So, my name is Matt Bender. I'm a sixth-year neurosurgery resident at Johns Hopkins, completing my second year of an unfolded endovascular fellowship, here to talk about our experience with the precision of VerifyNow P2Y12 assessment of a clopidogrel response in patients undergoing cerebral aneurysm flow diversion. The senior authors have relationships with some of the companies involved in the neurointerventional field. I have no personal disclosures to make. By way of background, dual antiplatelet therapy, as we all know, with aspirin and Plavix, is a standard of care in intracranial stenting procedures, which we inherited from cardiology, where we're shown to be safe in patients undergoing percutaneous coronary invention. There is significant known variability in clopidogrel response, due to medication interactions, comorbidities, but chiefly due to genetics and variation in cytochrome P450 enzymes, the best characterized of which is the CYP2C19, you can see in the upper left, with common gain and loss of function polymorphism shown. Despite this genetic understanding, clinical practice relies on phenotype in antiplatelet therapy testing. There are numerous options for antiplatelet therapy testing, most of which are plagued by protracted processing times and a lack of standardization in their outcomes. Among these, VerifyNow has come to predominate due to its point of care availability and its comprehensible standardized results. P2I12, obviously, is a controversial topic, as anyone who's attended these in the past would know, with numerous retrospective studies suggesting a relationship between high and low values, respectively, and ischemic and hemorrhagic complications after neurointervention. On the other hand, there are meta-analyses showing that studies that incorporate antiplatelet therapy testing actually have higher rates of complications than those that do not. Within this context, this study arose based on our clinical experience at Hopkins, where we routinely observe discordance between patients who have serial P2I12 levels drawn, that is, within less than 24 hours. We developed a hypothesis that patients on a stable antiplatelet regimen would show significant variation in PRU. We had no idea how great this variation might be, but speculated that it could influence responder status, which at other institutions might lead to changes in antiplatelet therapy or procedure cancellation. We maintain a prospective IRB-approved aneurysm database, which between 2011, when pipeline was approved, and 2017, included 643 patients who underwent pipeline embolization. Our standard practice is to start these patients on dual antiplatelet therapy seven days before elective flow diversion. We went back and collected P2I12 values for all these patients, which were drawn in the course of routine clinical practice in a non-systematic fashion, and found more than 1,500 values. We identified the levels that were drawn within 24 hours of each other, and excluded patients who had received alternative antiplatelet medications like hepciximab, paracetamol, and diclodipine, as well as levels that were obtained before five days of therapy, which brought us to our study population, which included 140 patients who accounted for 230 P2I12 levels. To answer a couple of methodological questions, one patient can contribute multiple sets of levels to this series, the most common scenario being a patient who had multiple aneurysms embolized, such as this patient with mirror-large distal ICA aneurysms treated with a combination of pipeline and coiling. And how might patients have multiple draws taken within 24 hours? The most common scenario is for a patient to have a level sent in the pre-op area before embolization, and then another to sent by our closed NCC unit overnight. Closed NCC unit overnight. Inpatients, for instance, patients who had subarachnoid hemorrhage, a subtotal coiling strategy, and then underwent definitive flow diversion within the same same, might also have levels sent on consecutive days. And occasionally, levels were rechecked, for instance, in patients with significant bruising in a PRU of 200 or more that didn't make sense to us. This is a pretty simple study. So I want to focus, and there's only two slides of results. I want to make sure that I explain these clearly. The first way of visualizing our results is based on PRU range. So for each patient, we took the high and the low level within the set and calculated the range. So if a patient had a 50 and a 55 within 24 hours, they would be a 5. If a patient had a 150 and a 220 within 24 hours, they would be a 70. Those ranges are displayed on the y-axis here. We arranged those 230 sets in ascending order and found that the 25th percentile had a PRU range of 12 points. The 50th percentile or median had a PRU range of 26 points. And the 75th percentile had a PRU range of 48 points, which is to say that if you were to send repeat levels within 24 hours, a quarter of those patients would have a PRU range of nearly 50 points or greater. The second way of visualizing these results is based on responder category. So we took each level that was sent and assigned it a label of either hyper response if it was less than 60, hypo response if it was greater than 200, or therapeutic if it was between 60 and 200. The sets were then classified as either being stable if all of those labels were within the same therapeutic category or unstable if they fell into more than one therapeutic category. The three bars on the left represent the stable sets, which accounted for 76% of the sets. And the bars on the right describe the unstable sets. So 24% of patients who had multiple levels drawn within 24 hours, those levels would be in different therapeutic categories. Given the need for dual antiplatelet therapy for intracranial stenting procedures and what we know about interindividual variation in clavicle response, many have recognized this is a great target for personalization or antiplatelet tailoring. And yet the results of antiplatelet tailoring both in the cardiology and in neuro-interventional fields have been mixed. This is a representative study of one of the positive results from stroke of this year. A retrospective study across three institutions, including 399 patients, 115 non-responders who were either switched to ticagrelor, bolus with clopidogrel or continued on standard dual antiplatelet therapy, thromboembolic complication rates for patients continued on standard therapy were greater than 50% as compared with less than 10% for clopidogrel-boosted patients and less than 5% for patients switched to ticagrelor. On the other hand, there are studies showing that while tailoring can achieve a therapeutic PRU, it doesn't necessarily reduce complications. The University of Minnesota, they have a 17-day dual antiplatelet course that they put patients on. They check a level at day 10, found 72% of patients were within therapeutic range. They then adjust medication dosing based on their PRU result and an algorithm they have and are able to bring 89% of patients within range by day 17. Those patients go on to embolization, but ischemic stroke rates remained 4.9%, which is, you know, within range or at the high end of the range for contemporary flow diversion. So why have we seen these mixed results for antiplatelet therapy tailoring? One reason is for intra-individual, that is within the same person variation in PRU. This is a great study from the cardiology field. The Elevate Timmy trial showing that for a fixed dose, fixed duration of therapy, a patient's response is not stereotyped. Patients were given two 14-day cycles of Plavix 75 milligrams with a washout period in between, and they saw that 22% of patients shifted between therapeutic and hypotherapeutic response at the end of those two cycles. Forty-one percent of patients showed a difference of greater than 40 PRU points. They attributed this to biological variability due to fluctuations in platelet production, P2Y12 receptor expression, and changes in hepatic metabolism. We controlled for that biological variation by sending multiple levels within a 24-hour period, and this yields the conclusion that P2Y12 itself is an unstable phenomenon. Twenty-four percent of patients switched response groups. The average range was 35 points. The median was 28 points. We're not saying that there is not a connection between the effectiveness of antiplatelet therapy and ischemic and hemorrhagic complications of neurointervention, but rather that the imprecision of our existing diagnostics by misclassifying some percentage of patients based on the results of, like, you know, agrogometry or PRU may explain the mixed results of antiplatelet therapy tailoring. Optimization of diagnostics is needed, including genetic testing, more use of P2Y12 inhibitors with improved pharmacodynamics may be warranted. There are limitations to this study, which are many of the problems with retrospective observational studies. Obviously, it required difficult decisions about time cutoffs for inclusion, but pretty standard in the literature to treat patients after five days of therapy. There was also no standardized interval between the dosing and the lab tests. Some patients were morning embolization. Some were evening embolization. Some patients took their medications in the morning and some in the evening. But we thought this reflected clinical practice and was consistent with our goal of describing the real-world variation and precision of this test. Thank you, Dr. Bender. And with that, you know, welcome to the Cerebrovascular Scientific Session for today. Are there any questions for Dr. Bender while I ask the next author you lay to come up? I'm sorry, Dr. Cano to come up. Yes, one question. You over there. Yes, please. Hi, and I'm Koreshi from Hartford, Connecticut. I don't know what this is working on. Great talk. Just a question. You know, some of our cardiology colleagues have had similar issues with clopidogrel and aspirin. I'm sorry, and platelet function. And some of them have actually switched over to Berlinta. I don't know if you've had any experience with that or investigators or any thoughts about potentially another endoplatelet agent that might have a more easier profile in terms of platelet adhesion. I think, I mean, AdHOPC is at least the sort of next best agent that we've been using is paracigrel or Effiant. The challenge with that, particularly in our patient population, is that it's expensive. But Berlinta is another great option. I think it requires twice daily dosing. And, you know, it may have a more rapid onset, become therapeutic rapidly. But if you have a potentially noncompliant patient population, you also have to worry about patients missing doses and the ischemic risks associated with that. Okay, great.

neurosurgery resident

VerifyNow P2Y12 assessment

clopidogrel response

cerebral aneurysm flow diversion

dual antiplatelet therapy