In this prespecified exploratory analysis of SOCRATES, there was a trend toward a better treatment effect of ticagrelor over aspirin in patients who received aspirin in the 7 days before randomization, although the interaction for treatment by prior aspirin was not statistically significant when using the conservative threshold of P<0.05. Power to detect an interaction effect is generally less than that for the main effect. Failure to identify significant interaction does not imply homogeneity of effects and could be because of low power. In fact, the differences in the magnitude of subgroup-specific treatment effects (HR=0.76 in the prior-aspirin group versus HR=0.96 in no prior-aspirin group) suggests a degree of treatment effect heterogeneity. However, results from subgroup analyses must be interpreted with caution because these can increase both false-positive and false-negative errors. Therefore, the observation in this study should primarily be hypothesis-generating with necessary confirmation coming from a future study.
Interestingly, a recent publication based on reanalyses of clinical trial data with aspirin versus control in acute minor stroke and TIA demonstrated that aspirin substantially reduces the risk of early recurrent stroke and reduces disability after recurrent stroke. Thus, aspirin's preventive effect in the early period after acute cerebral ischemic events may be substantial, and a residual aspirin effect during the first week of treatment in SOCRATES may have provided additional benefit to ticagrelor, by conferring partial dual antiplatelet therapy.
An enhanced antiplatelet effect of clopidogrel with aspirin was seen in several studies. Studies investigating microembolization from atherosclerotic cerebral arteries in connection with acute cerebral ischemic events showed a reduction in events with dual antiplatelet therapy.[14,15] Furthermore, the CHANCE trial of Chinese patients with minor ischemic stroke or TIA found a 32% relative risk reduction of a stroke at 90 days with a regimen including clopidogrel with aspirin versus one that included only aspirin. The ongoing POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) is investigating whether the promising results of clopidogrel and aspirin versus aspirin in acute cerebral ischemic events demonstrated in CHANCE could be confirmed in a Western population.
The higher vascular disease burden in the prior-aspirin group may reflect that aspirin was used more frequently for prevention of atherothrombotic diseases in this subgroup. Potentially, patients with a higher vascular event risk in the prior-aspirin group, and with the index event occurring during aspirin treatment (breakthrough stroke), may have benefited more from intense antiplatelet therapy provided by ticagrelor. However, a large proportion of patients in the prior-aspirin group only received acute treatment before randomization, thus most likely after the start of the index event, and these patients benefited from ticagrelor at least as much as those with aspirin chronic treatment before randomization. Diminishing clinical effect of aspirin with long-term use has been hypothesized and could explain higher event rates in those previously taking aspirin who were randomized to aspirin and a trend toward better treatment effect of ticagrelor;[13,17] however, this would not explain the similar effect seen in those who received only acute aspirin treatment before randomization. The observation that patients who received only acute treatment with aspirin after the index event had a favorable outcome may indicate the benefit of dual antiplatelet with ticagrelor and aspirin in the acute setting of cerebral ischemic events. Finally, atherosclerotic phenotyping could not confirm an increased prevalence of ipsilateral atherosclerotic stenosis in the prior-aspirin group; a higher prevalence of ipsilateral atherosclerotic stenosis could have rendered this subgroup more responsive to ticagrelor, as shown in a recent SOCRATES publication. Although atherosclerotic phenotype was more common in the chronic treatment than in the acute treatment prior-aspirin group, this difference did not translate into a differentiated treatment effect.
Taking all these findings together, it is reasonable to assume that the initial dual antiplatelet effect from aspirin intake 7 days before randomization during the period with the highest risk for new stroke events was the major contributor to the potential treatment effect of ticagrelor in the prior-aspirin group, observed in the 7-day analysis, as well as at 90 days.
In a secondary publication from the PEGASUS-TIMI 54 trial (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54), addition of ticagrelor to aspirin for long-term secondary prevention in patients with coronary disease provided a significant relative risk reduction of stroke by 25%, but with more major bleeding (HR, 2.32; 95% CI, 1.68–3.21; P<0.001). In CHANCE, major bleeding event rates were similar for aspirin alone and the combination of clopidogrel and aspirin. In SOCRATES, the number of major bleeding events were few and similar for ticagrelor and aspirin. Overall, major or minor bleeding tended to be more common on ticagrelor than aspirin in the prior-aspirin group, which may reflect a more pronounced antiplatelet effect, whereas severe, life-threatening bleeding rates were not.
Although this global data set is of reasonable size to justify subgroup analyses, the results from these analyses should be interpreted with caution for several reasons. The primary outcome in SOCRATES was not statistically significant. The prior-aspirin usage was not randomly assigned and there were differences in baseline factors among the subgroups; however, the key comparator of interest was randomized: treatment with ticagrelor or aspirin. In addition, the effect of aspirin intake before randomization would gradually disappear during the first treatment week, providing only a partial dual antiplatelet therapy in the ticagrelor prior-aspirin subgroup. Therefore, the findings about bleeding risk and efficacy of combining ticagrelor and aspirin versus aspirin alone in patients with acute stroke or TIA need to be confirmed in a randomized trial.
In conclusion, the results of the present analyses and the literature on dual antiplatelet therapy in patients with acute cerebral ischemic events support the hypothesis that the combination of ticagrelor and aspirin may be a more effective treatment than aspirin alone in preventing subsequent ischemic events in patients with acute minor ischemic stroke or TIA. This hypothesis will be addressed in the THALES trial (Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death; URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429).
Editorial support (formatting tables and figures, coordinating reviews, and preparing the article for submission) was provided by Jackie Phillipson (Zoetic Science, an Ashfield company, part of UDG Healthcare plc, Macclesfield, United Kingdom); this assistance was funded by AstraZeneca.
Sources of Funding
The trial was funded by AstraZeneca.
Clinical Trial Registration—: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01994720.
Stroke. 2018;49(7):1678-1685. © 2018 American Heart Association, Inc.