV events with BRILINTA^® (ticagrelor) tablets plus aspirin compared to clopidogrel plus aspirin was consistent regardless of smoking habits. ¹ These data, slated for publication in the September issue of American Heart Journal, are currently available online, and were previously presented at the American College of Cardiology 2012 meeting.

“The potential impact of smoking on the effect of certain medications continues to be a topic of considerable interest and discussion among the cardiovascular community,” stated James Ferguson, MD, Executive Director, Medical Affairs and Strategic Development, and Vice President for Global Medical Affairs. “This sub-analysis suggests that the clinical benefits of BRILINTA vs clopidogrel on thrombotic CV events shown in PLATO were not significantly affected by smoking status, and were similar in both smokers and non-smokers.”

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]). In PLATO, BRILINTA has been shown to reduce the rate of a combined end point of CV death, myocardial infarction (MI), or stroke compared to clopidogrel. In PLATO, 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.

The sub-analysis was conducted because habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo.

Specific data from this sub-analysis showed:

• Among the 18,610 patients with known smoking status at randomization in the PLATO study, 6,678 (36%) were reported as being habitual smokers and 11,932 (64%) were ex/non-smokers
• Habitual smokers had an overall lower risk profile and presented more often with ST-elevation MI
• After adjustment for baseline differences, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points
• The effects of BRILINTA compared to clopidogrel were consistent for thrombotic CV events, regardless of smoking status.¹ Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/non-smokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P=0.50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/non-smokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P=0.61)

• There was no significant interaction between smoking habits and the effects of treatment on major bleeding or non-CABG related major bleeding. The adjusted hazard ratios for the rate of all PLATO-defined major bleeding for BRILINTA versus clopidogrel were 1.18 [95% CI, 0.98-1.43] in habitual smokers and 1.04 [95% CI, 0.92-1.18] in ex/non-smokers (interaction P=0.27). For non-CABG related major bleeding events the adjusted hazard ratios for BRILINTA versus clopidogrel were 1.22 [95% CI, 0.88-1.69] in habitual smokers and 1.35 [95% CI, 1.10 – 1.67] in ex/non-smokers (interaction P=0.59)

The conclusion of the sub-analysis of PLATO suggests results of BRILINTA versus clopidogrel were consistent for thrombotic cardiovascular (CV) events in patients with Acute Coronary Syndrome (ACS) regardless of smoking status and that habitual smoking was associated with a greater risk of subsequent stent thrombosis.

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 as peptic 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

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 similar federal or state program 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&ME^TM Prescription Savings Program. To determine eligibility, patients can visit www.AZandMe.com or call 1-800-AZandMe (292-6363).

Please read full Prescribing Information, including Boxed WARNINGS, and Medication Guide. This and additional information can also be found at 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 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).

2030202 8/12

Reference

1. Cornel, J.H., et al. Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes—Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial. American Heart Journal. July 30, 2012. Available at: http://www.ahjonline.com/article/S0002-8703(12)00383-3/abstract.