Aneurysmal subarachnoid hemorrhage (aSAH) accounts for 2–5% of all stroke.⁷⁾¹⁴⁾ This SAH causes several complications that lead to cognitive impairment and disabilities, significantly worsening their quality of life. Cerebral vasospasm and delayed cerebral ischemia (DCI) were identified as major complications of SAH, with approximately 17–40% of patients with SAH developing persistent neuropathy and dying.¹⁷⁾

Symptoms, however, do not occur in all cases. Clinical or symptomatic vasospasm is defined as a neurological deficit accompanied by angiographic vasospasm and develops in 20–40% of patients with SAH with cerebral aneurysm rupture.²⁾¹⁰⁾ Despite the extensive research effort for decades, there were no specific pharmacological treatments. DCI is defined as a delayed onset of neurologic deterioration which last for >1 hour and in addition to a newly confirmed cerebral infarction at imaging study, such as computed tomography (CT) or magnetic resonance imaging (MRI), and develops in approximately 30% of patients with aSAH. The mechanisms of DCI are still unclear, but several hypotheses are presented including vasospasm, early brain injury, microthrombi, cortical spreading depolarization, blood-brain barrier disruption, inflammation and impaired cerebral autoregulation.¹¹⁾¹⁶⁾ These mechanisms are very similar to those of cerebral vasospasm.

Referred to these hypotheses, we suggested that, antiplatelet drug could reduce inflammation and microthrombi formation, and finally reduce the incidence of DCI. Generally, a dual platelet aggregation inhibitor (aspirin, clopidogrel) is commonly used in the insertion of stents and flow diverters during endovascular aneurysm treatment. The relationship between dual antiplatelet treatment (DAPT) and symptomatic vasospasm and DCI has not been widely studied, thus we investigated the effect of DAPT on symptomatic vasospasm and DCI.

This study was approved by the local institutional review board. A retrospective single-center study was conducted on patients with aSAH treated at our center from January 2009 to December 2018. In patients with aSAH, CT, CT angiography (CTA) and MRI were essentially performed, and transfemoral cerebral angiography (TFCA) was also performed if necessary. Information about modified world federation of neurosurgical societies (WFNS) grade, whether antiplatelet was taken because of other disease, such as cerebral infarction or coronary arterial disease, modified fisher scale on admission brain CT was acquired. Also, we investigated whether or not external ventricular drainage (EVD) and ventriculoperitoneal shunt was done due to hydrocephalus and hemorrhagic complication caused by surgical treatment of hydrocephalus. The definition of modified WFNS grade, modified fisher scale are described in Table 1. For the treatment of patients with aSAH, clipping or coiling (simple or balloon-assisted [SB], stent-assisted coiling) was performed considering the patient’s age and location and size of aneurysm. Patients who were treated with stent-assisted coil embolization and had to take dual antiplatelet drug were classified as the DAPT group. In DAPT group, aspirin 100 mg and clopidogrel 75 mg per day were given after aneurysmal treatment. Those who were trated with coil embolization without stent (SB coiling) were classified as the control group. In the cases of neurologic deterioration. vascular studies such as CTA, MRA and TFCA were performed and if vasospasm was suspected, intra-arterial or balloon angioplasty was performed by two experts: one vascular neurosurgeon and one vascular neuroradiologist.

A total of 1,397 patients were treated for cerebral aneurysm, and 743 patients (53.2%) were treated for ruptured cerebral aneurysms. There were 563 patients (75.8%) who were treated with clipping, and 180 (24.2%) who were treated with endovascular treatment. SB coiling was performed in 115 patients (63.9%), while stent-assisted coiling was performed in 65 patients (36.1%). Of 115 SB coiling patients, 14 patients were excluded from this study because they had previously taken antiplatelet drugs. Finally, 101 (60.8%) patients in control group and 65 (39.2%) paitnets in DAPT group were selected (Fig. 1). A total of 66 patients (8.9%) had symptomatic vasospasm, while 56 patients (7.5%) had DCI. The average period to the development of symptomatic vasospasm was 7.6 days (range, 2–17 days).

Based on the location of the ruptured cerebral aneurysm, the most frequent site was the anterior communicating artery (A-ComA), followed by the posterior communicating artery (P-ComA). Demographics of patient treated with endovascular method is presented at Table 2. The demographics of two groups were similar in age, sex, location of aneurysm, modified fisher scale, modified WFNS grade, hydrocephalus (p>0.05).

Although there is no drug that has been clearly proven to prevent cerebral vasospasm and DCI, nimodipine, dihydropyridine-type calcium channel blocker (CCBs) have been sustained and used because they can potentially prevent cerebral vasospasm but not obviously reduce the incidence of DCI.⁹⁾ In the pathogenesis of cerebral vasospasm, smooth muscle contraction is an essential structural change. In early phase of cerebral vasospasm, smooth muscle contraction requires adenosine triphosphate (ATP) and calcium. Although myofilament activation depends on calcium and high-energy phosphate, chronid vasospasm does not. Unlike early phase, late phase of cerebral vasospasm needs contractile protein (protein kinase C, Rho kinase, etc.) instead of ATP and calcium. This second phase cerebral vasospasm is less reversible with pharmacologic vasodilator (CCBs) treatment.⁵⁾

Studies have been conducted to find the relationship between antiplatelet drugs and prevention of vasospasm. There are some studies in which cilostazol, antiplatelet agent, can prevent cerebral vasospasm. Yoshimoto et al.¹⁸⁾ reported that vasospasm was less and statistically meaningful in the patient group who took cilostazol from first day of surgery than those who did not. Also, Senbokuya et al.¹²⁾ showed that cilostazol could prevent vasospasm. But, few studies are reported about the relationship between DAPT and vasospasm.

There are several hypotheses on the mechanism of cerebral vasospasm and DCI. Among them, we focused on the theory about inflammation and microthrombi, which are the basis for DAPT in this study. Inflammation is triggered by leakage of blood that occurs during aneurysmal rupture, resulting in increased secretion of leukotrienes and cytokines. This causes the endothelium to secrete endothelin-1 and change it to increase the use of NO, triggering vasospasm by the same mechanism noted earlier.⁴⁾¹³⁾ Moreover, the production of the pro-inflammatory marker “NF-κB” by blood in the subarachnoid space increases, which increases the synthesis of cytokine and adhesion molecule.⁸⁾ Cytokine affects the maintenance of vasoconstriction, keeping the impact stronger and making vasospasm last longer.⁶⁾ Although a clear mechanism has not found about microthrombi, the procoagulant state activated by increased expression of pro-inflammatory markers is influential. This activates the aggregation of leukocytes and platelets, resulting in formation of microthrombi.¹⁵⁾ DAPT can be used together to inhibit the activation and aggregation of platelets and to suppress the formation of microthrombi. Based on this mechanisms, we suggested that inflammatory pathway activation can be suppressed too.

Cagnazzo et al.¹⁾ reported that the difference in the incidence of DCI due to the use of antiplatelet drugs was not statistically significant. However, in the endovascular treated group with antiplatelet therapy, DCI tends to have a lower incidence compared to that in the group without antiplatelet treatment (157/778 vs. 413/1,410, odds ratio [OR]=0.552; 95% confidence interval [CI], 0.273–1.115, p=0.06). Moreover, when antiplatelet therapy was applied for more than 2 weeks, the incidence of DCI tended to be lower (63/438 vs. 96/353, OR=0.379; 95% CI, 0.12–1.2; p=0.06). Additionally, Darkwah et al.³⁾ showed when aspirin was used after aSAH treatment, the incidence of DCI tended to be lower, which was also statistically significant (p<0.001, adjusted OR=0.41, 95% CI 0.24–0.65).

In this single-center study, DAPT after repair of aneurysm reduce the incidence of symptomatic vasospasm and DCI. To compensate for some limitations, further prospective and randomized studies should be concerned. For patients who have high risks for symptomatic vasospasm and DCI, it may be appropriate to consider the prophylactic use of DAPT after treatment of aneurysm.