Aspirin is one of the most frequently taken drugs, used either to treat cardiovascular disease or as an over-the-counter analgesic. Because of such wide-scale use, a remarkable number of patients ingest aspirin preoperatively. The American College of Chest Physicians (ACCP) recommends that patients scheduled for coronary artery bypass graft continue aspirin usage up to and throughout the time of coronary artery bypass graft.1 Preoperative aspirin administration may increase blood loss during bleeding-sensitive operations2–4; however, in high-risk patients, withdrawal of aspirin is associated with an increase in major adverse cardiac events.5,6 Thus, the ACCP suggests the cessation of aspirin intake 7 to 10 days before noncardiac surgery only in patients with low risk for cardiac disease.1
The detection of residual aspirin-related platelet dysfunction could result in the postponement of complex or bleeding-sensitive surgical interventions, such as neurosurgery. Similarly, the absence of aspirin effects after aspirin intake could prevent unnecessary postponement of surgical interventions. The prevalence of laboratory aspirin resistance, a condition in which aspirin inadequately inhibits platelet function, is inconsistent, and it varies from 5% to 80%,7 depending on the assessment method used.8 Nonetheless, laboratory aspirin resistance is associated with impaired outcomes.7,9
The preoperative assessment of aspirin effects has important ramifications in the clinical context. Thus, having convenient, standardized, and thoroughly validated methods for measuring the degree of platelet inhibition at the point-of-care is highly desirable. A recent study in healthy volunteers confirmed that multiple electrode aggregometry (MEA) (Multiplate®; Dynabyte, Munich, Germany) reliably detected the time-dependent antiplatelet effect of aspirin.10 Arachidonic acid (AA)-induced platelet aggregation uniformly achieved a level of >80% suppression in the first 2 days after aspirin intake, and by day 5, platelet aggregation had returned to baseline values. The timeframe for the antiplatelet effect of aspirin, as assessed by MEA, was in accordance with results obtained via other monitoring techniques, such as thromboxane B2 production11 and platelet function analyzer (PFA)-100.12
Based on previous findings in aspirin-treated healthy volunteers, we assumed that platelet function in patients who stopped taking aspirin before surgical intervention would normalize gradually, with wide interindividual variation on the third and fourth days (between 48 and 96 hours) after the patient's last drug ingestion. On the fifth day and thereafter (after 96 hours), we did not expect any detectable aspirin effect.10 Thus, this study was designed to assess preoperative residual aspirin-induced platelet dysfunction in consecutive patients scheduled for surgery, and who stopped all aspirin intake 0 to 10 days before the operation. We selected 3 different whole blood assays, all of which may be performed at the bedside. The aim of this study was to compare the diagnostic value of these 3 methods in the preoperative assessment of residual aspirin effects after the cessation of aspirin use. We hypothesized that there would be no differences in the diagnostic value of the methods in detecting the effects of aspirin.
After IRB approval, consecutive patients scheduled for various invasive procedures or surgery and older than 18 years, including both those with (test group) and without (control group) previous aspirin intake, were asked to participate in the study and to provide written informed consent. Age, gender, weight, height, the type of surgery/ invasive procedure to be performed, and the date of the patient's last dose of aspirin were documented. Those patients who presented with previous aspirin intake were classified into 3 groups according to the time of their most recent aspirin ingestion. In the full aspirin effect group, the last administration of aspirin had taken place within the 48 hours before blood sampling. Patients in the variable aspirin effect group had taken their last aspirin between 48 and 96 hours (3–4 days) before, and the last aspirin intake of those in the recovered aspirin effect group was >96 hours (4 days) before blood sampling. This classification scheme was based on the results of our previous study on the duration of aspirin effects.10 No aspirin intake was documented in the control group. Exclusion criteria for the study were a hematocrit level <20%, a platelet count <80/nL, or any known congenital or acquired hemostasis disorders, with the exception of aspirin-induced platelet dysfunction.
Intervention and Blood Sampling
After patients were selected for the study, in vivo bleeding time (BT) according to Duke's method was performed and measured, using a standardized lancet. This procedure, performed by one of the 2 skilled members of the laboratory staff, involved making an incision of 2 to 3 mm depth in the patient's earlobe and measuring the time until bleeding stopped.13
Next, 13 mL of blood was drawn from the antecubital vein by puncture without stasis, using a 21-gauge butterfly needle. The first 2 mL of blood was discarded. Blood was then collected into 3 different tubes containing 25 μg/mL hirudin (4.5 mL; Dynabyte), 0.129 mol/L buffered sodium citrate (3.8 mL; Sarstedt, Nümbrecht, Germany), or EDTA (2.7 mL; Sarstedt) as an anticoagulant. Laboratory analyses and platelet function assays were performed within 60 minutes after obtaining the blood. Hematocrit, leukocytes, and platelet count were determined from EDTA blood samples using an SF 3000 analyzer (Sysmex Corp., Kobe, Japan).
Platelet Function Assays
Multiple Electrode Aggregometry
The whole blood impedance aggregometer used for this study (Multiplate; Dynabyte) is based on classic whole blood impedance aggregometry.14 The device has 5 MEA test cells for parallel testing, and each test cell incorporates 2 independent sensor units. One unit consists of 2 silver-coated, highly conductive copper wires. Analysis is based on platelet adhesion upon activation, a property that results in aggregation onto the metal sensor wires in the test cell, thus increasing electrical impedance.15 For the measurement, 300 μL preheated saline (37°C) and 300 μL hirudin-anticoagulated whole blood were placed into the test cell, and the sample was stirred using a teflon-coated electromagnetic stirrer (800 rpm) over a 3-minute incubation period. Platelet aggregation was initiated with AA (0.5 mM) using a commercially available reagent (ASPItest; Dynabyte). Increased impedance was continuously measured for each sensor unit over a period of 6 minutes. Data were transformed to arbitrary aggregation units and plotted as 2 separate aggregation curves versus time. Aggregation measured by MEA was quantified as the area under the aggregation curve (AUC [U]). The duplicate sensors served as an internal control to reduce the occurrence of systematic errors.
Platelet Function Analyzer
The disposable cartridge of the PFA-100® device (Siemens, Eschborn, Germany) simulates a high-shear environment and measures the ability of platelets to occlude an aperture in a membrane.16 Whole blood is aspirated under controlled flow conditions through a microscopic aperture in a membrane that is coated with collagen and epinephrine (COL-EPI cartridge).16 This results in platelet adhesion and aggregation, during which the device measures the time required for the platelet plug to occlude the aperture (closure time [CT], seconds). The device has also been widely used for aspirin monitoring.17,18
Determination of the Effect of Aspirin
The manufacturer's reference range is 75 to 136 U and 85 to 165 seconds for ASPItest and COL-EPI, respectively; however, the determination of local reference ranges is suggested for whole blood assays.18 Normal ranges for the Duke BT vary between 120 and 240 and 180 and 300 seconds.19 Therefore, we defined institutional reference ranges between the 10th and 90th percentiles of the control group (no aspirin intake) for each assay. An aspirin effect was excluded if the value was within the institutional reference ranges; more precisely, above the 10th percentile of the control group in ASPItest and/or below the 90th percentile of the control group in terms of COL-EPI and BT (cutoff values). Laboratory aspirin resistance was determined to be present if the measurement value for the full aspirin effect group was within institutional reference ranges, and its prevalence was calculated for each method.
Statistical analysis was performed using Sigma Stat software (version 3.1; Jandel, San Rafael, CA). Data were tested for a normal distribution using the Kolmogorov-Smirnov test. Results are expressed as the mean ± SD or as the median (25th/75th percentile), according to the distribution of the data. One-way analysis of variance on ranks was used to detect differences among the groups. In case of significant differences in group medians, a post hoc multiple-comparison procedure versus the control group was applied according to Dunn's method. Categorical data were compared using the z test. The diagnostic accuracy of the platelet function assays in identifying aspirin-induced platelet inhibition was calculated using receiver operating characteristic (ROC) curves. For the generation of ROC curves, the data of the full, variable (aspirin positive), and control (aspirin negative) groups were included, but not the recovered aspirin group. The area under the ROC curve (AUC), sensitivity (true positives/[true positives + false negatives]), and specificity (true negatives/[true negatives + false positives]) of the assays were calculated. The level of statistical significance was set at P < 0.05.
Between March 2008 and January 2009, 405 consecutive adult patients were prospectively included in the study. One hundred forty-three participants denied having taken any antiplatelet drugs during the 10 days before surgery (control group). Two hundred sixty-two patients had longtime aspirin treatment or had taken aspirin in the previous 10 days (full, variable, and recovered aspirin effect groups) at a dose between 100 and 500 mg. Two patients in the control group were accidentally included twice in the study; thus, the duplicated case was deleted. Nine of the patients (1 aspirin treated and 8 in the control group) presented with platelet counts <80/nL and were excluded from the analysis. A total of 394 patients were analyzed, 133 patients in the control group and 261 patients who were further separated into 3 predefined aspirin groups. Group sizes, baseline characteristics, and laboratory variables of the patients are summarized in Table 1. Aspirin-treated patients were older, and more of them were male as compared with the control group. The proportion of patients who were scheduled for neurosurgery or otorhinolaryngologic surgery was higher in the full and variable aspirin effect groups than in the control group (45.1% and 54.9%, respectively, vs 29.3% in the control group; P = 0.027 and P < 0.001).
The results of AA-induced platelet aggregation in the ASPItest, closure time in COL-EPI in PFA-100, and in vivo BT are presented in Table 2 and Figure 1. All 3 assays showed significant differences between the full aspirin effect group and the control group. Furthermore, no difference in the measurement values was found between the recovered aspirin effect group and control group, irrespective of the assay. Measurement values in the variable aspirin effect group were different from those in the control group only in the ASPItest (MEA) and COL-EPI (PFA-100) (Fig. 1, Table 2). In vivo BT in the variable aspirin effect group did not differ from the controls. Institutional reference ranges and the cutoff values for excluding the aspirin effect are presented in Table 3.
Quantifying the diagnostic accuracy of the 3 methods with ROC analysis showed that the methods with the highest diagnostic value in detecting residual aspirin effects were the ASPItest (AUC 0.81, P < 0.001) and COL-EPI (AUC 0.78, P < 0.001), whereas the BT was not accurate (AUC 0.56) (Fig. 2). An AUC value >53 U in the ASPItest indicated a recovered antiplatelet effect of aspirin with a specificity of 71% and a sensitivity of 88%. A CT in COL-EPI <219 seconds excluded any aspirin effect with a specificity of 90% and a sensitivity of 58% (Table 3).
Laboratory aspirin resistance in the full aspirin effect group was observed in 16% of patients (13 of 82) using the ASPItest, 22% of patients (18 of 82) using COL-EPI, and 67% of patients (55 of 82) assessed by BT. Figure 3 demonstrates the correlation between platelet reactivity in MEA (ASPItest) and in vitro BT in PFA-100 (CT in COL-EPI) (r = 0.38, P < 0.001). No correlations were found between in vivo BT and CT in COL-EPI (r = 0.21, P = 0.08), or between in vivo BT and ASPItest (r = −0.08, P = 0.52).
The main finding of this study is that the diagnostic accuracy of in vivo BT and 2 platelet function assays in identifying antiplatelet effects of aspirin differed considerably. ASPItest in MEA and COL-EPI in PFA-100 were superior to in vivo BT, which did not deliver consistent and useful results. The areas under the ROC curves, 0.81 for ASPItest and 0.78 for COL-EPI, indicate the usefulness of these methods in preoperative assessment of aspirin-induced platelet dysfunction. In contrast, an AUC of 0.56 indicates the rather limited usefulness of the in vivo BT.
The incidence of laboratory aspirin resistance, i.e., normal laboratory results in the full aspirin effect group, varied considerably (between 16% and 67%) depending on the method. In 2 studies, several assays were compared to assess the effects of aspirin on platelet function,8,17 but only a moderate correlation was found between the different methods. Thus, the clinical consequences of laboratory aspirin resistance demand further clarification. BT is widely used in clinical medicine to screen for platelet function, although its shortcomings are well recognized, and studies have showed discordant results for PFA-100 and whole blood platelet aggregometry in detecting aspirin-induced platelet dysfunction.20 Our results support these findings. We found laboratory aspirin resistance in 16% and 22% of the patients in ASPItest and PFA-100, respectively, which is in the previously established range.7 Although the median BT in the full aspirin effect group compared with controls was higher (Fig. 1), the majority (67%) of patients in this group were classified as laboratory aspirin resistant.
The results of the ASPItest and PFA-100 coincided in 84% of patients: 73% were identified as aspirin responders and 11% as nonresponders in both tests (Fig. 3). However, 11% of patients with impaired platelet aggregation in MEA did not show prolonged CT in COL-EPI, and 5% vice versa. Such discordance in the diagnosis of aspirin responsiveness has been shown in several studies, even in healthy individuals.21,22 This might be attributable to the fact that the different tests focus on different aspects of platelet function. Furthermore, these systems also display a significant sensitivity to several other in vivo variables, which may variably interfere with in vitro test results. Besides individual variability in the absorption and metabolism of aspirin, the putative role of von Willebrand factor (vWF) is important. The PFA-100 is very sensitive to plasma changes in vWF,23 and CTs show a strong inverse relationship with plasma vWF concentration.24 Unfortunately, we did not analyze vWF concentration and/or activity in this study. PFA-100 is a semiquantitative test system with strengths in high shear stress conditions. In contrast, the advantage of MEA seems to be its reliable and quantitative assessment of the effects of various inhibitors of platelet aggregation.10,25–30
Although various studies have confirmed a correlation between MEA and PFA-100 results under aspirin treatment,18,25,31 the diagnostic value of these methods for preoperative assessments of residual aspirin effects has not yet been systemically investigated. A recent study of healthy volunteers and patients with coronary artery disease, comparing light transmission aggregometry, COL-EPI on PFA-100, ASPItest, and VerifyNow® aspirin, found MEA to be the most sensitive platelet function assay for aspirin.32 We also found ASPItest to have the highest diagnostic accuracy. MEA and PFA-100 had comparable sensitivity (88% and 90%, respectively); in contrast, the specificity of MEA (71%) was better than that of COL-EPI (specificity of 58%). The test's high sensitivity indicates that normal test results are unlikely to occur in patients with aspirin treatment; the lack of 100% sensitivity, however, indicates aspirin resistance (false-negative results). In contrast, the low specificity of PFA-100 denotes that pathological test results may occur in many patients without aspirin treatment (false-positive results). This is not surprising, because several variables such as hematocrit, platelet count, and/or vWF level influence PFA-100 CTs.33–35 Furthermore, PFA-100 is not specific for the aspirin-sensitive cyclooxygenase-1 pathway, and it has been reported to have only limited predictiveness for perioperative bleeding and transfusion requirements.36,37 In contrast, several studies have linked MEA data to bleeding38–40 or thrombotic outcomes.29,41,42 Both assays have also been shown to be affected by non-opioid analgesic drugs,26,43 which are often prescribed in the perioperative setting. In summary, both tests detected the antiplatelet effect in aspirin-treated patients, but quantitative assessment of platelet function in the perioperative setting might be superior in MEA.
Our results have several important clinical implications. First, the ACCP recommendation to stop aspirin intake 7 to 10 days before surgery in patients who are at low risk for cardiac disease may be too conservative.1 Based on our data, aspirin cessation for 4 days could be adequate; finally, low risk is not the same as no risk, and minimizing the duration of patients' aspirin break might be advantageous.44 Second, testing for platelet function before bleeding-sensitive operations in aspirin-treated patients is strongly recommended. Although both the ACCP1 and the European Society of Cardiology45 guidelines clearly recommend that patients with high cardiac risk do not stop aspirin preoperatively, particular operations nonetheless require the cessation of aspirin.44 Our study population reflects this issue well, because the majority of platelet function analyses were requested for patients scheduled for neurosurgery or otorhinolaryngologic surgery, both of which are associated with increased bleeding complications in aspirin-treated patients.4 In our clinical practice, it has become routine to perform preoperative assessments of platelet function in aspirin-treated patients before procedures with a major hazard of bleeding to minimize the duration of the interruption of aspirin. Recommendations for the optimal time at which to begin cessation of aspirin treatment before surgery remain contradictory.1,12,46 The observed variability of the aspirin effect in the present study supports the importance of individual preoperative assessments of platelet function in patients with aspirin intake.
There were some limitations to our study. First, our study was not designed to evaluate the clinical predictive value of the assay results for increased bleeding or enhanced prothromboembolic events. Second, we did not use standard laboratory platelet function testing methods, which are generally considered the “gold standard.” Although whole blood impedance aggregometry using MEA is a relatively new method, various studies have confirmed the correlation between MEA and light transmission aggregometry,28,31 as well as MEA and flow cytometry.27,47 Third, patients who presented with a platelet count <80/nL (n = 9; 2.2%) were excluded from analysis because PFA-100 CT has been shown not to be reliable in cases of low platelet count34 and platelet aggregation in MEA correlates with platelet count.48 Finally, the underlying disease of the patients, e.g., malignancy, may have influenced preoperative platelet function and plasmatic coagulation independent of aspirin ingestion.
Despite these limitations, our study has important clinical implications. We confirmed that the full therapeutic antiplatelet effects of aspirin can be expected within 48 hours after the last aspirin ingestion unless the patient is aspirin resistant. Platelet function generally recovers if aspirin cessation exceeds 96 hours (4 days); thus, preoperative platelet function testing in these patients is not required. To determine any residual aspirin effects in patients who ceased their aspirin intake between 48 and 96 hours before surgery, the ASPItest shows the highest diagnostic accuracy and may be recommended for routine preoperative determination of aspirin effects.
Name: Csilla Jámbor, MD.
Contribution: This author was responsible for the study initiation, study design, data collection, data analysis, performing statistical analysis, and writing and revising the manuscript.
Attestation: Csilla Jámbor approved the final version of the manuscript.
Conflicts of Interest: Csilla Jámbor has received speaking honoraria and research support from Dynabyte, Munich, Germany.
Name: Klaus-Werner von Pape.
Contribution: This author was responsible for the study initiation, study design, data collection, data analysis, performing statistical analysis, and editing the manuscript.
Attestation: Klaus-Werner von Pape approved the final version of the manuscript.
Conflicts of Interest: This author has no conflicts of interest to report.
Name: Michael Spannagl, MD, PhD.
Contribution: This author analyzed the data, performed the statistical analysis, and edited the manuscript.
Attestation: Michael Spannagl approved the final version of the manuscript.
Conflicts of Interest: Michael Spannagl has received speaking honoraria and research support from Dynabyte, Munich, Germany.
Name: Wulf Dietrich, MD, PhD.
Contribution: This author wrote and revised the manuscript.
Attestation: Wulf Dietrich approved the final version of the manuscript.
Conflicts of Interest: This author has no conflicts of interest to report.
Name: Andreas Giebl.
Contribution: This author analyzed the data, performed the statistical analysis, and edited the manuscript.
Attestation: Andreas Giebl approved the final version of the manuscript.
Conflicts of Interest: This author has no conflicts of interest to report.
Name: Heike Weisser, MD, PhD.
Contribution: This author edited the manuscript.
Attestation: Heike Weisser approved the final version of the manuscript.
Conflicts of Interest: This author has no conflicts of interest to report.
The authors thank Dr. A. Calatzis, University of Munich, for his valued commentary on the manuscript.
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