PLATO Safety Information
BRILINTA: PLATO Overall, Non-CABG, and CABG Bleeding rates
| Overall and Non–CABG-related Bleeding rates (K-M%) | BRILINTA + aspirin (n=9,235) | Clopidogrel + aspirin (n=9,186) |
|---|---|---|
| Total Major Bleeding (P=NS) | 11.6 | 11.2 |
| Non–CABG-related Bleeding | ||
| Total (Major + Minor) | 8.7 | 7.0 |
| Major | 4.5 | 3.8 |
| Fatal/Life-threatening | 2.1 | 1.9 |
| Fatal | 0.2 | 0.2 |
| Intracranial (Fatal/Life-threatening) | 0.3 | 0.2 |
| CABG-related Bleeding rates (K-M%) | BRILINTA + aspirin (n=770) | Clopidogrel + aspirin (n=814) |
| Total Major | 85.8 | 86.9 |
| Fatal/Life-threatening | 48.1 | 47.9 |
| Fatal | 0.9 | 1.1 |
No baseline demographic factor altered the relative risk of bleeding with BRILINTA compared to clopidogrel
PLATO used the following bleeding severity categorization:
| Major Bleed—Fatal/Life-threatening | Major Bleed—Other | Minor Bleed | Minimal Bleed |
|---|---|---|---|
Any one of the following:
| Any one of the following:
| Requires medical intervention to stop or treat bleeding (eg, epistaxis requiring visit to medical facility for packing). | All others (eg, bruising, bleeding gums, oozing from injection sites, etc) not requiring intervention or treatment. |
- About half of the Non–CABG-Bleeding events were in the first 30 days
- PLATO did not show an advantage for BRILINTA compared to clopidogrel for CABG-related Bleeding
- When antiplatelet therapy was stopped 5 days before CABG, Major Bleeding occurred in 75% of patients treated with BRILINTA and 79% of patients on clopidogrel
- In general, risk factors for bleeding include older age, a history of bleeding disorders, performance of percutaneous invasive procedures and concomitant use of medications that increase the risk of bleeding (eg, anticoagulant and fibrinolytic therapy, higher doses of aspirin, and chronic nonsteroidal anti-inflammatory drugs [NSAIDs])
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.
Other Adverse Reactions
Most Common 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%)
Common Adverse Events
- A variety of nonhemorrhagic adverse events occurred in PLATO at rates of 3% or more. In the absence of a placebo control, whether these are drug related cannot be determined in most cases, except where they are more common with BRILINTA or clearly related to the drug’s pharmacologic effect (dyspnea)
Percentage of patients reporting nonhemorrhagic adverse events at least 3% or more in either group
| BRILINTA + aspirin (N=9,235) | Clopidogrel + aspirin (N=9,186) | |
|---|---|---|
| Dyspneaa | 13.8 | 7.8 |
| Headache | 6.5 | 5.8 |
| Cough | 4.9 | 4.6 |
| Dizziness | 4.5 | 3.9 |
| Nausea | 4.3 | 3.8 |
| Atrial fibrillation | 4.2 | 4.6 |
| Hypertension | 3.8 | 4.0 |
| Noncardiac chest pain | 3.7 | 3.3 |
| Diarrhea | 3.7 | 3.3 |
| Back pain | 3.6 | 3.3 |
| Hypotension | 3.2 | 3.3 |
| Fatigue | 3.2 | 3.2 |
| Chest pain | 3.1 | 3.5 |
aIncludes: dyspnea, dyspnea exertional, dyspnea at rest, nocturnal dyspnea, dyspnea paroxysmal nocturnal.
Bradycardia
- In clinical studies, BRILINTA has been shown to increase the occurrence of Holter-detected bradyarrhythmias (including ventricular pauses). PLATO excluded patients at increased risk of bradycardic events. In PLATO, syncope, presyncope, and loss of consciousness were reported by 1.7% and 1.5% of BRILINTA and clopidogrel patients, respectively
- In a Holter substudy of about 3,000 patients in PLATO, more patients had ventricular pauses with BRILINTA (6.0%) than with clopidogrel (3.5%) in the acute phase; rates were 2.2% and 1.6% respectively after 1 month
Drug Discontinuation
- In PLATO, the rate of study drug discontinuation attributed to adverse reactions was 7.4% for BRILINTA and 5.4% for clopidogrel. Bleeding caused permanent discontinuation in 2.3% of BRILINTA patients and 1.0% of clopidogrel patients. Dyspnea led to study drug discontinuation in 0.9% of BRILINTA and 0.1% of clopidogrel patients
NEXT: PLATO Study Design
IMPORTANT SAFETY INFORMATION ABOUT BRILINTA
WARNING: 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
WARNING: 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 also 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
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.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.
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