原著 Active Target P2Y12 Reaction Unit Management 要旨 / P2Y12 Reaction UnitPRU Active Target PRU Management 61 2 7 9 15 25 41 PRU Active Target PRU Management 282412472017 キーワード : はじめに Cytochrome P450CYP 1 2017 1 30 2017 3 8 634-0813 840 TEL: 0744-22-3051FAX: 0744-29-0818 E-mail: nakagawa@naramed-u.ac.jp 2, 3 2, 3 4 / P2Y12 Reaction UnitPRU Active Target PRU Management doi: 10.16977/cbfm.28.2_241 241
28 2 方法 2013 1 2016 9 61 49 57 Biaspirin; Bayer AG, Leverkusen, Germany 100 mg Plavix; Sanofi Paris, France75 mg 7 VerifyNow Accumetrics, NY, USA 7 14 30 90 5 Active PRU target 95240 PRU 5, 6 PRU>240 PRU<95 200 mg 7 1 3 612 A: 75 mg/b: 50 mg/ C: 25 mg/d: 12.5 mg/ PRU 2 Fig. 1 1 7 PRU 95 75 mg/ 2 7 PRU 5094 50 mg/ 14 PRU 95 50 mg/ 14 PRU 5094 25 mg/ 14 PRU 50 12.5 mg/ 3 7 PRU 50 25 mg 14 PRU 95 25 mg/ 14 PRU 94 12.5 mg/ PRU PRU>240 Hyporesponse 95 PRU 240 Normo-response PRU<95 Hyper-response 3 PRU value >240 PRU 95-240 PRU 50-94 PRU <50 PRU 30 24 30 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 32 53 28 47 44 73 1 2 3 5 13 22 PRU Hypo-response 6 6 68 Normo-response 46 36 55 Hyper-response 9 7 57 Table 1simple technique, balloon assisted, stent assisted Table 2PRU 9 15 7 25 41Normo-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
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±13.0 57±15.6 0.098 Females 6 (100) 36 (78.3) 7 (77.8) 0.442 Risk factor Hypertension 5 (83) 26 (57) 5 (56) 0.443 Diabetes 1 (17) 1 (2) 1 (11) 0.197 Current smoker 0 (0) 17 (39) 3 (33) 0.193 CKD 1 (17) 2 (4) 0 (0) 0.322 Medications Statins 2 (33) 9 (20) 3 (33) 0.545 ARBs 4 (67) 12 (26) 3 (33) 0.129 PPIs 0 (0) 2 (4) 0 (0) 0.714 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) 0.933 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) 1.000 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±84.9 493.0±81.9 0.992 PRU 265.2±34.0 212.5±83.7 0.132 % inhibition 12.3±3.8 35.8±26.6 0.054 Normo-response group ARU 445.3±75.9 429.6±74.7 0.103 PRU 169.3±45.7 122.3±78.5 0.006 % inhibition 38.5±17.3 53.4±29.8 0.034 Hyper-response group ARU 405.8±70.4 443.1±87.8 0.210 PRU 63.0±24.8 91.0±43.6 0.119 % inhibition 76.6±10.1 58.5±22.9 0.052 ARU: aspirin reaction units, PRU: P2Y12 reaction units, : p<0.05 243
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 2 3 1 (PRU>240) Normo-response group 2 25 19 (95 PRU 240) Hyper-response group 0 4 5 (PRU<95) P2Y12 Reaction Units (PRUs) 360 320 280 240 200 160 120 80 40 0 p<0.01 Before Day 7 Day 14 Day 30 Day 90 7 7 90 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 P2Y12 2 1 2 2 CYP 7 percutaneous coronary intervention: PCIPCI 8 PCI 36 1 13 9 Hoshino 4 93 4 50 10 CYP 1 2, 3 3, 11, 12 PRU PRU AMP ADP PRU 11 3 3 244
Active Target PRU Management 4, 13 Goh 47 10 21 72 43 4 Delgado 100 13 14, 15 9 15 7 25 41 Delgado 13 3 P2Y12 PCI 16 17 18, 19 13 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: 154 161, 2010 2Angiolillo 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: 1505 1516, 2007 3Nakagawa 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: 163 171, 2016 4Goh C, Churilov L, Mitchell P, Dowling R, Yan B: Clopidogrel hyper-response and bleeding risk in neurointerventional procedures. AJNR. Am J Neuroradiol 34: 721 726, 2013 5Marcucci 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: 237 242, 2009 6Stone GW, Witzenbichler B, Weisz G, Rinaldi MJ, Neu- 245
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: 614 623, 2013 7Steinhubl 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: 2411 2420, 2002 8Angiolillo 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: 1903 1910, 2004 9Campo 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: 2474 2483, 2011 10Hoshino 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: 336 342, 2009 11Nakagawa 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: 761 767, 2014 12Nakagawa 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: 10.1080/01616412.2017.1301042. [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: 767 773, 2014 14Daou 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, 2016 15Delgado 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: 128 135, 2014 16Haq 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: 139 145, 2013 17Sedat 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, 2017 18Akbari SH, Reynolds MR, Kadkhodayan Y, Cross DT, 3rd, Moran CJ: Hemorrhagic complications after prasugrel (Effient) therapy for vascular neurointerventional procedures. J Neurointerv Surg 5: 337 343, 2013 19Leslie-Mazwi TM, Chandra RV, Yoo AJ, Rabinov JD, Hirsch JA: Hemorrhagic complications with prasugrel therapy for vascular neurointerventional procedures. J Neurointerv Surg 5: 344 345, 2013 246
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, 12.5-75 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