In our study, there was no difference in the incidence of thrombotic events between the two groups, although responders had hemorrhagic events at a significantly higher rate. In interventions for coronary arteries, the AHA/ American Stroke Association (ASA) guideline recommends patients to continue DAPT including P2Y12 inhibitors after stenting [10], and in the neuroendovascular treatment area, antiplatelet drugs are also employed for preventing thrombotic complications. However, the optimal duration of DAPT after stent assist coiling is uncertain. There are some reports on the timing and risk of thrombotic events, for instance, Matsumoto et al. reported that thrombotic events after the procedure are most likely to occur within 40 days after stent assisted coiling even if patients receive DAPT [11]. Furthermore, Song et al. reported that blood vessel tortuosity and large parent vessel size lead to incomplete stent apposition, becoming a risk factor of thrombotic complications [12].
Clopidogrel is an antiplatelet drug of widespread application. In Japan, it is administered in approximately 80% of cases in the perioperative period of neurovascular treatments [13]. Clopidogrel is a prodrug which needs to be converted into an active metabolite by CYP. Although CYP2C19 is the major enzyme involved this process, its genetic variants can affect individual clopidogrel responses. Therefore, measuring platelet reactivity before the procedure is relevant. There are some methods to measure platelet functions, VerifyNow being one of the major point of care platelet reactivity analysis tools and employed on large clinical trials [14,15]. Some studies have shown an association of hyper-responders to clopidogrel hemorrhagic events while hypo-responders are associated with thrombotic events, although a clear cutoff value has not been defined for neuroendovascular treatments and this value differed among studies [16–21]. Based on the ACCF/AHA 2011 guideline [8], we defined 208 as cutoff value and investigated hemorrhagic and thrombotic events both in the acute and delayed phase. In this study, occurrence of thrombotic events was not significantly different between the groups, although hemorrhagic events frequently occurred in responders. In addition, Hb levels decreased more from before until after the procedure and during chronic stages in responders than in hypo-responders. Despite not meeting the criteria of International Society of Thrombosis and Hemostasis for major bleeding [9], some patients complained of subcutaneous bleeding, epistaxis, or hematuria, which could be associated with low Hb levels in the chronic stage.
Although some studies of stent assisted coiling reported an association of hemorrhagic and thrombotic events with PRU values in the acute phase [17–21], there are few studies of association between platelet reactivity and these events in the delayed phase after stent assisted coiling. Goh et al. reported that evaluating hemorrhagic events up to 6 weeks after endovascular stenting treatment indicated that patients with > 72% PRU inhibition had more major bleeding than those with PRU < 72% [22]. Song et al. also referred to an association between clopidogrel response and thrombotic events in the delayed phase [21]. These authors reported that thrombotic events, symptomatic and asymptomatic ischemic stroke with positive findings on brain MRI in the territory of the treated aneurysm, or a transient ischemic attack more than 30 days after stent assisted coiling were not significantly correlated with PRU values. In agreement with this finding, our study showed a relationship between PRU values and hemorrhagic events, but not thrombotic events, in the delayed phase. Consequently, PRU appears to be more associated with hemorrhagic events in the delayed phase.
A previous study on DAPT duration in other treatment areas, reported that long-term DAPT use after ischemic stroke or after previous transient ischemic attacks increased the risk of major to life-threatening bleeding [23]. In addition, a recent study showed that, among patients undergoing coronary stents, one month of DAPT followed by clopidogrel single antiplatelet therapy resulted in a significantly lower rate of a composite of cardiovascular and bleeding events compared to 12 months of DAPT with clopidogrel and aspirin. Thus, a shorter DAPT duration after stenting may be more beneficial compared than long-term DAPT [24]. Even in cases of hemorrhagic events where DAPT was changed to single antiplatelet therapy one to three months before usual, there were no thrombotic events. Patients treated for aneurysm with neuro interventions are usually younger and thus, have fewer arteriosclerosis risk factors compared to patients treated with cerebrovascular or coronary revascularization [21], maybe reducing the risk of thrombotic events [22].
In our study, we found that clopidogrel responders had an increased risk of hemorrhagic events in the delayed phase, and PRU is useful for prediction of hemorrhagic events. Although DAPT is necessary for thrombotic event prevention, hemorrhagic risk and DAPT duration should be carefully considered in clopidogrel responders. Further studies are needed to determine the ideal duration of DAPT administration.