TREAT - Ticagrelor vs clopidogrel after fibrinolytic therapy for STEMI

Berwanger O, et al. Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a randomized clinical trial. JAMA Cardiol 2018

Bottom line:

  • In patients <75 y/o who received fibrinolytic therapy plus a loading dose of clopidogrel for STEMI & already not actively bleeding from this, switching to ticagrelor with a loading dose 8-24h after administration of the fibrinolytic agent does not appear to increase the risk of major, fatal or intracranial bleeding at 30 days versus continuing with clopidogrel.

  • Follow-up in TREAT is ongoing; 12-month outcomes as well as meta-analysis with PLATO STEMI subgroup will likely be reported in 2019.

Patients (n=3799)

  • Setting: 10 countries including Canada, enrolled from Nov 2015 to Nov 2017
  • Included:
    • 18-75 y/o
    • STEMI presenting <24h after symptom onset
    • Received fibrinolytic therapy
  • Excluded:
    • Contraindication to clopidogrel, ticagrelor or fibrinolysis
    • Use of oral anticoagulant therapy
    • Increased risk of bradycardia (not further defined)
    • Concomitant use of a strong CYP3A4 inhibitor/inducer
    • Dialysis-dependent
    • Clinically-important anemia or thrombocytopenia, or active bleeding (therefore excluding those who bled early with the initial fibrinolytic+antiplatelet regimen)
  • Baseline characteristics:
    • Age 59 y
    • Female 23%
    • White 57%, Asian 33%
    • STEMI type: Anterior only (~34%), inferior only (~31%), LBBB only (1%)
    • Killip class 2-4: 8-9%
    • PMHx: MI (8-9%), stroke (4-5%), PCI (5-6%), CABG (<1%)
    • Meds (baseline + in-hospital):
      • ASA 99%
      • Anticoagulant: Heparin (40%), LMWH (69%), fondaparinux (4%), bivalirudin (~1%), warfarin (<1%)
      • ACEI ~60%, ARB ~10%
      • Beta-blocker 74%
      • Statin 93%
      • PPI ~55%
    • PCI during initial ACS hospitalization: ~56% (DES ~34%)

Intervention & control

  • Intervention: Ticagrelor 180 mg PO x1, then 90 mg BID (plan to continue 12+ months per standard ACS management)
    • Mean 90% of doses taken within 30 days
  • Control: Clopidogrel 300-600 mg PO x1, then 75 mg daily (plan to continue 12+ months per standard ACS management)
    • Mean 91% of doses taken within 30 days
  • Co-interventions:
    • Clopidogrel dose administered before randomization: >300 mg (3%), 300 mg (87%), none or <300 mg (10%)
    • All received ASA 75-100 mg daily unless intolerant
    • Fibrinolytic selection: TNK ~40%, alteplase ~20%, reteplase, 17%, other 23%
    • Median 2.6 h from symptom onset to fibrinolytic administration
    • Median 11.4 h from fibrinolytic administration to randomization
    • PCI during hospitalization in 56%, drug-eluting stent in 34%

Results @ 30 days (follow-up up to 12 months ongoing)

Bleeding

  • 1o outcome (major bleed, TIMI definition): Ticagrelor 0.7%, clopidogrel 0.7%
    • (95% confidence interval for absolute risk difference -0.5% to +0.6%, p<0.001 for non-inferiority based on a non-inferiority margin of 1.0%)
  • Other bleeding definitions:
    • Intracranial hemorrhage: 0.4% vs 0.4% (95% CI -0.35% to +0.45%)
    • Fatal bleeding: 0.2% vs 0.1% (95% CI -0.2% to +0.3%)
    • BARC type 3-5: 1.2% vs 1.4%
    • PLATO, major: 1.2% vs 1.4%
    • TIMI
      • Major non-CABG: 0.7% vs 0.6%, p=0.57
      • Requiring medical attention: 2.0% vs 1.3%, p=0.06
      • Minor: 0.4% vs 0.6%, p=0.47
  • TIMI major bleed based on time from fibrinolytic administration to administration of study antiplatelet
    • <4h: 1.5% vs 1.2%
    • 4-8h: 0.8% vs 1.2%
    • 8-16h: 0.5% vs 0.3%
    • 16+h: 0.5% vs 0.2%

Other safety outcomes

  • Dyspnea: 13.9% vs 7.6% (NNH 16)
  • Premature discontinuation of study drug <30 days: 8.1% vs 6.4%
    • Due to dyspnea: 1.2% vs 0%
    • Due to patient refusal: 1.5% vs 0.3%

Efficacy

  • Death from any cause: 2.6% in both groups (HR 0.99, 0.66-1.47)
  • Vascular death, MI, stroke: 4.0% vs 4.3% (hazard ratio [HR] 0.91, 95% CI 0.67-1.25)
    • MI: 1.0% vs 1.3% (HR 0.79, 0.44-1.42)

Generalizability

  • TREAT enrolled a representative population of STEMI patients who received fibrinolytic therapy.
  • Note that the logistics of this trial are key to interpretation and application. Fibrinolytic therapy is generally reserved for patients who cannot get to a PCI-capable hospital in a reasonable timeframe, & is therefore administered in the pre-hospital or community hospital setting. This trial was undertaken at academic sites, and therefore generally enrolled patients & administered the study therapy hours after administering a fibrinolytic, with 90% having already received a clopidogrel load.
    • This is therefore NOT a trial comparing SIMULTANEOUS fibrinolysis + ticagrelor vs fibrinolysis + clopidogrel, but rather a trial comparing a switch from clopidogrel to ticagrelor within 24h of administering a fibrinolytic. With a median time from fibrinolytic administration to study P2Y12 administration of 11.4h, the fibrinolytic was long-gone by the time they entered the study (e.g. half-life <30 min for 3 most-commonly-used fibrinolytics)
    • Therefore the most direct application of these results would be to administer a loading dose of clopidogrel 300 mg PO with the fibrinolytic, & then switch to ticagrelor by starting with a loading dose 8-24h later (ensuring that the fibrinolytic is eliminated, & therefore pharmacodynamic interaction & bleed risk is minimized)

Internal validity

  • Low risk of allocation bias due to use of an automated web-based system in permuted blocks of 4 stratified according to site
  • Unclear risk of performance and detection bias due to open-label design with blinded adjudication of outcomes (though low risk for important "hard" endpoints of death, major, fatal and intracranial bleeds)
  • Low risk of attrition bias due to very low loss-to-follow-up (0.1-0.2%) & use of ITT analysis
  • Non-inferiority design was appropriate, design decisions were well-justified & conclusion of non-inferiority is reasonable based on threshold set & consistency in analyses
    • Justified based on potential long-term benefits of ticagrelor as observed in the PLATO trial (i.e. to 12 months after ACS)
    • Non-inferiority margin for major bleed set at an absolute risk increase of 1.0%, which the authors justify empirically based on thresholds used in other non-inferiority RCTs
    • Analyzed 3 separate definitions of "major bleed" using both ITT & per-protocol analyses, which were all nearly identical & consistent