Please Verify I’m Correct: P2Y12 Inhibiton Function Tests

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Lauren Igneri
Lauren Igneri
Critical care pharmacist and proud Rutgers University graduate. Enjoys rock climbing, cycling, travel, and lively discussions on the finer points of pharmacokinetics and critical care over a beer with friends.

Case

A 64-year-old woman presented with an acute ischemic stroke and ultimately underwent M1 thrombectomy and right carotid stent deployment. She received aspirin 324 mg and ticagrelor 180 mg loading doses prior to stenting. Unfortunately, the next morning she developed a severe headache and a CT scan revealed a large right intracerebral hemorrhage (ICH). Although she was neurologically intact, the neurosurgical team evaluated her risk for continued bleeding vs. benefit of taking her to surgery for ICH evacuation.

Upon assessing labs for risk of bleeding, P2Y12 receptor blockade was 66 P2Y12 Reaction Units (PRU, reference range 194-418 PRU) 11 hours after ticagrelor loading dose. 

As a critical care pharmacist with expertise in antithrombotic therapy, I am frequently asked to help with the interpretation of P2Y12 platelet function testing.

The Pre-brief

  • Thienopyridine therapy (e.g. clopidogrel, prasugrel, and ticagrelor) are potent antiplatelet therapies widely prescribed to ensure stent patency in cardiovascular, endovascular, and neuroendovascular disease. 
    • Inhibits P2Y12 receptors and ultimately prevents the production of adenosine diphosphate (ADP) and GPIIb/IIIa activation, resulting in inhibition of platelet aggregation.
  • VerifyNow PRUTest® assesses platelet reactivity through measurement of ADP-induced platelet aggregation expressed as P2Y12 Reaction Units (PRU).
    • In the setting of thienopyridine therapy use, PRU shows the extent of platelet aggregation in the presence of P2Y12 inhibitors.
    • Measures the “On-Treatment Platelet Reactivity” (OTPR) of the ADP P2Y12 receptor.
    • The reference range is 194-418 PRU. Values <194 PRU indicate evidence of P2Y12 inhibitor effect – said another way, low numbers = good thienopyridine antiplatelet activity

Platelet Reactivity Thresholds and Interpretation

Although there is emerging use of PRU testing in the neuroendovascular literature, most platelet reactivity thresholds were established in the percutaneous coronary intervention (PCI) world. 

ADAPT-DES was a prospective, multicenter registry of patients treated with one or more drug-eluting stents after successful PCI who received dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for secondary prevention of in-stent thrombosis. Platelet reactivity was assessed using the VerifyNow® point-of-care assays, with high platelet reactivity on clopidogrel defined as either VerifyNow P2Y12 >208 PRU or ≥230 PRU based on prior studies. VerifyNow P2Y12 measurements were taken in 8449 patients at a mean time of 20.3 h (SD 8.3 h) after PCI. The mean PRU was 188 (SD 97) following clopidogrel loading dose, but 42.7% and 35.0% of patients had high platelet reactivity (PRU >208 and ≥230, respectively). Clopidogrel was prescribed in 99.7% of patients at discharge. Although 1-year stent thrombosis was low (0.84%), it was more common in patients with high platelet reactivity when using either threshold PRU >208 (1.3%) vs. PRU ≤208 (0.5%) [HR 2.54, 95% CI 1.55-4.16, p=0.0002] or ≥230 PRU (1.3%) vs. <230 (0.6%) [HR 2.16, 95% CI 1.35-3.47, p=0.001].

There is increased utilization of neuroendovascular interventions for treating thromboembolic complications. While endoluminal stents are primarily treated with aspirin/clopidogrel DAPT, it is known that up 5-12% of patients are non-responders to clopidogrel. Therefore, the use of PRU testing with the VerifyNow P2Y12 assay is becoming increasingly common for neurosurgical patients despite limited data describing testing strategies or algorithms for modifying DAPT based on PRU. 

Corliss et al. compared 37 matched sets of PRU to thromboelastography (TEG)-platelet mapping (PM) in 23 patients that underwent carotid artery stenting, intracranial stent-assisted coiling, or flow diversion. Therapeutic platelet inhibition was defined as PRU <194 or TEG maximal amplitude-adenosine diphosphate (MA-ADP) values <50 mm. Overall, an agreement between the two tests for platelet inhibition was poor in that 39% of patients were clopidogrel non-responders based on PRU compared to 9% based on TEG-PM, p=0.035. PRU may overestimate clopidogrel resistance since 93% of patients with PRU >194 had appropriate platelet inhibition on TEG. The Pearson correlation coefficient for these values was 0.50, p=0.0026.

The same center then correlated the use of these tests with the ability to predict complications in a larger cohort of 172 patients that underwent craniocervical endovascular stenting. There was no statistically significant difference in mean MA-ADP for patients who developed thrombotic complications vs. no thrombotic complications (34.5 ± 15.2 mm vs. 35.1 ± 13.5 mm, p=0.87). However, the mean PRU was significantly higher in those patients who suffered thrombotic complications (180 ± 67 vs. 142 ± 77, p=0.048). Similarly, there was no difference in mean MA-ADP in patients experiencing hemorrhagic complications (35.7 ± 14.4 vs. 35.1 ± 13.5 mm, p=0.88), but mean PRU was significantly lower (71 ± 53 vs. 142 ± 77, p=0.0002). ROC analysis demonstrated PRU of 118 and 144 as the window needed to avoid hemorrhagic and thrombotic complications. Significant threshold values for MA-ADP could not be identified. 

Although the correlation between the MA-ADP and PRU to distinguish between clopidogrel non-responders is poor, PRU may be a useful tool to characterize the risk for bleeding and thrombotic complications.  

PRU Test Timing

Optimal timing for obtaining PRU Test depends on the choice of P2Y12 inhibitor choice and dosing:

De-brief

  • PRU testing is becoming increasingly common to characterize platelet reactivity in patients receiving thienopyridine therapy for neuroendovascular stenting. 
  • Although PRU thresholds of >208 are associated with increased thrombotic complications in the PCI literature, patients who developed thrombosis due to neuroendovascular stenting had a mean PRU of ~180. 
    • PRU 118 to 144 is likely the therapeutic window needed to avoid hemorrhagic and thrombotic complications in the neurosurgical population
  • Optimal timing of PRU testing depending on thienopyridine agent and dosing
    • Clopidogrel: 600 mg (≥ 6 hours post-loading dose), 300 mg (≥ 8 hours post-loading dose), and 75 mg daily (≥7 days on maintenance dose)
    • Prasugrel: 60 mg (≥ 45 minutes post-loading dose), 10 or 5 mg daily (≥5 days on maintenance dose)
    • Ticagrelor: 180 mg (≥ 2 hours post-loading dose, ideally within 8 hours), 90 mg twice daily (≥1 day on maintenance dose, ideally within 8 hours of the last dose)

References

  1. Accriva diagnostics. VerifyNow® Reference Guide. https://pbrainmd.files.wordpress.com/2016/04/verifynow-reference-guide.pdf
  2. Corliss BM, Freedman R, Brennan MM, et al. Laboratory assessments of therapeutic platelet inhibition in endovascular neurosurgery: complication prediction using the VerifyNow P2Y12 assay and thromboelastography with platelet mapping. J Neurosurg. 2020; 134(3):884-892.
  3. Corliss BM, Polifka AJ, Harris NS, et al. Laboratory assessments of therapeutic platelet inhibition in endovascular neurosurgery: comparing results of the VerifyNow P2Y12 assay to thromboelastography with platelet mapping. J Neurosurg. 2018; 129(5):1160-1165.
  4. Stone GW, Witzenbichler B, Weisz G, et al. ADAPT-DES Investigators. Platelet reactivity and clinical outcomes after coronary artery implantation of drug-eluting stents (ADAPT-DES): a prospective multicentre registry study. Lancet. 2013; 382(9892):614-23.

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