US Department of Justice Closes Investigation into PLATO Clinical Trial for BRILINTA

  US Department of Justice Closes Investigation into PLATO Clinical Trial for

Business Wire

WILMINGTON, Del. -- August 19, 2014

AstraZeneca today announced that it has received confirmation from the United
States Department of Justice that it is closing its investigation into PLATO,
a clinical trial with BRILINTA^® (ticagrelor) tablets. The government is not
planning any further action.

Pascal Soriot, Chief Executive Officer, said: “We welcome the Department of
Justice’s decision not to pursue further action. We have always had absolute
confidence in the integrity of the PLATO trial and we are proud of the
important benefit BRILINTA offers to patients around the world suffering from
acute coronary syndrome. As one of AstraZeneca’s growth platforms, we remain
committed to delivering the full potential of this important medicine.”

As part of our continued commitment to advancing the science behind
cardiovascular medicine, AstraZeneca has initiated a clinical trial program
for BRILINTA, its largest program involving more than 80,000 patients

In 2011 the US Food and Drug Administration approved BRILINTA in the treatment
of patients with acute coronary syndrome (ACS). BRILINTA has been approved by
regulatory authorities in over 100 countries and is included in 11 major ACS
management guidelines globally, including six established US guidelines. The
trial manuscript from the PLATO Executive Committee was first published in the
New England Journal of Medicine. Following additional rigorous peer-review,
over 30 PLATO sub-analyses articles have subsequently been published. The
combination of these global reviews makes the PLATO data set one of the most
widely analyzed clinical trials.

BRILINTA is the first and only oral antiplatelet (OAP) U.S. Food and Drug
Administration (FDA)-approved to demonstrate superior reductions in
cardiovascular (CV) death vs clopidogrel in patients with ACS. BRILINTA is
indicated to reduce the rate of thrombotic CV events in patients with ACS
(unstable angina [UA], non–ST-elevation myocardial infarction [NSTEMI], or
ST-elevation myocardial infarction [STEMI]). In PLATO, 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.




  *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


  *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


  *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


  *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
  *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


  *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 or call 1-800-FDA-1088.

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

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


About the civil investigative demand

On October 21, 2013, AstraZeneca received a civil investigative demand from
the US Department of Justice seeking documents and information related to the
PLATO trial. AstraZeneca has cooperated with the government enquiry, which
focused on questions that have been raised previously in public about the
trial. Similar questions have been responded to by the independent PLATO
Executive Committee which led the clinical trial.

About BRILINTA^® (ticagrelor) tablets

BRILINTA is an oral antiplatelet treatment for ACS. BRILINTA is a
direct-acting P2Y[12] 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.

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


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 cardiovascular (CV) events in acute
coronary syndrome (ACS) patients, above and beyond that afforded by
clopidogrel. Patients were treated for at least six months and up to 12

PLATO demonstrated that treatment with BRILINTA 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 (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 vs clopidogrel was seen at 30 days
and the Kaplan-Meier survival curves continued to diverge throughout the
12-month treatment period.

The PLATO study also demonstrated that treatment with BRILINTA 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 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 and
11.2% for clopidogrel) 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%,

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.

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

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