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P2Y12 Platelet Function Assay for Assessment of Bleeding Risk in Coronary Artery Bypass Grafting Pey-Jen Yu, M.D.,* Hugh A. Cassiere, M.D.,* Sophia L. Dellis, B.S.,* Frank Manetta, M.D.,* Joanna Stein, M.P.H.,y and Alan R. Hartman, M.D.* *North Shore University Hospital, Manhasset, New York; and yThe Feinstein Institute for Medical Research, Manhasset, New York ABSTRACT Background: The use of platelet function testing has been advocated to individualize the time needed between discontinuation of P2Y12 inhibitors and coronary artery bypass grafting (CABG). However, the use of specific point-of-care assays to predict bleeding risk in patients on P2Y12 inhibitors prior to CABG has not been fully validated. Methods: From September 2012 to May 2013, 81 patients on P2Y12 inhibitors underwent isolated CABG. Preoperative level of P2Y12 receptor blockade was measured using the VerifyNow P2Y12 assay. Packed red blood cell (pRBC) and platelet transfusions and postoperative chest tube output were correlated with preoperative P2Y12 reaction units (PRUs). Results: Patients who stopped P2Y12 inhibitors for 3 days received significantly more platelet transfusions as compared to those whose inhibitors were stopped for longer (0.71 W 1.05 units vs. 0.20 W 0.71 units, p = 0.01). They also had increased postoperative chest tube output (552.5 W 325.5 mL vs. 399.8 W 146.5 mL, p = 0.03). There was no significant difference in platelet transfusions and chest tube output between patients whose preoperative PRU value was 3 days prior to surgery (Table 4). Similar to PRU values, there was no significant difference in pRBC transfusion requirements between patients who stopped their P2Y12 inhibitors for 3 days or >3 days (Table 4). Univariate analysis of demographic and preoperative and intraoperative clinical variables revealed that increasing age (p < 0.01) and lower preoperative hematocrit (p < 0.001) predicted pRBC transfusion requirements. In addition to number of days of discontinuation of P2Y12 inhibitors, cardiopulmonary bypass time predicted the amount of platelet transfusions (p ¼ 0.03 and p ¼ 0.02, respectively). Only the number of days of discontinuation of P2Y12 inhibitors predicted chest tube output (p ¼ 0.02). Multivariable analyses demonstrated that there remains no significant predictive association between PRU levels and pRBC or platelet transfusion requirements, even after adjusting for differences in age and preoperative hematocrit (p ¼ 0.15). Table 5 lists predictors of bleeding and transfusion requirements based on multivariable analysis. Only preoperative hematocrit remained a significant predictor of pRBC transfusions. Number of days of discontinuation of P2Y12 inhibitors remained a significant predictor of number of platelet transfusions, after adjustment for age and perfusion time (p ¼ 0.02).

P-Value

CONCLUSIONS

0.39 1.00 0.31 0.55 1.00

This study showed that in patients on preoperative P2Y12 inhibitors undergoing isolated CABG, the time interval between discontinuation of the inhibitor and surgery correlates with both postoperative bleeding as measured by chest tube outputs and perioperative platelet transfusion requirements. In contrast, preoperative PRU values do not predict amount of bleeding or transfusion. While age and preoperative hematocrit were independent predictors of pRBC transfusions, neither timing of discontinuation of P2Y12 inhibitors nor PRU levels correlated with pRBC transfusions. There are different established and commercially available platelet function tests. Prior studies establishing the use of platelet function tests to determine the timing of CABG in patients on preoperative P2Y12 inhibitors and their risk of bleeding have used thrombelastography platelet mapping assay,11,12 multiple electrode whole-blood aggregometry,14,15 and platelet-rich

0.03 0.45 0.18 0.23 0.12 0.12 0.66 0.37 0.37

BMI, body mass index; CPB, cardiopulmonary bypass; INR, international normalized ratio; PRU, P2Y12 reaction units.

TABLE 3 Transfusion and Bleeding Based on PRU Level

pRBC transfusion Required transfusion, n (%) Platelet transfusion Required transfusion, n (%) 12 hours chest tube output, mL

PRU 3 Days, n = 26

P-Value

1.89  1.89 22 (63%) 0.71  1.05 14 (40%) 552.5  326.5

1.60  2.69 11 (44%) 0.20  0.71 2 (8%) 399.8  146.5

0.185 0.011 0.030

pRBC, packed red blood cell.

plasma ADP aggregometry.13 The VerifyNow system is a turbidimetry-based optical detection device that measures ADP-induced platelet aggregation in a system containing fibrinogen-coated beads in whole blood. Although widely utilized for preoperative evaluation of patients on P2Y12 inhibitors undergoing isolated CABG, its use for that indication has not been fully validated. Brizzio et al.16 reported that the use of VerfiyNow assay results to determine the timing of isolated off-pump CABG procedures for patients on preoperative P2Y12 inhibitors reduced the median waiting time for surgery from the last dose of inhibitor from six to three days and that patients with greater than 21% platelet inhibition by P2Y12 inhibitors prior to surgery were at higher risk for postoperative but not intraoperative transfusions of blood products. The study, however, did not account for confounding preoperative and intraoperative variables that were associated with increased risk of transfusion as those variables were not measured. Despite studies supporting the use of various pointof-care platelet function assays to reduce the waiting time from discontinuation of P2Y12 inhibitors to CABG and to determine the bleeding and transfusion risk of surgery, our study did not show an association between the results of preoperative platelet function testing as determined by the VerifyNow assay and perioperative bleeding and transfusion requirements. This highlights differences in specimen processing and the different aspects of platelet function that is measured between the various tests. Chen et al. reported the use of platelet function testing with ADP aggregometry to identify patients at high risk for perioperative bleeding and transfusions. However, in the same study, they

TABLE 5 Multivariable Analysis P-Value pRBC Transfusion Preoperative hematocrit Platelet transfusion Cardiopulmonary bypass time Time of last P2Y12 inhibitor (3 days vs. >3 days) Age 12 hours chest tube output Time of last P2Y12 inhibitor (3 days vs. >3 days) pRBC, packed red blood cell.

240,22 the cut-off value of 250 was chosen for this study to increase the specificity for determination of the risk of surgical bleeding. There are several limitations to the current study. First, although a multivariable analysis was performed, factors that were not accounted for in the multivariable analysis may confound the data. Second, as there is no transfusion protocol, the decision for transfusions is at the discretion of the surgeon. However, this study compares outcomes of patients divided by either PRU values or the number of days of discontinuation of ADP inhibitors; the variability in transfusion thresholds should be equally represented in both datasets. Furthermore, the correlation between number of days of discontinuation of ADP inhibitors and both platelet transfusion requirements and chest tube output

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validates that the increased transfusion is secondary to measurable increase in bleeding, not simply surgeon preference or variability. In addition, the sample size is small and the results represent a single-center experience. Studies involving patients from multiple centers with a larger sample size with defined triggers for blood product transfusion will be necessary to further evaluate these observations. In conclusion, this study demonstrates that in patients on P2Y12 inhibitors undergoing CABG surgery, discontinuation of P2Y12 inhibitors three days prior to surgery rather than PRU values predicts the need for platelet transfusions and increased postoperative bleeding. Furthermore, PRU values are not predictive of RBC transfusions. Strict reliance on platelet function testing to determine the timing of surgery for patients on P2Y12 inhibitors should therefore be done with caution.

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P2Y12 platelet function assay for assessment of bleeding risk in coronary artery bypass grafting.

The use of platelet function testing has been advocated to individualize the time needed between discontinuation of P2Y12 inhibitors and coronary arte...
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