Last-Recorded P2Y12 Reaction Units Value Is Strongly Associated with Thromboembolic and Hemorrhagic Complications Occurring Up to 6Months after Treatment in Patients with Cerebral Aneurysms Treated with the Pipeline Embolization Device

BACKGROUND AND PURPOSE: A recent study identified a preprocedural P2Y12 reaction units value of 60 or 240 as a strong independent predictor of perioperative thromboembolic and hemorrhagic complications after treatment of cerebral aneurysms with the Pipeline Embolization Device. This study aimed to determine whether a last-recorded P2Y12 reaction units value of 60 or 240 predicts thromboembolic and hemorrhagic complications up to 6 months after treatment of cerebral aneurysms with the Pipeline Embolization Device in the same patient cohort. MATERIALS ANDMETHODS: We recorded patient and aneurysm characteristics, P2Y12 receptor antagonist administered, P2Y12 reaction units value with VerifyNow, procedural variables, and thromboembolic and hemorrhagic complications up to 6 months after Pipeline Embolization Device procedures at our institution during an 8-month period. Complications causing a permanent disabling neurologic deficit or death were considered major. Multivariate regression analysis was performed to identify independent predictors of thromboembolic and hemorrhagic complications. RESULTS: Forty-four patients underwent 48 Pipeline Embolization Device procedures at our institution during the study period. There were 11 thromboembolic and hemorrhagic complications up to 6 months after treatment in our cohort (22.9%), 5 of which were major (10.4%). A last-recorded P2Y12 reaction units value of 60 or 240 was the only independent predictor of all (P .002) andmajor (P .03) thromboembolic and hemorrhagic complications in our cohort. Most patients (71%) required, on average, 2 adjustments to the dose or type of P2Y12 receptor antagonist to remain within the 60–240 target P2Y12 reaction units range. CONCLUSIONS: In our cohort, a last-recorded P2Y12 reaction units value of 60 or 240 was the only independent predictor of all and major thromboembolic and hemorrhagic complications up to 6 months after Pipeline Embolization Device procedures. ABBREVIATIONS: DAT dual antiplatelet therapy; ICH parenchymal intracerebral hemorrhage; PED Pipeline Embolization Device; PRU P2Y12 reaction units Endovascular treatment of cerebral aneurysms with the Pipeline Embolization Device (PED; Covidien/ev3, Irvine, California) requires its deployment within the lumen of the parent artery to allow the vessel to endothelialize along the PED and exclude the aneurysm from the circulation. This process carries the risk of thromboembolic complications because platelets could become activated, adhere to the PED, form thrombus, and cause either in situ PED thrombosis or distal thromboembolization. Hence, PED procedures are usually performed under dual antiplatelet therapy (DAT) with aspirin and a P2Y12 receptor antagonist such as clopidogrel, prasugrel, or ticagrelor. However, DAT carries the risk of hemorrhagic complications, with parenchymal intracerebral hemorrhage (ICH) being the most potentially devastating. Case series of 12–191 patients with cerebral aneurysms treated with the PED have reported a wide range of thromboembolic and hemorrhagic complications, with the risk of cerebral infarction ranging from 0% to 14% and the risk of ICH ranging from 0% to 11%. Among other factors, the variability in thromboembolic and hemorrhagic complications after PED procedures could be due to differences in patient responses to the P2Y12 receptor antagonists administered while the PED endothelializes. The P2Y12 receptor plays a central role in platelet activation and aggregation. Clopidogrel and prasugrel cause irreversible inhibition of the P2Y12 receptor, while ticagrelor causes reversible Received February 11, 2013; accepted after revision April 15. From the Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, Minneapolis, Minnesota. Paper previously presented in part at: Ninth Annual Meeting of the Society of NeuroInterventional Surgery, July 23–26, 2012, San Diego, California; and International Stroke Conference 2013, February 6–8, 2013, Honolulu, Hawaii. Please address correspondence to Josser E. Delgado Almandoz, MD, Division of Interventional Neuroradiology, Neuroscience Institute, Abbott Northwestern Hospital, 800 E 28th St, Minneapolis, MN 55407; e-mail: [email protected] Indicates open access to non-subscribers at www.ajnr.org Indicates article with supplemental on-line table http://dx.doi.org/10.3174/ajnr.A3621 128 Delgado Almandoz Jan 2014 www.ajnr.org inhibition of this receptor. VerifyNow (Accumetrics, San Diego, California) is a point-of-care platelet function test that measures the degree of P2Y12 receptor inhibition after stimulation with adenoside diphosphate, a P2Y12 receptor agonist. This assay has been found to correlate strongly with light transmittance aggregometry, the criterion standard for quantification of platelet reactivity, in patients treated with clopidogrel, prasugrel, or ticagrelor. VerifyNow results are reported in P2Y12 reaction units (PRUs), with a lower PRU value corresponding to a higher degree of P2Y12 receptor inhibition and, hence, a decreased likelihood of platelet activation and aggregation; and a higher PRU value corresponding to a lower degree of P2Y12 receptor inhibition and, hence, an increased likelihood of platelet activation and aggregation. A recent study of 44 patients who underwent 48 PED procedures for treatment of cerebral aneurysms at our institution found that a preprocedural PRU value of 60 or 240 measured with VerifyNow was the strongest independent predictor of perioperative thromboembolic and hemorrhagic complications occurring up to postoperative day 30. The aim of this study was to determine whether a last-recorded PRU value of 60 or 240 (up to the occurrence of a complication, if any) predicts thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in the same cohort of patients with cerebral aneurysms treated with the PED at our institution. MATERIALS AND METHODS Our study was approved by the institutional review board of our hospital and conducted in compliance with the Health Insurance Portability and Accountability Act. We conducted a retrospective analysis to examine the predictors of thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in patients who underwent treatment of cerebral aneurysms with the PED at our institution from November 17, 2011 to July 23, 2012. Medical Record Review We recorded baseline patient characteristics, dose and type of P2Y12 receptor antagonist administered, P2Y12 receptor inhibition with the VerifyNow test (in PRUs) up to the occurrence of a thromboembolic or hemorrhagic complication (if any), aspirin dose, aneurysm characteristics, number of PEDs deployed, technical difficulties, procedure time, postprocedural corticosteroid regimen, and the incidence and severity of thromboembolic and hemorrhagic complications occurring up to 6 months after the PED procedure. Procedures were considered technically difficult if there was PED herniation into the aneurysm, incomplete PED opening requiring balloon angioplasty for adequate wall apposition, PED migration during deployment requiring a second PED to cover the aneurysm neck, or concurrent treatment of another cerebral aneurysm. Thromboembolic and hemorrhagic complications were reviewed by a panel of 3 neurointerventionalists and were designated “major” if they caused a permanent disabling neurologic deficit or death. DAT Protocol P2Y12 receptor inhibition was assessed with the VerifyNow test in all patients before the procedure and 10 and 30 days after any changes to the dose or type of P2Y12 receptor antagonist administered, after changes to medications that may affect clopidogrel or prasugrel metabolism, or at any time if the patient was symptomatic with abnormal bruising/bleeding or focal neurologic deficits. The target P2Y12 receptor inhibition initially was 80 –200 PRUs and was subsequently expanded to 60 –240 PRUs after July 27, 2012. For most elective PED procedures (83%), DAT was started 10 days before the procedure with 325 mg aspirin daily and 75 mg clopidogrel daily. The clopidogrel response was assessed the day before the procedure. Clopidogrel hyporesponders received a 60-mg prasugrel loading dose the day before the procedure followed by 10 mg prasugrel daily, and the initial prasugrel response was assessed on the day of the procedure. Clopidogrel hyper-responders were placed on every other day, every third day, every Monday and Friday, every fourth day, or every fifth day dosing regimens as needed to reach the target PRU range. Prasugrel hyporesponders received a 180-mg loading dose of ticagrelor followed by 90 mg twice a day with the initial ticagrelor response assessed before the procedure. Prasugrel hyper-responders in follow-up testing initially had the daily prasugrel dose reduced to 5 mg and, if needed, were subsequently placed on every other day or every third day dosing regimens to reach the target PRU range. Although the aforementioned adjustments to the dose or type of the P2Y12 receptor antagonist administered were made according to the preprocedural PRU value, elective PED procedures were not rescheduled to a later date to reach the target PRU range before PED deployment. For urgent/emergent PED procedures, a 60-mg loading dose of prasugrel was administered followed by 10 mg prasugrel daily, with the initial prasugrel response assessed before the procedure and follow-up testing performed as described above. PED Procedure The PED procedure was performed with the patient under general anesthesia by a team of 2 neurointerventionalists by using transfemoral access in a dedicated biplanar neuroangiographic unit (Axiom Artis; Siemens, Erlangen, Germany). Heparinization was used throughout the procedure to achieve an activated clotting time 2–2.5 times baseline. A triaxial system was used with a 6F long sheath (Shuttle; Cook, Bloomington, Indiana), a distal access catheter (ReFlex; Covidien/ev3 or Neuron; Penumbra, Alameda, California), and a Marksman microcatheter (Covidien/ev3). A 0.016-inch (Headliner; Terumo, Tokyo, Japan) or 0.014-inch (Traxcess; MicroVention, Aliso Viejo, California or Avigo; Covidien/ev3) microwire was used to advance the Marksman microcatheter across the aneurysm neck. The PED device was deployed across the aneurysm neck under fluoroscopic guidance. A postdeployment DynaCT (Siemens) angiography performed to ensure adequate PED vessel wall apposition and aneurysm neck coverage. Final biplanar angiography was performed to document patency of the intracranial vasculature. Hemostasis was achieved with an Angio-Seal device (St. Jude Medical, Minnetonka, Minnesota). Heparinization was not continued postprocedure. Statistical Analysis Statistical analysis was performed using MedCalc 11.1 software package (MedCalc Software, Mariakerke, Belgium). First, we perAJNR Am J Neuroradiol 35:128–35 Jan 2014 www.ajnr.org 129 formed univariate analysis with the 2 or Fisher exact test for each variable to identify the predictors of all and major thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in our cohort. Then, we performed multivariate regression analysis to identify the independent predictors of all and major thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in our cohort. A P value .05 was considered statistically significant. RESULTS From November 17, 2011, to July 23, 2012, forty-four patients underwent 48 PED procedures to treat 54 cerebral aneurysms at our institution. Thirty-six patients were women (81.8%), and 8, men (18.2%). Mean age was 59.2 years (median, 63 years; range, 31– 81 years). Seven patients had a remote history of subarachnoid hemorrhage (15.9%), and 10, a family history of cerebral aneurysms (22.7%). Ten aneurysms were symptomatic (18.5%), 11 had recurred after coiling (20.4%), and 27 were incidental (50%). Mean maximum aneurysm size was 8.4 mm (median, 5.8 mm; range, 1.9 –27.6 mm). Mean aneurysm neck size was 4.8 mm (median, 4 mm; range, 1.1–17 mm). Mean procedure time was 67.7 minutes (median, 50.5 minutes; range, 28 –220 minutes). Seventeen procedures were technically difficult (35.4%), with a mean procedure time of 108.7 minutes (median, 91 minutes; range, 56 –220 minutes). Mean number of PEDs deployed was 1.3 (range, 1–5). Mean last-recorded PRU value up to the occurrence of a thromboembolic or hemorrhagic complication (if any) was 130.2 (median, 132.5; range, 0 –292). Mean time interval from initiation of DAT to the last P2Y12 receptor inhibition test up to the occurrence of a thromboembolic or hemorrhagic complication (if any) was 103.3 days (median, 83 days; range, 7–233 days). Thromboembolic and Hemorrhagic Complications Occurring Up to 6 Months after Treatment of Cerebral Aneurysms with the PED and Associated Last-Recorded PRU Values Table 1 summarizes the incidence of thromboembolic and hemorrhagic complications occurring up to 6 months after treatment in our cohort according to the last-recorded PRU value, using a PRU value of 240 as a proposed cutoff for P2Y12 receptor underinhibition and a PRU value of 60 as a proposed cutoff for P2Y12 receptor overinhibition. There were 6 thromboembolic (12.5%) and 5 hemorrhagic (10.4%) complications occurring up to 6 months after treatment in our cohort. Of these, 5 were major (10.4%): Three resulted in a permanent disabling neurologic deficit (6.2%, one thromboembolic, 2 hemorrhagic), and 2 ICHs resulted in death (4.2%). The 4 perioperative thromboembolic complications in our cohort (one of which was major) have been described previously. There were 2 additional thromboembolic complications occurring after the perioperative period in our cohort: 1 patient with an asymptomatic delayed PED thrombosis after treatment of a blister ICA aneurysm identified at the time of the 6-month follow-up angiogram (PRU 193), and 1 patient with a delayed perforator infarction causing nondisabling deficits in short-term memory and executive planning after treatment of an anterior cerebral artery aneurysm (PRU 205, Fig 1). The patient with the major perioperative thromboembolic complication had a markedly elevated PRU value (PRU 292) at the time of the