Efficacy and Safety of Mono Antiplatelet Treatment for Cardioembolic and Undetermined Etiological Stroke after Receiving Successful Mechanical Thrombectomy

Background Periprocedural antithrombotic medication after mechanical thrombectomy (MT) for acute intracranial large vessel occlusion (LVO) is still controversial. Recent studies have indicated that majority of stroke with undetermined etiology (SUE), as defined by the TOAST classification, showed strong overlap with cardioembolic stroke (CE). We intended to determine the efficacy of the mono antiplatelet (MA) therapy in both stroke types after receiving successful MT recanalization in the acute stage. Methods 178 consecutive stroke patients who received MT treatment were retrospectively analyzed. CE and SUE type stroke patients were chosed to received MA therapy. Aspirin 100mg or clopidogrel 75 mg was added immediate for patients who didn`t received intravenously recombinant tissue plasminogen activator (IV-rtPA) and after 24 hours for those received IV-rtPA if symptomatic intracranial hemorrhage (sICH) was not found. MA treatment outcomes included recanalized artery patency, subsequent sICH and functional independence (mRS score of 0-2) were compared between two stroke types. Results Successful recanalization (TICI 2b/3) was achieved in 75 CE stroke patients and 50 SUE patients without hemorrhagic transformation were included into final analysis. Target artery at 7 days after recanalization was confirmed 100% patency in the CE group and 97.5% in the SUE group. Hemorrhagic transformation after 24h was found in 26% patients in the SUE group and in 26.7% patients in the CE group (P > 0.05). sICH was confirmed in 3 patients in the SUE group and in 10 patients in the CE group. At 90 days, 45.8% in the SUE group and 46.5% in the CE group of patients had achieved good outcomes (mRs 0-2) (P=1.00). However, accumulative death was higher in the CE group than in the SUE group (21% vs. 15%; P=0.47)

for patients considered SUE stroke type, mono antiplatelet therapy after thrombectomy achieved similar treatment outcomes as compared to cardioembolic stroke patients.

Background
Cardioembolic (CE) stroke account for 14-30% of all ischemic strokes, which often indicate high loaded thrombus, large vessel occlusion and poor response to intravenous thrombosis, thus requires immediate intervention. Cardioembolic stroke is characterized by embolus occlusion and a non-arteriosclerotic cerebral arterial wall thus complete recanalization and good blood flow restoration can be achieved once the thrombus was removed. Re-occlusion is less while hemorrhagic transformation may more frequently observed in CE cases than in arteriosclerotic stroke cases [1][2] . Medicine strategy for CE stroke after mechanical thrombectomy (MT) remains controversial as balance should be considered between re-occlusion risk and hemorrhage transformation. Early anticoagulation does not reduce the recurrence of ischemic stroke; rather, it significantly increased symptomatic intracranial hemorrhage (sICH) in CE patients [3] . An observational study showed that the optimal time for anticoagulation initiation to prevent cardioembolic stroke recurrence was 4-14 days after stroke onset [4] , and during the accurate stage after MT, anti-platelet treatment required because stent retriever thrombectomy or catheter aspiration was likely to result in artery wall injury [5] . Unfortunately, very limited information of periprocedural antithrombotic medication for patients received MT is available in present. Based on previous experiment study, we had found injuries associated with thrombectomy devices to normal arterial wall was minimal and mainly restricted to endothelial cell and internal elastic lamina [6] . Thus, based on these findings, we believe mono antiplatelet (MA) therapy might become an appropriate treatment for CE stroke, which may balance the stroke recurrence risk and risk of hemorrhage transformation.
Based on TOAST classification, up to 39% of acute ischemic strokes are of undetermined etiology (SUE) [7] . Recent studies had indicated a similar pathological findings of thrombi composition between SUE and CE [8,9] , which indicating a substantial overlap between SUE and CE stroke types. Possible SUE etiology may involve artery-to-artery embolism from large artery atherosclerotic plaques without causing lumen stenosis [10] , thrombus from a thrombogenic atrial substrate [11] , paroxysmal or insidious atrial fibrillation [12] .
Based on these findings, periprocedural antithrombotic medication strategy for the cardioembolic stroke can be applied to cryptogenic stroke.
In present study, we intended to determine whether using MA therapy in SUE and CE strokes after receiving MT recanalization could be used as a safe and effective treatment in the acute stage.

Patients
The ethics committee of Shanghai Jiaotong university affiliated sixth people`s hospital approved this study. Consecutive patients with acute ischemic stroke who were referred for endovascular treatment in our hospital between March 2016 and December 2018 was retrospectively reviewed. The inclusion criteria include: i) Patients was confirmed anterior circulation stroke; ii) non-enhanced brain CT scan excluded sICH for patients received IV-rtPA bridged MT therapy at 24 hours or received directly MT immediately; iii) CE or SUE stroke types was considered before, during or after thrombectomy procedure. Patients were excluded if: i) large-artery atherosclerosis caused stroke or stroke of other determined etiology such as dissection was considered; ii) balloon dilation or stent insertion was applied as salvage treatment; iii) failed to achieve good blood flow restoration. The decide of stroke subtypes according to the TOAST classification was initially based on patients` medical history, EKG, emergency laboratory reports and more importantly by CT angiogram and intra-procedure DSA images, which decided following MA therapy in acute stage. Then stroke subtypes were further determined using magnetic resonance imaging, duplex sonography of the cervical arteries, coagulation tests, longterm electrocardiography, and transthoracic or transesophageal echocardiography.
Patency of target vessel received treatment was checked seven days after procedure using computed tomograph angiography (CTA) or magnetic resonance angiography (MRA).
Thrombectomy procedure Stent retriever thrombectomy was preferred and was used as first line technique as compared to catheter-based aspiration technique in out center. Solitaire stent retriever device (ev3 Neurovascular, Irvine, California) was mostly frequently applied in our center.
The retrieval attempt repeated up to 3 times per target artery. If stent thrombectomy failed, we prefer to use catheter aspiration as a supplementary method. Meanwhile, if large-artery atherosclerosis caused stenosis was confirmed during thrombectomy and reocclusion happened, then salvage balloon dilation or stent insertion was used.
Medication protocol IV rtPA (Alteplase,Boehringer Ingelheim, Ingelheim, Germany, 0.9-mg/kg) was given only for eligible patients if it could be initiated within 4.5 hours of symptom onset. Ten percent of the dose was infused as a bolus, with the remainder infused during 1 hour. In the acute stage, these patients were treated with standard mono antiplatelet therapy using aspirin 100 mg/day or clopidogrel 75 mg/day 24 hours after IV thrombolysis or immediately after direct MT. For patients with cardiac or other diseases require anticoagulation therapy, they were bridged to oral warfarin or dabigatran if warfarin intolerant 7-14 days after treatment based on its infarction size and risk of hemorrhage transformation. Systemic heparinization was not used in patients during MT procedure in our center. Anti-platelet aggregation or anticoagulation therapy was stopped if sICH was determinized. Intravenous tirofiban administration was used if distal embolization occurred by escaped thrombus, unsatisfied blood flow restoration, stenotic lumen restricting forward flow or when balloon dilation or stent insertion required. Intravenous tirofiban administration was then bridged to anti-platelet treatment after 8-24 hours.

Data Collection
Patients` onset to groin puncture time, hospital arrival to groin puncture time, room arrival to groin puncture time, Recanalization time and occurrence time/ Puncture to reperfusion were recorded. The baseline characters, stroke severity (NIHSS score) at admission, pre-operation and 24 hours, and 7 days after endovascular treatment were evaluated by an independent neurologist. Detailed thrombectomy procedure information like number of retriever device passages were recorded. Image data of CT, MR and DSA of all patients underwent mechanical thrombectomy were stored and analyzed using the picture archiving and communication system (PACS) database system. Images were evaluated by an experienced radiologist. Meanwhile, Modified Rankin Scale (mRS) at 90 days were also documented.

Definitions
Blood reperfusion was determined use the modified thrombolysis in cerebral infarction (mTICI) grading system. mTICI grade 2b (antegrade reperfusion of more than half of the previously occluded target artery ischemic territory) and grade 3 (complete antegrade reperfusion) were defined as good blood flow. Recanalization was defined if the target arterial achieved the good blood flow on the DSA or CTA or MRA. Intracranial hemorrhage (ICH) transformation was defined as hyperintensity on the CT scan. Haemorrhagic infarction 1 (HI1) was defined as small petechiae along the margins of the infarct; haemorrhagic infarction 2 (HI2) as confluent petechiae within the infarcted area but no space-occupying effect; parenchymal haemorrhage (PH1) as blood clots in 30% or less of the infarcted area with some slight space-occupying effect; and parenchymal haemorrhage (PH2) as blood clots in more than 30% of the infarcted area with substantial space-occupying effect [13] . Symptomatic ICH (sICH) was defined as its radiologic appearance plus an increase in National Institutes of Health Stroke Scale score of ≥ 4 points according to ECASS criteria grading [13] . Re-occlusion of the target artery was defined as a blood flow interruption determined by CT or MR angiography.

Statistical analysis
GraphPad Prism 5.0 software (San Diego, CA, USA) was used for statistical analysis. Data were expressed as the mean ± standard deviation for continuous variables, and as counts or proportions (%) for categorical variables. Fisher's exact test was used to compare categorical data. Grouped t-tests were used to compare the continuous variables. One-way ANOVA test was used to compare the difference of NIHSS changes at different time points.
All tests were two tailed and statistical significance was defined as P < 0.05.

Patient characteristics
A total of 191 consecutive stroke patients received MT treatment in our center, and 178 patients received MT in the anterior circulation were retrospectively enrolled into analyzed in present study. Fifty-three patients were excluded before MA therapy from this study, include i) 32 patients with stroke caused by large-artery atherosclerosis or other etiology such as arterial dissections; ii) 2 patients confirmed immediate sICH; iii) 17 patients recanalization with poor flow reperfusion (mTICI 0-2a) and iv) 2 cases died shortly after thrombectomy. Successful recanalization (mTICI 2b/3) achieved in 125 patients were included into final analyzed, and were divided into a SUE stroke group (n = 50) and a CE stroke group (n = 75). (Fig. 1) The two groups were comparable in terms of demographics, use of intravenous thrombolysis and clinical severity on presentation, except more frequent atrial fibrillation occurrence rate (P < 0.01), older age (P = 0.04), and hypertension occurrence rate (P = 0.03) in the CE group than those in the SUE group (Table 1) days post MT in the CE group (P < 0.01). However, at every follow up time point, there was no significant of the NIHSS score between the two groups. (Fig. 4) At 3 months follow up, good clinical outcomes (mRS 0-2) was revealed in 45.8% patients in the SUE group, and in 46.5% patients in the CE group (P = 1.00). However, the accumulative death rate was higher in the CE group than in the SUE group (21% vs. 15%; P = 0.47). (Table 2) (Fig. 4)

Discussion
In this study, mono antiplatelet therapy strategy was used for the treatment of a group of ACS patients caused by cardioembolic and undetermined etiological stroke who underwent successful good flow restoration. Our main findings revealed that: i) mono antiplatelet therapy can effectively maintain the target artery patency; ii) mono antiplatelet therapy did not resulting in higher risk of sICH in the acute stage; iii) mono antiplatelet therapy presented similar treatment outcomes between the cardioembolic stroke and undetermined etiological stroke.
Previous animal studies reported that the use of stent retriever thrombectomy devices may cause arterial wall damages from the intimal to medial layers in rabbit carotid arteries [5] . However, our results indicated that the use of stent retriever devices in canine external carotid arteries resulted in damage to the vessel wall is mainly restricted to the endothelium/intimal and occasionally involves the internal elastic lamina (IEL), which indicating that multiple passes with a stent retriever device may slightly increase the risk of arterial wall damage [6] . The canine models behave more like healthy human cerebral vessels than other small animal models, with respect to histological structure, vasospasm, recoil, neointimal proliferation and thrombotic potential. Consequently, we believe reequipment for antithrombotic therapy after stent thrombectomy may not so strong in a health vessel condition.
Recent studies based on histological analysis of the retrieved thrombi have revealed that cardioembolic and undetermined etiological strokes have similar histological thrombus features, with higher proportions of fibrin/platelets, less erythrocytes, and more leucocytes than large artery atherosclerosis thrombi [8,9] . These findings may indicate that underlying cause of most undetermined etiological strokes may derived from cardia embolism and the effected cerebral vessels are under healthy condition. Consequently, the medication strategy after thrombectomy for patients with undetermined etiological stroke can be borrowed from the cardioembolic stroke.
For in acute minor stroke, CHANCE study has confirmed that double antiplatelet therapy, with a combination of clopidogrel and aspirin, was superior to mono-antiplatelet therapy alone for reducing the risk of stroke in the first 90 days [14] . However, further the POINT study found despite double antiplatelet therapy can reduce stroke recurrence risk for patients with minor stroke, but did increase higher risk of major hemorrhage at 90 days than those who received mono-antiplatelet therapy alone [15] . Although anticoagulation therapy has been well established to prevent stroke in atrial fibrillation patients, no consensus was found in the optimal time of initiation for anticoagulation after stroke [16][17] . In patients with a large stroke or high risk of hemorrhagic conversion, aspirin is recommended, followed by anticoagulant for long-term secondary prevention [12] . Thus based on above knowledges, we believed that patients underwent successful thrombectomy recanalization with good flow restoration and a healthy vessel condition should be conservatively administered mono-antiplatelet therapy alone to get the maximum benefit, possible reasons may include: i) good flow restoration often means elevated reperfusion associated with an increased ICH risk; ii) cardioembolic or undetermined etiological stroke often indicated a relatively normal arterial wall and thrombectomy may cause little damage to the vessel wall; iii) acute stroke patient with large-vessel occlusion has a high chance to develop large area ischemic infarction and hemorrhage transformation, and iv) aspirin alone were associated with a similar reduction in recurrent stroke within 7 to 14 days and reduction of sICH as compared to anticoagulants application [12] .
The target vessel patency rate was a key important index for the evaluation of whether mono-antiplatelet alone can keep patency of the recanalized artery. Our results showed that the target vessel patency rate was 97.6% and 100% respectively in the SUE and CE group. Which indicate that mono-antiplatelet could well inhibit further thrombosis event in the artery subject to thrombectomy damage; moreover, this strategy also could prevent further embolism occurrence during the acute stage period before bridged to anticoagulation therapy. Moreover, this medication strategy may minimize the risk of cerebral hemorrhage transformation as compared to other medication plans.
The limitations of our study are as follows: firstly, this is a retrospective, single arm analyzed study with limited sample size, thus a randomized, double-blind, placebocontrolled trial may further need to fully investigate its efficacy and safety; secondly, we only focused on patients who received good blood flow restoration without sICH thus this imitated its wide clinical application; thirdly, the diagnosis of stroke type may not be accurate before, during or immediate after the thrombectomy treatment when antiplatelet strategy need to be decided.

Conclusions
Mono antiplatelet therapy is safe and effective for maintaining flow patency in ACS patients who received stent thrombectomy recanalization in the acute stage before the initiation of anticoagulation therapy. However, further randomized controlled trials are needed to provide more reliable evidence for the antithrombotic strategy for ACS patients who received endovascular MT.

Availability of data and material
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
We declare there in no competing interests in this study.  NIHSS score changes before, 24-hour and 7-day after thrombectomy and modified Rankin Scare at 90 days of the CE and SUE groups.