Introduction: Moyamoya disease (MMD) is an uncommon cause of stroke. Antiplatelet treatment is commonly prescribed for patients with MMD despite the lack of strong evidence supporting its efficacy. We conducted a systematic review to evaluate evidence of antiplatelet treatment and clinical outcomes among patients with MMD. Methods: A systematic literature search was performed to identify studies that evaluated the association between antiplatelet treatment and clinical outcomes, including ischemic stroke, hemorrhagic stroke, functional outcome, survival, and bypass patency, in patients with MMD. The following databases were searched: PubMed, Embase, Scopus, and the Cochrane Library, from the inception date to February 2022. Results: Eight studies were included in this systematic review. Six studies evaluated antiplatelet treatment and ischemic stroke. Most studies did not demonstrate a protective effect of antiplatelet treatment against ischemic stroke. Five studies evaluated antiplatelet treatment and hemorrhagic stroke. All of them did not demonstrate an increased risk of hemorrhagic stroke. One study found the benefit of antiplatelet treatment in terms of survival. Regarding the effect of antiplatelet treatment on functional outcome and patency of surgical bypass, the results were inconclusive. Conclusion: Current evidence suggests that antiplatelet treatment in patients with MMD did not demonstrate a protective effect against ischemic stroke. However, antiplatelet treatment did not increase the risk of hemorrhagic stroke in patients with MMD. The well-designed randomized controlled trial should be highlighted.

Moyamoya disease (MMD) was first described in Japan and characterized by progressive stenosis or occlusion of the arteries surrounding the Circle of Willis, including the distal internal carotid artery or proximal anterior or middle cerebral artery, with an abnormal vascular network near the stenotic or occlusive vessels [1‒3]. The term “moyamoya” is a Japanese word which means “hazy like a puff of smoke.” It is used to describe the appearance of abnormal collateral vessels on cerebral angiograms [2]. Common presentation of MMD, including ischemic and hemorrhagic stroke, depends on the age at the time of symptom onset [4, 5]. MMD has a higher prevalence among patients in East Asian countries such as Japan, Korea, and those of Asian ancestry [3, 5]. The pathogenesis of MMD has not yet been fully elucidated [3, 5, 6].

Revascularization surgery is the standard treatment for symptomatic MMD to prevent recurrent strokes [7, 8]. Several meta-analyses demonstrated the effectiveness of bypass surgery over conservative treatment in preventing future strokes. In addition, direct revascularization surgery provides better stroke prevention compared with indirect bypass [8‒11]. In contrast, medical management with antiplatelets is recommended for patients with MMD despite the lack of strong evidence supporting its efficacy [7]. Due to both the rarity of the disease and ethical considerations, no randomized controlled study has been established to evaluate the efficacy of antiplatelet therapy in patients with MMD. In clinical practice, antiplatelet agents are prescribed to treat patients with MMD at different stages of the disease, including asymptomatic MMD, ischemic MMD, and after surgical bypass. The regimens of antiplatelet treatment also varied across facilities [12]. Furthermore, a worldwide survey demonstrated that the majority of non-Asian experts recommended antiplatelet treatment, contradicting Asian experts [13]. Previous observational studies using various clinical outcomes to evaluate the efficacy of antiplatelet therapy demonstrated inconsistent results. The objective of this systematic review was to consolidate the evidence on the use of antiplatelet treatment and clinical outcomes, including ischemic stroke, hemorrhagic stroke, functional outcome, survival, and bypass patency in patients with MMD who underwent surgical or nonsurgical treatment.

We conducted this systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000539025) [14]. The protocol for this study was registered with PROSPERO (International Prospective Register of Systematic Reviews), CRD42022312634.

Literature Search

Systematic literature searches were carried out on PubMed, Embase, Scopus, and the Cochrane Library from the inception date to February 2022. Published articles reporting the association between antiplatelet treatment and clinical outcomes in patients with MMD were identified. Search terms included “moyamoya disease” OR “moya-moya” OR “moyamoya” AND “platelet aggregation inhibitors” OR “antiplatelet” OR “anti-platelet” OR “antiaggregant” OR “antithrombocytic agent” OR “aspirin” OR “clopidogrel” OR “cilostazol” OR “ticagrelor” OR “P2Y12 inhibitor.” Manual searches for potentially related studies were also performed based on references from identified articles. The complete search strategy for each database is provided in the online supplementary material.

Selection Criteria

Inclusion criteria were (1) studies that evaluated the effects of antiplatelet treatment in adult (with or without pediatric) patients with MMD, either randomized controlled trial or observational studies (cohort, case-control, or cross-sectional); (2) the diagnosis of MMD was made according to the diagnostic criteria of the Research Committee on Spontaneous Occlusion of the Circle of Willis [7, 15] or MMD was identified by the International Classification of Diseases, Tenth Revision (ICD-10) code I67.5 – moyamoya disease; (3) studies that reported the associations between antiplatelet treatment and any of the following clinical outcomes, including ischemic stroke, hemorrhagic stroke, the functional outcome determined by the modified Rankin Scale (mRS), survival, and bypass patency; and (4) hazard ratio (HR), relative risk, odds ratio, or the number (frequency) of events was provided for each outcome. No language limitation was applied. Exclusion criteria included (1) review articles, case reports, case series, and unpublished studies, (2) studies that evaluated moyamoya syndrome (quasi-MMD) or vascular pathology other than MMD, and (3) studies without a control group (no antiplatelet treatment).

Data Extraction

Two investigators (N.K. and C.A.) independently reviewed the articles. The title and abstract of the retrieved articles were independently screened for eligibility. The full texts of the selected articles were reviewed. Two investigators (N.K. and C.A.) independently extracted the data using a standardized form. Any discrepancies at any stage were resolved by the third investigator (K.S.). Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia: available at www.covidence.org) was used to track articles and decisions at each stage. The corresponding author of the included studies was contacted when there was unclear data.

Risk of Bias and Quality Assessment

To qualitatively assess the studies included in the systematic review, we performed both risk of bias and quality assessment. Risk of Bias in Nonrandomized Studies – Intervention Studies (ROBINS-I) was used to assess the risk of bias in the included studies [16, 17]. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of observational studies [18, 19]. The scoring system for cohort studies was applied to each included study. Two investigators (N.K. and C.A.) independently evaluated and gave a judgment on the risk of bias in ROBINS-I or assigned the NOS score for each article. Any discrepancies were resolved by the third investigator (K.S.).

A total of 1,461 studies of antiplatelet therapy in patients with MMD were identified, of which 642 were excluded due to duplication. After the title and abstract screening, 799 studies were excluded. The full texts of 20 studies were reviewed for eligibility. One study was excluded due to the inclusion of patients with cerebral atherosclerotic disease, and 11 studies were excluded due to the comparison not related to the protocol (either lack of a non-antiplatelet group or direct comparison between antiplatelet and surgical treatments) (Fig. 1). The eight included studies had a low to moderate risk of bias based on the ROBINS-I assessment (Fig. 2) and NOS scores of ≥7. Among the eight included studies, 3 studies compared antiplatelet therapy in patients who underwent bypass surgery [20‒22], 2 studies compared antiplatelet therapy in patients who received nonsurgical treatment [23, 24], 2 studies reported outcomes of antiplatelet therapy in a mixed population of patients who received surgical or nonsurgical treatment [25, 26], and 1 study compared antiplatelet therapy with conservative and surgical treatment [27]. Four studies included pediatric and adult patients with MMD [20, 23, 25, 26]. Four studies included only adult patients with MMD [21, 22, 24, 27]. Four studies included cohorts with propensity score-matched analysis [22, 23, 25, 27] (Table 1 and online suppl. material).

Fig. 1.

Preferred reporting items for systematic reviews and meta-analysis flow diagram of included studies.

Fig. 1.

Preferred reporting items for systematic reviews and meta-analysis flow diagram of included studies.

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Fig. 2.

Risk of bias evaluation of the included studies.

Fig. 2.

Risk of bias evaluation of the included studies.

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Table 1.

Study characteristics

Authors, year (study design)CountryPopulationSample size (%male)Mean age (SD)Intervention/comparisonAntiplatelet regimenTiming of antiplatelet treatmentMean F/U time, monthsNOS
Seo et al., 2021 [25] (multicenter RCS) Korea Pediatric and adult newly diagnosed MMD 25,978 (38.4%) 37.6 (19.9) Antiplatelet/no antiplatelet Aspirin, clopidogrel, cilostazol, and others (triflusal and ticlopidine) After a diagnosis of MMD 75.6 S4C2O3 
Ye et al., 2021 [27] (multicenter RCS) China Adult ischemic MMD 217 (53.9%) 47 (11.0) Antiplatelet/conservative/Sx Aspirin (100mg)/d After a diagnosis of ischemic MMD 34±18 S4C2O3 
Clopidogrel (75 mg)/d 
Aspirin+clopidogrel for 3 weeks and then aspirin daily 
Pang et al., 2021 [24] (single center RCS) Korea Adult hemodynamically stable MMD 243 (25.1%) 43.7 (11.4) Antiplatelet/conservative Antiplatelet 4 types of potency (such as aspirin, cilostazol, clopidogrel, and ticagrelor) After symptomatic MMD or prescribed for other medical problems 62±43.4 S4c0O3 
Kanamori et al., 2021 [20] (single center RCS) Japan Pediatric and adult MMD underwent bypass surgery 74b (27%) 21.99 (17.11) Antiplatelet+Sx/Sx Aspirin (100 mg)/d or weight-dependent dose Preoperative + postoperative (restart day 2 after surgery) N/A S4C0O3 
Onozuka et al., 2016 [23] (multicenter RCS) Japan Pediatric and adult nonhemorrhagic MMDa 1,925 (35.1%) 32.15 (19.1) Antiplatelet/conservative Aspirin, clopidogrel, and cilostazol Prehospital N/A S4C2O2 
Zhao et al., 2017 [21] (single center RCS) China Adult ischemic MMD underwent bypass surgery 197b (48.7%) 37.7 Antiplatelet+Sx/Sx Aspirin (100 mg)/d Postoperative day 1 until 1 month after surgery N/A S4C0O3 
Yamada et al., 2016 [26] (multicenter PCS) Japan Pediatric and adult ischemic MMDa 344 (32.8%) 32.85 (18.33) Antiplatelet/no antiplatelet N/A After a diagnosis of ischemic MMD 62.4±34.8 S4C0O3 
Lu et al., 2021 [22] (multicenter RCS) China Adult ischemic MMD underwent bypass surgery 217 (51.8%) 41.4 (10.2) Antiplatelet+Sx/Sx Aspirin (100 mg)/day Postoperative day 0 49.2±42 S4C2O3 
Authors, year (study design)CountryPopulationSample size (%male)Mean age (SD)Intervention/comparisonAntiplatelet regimenTiming of antiplatelet treatmentMean F/U time, monthsNOS
Seo et al., 2021 [25] (multicenter RCS) Korea Pediatric and adult newly diagnosed MMD 25,978 (38.4%) 37.6 (19.9) Antiplatelet/no antiplatelet Aspirin, clopidogrel, cilostazol, and others (triflusal and ticlopidine) After a diagnosis of MMD 75.6 S4C2O3 
Ye et al., 2021 [27] (multicenter RCS) China Adult ischemic MMD 217 (53.9%) 47 (11.0) Antiplatelet/conservative/Sx Aspirin (100mg)/d After a diagnosis of ischemic MMD 34±18 S4C2O3 
Clopidogrel (75 mg)/d 
Aspirin+clopidogrel for 3 weeks and then aspirin daily 
Pang et al., 2021 [24] (single center RCS) Korea Adult hemodynamically stable MMD 243 (25.1%) 43.7 (11.4) Antiplatelet/conservative Antiplatelet 4 types of potency (such as aspirin, cilostazol, clopidogrel, and ticagrelor) After symptomatic MMD or prescribed for other medical problems 62±43.4 S4c0O3 
Kanamori et al., 2021 [20] (single center RCS) Japan Pediatric and adult MMD underwent bypass surgery 74b (27%) 21.99 (17.11) Antiplatelet+Sx/Sx Aspirin (100 mg)/d or weight-dependent dose Preoperative + postoperative (restart day 2 after surgery) N/A S4C0O3 
Onozuka et al., 2016 [23] (multicenter RCS) Japan Pediatric and adult nonhemorrhagic MMDa 1,925 (35.1%) 32.15 (19.1) Antiplatelet/conservative Aspirin, clopidogrel, and cilostazol Prehospital N/A S4C2O2 
Zhao et al., 2017 [21] (single center RCS) China Adult ischemic MMD underwent bypass surgery 197b (48.7%) 37.7 Antiplatelet+Sx/Sx Aspirin (100 mg)/d Postoperative day 1 until 1 month after surgery N/A S4C0O3 
Yamada et al., 2016 [26] (multicenter PCS) Japan Pediatric and adult ischemic MMDa 344 (32.8%) 32.85 (18.33) Antiplatelet/no antiplatelet N/A After a diagnosis of ischemic MMD 62.4±34.8 S4C0O3 
Lu et al., 2021 [22] (multicenter RCS) China Adult ischemic MMD underwent bypass surgery 217 (51.8%) 41.4 (10.2) Antiplatelet+Sx/Sx Aspirin (100 mg)/day Postoperative day 0 49.2±42 S4C2O3 

RCS, retrospective cohort study; PCS, prospective cohort study; MMD, moyamoya disease; F/U, follow-up; N/A, not available; NOS, Newcastle-Ottawa Scale; S, C, and O, selection, comparability, and outcome.

aSubset of the total study population was included for analysis.

bUnit of sample size = operations.

Antiplatelet Treatment and Ischemic Stroke in Patients with MMD

Two studies evaluated antiplatelet treatment and perioperative ischemic stroke among patients with MMD who underwent bypass surgery [20, 21]. These two studies had different timing of antiplatelet treatment relative to the timing of surgery. One study evaluated perioperative antiplatelet treatment and perioperative ischemic stroke [20]. The other explored postoperative antiplatelet treatment and ischemic stroke after surgery [21]. There was no difference in the rate of perioperative ischemic stroke when an antiplatelet was prescribed perioperatively (antiplatelet+surgery 8/52 [15.4%] vs. surgery 2/22 [9.1%], p = 0.80) and postoperatively (antiplatelet+surgery 6/59 [10.2%] vs. surgery 19/138 [13.8%], p = 0.49) [20, 21]. In a study with a long-term follow-up period, there was no difference in the incidence of ischemic stroke among patients who underwent direct revascularization therapy between antiplatelet and non-antiplatelet groups (log rank test p = 0.09) [22].

In a study comparing antiplatelet, conservative, and surgical treatments in patients with ischemic MMD, incident ischemic stroke was lowest among patients who underwent surgical revascularization therapy, followed by those who received antiplatelet and conservative treatments, respectively, before (surgical vs. antiplatelet vs. conservative = 1/53 [1.9%] vs. 6/85 [7.1%] vs. 11/79 [13.9%], p = 0.04) and after (surgical vs. antiplatelet vs. conservative = 1/53 [1.9%] vs. 3/53 [5.7%] vs. 8/53 [15.1%], p = 0.03) propensity score matching. The risk of incident ischemic stroke during the follow-up period by Cox regression also demonstrated the lowest risk in patients with surgical treatment, while among nonsurgical treatment, those who received antiplatelet treatment had a significantly lower risk of incident ischemic stroke than conservative treatment (χ2 = 8.98, p = 0.01). However, there was no difference in the risk of incident ischemic stroke among different antiplatelet agents [27].

Among patients with hemodynamically stable MMD who received nonsurgical treatment, antiplatelets did not demonstrate a protective effect on preventing symptomatic cerebral infarction in both univariate analysis (HR 1.16, 95% CI: 0.30–4.47, p = 0.83) and multivariate analysis (HR 1.17, 95% CI: 0.27–5.18, p = 0.84) [24]. In addition, a registry of a mixed population of patients with ischemic MMD who received nonsurgical or surgical treatment (344 patients) showed that there was no difference in the rate of ischemic stroke between patients with and without antiplatelet therapy (antiplatelet: 2.9 ± 1.3%/5 years vs. no antiplatelet: 1.6 ± 1.2%/5 years; log rank test p = 0.398) [26] (Table 2).

Table 2.

Summaries of studies with ischemic and hemorrhagic stroke outcomes

Authors, yearIschemic strokeHemorrhagic stroke
ischemic outcome definitionsmain resultshemorrhagic outcome definitionsmain results
Kanamori et al. [20] (2021) Perioperative infarction (CT postoperative days 0 and 1 and MRI postoperative days 2–3) No difference regarding perioperative infarction in both antiplatelet and non-antiplatelet groups Perioperative hemorrhagic complication (CT postoperative days 0 and 1 and MRI postoperative days 2–3) No difference in perioperative hemorrhagic complication in both antiplatelet and non-antiplatelet groups 
Zhao et al. 2017 [21] (2021) Postoperative infarction on neuroimaging (CT postoperative day 0 or MRI postoperative days 4–7) No difference regarding postoperative infarction in both antiplatelet and non-antiplatelet groups Postoperative hemorrhagic complication on CT scan (CT postoperative days 0 and 1) No difference in postoperative hemorrhagic complication in both antiplatelet and non-antiplatelet groups 
Lu et al. [22] (2021) Ischemic stroke during follow-up period No difference in incident ischemic stroke in both antiplatelet and non-antiplatelet groups Hemorrhagic stroke during the follow-up period No difference in incident hemorrhagic stroke in both antiplatelet and non-antiplatelet groups 
Pang et al. [24] (2021) Symptomatic cerebral infarction Antiplatelets did not demonstrate a protective effect on symptomatic cerebral infarction Symptomatic hemorrhage Antiplatelets demonstrated a protective effect on symptomatic cerebral hemorrhage in univariate but not multivariate analysis 
Yamada et al. [26] (2016) Cerebral infarction (not include TIA) No difference in the rate of ischemic stroke in both antiplatelet and non-antiplatelet groups Intracerebral hemorrhage Lower rate of hemorrhagic stroke in the antiplatelet group 
Ye et al. [27] (2021) Symptoms ≥24 h: clinical and/or imaging evidence of infarction Surgical treatment had the lowest risk of recurrent stroke. Antiplatelet therapy prevented recurrent stroke better than conservative treatment (both before and after PPS matching) N/A N/A 
Symptoms <24 h: imaging evidence of infarction 
Authors, yearIschemic strokeHemorrhagic stroke
ischemic outcome definitionsmain resultshemorrhagic outcome definitionsmain results
Kanamori et al. [20] (2021) Perioperative infarction (CT postoperative days 0 and 1 and MRI postoperative days 2–3) No difference regarding perioperative infarction in both antiplatelet and non-antiplatelet groups Perioperative hemorrhagic complication (CT postoperative days 0 and 1 and MRI postoperative days 2–3) No difference in perioperative hemorrhagic complication in both antiplatelet and non-antiplatelet groups 
Zhao et al. 2017 [21] (2021) Postoperative infarction on neuroimaging (CT postoperative day 0 or MRI postoperative days 4–7) No difference regarding postoperative infarction in both antiplatelet and non-antiplatelet groups Postoperative hemorrhagic complication on CT scan (CT postoperative days 0 and 1) No difference in postoperative hemorrhagic complication in both antiplatelet and non-antiplatelet groups 
Lu et al. [22] (2021) Ischemic stroke during follow-up period No difference in incident ischemic stroke in both antiplatelet and non-antiplatelet groups Hemorrhagic stroke during the follow-up period No difference in incident hemorrhagic stroke in both antiplatelet and non-antiplatelet groups 
Pang et al. [24] (2021) Symptomatic cerebral infarction Antiplatelets did not demonstrate a protective effect on symptomatic cerebral infarction Symptomatic hemorrhage Antiplatelets demonstrated a protective effect on symptomatic cerebral hemorrhage in univariate but not multivariate analysis 
Yamada et al. [26] (2016) Cerebral infarction (not include TIA) No difference in the rate of ischemic stroke in both antiplatelet and non-antiplatelet groups Intracerebral hemorrhage Lower rate of hemorrhagic stroke in the antiplatelet group 
Ye et al. [27] (2021) Symptoms ≥24 h: clinical and/or imaging evidence of infarction Surgical treatment had the lowest risk of recurrent stroke. Antiplatelet therapy prevented recurrent stroke better than conservative treatment (both before and after PPS matching) N/A N/A 
Symptoms <24 h: imaging evidence of infarction 

TIA, transient ischemic attack; PPS, propensity score; CT, computed tomography; MRI, magnetic resonance imaging; N/A, not available.

Antiplatelet Treatment and Hemorrhagic Stroke in Patients with MMD

Two studies evaluated antiplatelet treatment and perioperative hemorrhagic stroke among patients with MMD who underwent bypass surgery [20, 21]. The rate of hemorrhagic stroke was similar in both perioperative (antiplatelet+surgery 2/52 [3.8%] vs. surgery 2/22 [9.1%], p = 0.58) and postoperative (antiplatelet+surgery 2/59 [3.4%] vs. surgery 7/138 [5.1%], p = 0.60) antiplatelet therapies when compared to no antiplatelet treatment [20, 21]. In a long-term follow-up study, there was no difference in the cumulative rate of hemorrhagic stroke between antiplatelet and non-antiplatelet groups (log test p = 0.09) [22].

Among patients who received nonsurgical treatment, antiplatelets demonstrated a protective effect against symptomatic cerebral hemorrhage in univariate analysis (HR 0.44, 95% CI: 0.20–0.99, p = 0.046) but not in multivariate analysis (HR 1.19, 95% CI: 0.24–1.34, p = 0.19) [24]. A registry study of patients with ischemic MMD who received conservative or surgical treatment showed that the hemorrhagic stroke rate was significantly lower in patients with antiplatelet therapy (0%/5 years) compared to those without antiplatelet therapy (4.2 ± 1.9%/5 years) (log rank test p = 0.021) [26] (Table 2).

Antiplatelet Treatment and Functional Outcome in Patients with MMD

Two studies evaluated the association between antiplatelet treatment and functional outcome defined by mRS in patients with MMD [23, 27]. Propensity score matching was performed in both studies. A nationwide retrospective cohort study included 1,925 patients admitted to the hospital due to nonhemorrhagic MMD. The study evaluated the association between prehospital antiplatelet treatment and the functional status of the patients upon admission. Prehospital antiplatelet treatment was associated with good functional status (mRS≤1) on admission compared to those without prehospital antiplatelet treatment in both the unmatched cohort (OR 1.52, 95% CI: 1.11–2.09) and the propensity score-matched cohort (OR 3.82, 95% CI: 1.22–11.99) [23]. However, there were no significant differences in the functional outcome between patients with ischemic MMD when treated with antiplatelets compared to those who received conservative or surgical treatment [27] (Table 3).

Table 3.

Summaries of studies with functional outcome and survival

Authors, yearOutcome definitionsMain results
Functional outcome 
 Onozuka et al. [23] (2016) No significant functional disability on hospital admission (mRS ≤1) Prehospital antiplatelet treatment was associated with a good functional outcome on hospital admission (both before and after PPS matching) 
 Ye et al. [27] (2021) Poor functional outcome (mRS >2) during follow-up No difference regarding the poor outcome among 3 groups (both before and after PPS matching) 
Survival 
 Seo et al. [25] (2021) Survival assessed by death dates recorded in the national database Antiplatelets associated with reduced mortality in both univariate and multivariate analyses 
Authors, yearOutcome definitionsMain results
Functional outcome 
 Onozuka et al. [23] (2016) No significant functional disability on hospital admission (mRS ≤1) Prehospital antiplatelet treatment was associated with a good functional outcome on hospital admission (both before and after PPS matching) 
 Ye et al. [27] (2021) Poor functional outcome (mRS >2) during follow-up No difference regarding the poor outcome among 3 groups (both before and after PPS matching) 
Survival 
 Seo et al. [25] (2021) Survival assessed by death dates recorded in the national database Antiplatelets associated with reduced mortality in both univariate and multivariate analyses 

mRS, modified Rankin Scale; PPS, propensity score.

Antiplatelet Treatment and Survival in Patients with MMD

A high-quality population-based cohort study (25,978 participants) evaluated the association between antiplatelet treatment and survival in patients with MMD. This cohort consisted of patients receiving medical and surgical treatment. Antiplatelet treatment was associated with a decreased chance of mortality (univariate analysis: HR 0.54, 95% CI: 0.47–0.63, p < 0.01; multivariate analysis: HR 0.77, 95% CI: 0.70–0.84, p < 0.01). The protective effect of antiplatelet therapy was also demonstrated in a propensity score-matched cohort (univariate analysis: HR 0.51, 95% CI: 0.43–0.60, p < 0.01; multivariate analysis: HR 0.60, 95% CI 0.50–0.71, p < 0.01). Cilostazol was the only antiplatelet associated with survival in both univariate (HR 0.64, 95% CI: 0.54–0.75, p < 0.01) and multivariate (HR 0.57, 95% CI: 0.49–0.68, p < 0.01) analyses. In subgroup analyses, only cilostazol was associated with lower mortality in patients with previous ischemic stroke, while aspirin, clopidogrel, and cilostazol were associated with a reduction in mortality in patients with prior hemorrhagic stroke (both univariate and multivariate analyses) [25] (Table 3).

Antiplatelet Treatment and Bypass Patency in Patients with MMD

Three studies evaluated the association between antiplatelet treatment, specifically aspirin, and postoperative bypass patency in patients with MMD who underwent surgical revascularization therapy (total 410 operations) [20‒22]. These studies had different timings for bypass patency evaluation. The rate of bypass patency is higher in patients receiving antiplatelets at the initial evaluation before white thrombus rescue (antiplatelet+surgery 41/52 [78.8%] vs. surgery 12/22 [54.5%], p = 0.049), but not at the final evaluation (antiplatelet+surgery 49/52 [94.2%] vs. surgery 21/22 [95.5%], p = 1.00) [20]. There was no difference in bypass patency when evaluating within 7 days [21] or 1 year [22]. However, during long-term follow-up, the rate of bypass patency is higher in patients receiving antiplatelets both before (antiplatelet+surgery 136/141 [96.5%] vs. surgery 87/97 [54.5%], p = 0.035) and after (antiplatelet+surgery 77/78 [98.7%] vs. surgery 70/78 [89.7%], p = 0.016) propensity score matching [22] (Table 4).

Table 4.

Summaries of studies with an evaluation of bypass patency

Authors, yearType of bypass surgeryBypass patency evaluationMain results
Kanamori et al. [20] (2021) Combined revascularization Bypass patency evaluated by intraoperative indocyanine green video angiography or Doppler sound in the initial (before white thrombus rescue) and final patency (after white thrombus rescue) Initial bypass patency is higher in the antiplatelet group. No difference regarding final bypass patency 
Zhao et al. [21] (2021) Direct or combined revascularization Bypass patency evaluated by postoperative angiography (CTA/MRA/DSA) in 4–7 days after surgery No difference regarding postoperative bypass patency in both antiplatelet and non-antiplatelet groups 
Lu et al. [22] (2021) Direct revascularization Short-term (3months–1year) and long-term (>1 year) follow-up by DSA, CTA, or MRA Higher rate of bypass patency in long-term follow-up in the antiplatelet group (both before and after PPS matching). Antiplatelet treatment was a predictor of bypass patency 
Authors, yearType of bypass surgeryBypass patency evaluationMain results
Kanamori et al. [20] (2021) Combined revascularization Bypass patency evaluated by intraoperative indocyanine green video angiography or Doppler sound in the initial (before white thrombus rescue) and final patency (after white thrombus rescue) Initial bypass patency is higher in the antiplatelet group. No difference regarding final bypass patency 
Zhao et al. [21] (2021) Direct or combined revascularization Bypass patency evaluated by postoperative angiography (CTA/MRA/DSA) in 4–7 days after surgery No difference regarding postoperative bypass patency in both antiplatelet and non-antiplatelet groups 
Lu et al. [22] (2021) Direct revascularization Short-term (3months–1year) and long-term (>1 year) follow-up by DSA, CTA, or MRA Higher rate of bypass patency in long-term follow-up in the antiplatelet group (both before and after PPS matching). Antiplatelet treatment was a predictor of bypass patency 

PPS, propensity score; CTA, computed tomography angiography; MRA, magnetic resonance angiography; DSA, digital subtraction angiography.

In this systematic review, we evaluated the benefits of antiplatelet treatment in patients with MMD. Most studies did not demonstrate the benefit of antiplatelet treatment in preventing ischemic stroke. Antiplatelet treatment did not prevent ischemic stroke among patients who underwent bypass surgery [20‒22] or who received nonsurgical treatment [24]. Yamada et al.t [26] also demonstrated that antiplatelet treatment did not reduce the rate of ischemic stroke among patients who received either surgical or nonsurgical treatmen. However, Ye et al. [27] found that the rate of ischemic stroke was lower in patients who received antiplatelet treatment compared to conservative treatment. There is no evidence from included studies that antiplatelet treatment increased the risk of hemorrhagic stroke in patients with MMD. Among patients who underwent bypass surgery, the rate of hemorrhagic stroke was not different in patients with and without antiplatelet treatment [20‒22]. The rate of hemorrhagic stroke was lower in the antiplatelet group among patients who received either surgical or nonsurgical treatment [26]. In addition, Pang et al. [24] found that antiplatelets prevent symptomatic intracerebral hemorrhage in a univariate but not multivariate analysis. Two studies evaluated antiplatelet treatment and functional outcome. Differences in the timing of antiplatelet treatment and the timing of assessment could explain conflicting results. Onozuka et al. [23] found the benefit of antiplatelet treatment when given prior to admission of nonhemorrhagic MMD. In contrast, Ye et al. [27] found no benefit of antiplatelets when administered after admission. Only one study evaluated the association between antiplatelet treatment and survival in patients with MMD. Although most of the studies included in this systematic review did not demonstrate the protective effect of aspirin in preventing ischemic or hemorrhagic stroke, Seo et al. [25] demonstrated that antiplatelet treatment was associated with a reduction in mortality. Regarding bypass patency, the results are inconclusive and vary depending on the timing of the assessment. The benefit of antiplatelet treatment was demonstrated when assessed during long-term [22] but not short-term follow-up [20, 21].

The neutral effect of antiplatelet treatment in preventing ischemic stroke among patients with MMD could partially be explained by the pathogenesis and pathophysiology of the disease. Histopathological findings of MMD are fibrocellular thickening of the intima, consisting of smooth muscle cell hyperplasia and accumulation of extracellular matrix within the intima, along with attenuation of the media, which leads to progressive decreases in outer diameter [28‒31]. Unlike atherosclerosis, which is characterized by chronic inflammation leading to cellular infiltration and intimal thickening, inflammatory cell infiltration is generally absent in MMD [28, 30]. The pathological changes of MMD are not caused by endothelial injury that results in platelet aggregation. Therefore, it is not surprising that most of the studies did not demonstrate the benefit of antiplatelet treatment in preventing ischemic stroke in patients with MMD.

However, antiplatelet treatment could potentially benefit a specific population of patients with MMD. The mechanism of ischemic stroke in MMD was previously thought to be primarily due to hemodynamic infarction from progressive cerebrovascular stenosis [6, 32]. Recent studies using transcranial Doppler ultrasound demonstrated that the presence of microembolic signals was associated with recent ischemic symptoms and could predict future ischemic events [33, 34]. In addition, a multimodal magnetic resonance imaging study reported that embolic stroke was the most common pattern of ischemic stroke among adult patients with MMD [35]. Histopathological changes in MMD also showed intraluminal thrombosis with the collapse of the arterial lumen [36]. Hypoperfusion and embolism are interrelated and often coexist. Luminal narrowing promotes clot formation and embolization. Furthermore, cerebral hypoperfusion impairs the ability to wash out the emboli [37, 38]. These findings suggested that artery-to-artery emboli could play an important role in ischemic stroke among patients with MMD. Collectively, antiplatelet treatment could potentially benefit patients with positive microembolic signals. However, more studies are required to evaluate this benefit.

There are some limitations in our study. All studies included in our analysis were observational studies. However, to ensure the quality of the included studies, we performed both risk of bias assessment by ROBINS-I and quality assessment by NOS. The included studies had NOS scores of ≥7, generally considered high-quality observational studies. Although during the literature search we did not apply language limitations to minimize publication bias due to a higher prevalence of the disease among East Asian countries, the included studies were from Asian countries. It is worth mentioning that the full text of 4 studies from Europe and North America was carefully reviewed but was excluded due to the inclusion of patients without MMD or no comparison between antiplatelet and non-antiplatelet groups. The association between antiplatelet therapy and clinical outcomes could not be quantitatively addressed due to the heterogeneity of the studies.

Prescription of antiplatelet medication for patients with MMD is a common practice despite the lack of evidence supporting its efficacy. In this systematic review, current evidence suggests that antiplatelet treatment in patients with MMD did not demonstrate a protective effect against ischemic stroke. However, antiplatelet treatment did not increase the risk of hemorrhagic stroke in patients with MMD. Whether antiplatelet treatment could be beneficial in a specific population, such as those with positive microembolic signals, has yet to be determined.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflict of interest to declare.

No funding was obtained in the preparation of this manuscript.

Conceptualization: N.K. and C.A. Data curation: N.K. and C.A. Data analysis and interpretation: N.K., C.A., K.S., and P.S. Drafting the article: N.K. Reviewing and editing: C.A., K.S., S.W., N.A., P.S., and N.S. Supervision: P.S. and N.C.S.

All data were extracted and presented in this systematic review. Further inquiries can be directed to the corresponding author.

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