NSC 27223

How do type of preoperative P2Y12 receptor inhibitor and withdrawal time affect bleeding

Andreas Voetsch1,2 MD, Gudrun Pregartner3 MSc, Andrea Berghold3 PhD, Rainald Seitelberger1 MD, Michael Schoerghuber4 MD, Wolfgang Toller4 MD, Elisabeth Mahla4 MD

Abstract

Background. Despite recommendations for standardized preoperative waiting of at least 3, 5, and 7 days for ticagrelor, clopidogrel, and prasugrel, respectively, there is still substantial inter-institutional variation in preoperative discontinuation of dual antiplatelet therapy in patients needing coronary artery bypass grafting (CABG).
Methods. In 299 patients undergoing CABG ± valve intervention <7 days after last P2Y12 receptor inhibition, we evaluated calculated red blood cell loss. and Bleeding Academic Research Consortium (BARC)-4 bleeding. Results. 83% of patients underwent CABG within <48 hours of last drug intake. Calculated blood loss was lower in patients on clopidogrel as compared to prasugrel or ticagrelor [1063 (690-1394) vs. 1351 (876-1829) vs. 1330 (994-1691) ml, p<0.001]. Overall, 135 (45%) patients sustained BARC-4 bleeding; incidence differed between groups (p=0.015) and was significantly higher in prasugrel-, as compared to clopidogrel-treated patients. In multivariable linear regression analysis, EuroSCORE II, aspirin dose, cardio-pulmonary-bypass time, drug withdrawal time, and type of P2Y12 receptor inhibitor were significantly associated with RBC loss. Compared to 0-24, >48 hours preoperative discontinuation substantially reduced calculated blood loss by 37-48% und BARC-4 bleeding by 5871%, depending on P2Y12 receptor inhibitor.
Conclusions. Exposure to prasugrel and ticagrelor within 24 hours before CABG increases both calculated blood loss and BARC-4 bleeding as compared to clopidogrel. Although a >48 hours discontinuation substantially reduced calculated blood loss and BARC-4 bleeding across all P2Y12 receptor inhibitors, our single center data further support strict adherence to the 2017 guidelines whenever justified by stable hemodynamics and non-jeopardized myocardium.

Key words: dual antiplatelet therapy, acute coronary syndrome, cardiac surgery, bleeding

Introduction

Bleeding and transfusion are common issues in cardiac surgery, precipitated by the specifics of cardiopulmonary-bypass inducing hemodilution, thrombin generation, fibrinolysis, and platelet dysfunction [1]. Abundant evidence demonstrates an association between severity of bleeding, as defined by various consensus-based bleeding definitions, and postoperative morbidity and mortality [2-5]. Dual antiplatelet therapy (DAPT) with a P2Y12 receptor inhibitor on top of aspirin is the cornerstone in the treatment of patients after coronary artery stenting and patients presenting with acute coronary syndrome (ACS) [6]. In the latter patients, current guidelines issue a class I recommendation for the new more potent thienopyridines ticagrelor or prasugrel [6] but this comes at the expense of increased bleeding [4, 5, 7]. Up to 11% of patients presenting with ACS need coronary artery bypass grafting (CABG) during DAPT [8]. However, optimal timing of P2Y12 receptor inhibitor discontinuation, balancing ischemic and bleeding risk, is uncertain [9]. Although preoperative DAPT may reduce the incidence of ischemic events, DAPT ≤5 days of cardiac surgery has been associated with increased surgery-related bleeding and mortality [10]. There is evidence of a graded relation between the extent of platelet inhibition and bleeding [3, 4, 11]. However, validated bleeding cutoffs are elusive so far and there is only a class II b recommendation for preoperative platelet function monitoring to time surgery [6, 12]. In order to reduce surgery-related bleeding in patients undergoing elective cardiac surgery, recent guidelines recommend a standardized preoperative waiting period of at least 3 days for ticagrelor, 5 days for clopidogrel, and 7 days for prasugrel (class IIa) [6]. However, there is still substantial inter-institutional variation in preoperative management of ACS patients on DAPT needing CABG, based on the extent of jeopardized myocardium, coronary anatomy, and economic constraints [6]. Moreover, data on CABG-related bleeding depending on preoperative discontinuation of prasugrel are sparse [3]. Therefore, the aim of our study was to evaluate bleeding in patients on clopidogrel as compared to prasugrel and ticagrelor, respectively, and the association between withdrawal time and surgery-related bleeding.

Patients and Methods

After approval by the institutional review board (EK26-032 ex 13/15), all patients aged 18-90 years referred to the Medical University of Graz for first time CABG or CABG and valve surgery between December 2013 and November 2016 were screened for eligibility for this prospective observational study (NCT02030548; study II). Patients were screened by the anesthesiologist on duty and enrolled after obtaining written informed consent, if they were on DAPT with aspirin and a P2Y12 receptor inhibitor within 7 days preoperatively. If this was impossible (emergency surgery with poor health prohibiting preoperative consent), consent was obtained in accordance with the institutional review board approval after recovery from index surgery and before discharge. Patients unable to provide informed consent, patients on chronic dialysis, patients on oral anticoagulants, patients undergoing

Data management

Study endpoints

The secondary outcome was Bleeding Academic Research Consortium (BARC)-4 bleeding defined as either of the following:
• perioperative intracranial bleeding within 48 hours,
• re-operation after closure of sternotomy for the purpose of controlling bleeding
• transfusion of ≥5 units of packed RBCs within 48 hours, or
• 24-hour chest tube drainage ≥2000 ml [14].
In addition, re-thoracotomy, percutaneous coronary intervention, ischemic cerebral insult during index hospital stay, as well as 30-day mortality were recorded.

Clinical management

DAPT was discontinued once the indication for surgery was established. As per institutional protocol, glycoprotein IIb/IIIa inhibitors were stopped preoperatively for at least 4 hours in patients with normal renal function and 8 hours in patients with a glomerular filtration rate ≤30 ml/min, respectively. Perioperative care was at discretion of the attending physicians. Surgery was performed by the individual cardiac surgeon on duty. A loading dose of 300 IU/kg unfractionated heparin was administered to obtain activated clotting time ≥400 seconds before initiation of cardio-pulmonarybypass, which was maintained by additional doses of unfractionated heparin. Upon completion of cardio-pulmonary-bypass, anticoagulation was reversed by protamine chloride in a 1:1 ratio and additional protamine was given to achieve an activated clotting time <140 seconds. All patients received tranexamic acid. In case of post-pump bleeding, thrombelastometry or thrombelastography were used to guide hemostatic management. Platelets were administered in abnormal post-pump bleeding [12]. Transfusion triggers were set to a hematocrit of at least 20% on cardio-pulmonarybypass and 25% thereafter, unless active bleeding or low cardiac output suggested a need to increase this level. As per institutional protocol, re-thoracotomy was performed in cases of hemodynamic instability, cardiac tamponade or chest tube output of ≥1000 ml after excluding or correcting for residual heparin effect or dilutional coagulopathy. Statistical analysis As estimations of calculated RBC loss depending on a 0-7 days preoperative withdrawal time of clopidogrel and the new P2Y12 receptor inhibitors prasugrel and ticagrelor were unavailable before the start of the study, a formal sample size calculation could not be performed. Based on the experience of our last study [11], we estimated that 160 patients could be recruited within three years. Based on an expected, lower incidence of patients on clopidogrel due to then valid guidelines accounting for the benefits of prasugrel and ticagrelor over clopidogrel in ACS patients [15], we prespecified a combined analysis of our former [11] and the current study. We assessed that the two collectives were similar regarding Euroscore II and procedural variables (cardio-pulmonary-bypass time, aortic cross clamping time and duration of surgery) and could indeed be analyzed together (supplemental table 1). Categorical parameters are summarized using absolute and relative frequencies, whereas continuous parameters are presented as either mean and standard deviation (SD) or median and interquartile range (Q1-Q3). Differences between patients receiving clopidogrel, prasugrel or ticagrelor were assessed by Results Baseline variables The study flow diagram is presented in Fig 1; 134 patients were included in the current study (study II) and 167 patients from our former study (study I) met the same inclusion/exclusion criteria. However, one patient from study I was excluded from statistical analysis as lab data for the calculation of RBC loss were missing and one patient from study II was excluded due to protocol violation (redo case). Overall, 133 patients (44%) were on clopidogrel, 55 (18%) on prasugrel and 111 (37%) were on ticagrelor in addition to aspirin. Baseline characteristics are presented in table 1. Mean (SD) patient age was 67.9 (9.6) years and differed between the three groups. Median (IQR) EuroSCORE II was 2.9 (1.8-4.7) with slightly higher values in ticagrelor treated patients. Two hundred and eighty-three (95%) patients presented with ACS. Fifty-five, 28 and 17 percent of the patients underwent surgery within 0-24, 24-48 or more than 48 hours after drug withdrawal, respectively. Preoperatively, 71 (24%) patients were anemic according to the World Health Organization-definition of <13g/dl for men and <12g/dl for women [clopidogrel: 33 (25%), prasugrel: 11 (20%), ticagrelor: 27 (24%); p=0.819]. Perioperative levels of hemoglobin did not differ between the three groups but there was a significant decrease over time (p<0.001; supplemental fig 1). Procedural and bleeding characteristics are presented in table 2. While there was a difference in duration of surgery, there was no significant difference in cardio-pulmonary-bypass time or aortic cross clamping time. 24-h chest tube drainage was similar across the three patient groups. However, calculated RBC loss was lower in clopidogrel-treated patients as compared to patients on prasugrel or ticagrelor [1063 (690-1394) vs. 1351 (876-1829) vs. 1330 (994-1691) ml; p<0.001]. Transfusion rate of red blood cells and platelets was 87% and 63%, respectively. Forty-seven % of the patients received more than 4 units of red blood cells and about half of the patients received 1-2 platelet units. There were significant differences between the transfusion rates for patients treated with clopidogrel and prasugrel. Overall, 135 (45%) patients sustained BARC-4 bleeding. The incidence of BARC-4 bleeding differed between the groups (p=0.015) and was significantly higher in prasugrel-treated patients and higher in ticagrelor-treated patients as compared to patients on clopidogrel. A surgical bleeding site was identified in 18 out of 33 patients who underwent re-thoracotomy. Six patients had to undergo post-CABG reoperation or percutaneous coronary intervention because of recurrent ischemia (clopidogrel: n=3, prasugrel: n=1, ticagrelor: n=2). Five patients sustained a neurologic ischemic insult (prasugrel: n=2, ticagrelor: n=3). Baseline characteristics and perioperative outcome of the 133 analyzed patients of study II are presented in supplemental table 2. Calculated blood loss significantly decreased over time and differed significantly between the three P2Y12 receptor inhibitors (p<0.001). Specifically, compared to clopidogrel-treated patients, calculated blood loss was significantly higher with prasugrel and ticagrelor when patients underwent surgery within 24 hours after last drug intake (figure 2; detailed description of the post-hoc analysis is provided in the figure legend). Compared to 0-24 hours, >48 hours discontinuation significantly reduced BARC-4 bleeding in clopidogrel (p=0.015) and prasugrel (p=0.010) and reduced BARC-4 bleeding in ticagrelor patients (supplemental figure 2).
Univariable linear regression analysis for the calculated RBC loss showed a significant association with EuroSCORE II, cardio-pulmonary-bypass time, duration of surgery, concomitant valve surgery, and aspirin dose in addition to drug withdrawal time and type of P2Y12 receptor inhibitor (supplemental table 3). In the multivariable regression model, EuroSCORE II, cardio-pulmonarybypass time, aspirin dose, drug withdrawal time, and the type of P2Y12 receptor inhibitors remained significantly associated with calculated RBC loss (table 3). Specifically, as compared to clopidogrel, prasugrel and ticagrelor increased calculated RBC loss by 279 and 194 milliliters, respectively.

Comment

To the best of our knowledge, this is the first prospective study evaluating how clopidogrel, prasugrel, ticagrelor, and preoperative withdrawal time determine calculated RBC loss and BARC-4 bleeding in patients undergoing non-elective first time on-pump CABG with or without additional valve intervention. Fifty-five, 28 and 17 percent of the patients underwent surgery within 0-24, 24-48 or more than 48 hours after drug withdrawal, respectively. Compared to clopidogrel, calculated RBC loss was significantly higher in patients on prasugrel or ticagrelor and significantly decreased over time. Moreover, compared to clopidogrel, the incidence of BARC-4 was significantly higher in patients on prasugrel and was similar between prasugrel- and ticagrelor-treated patients. Finally, >48 hour preoperative drug withdrawal time substantially reduced both calculated RBC loss und BARC-4 bleeding.
There is evidence of a graded association between platelet inhibition and CABG-related bleeding, which increases postoperative morbidity and mortality [3-5, 11]. To reduce bleeding, current guidelines recommend (class IIa) to postpone non-emergent CABG for at least 3, 5, and 7 days after discontinuation of ticagrelor, clopidogrel, and prasugrel, respectively [6]. However, an individualized approach is warranted in patients with ongoing ischemia and hemodynamic instability [6].
A Swedish registry including 2,244 ACS patients undergoing CABG demonstrated a 5% lower incidence of BARC-4 bleeding in patients on ticagelor as compared to clopidogrel. This difference was mainly driven by a sharp decline in bleeding after 72 hours discontinuation of ticagrelor as compared to a more gradual decrease with clopidogrel [4].
The European multicenter study on coronary artery bypass grafting (E-CABG registry), including 7,118 patients, demonstrated substantial variation in preoperative P2Y12 receptor discontinuation and different rates of severe bleeding across participating centers. Discontinuation shorter than recommended by the guidelines resulted in a 50-60% increased relative risk of severe bleeding, defined either as Universal Definition of Perioperative Bleeding (UDPB) 3-4 or E-CABG bleeding grades 2-3, either of which is associated with a 6- to 8-fold increased 30-day mortality [3]. In a subgroup of 1,293 patients, Holm and coworkers evaluated incidence of bleeding after propensity score matching for baseline and perioperative covariates including center. Compared to 3 days, 4-5 days off clopidogrel reduced UDPB 3-4 bleeding by 7.3% (p=0.031). Likewise, compared to 0-2 days, 3 days off ticagrelor reduced bleeding by even 13.3% (p=0.003) [5]. Neither of the above referenced studies included patients on preoperative prasugrel [3-5].
TRITON TIMI 38 study illustrated an increased risk of CABG-related major bleeding in patients on prasugrel as compared to clopidogrel (13.4% vs. 3.2%, p<0.001) [7]. Vuilliomenet and coworkers recently demonstrated increased chest tube drainage when prasugrel was discontinued <24 hours as compared to 24-48 hours preoperatively [16]. However, larger studies evaluating consensus-based bleeding in relation to preoperative prasugrel discontinuation are currently lacking. In ACS patients, prasugrel has recently been demonstrated to reduce the incidence of death, myocardial infarction, or stroke at 1 year by 2.4% as compared to ticagrelor, without affecting the incidence in bleeding [17]. Therefore it is tempting to speculate that more patients on prasugrel will present for CABG in the future. In contrast to the studies cited above, we used calculated RBC loss to assess the impact of type of P2Y12 receptor inhibitor and discontinuation time on bleeding because this parameter accounts for preoperative anemia, which occurred in 24% of our patients, as well as for visible and hidden blood loss such as hematoma [3-5, 13]. Importantly, five days perioperative hemoglobin was similar between the three groups suggesting a consistent transfusion practice. However, contrary to what would be expected from studies evaluating measured platelet inhibition and bleeding, 24-hours chest tube drainage did not differ significantly between the three groups [18]. In the multivariable analysis, type of P2Y12 receptor inhibitor, discontinuation period, aspirin, cardiopulmonary-bypass time, and EuroScore II were significantly associated with calculated RBC loss. The clinical consequences of our results are that in patients undergoing non-elective surgery during DAPT every additional hour on cardio-pulmonary-bypass increases calculated blood loss by about 160 ml and that a >48 hours preoperative withdrawal period decreases calculated RBC loss by 400 ml, which with a median of 1187 accounts for about 30%.
Moreover, consistent with previous investigations using different consensus-based bleeding definitions [4, 5], incidence of BARC-4 bleeding decreased with increasing time off P2Y12 receptor inhibitors and differed between clopidogrel, prasugrel and ticagrelor. Of note, the incidence of BARC-4 bleeding in our study was higher than that reported previously in two multicenter registries, which demonstrated a different trend of BARC-4 bleeding over time in clopidogrel and ticagrelor treated patients, respectively [4, 5].
Limitations: This is a single center study with a low number of patients undergoing CABG after more than 48 hours P2Y12 receptor inhibitor discontinuation and there is no P2Y12 receptor inhibitor naïve control group. The withdrawal periods and administered aspirin doses differed between the two studies owing to different study designs, but we accounted for this circumstance by adjusting for withdrawal time, type of P2Y12 receptor inhibitor, aspirin dose and other possible confounders in the multivariable regression model.
We neither have data on preoperative plasma drug levels nor on preoperative “on treatment” platelet reactivity, both of which reflect intestinal absorption, drug-specific metabolism, drug-drug interactions, influence of comorbidities, and genetic polymorphism [19, 20]. Had preoperative platelet function been available to the treating physicians, it would have triggered targeted administration of blood components, as has been successfully demonstrated previously [21]. Although not yet validated regarding the risk of morbidity and mortality, we used the BARC-4 bleeding definition as a secondary endpoint since it has been introduced as a standardized bleeding endpoint for patients receiving antithrombotic therapy [14].

Conclusion:

Exposure to prasugrel and ticagrelor within 24 hours NSC 27223 before CABG increases both calculated blood loss and BARC-4 bleeding as compared to clopidogrel. Although a more than 48 hours preoperative discontinuation substantially reduced calculated RBC loss by 37-48% und BARC-4 bleeding by 5871%, depending on P2Y12 receptor inhibitor, the incidence of BARC-4 bleeding was higher than

References

1. Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011;113:1319-33.
2. Bartoszko J, Wijeysundera DN, Karkouti K et al. Comparison of two major perioperative bleeding scores for cardiac surgery trials: Universal definition of perioperative bleeding in cardiac surgery and European Coronary Artery Bypass Grafting Bleeding Severity Grade. Anesthesiology 2018;129:1092-100.
3. Biancari F, Mariscalco G, Gherli R et al. Variation in preoperative antithrombotic strategy, severe bleeding, and use of blood products in coronary artery bypass grafting: results from the multicentre E-CABG registry. Eur Heart J Qual Care Clin Outcomes 2018;4:246-57.
4. Hansson EC, Jideus L, Aberg B et al. Coronary artery bypass grafting-related bleeding complications in patients treated with ticagrelor or clopidogrel: a nationwide study. Eur Heart J 2016;37:189-97.
5. Holm M, Biancari F, Khodabandeh S et al. Bleeding in patients treated with ticagrelor or clopidogrel before coronary artery bypass grafting. Ann Thorac Surg 2019;107:1690-8.
6. Valgimigli M, Bueno H, Byrne RA et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2018;39:213-60.
7. Wiviott SD, Braunwald E, McCabe CH et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.
8. Masoudi FA, Ponirakis A, Yeh RW et al. Cardiovascular care facts: a report from the national cardiovascular data registry: 2011. J Am Coll Cardiol 2013;62:1931-47.
9. Russo JJ, James TE, Ruel M et al. Ischemic and bleeding outcomes after coronary artery bypass grafting among patients initially treated with a P2Y12 receptor antagonist for acute coronary syndromes: Insights on timing of discontinuation of ticagrelor and clopidogrel prior to surgery. Eur Heart J Acute Cardiovasc Care 2018;10.1177/2048872617740832.
10. Biancari F, Airaksinen KE, Lip GY. Benefits and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies. J Thorac Cardiovasc Surg 2012;143:665-75.
11. Mahla E, Prueller F, Farzi S et al. Does platelet reactivity predict bleeding in patients needing urgent coronary artery bypass grafting during dual antiplatelet therapy? Ann Thorac Surg 2016;102:2010-7.
12. Ferraris VA, Saha SP, Oestreich JH et al. 2012 Update to the Society of Thoracic Surgeons guideline on use of antiplatelet drugs in patients having cardiac and noncardiac operations. Ann Thorac Surg 2012;94:1761-81.
13. Gombotz H, Rehak PH, Shander A et al. Blood use in elective surgery: the Austrian benchmark study. Transfusion 2007;47:1468-80.
14. Mehran R, Rao SV, Bhatt DL et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47.
15. Hamm CW, Bassand JP, Agewall S et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999-3054.
16. Vuilliomenet T, Gebhard C, Bizzozero C et al. Discontinuation of dual antiplatelet therapy and bleeding in intensive care in patients undergoing urgent coronary artery bypass grafting: a retrospective analysis. Interact Cardiovasc Thorac Surg 2019;28:665-73.
17. Schupke S, Neumann FJ, Menichelli M et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. N Engl J Med 2019;38:1524-34
18. Mahla E, Tantry US, Pruller F et al. Is there a role for preoperative platelet function testing in patients undergoing cardiac surgery during antiplatelet therapy? Circulation 2018;138:2145-59.
19. McEvoy JW, Ibrahim K, Kickler TS et al. Effect of Intravenous Fentanyl on Ticagrelor Absorption and Platelet Inhibition Among Patients Undergoing Percutaneous Coronary Intervention: The PACIFY Randomized Clinical Trial (Platelet Aggregation With Ticagrelor Inhibition and Fentanyl). Circulation 2018;137:307-9.
20. Siller-Matula JM, Trenk D, Schror K et al. How to improve the concept of individualised antiplatelet therapy with P2Y12 receptor inhibitors–is an algorithm the answer? Thromb Haemost 2015;113:37-52.
21. Agarwal S, Johnson RI, Shaw M. Preoperative Point-of-Care Platelet Function Testing