- Email: [email protected]
Metamizole and Platelet Inhibition by Aspirin Following On-Pump Coronary Artery Bypass Grafting
Author’s Accepted Manuscript Metamizole and Platelet Inhibition by Aspirin Following on-Pump Coronary Artery Bypass Grafting Mirosław Wilczyński, Maciej T. Wybraniec, Marek Sanak, Joanna Góral, Katarzyna Mizia-Stec www.elsevier.com/locate/buildenv
PII: DOI: Reference:
S1053-0770(17)30542-6 http://dx.doi.org/10.1053/j.jvca.2017.06.016 YJCAN4200
To appear in: Journal of Cardiothoracic and Vascular Anesthesia Cite this article as: Mirosław Wilczyński, Maciej T. Wybraniec, Marek Sanak, Joanna Góral and Katarzyna Mizia-Stec, Metamizole and Platelet Inhibition by Aspirin Following on-Pump Coronary Artery Bypass Grafting, Journal of Cardiothoracic and Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2017.06.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metamizole and platelet inhibition by aspirin following on-pump coronary artery bypass grafting
Running title: Metamizole and platelet function
Mirosław Wilczyński a MD, PhD, Associate Professor; Maciej T. Wybraniec b MD, PhD Marek Sanak c MD, PhD, Professor; Joanna Góral d MSc Katarzyna Mizia-Stec b MD, PhD, Professor
a
Department of Cardiac Surgery, Medical University of Lodz, Lodz, Poland
b
First Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice,
Poland; Public Hospital No 7 in Katowice, Upper Silesia Medical Center c
II Department of Internal Medicine, Division of Molecular Biology and Clinical Genetics, Jagiellonian
University Medical College, Kraków, Poland d
Department of Laboratory Medicine, Public Hospital No 7 in Katowice, Upper Silesia Medical Center,
Katowice, Poland
Declaration of interests: The authors report no conflict of interests. Acknowledgements and funding: The authors declare no external sources of funding.
Corresponding Author: Maciej Wybraniec, MD, PhD First Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland 47 Ziolowa St., 40-635 Katowice, Poland Phone: +48 32 359 88 90; E-mail: [email protected]; [email protected]
Abstract Objective: The purpose of the study was to evaluate the impact of intravenous metamizole on platelet inhibition by aspirin in patients with coronary artery disease (CAD) early after on-pump coronary artery bypass grafting (CABG). Design: Prospective single-blind randomized trial Setting: Tertiary reference hospital Participants: The study comprised 43 patients with multi-vessel CAD undergoing CABG. Interventions: Patients were randomized to postoperative intravenous metamizole ± opioids (study group; n=23) or opioids alone (control group; n=20). Aspirin was withheld at least 7 days before the surgery and reinitiated (300 mg) immediately after the procedure prior to metamizole use, and continued daily thereafter (150 mg). Platelet function was evaluated using multi-electrode impedance aggregometry (ASPI and COL test), P-selectin expression and urinary 11-dehydro-thromboxane B2 (11-DTXB2) level at baseline, postoperative day 0, day 1, day 2 and day 6. Residual platelet reactivity (RPR) was defined as ASPI test >400 AU*min. Measurements and main results: In all study participants, postoperative ASPI test value moderately decreased (1058.2 vs.966.6 AU*min,p=0.047), urinary 11-DTXB2 level increased (923.4 vs.4367.3 pg/mg, p<0.001) and P-selectin expression and COL test value remained stable post-procedurally. The decrease of ASPI (p=0.146) and COL test (p=0.642), and P-selectin expression (p=0.318), did not differ between both groups. Patients in the control group had higher postoperative increase of urinary 11-DTXB2 level (p=0.001). The prevalence of RPR was high and comparable between study and control group (day 1 95.6% vs.100%, p=0.535; day 6 100% vs.90%, p=0.21). Multivariate analysis revealed that metamizole use did not predict the fluctuations of ASPI and COL test values and Pselectin expression, yet it independently predicted postoperative change of 11-DTXB2 level (b=0.518,p=0.001). Conclusions: Intravenous metamizole preceded by loading dose of aspirin does not modify platelet response to aspirin in the direct postoperative period after on-pump CABG.
Keywords: metamizole; dipyrone; coronary artery bypass grafting; CABG; multi-electrode impedance aggregometry; 11-dTXB2; 11-dehydro-thromboxane-B2; P-selectin
Introduction
Antiplatelet therapy with aspirin remains a mainstay of treatment for patients with coronary artery disease (CAD), including subjects referred for coronary artery bypass grafting (CABG) [1]. Patients undergoing CABG require effective postoperative analgesia based mainly on opioid drugs [2]. Opioid derivatives, however, confer a series of adverse actions, which limit dose escalation in selected subjects. Although non-steroidal anti-inflammatory drugs (NSAIDs) contribute significantly to multimodal pain management in the postoperative period [3], they were shown to negatively interfere with the inhibition of cyclooxygenase type 1 (COX-1) by aspirin, leading to increased thromboxane A2 generation, thereby translating into the increased incidence of major adverse cardiovascular events [4]. Pyrazolinone analgesics, represented mainly by metamizole (dipyrone), studied on intact cells preferentially inhibit COX-2 isoenzyme [5], exerting analgesic and antipyretic effect, yet without the systemic anti-inflammatory action [3, 6]. Unlike other NSAIDs, metamizole is devoid of a detrimental effect on ulcerative disease and kidney function [6], at the expanse of the rare, but potentially lethal agranulocytosis [7]. The addition of metamizole to opioid drugs could facilitate better control of postoperative pain, limiting the dose of opioid agents without the risk of increased platelet activation [6]. Still, certain reports delivered evidence that metamizole may essentially interact with the systemic COX-1 and blunt the response to aspirin, which could preclude its widespread use in cardiac surgery setting [8-9]. This contradicts another study which implied no interference between aspirin and metamizole in healthy volunteers [10]. Despite this conflicting data, no study has so far investigated this phenomenon in cardiac surgery subjects.
Thus, the purpose of the study was to evaluate the effect of metamizole and opioids, compared to opioids alone, on aspirin-mediated platelet inhibition in patients undergoing onpump CABG. Methods In this pilot prospective single-blind randomized controlled study we enrolled 43 patients with multivessel CAD who were admitted to Department of Cardiac Surgery of Medical University of Silesia and referred for elective CABG using cardiopulmonary bypass. Patients were enrolled for the study during the initial visit at hospital, prior to the procedure and randomized to: 1) postoperative analgesia with metamizole (metamizole) ± opioid drugs (study group; n=23) or 2) postoperative analgesia based on opioid drugs (control group; n=20). In the direct postoperative period platelet function was evaluated in both groups at 5 time points: preoperatively, at postoperative day 0, day 1, day 2 and day 6 using multiple electrode impedance aggregometer, P-selectin platelet expression and urinary thromboxane A2 metabolite concentration (11-dehydrothroboxane B2; 11-dTXB2). The sequence of data acquisition was highlighted in Figure 1. The arithmetic mean values of all 4 main platelet function parameters were calculated. The change of each parameter (∆) was defined as the difference between mean postoperative value and the preoperative value. The primary endpoint of the study was the change of ∆AUC ASPI. The secondary endpoints were all the other assessed platelet parameters, including mean and single day postoperative AUC ASPI. The study was conducted in adherence to Declaration of Helsinki Guidelines and was approved by the local Ethics Committee. On admission all patients gave their written informed consent to participation in the research. Inclusion criteria comprised: a) stable angina with multivessel CAD confirmed by coronary angiography. Exclusion criteria were as follows: a) acute coronary syndrome of any kind within 30days before the procedure; b) use of aspirin and P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor)
within 7 days before surgery; b) history of cardiac surgery; c) concomitant valvular heart disease or aortic aneurysm requiring complex surgery; d) infection within 30-days before the surgery; e) the use of any NSAIDs other than aspirin within 30 days prior to surgery; f) history of gastrointestinal bleeding or ulcerative disease; g) history of transient ischemic attack or stroke; h) history of agranulocytosis; i) liver dysfunction (alanine or aspartate aminotransferase exceeding threefold the upper reference limit); j) chronic kidney disease with eGFR <30 ml/min/1.73 m2.
Randomization and study treatment Following initial assessment, patients were randomized in near 1:1 ratio to study and control group [Figure 1]. A simple method of ‘toss of a coin’. Patients in the study group (n=23) received intravenous metamizole at a dose of 1.25g three times a day during 6-days following the procedure with simultaneous intravenous (or subcutaneous) opioid drugs in patients requiring additional analgesia. Metamizole treatment was initiated more than 3 hours after aspirin loading. Metamizole was diluted in 100 ml of 0.9% NaCl and infused over 30 minutes. In the control group (n=20) post-operative analgesia was maintained on intravenous (or subcutaneous) opioids and tramadol according to individual patient’s requirement. In both groups no other NSAIDs were used as per protocol. In the immediate postoperative period on day 0, as soon as hemostasis was achieved but at least 6 h prior to blood and urine collection, 300 mg of aspirin was administered to all patients. In the following days aspirin was administered at a daily dose of 150 mg [Figure 1].
Platelet reactivity testing All the three platelet function were employed so as to complementarily reflect several layers of platelet-induced hemostasis. First, multiple electrode aggregometry collectively evaluates the propensity for clot formation in response to a potent trigger: arachidonic acid or
collagen [11]. Although the method can be performed on whole blood samples, it has certain limitations, such as low sensitivity for the preformed platelet micro-aggregates [11]. In turn, P-selectin flow cytometry allows for precise evaluation of expression of a protein engaged in platelet mobility and stabilization of fibrinogen-IIa/IIIb bonds [12]. Pselectin expression was shown to be associated with overall volume and stability of platelet aggregates [12]. The analysis of urinary contents of thromboxane A2 metabolite, namely 11-dTXB2, remains the last, yet the most indirect way of platelet function assessment. It provides insight into the level of potent platelet-derived activator of hemostasis [13]. One should keep in mind that thromboxane A2 is also produced by activated leukocytes and does not necessarily represent the activation of hemostatic system [13].
Impedance aggregometer (ASPI and COL test) Whole blood samples (3 ml) were collected from antecubital vein into hirudin-coated probes and analyzed within 30 minutes following acquisition by means of Multiplate® impedance aggregometer [14]. In order to evaluate effectiveness of aspirin therapy, the arachidonic acid-stimulated impedance (ASPI) test was used, which measures COX-1dependent arachidonic acid-induced platelet aggregation. Residual platelet reactivity (RPR) to aspirin was defined as AUC of ASPI >400 AU*min [15]. In addition, platelet activity on aspirin treatment was assessed using collagen-induced aggregation test (COL). Following binding of collagen to its receptors, a signaling cascade of platelet activation is triggered, also involving endogenous arachidonic acid is release, a substrate for the platelet cyclooxygenase. In case of both test, the efficacy of inhibition of platelet aggregation was expressed as a number of aggregation units (AU) integrated as area under the curve (AUC) in a period of 10
minutes.
P-selectin expression Additional 5 ml of whole blood were acquired from antecubital vein into sodium citrate probe at each time point. Within 48 hours after the acquisition, blood samples were incubated with monoclonal fluorescence-labelled anti-CD62P antibodies, as well as with antibody isotype controls, and subsequently assessed by means FACSAria™ III digital flow cytometer (Beckton Dickinson Biosciences) to assess distribution of platelet with P-selectin expression. Urinary 11-dehydrothroboxane B2 concentration In order to determine thromboxane A2 systemic production, 5 ml of urine were collected at each time point and immediately frozen and stored at -80 ⁰C until analysis. At the laboratory, urine samples were thawed and creatinine concentration was assessed by a colorimetric method for compensation of variable urine concentration (Oxford Biomedical Research, Oxford, Michigan, USA). The specimens were then assayed for 11dehydrothroboxane B2 (11-dTXB2), a stable urinary metabolite of thromboxane A2, using enzyme-linked immunosorbent assay (ELISA, BioAssay™, USbio Lifesciences). Urinary 11dTXB2 level was expressed recalculated to creatinine concentration of urine samples and expressed as [pg/mg].
Operative techniques Patients received a standard pharmacotherapy according to 2013 European Society of Cardiology guidelines on management of stable coronary artery disease [16] Anaesthesia was induced and maintained using standard procedures. A median sternotomy was performed and patients were placed on cardiopulmonary bypass (CPB), under mild hypothermia of 34°C and cold cardioplegia in
4:1 ratio to protect against myocardial ischaemia. Cardiopulmonary bypass was based on a standard roller pump and membrane oxygenator. Pressure was maintained at 60-70 mmHg and flow was maintained between 2.0 and 3.0 l/min/m2 based on body surface area. Unfractionated heparin was delivered intravenously at a dose of 300 U/kg and then again every 60 minutes of CPB to maintain an activated clotting time of at least 480 seconds. Immediately after cardiopulmonary bypass cessation, heparin was reversed with protamine sulfate at a dose of 3mg/kg.
Statistical analysis Statistical analysis was performed using Statistica 10.0 (Statsoft Inc., Tulsa, Oklahoma). Distribution of variables was verified using Shapiro-Wilk test. Variance uniformity was verified with Levene’s test. Normally distributed variables were compared by means of student’s t-test, while nonnormally distributed variables were analysed using Mann-Whitney U test. For categorical data Fisher’s exact test was utilized. The same variables at different time points were compared using twoway repeated measures analysis of variance (ANOVA) or two-way Friedman analysis of variance (ANOVA). Univariate regression analysis was performed in order to indicate the predictors of the difference between pre- and post-procedural platelet activation parameters. Variables with p<0.1 were incorporated into multivariate regression model.
Results The study population represented typical subset of subjects with stable coronary artery disease fraught with numerous risk factors, including high prevalence of arterial hypertension (n=37, 86%), diabetes mellitus (n=15, 35%) and cigarette smoking habit (n=18, 42%). The majority of study participants were men (n=37, 86%) and mean age was 63.1 ± 8.7 years. Detailed demographic and clinical characteristics of the study and control group are summarized in Table 1.
The study and control group did not significantly differ in terms of the prevalence of cardiovascular risk factors and clinical characteristics, except for slightly elevated concentration of bilirubin in the study group [Table 1].
Platelet function in the whole population In all study participants (n=43), by comparison with baseline values, AUC of ASPI test significantly decreased following on-pump CABG, while AUC of COL test remained unchanged [Table 2]. The urinary concentration of 11-dTXB2 profoundly increased following the procedure but Pselectin expression remained unchanged [Table 2].
Platelet function – inter-group differences AUC of ASPI test was significantly higher in the study group than control patients at baseline and remained greater throughout 6 days. Although the mean post-operative AUC of ASPI test was higher in the study group, the change between pre-operative and mean postoperative (∆AUC ASPI) value was comparable in both groups [Table 3]. The two-way repeated measures ANOVA did not reveal significant difference between AUC*time curves of the study and control group (p=0.306; Figure 2). A high RPR was prevalent and comparable between study and control group. Only at day 0 there was a trend towards lower rate of RPR in the control group (p=0.065). The AUC of COL test was also initially greater in the study than control group and remained so during 6-days of platelet function monitoring. Although the mean postoperative AUC of COL test was higher in the study group, the change between pre- and mean post-operative values was comparable in both cohorts [Table 3]. The AUC*time curve for COL test did not differ between study and control group (p=0.058; Figure 2). The urinary concentration of 11-dTXB2 was comparable in both groups at baseline, but at post-operative day 0, day 1 and day 2 was significantly higher in the control group in comparison to
study group. At day 6 urinary 11-dTXB2 levels were similar in study and control group [Table 3]. The mean post-operative 11-dTXB2 concentration, as well as the change between pre- and mean postoperative values were higher in the control group [Table 3]. There was no significant difference between the 11-dTXB2 concentration*time curve in the study and control group (p=0.235; Figure 2).
At baseline, the platelet P-selectin expression was similar in the study and control group and remained comparable in both cohorts during 6-day monitoring, except for postoperative day 0, when it was higher in the control than study group [Table 3]. Also, both groups did not differ in terms of mean post-operative P-selectin expression, as well as change between pre- and mean postoperative platelet P-selectin expression [Table 3]. The curves of P-selectin expression vs. time were comparable in both groups (p=0.079; Figure 2).
Multivariate regression analysis The results of multivariate regression analysis of predictors of the change between pre- and mean post-operative values of different platelet function parameters are presented in Table 4. The change in AUC ASPI test value was independently and negatively corresponded with age and bilirubin concentration, whereas ∆ AUC COL test negatively correlated with age alone. The change in urinary 11-dTxB2 independently and positively correlated with serum creatinine concentration and negatively with metamizole use. P-selectin platelet expression remained independent of other variables in the model.
Discussion To our knowledge, this prospective randomized study constitutes the first report in literature concerning the possible effect of metamizole use on platelet inhibition by aspirin after CABG. Current findings suggest that the postoperative use of metamizole +/- opioids in order to combat post-surgical pain does not alter the response to aspirin in comparison to patients treated merely with opioids.
Although the preoperative values of AUC of ASPI and COL test, which preceded loading with aspirin, were higher in the study group, the primary endpoint of ∆AUC ASPI, as well as ∆AUC COL test were comparable in both cohorts [Table 3]. Also, the number of patients with RPR was comparably high throughout the observation in the study and control group, suggesting a uniform suboptimal response to aspirin administration in both groups. The initial discrepancy between groups, despite proper randomization, remains unanswered. Still, the primary endpoint of the change of ∆AUC ASPI and ∆AUC COL partially compensates for this phenomenon and supports the concept of metamizole’s use in postoperative period. Both P-selectin expression and its postoperative change were comparable between both groups, except the initial higher expression in the control group on postoperative day 0. Although not a primary endpoint, P-selectin test remains one of the most sensitive markers of platelet activation [12] and its stable concentration in patients treated with metamizole is of paramount clinical significance. Patients in the study group were characterized by significantly lower surge of urinary 11-dTXB2 level than patients not treated with metamizole, implying suppression of thromboxane A2 release from activated platelets following administration of metamizole. These findings were finally corroborated in multivariate analysis, which indicated that metamizole use was the only one and independent predictor of ∆11-dTXB2 change, associated with decreased systemic biosynthesis and release of vasoconstrictory and proaggregatory thromboxane A 2 [Table 4]. Noteworthy, the use of metamizole did not independently predict the postoperative fluctuations of AUC of ASPI and COL test, as well as P-selectin expression [Table 4]. Since no other study investigated the antiplatelet sequelae of co-treatment with metamizole and aspirin in cardiac surgery patients, our results cannot be directly compared with other reports in literature. In one study by Boergermann et al., 101 patients submitted to various cardiac surgery procedures and receiving metamizole for the purpose of analgesia were characterized by suboptimal response to aspirin in the direct postoperative period [10]. Given this worrisome data, the possible interaction between metamizole and aspirin was verified in the parallel group of healthy individuals, yet metamizole seemed not to interfere with platelet inhibition by aspirin [10]. Conversely,
metamizole administered to patients without aspirin, was long ago proven to exhibit a rapid antiplatelet effect by inhibiting thromboxane A2 generation through competitive inhibition of COX-1 [17]. Of note, the results of our study stay in contradiction to former reports in the field. Papp et al. suggested that aspirin and metamizole may have competitive effect on COX-1 and their individual antiplatelet effect may be comparable [18]. Still, the authors showed that metamizole caused transient and reversible COX-1 inhibition, in contradistinction to irreversible blockade by aspirin [18]. Saxena and coworkers found that active metabolite of metamizole, similarly to NSAIDs, could alter the antiplatelet effect of aspirin, thereby translating into serious clinical implications of co-medication with both drugs [19]. Further evidence was provided by Hohlfeld and coworkers, who demonstrated that in healthy volunteers, 4-methyl-aminoantipyrine (MAA), an active metabolite of metamizole, resulted in the attenuation of platelet inhibition, thromboxane A2 formation and P-selectin expression mediated by aspirin, which was demonstrated to be caused by competition with aspirin at COX-1 docking region [9]. The MAA metabolite hindered COX-1 acetylation by aspirin by means of formation of a hydrogen bond with serine 530 within the COX-1 structure [9]. A further insight into the problem was provided by Polzin and coworkers, who also documented that metamizole use can lessen platelet inhibition by aspirin in patients with coronary artery disease in up to 50% of patients taking both agents [8], which could be partially overcome by increased doses of aspirin [19]. Of note, the administration of aspirin prior to metamizole intake preserved the antiplatelet effect of aspirin, presumably by means of obscuring of COX-1 metamizole binding site [20]. Accordingly, in our study all the patients received metamizole at least 3 hours following loading dose of aspirin, which might have protected against deleterious effect of metamizole on antiplatelet properties of aspirin. In this sense, the adequate sequence of treatment with initial loading with aspirin and subsequent analgesia with metamizole seems crucial in preserving antiplatelet effect of aspirin [19].
Elevated platelet reactivity on aspirin treatment is not unique for our study and was reported in numerous former reports concerning patients subject to CABG [10, 21]. In the study by Bednar et al. performed on 30 patients undergoing CABG, who received 200 mg aspirin daily, adequate inhibition of thromboxane A2 spill over was achieved on day 5 after the procedure, while only 34% of patients achieved effective platelet inhibition on day 5 defined by AUC of ASPI test <300 AU*min [21]. Petricevic and coworkers demonstrated that even if maintained on aspirin at a daily dose of 300 mg, patients exhibited suboptimal inhibition of platelets, resulting in 46.5% of patients with residual platelet reactivity (AUC ASPI >300 AU*min) [22]. This subset of patients additionally received clopidogrel with the intension to overcome the suboptimal platelet inhibition [22]. It is vital to note that aspirin dose of 325 mg was proven to be superior to 100 mg in the early postoperative period after CABG, as the incidence of RPR was significantly lower as assessed by light-transmission aggregometry [23]. The reason for the widespread resistance to aspirin in CABG patients may be related with the use of cardiopulmonary bypass [24]. Although, patients subject to off-pump CABG were also characterized by unacceptably high RPR rate of 30% [25], the suboptimal platelet inhibition was much higher in on-pump procedures [24], which was also corroborated in our study. In the present study it was documented that, although the AUC of ASPI test moderately decreased after the procedure [Table 2], the magnitude of the reduction was generally weak and as a consequence almost all the patients exhibited RPR during 6-day observation [Table 3]. Noteworthy, directly after the procedure the urinary concentration of 11-dTXB2 rapidly increased suggesting an increased platelet production of thromboxane A2 following cardiopulmonary bypass [Table 2]. Still the P-selectin expression remained stable [Table 2]. However, both P-selectin expression and urinary 11-dTXB2 are only indirect measures of platelet function. Paradoxical elevation of thromboxane A2 generation following the procedure may be related with cardiopulmonary bypass use. Initially, the inducible COX-2 isoform in platelets was thought to be responsible for the resistance to aspirin [26]. Zimmermann and coworkers delineated that increased platelet turnover in the aftermath of cardiopulmonary bypass might be the underlying cause of increased thromboxane
formation [24]. In the present study we have documented that, unlike P-selectin and AUC ASPI and COL, postoperative 11-dTXB2 levels are elevated in comparison to preoperative values. This may be conditioned by increased production of thromboxane A2 in lungs during CPB, which was denoted in an animal model [27]. Since thromboxane A2 was documented to be secreted from macrophages [13], CPB may induce its production by accelerating the systemic inflammatory response, leading to aspirin resistance [24]. More recently, multidrug resistance protein-4 (MRP-4) was found to be up-regulated in patients following CABG, which could facilitate the efflux of aspirin from platelets, leading to impaired platelet function inhibition [28].
Limitations of the study The number of study participants is rather low and the results of the study should be interpreted with caution. The statistical power for primary endpoint of ∆AUC ASPI is 44.9% and for mean postoperative AUC ASPI is 85.9%. In this study we did not evaluate ADP test, however, the use of P2Y12 inhibitors was discontinued 7 days before the surgery, hence it could not interfere with study results. Despite randomization, there was a difference between baseline aggregometry-derived platelet function (ASPI and COL test), which cannot be explained. However, it did not preclude assessment of the impact of metamizole use on platelet function, since temporal changes of parameters analysed. The study did not include assessment of platelet count after the CABG procedure. Lack of structured comparison between modes of analgesia (opioids and metamizole vs. opioids alone) constitutes a certain limitation of the study. Yet, the primary aim of the research was to assess the safety of metamizole and based on former studies, it was found to be an effective form of auxiliary analgesia in the direct postoperative period [29].
Conclusions Providing that it is preceded by aspirin loading dose, the use of metamizole in order to overcome postoperative pain after CABG seems to be safe and appears not to interfere with platelet function in the postoperative period. Dipyrone moderately reduces systemic production of TXA2, possibly by inhibition of COX-2 isoenzyme. Despite post-procedural administration of aspirin, platelet inhibition remains suboptimal in patients submitted to on-pump CABG, regardless of the mode postoperative analgesia.
References 1. Ferraris VA, Saha SP, Oestreich JH, et al; Society of Thoracic Surgeons. 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;94:1761-1781. 2. Barry AE, Chaney MA, London MJ. Anesthetic management during cardiopulmonary bypass: a systematic review. Anesth Analg 2015;120:749-769. 3. Konijnenbelt-Peters J, van der Heijden C, Ekhart C, et al. Metamizole (Dipyrone) as an Alternative Agent in Postoperative Analgesia in Patients with Contraindications for Nonsteroidal
Anti-Inflammatory
Drugs.
Pain
Pract.
2016
Jun
27.
doi:
10.1111/papr.12467. 4. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003;361:573-574. 5. Campos C, deGregorio R, Garcia-Nieto R, et al. Regulation of cyclooxygenase activity by metamizol. Eur J Pharmacol 1999;378:339-347. 6. Edwards J, Meseguer F, Faura C, et al. Single dose dipyrone for acute postoperative pain. Cochrane Database Syst Rev 2010;9:CD003227.
7. Stammschulte T, Ludwig WD, Mühlbauer B, et al. Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990-2012. Eur J Clin Pharmacol 2015;71:1129-1138. 8. Polzin A, Zeus T, Schrör K, et al. Dipyrone (metamizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease. J Am Coll Cardiol 2013;62:1725-1726. 9. Hohlfeld T, Zimmermann N, Weber AA, et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 2008;6:166-173. 10. Börgermann J, Kanashnik A, Sossdorf M, et al. Individual variability of response and non-response to acetyl salicylic acid after cardiac surgery. Platelets 2010;21:610-615. 11. McGlasson DL, Fritsma GA. Whole blood platelet aggregometry and platelet function testing. Semin Thromb Hemost 2009; 35: 168-180. 12. Merten M, Thiagarajan P. P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 2000; 102: 1931-1936. 13. Gabrielsen A, Qiu H, Bäck M, et al. Thromboxane synthase expression and thromboxane A2 production in the atherosclerotic lesion. J Mol Med (Berl) 2010;88:795-806. 14. Toth O, Calatzis A, Penz S, et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006;96:781-788. 15. Kuliczkowski W, Sliwka J, Kaczmarski J, et al. Predicting Bleeding Risk by Platelet Function Testing in Patients Undergoing Heart Surgery. Clin Cardiol 2015;38:679683. 16. Task Force Members, Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the
management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003. 17. Eldor A, Polliack G, Vlodavsky I, et al. Effects of dipyrone on prostaglandin production by human platelets and cultured bovine aortic endothelial cells. Thromb Haemost 1983;49:132-137. 18. Papp J, Sandor B, Vamos Z, et al. Antiplatelet effect of acetylsalicylic acid, metamizole and their combination - in vitro and in vivo comparisons. Clin Hemorheol Microcirc 2014;56:1-12. 19. Saxena A, Balaramnavar VM, Hohlfeld T, et al. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur J Pharmacol 2013;721:215-224. 20. Polzin A, Richter S, Schrör K, et al. Prevention of dipyrone (metamizole) induced inhibition of aspirin antiplatelet effects. Thromb Haemost 2015;114:87-95. 21. Bednar F, Tencer T, Plasil P, et al. Evaluation of aspirin's effect on platelet function early after coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2012;26:575580. 22. Petricevic M, Biocina B, Konosic S, et al. Assessment of platelet function by whole blood impedance aggregometry in coronary artery bypass grafting patients on acetylsalicylic acid treatment may prompt a switch to dual antiplatelet therapy. Heart Vessels 2013;28:57-65. 23. Brambilla M, Parolari A, Camera M, et al. Effect of two doses of aspirin on thromboxane biosynthesis and platelet function in patients undergoing coronary surgery. Thromb Haemost 2010;103:516-524. 24. Zimmermann N, Kurt M, Wenk A, et al. Is cardiopulmonary bypass a reason for aspirin resistance after coronary artery bypass grafting? Eur J Cardiothorac Surg
2005;27:606-610. 25. Wang Z, Gao F, Men J, et al. Aspirin resistance in off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg 2012;41:108-112. 26. Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003;108:542-547. 27. Erez E, Erman A, Snir E, et al. Thromboxane production in human lung during cardiopulmonary bypass: beneficial effect of aspirin? Ann Thorac Surg 1998;65:101106. 28. Mattiello T, Guerriero R, Lotti LV, et al. Aspirin extrusion from human platelets through multidrug resistance protein-4-mediated transport: evidence of a reduced drug action in patients after coronary artery bypass grafting. J Am Coll Cardiol 2011;58:752-761. 29. Oreskovic Z, Bicanic G, Hrabac P, et al. Treatment of postoperative pain after total hip arthroplasty: comparison between metamizol and paracetamol as adjunctive to opioid analgesics-prospective, double-blind, randomised study. Arch Orthop Trauma Surg 2014; 134: 631-636.
Figure legends Figure 1. Study flow chart illustrating randomization, study treatment allocation and diagnostic tests. R – randomization; ASA – aspirin; ASPI – impedance aggregometry-derived arachidonic acid-induced platelet activation; COL – impedance aggregometry-derived collagen-induced platelet activation; CABG – coronary artery bypass grafting; 11-dTxB2 - 11-dehydro-thromboxane-B2
Figure 2. Fluctuations of platelet function assessed by impedance aggregometry, urinary 11-dTxB-2 concentration and platelet P-selectin expression. PANEL A: Platelet activation induced by arachidonic acid (ASPI); AUC – area under curve [AU*min] PANEL B: Platelet activation induced by collagen (COL); AUC – area under curve [AU*min] PANEL C: Platelet activation reflected by urinary 11-dehydro-thromboxane-B2 concentration [pg/mg] PANEL D: Platelet activation reflected by platelet P-selectin expression [%]
‡ - two-way repeated measures analysis of variance (ANOVA); ¶ - two-way Friedman analysis of variance (ANOVA)
Table 1. Baseline characteristics of the study population and comparison of Metamizole (+) and metamizole (-) group in terms of different preoperative variables N=43
N=23
N=20
Variable
P Value Study population
Metamizole (+)
Metamizole (-)
Age [years]
63.1 ± 8.7
61.0 ± 9.1
65.5 ± 7.8
0.089 a
Body mass index [kg/m2]
27.8 ± 3.8
27.3 ± 4.0
28.3 ± 3.6
0.411 a
Men
37 (86%)
20 (87%)
17 (85%)
0.597 c
Cigarette smoking
18 (42%)
9 (39%)
9 (45%)
0.468 c
Arterial hypertension
37 (86%)
18 (78%)
19 (95%)
0.127 c
Atrial fibrillation
5 (12%)
3 (13%)
2 (10%)
0.569 c
Diabetes mellitus
15 (35%)
9 (39%)
6 (30%)
0.381 c
History of PCI
13 (30%)
5 (22%)
8 (40%)
0.167 c
54 (50; 60)
50 (50; 55)
55 (50; 60)
0.171 b
4.9 ± 0.4
4.8 ± 0.5
4.9 ± 0.3
0.492 a
14.8 (14.1; 15.3)
14.6 (14.0; 15.3)
15.0 (14.2; 15.5)
0.364 b
WBC [1000/mm3]
7.6 ± 1.7
7.9 ± 1.9
7.3 ± 1.5
0.303 a
PLT [1000/mm3]
208 (171; 256)
216 (183; 294)
201 (166.5; 227.5)
0.250 b
0.9 (0.7; 1.0)
0.85 (0.7; 1.0)
0.9 (0.7; 0.9)
0.928 b
95.3 ± 25.0
96.5 ± 25.4
93.8 ± 25.1
0.736 a
0.5 (0.4; 0.8)
0.7 (0.4; 1.0)
0.5 (0.35; 0.6)
0.025 b
16.2 ± 3.4
17.0 ± 3.8
15.4 ± 2.7
0.116 a
LVEF [%] RBC [mln/mm3] Hgb [g/dL]
SCr [mg/dL] eGFR [ml/min/1.73 m2] Bilirubin [mg/dL] Alanine transferase [U/L]
CPB time [min]
74 (52; 96)
72 (50; 88)
74 (52; 98)
0.862 b
Aortic cross-clamp time [min]
44 (35; 63)
44 (34; 72)
45 (35; 63)
0.782 b
38 (88.4%)
20 (87.0%)
18 (90.0%)
>1 coronary graft
a
0.612 c
– Student t test; b – Mann-Whitney U test; c – Fisher’s exact test; CPB – cardiopulmonary bypass
time; LVEF – left ventricular ejection fraction; RBC – red blood cell count; Hgb – hemoglobin; WBC –white blood cell count; PLT – platelet count; SCr- serum creatinine concentration; eGFR – estimated glomerular filtration rate
Table 2. Comparison of preoperative and mean postoperative platelet function parameters in the whole study population
Variable
AUC ASPI [AU*min] AUC COL [AU*min] Urinary 11-dTXB2 level [pg/mg] P-selectin expression [%] a
Pre-procedural
Mean post-procedural
P Value
1058.2 ± 417.5
966.6 ± 332.4
0.047 a
1508.7 ± 511.1
1501.0 ± 456.2
0.889 a
923.4 ± 521.4
4367.3 ± 3137.4
<0.001 b
0.97 ± 0.95
1.04 ± 0.45
0.082 b
– student’s t test for paired samples; b – Wilcoxon matched pairs test; 11-dTxB2 – 11-dehydro-
thromboxane-B2; ASPI – arachidonic acid-induced platelet activation measured by multiple electrode aggregometry; COL – collagen-induced platelet activation; AU – aggregation units
Table 3. Comparison of platelet activation in metamizole (+) and metamizole (-) group N=23
N=20
Variable
P Value Metamizole (+)
Metamizole (-)
1236.2 ± 411.5
853.5 ± 326.9
964.8 ± 462.8
651.7 ± 338.9
1053.9 ± 418.9
870.1 ± 302.7
951.4 ± 431.2
787.3 ± 300.1
1363.9 ± 549.8
1019.1 ± 458.8
0.033 a
AUC ASPI – mean postop. [AU*min]
1083.5 ± 348.8
832.0 ± 260.1
0.012 a
∆ AUC ASPI [AU*min]
-152.7 ± 334.0
-21.5 ± 228.6
0.146 a
RPR – preproc**
22 (95.6%)
19 (95.0%)
0.720 b
RPR – day 0
22 (95.6%)
15 (75.0%)
0.065 b
RPR – day 1
22 (95.6%)
20 (100.0%)
0.535 b
RPR – day 2
23 (100.0%)
19 (95.0%)
0.465 b
RPR – day 6
23 (100.0%)
18 (90.0%)
0.210 b
1810.9 ± 479.7
1222.7 ± 335.5
0.0002 a
1391.7 ± 584.1
1177.8 ± 373.9
0.248 a
1849.6 ± 497.2
1163.5 ± 333.8
0.0001 a
1676.9 ± 601.5
1031.2 ± 234.6
2213.6 ± 395.4
1444.2 ± 527.3
AUC ASPI – preproc. [AU*min] AUC ASPI – day 0 [AU*min] AUC ASPI – day 1 [AU*min] AUC ASPI – day 2 [AU*min] AUC ASPI – day 6 [AU*min]
AUC COL – preproc. [AU*min] AUC COL – day 0 [AU*min] AUC COL – day 1 [AU*min] AUC COL – day 2 [AU*min] AUC COL – day 6 [AU*min]
0.002 a 0.008 a 0.111 a 0.289 a
0.004 a 0.0001 a
AUC COL – mean postop. [AU*min]
1776.9 ± 429.5
1225.0 ± 288.2
0.0001 a
∆ AUC COL [AU*min]
-33.9 ± 415.1
18.4 ± 197.9
0.642 a
11-dTXB2 – preproc. [pg/mg]
899.3 ± 634.6
950.0 ± 508.7
11-dTXB2 – day 0 [pg/mg]
8218.2 ± 4734.7
12948.9 ± 7247.6
11-dTXB2 – day 1 [pg/mg]
2434.9 ± 3506.7
6680.1 ± 8409.2
11-dTXB2 – day 2 [pg/mg]
1181.2 ± 304.7
3414.3 ± 4271.1
11-dTXB2 – day 6 [pg/mg]
1021.6 ± 1271.3
983.8 ± 816.7
11-dTXB2 – mean postop. [pg/mg]
3014.6 ± 1853.2
5855.4 ± 3605.0
0.002 c
∆ 11-dTXB2 [pg/mg]
2115.3 ± 1676.1
4905.4 ± 3253.9
0.001 c
1.2 ± 2.0
0.8 ± 0.4
0.9 ± 2.1
1.7 ± 0.9
1.2 ± 5.4
1.2 ± 0.5
0.7 ± 3.0
0.8 ± 0.7
1.1 ± 2.9
0.6 ± 0.5
P-selectin – mean postop. [%]
1.0 ± 0.5
1.1 ± 0.4
0.752 c
∆ P-selectin [%]
-0.1 ± 1.4
0.3 ± 0.4
0.318 c
P-selectin – preproc. [%] P-selectin – day 0 [%] P-selectin – day 1 [%] P-selectin – day 2 [%] P-selectin – day 6 [%]
a
0.537 c 0.035 c 0.002 c 0.0007 c 0.417 c
0.913 c 0.013 c 0.471 c 0.678 c 0.230 c
– Student t test; b - Fisher’s exact test; c – Mann-Whitney U test; **- patients were not treated with
aspirin prior to procedure; 11-dTxB2 – 11-dehydro-thromboxane-B2; ASPI – arachidonic acid-induced platelet activation measured by multiple electrode aggregometry; COL – collagen-induced platelet activation; AU – aggregation units; RPR – residual platelet reactivity
Table 4. Multivariate regression analysis of different predictors of platelet function variability in the perioperative period ∆ AUC ASPI R2= 0.292; Adjusted R2= 0.218; p<0.009 b
Variable
SE of b
P value
Age
-0.299
0.142
0.043
Metamizole use (study group)
-0.142
0.157
0.371
0.233
0.139
0.102
-0.336
0.150
0.031
Body mass index Bilirubin concentration
∆ AUC COL R2= 0.195; Adjusted R2= 0.143; p<0.035 b
Variable
SE of b
P value
Age
-0.366
0.164
0.034
Diabetes mellitus type 2
-0.330
0.164
0.054
∆ urinary 11-dTxB2 R2= 0.386; Adjusted R2= 0.335; p<0.0005 Variable
b
SE of b
P value
Serum creatinine concentration
0.309
0.132
0.025
Bilirubin concentration
-0.049
0.148
0.742
Metamizole use (study group)
-0.518
0.146
0.001
∆ P-selectin No predictors of P-selectin with p<0.1 in univariate analysis were reported.
b- regression coefficient, ∆ - difference between mean postoperative concentration/level and preoperative value; 11-dTxB2 - 11-dehydro-thromboxane-B2; AUC ASPI – area under curve of
arachidonic acid-induced platelet activation; AUC COL - area under curve of collagen-induced platelet activation
PII: DOI: Reference:
S1053-0770(17)30542-6 http://dx.doi.org/10.1053/j.jvca.2017.06.016 YJCAN4200
To appear in: Journal of Cardiothoracic and Vascular Anesthesia Cite this article as: Mirosław Wilczyński, Maciej T. Wybraniec, Marek Sanak, Joanna Góral and Katarzyna Mizia-Stec, Metamizole and Platelet Inhibition by Aspirin Following on-Pump Coronary Artery Bypass Grafting, Journal of Cardiothoracic and Vascular Anesthesia, http://dx.doi.org/10.1053/j.jvca.2017.06.016 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Metamizole and platelet inhibition by aspirin following on-pump coronary artery bypass grafting
Running title: Metamizole and platelet function
Mirosław Wilczyński a MD, PhD, Associate Professor; Maciej T. Wybraniec b MD, PhD Marek Sanak c MD, PhD, Professor; Joanna Góral d MSc Katarzyna Mizia-Stec b MD, PhD, Professor
a
Department of Cardiac Surgery, Medical University of Lodz, Lodz, Poland
b
First Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice,
Poland; Public Hospital No 7 in Katowice, Upper Silesia Medical Center c
II Department of Internal Medicine, Division of Molecular Biology and Clinical Genetics, Jagiellonian
University Medical College, Kraków, Poland d
Department of Laboratory Medicine, Public Hospital No 7 in Katowice, Upper Silesia Medical Center,
Katowice, Poland
Declaration of interests: The authors report no conflict of interests. Acknowledgements and funding: The authors declare no external sources of funding.
Corresponding Author: Maciej Wybraniec, MD, PhD First Department of Cardiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland 47 Ziolowa St., 40-635 Katowice, Poland Phone: +48 32 359 88 90; E-mail: [email protected]; [email protected]
Abstract Objective: The purpose of the study was to evaluate the impact of intravenous metamizole on platelet inhibition by aspirin in patients with coronary artery disease (CAD) early after on-pump coronary artery bypass grafting (CABG). Design: Prospective single-blind randomized trial Setting: Tertiary reference hospital Participants: The study comprised 43 patients with multi-vessel CAD undergoing CABG. Interventions: Patients were randomized to postoperative intravenous metamizole ± opioids (study group; n=23) or opioids alone (control group; n=20). Aspirin was withheld at least 7 days before the surgery and reinitiated (300 mg) immediately after the procedure prior to metamizole use, and continued daily thereafter (150 mg). Platelet function was evaluated using multi-electrode impedance aggregometry (ASPI and COL test), P-selectin expression and urinary 11-dehydro-thromboxane B2 (11-DTXB2) level at baseline, postoperative day 0, day 1, day 2 and day 6. Residual platelet reactivity (RPR) was defined as ASPI test >400 AU*min. Measurements and main results: In all study participants, postoperative ASPI test value moderately decreased (1058.2 vs.966.6 AU*min,p=0.047), urinary 11-DTXB2 level increased (923.4 vs.4367.3 pg/mg, p<0.001) and P-selectin expression and COL test value remained stable post-procedurally. The decrease of ASPI (p=0.146) and COL test (p=0.642), and P-selectin expression (p=0.318), did not differ between both groups. Patients in the control group had higher postoperative increase of urinary 11-DTXB2 level (p=0.001). The prevalence of RPR was high and comparable between study and control group (day 1 95.6% vs.100%, p=0.535; day 6 100% vs.90%, p=0.21). Multivariate analysis revealed that metamizole use did not predict the fluctuations of ASPI and COL test values and Pselectin expression, yet it independently predicted postoperative change of 11-DTXB2 level (b=0.518,p=0.001). Conclusions: Intravenous metamizole preceded by loading dose of aspirin does not modify platelet response to aspirin in the direct postoperative period after on-pump CABG.
Keywords: metamizole; dipyrone; coronary artery bypass grafting; CABG; multi-electrode impedance aggregometry; 11-dTXB2; 11-dehydro-thromboxane-B2; P-selectin
Introduction
Antiplatelet therapy with aspirin remains a mainstay of treatment for patients with coronary artery disease (CAD), including subjects referred for coronary artery bypass grafting (CABG) [1]. Patients undergoing CABG require effective postoperative analgesia based mainly on opioid drugs [2]. Opioid derivatives, however, confer a series of adverse actions, which limit dose escalation in selected subjects. Although non-steroidal anti-inflammatory drugs (NSAIDs) contribute significantly to multimodal pain management in the postoperative period [3], they were shown to negatively interfere with the inhibition of cyclooxygenase type 1 (COX-1) by aspirin, leading to increased thromboxane A2 generation, thereby translating into the increased incidence of major adverse cardiovascular events [4]. Pyrazolinone analgesics, represented mainly by metamizole (dipyrone), studied on intact cells preferentially inhibit COX-2 isoenzyme [5], exerting analgesic and antipyretic effect, yet without the systemic anti-inflammatory action [3, 6]. Unlike other NSAIDs, metamizole is devoid of a detrimental effect on ulcerative disease and kidney function [6], at the expanse of the rare, but potentially lethal agranulocytosis [7]. The addition of metamizole to opioid drugs could facilitate better control of postoperative pain, limiting the dose of opioid agents without the risk of increased platelet activation [6]. Still, certain reports delivered evidence that metamizole may essentially interact with the systemic COX-1 and blunt the response to aspirin, which could preclude its widespread use in cardiac surgery setting [8-9]. This contradicts another study which implied no interference between aspirin and metamizole in healthy volunteers [10]. Despite this conflicting data, no study has so far investigated this phenomenon in cardiac surgery subjects.
Thus, the purpose of the study was to evaluate the effect of metamizole and opioids, compared to opioids alone, on aspirin-mediated platelet inhibition in patients undergoing onpump CABG. Methods In this pilot prospective single-blind randomized controlled study we enrolled 43 patients with multivessel CAD who were admitted to Department of Cardiac Surgery of Medical University of Silesia and referred for elective CABG using cardiopulmonary bypass. Patients were enrolled for the study during the initial visit at hospital, prior to the procedure and randomized to: 1) postoperative analgesia with metamizole (metamizole) ± opioid drugs (study group; n=23) or 2) postoperative analgesia based on opioid drugs (control group; n=20). In the direct postoperative period platelet function was evaluated in both groups at 5 time points: preoperatively, at postoperative day 0, day 1, day 2 and day 6 using multiple electrode impedance aggregometer, P-selectin platelet expression and urinary thromboxane A2 metabolite concentration (11-dehydrothroboxane B2; 11-dTXB2). The sequence of data acquisition was highlighted in Figure 1. The arithmetic mean values of all 4 main platelet function parameters were calculated. The change of each parameter (∆) was defined as the difference between mean postoperative value and the preoperative value. The primary endpoint of the study was the change of ∆AUC ASPI. The secondary endpoints were all the other assessed platelet parameters, including mean and single day postoperative AUC ASPI. The study was conducted in adherence to Declaration of Helsinki Guidelines and was approved by the local Ethics Committee. On admission all patients gave their written informed consent to participation in the research. Inclusion criteria comprised: a) stable angina with multivessel CAD confirmed by coronary angiography. Exclusion criteria were as follows: a) acute coronary syndrome of any kind within 30days before the procedure; b) use of aspirin and P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor)
within 7 days before surgery; b) history of cardiac surgery; c) concomitant valvular heart disease or aortic aneurysm requiring complex surgery; d) infection within 30-days before the surgery; e) the use of any NSAIDs other than aspirin within 30 days prior to surgery; f) history of gastrointestinal bleeding or ulcerative disease; g) history of transient ischemic attack or stroke; h) history of agranulocytosis; i) liver dysfunction (alanine or aspartate aminotransferase exceeding threefold the upper reference limit); j) chronic kidney disease with eGFR <30 ml/min/1.73 m2.
Randomization and study treatment Following initial assessment, patients were randomized in near 1:1 ratio to study and control group [Figure 1]. A simple method of ‘toss of a coin’. Patients in the study group (n=23) received intravenous metamizole at a dose of 1.25g three times a day during 6-days following the procedure with simultaneous intravenous (or subcutaneous) opioid drugs in patients requiring additional analgesia. Metamizole treatment was initiated more than 3 hours after aspirin loading. Metamizole was diluted in 100 ml of 0.9% NaCl and infused over 30 minutes. In the control group (n=20) post-operative analgesia was maintained on intravenous (or subcutaneous) opioids and tramadol according to individual patient’s requirement. In both groups no other NSAIDs were used as per protocol. In the immediate postoperative period on day 0, as soon as hemostasis was achieved but at least 6 h prior to blood and urine collection, 300 mg of aspirin was administered to all patients. In the following days aspirin was administered at a daily dose of 150 mg [Figure 1].
Platelet reactivity testing All the three platelet function were employed so as to complementarily reflect several layers of platelet-induced hemostasis. First, multiple electrode aggregometry collectively evaluates the propensity for clot formation in response to a potent trigger: arachidonic acid or
collagen [11]. Although the method can be performed on whole blood samples, it has certain limitations, such as low sensitivity for the preformed platelet micro-aggregates [11]. In turn, P-selectin flow cytometry allows for precise evaluation of expression of a protein engaged in platelet mobility and stabilization of fibrinogen-IIa/IIIb bonds [12]. Pselectin expression was shown to be associated with overall volume and stability of platelet aggregates [12]. The analysis of urinary contents of thromboxane A2 metabolite, namely 11-dTXB2, remains the last, yet the most indirect way of platelet function assessment. It provides insight into the level of potent platelet-derived activator of hemostasis [13]. One should keep in mind that thromboxane A2 is also produced by activated leukocytes and does not necessarily represent the activation of hemostatic system [13].
Impedance aggregometer (ASPI and COL test) Whole blood samples (3 ml) were collected from antecubital vein into hirudin-coated probes and analyzed within 30 minutes following acquisition by means of Multiplate® impedance aggregometer [14]. In order to evaluate effectiveness of aspirin therapy, the arachidonic acid-stimulated impedance (ASPI) test was used, which measures COX-1dependent arachidonic acid-induced platelet aggregation. Residual platelet reactivity (RPR) to aspirin was defined as AUC of ASPI >400 AU*min [15]. In addition, platelet activity on aspirin treatment was assessed using collagen-induced aggregation test (COL). Following binding of collagen to its receptors, a signaling cascade of platelet activation is triggered, also involving endogenous arachidonic acid is release, a substrate for the platelet cyclooxygenase. In case of both test, the efficacy of inhibition of platelet aggregation was expressed as a number of aggregation units (AU) integrated as area under the curve (AUC) in a period of 10
minutes.
P-selectin expression Additional 5 ml of whole blood were acquired from antecubital vein into sodium citrate probe at each time point. Within 48 hours after the acquisition, blood samples were incubated with monoclonal fluorescence-labelled anti-CD62P antibodies, as well as with antibody isotype controls, and subsequently assessed by means FACSAria™ III digital flow cytometer (Beckton Dickinson Biosciences) to assess distribution of platelet with P-selectin expression. Urinary 11-dehydrothroboxane B2 concentration In order to determine thromboxane A2 systemic production, 5 ml of urine were collected at each time point and immediately frozen and stored at -80 ⁰C until analysis. At the laboratory, urine samples were thawed and creatinine concentration was assessed by a colorimetric method for compensation of variable urine concentration (Oxford Biomedical Research, Oxford, Michigan, USA). The specimens were then assayed for 11dehydrothroboxane B2 (11-dTXB2), a stable urinary metabolite of thromboxane A2, using enzyme-linked immunosorbent assay (ELISA, BioAssay™, USbio Lifesciences). Urinary 11dTXB2 level was expressed recalculated to creatinine concentration of urine samples and expressed as [pg/mg].
Operative techniques Patients received a standard pharmacotherapy according to 2013 European Society of Cardiology guidelines on management of stable coronary artery disease [16] Anaesthesia was induced and maintained using standard procedures. A median sternotomy was performed and patients were placed on cardiopulmonary bypass (CPB), under mild hypothermia of 34°C and cold cardioplegia in
4:1 ratio to protect against myocardial ischaemia. Cardiopulmonary bypass was based on a standard roller pump and membrane oxygenator. Pressure was maintained at 60-70 mmHg and flow was maintained between 2.0 and 3.0 l/min/m2 based on body surface area. Unfractionated heparin was delivered intravenously at a dose of 300 U/kg and then again every 60 minutes of CPB to maintain an activated clotting time of at least 480 seconds. Immediately after cardiopulmonary bypass cessation, heparin was reversed with protamine sulfate at a dose of 3mg/kg.
Statistical analysis Statistical analysis was performed using Statistica 10.0 (Statsoft Inc., Tulsa, Oklahoma). Distribution of variables was verified using Shapiro-Wilk test. Variance uniformity was verified with Levene’s test. Normally distributed variables were compared by means of student’s t-test, while nonnormally distributed variables were analysed using Mann-Whitney U test. For categorical data Fisher’s exact test was utilized. The same variables at different time points were compared using twoway repeated measures analysis of variance (ANOVA) or two-way Friedman analysis of variance (ANOVA). Univariate regression analysis was performed in order to indicate the predictors of the difference between pre- and post-procedural platelet activation parameters. Variables with p<0.1 were incorporated into multivariate regression model.
Results The study population represented typical subset of subjects with stable coronary artery disease fraught with numerous risk factors, including high prevalence of arterial hypertension (n=37, 86%), diabetes mellitus (n=15, 35%) and cigarette smoking habit (n=18, 42%). The majority of study participants were men (n=37, 86%) and mean age was 63.1 ± 8.7 years. Detailed demographic and clinical characteristics of the study and control group are summarized in Table 1.
The study and control group did not significantly differ in terms of the prevalence of cardiovascular risk factors and clinical characteristics, except for slightly elevated concentration of bilirubin in the study group [Table 1].
Platelet function in the whole population In all study participants (n=43), by comparison with baseline values, AUC of ASPI test significantly decreased following on-pump CABG, while AUC of COL test remained unchanged [Table 2]. The urinary concentration of 11-dTXB2 profoundly increased following the procedure but Pselectin expression remained unchanged [Table 2].
Platelet function – inter-group differences AUC of ASPI test was significantly higher in the study group than control patients at baseline and remained greater throughout 6 days. Although the mean post-operative AUC of ASPI test was higher in the study group, the change between pre-operative and mean postoperative (∆AUC ASPI) value was comparable in both groups [Table 3]. The two-way repeated measures ANOVA did not reveal significant difference between AUC*time curves of the study and control group (p=0.306; Figure 2). A high RPR was prevalent and comparable between study and control group. Only at day 0 there was a trend towards lower rate of RPR in the control group (p=0.065). The AUC of COL test was also initially greater in the study than control group and remained so during 6-days of platelet function monitoring. Although the mean postoperative AUC of COL test was higher in the study group, the change between pre- and mean post-operative values was comparable in both cohorts [Table 3]. The AUC*time curve for COL test did not differ between study and control group (p=0.058; Figure 2). The urinary concentration of 11-dTXB2 was comparable in both groups at baseline, but at post-operative day 0, day 1 and day 2 was significantly higher in the control group in comparison to
study group. At day 6 urinary 11-dTXB2 levels were similar in study and control group [Table 3]. The mean post-operative 11-dTXB2 concentration, as well as the change between pre- and mean postoperative values were higher in the control group [Table 3]. There was no significant difference between the 11-dTXB2 concentration*time curve in the study and control group (p=0.235; Figure 2).
At baseline, the platelet P-selectin expression was similar in the study and control group and remained comparable in both cohorts during 6-day monitoring, except for postoperative day 0, when it was higher in the control than study group [Table 3]. Also, both groups did not differ in terms of mean post-operative P-selectin expression, as well as change between pre- and mean postoperative platelet P-selectin expression [Table 3]. The curves of P-selectin expression vs. time were comparable in both groups (p=0.079; Figure 2).
Multivariate regression analysis The results of multivariate regression analysis of predictors of the change between pre- and mean post-operative values of different platelet function parameters are presented in Table 4. The change in AUC ASPI test value was independently and negatively corresponded with age and bilirubin concentration, whereas ∆ AUC COL test negatively correlated with age alone. The change in urinary 11-dTxB2 independently and positively correlated with serum creatinine concentration and negatively with metamizole use. P-selectin platelet expression remained independent of other variables in the model.
Discussion To our knowledge, this prospective randomized study constitutes the first report in literature concerning the possible effect of metamizole use on platelet inhibition by aspirin after CABG. Current findings suggest that the postoperative use of metamizole +/- opioids in order to combat post-surgical pain does not alter the response to aspirin in comparison to patients treated merely with opioids.
Although the preoperative values of AUC of ASPI and COL test, which preceded loading with aspirin, were higher in the study group, the primary endpoint of ∆AUC ASPI, as well as ∆AUC COL test were comparable in both cohorts [Table 3]. Also, the number of patients with RPR was comparably high throughout the observation in the study and control group, suggesting a uniform suboptimal response to aspirin administration in both groups. The initial discrepancy between groups, despite proper randomization, remains unanswered. Still, the primary endpoint of the change of ∆AUC ASPI and ∆AUC COL partially compensates for this phenomenon and supports the concept of metamizole’s use in postoperative period. Both P-selectin expression and its postoperative change were comparable between both groups, except the initial higher expression in the control group on postoperative day 0. Although not a primary endpoint, P-selectin test remains one of the most sensitive markers of platelet activation [12] and its stable concentration in patients treated with metamizole is of paramount clinical significance. Patients in the study group were characterized by significantly lower surge of urinary 11-dTXB2 level than patients not treated with metamizole, implying suppression of thromboxane A2 release from activated platelets following administration of metamizole. These findings were finally corroborated in multivariate analysis, which indicated that metamizole use was the only one and independent predictor of ∆11-dTXB2 change, associated with decreased systemic biosynthesis and release of vasoconstrictory and proaggregatory thromboxane A 2 [Table 4]. Noteworthy, the use of metamizole did not independently predict the postoperative fluctuations of AUC of ASPI and COL test, as well as P-selectin expression [Table 4]. Since no other study investigated the antiplatelet sequelae of co-treatment with metamizole and aspirin in cardiac surgery patients, our results cannot be directly compared with other reports in literature. In one study by Boergermann et al., 101 patients submitted to various cardiac surgery procedures and receiving metamizole for the purpose of analgesia were characterized by suboptimal response to aspirin in the direct postoperative period [10]. Given this worrisome data, the possible interaction between metamizole and aspirin was verified in the parallel group of healthy individuals, yet metamizole seemed not to interfere with platelet inhibition by aspirin [10]. Conversely,
metamizole administered to patients without aspirin, was long ago proven to exhibit a rapid antiplatelet effect by inhibiting thromboxane A2 generation through competitive inhibition of COX-1 [17]. Of note, the results of our study stay in contradiction to former reports in the field. Papp et al. suggested that aspirin and metamizole may have competitive effect on COX-1 and their individual antiplatelet effect may be comparable [18]. Still, the authors showed that metamizole caused transient and reversible COX-1 inhibition, in contradistinction to irreversible blockade by aspirin [18]. Saxena and coworkers found that active metabolite of metamizole, similarly to NSAIDs, could alter the antiplatelet effect of aspirin, thereby translating into serious clinical implications of co-medication with both drugs [19]. Further evidence was provided by Hohlfeld and coworkers, who demonstrated that in healthy volunteers, 4-methyl-aminoantipyrine (MAA), an active metabolite of metamizole, resulted in the attenuation of platelet inhibition, thromboxane A2 formation and P-selectin expression mediated by aspirin, which was demonstrated to be caused by competition with aspirin at COX-1 docking region [9]. The MAA metabolite hindered COX-1 acetylation by aspirin by means of formation of a hydrogen bond with serine 530 within the COX-1 structure [9]. A further insight into the problem was provided by Polzin and coworkers, who also documented that metamizole use can lessen platelet inhibition by aspirin in patients with coronary artery disease in up to 50% of patients taking both agents [8], which could be partially overcome by increased doses of aspirin [19]. Of note, the administration of aspirin prior to metamizole intake preserved the antiplatelet effect of aspirin, presumably by means of obscuring of COX-1 metamizole binding site [20]. Accordingly, in our study all the patients received metamizole at least 3 hours following loading dose of aspirin, which might have protected against deleterious effect of metamizole on antiplatelet properties of aspirin. In this sense, the adequate sequence of treatment with initial loading with aspirin and subsequent analgesia with metamizole seems crucial in preserving antiplatelet effect of aspirin [19].
Elevated platelet reactivity on aspirin treatment is not unique for our study and was reported in numerous former reports concerning patients subject to CABG [10, 21]. In the study by Bednar et al. performed on 30 patients undergoing CABG, who received 200 mg aspirin daily, adequate inhibition of thromboxane A2 spill over was achieved on day 5 after the procedure, while only 34% of patients achieved effective platelet inhibition on day 5 defined by AUC of ASPI test <300 AU*min [21]. Petricevic and coworkers demonstrated that even if maintained on aspirin at a daily dose of 300 mg, patients exhibited suboptimal inhibition of platelets, resulting in 46.5% of patients with residual platelet reactivity (AUC ASPI >300 AU*min) [22]. This subset of patients additionally received clopidogrel with the intension to overcome the suboptimal platelet inhibition [22]. It is vital to note that aspirin dose of 325 mg was proven to be superior to 100 mg in the early postoperative period after CABG, as the incidence of RPR was significantly lower as assessed by light-transmission aggregometry [23]. The reason for the widespread resistance to aspirin in CABG patients may be related with the use of cardiopulmonary bypass [24]. Although, patients subject to off-pump CABG were also characterized by unacceptably high RPR rate of 30% [25], the suboptimal platelet inhibition was much higher in on-pump procedures [24], which was also corroborated in our study. In the present study it was documented that, although the AUC of ASPI test moderately decreased after the procedure [Table 2], the magnitude of the reduction was generally weak and as a consequence almost all the patients exhibited RPR during 6-day observation [Table 3]. Noteworthy, directly after the procedure the urinary concentration of 11-dTXB2 rapidly increased suggesting an increased platelet production of thromboxane A2 following cardiopulmonary bypass [Table 2]. Still the P-selectin expression remained stable [Table 2]. However, both P-selectin expression and urinary 11-dTXB2 are only indirect measures of platelet function. Paradoxical elevation of thromboxane A2 generation following the procedure may be related with cardiopulmonary bypass use. Initially, the inducible COX-2 isoform in platelets was thought to be responsible for the resistance to aspirin [26]. Zimmermann and coworkers delineated that increased platelet turnover in the aftermath of cardiopulmonary bypass might be the underlying cause of increased thromboxane
formation [24]. In the present study we have documented that, unlike P-selectin and AUC ASPI and COL, postoperative 11-dTXB2 levels are elevated in comparison to preoperative values. This may be conditioned by increased production of thromboxane A2 in lungs during CPB, which was denoted in an animal model [27]. Since thromboxane A2 was documented to be secreted from macrophages [13], CPB may induce its production by accelerating the systemic inflammatory response, leading to aspirin resistance [24]. More recently, multidrug resistance protein-4 (MRP-4) was found to be up-regulated in patients following CABG, which could facilitate the efflux of aspirin from platelets, leading to impaired platelet function inhibition [28].
Limitations of the study The number of study participants is rather low and the results of the study should be interpreted with caution. The statistical power for primary endpoint of ∆AUC ASPI is 44.9% and for mean postoperative AUC ASPI is 85.9%. In this study we did not evaluate ADP test, however, the use of P2Y12 inhibitors was discontinued 7 days before the surgery, hence it could not interfere with study results. Despite randomization, there was a difference between baseline aggregometry-derived platelet function (ASPI and COL test), which cannot be explained. However, it did not preclude assessment of the impact of metamizole use on platelet function, since temporal changes of parameters analysed. The study did not include assessment of platelet count after the CABG procedure. Lack of structured comparison between modes of analgesia (opioids and metamizole vs. opioids alone) constitutes a certain limitation of the study. Yet, the primary aim of the research was to assess the safety of metamizole and based on former studies, it was found to be an effective form of auxiliary analgesia in the direct postoperative period [29].
Conclusions Providing that it is preceded by aspirin loading dose, the use of metamizole in order to overcome postoperative pain after CABG seems to be safe and appears not to interfere with platelet function in the postoperative period. Dipyrone moderately reduces systemic production of TXA2, possibly by inhibition of COX-2 isoenzyme. Despite post-procedural administration of aspirin, platelet inhibition remains suboptimal in patients submitted to on-pump CABG, regardless of the mode postoperative analgesia.
References 1. Ferraris VA, Saha SP, Oestreich JH, et al; Society of Thoracic Surgeons. 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;94:1761-1781. 2. Barry AE, Chaney MA, London MJ. Anesthetic management during cardiopulmonary bypass: a systematic review. Anesth Analg 2015;120:749-769. 3. Konijnenbelt-Peters J, van der Heijden C, Ekhart C, et al. Metamizole (Dipyrone) as an Alternative Agent in Postoperative Analgesia in Patients with Contraindications for Nonsteroidal
Anti-Inflammatory
Drugs.
Pain
Pract.
2016
Jun
27.
doi:
10.1111/papr.12467. 4. MacDonald TM, Wei L. Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003;361:573-574. 5. Campos C, deGregorio R, Garcia-Nieto R, et al. Regulation of cyclooxygenase activity by metamizol. Eur J Pharmacol 1999;378:339-347. 6. Edwards J, Meseguer F, Faura C, et al. Single dose dipyrone for acute postoperative pain. Cochrane Database Syst Rev 2010;9:CD003227.
7. Stammschulte T, Ludwig WD, Mühlbauer B, et al. Metamizole (dipyrone)-associated agranulocytosis. An analysis of German spontaneous reports 1990-2012. Eur J Clin Pharmacol 2015;71:1129-1138. 8. Polzin A, Zeus T, Schrör K, et al. Dipyrone (metamizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease. J Am Coll Cardiol 2013;62:1725-1726. 9. Hohlfeld T, Zimmermann N, Weber AA, et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J Thromb Haemost 2008;6:166-173. 10. Börgermann J, Kanashnik A, Sossdorf M, et al. Individual variability of response and non-response to acetyl salicylic acid after cardiac surgery. Platelets 2010;21:610-615. 11. McGlasson DL, Fritsma GA. Whole blood platelet aggregometry and platelet function testing. Semin Thromb Hemost 2009; 35: 168-180. 12. Merten M, Thiagarajan P. P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 2000; 102: 1931-1936. 13. Gabrielsen A, Qiu H, Bäck M, et al. Thromboxane synthase expression and thromboxane A2 production in the atherosclerotic lesion. J Mol Med (Berl) 2010;88:795-806. 14. Toth O, Calatzis A, Penz S, et al. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006;96:781-788. 15. Kuliczkowski W, Sliwka J, Kaczmarski J, et al. Predicting Bleeding Risk by Platelet Function Testing in Patients Undergoing Heart Surgery. Clin Cardiol 2015;38:679683. 16. Task Force Members, Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the
management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003. 17. Eldor A, Polliack G, Vlodavsky I, et al. Effects of dipyrone on prostaglandin production by human platelets and cultured bovine aortic endothelial cells. Thromb Haemost 1983;49:132-137. 18. Papp J, Sandor B, Vamos Z, et al. Antiplatelet effect of acetylsalicylic acid, metamizole and their combination - in vitro and in vivo comparisons. Clin Hemorheol Microcirc 2014;56:1-12. 19. Saxena A, Balaramnavar VM, Hohlfeld T, et al. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur J Pharmacol 2013;721:215-224. 20. Polzin A, Richter S, Schrör K, et al. Prevention of dipyrone (metamizole) induced inhibition of aspirin antiplatelet effects. Thromb Haemost 2015;114:87-95. 21. Bednar F, Tencer T, Plasil P, et al. Evaluation of aspirin's effect on platelet function early after coronary artery bypass grafting. J Cardiothorac Vasc Anesth 2012;26:575580. 22. Petricevic M, Biocina B, Konosic S, et al. Assessment of platelet function by whole blood impedance aggregometry in coronary artery bypass grafting patients on acetylsalicylic acid treatment may prompt a switch to dual antiplatelet therapy. Heart Vessels 2013;28:57-65. 23. Brambilla M, Parolari A, Camera M, et al. Effect of two doses of aspirin on thromboxane biosynthesis and platelet function in patients undergoing coronary surgery. Thromb Haemost 2010;103:516-524. 24. Zimmermann N, Kurt M, Wenk A, et al. Is cardiopulmonary bypass a reason for aspirin resistance after coronary artery bypass grafting? Eur J Cardiothorac Surg
2005;27:606-610. 25. Wang Z, Gao F, Men J, et al. Aspirin resistance in off-pump coronary artery bypass grafting. Eur J Cardiothorac Surg 2012;41:108-112. 26. Zimmermann N, Wenk A, Kim U, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003;108:542-547. 27. Erez E, Erman A, Snir E, et al. Thromboxane production in human lung during cardiopulmonary bypass: beneficial effect of aspirin? Ann Thorac Surg 1998;65:101106. 28. Mattiello T, Guerriero R, Lotti LV, et al. Aspirin extrusion from human platelets through multidrug resistance protein-4-mediated transport: evidence of a reduced drug action in patients after coronary artery bypass grafting. J Am Coll Cardiol 2011;58:752-761. 29. Oreskovic Z, Bicanic G, Hrabac P, et al. Treatment of postoperative pain after total hip arthroplasty: comparison between metamizol and paracetamol as adjunctive to opioid analgesics-prospective, double-blind, randomised study. Arch Orthop Trauma Surg 2014; 134: 631-636.
Figure legends Figure 1. Study flow chart illustrating randomization, study treatment allocation and diagnostic tests. R – randomization; ASA – aspirin; ASPI – impedance aggregometry-derived arachidonic acid-induced platelet activation; COL – impedance aggregometry-derived collagen-induced platelet activation; CABG – coronary artery bypass grafting; 11-dTxB2 - 11-dehydro-thromboxane-B2
Figure 2. Fluctuations of platelet function assessed by impedance aggregometry, urinary 11-dTxB-2 concentration and platelet P-selectin expression. PANEL A: Platelet activation induced by arachidonic acid (ASPI); AUC – area under curve [AU*min] PANEL B: Platelet activation induced by collagen (COL); AUC – area under curve [AU*min] PANEL C: Platelet activation reflected by urinary 11-dehydro-thromboxane-B2 concentration [pg/mg] PANEL D: Platelet activation reflected by platelet P-selectin expression [%]
‡ - two-way repeated measures analysis of variance (ANOVA); ¶ - two-way Friedman analysis of variance (ANOVA)
Table 1. Baseline characteristics of the study population and comparison of Metamizole (+) and metamizole (-) group in terms of different preoperative variables N=43
N=23
N=20
Variable
P Value Study population
Metamizole (+)
Metamizole (-)
Age [years]
63.1 ± 8.7
61.0 ± 9.1
65.5 ± 7.8
0.089 a
Body mass index [kg/m2]
27.8 ± 3.8
27.3 ± 4.0
28.3 ± 3.6
0.411 a
Men
37 (86%)
20 (87%)
17 (85%)
0.597 c
Cigarette smoking
18 (42%)
9 (39%)
9 (45%)
0.468 c
Arterial hypertension
37 (86%)
18 (78%)
19 (95%)
0.127 c
Atrial fibrillation
5 (12%)
3 (13%)
2 (10%)
0.569 c
Diabetes mellitus
15 (35%)
9 (39%)
6 (30%)
0.381 c
History of PCI
13 (30%)
5 (22%)
8 (40%)
0.167 c
54 (50; 60)
50 (50; 55)
55 (50; 60)
0.171 b
4.9 ± 0.4
4.8 ± 0.5
4.9 ± 0.3
0.492 a
14.8 (14.1; 15.3)
14.6 (14.0; 15.3)
15.0 (14.2; 15.5)
0.364 b
WBC [1000/mm3]
7.6 ± 1.7
7.9 ± 1.9
7.3 ± 1.5
0.303 a
PLT [1000/mm3]
208 (171; 256)
216 (183; 294)
201 (166.5; 227.5)
0.250 b
0.9 (0.7; 1.0)
0.85 (0.7; 1.0)
0.9 (0.7; 0.9)
0.928 b
95.3 ± 25.0
96.5 ± 25.4
93.8 ± 25.1
0.736 a
0.5 (0.4; 0.8)
0.7 (0.4; 1.0)
0.5 (0.35; 0.6)
0.025 b
16.2 ± 3.4
17.0 ± 3.8
15.4 ± 2.7
0.116 a
LVEF [%] RBC [mln/mm3] Hgb [g/dL]
SCr [mg/dL] eGFR [ml/min/1.73 m2] Bilirubin [mg/dL] Alanine transferase [U/L]
CPB time [min]
74 (52; 96)
72 (50; 88)
74 (52; 98)
0.862 b
Aortic cross-clamp time [min]
44 (35; 63)
44 (34; 72)
45 (35; 63)
0.782 b
38 (88.4%)
20 (87.0%)
18 (90.0%)
>1 coronary graft
a
0.612 c
– Student t test; b – Mann-Whitney U test; c – Fisher’s exact test; CPB – cardiopulmonary bypass
time; LVEF – left ventricular ejection fraction; RBC – red blood cell count; Hgb – hemoglobin; WBC –white blood cell count; PLT – platelet count; SCr- serum creatinine concentration; eGFR – estimated glomerular filtration rate
Table 2. Comparison of preoperative and mean postoperative platelet function parameters in the whole study population
Variable
AUC ASPI [AU*min] AUC COL [AU*min] Urinary 11-dTXB2 level [pg/mg] P-selectin expression [%] a
Pre-procedural
Mean post-procedural
P Value
1058.2 ± 417.5
966.6 ± 332.4
0.047 a
1508.7 ± 511.1
1501.0 ± 456.2
0.889 a
923.4 ± 521.4
4367.3 ± 3137.4
<0.001 b
0.97 ± 0.95
1.04 ± 0.45
0.082 b
– student’s t test for paired samples; b – Wilcoxon matched pairs test; 11-dTxB2 – 11-dehydro-
thromboxane-B2; ASPI – arachidonic acid-induced platelet activation measured by multiple electrode aggregometry; COL – collagen-induced platelet activation; AU – aggregation units
Table 3. Comparison of platelet activation in metamizole (+) and metamizole (-) group N=23
N=20
Variable
P Value Metamizole (+)
Metamizole (-)
1236.2 ± 411.5
853.5 ± 326.9
964.8 ± 462.8
651.7 ± 338.9
1053.9 ± 418.9
870.1 ± 302.7
951.4 ± 431.2
787.3 ± 300.1
1363.9 ± 549.8
1019.1 ± 458.8
0.033 a
AUC ASPI – mean postop. [AU*min]
1083.5 ± 348.8
832.0 ± 260.1
0.012 a
∆ AUC ASPI [AU*min]
-152.7 ± 334.0
-21.5 ± 228.6
0.146 a
RPR – preproc**
22 (95.6%)
19 (95.0%)
0.720 b
RPR – day 0
22 (95.6%)
15 (75.0%)
0.065 b
RPR – day 1
22 (95.6%)
20 (100.0%)
0.535 b
RPR – day 2
23 (100.0%)
19 (95.0%)
0.465 b
RPR – day 6
23 (100.0%)
18 (90.0%)
0.210 b
1810.9 ± 479.7
1222.7 ± 335.5
0.0002 a
1391.7 ± 584.1
1177.8 ± 373.9
0.248 a
1849.6 ± 497.2
1163.5 ± 333.8
0.0001 a
1676.9 ± 601.5
1031.2 ± 234.6
2213.6 ± 395.4
1444.2 ± 527.3
AUC ASPI – preproc. [AU*min] AUC ASPI – day 0 [AU*min] AUC ASPI – day 1 [AU*min] AUC ASPI – day 2 [AU*min] AUC ASPI – day 6 [AU*min]
AUC COL – preproc. [AU*min] AUC COL – day 0 [AU*min] AUC COL – day 1 [AU*min] AUC COL – day 2 [AU*min] AUC COL – day 6 [AU*min]
0.002 a 0.008 a 0.111 a 0.289 a
0.004 a 0.0001 a
AUC COL – mean postop. [AU*min]
1776.9 ± 429.5
1225.0 ± 288.2
0.0001 a
∆ AUC COL [AU*min]
-33.9 ± 415.1
18.4 ± 197.9
0.642 a
11-dTXB2 – preproc. [pg/mg]
899.3 ± 634.6
950.0 ± 508.7
11-dTXB2 – day 0 [pg/mg]
8218.2 ± 4734.7
12948.9 ± 7247.6
11-dTXB2 – day 1 [pg/mg]
2434.9 ± 3506.7
6680.1 ± 8409.2
11-dTXB2 – day 2 [pg/mg]
1181.2 ± 304.7
3414.3 ± 4271.1
11-dTXB2 – day 6 [pg/mg]
1021.6 ± 1271.3
983.8 ± 816.7
11-dTXB2 – mean postop. [pg/mg]
3014.6 ± 1853.2
5855.4 ± 3605.0
0.002 c
∆ 11-dTXB2 [pg/mg]
2115.3 ± 1676.1
4905.4 ± 3253.9
0.001 c
1.2 ± 2.0
0.8 ± 0.4
0.9 ± 2.1
1.7 ± 0.9
1.2 ± 5.4
1.2 ± 0.5
0.7 ± 3.0
0.8 ± 0.7
1.1 ± 2.9
0.6 ± 0.5
P-selectin – mean postop. [%]
1.0 ± 0.5
1.1 ± 0.4
0.752 c
∆ P-selectin [%]
-0.1 ± 1.4
0.3 ± 0.4
0.318 c
P-selectin – preproc. [%] P-selectin – day 0 [%] P-selectin – day 1 [%] P-selectin – day 2 [%] P-selectin – day 6 [%]
a
0.537 c 0.035 c 0.002 c 0.0007 c 0.417 c
0.913 c 0.013 c 0.471 c 0.678 c 0.230 c
– Student t test; b - Fisher’s exact test; c – Mann-Whitney U test; **- patients were not treated with
aspirin prior to procedure; 11-dTxB2 – 11-dehydro-thromboxane-B2; ASPI – arachidonic acid-induced platelet activation measured by multiple electrode aggregometry; COL – collagen-induced platelet activation; AU – aggregation units; RPR – residual platelet reactivity
Table 4. Multivariate regression analysis of different predictors of platelet function variability in the perioperative period ∆ AUC ASPI R2= 0.292; Adjusted R2= 0.218; p<0.009 b
Variable
SE of b
P value
Age
-0.299
0.142
0.043
Metamizole use (study group)
-0.142
0.157
0.371
0.233
0.139
0.102
-0.336
0.150
0.031
Body mass index Bilirubin concentration
∆ AUC COL R2= 0.195; Adjusted R2= 0.143; p<0.035 b
Variable
SE of b
P value
Age
-0.366
0.164
0.034
Diabetes mellitus type 2
-0.330
0.164
0.054
∆ urinary 11-dTxB2 R2= 0.386; Adjusted R2= 0.335; p<0.0005 Variable
b
SE of b
P value
Serum creatinine concentration
0.309
0.132
0.025
Bilirubin concentration
-0.049
0.148
0.742
Metamizole use (study group)
-0.518
0.146
0.001
∆ P-selectin No predictors of P-selectin with p<0.1 in univariate analysis were reported.
b- regression coefficient, ∆ - difference between mean postoperative concentration/level and preoperative value; 11-dTxB2 - 11-dehydro-thromboxane-B2; AUC ASPI – area under curve of
arachidonic acid-induced platelet activation; AUC COL - area under curve of collagen-induced platelet activation