The use of antiplatelet agents, such as P2Y12 inhibitors, is standard care in the management of numerous neurological pathologies and neuroendovascular procedures.¹ These antiplatelet therapies are essential for maintaining vasculature and intracerebral stent patency during and immediately following a neuroendovascular procedure. In many cases, the use of oral P2Y12 agents (ticagrelor, clopidogrel, and prasugrel) may not be feasible due to the time required for adequate platelet inhibition, lack of enteral access and prolonged platelet inhibition in patients with high risk of hemorrhage or requiring additional invasive procedures. Historically, many neuroendovascular centers have utilized intravenous glycoprotein IIb/IIIa inhibitors.^2,3 Despite their faster onset and offset, these agents can also be problematic due to their duration of effects. (Table 1). Although an offset time of up to 8 hours may not seem lengthy compared to the oral P2Y12 inhibitors, an agent with even shorter duration of effects would be preferred if a patient experiences a life threating hemorrhage. Since the approval of cangrelor, an intravenous P2Y12 inhibitor, there is an increased interest in utilizing it during and immediately following neuroendovascular procedures due to its favorable pharmacokinetic properties.

Table 1: Pharmacokinetic Properties of Anti-platelet Agents⁴

Key: GP – glycoprotein; PLT – platelet; *onset of antiplatelet effects can be as early as 30 minutes when ticagrelor is crushed

Despite these favorable characteristics, the ideal dosing regimen of cangrelor for neuroendovascular procedures is unknown. The available literature is limited by small sample sizes and retrospective design. Many of these studies utilize various dosing strategies, with reported dosing of an initial bolus ranging from 5-30 mcg/kg, followed by a continuous infusion ranging from 0.5-4 mcg/kg/min⁶. With these dosing strategies, the practice of monitoring platelet function tests to ensure adequate platelet inhibition while minimizing the risk of intracranial hemorrhage has emerged. The VerifyNow™ P2Y12 assay is a point-of-care laboratory test that assesses platelet function by exposing the patient’s blood sample to fibrinogen-coated beads. The interaction between the blood and the beads results in activation of platelets in the blood sample and consequential aggregation that alters the transmittance of light through the sample.⁷ The resulting P2Y12 Reaction Unit (PRU) value informs the clinician of the patient’s response to P2Y12 inhibitor therapy.  Per the manufacturer, a reference range of 194-418 PRU is indicative of no platelet inhibition, while values < 194 PRU indicate decreased platelet activity.⁸ In studies that have assessed cangrelor in neuroendovascular patients, a goal PRU of 50-150 is commonly used and was derived from a previous study in cardiac patients showing adequate platelet inhibition in a majority of patients with a PRU within this range.⁶ Platelet function tests like the VerifyNow™ P2Y12 assay were developed to streamline testing of patients receiving antiplatelet therapies, with the majority of data supporting its use with clopidogrel, as well as the other oral P2Y12 inhibitors in cardiac patients¹. Importantly, there are some limitations to using the VerifyNow™ P2Y12 assay, specifically factors that may interfere with results and impact the ability of a clinician to make accurate therapeutic decisions. Per the manufacturer, these include other antiplatelet therapies, such as the glycoprotein IIb/IIIa inhibitors and cilostazol, which have interfered with PRU results during assay performance testing. Additionally, low hematocrit levels (<33%), low platelet counts (<119,000/µL), high triglyceride levels (>824 mg/dL), or hemolysis of the blood sample may also interfere with results.⁸

There is a paucity of data elucidating a dose-response relationship with cangrelor dose titrations and PRU results and if this practice is associated with improved clinical outcomes. In a retrospective review published in 2021, Holden et al., explored the effect of dose adjustments of cangrelor using the VerifyNow™ P2Y12 results in 72 patients. This study demonstrated a potential dose-response relationship of cangrelor with 17% of patients having a PRU within the desired range (PRU 50-150) with an initial 5 mcg/kg bolus and a 0.75-1 mcg/kg/min infusion. This percentage subsequently increased to 67% of patients in the desired range following dose adjustments in response to PRU results⁶. In a second retrospective review utilizing similar cangrelor dosing (5 mcg/kg bolus and 0.75-1 mcg/kg/min initial infusion), there was an increase in the number of patients (44% to 62% of patients) within the study’s target PRU range (10-150) following dose titrations using PRU results.⁹ To the authors’ knowledge, these are the only two studies that evaluate a potential dose-response relationship between the PRU value and cangrelor dosing, though there are other studies that utilize similar dosing and monitoring strategies in neuroendovascular patients.¹⁰ Currently, it remains unclear whether this dose-response relationship leads to improved clinical outcomes.

Based on the available literature, our institution uses a cangrelor 15 mcg/kg bolus, followed by an initial infusion rate of 2 mcg/kg/min. The infusion rate is subsequently titrated by the interventionalist based on the VerifyNow™ P2Y12 assay results. For most patients, a goal PRU of 50-150 is utilized but may vary at the discretion of the neuroendovascular team.  While our institution does not have a set titration protocol in place, there are plans for an upcoming study to evaluate our dosing and titration strategy and subsequent PRU results to help establish a protocol for cangrelor use in this patient population.

With evolving antiplatelet practices in neuroendovascular procedures, there are many opportunities for research. Future analysis should seek to answer the following questions:

1. What is the ideal dose of cangrelor during and after neuroendovascular procedures?
2. Can platelet function tests, such as the VerifyNow™ assay, be used to guide cangrelor doses?
3. Is there a dose-response relationship between cangrelor dose titrations and PRU results?
4. Does titration of cangrelor to a specific PRU goal decrease rates of bleeding while maintaining stent or vasculature patency?
5. If titrations are clinically necessary, what is the ideal PRU goal for neuroendovascular patients?

Given the perceived benefit and increased use of cangrelor in neuroendovascular procedures, it is vital that further research be conducted to help answer the aforementioned gaps in knowledge.