Efficacy and Safety of Ticagrelor in Relation to Aspirin Use Within the Week Before Randomization in the SOCRATES Trial

K.S. Lawrence Wong, MD; Pierre Amarenco, MD; Gregory W. Albers, MD; Hans Denison, MD, PhD; J. Donald Easton, MD; Scott R. Evans, PhD; Peter Held, MD, PhD; Anders Himmelmann, MD, PhD; Scott E. Kasner, MD; Mikael Knutsson, PhD; Per Ladenvall, MD, PhD; Kazuo Minematsu, MD, PhD; Carlos A. Molina, MD; Yongjun Wang, MD; S. Claiborne Johnston, MD, PhD


Stroke. 2018;49(7):1678-1685. 

In This Article


Baseline characteristics were balanced among ticagrelor and aspirin groups.[3] Criteria for prior-aspirin usage was met in 4232 patients (ticagrelor, 2130; aspirin, 2102), whereas 8967 patients (ticagrelor, 4459; aspirin, 4508) did not use aspirin in the 7 days before randomization (Table 1). There were multiple differences in baseline factors among prior- and no prior-aspirin subgroups, mainly driven by the chronic treatment prior-aspirin group (Table 1). There were some patients who had received clopidogrel before randomization (Table 1); a sensitivity analysis excluding these patients did not impact on the overall results of this study. The distribution of patients with ipsilateral atherosclerotic stenosis (A1–A2) was similar in the prior-aspirin and no prior-aspirin subgroups. However, patients with chronic treatment in the prior-aspirin subgroup had higher atherosclerotic burden overall (A1–A3) and higher presence of ipsilateral stenosis versus patients with acute treatment (Table 2).

In the prior-aspirin group, a primary end point occurred in 138/2130 (Kaplan-Meier%, 6.5%) patients randomized to ticagrelor and in 177/2102 (Kaplan-Meier%, 8.3%) patients randomized to aspirin (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.61–0.95; P=0.02). For the no prior-aspirin group, 304/4459 (Kaplan-Meier%, 6.9%) of patients randomized to ticagrelor and 320/4508 (Kaplan-Meier%, 7.1%) of patients randomized to aspirin experienced a primary end point (HR, 0.96; 95% CI, 0.82–1.12; P=0.59; Table 3; Figure A). The treatment-by-prior-aspirin interaction did not reach statistical significance (P=0.10). The stroke component was the major contributor to primary end point events. There was a consistent pattern for the effect in patients in the prior-aspirin group randomized to ticagrelor on deaths and myocardial infarctions (Table 3).


Figure. Kaplan-Meier curves for the primary end point (time to stroke, myocardial infarction, or death) in patients randomized to the aspirin or ticagrelor groups with or without taking aspirin before randomization: (A) full 90-d treatment period; (B) censored at 7 d. bd indicates twice daily; CI, confidence interval; HR, hazard ratio; and od, once daily.

The effect on the secondary efficacy end point, ischemic stroke, in patients with prior-aspirin usage randomized to ticagrelor (HR, 0.78; 95% CI, 0.62–0.99; P=0.04) was consistent with that on the primary end point (Table 3).

The primary end point censored at day 7 in the prior-aspirin subgroup showed that 80/2130 (3.8%) of patients treated with ticagrelor and 107/2102 (5.1%) treated with aspirin experienced a primary end point (HR, 0.73; 95% CI, 0.55–0.98; P=0.04). In the no prior-aspirin group, a primary end point occurred within 7 days in 175/4459 (3.9%) in the ticagrelor group and 209/4508 (4.6%) in the aspirin group (HR, 0.84; 95% CI, 0.69–1.03; P=0.10; Figure [B]).

Table 3 shows the impact of timing and dose of prior aspirin on outcome. The HR for the primary end point for patients with prior-aspirin usage randomized to ticagrelor versus aspirin was similar in patients receiving an acute treatment (HR, 0.72; 95% CI, 0.54–0.97; P=0.03) and patients on chronic treatment (HR, 0.82; 95% CI, 0.58–1.17; P=0.27); P value for interaction was 0.58.

In the prior-aspirin group, major bleeding occurred in 0.7% of patients randomized to ticagrelor and in 0.4% randomized to aspirin (HR, 1.58; 95% CI, 0.68–3.65; P=0.28), with no increase of life-threatening bleedings, including intracranial bleedings (Table 4). The combination of major or minor bleedings in the prior-aspirin group was more common among patients randomized to ticagrelor versus aspirin (HR, 1.76; 95% CI, 1.09–2.85; P=0.02).