PLATO* Trial Design1

PLATO Trial worldwide participation

BRILINTA 90 mg 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 diagnosis1

Based upon the results of the PLATO (PLATelet inhibition and patient Outcomes) study, in patients with ACS, BRILINTA 90 mg plus aspirin has been shown to reduce the rate of a combined end point of cardiovascular (CV) death, myocardial infarction (MI), or stroke compared to clopidogrel plus aspirin. The difference between treatments was driven by CV death and MI with no difference in stroke. BRILINTA also reduces the rate of stent thrombosis in patients who have been stented for treatment of ACS.

WARNING: ASPIRIN DOSE AND BRILINTA EFFECTIVENESS
Maintenance doses of aspirin above 100 mg reduce the effectiveness of BRILINTA and should be avoided.

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.

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 90 mg plus aspirin was superior to clopidogrel plus aspirin 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)

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.

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
1975408-3218312 Last Updated 10/16

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
  • 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 full Prescribing Information , including Boxed WARNINGS, and Medication Guide  .

*The PLATO study compared 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 thrombotic CV events (CV death, MI, or stroke) in 18,624 patients with ACS (UA, NSTEMI, STEMI). Patients were treated for at least 6 months and up to 12 months. Patients were excluded if they had a previous intracranial hemorrhage, gastrointestinal bleeding within 6 months, had a known bleeding diathesis or coagulation disorder, or required treatment with anticoagulants. 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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