Discussion
TIA, bleeding, stroke, ischemic stroke, haemorrhage, pre-morbid dependency, acute non-cardioembolic ischaemic stroke
ACUTE CEREBRAL ISCHAEMIA, BLEEDING, STROKE, MINOR, BLEEDS, BLEED, ISCHEMIC STROKE, HAEMORRHAGE, SECONDARY, EVENTS, TIA
In this large trial assessing triple versus guideline antiplatelet therapy in acute non-cardioembolic ischaemic stroke or TIA, fatal or major bleeding occurred more frequently in those randomised to triple vs guideline antiplatelet therapy. The divergence in major bleeding between the treatment groups occurred in the 8–35 day period but not in the earlier 0–7 and later 36–90 day periods. In multivariate analysis more, and more severe, bleeding events were seen with increasing age, female sex, increasing pre-morbid dependency, longer time from onset to randomisation, prior major bleed, prior antiplatelet therapy and in those randomised to triple vs guideline antiplatelet therapy. More severe bleeding was associated with worse clinical outcomes across multiple physical, emotional and quality of life domains. Those patients who underwent thrombolysis prior to enrolment had more, and more severe, bleeding in the presence of triple than guideline antiplatelet therapy. Of the bleeding scores assessed, the SThe Platelet-Oriented Inhibition in New TIA and minor ischemic stroke (POINT)Multivariate associations between baseline variables and ordinal bleeding revealed that increasing age, female sex, increasing pre-morbid dependency, a previous major bleed, previous antiplatelet therapy, and a longer time from onset to randomisation were associated with more severe bleeding events. In contrast, a secondary analysis of POINT reported that the only baseline variable significantly associated with the risk of major haemorrhage was increasing ageIn the present study, the only bleeding score to moderately predict bleeding for which it was designed was the STARDIS used an ordinal bleeding scaleThis secondary analysis of TARDIS has several strengths including wide inclusion criteria and therefore generalisability, use of locally-sourced antiplatelet agents from a variety of manufacturers increasing validity, and an ordinal bleeding safety outcome incorporating minor bleeding. However, there are several limitations. First, the wide inclusion criteria included no upper stroke severity limit and allowed inclusion of patients up to 48 h after symptom onset. Although this allowed generalisability, increasing time to randomisation was associated with increased bleeding. Second, patients could be recruited 24–48 h after thrombolysis; hence, TARDIS shows, for the first time in a large trial, that acute intensive antiplatelet therapy should not be administered to patients 24–48 h after thrombolysis. Third, trial treatments were open label and therefore participants knew what they were taking and may have been more likely to report bleeding events, especially minor bleeds. Last, 30 days of triple treatment may have been too long given the associated bleeding risk and that bleeding events diverged between treatment groups in the 8–35 day period, but not before or after. Hence, the effect on bleeding occurred whilst on treatment and not after. The lack of divergence in the 0–7 day period implies that the duration of intensive antiplatelet therapy likely contributes to the risk of bleeding as demonstrated in the aforementioned meta-analysisFurther research, including meta-analysis of trials, should seek to establish the optimum timing of initiation, duration and types of antiplatelet therapy in acute minor ischaemic stroke and TIA. Triple antiplatelet therapy should be avoided in acute ischaemic stroke and TIA and particularly 24–48 h following thrombolysis pending further data. Stratifying patients using bleeding scores may help to minimise bleeding risk and rationalise antiplatelet treatment in future studies.In summary, triple antiplatelet therapy in acute non-cardioembolic ischaemic stroke and TIA patients was associated with more fatal or major bleeds and more, and more severe, bleeding. For major bleeding events, the treatment groups separated after one week supporting the rationale for a short period of intensive treatment in dual antiplatelet trials of minor ischaemic stroke and TIA patients to maximise benefit whilst minimising bleeding risk. Increasing age, female sex, increasing pre-morbid dependency, longer time from onset to randomisation, previous major bleed and prior antiplatelet therapy were all associated with more, and more severe, bleeding. Clinicians should take these factors into consideration when counselling patients with acute cerebral ischaemia on the bleeding risk with intensive antiplatelet therapy.