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Effect of Adjusted Antiplatelet Therapy on Preventing Ischemic Events After Stenting for Intracranial Aneurysms

Originally publishedhttps://doi.org/10.1161/STROKEAHA.120.032989Stroke. 2021;52:3815–3825

Abstract

Background and Purpose:

This study tests whether patients with unruptured intracranial aneurysm who underwent stent placement benefitted from platelet function monitoring–guided adjustment of antiplatelet therapy.

Methods:

We conducted a randomized, open-label, parallel group, assessor-blinded trial. Patients with unruptured intracranial aneurysm who underwent stent placement were assigned in a 1:1 ratio to receive either drug adjustment (patients who had high on-treatment platelet reactivity to antiplatelet therapy on the basis of platelet function monitoring [monitoring group]) or conventional therapy (without monitoring and drug adjustment [conventional group]). The second monitoring was performed 14 days after randomization in patients with drug adjustment. The primary outcome was the composite frequency of ischemic stroke, transient ischemic attack, stent thrombosis, urgent revascularization, and cerebrovascular death within 7 days after stent implantation. The safety outcome was the composite frequency of major, minor, or minimal bleeding within 1 month after stent implantation.

Results:

In total, 314 patients were included (n=157 per group). The primary combined outcome occurred in 19 patients (12.1%) in the conventional group and 8 patients (5.1%) in the monitoring group (hazard ratio, 0.39 [95% CI, 0.17–0.92]; P=0.03). Ischemic stroke occurred at a lower frequency in the monitoring group compared with that in the conventional group (4.5% versus 12.1%; hazard ratio, 0.34 [95% CI, 0.14–0.83]; P=0.01), which drove the overall primary combined outcome. The safety outcome occurred in the monitoring group (7.0%) and in the conventional group (1.9%; hazard ratio, 3.87 [95% CI, 1.06–14.14]; P=0.03). A significant difference was observed in the frequency of minor or minimal bleeding events between the two groups (monitoring group versus conventional group, 6.4% versus 1.3%; P=0.02) but not in the frequency of major bleeding events between the two groups.

Conclusions:

Platelet function monitoring–guided antiplatelet therapy reduces thromboembolic events in patients with unruptured intracranial aneurysm after stent placement, significantly enhancing minor or minimal bleeding events but not major bleeding events.

Registration:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT03989557.

Introduction

See related article, p 3826

Endovascular embolization with additional stents, such as nonflow diverter stents (laser cut stents, braided stents, etc) or flow diverter, is considered an effective treatment modality for wide-necked or complex unruptured intracranial aneurysms (UIAs).1,2 Stents facilitate aneurysm coiling. Several studies reported that flow diverter and stent-assisted coiling might result in less aneurysm recanalization over time compared with coil embolization alone for wide-necked UIAs.3,4 However, thromboembolic events are the most common cause of morbidity after neurointerventional procedures. Standard dual antiplatelet therapy (DAPT), consisting of 100 mg aspirin and 75 mg clopidogrel, is important in the treatment of patients undergoing cerebral aneurysm stent placement for reduction of thromboembolic events. However, a substantial proportion of patients with high on treatment platelet reactivity (HPR) have inadequate platelet inhibition, exhibiting an increased risk of thromboembolic events.5

Platelet function monitoring has the potential for measurement of platelet reactivity in individual patients, thereby enabling adjustment of antiplatelet therapy and possible improvement in clinical outcomes.5,6 Several retrospective studies have shown that platelet function monitoring–guided adjustment of antiplatelet therapy for patients with HPR could reduce the risk of thromboembolic complications.6,7 To the best of our knowledge, there have been few prospective randomized controlled trials on platelet function monitoring of cerebrovascular disease. One randomized controlled trial demonstrated that platelet function monitoring–guided alteration of antiplatelet therapy could reduce the frequency of thromboembolic events without increased bleeding, compared with standard antiplatelet therapy, in patients with HPR who underwent coiling for an unruptured aneurysm.8 However, one-third of patients without stent placement did not receive DAPT after neurointerventional procedures in that study. Considering the limitations of the previous study, we performed the application of platelet function monitoring to prevent ischemic events after intracranial aneurysm stent placement study to investigate the value of platelet function monitoring in patients with UIA who underwent stent placement. This study used ticagrelor (a more potent platelet inhibitor than clopidogrel), which might be more effective for prevention of thrombotic events; additionally, our study only enrolled patients with UIA who underwent stent placement.

We investigated whether platelet function monitoring to adjust antiplatelet therapy would improve clinical outcomes in patients with UIA with stent placement, compared with patients who received standard DAPT without platelet function monitoring. The primary and safety outcomes were the difference in the composite frequency of ischemic events within 7 days and bleeding events within 30 days after stent implantation, respectively.

Methods

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Study Design and Patients

The study was designed according to CONSORT 2010 (Consort Checklist in the Data Supplement). The study was a prospective randomized, parallel-design, open-label study (https://www.clinicaltrials.gov; unique identifier: NCT03989557). The protocol and statistical analysis plan were approved by the ethics committee of our hospital and are shown in the Data Supplement. The study was conducted from July 1, 2019, to August 13, 2020, at our hospital in Beijing, China. Patients were eligible if they had UIAs planned for stenting. Table I in the Data Supplement lists all inclusion and exclusion criteria. All patients provided written informed consent to participate.

Randomization and Study Groups

Patients were allocated through a block randomization process by investigators at participating clinical centers. The randomization sequence was provided by an independent statistician using computer-generated random numbers (Data Supplement) Patients with UIA planned for stenting in this trial were randomized in a 1:1 manner to either of the two study groups: (1) DAPT adjustment guided by platelet function monitoring (monitoring group) or (2) standard DAPT treatment without platelet function monitoring (conventional group). Randomization codes made by an independent statistician were used to label the internal and external packages of the monitoring and conventional groups. After determination of treatment based on computed tomography angiography or digital subtraction angiography results, randomization always occurred before initiation of the stenting procedure.

Study Procedures

Six types of stents and flow diverters were used, including Solitaire (Medtronic), Neuroform (Stryker), Enterprise (Cordis), Low-Profile Visualized Intraluminal Support stent (MicroVention), Pipeline embolization device (Coviden/ev3) and Tubridge flow diverter (MicroPort). Stent-assisted coiling was used if the aneurysm neck was wide or the dome-neck ratio was unfavorable for standard coiling. The main indication for flow diverter was large, giant, fusiform, technically challenging aneurysm for conventional coiling. In patients with planned stenting of UIAs, standard DAPT therapy was performed for >5 days. At the time of recruitment, a participating investigator completed a questionnaire (including inclusion/exclusion criteria, physical examination findings, laboratory examination data, and medical history) and randomized each patient. Patients in the conventional group underwent stent placement without any platelet function monitoring; standard antiplatelet therapy was continued after the procedure.

Patients in the monitoring group underwent platelet function monitoring 1 day before intracranial stent placement. Platelet function was assessed by standard light transmittance aggregometry to measure platelet aggregation. Light transmittance aggregometry was conducted using platelet-rich plasma by the turbidimetric method in a 4-channel aggregometer (AG800; Techlink Biomedical, Inc, Beijing, China). For identification of clopidogrel nonresponders or the detection of HPR in patients receiving clopidogrel therapy, 5 μmol/L ADP was used; 1 mg/mL arachidonic acid was used to specifically and sensitively evaluate the effect of acetylsalicylic acid on platelets. Curves were recorded for 6 minutes; maximal platelet aggregation (MPA) was defined as the percent change in light transmittance. Subsequently, HPR was defined as follows: >50% MPA response to ADP and >20% MPA response to arachidonic acid. The MPA of low on-treatment reactivity response to ADP was defined as ≤25%, whereas it was 0% response to arachidonic acid.9–11 When defining HPR to clopidogrel, several cutoff values are used in light transmittance aggregometry. In standard cardiovascular surgery, >46% MPA response to ADP is considered an optimal threshold for the prediction of thromboembolic events.9 Because there are limited data regarding neurointerventional surgery, a higher cutoff value is used (>50% MPA response to ADP), based on the findings in previous studies,6,12 to prevent ticagrelor-related adverse events.

For patients with HPR on clopidogrel, clopidogrel 75 mg was switched to 1 dose of ticagrelor 180 mg before the procedure, followed by 2 daily doses of 90 mg of ticagrelor after the procedure.13 For patients with HPR on aspirin, the aspirin dose was increased to 200 mg. The treatment adjustment was administered at least 1 day before stenting. For patients who had adequate response to antiplatelet therapy or low platelet reactivity on clopidogrel 75 mg and aspirin 100 mg, no further changes were performed.

Platelet function monitoring was repeated at 14 days after treatment adjustment for patients who required adjustment after the first monitoring. Patients with low platelet reactivity to 90 mg ticagrelor during treatment adjustment were switched to ticagrelor at a lower dose (2 daily doses of 45 mg); previously, 45 mg ticagrelor has been shown to achieve a greater platelet aggregation inhibitory effect, compared with 75 mg clopidogrel, and a slightly lower inhibitory effect, compared with 90 mg ticagrelor.13 Patients with low platelet reactivity to 200 mg aspirin were switched to a dose of 100 mg. For patients with an adequate response or HPR to antiplatelet therapy on ticagrelor (2 daily doses of 90 mg) or doubling of the aspirin dose, no further changes were performed. Figure I in the Data Supplement shows the algorithm for dose and drug adjustment in the monitoring group.

Outcomes

The primary outcome was the composite frequency of thromboembolic events (ie, ischemic stroke, transient ischemic attack, stent thrombosis, urgent revascularization, or cerebrovascular death) within 7 days after the procedure. Ischemic stroke was defined as the rapid onset of a new focal neurological deficit with clinical or imaging evidence of infarction, which was not attributable to a nonischemic etiology; alternatively, it comprised rapid worsening of an existing focal neurological deficit, which was attributable to a new infarction.14 Transient ischemic attack was defined as brief episodes of neurological dysfunction resulting from focal cerebral ischemia, which were not associated with permanent cerebral infarction. Stent thrombosis was that thrombosis was confirmed at the stent site after implantation of stent by cerebral angiography. Cerebrovascular (any vessel) revascularization after stent placement was performed if disorder of blood flow in the target vessel was observed. Cerebrovascular death was defined as death due to a documented cerebrovascular cause. The secondary outcome was the frequency of thromboembolic events within 1 month after the procedure.

The safety outcome was the composite frequency of major, minor, or minimal bleeding within 1 month after the procedure, defined in accordance with the Thrombolysis in Myocardial Infarction classification15 of hemorrhagic events. Major bleeding was defined as fatal or intracranial hemorrhage or other hemorrhage that caused hemodynamic compromise requiring treatment. Minor bleeding was defined as bleeding that required medical attention; minimal bleeding was any overt bleeding event that did not meet the major or minor criteria. More detailed definitions of primary and safety outcomes are shown in the Protocol (Data Supplement). Finally, computed tomography and magnetic resonance imaging were performed if the patients had neurological worsening, and neurological worsening was defined as the new onset of neurological symptom or the aggravation of the preexisting neurological symptom.

Each reported composite clinical thromboembolic event and safety outcome was independently adjudicated by 2 members of the clinical event adjudication committee, who were blinded to the treatment group assignments. Disagreements were determined by the third member of the clinical event adjudication committee.

Statistical Methods

The thromboembolic event frequencies were presumed to be 15.5% after neurointervention among patients with HPR to standard DAPT, 1% among patients without HPR, and 1.6% among patients with HPR after antiplatelet therapy modification. The frequency of patients with HPR was 47.5% to 72.3% in Asian patients undergoing neurointervention.5,8 Considering this reported incidence, the event frequencies in the conventional group were anticipated to be a maximum of 7.9%, for which the minimum 47.5% of patients with HPR had a thromboembolic event frequency of 15.5% after antiplatelet therapy modification; the remaining 52.5% of patients without HPR had a 1.0% thromboembolic event frequency. Similarly, the event frequency was anticipated to be a maximum of 1.3% in the monitoring group. To achieve 80% power for detection of this frequency difference in the primary outcome (ie, thromboembolic events after intracranial stent placement) at a 2-sided significance level of 0.05 (assuming no attrition), this study required randomization of 314 patients (157 per group). All analyses were performed on the basis of intention to treat; thus, they included all patients who underwent randomization. All main and subgroup analyses were prespecified in a statistical analysis plan.

The baseline characteristics of the two groups were tabulated, and comparability was assessed using descriptive statistics. Categorical variables were summarized as percentages; differences between groups were compared by the χ2 test. Continuous variables were summarized as mean (SD); differences between groups were analyzed by 2-sided unpaired Wilcoxon tests or Student t tests. Differences in outcomes were analyzed using Cox regression models for survival analysis. Hazard ratios (HRs) and 95% CIs were calculated. Relevant clinical variables were subjected to covariate subgroup analyses for the primary and secondary end point; covariate subgroups included age (>65 or ≤65 years), sex, body mass index (>30 or ≤30 kg/m2), smoking, procedure time (≤2 or >2 hours), stent type (flow diverter or nonflow diverter), stent number (1 or ≥2), prior ischemic stroke, or atherosclerotic lesions. Cumulative event-free frequencies were calculated by the Kaplan-Meier method. A 2-sided P<0.05 was considered statistically significant. Statistical tests were performed using the SAS software, version 9.4 (SAS Institute, Cary, NC), and GraphPad Prism, version 6.0 (GraphPad, Inc, La Jolla, CA).

Results

Patients and Aneurysm Characteristics

Between July 1, 2019, and August 13, 2020, 584 patients with UIAs who received stenting treatment underwent screening for this study; 314 patients (mean age, 56.1 [SD, 10.6] years) were enrolled. From this intention-to-treat population, 157 patients were randomly assigned to the conventional group, and 157 patients were assigned to the monitoring group. The CONSORT (Consolidated Standards of Reporting Trials) flowchart is shown in Figure 1. The conventional and monitoring groups were well balanced with regard to baseline characteristics, medications, and procedures (Table 1). The high-risk characteristics were also compared between the two groups, including smoking, hypertension, diabetes, hyperlipidemia, prior cerebrovascular events, and prior cardiovascular events. The mean aneurysm maximal diameter was 7.8 mm, and 141 patients (44.9%) underwent flow diversion (Table 1).

Table 1. Demographic, Clinical, and Procedural Characteristics of the Patients at Baseline

CharacteristicMonitoringConventionalP value
Age, y56.31±9.5155.88±11.620.72
Women105 (66.9)102 (65.0)0.72
Symptom101 (64.2)94 (59.9)0.42
Pre-mRS0.60±0.520.54±0.650.39
Body mass index, kg/m224.70±3.3624.41±3.470.46
Smoking30 (19.1)35 (22.3)0.49
Drinking20 (12.7)27 (17.2)0.27
Medical history
 Hypertension68 (43.3)78 (49.7)0.30
 Diabetes22 (14.0)16 (10.2)0.30
 Hyperlipidemia75 (47.8)71 (45.2)0.65
Prior cerebrovascular event
 Ischemic stroke32 (20.4)38 (24.2)0.42
 Hemorrhagic stroke2 (1.3)1 (0.6)0.56
Prior cardiovascular event
 Heart failure1 (0.6)2 (1.3)0.56
 Coronary artery disease6 (3.8)5 (3.2)0.76
 PCI1 (0.6)1 (0.6)1.00
Concomitant medication
 Insulin13 (8.3)10 (6.4)0.52
 Metformin17 (10.8)12 (7.6)0.33
 ACE inhibitor8 (5.1)11 (7.0)0.48
 Angiotensin II receptor blocker33 (21.0)30 (19.1)0.67
 β-Blocker7 (4.5)7 (4.5)1.00
 Calcium channel blocker51 (32.5)49 (31.2)0.81
 Proton-pump inhibitor19 (12.1)20 (12.7)0.86
 Statin80 (51.0)78 (49.7)0.82
 DAPT, d6.06±1.196.05±1.600.90
Laboratory data, mean (SD)
 White blood cell count, per μL6.26±1.756.22±1.790.84
 Red blood cell count, ×106/μL4.46±0.454.43±0.500.51
 Hemoglobin level, g/dL138.48±15.76136.46±14.190.23
 Hematocrit, %40.22±4.0139.85±3.990.42
 Platelet count, ×103/μL236.17±53.60227.94±55.770.18
 APTT, s30.24±3.6030.69±3.860.29
 INR, %1.00±0.071.00±0.060.90
 Total cholesterol level, mg/dL4.45±1.174.49±1.040.74
 Triglyceride level, mg/dL1.95±2.521.81±2.470.62
 HDL-C level, mg/dL1.29±0.481.26±0.310.45
 Blood group0.21
  A34 (21.7)40 (25.5)
  B49 (31.2)57 (36.3)
  O47 (29.9)45 (28.7)
  AB27 (17.2)15 (9.6)
Aneurysm data
 Maximum size, mm; mean (SD)8.00±5.907.63±6.030.58
 Neck size, mm; mean (SD)5.25±3.745.60±4.450.46
 Size ratio2.22±1.672.03±1.500.29
 Aspect ratio1.47±0.541.39±0.370.13
 Atherosclerotic lesions in cerebral circulation24 (15.3)19 (12.1)0.41
 Location0.70
  Anterior cerebral artery17 (10.8)19 (12.1)
  Internal carotid artery106 (67.5)97 (61.8)
  Middle cerebral artery13 (8.3)18 (11.5)
  Posterior circulation21 (13.4)23 (14.6)
Procedural data
 Procedure time, h; mean (SD)2.01±0.991.99±0.810.81
 Flow diverter76 (48.4)65 (41.4)0.21
 Stent amount1.03±0.161.06±0.260.19
 Stent length, mm20.29±5.4820.69±7.080.58
 Immediate occlusion grade0.31
  Complete125 (79.6)134 (85.4)
  Residual neck19 (12.1)16 (10.2)
  Residual sac13 (8.3)7 (4.5)

ACE indicates angiotensin-converting enzyme; APTT, activated partial thromboplastin time; DAPT, dual antiplatelet therapy; HDL-C, high-density lipoprotein cholesterol; INR, international normalized ratio; mRS, modified Rankin Scale; and PCI, percutaneous coronary intervention.

Figure 1.

Figure 1. CONSORT (Consolidated Standards of Reporting Trials) flowchart.

Platelet Reactivity and Treatment Adjustment

In the monitoring group, 55 patients (35.0%) had HPR to standard DAPT and underwent antiplatelet therapy adjustment after the first platelet function monitoring; of these 55 patients, two (1.3%) had HPR to aspirin and 53 (33.8%) had HPR to clopidogrel. The distributions of MPA responses to arachidonic acid and ADP at first monitoring are shown in Figure II in the Data Supplement. Following antiplatelet therapy adjustment, the second monitoring was performed at 14 days after the randomization in patients who initially had HPR to standard DAPT. Patients with HPR to aspirin reached the prespecified target of platelet inhibition. For patients with HPR to clopidogrel, the mean MPA response to ADP significantly decreased at the second platelet function monitoring, compared with the first monitoring (31.24% versus 58.73%; P<0.001; Figure III in the Data Supplement). Twenty-eight patients (17.8%) reached the prespecified target of platelet inhibition, while 7 patients (4.5%) exhibited HPR to ticagrelor. However, 18 patients (11.5%) switched from 90 to 45 mg ticagrelor because of low on-treatment platelet reactivity to 90 mg ticagrelor.

Following the 2-step strategy of treatment adjustment, 35 patients (22.3%) were using 90 mg ticagrelor, 18 patients (11.5%) were using 45 mg ticagrelor, and 2 patients (1.3%) were using 200 mg aspirin in the monitoring group (Table II in the Data Supplement).

Primary Outcome

Assessment of the primary outcome in all 314 patients revealed that thromboembolic events developed in 27 patients (8.6%; Table III in the Data Supplement). The frequency of thromboembolic events was significantly lower in the monitoring group than in the conventional group (5.1% versus 12.1%; HR, 0.39 [95% CI, 0.17–0.92]; P=0.03; Table 2; Figure 2A). Ischemic stroke occurred at a lower frequency in the monitoring group than in the conventional group (4.5% versus 12.1%; HR, 0.34 [95% CI, 0.14–0.83]; P=0.01). There was no significant difference in relation to the other kinds of ischemic events (stent thrombosis, urgent revascularization, transient ischemic attack, and death from cerebrovascular causes) between the two groups. Primary outcomes were also compared between patients in the monitoring group without HPR at first monitoring and patients in the conventional group. The frequency of thromboembolic events was significantly higher in the conventional group than in patients without HPR in the monitoring group (12.1% versus 3.9%; P=0.02; Figure IV in the Data Supplement). Comparison of secondary outcomes revealed a significantly lower frequency of thromboembolic events among patients in the monitoring group (8.9% versus 16.6%; HR, 0.49 [95% CI, 0.25–0.99]; P=0.04; Table 2; Figure 2B).

Table 2. Primary and Secondary Outcomes of the Monitoring and Conventional Groups

OutcomesMonitoring (n=157)Conventional (n=157)HR (95% CI)P value
Primary thromboembolic outcome*8 (5.1)19 (12.1)0.39 (0.17–0.92)0.03
 Ischemic stroke7 (4.5)19 (12.1)0.34 (0.14–0.83)0.01
 Stent thrombosis, urgent revascularization1 (0.6)2 (1.3)0.50 (0.04–5.54)0.56
 Transient ischemic attack1 (0.6)0 (0.0)
 Death from cerebrovascular causes0 (0.0)0 (0.0)
 Death from any cause0 (0.0)0 (0.0)
Secondary thromboembolic outcomes14 (8.9)26 (16.6)0.49 (0.25–0.99)0.04
 Ischemic stroke13 (8.2)22 (14.0)0.55 (0.27–1.14)0.11
 Stent thrombosis, urgent revascularization1 (0.6)2 (1.3)0.50 (0.04–5.54)0.56
 Transient ischemic attack1 (0.6)4 (2.6)0.25 (0.03–2.22)0.18
 Death from cerebrovascular causes1 (0.6)0 (0.0)0.32
 Death from any cause1 (0.6)0 (0.0)0.32
Primary bleeding outcome: any bleeding11 (7.0)3 (1.9)3.87 (1.06–14.14)0.03
 Major1 (0.6)1 (0.6)1.00 (0.06–16.13)1.00
 Minor2 (1.3)0 (0.0)0.16
 Minimal8 (5.1)2 (1.3)4.16 (0.87–19.91)0.05
 Minor or minimal10 (6.4)2 (1.3)5.27 (1.14–24.45)0.02

HR indicates hazard ratio.

* The primary thromboembolic outcome was the ischemic events within 7 d. Thromboembolic outcome was a composite of ischemic stroke, transient ischemic attack, stent thrombosis, urgent revascularization, and cerebrovascular death.

† The secondary ischemic outcomes were the thromboembolic events within 30 d.

Figure 2.

Figure 2. Cumulative incidence of the primary outcomes, secondary outcomes, and safety outcome.A–C, The Kaplan-Meier curves show the cumulative incidence of the thromboembolic events (including ischemic stroke, transient ischemic attack, stent thrombosis, urgent revascularization, myocardial infarction, and cerebrovascular death) at 7 d (A) and 1 mo (B). The Kaplan-Meier curves show the cumulative incidence of the safety outcome, which was the incidence of Thrombolysis in Myocardial Infarction (TIMI) bleeding (including major, minor, and minimal bleedings) at 1 mo. C, The inset shows the same data on an enlarged y axis. HR indicates hazard ratio.

An exploratory analysis of covariate subgroups (eg, age, sex, body mass index, smoking, procedure time, stent type, stent number, prior ischemic stroke, or atherosclerotic lesions) was performed concerning the primary outcome. Thromboembolic events within 7 days did not significantly differ between the monitoring and conventional groups, and no statistical interactions were observed (Figure 3). Among patients with flow diversion, the frequency of thromboembolic events within 7 days was markedly lower in the monitoring group than in the conventional group (7.9% versus 20.0%; HR, 0.34 [95% CI, 0.12–0.96]; P=0.04; Figure 3). However, among patients with nonflow diverter, the frequency of thromboembolic events within 7 days was similar in the monitoring group and conventional group (2.5% versus 6.5%; HR, 0.36 [95% CI, 0.07–1.85]; P=0.21; Figure 3). Although the interaction of treatment with region was not statistically significant, the results were similar to previously published findings, such that greater benefit of platelet function monitoring (2.7% versus 24.4%; P=0.004) was observed for patients with flow diversion.6 Exploratory analysis of covariate subgroups for the secondary outcome revealed the results trend, which was similar to those for the primary outcome (Figure V in the Data Supplement).

Figure 3.

Figure 3. Subgroup analysis of the primary outcomes. BMI indicates body mass index; and HR, hazard ratio.

Safety Outcome

For the safety outcome, 14 patients (8.9%) developed bleeding within 1 month after the procedure (Table IV in the Data Supplement). The safety outcome occurred more frequently in the monitoring group (11 of 157; 7.0%) than in the conventional group (3 of 157; 1.9%; HR, 3.87 [95% CI, 1.06–14.14]; P=0.03; Table 2; Figure 2C). The frequency of minor or minimal bleeding events was significantly higher in the monitoring group than in the conventional group (6.4% versus 1.3%; HR, 5.27 [95% CI, 1.14–24.45]; P=0.02). In the two patients with minor bleeding event in monitoring group, one had genitourinary bleeding 5 days after treatment, received blood transfusion, and prolonged hospitalization. The other had gastrointestinal bleeding 21 days after treatment and underwent endoscopic intervention to stop the bleeding. However, the frequency of major bleeding events did not significantly differ between the two groups (0.6% versus 0.6%; P=1.00). Comparison of the safety outcome among patients with ticagrelor in the monitoring group, patients with clopidogrel in the monitoring group, and patients in the conventional group revealed that the frequency was significantly higher in patients with ticagrelor than in patients with clopidogrel (P<0.01; Figure VI in the Data Supplement).

Discussion

Principal Findings

Among UIA patients with stent placement, those with HPR to aspirin and clopidogrel might experience a greater risk of thromboembolic events. Platelet function monitoring led to a change of treatment in 35.0% of patients who were considered undertreated based on measurements of aspirin and clopidogrel inhibition levels. Moreover, the frequency of HPR to DAPT exhibited a significant reduction after the first antiplatelet therapy adjustment. Platelet function monitoring might aid in reduction of thromboembolic events during adjustment of antiplatelet therapy. Moreover, the results showed a greater benefit of platelet function monitoring in patients with flow diversion, compared with patients who had nonflow diverter stents. However, the frequency of minor or minimal bleeding events was higher in the monitoring group than in the conventional group, presumably because of the switch from clopidogrel to ticagrelor in patients with HPR.

Comparison With Other Studies

The cardiology literature presumably contains the most extensive documentation of both aspirin/clopidogrel responsiveness and platelet function monitoring; here, we briefly consider the findings of cardiology trials. Cardiology trials showed no significant improvements in clinical prognosis with platelet function monitoring and treatment adjustment for coronary stenting, compared with standard antiplatelet therapy in patients who did not undergo monitoring.16–18 However, a randomized controlled trial in neurointervention by Hwang et al8 revealed that platelet function monitoring–guided modification of antiplatelet therapy could reduce the thromboembolic event frequency, compared with standard antiplatelet therapy, in patients with HPR who underwent coiling (coiling alone or stent-assisted coiling) treatment for unruptured aneurysm without increasing bleeding. This result conflicts with the findings of the cardiology trails, potentially because of the substantial differences in tissues and vasculature between heart and brain. Moreover, the study including one-third of the patients without stent placement did not receive DAPT after treatment. In our study, we only enrolled the patients with stent placement (including regular stents and flow diverter) to reduce the bias. The results in our study were consistent with the findings reported by Hwang et al8; we found that the frequency of thromboembolic events was lower in patients with platelet function monitoring–guided adjustment of antiplatelet therapy than in patients who received standard DAPT without platelet function monitoring.

Furthermore, a cardiology trial showed that platelet function monitoring–guided adjustment of antiplatelet therapy (high-dose clopidogrel, 150 mg), compared with standard-dose clopidogrel (75 mg), did not reduce the incidences of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis among patients with coronary stenting.19 Ticagrelor is a more potent antiplatelet agent, compared with clopidogrel; thus, use of ticagrelor might significantly reduce the incidence of adverse thromboembolic events.20 Adeeb et al6 reported that identification of clopidogrel nonresponders and initiation of an alternative platelet P2Y12 receptor antagonist (ie, ticagrelor)—within 24 hours preprocedure—was sufficient to reduce thromboembolic complications associated with stenting treatment of intracranial aneurysms. Thus, we presumed that ticagrelor might be a more effective strategy as an alternative antagonist for UIA patients with HPR to clopidogrel; accordingly, ticagrelor was used in this study as a replacement for clopidogrel.

Study Drug Safety

Although the frequency of any bleeding events significantly differed between the two groups in our study, platelet function monitoring–guided adjustment of antiplatelet therapy did not increase the risk of major bleeding. However, using other bleeding criteria may produce different results. One of the minor bleeding events in the study might belong to major bleeding event according to the GUSTO criteria (Global Use of Strategies to Open Occluded Coronary Arteries).15 We also compared the primary bleeding outcome between the two groups according to the GUSTO criteria and summarized in Table V in the Data Supplement. The results according to the GUSTO criteria are similar to the results according to the Thrombolysis in Myocardial Infarction (TIMI) criteria. The frequency of moderate or mild bleeding events was higher in the monitoring group than in the conventional group. However, severe bleeding events did not occur more frequently among patients in the monitoring group. Patients using ticagrelor after intracranial stent placement had a higher minor or minimal bleeding frequency, which implies that the adjustment of clopidogrel to ticagrelor might be an important contributor to an increased frequency of bleeding events. Several clinical trials have demonstrated that treatment with ticagrelor significantly increased the risk of major bleeding, including intracranial hemorrhage.21–23 However, major bleeding events in our study did not occur more frequently among patients in the monitoring group. Our results are similar to the findings of Wang et al,24 who compared the efficacy and safety of ticagrelor and clopidogrel. They found that the use of ticagrelor did not increase the frequency of major hemorrhagic events but increased the frequency of minimal hemorrhagic events. The results might set up the basis for future studies using different antiplatelet medications including ticagrelor for patients treated for intracranial aneurysms with stents or flow diverters.

Clinical Efficacy

Investigation of clinical efficacy revealed that the frequency of thromboembolic events within 7 days after intracranial stent placement was significantly lower among patients in the monitoring group (5.1%), compared with patients in the conventional group (12.1%). These results suggest that platelet function monitoring might reduce the frequency of thromboembolic events during adjustment of antiplatelet therapy. The frequencies of HPR to aspirin and clopidogrel (1.3% and 33.5%) were lower in our study than previously reported in the literature.5,8 This discrepancy is presumably because we used a higher cutoff value (50% MPA response to ADP) to prevent more adverse events or safety events involving ticagrelor than that of prior studies.9 The optimized cutoff value for platelet function monitoring in neurointerventional surgery remains a controversial topic. Our results are supported by the findings of a prospective validation study, which showed that adjustment of antiplatelet therapy was effective for prevention of thromboembolic events in clopidogrel nonresponders, although the optimal clopidogrel threshold for use in platelet function monitoring–guided therapy requires further investigation.25

A previous multicenter cohort study investigated the use of platelet function testing before flow diverter placement for the treatment of intracranial aneurysms, with the aim of exploring thromboembolic complications and clopidogrel responsiveness.6 In that study, clopidogrel nonresponders experienced a higher frequency of thromboembolic complications, compared with patients with flow diversion who were clopidogrel responders; the risk of thromboembolic complications appeared to be reduced in patients with HPR who were switched to ticagrelor. Similarly, Kim et al26 explored the role of platelet function testing and the use of antiplatelet regimens for thromboembolic rescue and found that platelet function testing might be helpful in identifying patients at risk for HPR, and the use of alternative antiplatelet agents such as prasugrel, ticagrelor, or cilostazol might be necessary to reduce the risk of thrombosis. Conversely, Neyens et al27 and Brinjikji et al28 reported that platelet function testing and personalized antiplatelet therapy in patients undergoing stenting to treat intracranial aneurysms did not demonstrate a benefit in reducing thrombotic complications. The primary limitation of the prior studies was their retrospective design, with the data from prospective randomized studies thus limited. The present study was a prospective randomized controlled trial, which explored whether platelet function monitoring–guided adjustment of antiplatelet therapy would improve clinical outcomes in UIA patients with HPR after stent placement. Subgroup analysis of patients with flow diversion demonstrated that the frequency of thromboembolic events was significantly lower in the monitoring group with antiplatelet therapy adjustment than in the conventional group. These results imply that patients with flow diversion might experience greater benefit from platelet function monitoring–guided adjustment of antiplatelet therapy, compared with patients who had nonflow diverter stents. Considering the large numbers required for subgroup analysis of patients with flow diversion, our results should be considered exploratory and hypothesis generating; additional prospective studies are needed to confirm our findings. Flow diverters are designed with a high surface coverage ratio to increase the flow-diverting effect (ie, redirect blood flow away from the aneurysm to the parent artery). However, this design might enable platelet activation and thrombus formation. Our results indicate that platelet function monitoring–guided individual antiplatelet therapy was an effective method for reduction of thromboembolic events after flow diverter placement.

Limitations

This study had several limitations. First, it was a single-center, open-label study, so the results may not be generalizable to other patient populations. Although this limitation was discussed when planning the present study, a single-center design was selected because of the need to control important confounding factors (eg, patient selection and stenting technique). The open-label design is also a potential limitation, but this approach was the only realistic method for performance of a strategy trial with numerous interventions. Second, outcomes were only evaluated during the short-term follow-up period because the results of some prior studies have suggested that delayed events beyond this period are not associated with platelet reactivity.25,29 To better assess outcomes involving delayed events, we plan to perform long-term follow-up of future patients with stent-assisted coil embolization. Third, this study focused only on stenting for the treatment of UIAs. Other procedures with stent placement require separate studies to investigate the diverse array of stenting procedures (eg, intracranial artery stenosis). Fourth, the platelet function test cutoff values might have led to bias in this study. In particular, we used a relatively high cutoff value (ADP, >50%) to prevent adverse events involving ticagrelor, which might have reduced the statistical strength of the findings. Fifth, we mainly focused on the clinical stroke evidence in this study. Silent infarction with imaging evidence (computed tomography or magnetic resonance imaging) was not considered because a routine imaging evaluation after coil embolization is not recommended. However, clinically silent infarction might be a question worth investigating in future studies, for which it might cause cognitive impairment. Finally, the study was performed in an Asian-only population, and the results of our study should be evaluated in a multicenter, more diverse population, with a larger sample size in the future.

Conclusions

Patients with HPR to standard DAPT might exhibit an increased risk of thromboembolic events, and adjustments involving double-dose aspirin and ticagrelor therapy have been associated with a reduction in the frequency of HPR. UIA patients who underwent platelet function monitoring–guided antiplatelet therapy before stent placement exhibited an increased clinical benefit related to fewer thromboembolic complications, especially ischemic stroke. Moreover, patients with flow diversion experienced a significantly greater benefit from platelet function monitoring–guided adjustment of antiplatelet therapy, compared with patients who had nonflow diverter stents. Although a significant increase in bleeding events was observed in patients with antiplatelet therapy adjustment, this did not involve major bleeding. These results suggest that guided antiplatelet therapy may be a safe and attractive alternative treatment option for UIA patients who have undergone stent placement.

Article Information

Supplemental Materials

CONSORT Checklist

Protocol, Statistical Analysis Plan, Major Summary of Protocol and SAP Amendments

Online Tables I–V

Online Figures I–VI

References 30–45

Nonstandard Abbreviations and Acronyms

DAPT

dual antiplatelet therapy

HPR

high on-treatment platelet reactivity

HR

hazard ratio

MPA

maximal platelet aggregation

UIA

unruptured intracranial aneurysm

Footnotes

The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.032989.

For Sources of Funding and Disclosures, see page 3824.

Correspondence to: Xinjian Yang, MD, PhD, Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, NansihuanXilu 119, Fengtai District, Beijing 100070, China, Email
Jian Liu, MD, Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, NansihuanXilu 119, Fengtai District, Beijing 100070, China, Email

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