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Safety and Efficacy of Prasugrel with Endovascular Treatment for Unruptured Cerebral Aneurysm

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Safety and Efficacy of Prasugrel with Endovascular Treatment for Unruptured Cerebral Aneurysm Online July 5, 2017 Journal of Neuroendovascular Therapy 2017; 11: 553–557 DOI: 10.5797/jnet.oa.2017-0047 Safety and Efficacy of Prasugrel 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 clopidogrel (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 thienopyridine antiplatelet drug 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 aspirin and 75 mg CLP daily, and antiplatelet function was evaluated by VerifyNow (Accumetrics, San Diego, CA, USA). In patients with P2Y12 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 nucleotide polymorphisms (SNPs) in (CLP) has been widely accepted with endovascular treat- cytochrome P450 2C19 (CYP2C19), and an adequate anti- ment for unruptured cerebral aneurysm. However, patients platelet 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. not reduced to the effective range (PRU effective to the not reduced PRU were re-examined. However, PRU were in which Mean PRUwasdecreasedto 159 Rankin Scaledidnotdeteriorate inanypatientatdischarge. modified the and complications, ischemic and hemorrhagic one patient.Duringtheperioperativeperiod,therewereno diverters, andsimplecoilembolizationwasperformedin flow received patients 4 which of patients, 11 in performed Adjunctive coilembolizationusingintracranialstentswas dose of20mgandamaintenance3.75daily. had PRU 480 were VerifyNow with PRU units and aspirin reaction of The meanpreoperativevalues ernous portionoftheICA. atic aneurysms(16.7%),andallofthesewereatthecav were onethrombosedaneurysm(8.3%)andtwosymptom There patient, andvertebralarteryinone(8.3%)patient. artery-superior cerebellararterybifurcationinone(8.3%) intwo(16.7%)patients,basilar ernous portionoftheICA internal carotidartery(ICA)ineight(66.7%)patients,cav the aneurysmswereasfollows:paraclinoidportionof The locationsof 13.0 years,and10(83.3%)werefemales. ( istered to12patientsduringtheperioperativeperiod during theobservationalperiod,prasugrelwasadmin who underwentendovasculartreatmentinourhospital Of the108patientswithanunrupturedcerebralaneurysm informed consentforparticipationwaswaived. written enrollment ofeachpatientinthepresentstudy, retrospectivewith neuroendovasculartreatment.Giventhe fortheantithrombotictherapy weresimilarlyoff-label CLP consent was sufficient for each patient because aspirin and Then, wegotareplythatinformed with theethicscommittee. therapy withneuroendovasculartreatment,weconsulted fortheantithrombotic Sinceprasugrelisoff-label mg daily. with aloadingdoseof20mgandmaintenance3.75 was administered230, prasugrel (PRU) over reaction units (Accumetrics, SanDiego,CA,USA).InpatientswithP2Y12 VerifyNow was evaluated by and antiplateletfunction daily, with100mgaspirin(ASA)and75CLP received DAPT All patients from March2015toJanuary2016inourhospital. endovascular treatmentforanunrupturedcerebralaneurysm investigated108consecutivepatientswhounderwent We Table 1 Table 554 Results Materials andMethods ± 81 and 272 81 and > ). Ofthesepatients,themeanagewas63.1 230, prasugrel was administered with a loading prasugrel wasadministeredwitha 230, ± 20, respectively. Since all 12 patients all 12 Since 20, respectively. ± 63insixpatients < 230) after the 230) after ± - - - - Table 1 Demographics and outcomes of 12 patients who received dual-antiplatelet therapy with aspirin and prasugrel Age Risk Periprocedural FU period Ischemic Hemorrhagic No. Sex Site Microbleeds Stent ARU PRU (years) factors complications (months) complications complications 1 48 M L ICA paraclinoid None No Neck bridge 431 257 No 8 No No 2 73 F L ICA paraclinoid HT N/A FD 417 292 No 6 No No 3 81 F L ICA paraclinoid HT, DLP N/A Neck bridge 401 267 No 6 No No 4 81 F L ICA cavernous HT, DLP No FD 392 286 No 6 No No 5 63 F R ICA paraclinoid None No Neck bridge 413 293 No 6 No No 6 82 F L ICA cavernous HT No FD 395 254 No 5 No No 7 52 M R VA None N/A FD 503 257 No 13 No No 8 51 F L ICA paraclinoid None N/A None 586 237 No 11 No No 9 57 F L ICA paraclinoid HT N/A Neck bridge 551 281 No 9 No No 10 62 F L BA-SCA DLP Yes Neck bridge 493 307 No 7 No No 11 58 F L ICA paraclinoid None N/A Neck bridge 583 270 No 8 No No 12 49 F R ICA paraclinoid None N/A Neck bridge 590 268 No 6 No No ARU: aspirin reaction units; BA-SCA: basilar artery-superior cerebellar artery; DLP: dyslipidemia; FD: flow diverter; FU: follow-up; HT: hypertension; ICA: internal carotid artery; N/A: not available; PRU: P2Y12 reaction units; VA: vertebral artery 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 Cilostazol 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 stroke, 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 thienopyridines, 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 prodrug that requires biotransfor- CLP or add cilostazol for CLP-PMs, but after we experi- mation mediated mainly by the enzyme 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 receptor for adenosine sugrel for CLP-PMs
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