BLEEDING

 
 

BLEEDING OUTCOMES FOR BRILINTA COMPARED WITH CLOPIDOGREL IN THE PLATO STUDY1

PLATO SAFETY END POINTS: PLATO-DEFINED NON‒CABG-RELATED BLEEDING1

NON‒CABG-RELATED BLEEDING RATES BRILINTA 90 MG + ASPIRIN (n=9235) % (n) PATIENTS WITH EVENT CLOPIDOGREL + ASPIRIN (n=9186) % (n) PATIENTS WITH EVENT
PLATO MAJOR + MINOR 7.7 (713) 6.2 (567)
MAJOR 3.9 (362) 3.3 (306)
FATAL/LIFE-THREATENING 1.9 (171) 1.6 (151)
FATAL 0.2 (15) 0.2 (16)
INTRACRANIAL HEMORRHAGE
(FATAL/LIFE-THREATENING)
0.3 (26) 0.2 (15)
  • About half of non‒CABG-related major bleeding events were in the first 30 days1

PLATO SAFETY END POINTS: PLATO-DEFINED CABG-RELATED BLEEDING1

CABG-related bleeding rates BRILINTA 90 mg + aspirin (n=770) n (%) patients with event Clopidogrel + aspirin (n=814) n (%) patients with event
PLATO total major 626 (81.3) 666 (81.8)
Fatal/life-threatening 337 (43.8) 350 (43.0)
Fatal 6 (0.8) 7 (0.9)
  • The PLATO trial did not show an advantage for BRILINTA 90 mg compared with clopidogrel for CABG-related bleeding1
  • Rates of major/fatal life-threatening CABG-related bleeding were similar between BRILINTA 90 mg and clopidogrel when study drug was withheld 1-5 days before CABG surgery1
  • When antiplatelet therapy was stopped 5 days before CABG, major bleeding occurred in 75% of patients receiving BRILINTA 90 mg and in 79% of patients receiving clopidogrel1
    • PLATO used the following bleeding severity categorization1:
    • PLATO minor bleed: requires medical intervention to stop or treat bleeding
    • PLATO major bleed: any one of the following: fatal; intracranial; intrapericardial with cardiac tamponade; hypovolemic shock or severe hypotension requiring intervention; significantly disabling (eg, intraocular with permanent vision loss); associated with a decrease in Hb of at least 3 g/dL (or a fall in Hct of at least 9%); transfusion of 2 or more units
    • PLATO major bleed, fatal/life-threatening: any major bleed as described above and associated with a decrease in Hb of more than 5 g/dL (or a fall in Hct of at least 15%); transfusion of 4 or more units
    • Fatal: a bleeding event that directly led to death within 7 days

PLATO-DEFINED NON‒CABG-RELATED TOTAL MAJOR BLEEDING IN FINAL DIAGNOSIS SUBGROUP K-M% AT 12 MONTHS2

BRILINTA 90 mg + aspirin Clopidogrel + aspirin HR 95% CI
NSTEMI 5.1 4.4 1.17 0.94-1.45
STEMI 4.0 3.3 1.17 0.91-1.51
UA 3.9 3.2 1.29 0.85-1.95
  • Within subgroups, non‒CABG-related total major bleeding rates were higher for BRILINTA vs clopidogrel2

Additional safety

See additional information for dyspnea and other adverse reactions.

 
 

BLEEDING OUTCOMES FROM PATIENTS STUDIED IN A REAL-WORLD REGISTRY WERE CONSISTENT WITH THOSE SEEN IN PLATO3,4

TICAGRELOR REAL-WORLD STUDY: BLEEDING REQUIRING HOSPITALIZATION3,4

CUMULATIVE PROBABILITY OF EVENTS PER 100 PATIENT-YEARS

BRILINTA 90 mg + aspirin Clopidogrel + aspirin
12 months* 4.43 3.85
24 months 5.5 5.2

*The 12-month bleeding outcome estimate was based on the assumption of similar proportions of event rates for years 1 and 2.

Adjusted HR: 1.20 (95% CI: 1.04-1.40).

Bleeding was defined by the patient receiving treatment for at least 1 of the following: hemorrhagic stroke, gastrointestinal bleeding, anemia-related bleeding, or other bleeding.4

  • The absolute bleeding risk was lower than that observed in the PLATO trial, possibly due to underreporting4
  • This was an observational study in patients enrolled in the Swedish Web system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) registry4
  • Acute MI patients enrolled in the SWEDEHEART registry were discharged on aspirin and either BRILINTA or clopidogrel from 2010 to 2013 (N=45,073) and followed for 24 months. Patients undergoing CABG were excluded from this analysis4

BLEEDING OUTCOMES IN A PATIENT POPULATION WITH A HISTORY OF MI

PEGASUS safety end points: TIMI bleeding1

BRILINTA 60 mg + aspirin (N=6958) Placebo + 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.

Additional safety

See additional information for dyspnea and other adverse reactions.

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.