Pharmacy-Mediated Antiplatelet Management Algorithm Surrounding Neurointerventional Stenting and Flow Diversion Procedures LETTER: I n a recent survey of major academic neurovascular centers in the United States published in WORLD NEUROSURGERY, 1 VerifyNow (Accriva Diagnostics, San Diego, California, USA) was the preferred platelet function test before Pipeline (Covidien-Ev3, Plymouth, Minnesota, USA) embolization. Thromboembolic and hemorrhagic complications are the major source for morbidity and mortality surrounding neurointerventional procedures. Risks are particularly high with permanent implantation of intraluminal devices such as flow diverters or extracranial and intracranial stents. To mitigate these risks, patients are routinely started on dual antiplatelet therapy consisting of aspirin and clopidogrel 1 for a period of time leading up to the procedure and thereafter. Aspirin irreversibly inhibits the cyclooxygenase-1 isoform within platelets, which prevents thromboxane A2 production. Regular dose aspirin usually results in 95% inhibition of the thromboxane A2 formation capacity, the level required for clinical effectiveness. 2 Clopidogrel is a second generation thienopyridine prodrug that needs to be converted into its active thiol metabolite by various hepatic cytochrome P450 enzymes, mainly CYP2C19. It exhibits platelet inhibition by irreversibly binding to the adenosine diphosphate (ADP) P2Y12 receptor. An appropriate response to these medications, however, cannot be reliably expected as there is variability in the degree of platelet inhibition from patient to patient. Prevalence of aspirin and clo- pidogrel resistance range from 0.4% to 83% and 4% to 30%, respectively. 2 The main mechanisms for aspirin and clopidogrel resistance are noncompliance, inappropriate dosing, drug interactions (nonsteroidal anti-inflammatory agents intact with aspirin. whereas statins, calcium channel blockers, and proton pump inhibitors with clopidogrel), genetic variability at the metabolism or target level, increased ADP release, alternate platelet activation pathways, and high platelet turn over. 2 Platelet function testing before implantation of an intravascular de- vice to assure adequate platelet inhibition has become popular among neurointerventionalists, in particular before flow diverter placement. 1 Inadequate platelet inhibition by clopidogrel, referred to as clopidogrel hyporesponse, is associated with an increased risk for thromboembolic complications after stent-assisted coil embolization or flow diversion for cerebral aneurysms. 3,4 Conversely, excessive platelet inhibition by clopidogrel, or clopidogrel hyper-response, may increase the risk for hemorrhagic complications. 3 Evidence suggests, however, that tailored antiplatelet management based on the results of platelet function testing leads to a reduction of thromboembolic complication rates after flow diversion. 4 Point-of-care platelet function tests, such as VerifyNow, are becoming increasingly popular. In an aforementioned survey, VerifyNow was named the preferred test before Pipeline emboliza- tion by 69% of respondents. 1 Platelet aggregation in whole blood is measured by VerifyNow using light transmission quantification. Cartridges with agonist measure platelet response to aspirin (VerifyNow aspirin [VNA]) and clopidogrel (VerifyNow P2Y12 [PNA]). Intra-assay variation of coefficients (CV) for VNA and PNA are 0.5%e19% and 4.4%e7.3%, respectively. Interassay (e.g., day-to-day) CVs are <5% and 5.2%e12.9%, respectively. 2 In a study of healthy volunteers and patients with stable coronary artery disease, VNA intra-assay and interassay CVs were lower than with light transmission aggregometry (LTA), an alternative platelet function test, often referred to as the gold standard. 2 However, a aspirin reaction unit cutoff 550 (manufacturer recommendation) is associated with a poor sensitivity and good specificity using arachidonic acid-LTA as a reference. 5,6 A different study showed intra-assay CV of 19% and a high correlation with LTA. 7 For PNA, the cartridge has 2 chambers. One chamber houses the platelet activator ADP and the P2Y1 receptor inhibitor prostaglandin E 1 . Both reagents increase the sensitivity and specificity for ADP-induced platelet activation. The second chamber contains thrombin receptor-activating peptide and measures maximum platelet aggregation. The P2Y12 reaction unit (PRU) value relates to the inhibition of the ADP-induced P2Y12-mediated platelet activa- tion compared with maximum platelet aggregation. 8 Several studies have demonstrated good correlation of PRU with ADP-LTA. 2 In a significant number of patients, VerifyNow-directed antiplatelet management is cumbersome as frequent dose adjustments are necessary to maintain the patient in the therapeutic range. Coupled with time and personnel restrains of an active neurovascular prac- tice, antiplatelet regimens may not be optimally managed in some patients. To overcome this issue and standardize antiplatelet management surrounding neurointerventional stenting and flow diversion procedures, we have collaborated with the hospital and system pharmacy and developed an algorithm for patients treated in our health care system. The pharmacy team takes an active role in the adjustment of antiplatelet agents before the procedure and thereafter comparable to an anticoagulation or warfarin clinic. Upon booking of a neurointerventional procedure that involves the placement of an intraluminal device, the neurointerventionalist notifies the pharmacy of the procedure date. Aspirin and clopi- dogrel are started 3 weeks before the procedure with a first aspirin reaction unit and PRU check after 1 week. The doses of both med- ications are adjusted, as outlined in Figure 1. Patients that are difficult to manage beyond the outlined algorithm are discussed with the neurointerventionalist on a case by case basis. Patients are tested immediately before the procedure, on postprocedure day 1, and at 1 week, 1 month, 3 months, and 6 months after the procedure and appropriate dose adjustments are made. This protocol was first implemented 2.5 years ago and has since expanded to other indications such as patients on dual antiplatelet agents for secondary stroke prevention. We believe that this approach may be of interest to other neurovascular centers looking to adapt a similar approach for their patients. Christoph J. Griessenauer 1 , Shamsher S. Dalal 2 , Stacey A. Grassi 3 , Tarun Bhalla 4 , Clemens M. Schirmer 1 From the Departments of 1 Neurosurgery, 2 Radiology, and 3 Pharmacy, Geisinger Health System, Danville, Pennsylvania; and 4 Department of Neurosurgery, University of Rochester, Rochester, New York, USA To whom correspondence should be addressed: Christoph J. Griessenauer, M.D. [E-mail: christoph.griessenauer@gmail.com] http://dx.doi.org/10.1016/j.wneu.2017.06.189. WORLD NEUROSURGERY 106: 981-982, OCTOBER 2017 www.WORLDNEUROSURGERY.org 981 Letter to the Editor