BRILINTA Preferred Over Clopidogrel in 2014 AHA/ACC Guideline for the Management of Non–ST-Elevation Acute Coronary Syndromes

WILMINGTON, Del.--(BUSINESS WIRE)--

AstraZeneca AZN today confirmed that the American Heart Association (AHA) and American College of Cardiology (ACC) have updated the guideline for the management of patients with non–ST-elevation acute coronary syndromes (NSTE-ACS). The guideline supports differentiation among currently available P2Y₁₂ inhibitors, including ticagrelor, clopidogrel, and prasugrel, for these patients. BRILINTA is now preferred over clopidogrel for the management of NSTE-ACS patients who undergo an early invasive (angiography with intent for PCI if appropriate) or ischemia-guided strategy (i.e., medically managed), or those who receive a coronary stent. This is the first time the AHA and ACC have recommended one P2Y₁₂ over another in the treatment of acute coronary syndrome (ACS).

“AstraZeneca is pleased that the AHA/ACC guideline recognizes the role of BRILINTA over clopidogrel in the treatment of NSTE-ACS patients undergoing a broad range of treatment strategies,” said Gregory F. Keenan, MD, Vice President and US Head Medical Officer, AstraZeneca. “This guideline update demonstrates how the standards of ACS care continue to evolve and include BRILINTA, reinforcing the confidence the guideline committee has in both the medicine and the PLATO data that supports these new recommendations.”

This new guideline is based on a review of multiple clinical trials, including PLATO. There are no clinical outcome trials that compare prasugrel and BRILINTA. In total, BRILINTA is included in 12 major US and Global ACS management guidelines and recognized in several of them as an important part of the standard of care in a broad range of invasively or noninvasively managed patients with ACS.

BRILINTA is indicated to reduce the rate of thrombotic cardiovascular (CV) events in patients with 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 percutaneous coronary intervention (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.

The approved Prescribing Information for BRILINTA includes information about the approved uses for BRILINTA. BRILINTA has two Boxed WARNINGS, one for bleeding risk and the other for aspirin dose and reduced BRILINTA effectiveness. The Boxed WARNING on BLEEDING RISK states, like other antiplatelet agents, BRILINTA can cause significant, sometimes fatal, bleeding. For ASPIRIN DOSE AND BRILINTA EFFECTIVNESS, 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. See the additional Important Safety Information about BRILINTA below.

Following are recommendations within the updated AHA/ACC NSTE-ACS guideline specific to oral P2Y₁₂ inhibitors only.

Initial Oral Antiplatelet Therapy in Patients With Definite or Likely NSTE-ACS Treated With an Initial Invasive or Ischemia-Guided Strategy

Class I^*

	1.		A P2Y12 inhibitor (either clopidogrel or ticagrelor) in addition to aspirin should be administered for up to 12 months to all patients with NSTE-ACS without contraindications who are treated with either an early invasive or ischemia-guided strategy. Options include:
			a. Clopidogrel: 300-mg or 600-mg loading dose, then 75 mg daily (Level of Evidence [LOE]: B)
			b. Ticagrelor(§): 180-mg loading dose, then 90 mg twice daily (LOE: B)

Class IIa^†

1.

It is reasonable to use ticagrelor in preference to clopidogrel for P2Y12 treatment in patients with NSTE-ACS who undergo an early invasive or ischemia-guided strategy (LOE: B)

PCI—Oral Antiplatelet Agents

Class I

	1.		A loading dose of a P2Y12 receptor inhibitor should be given before the procedure in patients undergoing PCI with stenting. (LOE: A) Options include:
			a. Clopidogrel: 600 mg (LOE: B) or
			b. Prasugrel(‡): 60 mg (LOE: B) or
			c. Ticagrelor(§): 180 mg (LOE: B)
	2.		In patients receiving a stent (bare-metal stent or drug-eluting stent [DES]) during PCI for NSTE-ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include:
			a. Clopidogrel: 75 mg daily (LOE: B) or
			b. Prasugrel(‡): 10 mg daily (LOE: B) or
			c. Ticagrelor(§): 90 mg twice daily (LOE: B)

Class IIa

	1.		It is reasonable to choose ticagrelor over clopidogrel for P2Y12 inhibition treatment in patients with NSTE-ACS treated with an early invasive strategy and/or coronary stenting (LOE: B)
	2.		It is reasonable to choose prasugrel over clopidogrel for P2Y12 treatment in patients with NSTE-ACS who undergo PCI who are not at high risk of bleeding complications (LOE: B)
	3.		If the risk of morbidity from bleeding outweighs the anticipated benefit of a recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (e.g., <12 months) of P2Y12 inhibitor therapy is reasonable (LOE: C)

Class III: Harm

1.

Prasugrel should not be administered to patients with a prior history of stroke or transient ischemic attack (LOE: B)

Late Hospital and Posthospital Oral Antiplatelet Therapy

Class I

	1.		Aspirin should be continued indefinitely. The maintenance dose should be 81 mg daily in patients treated with ticagrelor and 81 mg to 325 mg daily in all other patients (LOE: A)
	2.		In addition to aspirin, a P2Y12 inhibitor (either clopidogrel or ticagrelor) should be continued for up to 12 months in all patients with NSTE-ACS without contraindications who are treated with an ischemia-guided strategy. Options include:
			a. Clopidogrel: 75 mg daily (LOE: B) or
			b. Ticagrelor§: 90 mg twice daily (LOE: B)
	3.		In patients receiving a stent (bare-metal stent or DES) during PCI for NSTE-ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include:
			a. Clopidogrel: 75 mg daily (LOE: B) or
			b. Prasugrel‡: 10 mg daily (LOE: B) or
			c. Ticagrelor§: 90 mg twice daily (LOE: B)

Class IIa

	1.		It is reasonable to choose ticagrelor over clopidogrel for maintenance P2Y12 treatment in patients with NSTE-ACS treated with an early invasive strategy and/or PCI (LOE: B)
	2.		It is reasonable to choose prasugrel over clopidogrel for maintenance P2Y12 treatment in patients with NSTE-ACS who undergo PCI who are not at high risk for bleeding complications (LOE: B)
	3.		If the risk of morbidity from bleeding outweighs the anticipated benefit of a recommended duration of P2Y12 inhibitor therapy after stent implantation, earlier discontinuation (e.g., <12 months) of P2Y12 inhibitor therapy is reasonable (LOE: C)

_{*Class I: Procedure/Treatment SHOULD be performed/administered
†Class II: Additional studies with focused objectives needed. IT IS REASONABLE to peform procedure/administer treatment
‡Patients should receive a loading dose of prasugrel provided that they were not pretreated with another P2Y12 receptor inhibitor
§The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily}

To read the full AHA/ACC guideline, please visit: http://circ.ahajournals.org/content/early/2014/09/22/CIR.0000000000000134

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA (ticagrelor)

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 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

B. 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 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. BRILINTA is also contraindicated in patients with hypersensitivity (e.g., angioedema) to ticagrelor or any component of the product

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.

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.

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

AstraZeneca offers the AZ&Me^TM Prescription Savings Program. To determine eligibility, patients can visit www.AZandMe.com or call 1-800-AZandMe (292-6363).

NOTES TO EDITORS

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. The difference between treatments was driven by CV death and MI with no difference in stroke.

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 vs 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 CV events in ACS patients, above and beyond that afforded by clopidogrel. Patients were treated for at least six months and up to 12 months.

PLATO^‖ demonstrated that treatment with BRILINTA plus aspirin led to a significantly greater reduction in the primary end point – a composite of CV death, MI (excluding silent MI), or stroke – compared to patients who received clopidogrel plus aspirin (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.

The PLATO study also demonstrated that treatment with BRILINTA plus aspirin 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 (excluding silent MI) compared to clopidogrel plus aspirin 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, which includes Fatal and Life-threatening bleeding, (11.6% for BRILINTA plus aspirin and 11.2% for clopidogrel plus aspirin) at 12 months. In PLATO, Non-CABG-related major + minor bleeding events were more common with BRILINTA vs clopidogrel (8.7% vs 7% respectively). The rate of non-CABG-related major bleeding was higher for BRILINTA (4.5%) vs clopidogrel (3.8%). The PLATO trial did not show an advantage for BRILINTA compared with clopidogrel for CABG-related Bleeding (Total Major 85.8% vs 86.9% and Fatal/Life-threatening 48.1% vs 47.9%, respectively).

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.

_{‖PLATO used the following bleeding severity categorization: Major Bleed–Fatal/Life-threatening. Any one of the following: fatal; intracranial; intrapericardial bleed with cardiac tamponade; hypovolemic shock or severe hypotension due to bleeding and requiring pressors or surgery; clinically overt or apparent bleeding associated with a decrease in hemoglobin (Hb) of more than 5 g/dL; transfusion of 4 or more units (whole blood or packed red blood cells [PRBCs]) for bleeding. Major Bleed–Other. Any one of the following: significantly disabling (e.g., intraocular with permanent vision loss); clinically overt or apparent bleeding associated with a decrease in Hb of 3 g/dL; transfusion of 2-3 units (whole blood or PRBCs) for bleeding. Minor Bleed. Requires medical intervention to stop or treat bleeding (e.g., epistaxis requiring visit to medical facility for packing). Minimal Bleed. All others (e.g., bruising, bleeding gums, oozing from injection sites, etc.) not requiring intervention or 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 include unstable angina (UA), non–ST-elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI). The conditions are defined by ECG changes and heart muscle enzyme leakage. Non–ST-elevation acute coronary syndrome (NSTE-ACS) includes unstable angina (UA) and non–ST-elevation myocardial infarction (NSTEMI); the term is usually used before heart muscle enzymes have been analyzed. The goal of treating ACS is to restore, improve, and/or stabilize blood flow to the heart muscle and to reduce the risk of recurrent cardiovascular (CV) events. Depending on the severity of the condition and the resources available, the patient will either be managed with medicines or undergo more invasive procedures. These procedures may include using catheters, balloons, and/or stents that treat the narrowed arteries of the heart called percutaneous coronary intervention (PCI) and/or a type of surgery that improves blood flow to the heart called coronary artery bypass grafting (CABG).

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 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.