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J Thorac Cardiovasc Surg 2008;135:947-948
© 2008 The American Association for Thoracic Surgery

Brief Communication

Detection and duration of aspirin resistance after coronary artery bypass grafting

^a Federal Institute for Drugs and Medical Devices, Bonn, Germany
^b Department of Thoracic and Cardiovascular Surgery, Heinrich Heine—University Düsseldorf, Düsseldorf, Germany
^c Department of Hemostasis and Transfusion Medicine, Heinrich Heine—University Düsseldorf, Düsseldorf, Germany
^d Department of Pharmacology and Clinical Pharmacology, Heinrich Heine—University Düsseldorf, Düsseldorf, Germany

Received for publication September 3, 2007; accepted for publication November 15, 2007.

^_* Address for reprints: Norbert Zimmermann, MD, Federal Institute for Drugs and Medical Devices, Kurt Georg Kiesinger Allee, D-53175 Bonn, Germany. (Email: nzimmermann{at}bfarm.de).

Aspirin resistance is associated with a significant increase in major adverse cardiovascular events.^1,2 We have previously reported an insufficient antiplatelet effect of aspirin in most patients after coronary artery bypass grafting (CABG).³ Nevertheless, the duration of aspirin resistance after CABG remains unknown, and the suitability of available tools to discriminate those with reduced response to aspirin is controversial. This work determined the antiplatelet effect of aspirin at the time of CABG and 6 months later and examined the reliability of different methods for the diagnosis of aspirin resistance.

Materials and Methods

Subjects and Drug Administration
This study was conducted in agreement with the Declaration of Helsinki and was approved by the institutional ethics committee. Twenty-five consecutive patients undergoing elective CABG for stable three-vessel disease were included. Informed consent was obtained from each participant. Drugs affecting hemostasis had been discontinued at least 10 days before surgery. Starting on day 1 after CABG, 100 mg aspirin (Aspirin 100; Bayer AG, Leverkusen, Germany) was administered every morning.

Measurement of Platelet Function
The following parameters were determined: platelet counts (automated counting), arachidonic acid– (1 mmol/L) or collagen (1 µg/mL)–induced aggregation (turbidimetry), thromboxane formation (radioimmunoassay), and membrane closure times (platelet function analyzer PFA-100 (Dade Behring, Marburg, Germany), membrane coated with collagen and epinephrine) before and on days 1, 5, and 10 after surgery, as well as after a follow-up period of 6 months. Because thromboxane formation is the pharmacologic target of aspirin, platelet function was investigated in vitro in the absence and presence of 30 µmol/L aspirin, a concentration comparable to or exceeding plasma levels after oral aspirin treatment.⁴ Aspirin resistance during oral antiplatelet treatment was defined as less than 90% inhibition of thromboxane synthesis (vs before aspirin) or PFA-100 closure times less than 171 seconds.

Statistical Analysis
Data are shown as mean ± SEM. Statistical analyses were performed by t test or analysis of variance, as appropriate.

Results

Platelet counts decreased after extracorporeal circulation, from 251 ± 30 cells/nL before CABG to 167 ± 15 cells/nL at day 1 after CABG, and subsequently increased to 256 ± 13 cells/nL (day 5) and 414 ± 31 cells/nL (day 10). At 6-month follow-up, platelet counts were comparable to values before surgery (268 ± 45 cells/nL).

Before CABG, arachidonic acid effectively induced platelet aggregation in vitro and evoked a marked platelet thromboxane release ( Figure 1). Addition of aspirin in vitro significantly inhibited platelet function. At day 1 after surgery, platelet function was blunted, probably as a result of extracorporeal circulation. On days 5 and 10 after CABG, platelet aggregation was not significantly different from values before surgery (despite oral aspirin therapy), and 30 µmol/L aspirin failed to inhibit platelet function in vitro. Platelet function was nearly completely inhibited, however, 6 months after CABG. The results obtained after stimulation with collagen were similar to those with arachidonic acid (not shown).

View larger version (23K): [in this window] [in a new window]   Figure 1. Arachidonic acid (1 mmol/L)—induced platelet aggregation (top) and thromboxane formation (bottom) in platelet-rich plasma of patients (n = 25) before (control) and at indicated times after coronary artery bypass grafting (CABG). Measurements were obtained in absence (black bars) or presence (white bars) of aspirin (ASA) in vitro (30 µmol/L). Asterisk indicates P < .05 versus control values before surgery; plus sign indicates P < .05 versus values without aspirin.

View larger version (17K): [in this window] [in a new window]   Figure 2. PFA-100 closure times with cartridges coated with collagen and epinephrine. Whole blood from 25 patients was investigated before (control) and at indicated times after coronary artery bypass grafting (CABG). Asterisk indicates P < .05 versus control values before surgery. ASA, Aspirin.

Discussion

These data show aspirin resistance early after CABG but a sufficient antiplatelet effect 6 months thereafter. This pattern may explain why the elevated risk of graft thrombosis declines within the first months after surgery.² Another important finding is that the thromboxane assay and PFA-100 test showed comparable results early after CABG, whereas these methods differently classified the responder status of a third of the patients at follow-up. In accordance with thromboxane, arachidonic acid- and collagen-induced aggregations showed near-complete platelet inhibition at follow-up.

The observed differences between thromboxane and turbidimetry on one hand and PFA-100 on the other hand may be explained by variables unaffected by aspirin, such as von Willebrand factor, which may outweigh platelet inhibition by aspirin in the PFA-100 method. Our results agree with the unfavorable correlation between PFA-100 and optical aggregation described in other study populations.⁵

In conclusion, PFA-100 is a convenient bedside test. This advantage, however, seems outweighed by its reduced accuracy in comparison with turbidimetry and the criterion standard of thromboxane.

References

1. Gum PA, Kottke-Marchant K, Welsh PA, White J, Topol EJ. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003;41:961-965.[Abstract/Free Full Text]
   
2. Poston RS, Gu J, Brown JM, Gammie JS, White C, Nie L, et al. Endothelial injury and acquired aspirin resistance as promoters of regional thrombin formation and early vein graft failure after coronary artery bypass grafting. J Thorac Cardiovasc Surg 2006;131:122-130.[Abstract/Free Full Text]
   
3. Zimmermann N, Wenk A, Kienzle P, Weber AA, Gams E, Schrör K, et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 2003;108:542-547.[Abstract/Free Full Text]
   
4. Benedek IH, Joshi AS, Pieniaszek HJ, King SY, Kornhauser DM. Variability in the pharmacokinetics and pharmacodynamics of low dose aspirin in healthy male volunteers. J Clin Pharmacol 1995;35:1181-1186.[Abstract]
   
5. Gum PA, Kottke-Marchant K, Poggio ED, Gurm H, Welsh PA, Brooks L, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol 2001;88:230-235.[Medline]
   

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Norbert Zimmermann Joachim Winter Emmeran Gams Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zimmermann, N. Articles by Hohlfeld, T. Search for Related Content PubMed Articles by Zimmermann, N. Articles by Hohlfeld, T. Related Collections Cardiac - pharmacology Coronary disease