Platelet Function Inhibitors in Neurointerventional Procedures
Platelet Function Inhibitors in Neurointerventional Procedures
Over the past decade there has been a growing use of intracranial stents for the treatment of both ischemic and hemorrhagic cerebrovascular disease, including stents to assist in the remodeling of the neck of aneurysms as well as the use of flow diverting devices for aneurysm treatment. With this increase in stent usage has come a growing need for the neurointerventional (NI) community to understand the pharmacology of medications used for modifying platelet function, as well as the testing methodologies available. Platelet function testing in NI procedures remains controversial. While pre-procedural antiplatelet assays might lead to a reduced rate of thromboembolic complications, little evidence exists to support this as a standard of care practice. Despite the routine use of dual antiplatelet therapy (DAT) with aspirin and a P2Y12 receptor antagonist (such as clopidogrel, prasugrel, or ticagrelor) in most neuroembolization procedures necessitating intraluminal reconstruction devices, thromboembolic complications are still encountered. Moreover, DAT carries the risk of hemorrhagic complications, with intracerebral hemorrhage (ICH) being the most potentially devastating.
Light transmission aggregometry (LTA) is the gold standard to test for platelet reactivity, but it is usually expensive and may not be easily obtainable at many centers. This has led to the development of point-of-care assays, such as the VerifyNow (Accumetrics, San Diego, California, USA), which correlates strongly with LTA and can reliably measure the degree of P2Y12 receptor inhibition. VerifyNow results are reported in P2Y12 reaction units (PRUs), with a lower PRU value corresponding to a higher level of P2Y12 receptor inhibition and, presumably, a lower probability of platelet aggregation, and a higher PRU value corresponding to a lower level of P2Y12 receptor inhibition and, hence, a higher chance of platelet activation and aggregation.
While aspirin resistance is perhaps less common, clopidogrel resistance may be more challenging as it is reported in the monitoring cohort to be as high as 30–35% and is usually due in part to genetic variation, which is reported to increase thromboembolic complications even with escalating dosing of clopidogrel. Patients who have CYP2C19 allelic variants are highly likely to exhibit clopidogrel resistance. The cardiology literature, representing many large multicenter randomized controlled trials, did not show an overall clinical outcome benefit of antiplatelet therapy modification based on pre-procedural assays. However, there is evidence in the cardiology literature to suggest that clopidogrel resistance leads to a higher level of thrombotic complications. The validity of extrapolating the cardiology literature to the NI population is questionable, especially since the underlying vessel in the setting of cerebral aneurysm treatment with concomitant stent placement may not be as diseased with atherosclerotic plaque and precedent angioplasty as in the coronary circulation. Furthermore, NI procedures using stents and flow diverters have been associated with perioperative ICH, and some studies indicate that P2Y12 receptor over-inhibition may play a role. Many NI procedures necessitate patient treatment with mono antiplatelet therapy or DAT for variable periods of time, with or without pre-procedural loading doses. The purpose of this consensus paper is to develop recommendations for the use of platelet function testing in this unique patient population.
Abstract and Introduction
Introduction
Over the past decade there has been a growing use of intracranial stents for the treatment of both ischemic and hemorrhagic cerebrovascular disease, including stents to assist in the remodeling of the neck of aneurysms as well as the use of flow diverting devices for aneurysm treatment. With this increase in stent usage has come a growing need for the neurointerventional (NI) community to understand the pharmacology of medications used for modifying platelet function, as well as the testing methodologies available. Platelet function testing in NI procedures remains controversial. While pre-procedural antiplatelet assays might lead to a reduced rate of thromboembolic complications, little evidence exists to support this as a standard of care practice. Despite the routine use of dual antiplatelet therapy (DAT) with aspirin and a P2Y12 receptor antagonist (such as clopidogrel, prasugrel, or ticagrelor) in most neuroembolization procedures necessitating intraluminal reconstruction devices, thromboembolic complications are still encountered. Moreover, DAT carries the risk of hemorrhagic complications, with intracerebral hemorrhage (ICH) being the most potentially devastating.
Light transmission aggregometry (LTA) is the gold standard to test for platelet reactivity, but it is usually expensive and may not be easily obtainable at many centers. This has led to the development of point-of-care assays, such as the VerifyNow (Accumetrics, San Diego, California, USA), which correlates strongly with LTA and can reliably measure the degree of P2Y12 receptor inhibition. VerifyNow results are reported in P2Y12 reaction units (PRUs), with a lower PRU value corresponding to a higher level of P2Y12 receptor inhibition and, presumably, a lower probability of platelet aggregation, and a higher PRU value corresponding to a lower level of P2Y12 receptor inhibition and, hence, a higher chance of platelet activation and aggregation.
While aspirin resistance is perhaps less common, clopidogrel resistance may be more challenging as it is reported in the monitoring cohort to be as high as 30–35% and is usually due in part to genetic variation, which is reported to increase thromboembolic complications even with escalating dosing of clopidogrel. Patients who have CYP2C19 allelic variants are highly likely to exhibit clopidogrel resistance. The cardiology literature, representing many large multicenter randomized controlled trials, did not show an overall clinical outcome benefit of antiplatelet therapy modification based on pre-procedural assays. However, there is evidence in the cardiology literature to suggest that clopidogrel resistance leads to a higher level of thrombotic complications. The validity of extrapolating the cardiology literature to the NI population is questionable, especially since the underlying vessel in the setting of cerebral aneurysm treatment with concomitant stent placement may not be as diseased with atherosclerotic plaque and precedent angioplasty as in the coronary circulation. Furthermore, NI procedures using stents and flow diverters have been associated with perioperative ICH, and some studies indicate that P2Y12 receptor over-inhibition may play a role. Many NI procedures necessitate patient treatment with mono antiplatelet therapy or DAT for variable periods of time, with or without pre-procedural loading doses. The purpose of this consensus paper is to develop recommendations for the use of platelet function testing in this unique patient population.
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