Perioperative outcomes of cardiac surgery patients ... - Oxford Journals

ORIGINAL ARTICLE

European Journal of Cardio-Thoracic Surgery 46 (2014) 198–205 doi:10.1093/ejcts/ezt571 Advance Access publication 12 January 2014

Perioperative outcomes of cardiac surgery patients with ongoing ticagrelor therapy: boon and bane of a new drug Hanna Schotolaa,*, Anselm Bräuera, Katharina Meyera, José Hinza, Friedrich Albert Schöndubeb, Martin Bauera, Prashant Nanasaheb Mohitec, Bernd Christoph Dannerb, Samuel Sossallad and Aron Frederik Popovb a b c d

Department of Anesthesiology, Emergency and Intensive Care Medicine, Georg-August-University Goettingen, Goettingen, Germany Department of Thoracic and Cardiovascular Surgery, Georg-August-University Goettingen, Goettingen, Germany Department of Cardiothoracic Transplantation and Mechanical Support, Brompton and Harefield Hospital, Harefield, London, UK Department of Cardiology and Respiratory Medicine, Georg-August-University Goettingen, Goettingen, Germany

* Corresponding author. Department of Anesthesiology, Emergency and Intensive Care Medicine, Georg-August-University Goettingen, Robert-Koch-Str. 40, D–37075 Goettingen, Germany. Tel: +49-551-398828; fax: +49-551-3913886; e-mail: [email protected] (H. Schotola). Received 25 June 2013; received in revised form 29 October 2013; accepted 5 November 2013

Abstract OBJECTIVES: Ticagrelor (Brilique®) is a novel reversible platelet inhibitor at P2Y12 receptor used in patients with acute coronary syndrome and patients undergoing percutaneous coronary interventions. Unlike clopidogrel (Plavix®), ticagrelor has a quicker offset of action, and therefore, it seems that platelet function recovers faster on discontinuation of therapy. These drugs sometimes cannot be stopped before coronary artery bypass grafting due to the risk of stent thrombosis or in case of emergency operations. Therefore, we investigated whether the continued preoperative use of ticagrelor influences the perioperative course of cardiac surgical patients. METHODS: The perioperative course and clinical outcomes of patients preoperatively receiving ticagrelor + acetylsalicylic acid (ASA) (n = 32) or clopidogrel + ASA (n = 49) until cardiac surgery, performed at University of Goettingen between January 2012 and December 2012, were studied. The study was designed as a retrospective observational study. The observation period started with the surgery and ended after 3 days. P < 0.05 was considered statistically significant. RESULTS: Preoperative data and intraoperative characteristics were almost similar among the groups. In the first 24 h, the median blood loss was 850 [780–1600] ml in the ticagrelor group and 680 [400–860] ml in the clopidogrel group (P = 0.0006). Furthermore, the median red blood cell transfusion (P = 0.0031), the median pooled platelet transfusion (P = 0.0012), the median prothrombin complex concentrate use (P = 0.0114) and the median fibrinogen use (P = 0.0118) were significantly higher in the ticagrelor group compared with the clopidogrel group. However, there was no statistical significance between the two groups regarding intensive care unit and hospital stay, mechanical ventilation time, incidence of acute kidney injury and mortality. Hence, a tendency towards more rethoracotomies due to bleeding in the ticagrelor group was observed (P = 0.0632). CONCLUSIONS: In cardiac surgical patients who are treated with ticagrelor + ASA until surgery, ticagrelor therapy is associated with a significantly higher blood loss, a significantly higher use of blood products and coagulation factors and higher incidence of rethoracotomies for bleeding compared with patients treated with clopidogrel + ASA. Keywords: Continued ticagrelor application • CABG • Perioperative outcome

INTRODUCTION In patients with platelet derived hyper-reactivity in acute coronary syndrome (ACS) after plaque rupture and stent implantation, the dual antiplatelet therapy (DAPT) consists essentially of the cyclooxygenase inhibitor acetylsalicylic acid (ASA) and a P2Y12-receptor blocker [1, 2]. Both the current European and the American Society of Cardiology recommend DAPT for 6–12 months in patients with ACS and after stent implantation [3, 4]. As early termination of DAPT clearly increases the risk of stent thrombosis and deadly reinfarction, the discontinuation of this therapy is not recommended [5].

ACS patients with left main and/or diffuse coronary disease in which stent implantation is not deemed convenient or sufficient are referred for urgent coronary artery bypass grafting (CABG). As these surgical interventions are urgent and not deferrable, the DAPT often cannot be stopped in time as recommended by the Platelet Inhibition and Patient Outcomes (PLATO) trial [1]. Ticagrelor (Brilique®, AstraZeneca, London, UK) is a novel oral, reversible platelet inhibitor at the adenosine diphosphate receptor P2Y12, used in patients with ACS and patients undergoing percutaneous coronary interventions. Unlike clopidogrel (Plavix®, Sanofi, Paris, France; Iscover, Import Westen Pharma, Leverkusen,

© The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

H. Schotola et al. / European Journal of Cardio-Thoracic Surgery

METHODS The study protocol was approved by the local ethics committee of the Medical Faculty, University of Goettingen, Germany. It was designed as a retrospective observational study in a cohort of patients treated with DAPT prior to CABG surgery under cardiopulmonary bypass (CPB) at the University of Goettingen. The study was conducted from January 2012 till December 2012. Patients with continued DAPT (ASA and ticagrelor or ASA and clopidogrel) until their cardiac surgery were included into the study. In these patients, DAPT could not be discontinued before surgery due to clearly increased risk of stent thrombosis and deadly reinfarction. Two groups were identified: (i) Ticagrelor group: treatment with ticagrelor and ASA until surgery. (ii) Clopidogrel group: treatment with clopidogrel and ASA until surgery. The antiplatelet drugs were administered according to the recommendations of the European Society of Cardiology guidelines for ACS [3]. (i) Ticagrelor group: ticagrelor 90 mg twice a day + ASA 100 mg/day. (ii) Clopidogrel group: clopidogrel 75 mg/d + ASA 100 mg/day. In case of reduced mobilization before surgery, patients received prophylactic low-molecular-weight heparin (Enoxaparin). Phenprocoumon was paused 3–5 days before surgery and its blood-thinning effect was bridged by heparin.

Exclusion criteria Patients who received an extracorporeal membrane oxygenation (ECMO) intra- or postoperatively were not included in this study due to generally known haemorrhagic complications with ECMO therapy. Also coagulation disorders would have resulted in exclusion of the study due to incalculable bleeding complications.

Perioperative data collection Patients’ anaesthesia protocol was checked for DAPT treatment. If no exclusion criteria existed, patient characteristics and preoperative lab were noted (see Tables 1 and 2). The observation period started with anaesthetic induction and was terminated 72 h after surgery. The majority of the data was collected with the following softwares: ANDOKlive (DATAPEC GmbH, Pliezhausen, Germany), IXSERV® (ixmid Software Technologie GmbH, Cologne, Germany) and ICIP® (Philips Healthcare, Best, Netherlands).

Intraoperative settings Patients treated with DAPT and undergoing isolated CABG or CABG with combined main procedures (see Table 3) via median sternotomy by using CPB were identified. All patients were operated on via median sternotomy and use of CPB. Before cannulation, a loading dose of unfractionated heparin (300 IU/kg body weight) was administered. The priming volume (1500 ml) of the heart–lung machine (Maquet Jostra HL20, SOMA Technology, Inc., Bloomfield, NJ, USA) also included 7500 IU of unfractionated heparin. Before the beginning of CPB, activated clotting time (ACT) was measured and if found to be 1.2 mg/dl) Preoperative medications (n) Beta-blocker ACE inhibitor Oral nitrate Antiarrhythmic Diuretic Antilipid agent Antidiabetic Bronchodilatator EuroSCORE Additive Euro (points) Logistic Euro (%) Operation Elective (n) Urgent (500 ml/h during the first 30 min in the intensive care unit (ICU). Furthermore, a rethoracotomy was evaluated by intensive care doctors and cardiac surgeons at patient’s bedside if blood loss was >400 ml/h in the first postoperative hour (or >1000 ml in the first 4 h) despite satisfying coagulation tests (see our SOP ‘Therapy of bleeding and coagulation failure for CABG surgery’).

Statistical analysis Continuous variables are presented as mean ± standard deviation (SD) or median [25% percentile to 75% percentile] and categorical

variables are presented as percentage. Data were checked for normality before statistical analysis (D’Agostino and Pearson omnibus normality test, PRISM 5.02, GraphPad Software, Inc., La Jolla, USA). Comparisons of continuous variables were made with Student’s unpaired t-test or Mann–Whitney U-test (PRISM 5.02). Comparisons of categorical variables were made with Pearson χ 2 test (STATISTICA 10, StatSoft GmbH, Hamburg, Germany). P < 0.05 was considered statistically significant.

RESULTS We found in total 253 CABG patients treated with DAPT (ASA and ticagrelor or ASA and clopidogrel) before cardiac surgery. We included 81 patients in the study who received either ticagrelor or clopidogrel with ASA, and DAPT could not be discontinued before surgery due to clearly increased risk of stent thrombosis and deadly reinfarction. Three of the 253 patients were treated with DAPT till surgery but had to be excluded in advance due to ECMO therapy. Coagulation disorders would have resulted in exclusion


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Preoperative lab analysis Coagulation INR aPTT (s) Fibrinogen (mg/dl) Blood cell count Haemoglobin (g/dl) Haematocrit (%) Erythrocyte (106/µl) MCV (fl) MCH (pg) MCHC (g/dl) Platelet (103/µl) White cell counts (103/µl) Serological markers of renal function Serum creatinine (mg/dl) Serum urea (mg/dl) Estimated creatinine clearance CK (U/l) CK-MB (U/l) CRP (mg/l)

Ticagrelor group (n=32)

Clopidogrel group (n=49)

P-value

1.1 [1.0–11] 28 [26–33] 487 ± 131

1.0 [1.0–1.1] 27 [25–30] 403 ± 102

0.81 0.23 0.025

13.0 ± 2.0 38.5 ± 6.2 4.2 ± 0.6 91 ± 4 30.6 ± 1.5 33.6 [33.1–33.9] 227 [199–290] 7.7 [6.5–10.2]

13.4 ± 1.8 40.0 ± 5.3 4.4 ± 0.6 91 ± 4 30.6 ± 1.5 33.6 [32.8–34.1] 245 [197–290] 8.6 [7.2–10.4]

0.32 0.24 0.31 0.90 0.92 0.85 0.77 0.37

0.94 [0.84–1.11] 18 [12–21] 78.93 [53.32–107.90] 84 [48–125] 15 [12–25] 7.7 [3.0–24.4]

1.05 [0.86–1.30] 17 [14–27] 67.46 [50.62–94.81] 93 [61–180] 15 [12–18] 5.0 [2.0–17]

0.18 0.93 0.28 0.38 0.55 0.36

Continuous variables are presented as mean ± SD or median [25% percentile to 75% percentile]. aPTT: activated partial thromboplastin time; CK: creatine kinase; CK-MB: creatine kinase-muscle/brain; CRP: C-reactive protein; INR: international normalized ratio; MCH: mean corpuscular haemoglobin; MCHC: mean corpuscular haemoglobin concentration; MCV: mean corpuscular volume.

Table 3: Operation data Operation data

Ticagrelor group (n = 32)

Clopidogrel group (n = 49)

P-value

Number of distal anastomoses IMA harvesting (n) Combined main procedures (n) Operative time (min) Perfusion time (min) Cross-clamp time (min) Minimum temperature (°C) Unfractionated heparin (IU) Protamine (IU)

4.0 [3.0–4.0] 28 7§ 260 [205–306] 130 ± 36 71 ± 17 32.9 [32.0–35.0] 24 000 [22 000–28 500] 23 190 ± 4740

3.0 [3.0–4.0] 46 6& 269 [232–295] 133 ± 44 83 ± 29 33.4 [32.4–35.4] 27 500 [24 625–33 225] 23 385 ± 4381

0.19 0.33 0.25 0.98 0.76 0.053 0.60 0.015 0.85

Continuous variables are presented as mean ± SD or median [25% percentile to 75% percentile]. Combined main procedures: §=5 × CABG + aortic valve replacement, 1 × CABG + Bentall procedure, 1 × CABG + mitral valve repair; &=2 × CABG + aortic valve replacement, 1 × CABG + maze procedure, 2 × CABG + mitral valve repair, 1 × CABG + aneurysmectomy. IMA: internal mammary artery.

of the study, but none of the identified patients had a coagulation disorder.

Patient characteristics and preoperative laboratory Ticagrelor and clopidogrel group patients showed no statistically significant differences with respect to their demographic characteristics (Table 1) except the incidence of diabetes mellitus, which was significantly lower in the ticagrelor group (P = 0.0220, Table 1). Except the mean fibrinogen levels, which were significantly higher in the ticagrelor group (P = 0.0249, Table 2), the preoperative laboratory parameters showed no significant difference between the two groups (Table 2).

Intraoperative data Operative, perfusion and cross-clamp time, temperature and number of distal anastomoses were not statistically different between the groups (Table 3). The usage of intraoperative unfractionated heparin was higher in the clopidogrel group compared with the ticagrelor group (P = 0.0154).

Postoperative data ICU and hospital stay did not achieve statistical significance (P = 0.9515 and P = 0.2687), when the groups were compared (Table 4). Also, the mechanical ventilation time at ICU and AKI,

ADULT CARDIAC

Table 2: Preoperative lab analysis


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defined by the acute kidney injury network (AKIN), showed no statistically significant differences between the two groups (P = 0.6735 and P = 0.3271, Table 4). A strong trend towards a higher incidence of rethoracotomy due to major bleeding was observed in the ticagrelor group, which did not reach statistical significance (P = 0.0632, Table 4).

Blood loss and treatment with transfusion and coagulations factors Blood loss from the arrival at the ICU until the first postoperative morning was significantly higher in the ticagrelor group compared

Table 4: Postoperative data Postoperative data



P-value

ICU stay (days) Hospital stay (days) Mechanical ventilation time (h) Rethoracotomy rate (n) IABP (n) Total AKI (n) AKI I (n) AKI II (n) 30-day mortality rate (n)

3 [2–6] 11 [8.25–13.75] 27 [11–63]

4 [1–7] 11 [9–21] 18 [8–71]

0.95 0.27 0.67

5

2

0.063

8 11 9 2 3

5 12 10 2 2

0.076 0.33 0.42 0.57 0.33

Continuous variables are presented as mean ± SD or median [25% percentile to 75% percentile], and categorical variables are presented as percentage. AKI: acute kidney injury; IABP: intra-aortic balloon pump; ICU: intensive care unit.

with the clopidogrel group (P = 0.0006, Table 5). In addition, blood loss 72 h after surgery was still significantly higher in patients treated with ticagrelor compared with the clopidogrel patients (P = 0.0038, Table 5). Intraoperatively, there was significantly higher usage of red blood cells (P = 0.0442), pooled platelet transfusion ( platelet pool of five donors) (P = 0.0017) and PCC (P = 0.0141) in the ticagrelor group compared with the clopidogrel group (Table 5). Also, a tendency of more fibrinogen application was observed in patients treated with ticagrelor (P = 0.0617, Table 5). Postoperative red blood cell, pooled platelet, PCC and fibrinogen administration were significantly higher in the ticagrelor group compared with the clopidogrel group (red blood cell transfusion: P = 0.0031, pooled platelet transfusion: P = 0.0012, PPCs: P = 0.0114 and fibrinogen: P = 0.0118, Table 5). Comparable results were found 72 h after surgery with platelet and fibrinogen administration (red blood cell transfusion: not significant P = 0.0941, pooled platelet transfusion: P = 0.0047, PPC: P = 0.0075 and fibrinogen: P < 0.0001, Table 5).

DISCUSSION The objective of this study was to investigate whether the continued preoperative use of ticagrelor till surgery influences the perioperative course of cardiac surgical patients in comparison with clopidogrel. Our data clearly show that patients receiving ticagrelor until cardiac surgery experienced significantly higher red blood cell and pooled platelet transfusion and coagulation factors administration rates perioperatively. Blood loss via drains was significantly higher in the ticagrelor group compared with the clopidogrel group. Additionally, there was a strong tendency towards a higher incidence of rethoracotomies four times higher with the use of ticagrelor (P = 0.0632). DAPT plays an important role in the management of ACS [1, 2, 11]. Large clinical trials showed an increased survival in patients

Table 5: Blood loss and application of blood products and coagulations factors

Blood loss (ml) Operation day Total in 72 h Application intraoperative Red blood cell transfusion (units) Pooled platelet transfusion (units) Fibrinogen (g) PCC (IU) Application operation day Red blood cell transfusion (units) Pooled platelet transfusion (units) Fibrinogen (g) PCC (IU) Total application in 72 h Red blood cell transfusion (units) Pooled platelet transfusion (units) Fibrinogen (g) PCC (IU)

P-value



850 [780–1600] 1790 [1250–2840]

680 [400–860] 1165 [791–1889]

0.0006 0.0038

2 [0–5] 2 [0–2] 0 [0–2] 0 [0–1875]

1.5 [0–3.75] 0 [0–2] 0 [0–0] 0 [0–0]

0.044 0.0017 0.062 0.014

5 [2–8.75] 2 [0.25–2] 0 [0–4] 0 [0–2000]

2 [0–5] 0 [0–2] 0 [0–0] 0 [0–0]

0.0031 0.0012 0.012 0.011

4.5 [0.25–10] 2 [0–3.75] 2.5 [0–4] 0 [0–2000]

3 [0–6] 0 [0–2] 0 [0–0] 0 [0–0]

0.094 0.0047