In PLATO patients with ACS, randomization to clopidogrel resulted in a 27% higher risk of CV death than BRILINTA1

PLATO secondary end point

CV death at 12 months2,3*

The PLATO Secondary End Point
The PLATO Secondary End Point

*K-M rate is the rate of first events only.

 

Hazard ratio derived from a Cox proportional-hazards model on data from the primary and secondary end points.3

 

NNT=number needed to treat and is calculated as 1/ARR.

 

  • Secondary efficacy end point of CV death at 12 months for BRILINTA plus aspirin vs clopidogrel plus aspirin: Events per 1000 patient years: 45 vs 57, respectively

Additional PLATO secondary efficacy end points2

Patients with outcome events (events/1000 patient years)

Patients with outcome events (events/1000 patient years)

 


MIǂ§


Stroke§


All-cause mortality

BRILINTA 90 mg + aspirin (N=9333)

MIǂ§65

Stroke§16

All-cause mortality51

Clopidogrel + aspirin (N=9291)

MIǂ§76

Stroke§14

All-cause mortality65

Outcomes at 12 months (K-M%)

Outcomes at 12 months (K-M%)

 


MIǂ§


Stroke§


All-cause mortality

BRILINTA 90 mg + aspirin (N=9333)

MIǂ§5.8

Stroke§1.5

All-cause mortality4.5

Clopidogrel + aspirin (N=9291)

MIǂ§6.9

Stroke§1.3

All-cause mortality5.9

HR (95% CI)

MIǂ§0.84 (0.75–0.95)

Stroke§1.17 (0.91–1.52)

All-cause mortality0.78 (0.69–0.89)

P-value

MIǂ§0.0045

Stroke§0.22

All-cause mortality0.0003ǁ

Hazard ratio derived from a Cox proportional-hazards model on data from the primary and secondary end points.3

 

Excluding silent MI.

 

§Including patients who could have had other nonfatal events or died.

 

||Due to the hierarchical test sequence in PLATO, all-cause mortality was an exploratory analysis and, therefore, the P value is nominal.3

 

In PLATO patients with ACS, NSTEMI subgroup: BRILINTA vs clopidogrel

Primary end point in the PLATO final diagnosis NSTEMI subgroup at 12 months

Composite of CV death, MI,* or stroke3,5-7

Primary End Point in NSTEMI Subgroup
Primary End Point in NSTEMI Subgroup

*Excluding silent MI.

 

NNT=number needed to treat and is calculated as 1/ARR.

Additional final diagnosis subgroups

Composite efficacy end point K-M% at 12 months6

     

  • BRILINTA 90 mg plus aspirin vs clopidogrel plus aspirin, respectively:

       

    • STEMI 8.5% (N=3496) vs 10.1% (N=3530), HR: 0.84; 95% CI: 0.72–0.98
    •  

    • UA 8.6% (N=1549) vs 9.1% (N=1563), HR: 0.96; 95% CI: 0.75–1.22

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

 

CKD (CrCl <60 mL/min): BRILINTA vs clopidogrel in PLATO

A post hoc analysis of CV events in the PLATO CKD subgroup at 12 months8

Composite of CV death, MI,* or stroke8

Post Hoc Analysis of CV Events in PLATO CKD Subgroup
Post Hoc Analysis of CV Events in PLATO CKD Subgroup

*Excluding silent MI.

 

NNT=number needed to treat and is calculated as 1/ARR.

 

  • Central laboratory serum creatinine levels were available in 15,202 (81.9%) of PLATO patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated in a post hoc analysis of the subgroup8
  • CKD was defined as creatinine clearance <60 mL/min (n=3237).8 PLATO excluded patients requiring dialysis2
  • No dosage adjustment is needed in patients with renal impairment2

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

  • A post hoc analysis of the primary efficacy end point in the non-CKD subgroup (n=11,965), K-M% at 12 months: 7.9% vs 8.9% with BRILINTA and clopidogrel, respectively (HR 0.90; 95% CI 0.79–1.02)8

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.1,2

ACS=acute coronary syndrome; ARR=absolute risk reduction; CABG=coronary artery bypass graft; CI=confidence interval; CKD=chronic kidney disease; CrCl=creatinine clearance; CV=cardiovascular; HR=hazard ratio; K-M=Kaplan-Meier; MI=myocardial infarction; NSTEMI=non–ST-elevation myocardial infarction; PLATO=PLATelet inhibition and patient Outcomes; RRR=relative risk reduction; STEMI=ST-elevation myocardial infarction; UA=unstable angina.

References
  1. Data on file, REF-4911, AstraZeneca Pharmaceuticals LP.
  2. BRILINTA® (ticagrelor) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2021.
  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. Data on file, REF-72872, AstraZeneca Pharmaceuticals LP.
  6. 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
  7. Data on file, REF-4934, 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.