AstraZeneca PLC Release: New Sub-Analyses Show Benefit Of Long-Term Use Of BRILINTA In High-Risk Patients With Prior Heart Attack

PEGASUS-TIMI 54 data presented at ACC increases understanding of the role of ticagrelor in treating patients with a history of heart attack and either peripheral artery disease or diabetes

WILMINGTON, Del.--(BUSINESS WIRE)--AstraZeneca today announced results of two separate sub-analyses of PEGASUS-TIMI 54, which investigated the long-term use of BRILINTA^® (ticagrelor) tablets in patients with a history of myocardial infarction (MI) and at least one additional risk factor for thrombotic cardiovascular (CV) events at three years. The first sub-analysis included patients with peripheral artery disease (PAD) and the second with diabetes. The results of both analyses show a reduction in major adverse cardiac events [(MACE), defined as a composite of CV death, MI or stroke] with ticagrelor plus aspirin compared to placebo plus aspirin that was consistent with the overall PEGASUS-TIMI 54 population. The data were presented at the American College of Cardiology’s 65^th Annual Scientific Session, being held April 2-4 in Chicago, IL. The data was simultaneously published in Journal of American College of Cardiology (JACC).

“The PEGASUS-TIMI 54 trial enhanced our understanding of BRILINTA in addressing recurrent atherothrombotic events, particularly in high-risk patient populations where the need is greatest. These sub-analyses help further support BRILINTA as an effective treatment option for patients with prior MI in the longer term.”

Steven Zelenkofske, D.O., FACC, Vice President, US Medical Affairs, AstraZeneca said: “The PEGASUS-TIMI 54 trial enhanced our understanding of BRILINTA in addressing recurrent atherothrombotic events, particularly in high-risk patient populations where the need is greatest. These sub-analyses help further support BRILINTA as an effective treatment option for patients with prior MI in the longer term.”

• In the first sub-analysis, 1,143 patients with a prior MI and PAD had higher rates of MACE at 3 years compared to those without PAD, which persisted after adjusting for baseline differences, with higher risk of MACE (HR 1.60, 95% CI 1.20-2.13, p=0.0013), CV death (HR 1.84, 95% CI 1.16-2.94, p=0.0102), stroke (HR 2.31, 95% CI 1.26 – 4.25, p=0.0071), mortality (HR 2.05, 95% CI 1.43-2.94, p<0.001), and TIMI major bleeding (HR 1.57, 95% CI 0.47-5.22, p=0.46). Pooled doses of ticagrelor plus aspirin compared to placebo plus aspirin reduced the risk of MACE in both patients with PAD (HR 0.75, 95% CI 0.55-1.01) and without PAD (HR 0.86, 95% CI 0.77-0.96) at 3 years. TIMI major bleeding occurred more frequently with ticagrelor 90 mg plus aspirin vs placebo plus aspirin (HR 1.46, 95% CI 0.39-5.43) and with ticagrelor 60 mg plus aspirin vs placebo plus aspirin (HR 1.18, 95% CI 0.29-4.70).
• A second sub-analysis of 6,806 patients with a prior MI and diabetes suggested that pooled doses of ticagrelor plus aspirin compared to placebo plus aspirin reduce the risk of MACE in both non-diabetics (HR 0.84, 95% CI 0.74-0.96) and diabetics (HR 0.84, 95% CI 0.72-0.99) at 3 years. Similar to non-diabetic patients, there was an increase in TIMI major bleeding in diabetic patients (HR 2.56, 95% CI 1.52-4.33) treated with ticagrelor.

Marc Bonaca, MD, Thrombolysis in Myocardial Infarction [TIMI] Study Group, Brigham and Women’s Hospital, Boston, MA and lead investigator for the PAD sub-analysis of PEGASUS, said: “Patients with prior MI and PAD are at further heightened risk of ischemic events relative to patients with prior MI and no PAD even when accounting for other risk factors. Because of their heightened ischemic risk, patients in the subgroup analysis with a prior MI and PAD appear to have a higher absolute risk reduction with ticagrelor than those without. These findings may be helpful to clinicians in identifying patients with prior MI who they feel could benefit from prolonged therapy with ticagrelor.”

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 atherothrombotic CV events. Only the 60-mg dosage strength is approved for use in patients with a history of MI.

The full results of the PEGASUS-TIMI 54 study were presented at last year’s American College of Cardiology’s 64^th Annual Scientific Session and simultaneously published in the New England Journal of Medicine.

PEGASUS-TIMI 54 is part of PARTHENON, the largest ever AstraZeneca CV outcomes program, involving nearly 80,000 patients at high risk of CV events (MI, stroke and/or CV death) due to their underlying disease. In the second half of 2016, data are expected from the ongoing EUCLID trial in PAD, which is the fourth trial to read-out from the PARTHENON program, assessing the potential of BRILINTA in additional high-risk patient populations.

BRILINTA is not approved for the prevention of cardiovascular events in patients with PAD, stroke or diabetes who have not experienced a prior MI.

BRILINTA is now preferred over clopidogrel in the updated American College of Cardiology (ACC) and American Heart Association (AHA) guideline in ACS (STEMI and NSTE-ACS) who have received a coronary stent and in non-ST Elevation Acute Coronary Syndrome (NSTE-ACS) patients treated with medical therapy alone (Class IIa LOE: B-R). The update is the first time the ACC/AHA has recommended BRILINTA over clopidogrel in patients who have experienced a ST-elevation myocardial infarction (STEMI). It is also the first major US guideline to provide the medical community with insights drawn from the PEGASUS-TIMI 54 trial, and includes the expanded indication for BRILINTA in patients with a heart attack beyond one year.

This follows the US FDA recognition within the indication that BRILINTA is superior to clopidogrel in patients with ACS for at least the first 12 months. 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. BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

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

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.

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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 one of 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 the PARTHENON Program

PEGASUS-TIMI 54 is part of PARTHENON, the largest ever AstraZeneca CV outcomes program, involving nearly 80,000 patients at high risk of CV events (MI, stroke and/or CV death) due to their underlying disease. Through the PARTHENON program, AstraZeneca aims to address unmet patient needs by enhancing scientific understanding of the potential role of BRILINTA in the treatment of atherothrombotic conditions. . It includes five key studies covering broad patient populations across varying timescales, including the completed PEGASUS-TIMI 54, PLATO and SOCRATES trials, and the ongoing EUCLID [peripheral arterial disease (PAD)] and THEMIS (type 2 diabetes at high risk for CV events) trials.

About BRILINTA^® (ticagrelor) tablets

BRILINTA is an oral antiplatelet treatment for ACS or prior-MI. BRILINTA is a direct-acting P2Y₁₂ receptor antagonist in a chemical class called cyclo-pentyl-triazolo-pyrimidines (CPTPs) and works by inhibiting platelet activation.

BRILINTA is indicated to reduce the rate of CV death, 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.

BRILINTA is available in 90-mg and 60-mg tablets and, in the management of ACS, treatment is initiated with a 180-mg loading dose. During the first year after an ACS event, 90 mg is administered twice daily. After one year, 60 mg is administered twice daily. BRILINTA should be used with a daily maintenance dose of aspirin of 75-100 mg.

BRILINTA is a registered trademark of the AstraZeneca group.

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three main therapy areas - respiratory, inflammation, autoimmune disease (RIA), cardiovascular and metabolic disease (CVMD) and oncology – as well as in infection and neuroscience. 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.

3216920 Last updated 4/16