Principal Findings:

The primary outcome of Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 12 months, for ticagrelor monotherapy vs. aspirin + ticagrelor, was 4.0% vs. 7.1% (p < 0.001).

• All-cause mortality, MI, stroke: 3.9% vs. 3.9% (p < 0.001 for noninferiority)
• MI: 2.7% vs. 2.7%

Secondary outcomes for ticagrelor monotherapy vs. aspirin + ticagrelor:

• Stent thrombosis, definite + probable: 0.4% vs. 0.6% (p < 0.05)
• Ischemic stroke: 0.5% vs. 0.2% (p > 0.05)

Thrombogenicity platelet substudy: Ex vivo thrombogenicity measurements were performed in 42 patients. Platelet reactivity to collagen and arachidonic acid was increased in the absence of aspirin, while aggregation to adenosine diphosphate and thrombin was unchanged with or without aspirin. The adjusted mean difference in post-randomization thrombus area was similar between groups: −218.2 μm2; p = 0.22.

NSTE-ACS subset (n = 4,614): The primary endpoint for ticagrelor monotherapy vs. aspirin + ticagrelor was 3.6% vs. 7.6% (p < 0.001); TIMI major bleeding: 0.5% vs. 1.0% (p = 0.08); all-cause mortality, MI, stroke: 4.3% vs. 4.4% (p = 0.84); all-cause mortality: 1.0% vs. 1.5% (p = 0.14); any MI: 3.1% vs. 3.1% (p = 0.99); stent thrombosis: 0.4% vs. 0.6% (p = 0.38).

Diabetes mellitus subset (n = 2,620, 37%): BARC 2, 3, or 5 bleeding with ticagrelor vs. placebo was 4.5% vs. 6.7% (p = 0.012); ischemic events: 4.6% vs. 5.9% (p = 0.14).

Complex PCI (n = 2,342): Defined as 3 vessels treated, ≥3 lesions treated, total stent length >60 mm (52% of all), bifurcation with 2 stents implanted, atherectomy device use, left main PCI, surgical bypass graft, or chronic total occlusion as target lesions. BARC 2, 3, or 5 bleeding with ticagrelor vs. placebo was 4.2% vs. 7.7% (p < 0.05); ischemic events: 3.8% vs. 4.9% (p > 0.05); stent thrombosis: 0.4% vs. 0.8% (p > 0.05).

Sex differences: Women (23.9%); Ticagrelor monotherapy vs ticagrelor + aspirin reduced BARC type 2, 3, or 5 bleeding in women (5.0% vs. 8.6%; adjusted HR 0.62; 95% CI 0.42-0.92; p= 0.02) and in men (3.7% vs. 6.6%; adjusted HR 0.57; 95% CI 0.44-0.73; p< 0.001) (p for interaction = 0.69). Composite of death, MI, or stroke similar for ticagrelor monotherapy vs. ticagrelor plus aspirin in women (3.5% vs. 3.5%; adjusted HR 1.04, 95% CI 0.61-1.77; p = 0.88) and men (4.0% vs 4.1%; adjusted HR 1.06, 95% CI 0.80-1.39; p = 0.69) (p for interaction = 0.95).

High bleeding risk (HBR) patients (n = 1,064, 17.2%): Patients meeting ARC-HBR criteria were older, more likely to be female, non-White race, and had a higher burden of most comorbidities; they were also more likely to undergo complex PCI. BARC 2, 3, or 5 bleeding was significantly lower in the ticagrelor monotherapy arm compared with ticagrelor + aspirin in both HBR (6.3% vs. 11.4%, p = 0.004) and non-HBR (3.5% vs. 5.9%, p < 0.0001) patients (p for interaction = 0.67). TIMI major bleeding (0.4% vs. 2.2%, p for interaction = 0.021) and GUSTO moderate or severe bleeding (1.6% vs. 4.5%, p for interaction = 0.016) were significantly reduced among HBR patients with ticagrelor monotherapy. No difference in ischemic endpoints was noted in HBR and non-HBR patients.

Patients with prior MI (n = 1,937, 29.7%): At 1 year after randomization, patients with prior MI experienced higher rates of death, MI, or stroke (5.7% vs. 3.2%; p < 0.001) but similar BARC types 2-5 bleeding (5.0% vs. 5.5%; p = 0.68). Ticagrelor monotherapy consistently reduced the risk for the primary bleeding outcome in patients with (3.4% vs. 6.7%; HR 0.50, 95% CI 0.33-0.76) and without (4.2% vs. 7.0%; HR 0.58, 95% CI 0.45-0.76, p interaction = 0.54) prior MI. No differences were noted for individual ischemic endpoints including cardiovascular death, MI, ischemic stroke, and stent thrombosis.

TWILIGHT-CKD: Chronic kidney disease (CKD) was present in 16.3%. BARC type 2, 3, or 5 bleeding was lower for ticagrelor monotherapy vs. ticagrelor + aspirin among patients with CKD (4.6% vs. 9.0%; HR 0.50, 95% CI 0.31-0.80) and without CKD (4.0% vs. 6.7%; HR 0.59, 95% CI 0.47-0.75), p for interaction = 0.50. Death, MI, or stroke for ticagrelor monotherapy vs. ticagrelor + aspirin was similar among patients with CKD (7.9% vs. 5.7%; HR 1.40, 95% CI 0.88-2.22) and without CKD (3.2% vs. 3.6%; HR 0.90, 95% CI 0.68-1.20), p for interaction = 0.11.