Risk Factors of Subacute Thrombosis After Intracranial Stenting for Symptomatic Intracranial Arterial Stenosis
Background and Purpose—We aimed to explore the risk factors of subacute thrombosis (SAT) after intracranial stenting for patients with symptomatic intracranial arterial stenosis.
Methods—From January to December 2013, all symptomatic intracranial arterial stenosis patients who underwent intracranial stenting in Beijing Tiantan Hospital were prospectively registered into this study. Baseline clinical features and operative data were compared in patients who developed SAT with those who did not. Binary logistic regression model was used to determine the risk factors associated with SAT.
Results—Of the 221 patients enrolled, 9 (4.1%) cases had SAT 2 to 8 days after stenting. Binary logistic analysis showed that SAT was related with tandem stenting (odds ratio [OR], 11.278; 95% confidence interval [CI], 2.422–52.519) and antiplatelet resistance (aspirin resistance: OR, 6.267; 95% CI, 1.574–24.952; clopidogrel resistance: OR, 15.526; 95% CI, 3.105–77.626; aspirin and clopidogrel resistance: OR, 12.246; 95% CI, 2.932–51.147; and aspirin or clopidogrel resistance: OR, 11.340; 95% CI, 2.282–56.344).
Conclusions—Tandem stenting and antiplatelet resistance might contribute to the development of SAT after intracranial stenting in patients with symptomatic intracranial arterial stenosis.
Stent thrombosis is one of the devastating complications that may occur after stent placement. According to the definition specified by the Academic Research Consortium, stent thrombosis is classified as acute, subacute, late, and very late based on the timing of events. Subacute thrombosis (SAT) refers to thrombosis occurring 1 to 30 days after stent implantation.1 But to date, there have been few reports on the risk factors of SAT after intracranial stenting.
In this study, we prospectively enrolled the patients with symptomatic intracranial arterial stenosis (sICAS) undergoing stent placement in Beijing Tiantan Hospital and aimed to find the risk factors for SAT.
This was a prospective single-center cohort study approved by the Institutional Review Board of Beijing Tiantan Hospital. All sICAS patients treated with stent implantation in Beijing Tiantan Hospital from January to December 2013 were eligible to be entered into this study. Signed informed consent was obtained from each participating patient. The inclusion criteria for elective intracranial stenting were as follows: (1) severe intracranial atherosclerotic stenosis ≥70% as defined by the WASID trial (Warfarin Versus Aspirin for Symptomatic Intracranial Disease) criteria,2 (2) ischemic stroke or transient ischemic attack within 3 months attributable to the culprit artery, despite being on dual antiplatelets and vascular risk factor control, and (3) cerebral hypoperfusion on computed tomographic perfusion imaging in the territory supplied by the culprit artery. Patients’ demographic and clinical characteristics, stenting procedures, perioperative management, and 90-day outcomes were recorded.
Stenting Procedure and Perioperative Management
All patients were on dual antiplatelet agents (100 mg aspirin and 75 mg clopidogrel) daily for at least 3 to 5 days before stenting, except for patients with stenting done as an emergency procedure, where a loading dose of aspirin (300 mg) and clopidogrel (300 mg) was given. Thromboelastography was performed using the instrument TEG 5000 (Haemoscope Corporation) to estimate the efficiency of platelet aggregation. The inhibition rate of arachidonic acid–induced and adenosine diphosphate–induced platelet aggregation was measured. Aspirin resistance was defined as <50% inhibition of arachidonic acid–induced platelet aggregation, and clopidogrel resistance was considered as <30% inhibition of adenosine diphosphate–induced platelet aggregation.3,4 Stenting was performed under general anesthesia. Depending on lesion and vascular characteristics, either direct placement of a balloon-mounted stent or balloon predilation followed by the deployment of a self-expanding stent would be used to treat the stenosis. If a stent failed to provide full coverage of a long lesion, another stent would be deployed with stent struts overlapping by ≈5 mm (tandem stenting). After the procedure, low-molecular-weight heparin was given every 12 hours for 3 days if no bleeding was noted on the computed tomographic imaging. All patients were treated with dual antiplatelet agents for 3 months followed by lifelong single antiplatelet agent (100 mg aspirin or 75 mg clopidogrel daily).
Diagnosis and Treatment of SAT
SAT was defined as the development of stent thrombosis within 1 to 30 days after the procedure. The angiographic confirmation of SAT was the presence of a thrombus that originated in the stent or within 5 mm of the stent edge, and stent occlusion must be associated with new ischemic stroke. Patients with SAT were treated with intra-arterial thrombolysis, balloon dilation, and restenting.
The baseline data were compared between patients with and without SAT. The t test or the Mann–Whitney U test was used to compare means or medians for continuous variables. The Pearson χ2 test or Fisher exact test was used to compare the proportions for categorical variables. For exploring the risk factors of SAT, the baseline variables with a statistical difference of P<0.05 (2-tailed) between the 2 groups were entered in a binary logistic regression model to calculate the odds ratio (OR) with its 95% confidence interval (CI). All analyses were performed with SPSS Statistics version 21.0 (IBM SPSS, Armonk, NY).
From January to December 2013, a total of 221 consecutive patients with sICAS underwent intracranial stenting. Among them, 9 patients (4.1%) had SAT (Table I in the online-only Data Supplement).
Baseline Characteristics of Patients With and Without SAT
Patients with SAT had longer stent length (median: 15 versus 13 mm, P=0.033), higher proportion of tandem stenting (33.3% versus 4.2%, P=0.009), aspirin resistance (44.4% versus 11.3%, P=0.017), clopidogrel resistance (77.8% versus 18.4%, P<0.001), aspirin and clopidogrel resistance (44.4% versus 6.1%, P=0.002), and aspirin or clopidogrel resistance (77.8% versus 23.6%, P=0.001) than those without SAT. Other baseline variables did not have statistically significant differences between the 2 groups (P>0.05; Table).
Risk Factors Associated With SAT
Binary logistic analysis revealed that the occurrence of SAT was associated with tandem stenting (OR, 11.278; 95% CI, 2.422–52.519) and antiplatelet resistance (aspirin resistance: OR, 6.267; 95% CI, 1.574–24.952; clopidogrel resistance: OR, 15.526; 95% CI, 3.105–77.626; aspirin and clopidogrel resistance: OR, 12.246; 95% CI, 2.932–51.147; and aspirin or clopidogrel resistance: OR, 11.340; 95% CI, 2.282–56.344). Stent length (per increase by 10 mm) tended to double the risk of SAT, but the differences did not reach statistical significance (OR, 2.21; 95% CI, 0.850–5.772) (Figure).
In this cohort study, the incidence of SAT was 4.1%, which was lower than Riedel report (10.4%)5 but higher than that of SAMMPRIS trial (Stenting vs Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis) (0.9%) and coronary stenting (0.7%–0.9%).6–8 The risk factors for SAT remained uncertain, though studies on coronary stent thrombosis indicated antiplatelet resistance as a contributing factor.9,10 In this study, we also found very high proportions of antiplatelet resistance in patients who developed SAT. Of the 9 patients with SAT, there were 7 cases (77.8%) with clopidogrel resistance and 4 cases (44.4%) with aspirin resistance. On the other hand, among the 212 patients without SAT, there were only 39 cases (18.4%) with clopidogrel resistance and 24 cases (11.3%) with aspirin resistance. Thus, antiplatelet resistance likely increased the risk of SAT after intracranial stenting. In addition, we observed that tandem stenting significantly increased the odds of SAT, and stent length might be related to the occurrence of SAT. Similarly, stent length has been shown to be associated with the development of stent thrombosis in patients undergoing coronary stenting.11
The main weakness of the study was that it was an analysis of a single-center cohort with a homogeneous ethnic group (Chinese). This introduced selection bias and limited the generalizability of the results. But as far as we know, this is the first report to explore the risk factors of SAT after intracranial stenting in patients with sICAS. Our study suggested that tandem stenting and antiplatelet resistance might contribute to the development of SAT. According to our findings, antiplatelet resistance testing should be considered before intracranial stenting. In our center, we would increase the dose of aspirin or clopidogrel if inadequate inhibition was found. Cilostazol may be another option. There is at present no consensus on the best treatment regimen to overcome this problem. Whether adjusting the dose of antiplatelets, using other antiplatelets, for example, the newer P2Y12 inhibitors or cilostazol can improve outcome for low responders still needs further investigation. Tandem stenting or placement of a long stent should be avoided if there is an alternative option. To reduce the incidence of SAT, heparin-coated stent was also tested in a few patients with sICAS and showed favorable short-term outcomes.12
We thank all relevant clinicians, statistician, and imaging technicians.
Sources of Funding
This study was funded by Beijing High-Level Personnel Funds (2013-2-19 to Dr Miao) and National Natural Science Foundation of China (81371290 to Dr Miao).
Guest Editor for this article was Ajay K. Wakhloo, MD, PhD.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.116.015538/-/DC1.
- Received August 10, 2016.
- Revision received October 31, 2016.
- Accepted November 21, 2016.
- © 2017 American Heart Association, Inc.
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