BRILINTA™ (ticagrelor) Receives Additional Class I Recommendation in New U.S. Guidelines from ACCF/AHA/SCAI for PCI

Guidelines based on study showing BRILINTA reduces risk of cardiovascular events over clopidogrel in patients with Acute Coronary Syndrome

WILMINGTON, Del.--(BUSINESS WIRE)-- AstraZeneca (NYSE: AZN) announced today that a combined expert committee of American College of Cardiology Foundation (ACCF), the American Heart Association (AHA), and Society for Cardiovascular Angiography and Interventions (SCAI) has updated its guidelines for the management of patients undergoing percutaneous coronary intervention (PCI) to provide a Class I recommendation for giving the oral antiplatelet medicine, BRILINTA™ (ticagrelor) tablets for patients undergoing PCI.

"Class I" means that a given "procedure/treatment should be performed/administered" to patients, given it was found to be "useful/effective/beneficial." Class I is the highest recommendation provided by the guidelines committee.

In patients with acute coronary syndrome (ACS), BRILINTA is the first and only oral antiplatelet FDA-approved to significantly reduce cardiovascular (CV) death versus clopidogrel. BRILINTA significantly reduced the primary composite end point of CV death, myocardial infarction (MI), or stroke versus clopidogrel. The difference between treatments was driven by CV death and MI with no difference in stroke. The secondary end points included the individual components of CV death, MI, and 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.

“We are pleased to learn BRILINTA has been included in revised guidelines issued by AHA, ACCF and SCAI,” said Alex Gold, MD, Executive Director of Clinical Development, BRILINTA, AstraZeneca. “The addition to yet another set of important clinical guidelines highlights the value BRILINTA can bring to patients with ACS and health care professionals trying to reduce the rate of thrombotic cardiovascular events and the momentum this important treatment option is gaining just four months after FDA approval.”

Specifically, the 2011 ACCF/AHA/SCAI Guidelines for PCI state that:

Class I

A loading dose of a P2Y12 receptor inhibitor should be given to patients undergoing PCI with stenting (Level of Evidence: A)

Options include:

  • Clopidogrel 600 mg (ACS and non-ACS patients) (Level of Evidence: B)
  • Prasugral 60 mg (ACS patients) (Level of Evidence: B)
  • Ticagrelor 180 mg (ACS patients) (Level of Evidence: B)

The duration of P2Y12 inhibitor therapy after stent implantation should generally be as follows:

  • In patients receiving a stent (bare-metal stent [BMS] or drug-eluting stent [DES]) during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel 75 mg daily, prasugrel 10 mg daily, and ticagrelor 90 mg twice daily. (Level of Evidence: B)

Class IIa

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

2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery

In addition, the 2011 ACCF/AHA Guidelines for Coronary Artery Bypass Graft (CABG) Surgery were also released today and notes as Class I that aspirin should be administered to CABG patients preoperatively (Level of Evidence: B), and that in patients referred for elective CABG, clopidogrel and ticagrelor should be discontinued for at least 5 days before surgery (Level of Evidence: B) and prasugrel for at least 7 days (Level of Evidence: C) to limit blood transfusions.

BRILINTA received approval from the U.S. Food & Drug Administration (FDA) on July 20, 2011, and is indicated to reduce the rate of thrombotic cardiovascular (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, 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.

On November 3, 2011, AHA/ACCF 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 BMS or DES during PCI for ACS.

The revised guidelines are available online at www.cardiosource.org, www.heart.org, and www.scai.org and will be published in the December 6, 2011, issues of the Journal of the American College of Cardiology and Circulation: Journal of the American Heart Association. The guideline for PCI will also be published in the December 2011 issue of Catheterization and Cardiovascular Interventions.

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

ABOUT PLATO

The PLATO trial was a large (18,624 patients in 43 countries) head-to-head outcomes study of ticagrelor versus clopidogrel, both given in combination with aspirin and other standard therapy, designed to establish whether ticagrelor could achieve a clinically meaningful reduction in cardiovascular end points in ACS patients, above and beyond those afforded by clopidogrel.

The PLATO study demonstrated that treatment with BRILINTA led to a 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 continue to diverge throughout the 12-month treatment period.

It’s important to know that BRILINTA does have a Boxed Warning for bleeding risks. BRILINTA, like other antiplatelet agents, can cause significant, sometimes fatal, bleeding. In addition, BRILINTA has a Boxed Warning concerning 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.

The PLATO study also demonstrated that treatment with BRILINTA for 12 months was associated with a 21 percent RRR in CV death (4% vs 5.1%; 1.1% ARR; P=0.001) and a 16 percent 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, the rate of non–CABG-related major bleeding was higher for BRILINTA (4.5%) vs clopidogrel (3.8%).

In a post hoc analysis of PLATO, it was determined that more than 80 percent of patients worldwide, including more than 40 percent of patients in the US, received low maintenance doses of aspirin (100 mg or less). Results for US and non-US patients taking BRILINTA with these low maintenance doses of aspirin were similar. Maintenance doses of aspirin above 100 mg reduced the effectiveness of BRILINTA, and should be avoided. After any initial dose, BRILINTA should be used with maintenance aspirin doses of 75 mg - 100 mg per day. As with any unplanned subset analysis, the post hoc analysis should be treated with caution.

About BRILINTA (ticagrelor) tablets

BRILINTA is an oral antiplatelet treatment for acute coronary syndrome (ACS) in a new chemical class called cyclopentyltriazolopyrimidines (CPTPs). BRILINTA works by inhibiting platelet activation and has been shown to reduce the rate of thrombotic cardiovascular events, such as a heart attack or cardiovascular death, in patients with ACS. BRILINTA is a reversibly binding oral platelet P2Y12 adenosine diphosphate (ADP) receptor antagonist.

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 trademark of the AstraZeneca group of companies.

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).

-ENDS-

NOTES TO EDITORS:

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 US or our AZ&Me™ Prescription Savings programs, please visit: www.astrazeneca-us.com or call 1-800-AZandMe (292-6363).

1419016 11/11

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