PLATO*1 Trial

PLATO Trial worldwide participation

BRILINTA plus aspirin was studied vs clopidogrel plus aspirin in more than 18,000 patients, including STEMI (ST-elevation myocardial infarction), NSTEMI (non–ST-elevation myocardial infarction), and UA (Unstable Angina) patients, across 43 countries and 862 sites.1,2

PLATO Trial Worldwide Participation

PLATO was designed to mirror real-world clinical practice across ACS diagnoses and medical or invasive treatment approaches†1,3

  • In PLATO, 85% of patients tested troponin positive at baseline. A positive result on testing for troponin I consisted of a troponin level of 0.08 μg or more per liter for the first sample taken, as measured at the central laboratory with the use of the ADVIA Centaur® TnI-Ultra immunoassay1
  • In PLATO, there were 7,026 STEMI patients and 7,955 NSTEMI (non–ST-elevation myocardial infarction) patients at final diagnosis

Based upon the results of the PLATO (PLATelet inhibition and patient Outcomes) study, in patients with ACS, BRILINTA has been shown to reduce the rate of a combined end point of cardiovascular (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 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.

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 (eg, angioedema) to ticagrelor or any component of the product.

Efficacy and Safety

See clinical efficacy results and safety data, including bleeding and other adverse reactions, from the PLATO trial.

Objective

  • A randomized, double-blind, parallel-group study to determine whether BRILINTA is superior to clopidogrel for the prevention of vascular events and death in a broad population of patients presenting with an acute coronary syndrome (ACS)

Randomization

  • Patients randomized within 24 hours of symptom onset
  • Included patients taking clopidogrel at time of randomization
  • Conducted in >18,000 patients

Final ACS diagnoses

Hospitalized patients with ACS, with or without ST-segment elevation, with onset of symptoms in previous 24 hours

STEMI

(n=7,026)

NSTEMI

(n=7,955)

UA

(n=3,112)

Planned Treatment Approaches

Patients were randomized to treatment prior to assessment of coronary anatomy

Invasive management

PCI or CABG

(n=13,408)

Medical management

(n=5,216)

STEMI=ST-elevation myocardial infarction; NSTEMI=non–ST-elevation myocardial infarction; UA=unstable angina.

BRILINTA and clopidogrel were studied with aspirin and other standard therapies.

Treatment Duration

  • Designed as a 12-month, event-driven trial
  • Median exposure was 277 days

End Points

  • Primary Efficacy End Point: Time to first occurrence of any event from the composite of vascular (CV) death, MI (excluding silent MI), or stroke
  • Key Secondary Efficacy End Points
    • Primary efficacy variable in patients with intent for invasive management
    • CV death
    • MI (excluding silent MI)
    • Stroke
  • Primary Safety End Point: Time to first occurrence of any PLATO-defined Major Bleeding event
  • Secondary Safety End Points: Included Minor Bleeding, dyspnea, bradyarrhythmia, any other clinical adverse event, and results of laboratory safety tests

Inclusion Criteriaa

Hospitalized for potential ST-segment elevation or non–ST-segment elevation ACS, with onset during the previous 24 hours, documented by cardiac ischemic symptoms due to atherosclerosis of ≥10 minutes duration at rest, ≥18 years of age, not pregnant, and with informed consentb

And

≥2 of the following for ACS patients without ST-segment elevation:

  1. ST-segment changes on electrocardiogram (ECG) indicating ischemia
  2. Positive biomarker indicating myocardial necrosis. Troponin I or T or CK-MB (myocardial fraction of creatine kinase) greater than the upper limit of normal
  3. One of the following:
  • ≥60 years of age
  • Previous MI or coronary artery bypass graft (CABG)
  • Coronary artery disease (CAD) with ≥50% stenosis in ≥2 vessels
  • Previous ischemic stroke, TIA (hospital-based diagnosis), carotid stenosis (≥50%), or cerebral revascularization
  • Diabetes mellitus
  • Peripheral artery disease
  • Chronic renal dysfunction

Or

Both of the following for ACS patients with ST-segment elevation:

  1. Persistent ST-segment elevation ≥1 mm (not known to be preexisting or due to a coexisting disorder) in ≥2 contiguous leads or new left bundle-branch block (LBBB)
  2. Primary PCI planned

aThe requirement of additional risk factors needed for inclusion ensured that lower-risk patients were excluded from the study.

bUrinary and/or blood pregnancy tests are to be performed in women of child-bearing potential and repeated at least every 6 months. Women of child-bearing potential must be using ≥2 forms of reliable contraception, including 1 barrier method.

Exclusion Criteria

Drug related

  1. Contraindication to clopidogrel or other reason that study drug should not be administered
  2. Oral anticoagulation therapy that cannot be stopped
  3. Fibrinolytic therapy planned or within previous 24 hours
  4. Concomitant oral or IV therapy with strong CYP3A inhibitors or inducers

Treatment related

  1. Index event is an acute complication of PCI
  2. PCI after index event and before first study dose

Medical

  1. Increased risk of bradycardiac events
  2. Dialysis required
  3. Known clinically important thrombocytopeniaa
  4. Known clinically important anemiaa
  5. Any other condition that may put patient at risk or influence study resultsa

General

  1. Participant in another investigational drug or device study within 30 days
  2. Pregnancy or lactation
  3. Any condition that increases the risk for noncompliance or being lost to follow-up
  4. Involvement in the study planning or conduct
  5. Previous enrollment or randomization in this study

aAccording to investigator.

1733068-2974913 Last Updated 11/14

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA

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 (eg, 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

INDICATIONS

BRILINTA is indicated to reduce the rate of thrombotic cardiovascular (CV) events in patients with acute coronary syndrome (ACS) (unstable angina, non–ST-elevation myocardial infarction, or ST-elevation myocardial infarction). 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 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.

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

*The PLATO (PLATelet inhibition and patient Outcomes) study was a randomized, double-blind, parallel-group trial comparing BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of CV events in 18,624 patients admitted to the hospital within 24 hours of symptom onset of ACS (UA [unstable angina], NSTEMI [non–ST-elevation MI], or STEMI [ST-elevation MI]). Patients were treated for at least 6 months and up to 12 months. BRILINTA and clopidogrel were studied with aspirin and other standard therapies.

PLATO included both medical and invasive (PCI or CABG) treatment approaches. Patients who received fibrinolytic therapy within the previous 24 hours or who had a need for chronic oral anticoagulation therapy were excluded.

REFERENCES:

  1. Wallentin L, Becker RC, Budaj A, et al; for the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057 and Appendix.
  2. Wallentin L, Becker RC, Budaj A, et al; on behalf of the PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes: the PLATelet inhibition and patient Outcomes (PLATO) trial. Presented at: European Society of Cardiology Congress; August 29-September 2, 2009; Barcelona, Spain.
  3. James S, Åkerblom A, Cannon CP, et al. Comparison of ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J. 2009;157(4):599-605. doi:10.1016/j.ahj.2009.01.003.

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