Wallentin L, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med 2009;361:1045-57.
Bottom line: In patients with ACS (excluding STEMI treated with fibrinolysis, or low-risk unstable angina), ticagrelor reduced the risk of death (NNT 72) or MI (NNT 91) compared to clopidogrel at 1 year. Conversely, ticagrelor increased the risk of certain adverse events compared to clopidogrel, including non-CABG major bleed (NNH 143) and dyspnea (NNH 17).
Patients
- Inclusion:
- ACS with symptom onset <24h, including:
- STEMI treated with primary PCI
- NSTE-ACS with at least 2 of the following:
- EKG - ST-segment changes suggesting ischemia
- Troponin or CK-MB positive
- 1+ additional risk factor (age 60+ y; previous MI, CABG or ischemic stroke/TIA; CAD with stenosis at least 50% in 2+ vessels; carotid stenosis of at least 50% or cerebral revascularization; CKD with eGFR <60 mL/min; diabetes; PAD)
- Exclusion:
- Fibrinolytic <24h before randomization
- Need for oral anticoagulation
- Increased risk of bradycardia
- Taking medication that is a strong CYP 3A inhibitor/inducer
- ? screened -> 18,624 randomized & analyzed for efficacy (18,421 analyzed for safety outcomes)
- "Average" patient
- Age 62 y (75+ y - 15%)
- Female 28%
- White 92%
- ACS final diagnosis
- STEMI 38%
- NSTEMI 42%
- Unstable angina 17%
- CV history
- MI 21%
- PCI 13%
- CABG 6%
- HF 5%
- Non-hemorrhagic stroke 4%
- PAD 6%
- CV risk factors
- Smoker 36%
- HTN 65%
- CKD 4%
- Dyslipidemia 47%
- Diabetes 25%
Interventions & co-interventions
- I: Ticagrelor x up to 12 months (median 9 months)
- Loading dose of 180 mg PO x1, followed by
- Maintenance dose of 90 mg PO BID
- Started at median 11 hours from start of chest pain
- % of patients taking at least 80% of study drug: 83%
- C: Clopidogrel x up to 12 months (median 9 months)
- Loading dose of 300 mg PO x1 (additional 300 mg for total loading dose 600 mg could be given prior to PCI), followed by
- Maintenance dose of 75 mg PO once daily
- Started at median 11 hours from start of chest pain
- % of patients taking at least 80% of study drug: 83%
- Co-interventions
- ASA 75-100 mg PO daily (could be increased to 325 mg PO daily for 1st 6 months after stent placement)
- Procedures
- Coronary angiography 81%
- PCI during index hospitalization 61%
- Other meds at discharge
- Statin, ACEI/ARB, beta-blocker ~90%
- PPI 45%
Results @ median 9 months
- Statistically significant reduction with ticagrelor in:
- Death from any cause: 4.5% vs 5.9% (NNT 72)
- Primary outcome (vascular death, MI, stroke): Ticagrelor 9.8%, clopidogrel 11.7% (NNT 53)
- MI 5.8% vs 6.9% (NNT 91)
- Stent thrombosis (probable or definite): 2.2% vs 2.9% (NNT 143)
- No statistically significant difference in:
- Ischemic stroke: 1.1% in both groups
- Hemorrhagic stroke: 0.2% vs 0.1% (p=0.10)
- Recurrent ischemia: 5.8% vs 6.2% (p=0.22)
- Safety:
- Premature discontinuation: 23.4% vs 21.5% (NNH 53)
- Because of adverse event: 7.4% vs 6.0% (NNH 72)
- Major bleed: 11.6% vs 11.2% (p=0.43)
- Not related to CABG: 4.5% vs 3.8% (NNH 143)
- Dyspnea: 13.8% vs 7.8% (NNH 17)
- Requiring study drug discontinuation: 0.9% vs 0.1% (NNH 125)
- Bradycardia requiring pacemaker insertion: 0.9% in both groups
- Transient reversible increases in SCr & uric acid greater in ticagrelor group
- Subgroup analyses: 3 of 25 subgroups had a positive test for interaction (each with p=0.05 or lower). Of interest:
Issues with internal validity?
- Unclear risk of bias: Incompletely described as a "randomized, double-blind trial". No description of sequence generation, allocation concealment, blinding method.
- Low risk of attrition bias (loss-to-follow-up <0.5%), and analysis properly included all randomized patients (intention-to-treat population).
