PRAGUE-18: Ticagrelor vs prasugrel in ACS

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References:

Bottom line: PRAGUE-18 was underpowered to identify clinically-important differences & was at high risk of bias. As a result, it could not rule out differences between prasugrel & ticagrelor.

Patients (n=1230)

  • Multicentre (14 tertiary-care cardiology centres in the Czech Republic)
  • Included MI (STEMI or NSTE-ACS with ST depression) requiring emergent (<120 min of admission to cardiac centre) angiography +/- PCI 
  • Key exclusion criteria:
    • Administration of clopidogrel loading dose or non-ASA antiplatelet before randomization (but could be on long-term clopidogrel-based DAPT before enrolment)
    • Indication for oral anticoagulant
    • Serious bleeding in past 6 months
    • Stroke, age >75 years, body weight <60 kg
  • Baseline characteristics
    • Age 62 y
    • Female 23-26%
    • At admission
      • EKG: STEMI 89%, LBBB 5%, NSTEMI 6%
      • Killip class: 1 (89%), 2 (6-7%), 3-4 (5-6%)
    • PMHx: Prior MI (7-9%), prior PCI (~7%), prior CABG (<2%), HF (1%), CKD (1%)
    • Procedural characteristics: PCI >99%, stent 96%, drug-eluting stent 68%
    • Meds @ discharge: ASA (97%), ACEI/ARB (83%), beta-blocker (82%), statin (94%), PPI 61%

Interventions

  • I: Ticagrelor (180 mg PO load, then 90 mg BID)
  • C: Prasugrel (60 mg PO load, then 10 mg daily [or 5 mg daily if age >75 y or wt <60 kg])
  • Common for both groups
    • Load generally administered immediately on hospital arrival before angiography
    • Duration recommended for 12 months
    • ASA administration required, with dose 100 mg/d recommended
    • Switch to clopidogrel if cost of prasugrel/ticagrelor was prohibitive for the patient

Results (prasugrel vs ticagrelor)

@ day 7 (or at discharge if discharged early)

  • Primary outcome (all-cause death, re-MI, stroke, serious bleed requiring transfusion or prolonging hospitalization, or urgent target vessel revascularization): 4.0% vs 4.1% (odds ratio [OR] 0.98, 0.55-1.73)
    • All-cause death: 1.3% vs 2.0% (p=0.30)
    • Re-MI: 1.0% vs 0.7% (p=0.59)
    • Urgent revascularization: 1.4% vs 1.2% (p=0.71)
    • Stroke: 0.2% vs 0.2% (p=0.96)
    • Serious bleed: 1.3% vs 1.2% (p=0.90)

@ day 30

  • CV composite (CV death, MI, stroke): 2.7% vs 2.5% (p=0.86)
  • All-cause death: 2.2% vs 2.7% (p=0.59)
  • Definite stent thrombosis: 0.5% vs 0.9% (p=0.43)
  • TIMI major bleed: 0.6% vs 0.7% (OR 0.86, 0.17-4.27)
  • No difference in bleeds based on BARC definition

@ 1 year

  • CV composite (CV death, MI, stroke): 6.6% vs 5.7% (hazard ratio [HR] 1.17, 0.74-1.84)
    • CV death: 3.3% vs 3.0% (p=0.77)
    • Non-fatal MI: 3.0% vs 2.5% (p=0.61)
    • Stroke: 1.1% vs 0.7% (p=0.42)
  • All-cause death: 4.7% vs 4.2% (p=0.65)
  • Definite stent thrombosis: 1.1% vs 1.5% (p=0.53)
  • TIMI major bleed: 0.9% vs 0.7% (p=0.75)
  • BARC major bleed: 2.4% vs 1.5% (p=0.31)
  • Dyspnea: Not reported

Considerations

  • Generalizability: Widely applicable to patients with STEMI requiring primary PCI.
  • High risk of several biases
    • High risk for allocation bias
      • Simple randomization, no use of permuted blocks or stratification by site;
      • Allocation concealment by sealed envelopes (prone to tampering).
    • High risk for performance & detection bias
      • No blinding of patients & clinicians to study drug;
      • Differential study drug discontinuation
        • Patients who could not afford the study drug could switch to clopidogrel
        • Study drug not free for participants, & there was differential funding for prasugrel & ticagrelor, as ticagrelor was not funded by the public insurance plan, whereas prasugrel was covered for patients with STEMI plus either left main disease, pLAD or multivessel disease
        • Switch to clopidogrel for financial reasons higher in ticagrelor group (44.4%) vs prasugrel (34.1%, p=0.003).
      • Blinded endpoint adjudication, however issues upstream as described above limit the value of blinded adjudication of potentially biased reports.
    • Low risk of attrition bias: Loss to follow-up: <1% at 30 days, 0% at 1 year.
  • Other issue: Study completely underpowered to detect a clinically-significant difference.
    • Initial power calculation with target sample size 2500 was based on unrealistic expectations
      • Done to detect a 2.5% absolute risk difference (or 39% relative risk difference) between ticagrelor & prasugrel (larger than difference between either drug compared to clopidogrel)
    • Confidence around point estimate of trial stopped early with sample size of 1230 cannot rule out a ~3% absolute risk difference in CV events between these drugs.