Clinical Investigations

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1 Clinical Investigations Predicting Bleeding Risk by Platelet Function Testing in Patients Undergoing Heart Surgery Wiktor Kuliczkowski, MD; Joanna Sliwka, MD; Jacek Kaczmarski, MD; Dorota Zysko, MD; Michal Zembala, MD; Damian Steter, MD; Marian Zembala, MD; Seth Fortmann, MD; Victor Serebruany, MD Department of Cardiology (Kuliczkowski), Wroclaw Medical University, Wroc / law, Poland; Department of Cardiac Surgery and Transplantation (Sliwka, Kaczmarski, Zembala, Steter, Zembala), Silesian Center for Heart Diseases, Zabrze, Poland; Department of Medical Emergency (Zysko), Wroclaw Medical University, Wroclaw, Poland; HeartDrug Research Laboratories (Fortmann, Serebruany), Johns Hopkins University, Baltimore, Maryland Address for correspondence: Victor Serebruany, Associate Professor HeartDrug Research Laboratories Johns Hopkins University Osler Medical Building 7600 Osler Drive, Suite 307 Towson, MD heartdrug@aol.com Background: Predicting bleeding events in patients with coronary artery bypass grafting (CABG) represents an unmet medical need that may improve CABG outcomes. Hypotesis: To assess the potential link between platelet function testing and bleeding risk in patients undergoing CABG. Methods: Platelet aggregation and clinical outcomes in 478 patients treated with aspirin and/or clopidogrel were retrospectively analyzed. Platelet activity was assessed prior to CABG with arachidonic acid (ASPI Test), and adenosine diphosphate(adp Test) utilizing multiple-electrode aggregometry. Results: In the study group of 478 patients, mean age was 65.2±15.2 years; 138 were women. The majority of patients (n = 198) underwent on-pump surgery, with 162 undergoing off-pump and 30 undergoing minimally invasive surgery. Forty-eight patients received artificial valve implantation alone, and 40 received valve implantation in combination with CABG. The analysis of the entire pool revealed that an ASPI test value <407 area under curve per minute (AUC*min) may be useful in predicting postoperative drainage. In CABG patients only, an ASPI test value <271 AUC*min predicted the need for red blood cell concentrate transfusion following surgery. In patients who stopped clopidogrel for up to 5 days before surgery, the ADP test failed to exhibit prognostic utility for predicting bleeding risk. Conclusions: In patients undergoing heart surgery, an ASPI test value <407 AUC*min may predict higher postoperative drainage, whereas <271 AUC*min may be linked to postoperative use of red blood cell concentrate. Introduction The combination of clopidogrel with aspirin in acute coronary syndrome (ACS) patients has revealed repeatedly improved vascular outcomes. 1,2 However, the improvements come at the cost of elevated bleeding risk. Bleeding can deteriorate well-being and even survival following coronary artery bypass grafting (CABG); a potential subsequent need for blood transfusion can impact long-term mortality. 3,4 The problem of bleeding is evident in the management of patients scheduled for various surgeries, including elective CABG. There is a consensus that aspirin and clopidogrel should be stopped about 5 days before preplanned surgery. 5 Such a time frame is sufficient for generation of new young platelets that would be adequate to maintain firm hemostasis. However, in the case of urgent surgery, there is no option for a 5-day delay and patients The authors have no funding, financial relationships, or conflicts of interest to disclose. Received: July 15, 2015 Accepted with revision: August 25, 2015 must undergo surgery while on aspirin or 1 antiplatelet agent. The more critical issue at hand nowadays is that although stopping aspirin before surgery and restarting it during the first 48 hours after CABG is recommended, there is the tendency to operate on top of aspirin even in elective patients. Such a strategy has revealed virtually no difference in terms of the effect of vascular graft patency compared with the effects of operating without aspirin. 5 Nevertheless, operating on top of dual or single antiplatelet therapy exposes the patient to elevated risk of bleeding. 6 Unfortunately, conventional coagulation tests do not reflect the level of platelet blockade. This problem prompted the use of existing instruments and/or development of novel devices designed to monitor the platelet activity. Those devices range from highly sophisticated ones, such as light transmittance aggregometers and wholeblood flow cytometers, to simple point-of-care technologies. The problem is that no consensus exists concerning a number of issues: which device is optimal, what cutoff values to apply for discrimination of bleeding risk, and, 679 DOI: /clc Wiley Periodicals, Inc.

2 finally, how to proceed with antiplatelet strategies once the results of platelet testing are determined. 7 In this context, especially focusing on the consideration of the topical importance of bleeding in CABG, there is an unmet need for an optimal antithrombotic algorithm for such patients. This retrospective observational study tested a novel whole-blood platelet function analyzer to assess its clinical utility in patients scheduled for urgent and elective cardiac surgery. Methods Data were collected during 2008 and 2009 at the Silesian Center for Heart Diseases in Zabrze, Poland. All patients with a history of aspirin and/or clopidogrel use up to 10 days before surgery were included. Patients were excluded from the study if they had stopped antiplatelet treatment >10 days before surgery. Such a broad window included all incoming patients who could still have some antiplatelet effect. We tried to obtain all data carefully; however, 9 patients were excluded from the study because their laboratory data were missing, and 6 patients were excluded due to missed clinical outcomes. The primary endpoint was postoperative drainage (POD; cutoff value derived from receiver operating characteristic [ROC] analysis) and need for red blood cell (RBC) transfusion. There were no secondary endpoints in the study. Cardiac surgery types were also broad, including on-pump and off-pump CABG, minimally invasive CABG, artificial valve implantation, and the combination of CABG with valve implantation. The time point for blood sampling varied from 3 days before up to the same day of surgery (Table 1). For the platelet-activity studies, we used the Multiplate impedance aggregometer (Dynabyte, Munich, Germany). Whole-blood samples were collected into hirudin-containing anticoagulant tubes (S-Monovette; Sarstedt, Nümbrecht, Germany). The agonists used were arachidonic acid (AA) and adenosine diphosphate (ADP). The aggregometer manufacturer provided all reagents. Blood was collected in the morning after 6 hours of fasting, and aggregation was performed within 2 hours after collection. The area under the aggregation curve (AUC*min) was calculated from the Multiplate aggregometer measurements. Every measurement was done in duplicate with the mean calculation, but in case of measurements with a >20% difference of the mean curve from 1 curve or a correlation coefficient <0.98, the measurement was discharged and the calculation was performed again. Statistical analysis was performed using STATISTICA software, version 9.0 (StatSoft, Tulsa, OK). Results are presented as mean ± SD or median when applicable. Distributions of analyzed parameters were also analyzed, and thus, depending on normal or non-normal distribution, different statistical tests were performed. To assess statistical differences, various tests were applied where appropriate: the t test, Mann-Whitney U test, χ 2 test (with or without Yates correction), or Fisher exact test. Correlations were calculated using Pearson or Spearman correlation coefficients. To detect the sensitivity and specificity of the tests predicting bleeding risk, ROC analysis was performed. A P value <0.05 was considered statistically significant. Table 1. Demographics and Clinical Characteristics of the Study Group Variable Value Age, y (min max) 63.7 ± 9.7 (22 88) Sex, M/F 340/138 Active smoker 65 (13) BMI, kg/m ± 3.9 HTN 378 (79) DM 162 (33) Days without aspirin before surgery, median (min max) Days without clopidogrel before surgery, median (min max) 1 (0 10) 5 (0 10) EuroSCORE, median (min max) 5 (1 14) LVEF before surgery, % 50 ± 9.8 Timing of platelet testing and surgery Same day 104 (21.8) 1 day before 305 (63.8) 2 days before 49 (10.2) 3 days before 20 (4.2) Urgent/elective surgery 130/348 Type of surgery, n On-pump 198 Off-pump 162 Minimally invasive 30 Valve surgery 48 CABG + valve surgery 40 Repeated surgery 11 Bypass time, min ± 48.3 POD, ml 711 ± 519 Aorta clamping time, min 65.8 ± 32.6 NYHA class, median (min max) CCS class, median (min max) I (I IV) II (I IV) Any transfusion 285 (59) This study was approved by the Ethics Committee. Informed consent was obtained from all study participants. Results The study included 478 patients. The clinical characteristics of the entire group are presented in the Table 1. Overall, patients with <407 AUC*min had significantly higher POD in comparison with the rest of the group (802 ± 926 ml 680

3 Table 1. Continued Variable Value RBC concentrate 274 (57) FFP 285 (59) Platelet concentrate 67 (14) Length of hospital stay, d 7.7 ± 6.1 In-hospital death 10 (2.1) 30-day mortality 22 (4.6) Abbreviations: BMI, body mass index; CABG, coronary artery bypass grafting; CCS, Canadian Cardiovascular Society; DM, diabetes mellitus; EuroSCORE, European System for Cardiac Operative Risk Evaluation; F, female; FFP, fresh frozen plasma; HTN, hypertension; LVEF, left ventricular ejection fraction; M, male; min max, minimum maximum; NYHA, New York Heart Association; POD, postoperative drainage; RBC, red blood cell; SD, standard deviation. Dataare presented as n (%) or mean± SD unless otherwise noted. Figure 2. ROC curves for ASPI test before surgery in predicting chest tube age. An ASPI test value <407 AUC*min with 68% sensitivity and 46% specificity predicted the POD above the median (610 ml) for the whole group (AUC*min: 0.558, 95% CI: , P < 0.05). Abbreviations: AUC*min, area under the curve; CI, confidence interval; POD, postoperative drainage; ROC, receiver operating characteristic. Figure 1. Platelet aggregation induced by arachidonic acid (ASPI test) in subgroups of heart surgery patients. ASPI test values in the CABG + Valve and Valve subgroups were significantly higher (P < 0.05) in comparison with the rest of the subgroups. Abbreviations: AUC*min, area under the curve; CABG, coronary artery bypass grafting; CABG + Valve, coronary artery bypass grafting and artificial valve implantation; CI, confidence interval; MIDCAB, minimally invasive direct coronary artery bypass; min max, minimum maximum; OPCAB, off-pump coronary artery bypass; Valve, artificial valve implantation. Figure 3. Significant difference in POD dependent on ASPI test results with the cutoff value of 407 AUC*min. Abbreviations: AUC*min, area under the curve; POD, postoperative drainage. vs 633 ± 458 ml; P < 0.05; Figure 1). This association was mainly due to the subgroup of patients with artificial valve implantation whose cutoff point in the ASPI test was <407 AUC*min, resulting in higher POD in comparison with ASPI test results >407 AUC*min (803 ± 492 ml vs 511 ± 290 ml; P < 0.05). More specifically, in the ROC analysis of the whole group, an ASPI test result <407 AUC*min with 68% sensitivity and 46% specificity predicted POD >610 ml, which was the median value for the whole group (95% confidence interval [CI]: , P < 0.05; Figure2). Moreover, patients with the ASPI test <407 AUC*min who did not receive platelet transfusion during surgery had higher POD in comparison with patients with ASPI test >407 AUC*min (701 ± 303 ml vs 575 ± 335 ml; P < 0.01). On the other hand, this effect was not observed in patients with ASPI test <407 AUC*min who later received platelets (Figure 3). Considering and paying special attention to the heterogeneity of the entire patient cohort, an examination of the subgroups to establish the usefulness of platelet monitoring in predicting bleeding risk followed. In the CABG group, we found that ASPI test <271 AUC*min predicted with 54% sensitivity and 68% specificity the need for the use of RBC concentrate (P = ), whereas in the valve surgery group, the ASPI test <513 AUC*min predicted with 52% sensitivity and 82% specificity the need for RBC concentrate during hospitalization (P = ). The ROC analysis did not reveal a significant cutoff value for ASPI test for 681

4 Figure 4. Platelet aggregation induced by ADP test in subgroups of patients. There were no significant differences between subgroups. Abbreviations: ADP, adenosine diphosphate; AUC*min, area under the curve; CABG, coronary artery bypass grafting; CABG + Valve, coronary artery bypass grafting and artificial valve implantation; CI, confidence interval; MIDCAB, minimally invasive direct coronary artery bypass; min max, minimum maximum; OPCAB, off-pump coronary artery bypass; Valve, artificial valve implantation. future need for blood transfusions for other subgroups of patients. The ADP test, which was estimated in patients who stopped clopidogrel up to 5 days before surgery, did not show utility in predicting bleeding risk or need for blood products (Figure 4). Discussion Recently, there was an explosion of publications regarding the monitoring of platelet activity concerning the impact of determined cutoff values on clinical outcomes, especially in patients with ACS treated invasively. 8,9 The main objective of these studies was to define the incidence of thrombotic occlusions and link such adverse events with high ontreatment platelet reactivity. Recently, some evidence emerged assessing the risk of bleeding and specific cutoff values for its predictability in ACS patients. 10 In contrast, CABG patients are at the highest obvious risk of bleeding rather than immediate ischemia. Thrombosis in newly implanted grafts and/or early graft failure are rare complications that can be prevented by aspirin within the first 48 hours after surgery. 11 Therefore, the issue of impact of concomitant antiplatelet therapy on bleeding risk is critical for CABG success. Interestingly enough, and contrary to general and/or interventional cardiology trends, there are very few studies regarding the usefulness of platelet monitoring in regard to predicting risk of bleeding in CABG patients. Some evidence with the platelet function analyzer (PFA)-100 device failed to predict postoperative bleeding in CABG patients. 12 Similar disappointment emerged from the study by Dietrich et al in which different measures of platelet reactivity were not helpful in predicting risk of bleeding or transfusion. 13 In our study, focus on the utilization of whole-blood aggregometry in a broad group of patients taking aspirin and scheduled for cardiac surgery provided the ideal scenario to gather data to establish a cutoff value predicting higher POD with regard to the considerable sensitivity and specificity. An ASPI test of <407 AUC*min is higher than recommended by a device manufacturer, whereas the adequate aspirin effect is proposed at <300 AUC*min. This discrepancy could be attributable to the heterogeneous group of patients included in the index study due to its retrospective design. On the other hand, the value of 300 provided by the device manufacturer was established on the basis of 85% cutoff value for healthy donors on aspirin with no testing for bleeding, whereas our study tried to use the device for new estimation in a totally different highest-risk population. In this regard, our results could be additive rather than conflicting ones. In terms of ROC analysis regarding different subgroups separated by type of surgery, statistically significant cutoff values reflected the need for RBC concentrate use for general CABG and valve-surgery patient cohorts. The RBC concentrates were more likely to be used in cases where CABG was performed in patients with ASPI test <271 AUC*min and/or in valve-surgery patients with <513 AUC*min. Importantly, the summary receiver operating characteristic (SROC) curves per se clearly indicate that the clinical utility of a single platelet-function test is limited because the AUC*min percentage was low, indicating that it is only slightly better than guesswork. Our results in the CABG cohort are near the 300 value, consequently agreeing with the proposition by the device manufacturer to characterize patients on aspirin. In valve-surgery patients, the result is somehow striking and could be attributed to the nature of these rather small groups and borderline statistical significance of the ROC analysis performed. Nevertheless, there remain further tests that more importantly focus on randomly designed larger groups of patients. The likely clinical significance of differences in blood loss in those with test results above and below the SROC cutoffs is uncertain, but should be further explored in detail. Somewhat surprising was the lack of association between ADP test and bleeding risk. In the index study, patients were mostly clopidogrel-free after 5-day washout; hence, these results could not be matched to the study by Mengistu et al, whereas ADP-induced aggregation preoperatively was shown to be able to predict postoperative transfusion requirements in patients scheduled for CABG while on clopidogrel. 14 Moreover, challenging the scientific validity of the data, this paper was retracted by the Journal of Cardiothoracic and Vascular Anesthesia. On the other hand, Rahe-Meyer et al showed that ADP-induced aggregation in clopidogrel-naive patients could predict a further need for platelet concentrate transfusion. 15 However, it is important to note that the aforementioned study was performed using only 60 patients, therefore not fairly analyzing the predictability of RBC concentrate use. Furthermore, the study could be subject to bias and scrutiny because the physician ordering platelet concentrate transfusion was not blinded for the platelet-monitoring study results. Study Limitations There are certain limitations worth mentioning. It should be emphasized that there might be important confounders 682

5 in our analysis potentially impacting the conclusions. Among the most important factors are the nonrandomized observational design, no fixed standard timing of platelet tests, and single test assessment. We failed to obtain all laboratory biomarkers and all clinical outcomes, limiting the sample size further. In addition, the background differences among the patients and pooled analyses of various heartsurgery techniques also limit the applicability of the index dataset. For example, there is such a substantioal difference in cutoff for patients undergoing CABG vs valve surgery, limiting the clinical utility of the combination data. From a pragmatic point of view, it will be necessary to determine whether the ASPI and particularly the ADP test adds more information than simply knowing how long ago the last dose of antiplatelet drug was given. Finally, beyond urgency and type of surgery, future studies should adjust for case complexity, perhaps using a variable such as pump time or clamp time. Conclusion The main discovery of our study suggests 2 things. Despite the discontinuation of aspirin and/or clopidogrel in CABG patients, an ASPI test value before surgery of <407 AUC*min was associated with higher POD, and <271 AUC*min is associated with higher postoperative RBC concentrate usage. References 1. Reed GW, Kumar A, Guo J, et al. Point-of-care platelet function testing predicts bleeding in patients exposed to clopidogrel undergoing coronary artery bypass grafting: Verify Pre-Op TIMI 45 a pilot study. Clin Cardiol. 2015;38: Petricevic M, Biocina B, Milicic D, et al. Platelet function testing and prediction of bleeding in patients exposed to clopidogrel undergoing coronary artery surgery. Clin Cardiol. 2015;38: Engoren MC, Habib RH, Zacharias A, et al. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74: Ferraris VA, Ferraris SP, Moliterno DJ, et al. The Society of Thoracic Surgeons practice guideline series: aspirin and other antiplatelet agents during operative coronary revascularization (executive summary). Ann Thorac Surg. 2005;79: Mangano DT. Aspirin and mortality from coronary bypass surgery. N Engl J Med. 2002;347: Kulik A, Chan V, Ruel M. Antiplatelet therapy and coronary artery bypass graft surgery: perioperative safety and efficacy. Expert Opin Drug Saf. 2009;8: Cannon CP, Mehta SR, Aranki SF. Balancing the benefit and risk of oral antiplatelet agents in coronary artery bypass surgery. Ann Thorac Surg. 2005;80: Hovens MM, Snoep JD, Eikenboom JC, et al. Prevalence of persistent platelet reactivity despite use of aspirin: a systematic review. Am Heart J. 2007;153: Snoep JD, Hovens MM, Eikenboom JC, et al. Clopidogrel nonresponsiveness in patients undergoing percutaneous coronary intervention with stenting: a systematic review and meta-analysis. Am Heart J. 2007;154: Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol. 2009;53: Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass graft surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft Surgery) [published correction appears in Circulation. 2005;111:2014]. Circulation. 2004;110:e340 e Fattorutto M, Pradier O, Schmartz D, et al. Does the platelet function analyser (PFA-100) predict blood loss after cardiopulmonary bypass? Br J Anaesth. 2003;90: Dietrich GV, Schueck R, Menges T, et al. Comparison of four methods for the determination of platelet function in whole blood in cardiac surgery. Thromb Res. 1998;89: Mengistu AM, Mayer J, Boldt J, et al. Usefulness of monitoring platelet function by multiple electrode aggregometry in primary coronary artery bypass surgery [article retracted due to lack of IRB approval; see J Cardiothorac Vasc Anesth. 2011;25: ]. JCardiothoracVascAnesth.2011;25: Rahe-Meyer N, Winterhalter M, Boden A, et al. Platelet concentrates transfusion in cardiac surgery and platelet function assessment by multiple electrode aggregometry. Acta Anaesthesiol Scand. 2009;53: