PRAGUE-18: Ticagrelor vs prasugrel in ACS
References:
- Motovska Z, et al. Prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention: Multicenter randomized PRAGUE-18 study. Circulation 2016;134:1603-12.
- Motovska Z, et al. One-year outcomes of prasugrel versus ticagrelor in acute myocardial infarction treated with primary angioplasty: The PRAGUE-18 study. J Am Coll Cardiol 2017 Nov 9 [Epub ahead of print].
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.
- High risk for allocation bias
- 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.
- Initial power calculation with target sample size 2500 was based on unrealistic expectations
