We analyzed the antiplatelet effects of different P2Y(12) receptor blockers with VerifyNow P2Y12 assay (VN-P2Y12) and light transmittance aggregometry (LTA).
The point-of-care VN-P2Y12 has been used to assess the antiplatelet effects in clopidogrel-treated patients but has not been evaluated in detail in patients treated with ticagrelor.
Patients were randomly assigned to either ticagrelor [180 mg loading/90 mg twice daily (n = 37)] or clopidogrel [600 mg loading/75 mg daily (n = 39)] on top of aspirin treatment, and platelet reactivity was measured serially during onset, maintenance, and offset phases. High on-treatment platelet reactivity (HPR) was defined as 5 and 20 μM adenosine diphosphate-induced maximal platelet aggregation ≥46% and ≥59%, respectively, and P2Y12 reaction units ≥235.
Platelet function measured by VN-P2Y12 correlated well with LTA (.812 ≤ ρ ≤ .823, P < .001). VN-P2Y12 "BASE" values were consistent during administration of both agents. Calculated and reported percent inhibitions by VN-P2Y12 were similar (difference, -0.6%; 95% agreement limits, -22.9% to 21.6%). Platelet inhibition by VN-P2Y12 during clopidogrel and ticagrelor administrations was comparable to platelet inhibition by LTA. HPR determined by LTA and VN-P2Y12 were well matched, and the risk stratification between the two methods showed strong agreement after both therapies (κ > .7).
The VerifyNow P2Y12 assay is effective in assessing the antiplatelet effects and in identifying HPR during clopidogrel or ticagrelor therapy.
"Interestingly, in comparing the clinical utility of this microfluidic assay to the VerifyNow P2Y12 system, ROC curve AUC values were strikingly similar. A ROC curve value of 0.929 was found in the assessment of the VerifyNow P2Y12 assay to detect antiplatelet effects during clopidogrel therapy, comparable to the 0.966 value found for 2MeSAMP in this study . Often, microfluidic chambers utilize a single flow path comprised of a millimeter length collagen coated cover slip or capillary tube enabling platelets to tether, activate, and re-adhere along the entire length . "
[Show abstract][Hide abstract] ABSTRACT: Microfluidic devices recreate the hemodynamic conditions of thrombosis.
Whole blood inhibited with PPACK was treated ex vivo with inhibitors and perfused over collagen for 300s (wall shear rate=200s(-1)) using a microfluidic flow assay. Platelet accumulation was measured in the presence of COX-1 inhibitor (aspirin, ASA), P2Y1 inhibitor (MRS 2179), P2Y12 inhibitor (2MeSAMP) or combined P2Y1 and P2Y12 inhibitors.
High dose ASA (500μM), 2MeSAMP (100μM), MRS 2179 (10μM), or combined 2MeSAMP and MRS 2179 decreased total platelet accumulation by 27.5%, 75.6%, 77.7%, and 87.9% (p<0.01), respectively. ASA reduced secondary aggregation rate between 150 and 300s without effect on primary deposition rate on collagen from 60 to 150s. In contrast, 2MeSAMP and MRS 2179 acted earlier and reduced primary deposition to collagen between 60 and 105s and secondary aggregation between 105 and 300s. RCOX and RP2Y (defined as a ratio of secondary aggregation rate to primary deposition rate) demonstrated 9 of 10 subjects had RCOX<1 or RP2Y<1 following ASA or 2MeSAMP addition, while 6 of 10 subjects had RP2Y<1 following MRS 2179 addition. Combined MRS 2179 and 2MeSAMP inhibited primary platelet deposition rate and platelet secondary aggregation beyond that of each individual inhibitor. Receiver-Operator Characteristic area under the curve (AUC) indicated the robustness of RCOX and RP2Y to detect inhibition of secondary platelet aggregation by ASA, 2MeSAMP, and MRS 2179 (AUC of 0.874 0.966, and 0.889, respectively).
Microfluidic devices can detect platelet sensitivity to antiplatelet agents. The R-value can serve as a self-normalized metric of platelet function for a single blood sample.
Thrombosis Research 11/2013; 133(2). DOI:10.1016/j.thromres.2013.10.043 · 2.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study examined the effects of grapefruit juice on the new P2Y12 inhibitor ticagrelor, which is a substrate of CYP3A4 and P-glycoprotein.
In a randomized crossover study, 10 healthy volunteers ingested 200 ml of grapefruit juice or water thrice daily for 4 days. On day 3, they ingested a single 90 mg dose of ticagrelor.
Grapefruit juice increased ticagrelor geometric mean peak plasma concentration (Cmax) to 165% (95% confidence interval 147, 184%) and area under the concentration–time curve (AUC(0,∞)) to 221% of control (95% confidence interval 200, 245%). The Cmax and AUC(0,34 h) (P < 0.05) but not the AUC(0,∞) of the active metabolite C12490XX were decreased significantly. Grapefruit juice had a minor effect on ticagrelor elimination half-life prolonging it from 6.7 to 7.2 h (P = 0.036). In good correlation with the elevated plasma ticagrelor concentrations, grapefruit juice enhanced the antiplatelet effect of ticagrelor, assessed with VerifyNow® and Multiplate® methods, and postponed the recovery of platelet reactivity.
Grapefruit juice increased ticagrelor exposure by more than two-fold, leading to an enhanced and prolonged ticagrelor antiplatelet effect. The grapefruit juice–ticagrelor interaction seems clinically important and indicates the significance of intestinal metabolism to ticagrelor pharmacokinetics.
British Journal of Clinical Pharmacology 11/2012; 75(6). DOI:10.1111/bcp.12026 · 3.88 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
There is wide variability in the reported incidence of perioperative thromboembolic (0-14%) and hemorrhagic (0-11%) complications after Pipeline Embolization Device (PED) procedures for cerebral aneurysm treatment, which could be partly due to differences in patient response to the P2Y12 receptor antagonist administered while the PED endothelializes. This study aims to identify an optimal pre-procedure P2Y12 reaction units (PRU) value range and determine the independent predictors of perioperative thromboembolic and hemorrhagic complications after PED procedures.
We recorded patient and aneurysm characteristics, P2Y12 receptor antagonist administered, pre-procedure PRU value with VerifyNow, procedural variables and perioperative thromboembolic and hemorrhagic complications up to postoperative day 30 after PED procedures at our institution during an 8-month period. Perioperative complications were considered major if they caused a permanent disabling neurological deficit or death. Multivariate regression analysis was performed to identify independent predictors of perioperative complications in our cohort.
Forty-four patients underwent 48 PED procedures at our institution during the study period. There were eight thromboembolic and hemorrhagic perioperative complications in our cohort (16.7%), four of which were major (8.3%). A pre-procedure PRU value of <60 or >240 (p=0.02) and a technically difficult procedure (p=0.04) were independent predictors of all perioperative complications. A pre-procedure PRU value of <60 or >240 (p=0.004) and a history of hypertension (p=0.03) were independent predictors of major perioperative complications.
In our cohort, a pre-procedure PRU value of <60 or >240 was the strongest independent predictor of all and major perioperative thromboembolic and hemorrhagic complications after PED procedures.
Journal of Neurointerventional Surgery 01/2013; 5(Suppl 3). DOI:10.1136/neurintsurg-2012-010582 · 2.77 Impact Factor
Chenlin Shen, Xiaohui Huang, Jun Li, Ping Zhang, Lin Li, Wei Zhang, Tingting Hu, Faustina Pappoe, Jihan Huang, Haiqin Tang
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