EFFICACY IN THE PEGASUS* TRIAL

EXTENDING RISK REDUCTION BEYOND 12 MONTHS IN PATIENTS WITH A HISTORY OF MI

BRILINTA 60 MG + ASPIRIN WAS SUPERIOR TO PLACEBO + ASPIRIN IN HELPING PROTECT AGAINST RECURRENT THROMBOTIC CV EVENTS AT 3 YEARS1,2

PEGASUS Primary Efficacy End Point: Composite of CV Death, MI, or Stroke at 36 Months

BRILINTA PEGASUS study primary efficacy end point.

PEGASUS Primary Efficacy End Point: Composite of CV Death, MI, or Stroke at 36 Months

BRILINTA PEGASUS study primary efficacy end point.

*PEGASUS-TIMI 54 STUDY DESCRIPTION

  • Treatment comparison: BRILINTA (90 mg twice daily or 60 mg* twice daily) vs placebo, each given with low-dose aspirin
  • Treatment scenario: prevention of thrombotic CV events (CV death, MI, or stroke) in patients ≥50 years of age with a history of MI (1 to 3 years prior to randomization) and at least 1 risk factor for thrombotic CV events.
  • Treatment duration: Patients were treated for at least 12 months and up to 48 months with a median follow-up time of 33 months.
  • Number of patients: 21,162
  • Inclusion criteria:
    • A history of MI 1 to 3 years prior to randomization
    • ≥50 years of age
    • Had at least 1 of the following risk factors for thrombotic CV events:
      • Age ≥65 years
      • Diabetes mellitus requiring medication
      • At least 1 other prior MI
      • Evidence of multivessel coronary artery disease
      • Creatinine clearance <60 mL/min
  • Select exclusion criteria:
    • Patients required renal dialysis
    • Previous intracranial hemorrhage
    • Gastrointestinal bleeding within 6 months
    • Known bleeding diathesis or coagulation disorder or required treatment with anticoagulants

*Only the 60-mg dose strength is approved for use in patients with a history of MI 1 year after an ACS event.

VIEW THE PEGASUS STUDY DESCRIPTION

VIEW THE PEGASUS STUDY DESCRIPTION

PEGASUS secondary and prespecified exploratory end points at 3 years1,2

BRILINTA 60 mg + aspirin (N=7045) aspirin (N=7067) HR (95% CI)
N (PATIENTS WITH EVENT) K-M % N (PATIENTS WITH EVENT) K-M %
CV death//¶ 174 2.9 210 3.4 0.83 (0.68-1.01)
MI//# 285 4.5 338 5.2 0.84 (0.72-0.98)
Stroke//# 91 1.5 122 1.9 0.75 (0.57-0.98)
All-cause mortality 289 4.7 326 5.2 0.89 (0.76-1.04)

//The numbers of first events for the components CV death, MI, or stroke are the actual numbers of first events for each component and do not add up to the number of events in the composite end point.

Secondary end points.

#Prespecified exploratory end points.

  • The secondary end point of CV death was not statistically significant. Therefore, on the basis of the prespecified hierarchical test sequence, assessment of all-cause mortality was considered to be exploratory.1

BLEEDING OUTCOMES IN A PATIENT POPULATION WITH A HISTORY OF MI

PEGASUS safety end points: TIMI bleeding1

BRILINTA 60 mg + aspirin (N=6958) aspirin (N=6996)
N (%) PATIENTS WITH EVENT EVENTS/100 PATIENT-YEARS N (%) PATIENTS WITH EVENT EVENTS/100 PATIENT-YEARS
TIMI MAJOR** 115 (1.7) 0.78 54 (0.8) 0.34
FATAL†† 11 (0.2) 0.08 12 (0.2) 0.08
INTRACRANIAL HEMORRHAGE 28 (0.4) 0.19 23 (0.3) 0.14
TIMI MAJOR OR MINOR‡‡ 168 (2.4) 1.15 72 (1.0) 0.45

**TIMI major: fatal bleeding or any intracranial bleeding or clinically overt signs of hemorrhage associated with a drop in Hb of ≥5 g/dL or a fall in Hct of ≥15%.

††Fatal: a bleeding event that directly led to death within 7 days.

‡‡TIMI minor: clinically apparent with 3-5 g/dL decrease in Hb.

Composite of CV death, MI, or stroke.

BRILINTA WAS STUDIED IN PATIENTS ALREADY ON STANDARD CV THERAPIES IN THE PEGASUS TRIAL1,2

PEGASUS was designed to test the hypothesis that long-term therapy with BRILINTA added to low-dose aspirin reduces the risk of thrombotic CV events among patients with a history of MI.

PEGASUS was a randomized, double-blind, placebo-controlled clinical trial. Patients underwent randomization at 1161 sites in 31 countries. The trial was designed as a collaboration among the TIMI Study Group, the executive and steering committees, and AstraZeneca, the trial sponsor. The study compared BRILINTA (90 mg twice daily or 60 mg twice daily) vs placebo, each given with low-dose aspirin, for the prevention of thrombotic CV events (CV death, MI, or stroke) in 21,162 patients ≥50 years of age with a history of MI (1 to 3 years prior to randomization) and at least 1 of the following risk factors for thrombotic CV events: age of 65 years or older, diabetes mellitus requiring medication, at least 1 other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min. Patients were treated for at least 12 months and up to 48 months with a median follow-up time of 33 months. Patients were excluded if they required renal dialysis, had a previous intracranial hemorrhage, had gastrointestinal bleeding within 6 months, had a known bleeding diathesis or coagulation disorder, or required treatment with anticoagulants.

  • Both BRILINTA 60-mg and 90-mg dosages were studied as part of the PEGASUS trial. Only the 60-mg dose strength is approved for use in patients with a history of an MI 1 year after an ACS event

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
  • Ticagrelor can cause ventricular pauses. Bradyarrhythmias including AV block have been reported in the post-marketing setting. PLATO and PEGASUS excluded patients at increased risk of bradyarrhythmias not protected by a pacemaker, and they may be at increased risk of developing bradyarrhythmias with ticagrelor
  • 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
  • As with other oral P2Y12 inhibitors, co-administration of opioid agonists delay and reduce the absorption of ticagrelor. Consider use of a parenteral anti-platelet in ACS patients requiring co-administration
  • 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.

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