Well-established safety profile from PLATO in patients with ACS

PLATO-defined non–CABG-related bleeding1,2

Non-CABG Bleeding Defined in PLATO
Non-CABG Bleeding Defined in PLATO
  • About half of non–CABG-related major bleeding events were in the first 30 days1

PLATO used the following bleeding severity categorization: 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.1

PLATO-defined non–CABG-related bleeding at 12 months1,3

Non-CABG Bleeding at 12 Months
Non-CABG Bleeding at 12 Months

PLATO-defined CABG-related bleeding1

PLATO-defined CABG-related bleeding1

CABG-RELATED BLEEDING RATES


PLATO total major


Fatal/life-threatening


Fatal

CABG-RELATED BLEEDING RATESBRILINTA 90 mg + aspirin (N=770) n (%) patients with event

PLATO total major626 (81.3)

Fatal/life-threatening337 (43.8)

Fatal6 (0.8)

CABG-RELATED BLEEDING RATESClopidogrel + aspirin (N=814) n (%) patients with event

PLATO total major666 (81.8)

Fatal/life-threatening350 (43.0)

Fatal7 (0.9)

  • PLATO 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 79% of patients receiving clopidogrel1

Non–CABG-related bleeding in the PLATO final diagnosis NSTEMI subgroup at 12 months3,5-7

PLATO-defined non–CABG-related major bleeding

Non-CABG Bleeding in PLATO Final Diagnosis of NSTEMI
Non-CABG Bleeding in PLATO Final Diagnosis of NSTEMI

 

NNH=number needed to harm and is calculated as 1/ARI.

Additional final diagnosis subgroups

PLATO-defined non–CABG-related major bleeding K-M% at 12 months6

  • BRILINTA 90 mg plus aspirin vs clopidogrel plus aspirin, respectively:
    • STEMI 4.0% vs 3.3%, HR 1.17; 95% CI 0.91–1.51
    • UA 3.9% vs 3.2%, HR 1.29; 95% CI 0.85–1.95

PLATO used the following bleeding severity categorization: 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.1

 

PLATO was not designed or powered to demonstrate the efficacy or safety of BRILINTA compared with clopidogrel in specific subgroups. Subgroup analyses were performed to evaluate consistency of results in different cohorts. Analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses. The final diagnosis subgroup was based on postrandomized determinations.3

A post hoc analysis of PLATO-defined non-CABG major bleeding events in the PLATO CKD (CrCl <60 mL/min) subgroup at 12 months8

PLATO-defined non-CABG major bleeding at 12 months8

Non-CABG Bleeding Events in PLATO CKD
Non-CABG Bleeding Events in PLATO CKD

NNH=number needed to harm and is calculated as 1/ARI.

PLATO-defined non-CABG major bleeding in post hoc analysis of CKD subgroup (n=3237) at 12 months: ARI 1.2%; HR 1.28; 95% CI 0.97–1.68.8

 

In PLATO non-CKD (CrCl ≥60 mL/min) patients

  • A post hoc analysis of the PLATO-defined non-CABG major bleeding in the non-CKD subgroup (n=11,965), K-M% at 12 months: 3.4% vs 2.8% with BRILINTA and clopidogrel, respectively (HR 1.22; 95% CI 0.98–1.51)8

PLATO used the following bleeding severity categorization: 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.1

 

PLATO was not designed or powered to demonstrate the efficacy or safety of BRILINTA compared with clopidogrel in specific subgroups. Subgroup analyses were performed to evaluate consistency of results in different cohorts. Analyses must be interpreted cautiously, as differences can reflect the play of chance among a large number of analyses.3

PLATO STUDY DESIGN

PLATO was a randomized, international, double-blind, controlled comparative study in patients with ACS hospitalized with or without ST-segment elevation, with an onset of symptoms within 24 hours (N=18,624). The study compared BRILINTA (180-mg loading dose, 90 mg twice daily thereafter) to clopidogrel (300-mg to 600-mg loading dose, 75 mg daily thereafter) for the prevention of thrombotic CV events (CV death, MI, or stroke). Study period was 12 months, with median duration of therapy of 277 days. BRILINTA and clopidogrel were studied with aspirin and other standard therapies.1,3

Bleeding outcomes in PEGASUS

PEGASUS safety end points: TIMI bleeding1,9

PEGASUS safety end points: TIMI bleeding1,9

 


TIMI major


Fatal


Intracranial hemorrhage


TIMI major or minor

BRILINTA 60 mg + aspirin (N=6958) Events/1000 pt years

TIMI major8

Fatal/life-threatening1

Intracranial hemorrhage2

TIMI major or minor11

Aspirin (N=6996) Events/1000 pt years

TIMI major3

Fatal/life-threatening1

Intracranial hemorrhage1

TIMI major or minor5

PEGASUS used the following bleeding severity categorization. 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.

 

NNH FOR TIMI MAJOR: 804

 

Due to rounding, the ARI is 1.24% and not 1.2%.

PEGASUS STUDY DESIGN

PEGASUS-TIMI 54 compared BRILINTA (90 mg twice daily or 60 mg twice daily) vs placebo, each given with low-dose aspirin (75 to 150 mg), for the prevention of thrombotic CV events (CV death, MI, or stroke) in 21,162 patients ≥50 years of age with a history of MI (1 to 3 years prior to randomization). Patients also had at least 1 risk factor for thrombotic CV events (age ≥65 years, diabetes mellitus requiring medication, at least 1 other prior MI, evidence of multivessel coronary artery disease, or creatinine clearance <60 mL/min). Only the 60-mg dose strength is approved for use in patients with a history of MI 1 year after an ACS event. Patients were treated for at least 12 months and up to 48 months with a median follow-up time of 33 months.1,9

ACS=acute coronary syndrome; ARI=absolute risk increase; CABG=coronary artery bypass graft; CI=confidence interval; CKD=chronic kidney disease; CrCl=creatinine clearance; CV=cardiovascular; Hb=hemoglobin; Hct=hematocrit; HR=hazard ratio; K-M=Kaplan-Meier; MI=myocardial infarction; NNH=number needed to harm; NSTEMI=non–ST-elevation MI; PEGASUS=Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin; PLATO=PLATelet inhibition and patient Outcomes; RRR=relative risk reduction; STEMI=ST-elevation MI; TIMI=Thrombolysis in Myocardial Infarction; UA=unstable angina.

References
  1. BRILINTA® (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021.
  2. Becker RC, Bassand JP, Budaj A, et al. Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2011;32(23):2933-2944.
  3. 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 Supplementary Appendix.
  4. Data on file, REF-51076, AstraZeneca Pharmaceuticals LP.
  5. US Food and Drug Administration; Center for Drug Evaluation and Research; Division of Cardiovascular and Renal Products. Complete Response Review Addendum. Accessed May 27, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/022433orig1s000medr.pdf
  6. Data on file, REF-4934, AstraZeneca Pharmaceuticals LP.
  7. Data on file, REF-72872, AstraZeneca Pharmaceuticals LP.
  8. James S, Budaj A, Aylward P, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2010;122(11):1056-1067.
  9. Bonaca MP, Bhatt DL, Cohen M, et al; for the PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med. 2015;372(19):1791-1800.