TREAT - Ticagrelor vs clopidogrel after fibrinolytic therapy for STEMI

does not appear to increase the risk of major, fatal or intracranial bleeding at 30 days versus continuing with clopidogrel.
does not clearly reduce the risk of cardiovascular events up to 1 year, but does increase the risk of any bleeding (NNH 25) & dyspnea (NNH 10).

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; dialysis-dependent; clinically-important anemia or thrombocytopenia, or active bleeding (therefore excluding those who bled early with the initial fibrinolytic+antiplatelet regimen)
- Increased risk of bradycardia (not further defined); concomitant use of a strong CYP3A4 inhibitor/inducer
Baseline characteristics:
- Age 59 y; female 23%; white 57%, Asian 33%
- STEMI type: Anterior involvement (~37%), inferior only (~30%), LBBB only (1%)
- Killip class 2-4: 9%
- PMHx: MI (8-9%), stroke (~5%), PCI (5-6%), CABG (<1%)
- Meds (baseline + in-hospital):
  - ASA 99%
  - Anticoagulant during admission: 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: Ticagrelor 180 mg PO x1, then 90 mg BID (plan to continue 12+ months per standard ACS management)
Control: Clopidogrel 300-600 mg PO x1, then 75 mg daily (plan to continue 12+ months per standard ACS management)
Co-interventions:
- Mean adherence of 90% to P2Y12 inhibitor at 30 days & 12 months
- 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%

@ 30 days

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 outcomes:
  - Intracranial hemorrhage: 0.4% in both groups (95% CI -0.35% to +0.45%)
  - Fatal bleeding: 0.2% vs 0.1% (95% CI -0.2% to +0.3%)
  - PLATO major bleed / BARC type 3-5: 1.2% vs 1.4%
  - 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%
Efficacy
- Death from any cause: 2.6% in both groups; Hazard ratio (HR) 0.99 (95% confidence interval 0.66-1.47)
- Vascular death, MI, stroke: 4.0% vs 4.3%; HR 0.91 (0.67-1.25)
  - MI: 1.0% vs 1.3%; HR 0.79 (0.44-1.42)
Dyspnea: 13.9% vs 7.6%

@ 1 year

Efficacy
- Vascular death/MI/stroke: Ticagrelor 6.7%, clopidogrel 7.3%; HR 0.93 (0.73-1.18)
- Death from any cause: 4.2% vs 4.6%; HR 0.92 (0.68-1.24)
Bleeding
- TIMI major: 1.0% vs 1.2%; HR 0.86 (0.47-1.56)
- TIMI clinically significant: 5.3% vs 3.8%; HR 1.41 (1.04-1.91)
- Any bleeding: 10.2% vs 6.2%; HR 1.69 (1.34-2.13)
- Intracranial hemorrhage: 0.5% in both groups; HR 1.10 (0.44-2.69)
Dyspnea: 23.9% vs 13.7% (NNH 10)

TREAT enrolled a representative population of STEMI patients who received fibrinolytic therapy.
Logistics of this trial are key to interpretation & application. Fibrinolytic therapy is generally reserved as 2nd-line to primary PCI for patients who cannot get to a PCI-capable hospital in a reasonable timeframe, & is therefore often 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 an early 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)

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 (for 30-day safety outcomes) 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