PEGASUS-TIMI 54 Sub-Analysis Outlines Long-Term Tolerability Data for BRILINTA

AstraZeneca (NYSE:AZN) today announced results of a sub-analysis of the PEGASUS-TIMI 54 study, which evaluated reasons and rates for discontinuation of BRILINTA^® (ticagrelor) in patients with a history of myocardial infarction (MI) (one to three years prior to study randomization) and the efficacy in those patients who stayed on therapy. The data were presented during a Late-Breaking Clinical Trials session at the 2015 American Heart Association (AHA) Scientific Sessions.

The pooled analysis of the results showed that in patients who stayed on therapy, BRILINTA reduced the rate of the composite efficacy endpoint of cardiovascular (CV) death, MI, or stroke at three years (HR 0.79, 95% CI 0.70-0.88), consistent with the results of the overall population of the PEGASUS study. Discontinuation resulting from an Adverse Event (AE) was 8.9% in the placebo arm, 19% and 16.4% in the BRILINTA 90 mg and 60 mg arms, respectively, and was most frequently due to bleeding and dyspnea. Rates of AEs leading to discontinuation were highest in the first year at 16% in the 90 mg arm, 13% in the 60 mg arm, and 6% in the placebo arm. In those patients who stayed on therapy, discontinuation rates over the subsequent two years were 6.5% in the 90 mg arm, 6.0% in the 60 mg arm, 4.6% in the placebo arm.

Marc Bonaca, MD, Thrombolysis in Myocardial Infarction [TIMI] Study Group, Brigham and Women’s Hospital, Boston, MA and lead investigator for the sub-analysis study, said: “This analysis pointed to important patterns with regards to common AEs associated with ticagrelor in the context of clinical benefit. Physicians must consider the overall risks, including higher rates of bleeding and dyspnea particularly within the first year. For patients at increased risk for recurrent cardiovascular events in the long-term, ticagrelor can provide an important benefit.”

"This sub-group analysis provides additional insight into the clinical profile of ticagrelor and reinforces its role in the reduction of the composite of CV death, MI, and stroke for these patients studied in PEGASUS,” Bonaca added.

Steven Zelenkofske, D.O., FACC, Vice President, US Medical Affairs, AstraZeneca said: “We welcome the results of this sub-analysis, which lends insights regarding the tolerability and efficacy of BRILINTA long-term during a time when questions remain regarding the appropriate length of dual antiplatelet therapy.”

On September 3, 2015, the US Food and Drug Administration (FDA) approved a new 60-mg tablet dosage strength for BRILINTA to be used in patients with a history of heart attack beyond the first year. With this expanded indication, BRILINTA is now indicated to reduce the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of MI. For at least the first 12 months following ACS, it is superior to clopidogrel. BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

The PEGASUS-TIMI 54 study investigated the efficacy and safety of ticagrelor at both 60 mg and 90 mg twice daily, plus low dose aspirin, compared to placebo plus low dose aspirin, for the long-term prevention of atherothrombotic events in patients ≥50 years of age who had suffered a heart attack one to three years prior to study enrollment and had one additional risk factor for thrombotic CV events. Only the 60-mg dosage strength is approved for use in patients with a history of MI. BRILINTA 60 mg tablets are now available in US pharmacies.

BRILINTA has been studied in multiple clinical trials, including the PLATO and PEGASUS trials. In PLATO and PEGASUS alone, nearly 40,000 patients have been studied with BRILINTA.

If patients have a history of a heart attack, they should ask their doctor about BRILINTA today. For patients who have been prescribed BRILINTA, AstraZeneca offers the BRILINTA Patient Support Service (BPSS) tool that provides resources and support to help patients and caregivers from hospital discharge throughout the ACS treatment journey. To help loved ones, the program offers important patient education and coaching in addition to savings offers, refill reminders, personal pharmacy locator, co-pay calculator, and coverage verification and information. To enroll in BPSS, call 1-888-512-7454 or enroll online at www.BRILINTA.com. Health care professionals can visit www.BRILINTAtouchpoints.com.

IMPORTANT SAFETY INFORMATION FOR BRILINTA (ticagrelor) 60-MG AND 90-MG TABLETS

WARNING: (A) BLEEDING RISK, (B) ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

A. 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 undergoing urgent coronary artery bypass graft surgery
• If possible, manage bleeding without discontinuing BRILINTA. Stopping BRILINTA increases the risk of subsequent cardiovascular events

B. ASPIRIN DOSE AND BRILINTA EFFECTIVENESS

• Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided

CONTRAINDICATIONS

• BRILINTA is contraindicated in patients with a history of intracranial hemorrhage or active pathological bleeding such as peptic ulcer or intracranial hemorrhage. BRILINTA is also contraindicated in patients with hypersensitivity (eg, angioedema) to ticagrelor or any component of the product

WARNINGS AND PRECAUTIONS

• Dyspnea was reported in about 14% of patients treated with BRILINTA, more frequently than in patients treated with control agents. Dyspnea resulting from BRILINTA is often self-limiting
• Discontinuation of BRILINTA will increase the risk of MI, stroke, and death. When possible, interrupt therapy with BRILINTA for 5 days prior to surgery that has a major risk of bleeding. If BRILINTA must be temporarily discontinued, restart as soon as possible
• Avoid use of BRILINTA in patients with severe hepatic impairment. Severe hepatic impairment is likely to increase serum concentration of ticagrelor and there are no studies of BRILINTA in these patients

ADVERSE REACTIONS

• The most common adverse reactions associated with the use of BRILINTA included bleeding and dyspnea: In PLATO, for BRILINTA vs clopidogrel, non-CABG PLATO-defined major bleeding (3.9% vs 3.3%) and dyspnea (14% vs 8%); in PEGASUS, BRILINTA vs aspirin alone, TIMI Total Major bleeding (1.7% vs 0.8%) and dyspnea (14% vs 6%)

DRUG INTERACTIONS

• Avoid use with strong CYP3A inhibitors and strong CYP3A inducers. BRILINTA is metabolized by CYP3A4/5. Strong inhibitors substantially increase ticagrelor exposure and so increase the risk of adverse events. Strong inducers substantially reduce ticagrelor exposure and so decrease the efficacy of ticagrelor
• Patients receiving more than 40 mg per day of simvastatin or lovastatin may be at increased risk of statin-related adverse events
• Monitor digoxin levels with initiation of, or change in, BRILINTA therapy

INDICATIONS

BRILINTA is indicated to reduce the rate of cardiovascular death, myocardial infarction (MI), and stroke in patients with acute coronary syndrome (ACS) or a history of myocardial infarction. For at least the first 12 months following ACS, it is superior to clopidogrel.

BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

DOSING

In the management of ACS, initiate BRILINTA treatment with a 180-mg loading dose. Administer 90 mg twice daily during the first year after an ACS event. After one year administer 60 mg twice daily. Use BRILINTA with a daily maintenance dose of aspirin of 75-100 mg.

Patients can find out more information about BRILINTA at www.BRILINTA.com or by calling 1-888-412-7454.

Please read full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

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

NOTES TO EDITORS

About PEGASUS-TIMI 54

PEGASUS-TIMI 54 (PrEvention with TicaGrelor of SecondAry Thrombotic Events in High-RiSk Patients with Prior AcUte Coronary Syndrome – Thrombolysis In Myocardial Infarction Study Group) is AstraZeneca’s largest outcomes trial with more than 21,000 patients from over 1,100 sites in 31 countries. The study assessed BRILINTA^® (ticagrelor) tablets at either 60 mg twice daily or 90 mg twice daily plus once daily low-dose aspirin compared to placebo plus once daily low-dose aspirin for the secondary prevention of atherothrombotic events in patients ≥ 50 years of age who had experienced a heart attack one to three years prior to study start and had at least 1 risk factor for thrombotic cardiovascular events ( age ≥ 65 years, Diabetes mellitus requiring medication, at least one other prior MI, evidence of multivessel coronary artery disease or a creatinine clearance < 60 ml/min). The primary efficacy endpoint was a composite of cardiovascular (CV) death, myocardial infarction (MI) or stroke at 36 months. Patients were treated for at least 12 months and up to 48 months with a median follow-up time of 33 months. BRILINTA 60 mg plus aspirin significantly reduced the primary composite end point of CV death, MI, or stroke by 16% RRR (ARR 1.27%) vs placebo plus aspirin at 3 years (7.8% vs 9.0% [HR: 0.84, 95% CI: 0.74–0.95]; P=0.0043). In PEGASUS, TIMI Major Bleeding rates were 1.7% for BRILINTA 60 mg plus aspirin vs 0.8% for placebo plus aspirin. TIMI Major or Minor Bleeding rates were 2.4% for BRILINTA 60 mg plus aspirin vs 1.0% for placebo plus aspirin. Only the 60 mg dose is approved for use in patients with a history of MI beyond 12 months. The study was conducted in collaboration with the Thrombolysis in Myocardial Infarction (TIMI) Study Group from Brigham and Women’s Hospital (Boston, MA, USA).

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit www.astrazeneca-us.com.

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

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