脳循環代謝28巻2号　pp

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1 原著 Active Target P2Y12 Reaction Unit Management 要旨 / P2Y12 Reaction UnitPRU Active Target PRU Management PRU Active Target PRU Management キーワード : はじめに Cytochrome P450CYP TEL: FAX: nakagawa@naramed-u.ac.jp 2, 3 2, 3 4 / P2Y12 Reaction UnitPRU Active Target PRU Management doi: /cbfm.28.2_

2 28 2 方法 Biaspirin; Bayer AG, Leverkusen, Germany 100 mg Plavix; Sanofi Paris, France75 mg 7 VerifyNow Accumetrics, NY, USA Active PRU target PRU 5, 6 PRU>240 PRU< mg A: 75 mg/b: 50 mg/ C: 25 mg/d: 12.5 mg/ PRU 2 Fig PRU mg/ 2 7 PRU mg/ 14 PRU mg/ 14 PRU mg/ 14 PRU mg/ 3 7 PRU mg 14 PRU mg/ 14 PRU mg/ PRU PRU>240 Hyporesponse 95 PRU 240 Normo-response PRU<95 Hyper-response 3 PRU value >240 PRU PRU PRU <50 PRU minor ischemic stroke, 30 major ischemic stroke Active Target PRU Management PRU 1 step down 2 step down Fig. 1.Clopidogrel dose reduction methods. Clopidogrel dose was determined by P2Y12 reaction units (PRU) value (stepdown methods). Kruskal-Wallis test, Fishers exact test, Repeated measure ANOVA mean±sd p<0.05 結 PRU Hypo-response Normo-response Hyper-response Table 1simple technique, balloon assisted, stent assisted Table 2PRU Normo-response 7 PRU inhibition Table 3, 4 Active Target PRU Management PRU 果 CLP dose 75mg/d 50mg/d 25mg/d 12.5mg/d 242

3 Active Target PRU Management Table 1.Clinical characteristics No. of Patients (%) Hypo-response (PRU>240) (n=6) Normo-response (95 PRU 240) (n=46) Hyper-response (PRU<95) (n=9) p value General characteristics Mean age 68±9.6 55± ± Females 6 (100) 36 (78.3) 7 (77.8) Risk factor Hypertension 5 (83) 26 (57) 5 (56) Diabetes 1 (17) 1 (2) 1 (11) Current smoker 0 (0) 17 (39) 3 (33) CKD 1 (17) 2 (4) 0 (0) Medications Statins 2 (33) 9 (20) 3 (33) ARBs 4 (67) 12 (26) 3 (33) PPIs 0 (0) 2 (4) 0 (0) PRU: P2Y12 reaction unit, CKD: chronic kidney disease, ARBs: Angiotensin receptor blockers, PPIs: proton pump inhibitors Table 2.Coil embolization procedure and clinical results No. of Patients (%) Hypo-response (PRU>240) (n=6) Normo-response (95 PRU 240) (n=46) Hyper-response (PRU<95) (n=9) p value Procedure Simple technique 1 (17) 8 (17) 2 (22) BAT or DCT 1 (17) 14 (30) 3 (33) Stent assist 4 (67) 24 (52) 4 (44) Clinical results Major ischemic events 0 (0) 0 (0) 0 (0) Minor ischemic events 0 (0) 3 (7) 0 (0) Hemorrhagic events 0 (0) 0 (0) 0 (0) PRU: P2Y12 reaction units, BAT: balloon assist technique, DCT: double catheter technique Table 3.Platelet function before and after the treatment Before the treatment Values 7 days after the treatment p value Hypo-response group ARU 492.5± ± PRU 265.2± ± % inhibition 12.3± ± Normo-response group ARU 445.3± ± PRU 169.3± ± % inhibition 38.5± ± Hyper-response group ARU 405.8± ± PRU 63.0± ± % inhibition 76.6± ± ARU: aspirin reaction units, PRU: P2Y12 reaction units, : p<

4 28 2 Table 4.Conversion of platelet reactivity 7 days after coil embolization pre-treatment 7 days after coil embolizatuion Hypo-response Normo-response Hyper-response (PRU>240) (95 PRU 240) (PRU<95) Hypo-response group (PRU>240) Normo-response group (95 PRU 240) Hyper-response group (PRU<95) P2Y12 Reaction Units (PRUs) p<0.01 Before Day 7 Day 14 Day 30 Day PRU Fig. 2 Normo-response minor ischemic stroke 3 major ischemic stroke 考察 p<0.01 Fig. 2.Changes of P2Y12 reaction units (PRU) value before and after coil embolization. Gray territory indicates target PRU range (95 PRU 240). Active Target PRU Management ADP P2Y CYP 7 percutaneous coronary intervention: PCIPCI 8 PCI Hoshino CYP 1 2, 3 3, 11, 12 PRU PRU AMP ADP PRU

5 Active Target PRU Management 4, 13 Goh Delgado , Delgado 13 3 P2Y12 PCI , PRU Active Target PRU Management 結論 PRU Active Target PRU Management COI 文献 1Jeong YH, Koh JS, Kang MK, Ahn YJ, Kim IS, Park Y, Hwang SJ, Kwak CH, Hwang JY: The impact of generic clopidogrel bisulfate on platelet inhibition in patients with coronary artery stents: results of the ACCEL-GENERIC study. Korean Journal of Intern Med 25: , Angiolillo DJ, Fernandez-Ortiz A, Bernardo E, Alfonso F, Macaya C, Bass TA, Costa MA: Variability in individual responsiveness to clopidogrel: clinical implications, management, and future perspectives. J Am Coll Cardiol 49: , Nakagawa I, Park HS, Yokoyama S, Wada T, Hironaka Y, Motoyama Y, Takayama K, Kichikawa K, Nakase H: Influence of diabetes mellitus and cigarette smoking on variability of the clopidogrel-induced antiplatelet effect and efficacy of active management of the Target P2Y12 Reaction Unit Range in patients undergoing neurointerventional procedures. J Stroke Cerebrovasc Dis 25: , Goh C, Churilov L, Mitchell P, Dowling R, Yan B: Clopidogrel hyper-response and bleeding risk in neurointerventional procedures. AJNR. Am J Neuroradiol 34: , Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, Buonamici P, Antoniucci D, Abbate R, Gensini GF: Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up. Circulation 119: , Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neu- 245

6 28 2 mann FJ, Metzger DC, Henry TD, Cox DA, Duffy PL, Mazzaferri E, Gurbel PA, Xu K, Parise H, Kirtane AJ, Brodie BR, Mehran R, Stuckey TD; ADAPT-DES Investigators: Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT- DES): a prospective multicentre registry study. Lancet 382: , Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, Topol EJ; CREDO Investigators. Clopidogrel for the Reduction of Events During Observation: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 288: , Angiolillo DJ, Fernández-Ortiz A, Bernardo E, Ramírez C, Sabaté M, Bañuelos C, Hernández-Antolín R, Escaned J, Moreno R, Alfonso F, Macaya C: High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 25: , Campo G, Parrinello G, Ferraresi P, Lunghi B, Tebaldi M, Miccoli M, Marchesini J, Bernardi F, Ferrari R, Valgimigli M: Prospective evaluation of on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention relationship with gene polymorphisms and clinical outcome. J Am Coll Cardiol 57: , Hoshino K, Horiuchi H, Tada T, Tazaki J, Nishi E, Kawato M, Ikeda T, Yamamoto H, Akao M, Furukawa Y, Shizuta S, Toma M, Tamura T, Saito N, Doi T, Ozasa N, Jinnai T, Takahashi K, Watanabe H, Yoshikawa Y, Nishimoto N, Ouchi C, Morimoto T, Kita T, Kimura T: Clopidogrel resistance in Japanese patients scheduled for percutaneous coronary intervention. Circ J 73: , Nakagawa I, Wada T, Park HS, Nishimura F, Yamada S, Nakagawa H, Kichikawa K, Nakase H: Platelet inhibition by adjunctive cilostazol suppresses the frequency of cerebral ischemic lesions after carotid artery stenting in patients with carotid artery stenosis. J Vasc Surg 59: , Nakagawa I, Park HS, Wada T, Yokoyama S, Yamada S, Motoyama Y, Kichikawa K, Nakase H: Efficacy of cilostazol-based dual antiplatelet treatment in patients undergoing carotid artery stenting. Neurol Res 2017, Mar 14. doi: / [Epub ahead of print] 13Delgado Almandoz JE, Kadkhodayan Y, Crandall BM, Scholz JM, Fease JL, Tubman DE: Variability in initial response to standard clopidogrel therapy, delayed conversion to clopidogrel hyper-response, and associated thromboembolic and hemorrhagic complications in patients undergoing endovascular treatment of unruptured cerebral aneurysms. J Neurointerv Surg 6: , Daou B, Starke RM, Chalouhi N, Barros G, Tjoumakaris S, Rosenwasser RH, Jabbour P: P2Y12 reaction units: effect on hemorrhagic and thromboembolic complications in patients with cerebral aneurysms treated with the pipeline embolization device. Neurosurgery 78: 27 33, Delgado Almandoz JE, Crandall BM, Scholz JM, Fease JL, Anderson RE, Kadkhodayan Y, Tubman DE: Lastrecorded P2Y12 reaction units value is strongly associated with thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in patients with cerebral aneurysms treated with the pipeline embolization device. AJNR. Am J Neuroradiol 35: , Haq MM, Ahsan CH, Amin MN, Karim MR, Ali ML, Khan SR, Chowdhury MZ, Mansur M, Millat MH, Rashid MA: Comparison of P2Y12 receptor inhibition by clopidogrel and prasugrel in patients undergoing percutaneous coronary intervention. Bangladesh Med Res Counc Bull 39: , Sedat J, Chau Y, Gaudart J, Sachet M, Beuil S, Lonjon M: Prasugrel versus clopidogrel in stent-assisted coil embolization of unruptured intracranial aneurysms. Interv Neuroradiol 23: 52 59, Akbari SH, Reynolds MR, Kadkhodayan Y, Cross DT, 3rd, Moran CJ: Hemorrhagic complications after prasugrel (Effient) therapy for vascular neurointerventional procedures. J Neurointerv Surg 5: , Leslie-Mazwi TM, Chandra RV, Yoo AJ, Rabinov JD, Hirsch JA: Hemorrhagic complications with prasugrel therapy for vascular neurointerventional procedures. J Neurointerv Surg 5: ,

7 Active Target PRU Management Abstract Possibility of active management of the target P2Y12 reaction unit range in patients undergoing aneurysmal neurointerventional procedures Ichiro Nakagawa, Shohei Yokoyama, Hun-Soo Park, Daisuke Wajima, Fumihiko Nishimura, Shuichi Yamada, Hiroshi Yokota, Yasushi Motoyama, Young-Su Park, and Hiroyuki Nakase Department of Neurosurgery, Nara Medical University, Nara, Japan Optimal antiplatelet inhibition is essential in patients undergoing neurointerventional procedures, however, variability in response to clopidogrel can contribute to thromboembolic and hemorrhagic complications. In the present study, we evaluated the impact of active management of antiplatelet reactivity in patients undergoing aneurysmal neurointerventional procedures. Between 2013 and 2016, 61 consecutive patients (male; 12, mean age; 57) underwent aneurysmal coil embolization and received clopidogrel (75 mg daily) and aspirin (100 mg daily) before the treatment under platelet function monitoring. Patients underwent prospective assessment of preoperative platelet function using VerifyNow assay and received adjunctive cilostazol (200 mg daily; triple antiplatelet therapy) in case of clopidogrel hypo-response. Patient with clopidogrel hyper-response underwent clopidogrel dose reduction according to the protocol (clopidogrel, mg daily). Successful coil embolization was performed in all patients. Stent-assisted coil embolization was performed in 32 patients (53%). Preoperative clopidogrel resistance was noted in 6 patients (10%) and clopidogrel hyper response was noted in 9 patients (24%). In active management of platelet reactivity resulted in optimization of P2Y12 reaction units (PRU) value within the target range during and after the treatment. There were no symptomatic thromboembolic or hemorrhagic events. In conclusion, active management of clopidogrel dosing for clopidogrel hyper-response and adjunctive cilostazol for clopidogrel hypo-response resulted in an adjustment of PRU value to within a target range, and there were no hemorrhagic complications after the treatment. Key words: unruptured aneurysm, coil embolization, platelet reactivity, clopidogrel hyper-responder 247

21-07_後藤論文.smd

21-07_後藤論文.smd 2015; 21: 5866 Yoichi Goto: Current status and future perspective of cardiac rehabilitation in Japan. J Jpn Coron Assoc 2015; 21: 5866 I 1 1 3 1 2 3 QOL 2 Fig. 1 1 196070 AMI AMI 1980 AMI CABG comprehensive

脳循環代謝28巻2号 pp

脳循環代謝28巻2号　pp