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Online July 5, 2017 Journal of Neuroendovascular Therapy 2017; 11: 553–557 DOI: 10.5797/jnet.oa.2017-0047

Safety and Efficacy of with Endovascular Treatment for Unruptured Cerebral Aneurysm

Koichi Arimura, Hirotoshi Imamura, Chiaki Sakai, Shoichi Tani, Hidemitsu Adachi, Takayuki Funatsu, Mikiya Beppu, Noriyoshi Takebe, Keita Suzuki, Tomohiro Okuda, Yuichi Matsui, Yasunori Yoshida, Syuhei Kawabata, and Nobuyuki Sakai

Objective: Recently, dual-antiplatelet therapy (DAPT) including (CLP) with endovascular treatment for unruptured cerebral aneurysm has been widely accepted. However, patients who are poor metabolizers of CLP (CLP- PMs) are more frequent in East Asians than in Caucasians, and an adequate antiplatelet effect may not be achieved with a normal dose in such patients. Prasugrel, which is a novel that is less likely to be poorly metabolized than CLP, is used widely for percutaneous coronary intervention, but its efficacy and safety with neuroendovascular treatment have not been elucidated. From this point of view, the purpose of this study was to elucidate the safety and efficacy of prasugrel with endovascular treatment for unruptured cerebral aneurysm. Methods: We investigated 108 consecutive patients with an unruptured cerebral aneurysm who underwent endovascular treatment from March 2015 to January 2016 in our hospital. All patients received DAPT with 100 mg and 75 mg CLP daily, and antiplatelet function was evaluated by VerifyNow (Accumetrics, San Diego, CA, USA). In patients with reaction units (PRU) over 230, prasugrel was administered with a loading dose of 20 mg and a maintenance dose of 3.75 mg daily. Results: Prasugrel was administered to 12 patients in our series. Of these patients, the mean age was 63.1 ± 13.0 years, and the mean PRU was 272 ± 20. Eleven patients received endovascular treatment with intracranial stents, of which four patients received treatment with flow diverters. The mean observational period was 5–13 months (median: 6.5), and no symptomatic hemorrhagic and ischemic complications occurred. Mean PRU was decreased to 159 ± 63 in the six patients in which PRU were re-examined. Conclusion: Prasugrel is safe and effective with endovascular treatment for unruptured cerebral aneurysm in CLP-PMs.

Keywords▶ prasugrel, poor metabolizer, clopidogrel, aneurysm, endovascular treatment

Introduction who are poor metabolizers of CLP (CLP-PMs) are more frequent in East Asians than in Caucasians because of the Dual-antiplatelet therapy (DAPT) including clopidogrel presence of single polymorphisms (SNPs) in (CLP) has been widely accepted with endovascular treat- 2C19 (CYP2C19), and an adequate anti- ment for unruptured cerebral aneurysm. However, patients effect may not be achieved with a normal dose in such patients.1,2) Moreover, it has been reported that the Department of Neurosurgery, Kobe City Medical Center General frequency of ischemic complications with neuroendovas- Hospital, Kobe, Hyogo, Japan cular treatment might increase in CLP-PMs.3) Prasugrel, which is another thienopyridine antiplatelet drug, is less Received: April 17, 2017; Accepted: June 1, 2017 Corresponding author: Nobuyuki Sakai. Department of Neuro- likely to be poorly metabolized than CLP because multiple surgery, Kobe City Medical Center General Hospital, 2-1-1 CYPs and esterases are associated with its activation. Minatojimaminami-machi, Chuo-ku, Kobe, Hyogo 650-0047, Although prasugrel is used widely as a percutaneous coro- Japan nary intervention (PCI), its safety and efficacy for neuroen- Email: [email protected] dovascular treatment have not been elucidated. From this This work is licensed under a Creative Commons Attribution-NonCommercial- point of view, we analyzed cases with an unruptured cere- NoDerivatives International License. bral aneurysm who underwent endovascular treatment ©2017 The Japanese Society for Neuroendovascular Therapy with prasugrel in our hospital.

Journal of Neuroendovascular Therapy Vol. 11, No. 11 (2017) 553 Arimura K, et al.

Materials and Methods

We investigated 108 consecutive patients who underwent No No No No No No No No No No No No endovascular treatment for an unruptured cerebral aneurysm Hemorrhagic from March 2015 to January 2016 in our hospital. All patients complications received DAPT with 100 mg aspirin (ASA) and 75 mg CLP daily, and antiplatelet function was evaluated by VerifyNow No No No No No No No No No No No (Accumetrics, San Diego, CA, USA). In patients with P2Y12 No reaction units (PRU) over 230, prasugrel was administered Ischemic complications with a loading dose of 20 mg and a maintenance dose of 3.75 mg daily. Since prasugrel is off-label for the 8 6 6 6 6 5 9 7 8 6

13 therapy with neuroendovascular treatment, we consulted 11 (months) with the ethics committee. Then, we got a reply that informed FU period consent was sufficient for each patient because aspirin and CLP were similarly off-label for the antithrombotic therapy with neuroendovascular treatment. Given the retrospective No No No No No No No No No No No enrollment of each patient in the present study, written No complications informed consent for participation was waived. Periprocedural 307 257 257 270 268 292 267 286 293 254 237 281 Results PRU 493 431 503 583 590 417 401 392 413 395 586 Of the 108 patients with an unruptured cerebral aneurysm 551 ARU who underwent endovascular treatment in our hospital during the observational period, prasugrel was admin- istered to 12 patients during the perioperative period FD FD FD FD Stent (Table 1). Of these patients, the mean age was 63.1 ± None Neck bridge Neck bridge Neck bridge Neck bridge Neck bridge Neck bridge 13.0 years, and 10 (83.3%) were females. The locations of Neck bridge the aneurysms were as follows: paraclinoid portion of the internal carotid artery (ICA) in eight (66.7%) patients, cav- No No No No Yes N/A N/A N/A N/A N/A ernous portion of the ICA in two (16.7%) patients, basilar N/A N/A

artery-superior cerebellar artery bifurcation in one (8.3%) Microbleeds patient, and vertebral artery in one (8.3%) patient. There were one thrombosed aneurysm (8.3%) and two symptom- HT HT HT DLP Risk None None None None None None

atic aneurysms (16.7%), and all of these were at the cav- factors HT, DLP HT, DLP HT, ernous portion of the ICA. The mean preoperative values of aspirin reaction units and PRU with VerifyNow were 480 ± 81 and 272 ± 20, respectively. Since all 12 patients had PRU >230, prasugrel was administered with a loading Site R VA

dose of 20 mg and a maintenance dose of 3.75 mg daily. L BA-SCA L ICA cavernous L ICA cavernous L ICA paraclinoid L ICA paraclinoid L ICA paraclinoid L ICA paraclinoid L ICA paraclinoid L ICA paraclinoid R ICA paraclinoid Adjunctive coil embolization using intracranial stents was R ICA paraclinoid performed in 11 patients, of which 4 patients received flow F F F F F F F F F F M M

diverters, and simple coil embolization was performed in Sex one patient. During the perioperative period, there were no hemorrhagic and ischemic complications, and the modified 62 58 49 48 73 81 81 63 82 52 51 57 Age Demographics and outcomes of 12 patients who received dual-antiplatelet therapy with aspirin prasugrel

Rankin Scale did not deteriorate in any patient at discharge. (years)

Mean PRU was decreased to 159 ± 63 in six patients

in which PRU were re-examined. However, PRU were 1 2 3 4 5 6 7 8 9 10 11 12 Table 1 Table No. hypertension; ICA: internalartery; N/A: not available; PRU: P2Y12 carotid artery; DLP: dyslipidemia; FD: flow diverter; FU: follow-up; HT: units; BA-SCA: basilar artery-superior cerebellar ARU: aspirin reaction vertebral artery units; VA: reaction not reduced to the effective range (PRU <230) after the

554 Journal of Neuroendovascular Therapy Vol. 11, No. 11 (2017) Safety and Efficacy of Prasugrel in Neuro EVT

Table 2 PRU changes before and after the administration (%) of prasugrel 100 No. Pre-PRU Post-PRU PRU FU (months) P=0.052 2 292 90 4 3 267 109 6 75 5 293 268 6 7 257 176 12 9 281 162 6 50 12 268 148 6 FU: follow-up; PRU: P2Y12 reaction units

PRU reduction rate 25 administration of prasugrel in one patient (Table 2). The 0 mean observational period was 5–13 months (median: 6.5), Prasugrel and no symptomatic hemorrhagic and ischemic complica- (n=6) (n=3) tions occurred. Fig. 1 PRU reduction rate with prasugrel and cilostazol. PRU: P2Y12 reaction units

Discussion Japan for ischemic , except for cardiogenic stroke. Since an adjunctive technique using neck bridge stents and However, the antiplatelet effect of cilostazol is thought to flow diverters has been performed commonly with endo- be weaker than that of other antiplatelet drugs because vascular treatment for unruptured cerebral aneurysm, cilostazol does not prolong bleeding time compared with perioperative DAPT including ASA and thienopyridine has other antiplatelet drugs.13,14) Besides, it is standard to become a standard therapy. Among , CLP is administer DAPT with ASA and CLP for flow divert- presently the first choice because of its reduced frequency ers.15,16) Our initial approach was to increase the dose of of side effects. CLP is a that requires biotransfor- CLP or add cilostazol for CLP-PMs, but after we experi- mation mediated mainly by the CYP2C19. The enced subacute in-stent thrombosis with a flow diverter, active metabolite of CLP provides the antiplatelet effect despite the use of such approaches, we decided to use pra- after binding to P2Y12, which is the for sugrel for CLP-PMs with endovascular treatment for diphosphate.4) However, it is known that a sufficient anti- unruptured cerebral aneurysm. According to our data, PRU platelet effect cannot be achieved in cases with SNPs in reduction rate with prasugrel and cilostazol was 42.6% and CYP2C19 (CYP2C19*2 and CYP2C19*3) because of 10.2%, respectively (Fig. 1). It suggests that antiplatelet reduced metabolic efficiency. Since SNPs in CYP2C19 are effect of prasugrel is much higher than that of cilostazol. more frequent in East Asians, including Japanese, than in Prasugrel and have been developed as novel Caucasians, CLP-PMs are common in Japan.1,2,5) alternative thienopyridines to CLP. Among them, prasugrel Ischemic complications with PCI are reportedly more has been used widely for the treatment of cardiovascular frequent in CLP-PMs than in normal metabolizers.6–9) Sim- disease in Japan. Although prasugrel is a prodrug similar to ilarly, ischemic complications with endovascular treatment CLP and its active metabolite provides the antiplatelet using stents for neurovascular disease are increased in effect, PMs of prasugrel are observed less frequently than CLP-PMs.3) Therefore, careful attention must be paid those of CLP because multiple CYPs and esterases contrib- during catheter intervention including neuroendovascular ute to its activation.17) Therefore, prasugrel could be an treatment in CLP-PMs to avoid ischemic complications. alternative drug to CLP with catheter intervention in CLP- To achieve an adequate antiplatelet effect in CLP-PMs, PMs, and if its safety is secured, it could become the first- increasing the dose of CLP or switching to other antiplate- choice treatment. let drugs should be considered. In the former, the dose of As prasugrel is used widely for PCI,18–20) some reports CLP should reportedly be increased to 150–300 mg of the use of prasugrel for neuroendovascular treatment daily;10,11) however, it has not been demonstrated that have been published recently.21–25) Prasugrel was reported increasing the dose of CLP improves the clinical outcome to be safe for neuroendovascular treatment;21) however, of patients who undergo catheter intervention.12) In the lat- another study indicated that hemorrhagic complications ter, another thienopyridine or cilostazol is usually adminis- may be increased with prasugrel.22) Furthermore, several tered as an alternative to CLP. Cilostazol is used widely in case reports on the use of prasugrel for neuroendovascular

Journal of Neuroendovascular Therapy Vol. 11, No. 11 (2017) 555 Arimura K, et al. treatment have been published. Prasugrel and ticagrelor Conclusion were effective for endovascular treatment with a flow diverter for cerebral aneurysm in CLP-PMs.23) Other case Prasugrel is safe and effective with endovascular treatment reports have indicated that a thrombus in a neck bridge for unruptured cerebral aneurysm in CLP-PMs. However, stent disappeared with prasugrel administration,24) and further investigations will be needed. prasugrel was safe in carotid artery stenting.25) Regarding the safety and efficacy of prasugrel, ischemic complica- Disclosure Statement tions were decreased but hemorrhagic complications were increased with prasugrel for PCI compared with Nobuyuki Sakai received a subsidy from Terumo Corpora- CLP in a large-scale study.18) Similarly, another study tion and lecture fees from Otsuka Pharmaceutical Co. Ltd., reported that hemorrhagic complications were increased Johnson & Johnson, Stryker, and Terumo Corporation. when prasugrel was used for neuroendovascular treat- All other authors have no conflict of interest. ment.22) However, it is still questionable whether prasu- grel contributes to hemorrhagic complications because References two of the six cases with hemorrhagic complications in 1) Desta Z, Zhao X, Shin JG, et al: Clinical significance of the that report had vessel perforation. Conversely, another cytochrome P450 2C19 genetic polymorphism. Clin Phar- report described that prasugrel is safe for neuroendovas- macokinet 2002; 41: 913–958. cular treatment.21) Although the number of cases was 2) Jinnai T, Horiuchi H, Makiyama T, et al: Impact of CYP2C19 small in the present study, our findings suggested the polymorphisms on the antiplatelet effect of clopidogrel in an safety of prasugrel for endovascular treatment of unrup- actual clinical setting in Japan. Circ J 2009; 73: 1498–1503. tured cerebral aneurysm, consistent with the previous 3) Fifi JT, Brockington C, Narang J, et al: Clopidogrel resis- report. However, as the recommendation from American tance is associated with thromboembolic complications in Heart Association, we still have to pay attention to hem- patients undergoing neurovascular stenting. AJNR Am J orrhagic complications with prasugrel for the patients Neuroradiol 2013; 34: 716–720. with past transient ischemic attack or stroke. 4) Gachet C: P2 receptors, platelet function and pharmacolog- Prasugrel has been used a loading dose of 60 mg and a ical implications. Thromb Haemost 2008; 99: 466–472. maintenance dose of 10 mg daily as a standard protocol; 5) Goldstein JA: Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol however, Stetler et al.21) reported that it was safe to use a 2001; 52: 349–355. loading dose of 40 mg and a maintenance dose of 5–10 mg 6) Shuldiner AR, O’Connell JR, Bliden KP, et al: Association daily. Furthermore, a good outcome was achieved with a of cytochrome P450 2C19 genotype with the antiplatelet maintenance dose of 5 mg daily in endovascular treat- effect and clinical efficacy of clopidogrel therapy. JAMA 26) ment with a flow diverter for cerebral aneurysm. In ran- 2009; 302: 849–857. domized studies of prasugrel and CLP for PCI in Japan, 7) Sawada T, Shinke T, Shite J, et al: Impact of cytochrome ischemic complications were decreased and hemorrhagic P450 2C19*2 polymorphism on intra-stent thrombus after complications were not changed with a loading dose of drug-eluting stent implantation in Japanese patients receiv- 20 mg and a maintenance dose of 3.75 mg daily.19,20) ing clopidogrel. Circ J 2011; 75: 99–105. 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Although there are less PMs of prasugrel 10) Simon T, Bhatt DL, Bergougnan L, et al: Genetic polymor- compared to those of CLP, increasing the dose of prasugrel phisms and the impact of a higher clopidogrel dose regimen or switching to another antiplatelet, such as ticagrelor, on active metabolite exposure and antiplatelet response in might be considered for PMs of prasugrel. healthy subjects. Clin Pharmacol Ther 2011; 90: 287–295.

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