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Prasugrel versus Clopidogrel for Acute Coronary Syndromes without Revascularization

Background

• Out of all ACS (UA/NSTEMI) patients, 40 to 60% are managed without revascularization (PCI/CABG).
• TRITON trial showed that prasugrel had better outcomes compared to clopidogrel in ACS patients undergoing PCI (but major bleeding is increased).

Aim

• To compare the effects of prasugrel and clopidogrel in ACS patients managed without revascularization.

Method

• Inclusion criteria
  
  • Within 10 days of UA or NSTEMI (UA- 1 mm or more ST depression & cardiac markers negative; NSTEMI- cardiac markers positive, but no ST elevation)

    Plus

  • At least one of the following four enrichment criteria
    • Age more than 60 yrs
    • Diabetes mellitus
    • Prior myocardial infarction
    • Prior PCI or CABG

    (Note- Coronary angiography may or may not have been done before randomization, but if it is planned, it has to be done before randomization. If it is done, at least one lesion of more than 30% should be present or patient must have prior PCI or CABG done.)

• Exclusion criteria
  
  • History of TIA or stroke
  • PCI or CABG in last 30 days
  • Renal failure needing dialysis
  • Co-treatment with oral anticoagulants.
• Plan
  
  • Multiple centers in 52 countries
  • Double blind double dummy study
  • Patients were classified into two depending on time after first medical contact and whether clopidogrel was already given
    • Less than or equal to 72 hrs and clopidogrel was not given
      • Clopidogrel 300 mg loading followed by 75 mg OD

        Or

      • Prasugrel 30 mg loading followed by 5 or 10 mg OD (5 mg OD if age 75 yrs or more or weight less than 60 kg)
    • More than 72 hrs or less than 72 hrs but patient already exposed to clopidogrel
      • Open label clopidogrel continued before randomization
      • No loading dose- clopidogrel 75 mg OD versus prasugrel 5 or 10 mg OD
  • All patients receive aspirin (strongly advised to keep to 100 mg OD or less).
  • Primary endpoint is a composite of
    • Death from cardiovascular cause
    • Non-fatal MI and
    • Non-fatal stroke
  • Duration
    • Minimum 6 months
    • Maximum 30 months

Results

• General facts
  
  • 9326 patients
    • Less than 75 yrs- 7243 patients
    • More than or equal to 75 yrs- 2083 patients
  • Angiogram was performed before randomization in slightly more than 40% cases.
  • Revascularization (PCI/CABG) was done during follow-up in 7.9% in less than 75 year group and median time to revascularization was 113 days.
• Age less than 75 yrs
  
  • Median follow-up was 17 months.
  • Primary endpoint-
    • For total time period
      • Prasugrel- 13.9%
      • Clopidogrel- 16%
      • P= 0.21
    • After 12 months, trend to reduced risk with prasugrel (P=0.07 when primary endpoints after 12 months were compared).
    • Thus divergence of Kaplan-Meier curve for primary endpoint was noted after 12 months.
    • Prasugrel provided better results in
      • Smokers
      • Those who underwent angiography before randomization and
      • Those taking PPI.
  • Components of primary endpoint
    • Same in both groups
  • Recurrent ischemic events
    • Lower with prasugrel compared to clopidogrel (P=0.04)
  • Bleeding
    • TIMI major bleeding- same (P=0.27)
    • GUSTO severe/life threatening bleed- same (P=0.87)
    • Intracranial hemorrhage- same (P=0.39)
    • TIMI major or minor bleed- more with prasugrel (P=0.02)
    • GUSTO severe/life threatening or moderate bleed- trend towards increase with prasugrel (P=0.06)
  • New non-benign neoplasms
    • Same (P=0.79)
  • All cause death
    • Same (P=0.4)
• Overall population
  
  • Primary outcome
    • Same (P=0.45)
  • Components of primary outcome
    • Same
  • Death from any cause
    • Same (P=0.40)
  • Bleeding
    • TIMI major bleeding- same (P=0.29)
    • GUSTO severe/life threatening bleed- same (P=0.53)
    • Intracranial hemorrhage- same (P=0.42)
    • TIMI major or minor bleed- same (P=0.11)
    • GUSTO severe/life threatening or moderate bleed- same (P=0.10)

Conclusions

• Prasugrel was not different from clopidogrel in ACS patients followed up for 2.5 years.
• After 1 year, trend towards benefit with prasugrel was seen in patients of age less than 75 years.
• Recurrent ischemic events were lower with prasugrel in patients of age less than 75 years.
• Major bleeds were same with prasugrel and clopidogrel in patients of age less than 75 years.
• All bleeds were more with prasugrel compared to clopidogrel in patients of age less than 75 years.

Links

For published article in NEJM

http://www.nejm.org/doi/full/10.1056/NEJMoa1205512#t=abstract

For study protocol

http://www.nejm.org/doi/suppl/10.1056/NEJMoa1205512/suppl_file/nejmoa1205512_protocol.pdf

For supplementary appendix

http://www.nejm.org/doi/suppl/10.1056/NEJMoa1205512/suppl_file/nejmoa1205512_appendix.pdf

Tags: ACS trial, NSTEMI, recent ACS trial, TRILOGY ACS trial, TRILOGY trial, Unstable angina