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From the Departments of Anesthesiology and Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticutt, USA.
Address correspondence to: Dr. David G. Silverman, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8051, USA. Phone 203-785-2802; Fax: 203-785-6664; E-mail david.silverman{at}yale.edu
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Abstract |
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Methods: In 20 patients scheduled for lower abdominal and pelvic surgery, 5 mL of blood were obtained for baseline platelet aggregometry. One hour prior to surgery, patients received an oral solution of either rofecoxib (ROF) 50 mg or placebo (PLAC) by randomized, double-blinded assignment. Approximately one hour after onset of anesthesia, an intraoperative blood sample was obtained.
Baseline and postdrug samples were centrifuged to generate platelet-rich plasma, which was challenged with adenosine diphosphate (ADP) and arachidonic acid (AA). Aggregometry was performed with and without incubation with aspirin. The data in each subject were normalized to baseline aggregation in response to AA alone and ADP alone. Intergroup differences were assessed using paired t test; P < 0.05 was considered significant.
Results: Consistent with known effects of anesthesia on platelet function, both groups had approximately 25% intraoperative declines in aggregation in response to ADP (P = NS for PLAC vs ROF) and even greater declines in response to AA (P = NS for PLAC vs ROF). Aspirin eliminated aggregation in response to AA in both groups (P = NS), and it caused similar declines in PLAC and ROF groups during exposure to ADP (P = NS).
Conclusion: This study provides strong evidence that ROF does not compromise platelet aggregation during anesthesia and surgery; nor does it interfere with the platelet inhibitory effect of aspirin.
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Introduction |
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Despite these favourable findings, many clinicians remain hesitant to administer COX-2 inhibitors perioperatively until there is more definitive evidence that these drugs do not alter platelet function during anesthesia and surgery. Such evidence may be provided by measuring platelet aggregation2,7,8 in response to an aggregatory stimulus such as arachidonic acid (AA) or adenosine diphosphate (ADP). Whereas a myriad of potentially offsetting perioperative factors – many of which are not directly related to platelet function – may affect measurements of blood loss, aggregometry is more sensitive to and more specific for the potential platelet inhibitory effects of a study drug. The present investigation addressed the potential for a COX-2 effect on perioperative platelet function by testing the hypothesis that, in the context of anesthesia and surgery, pretreatment with rofecoxib (ROF; Vioxx, Merck & Co., Inc, West Point, PA, USA) would not alter platelet aggregation in response to an aggregatory challenge.
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Methods |
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TOPAbstractIntroductionMethodsResultsDiscussionReferences |
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At the time of recruitment, 5 mL of blood were obtained for baseline (preoperative) platelet aggregometry. On the morning of surgery, patients received either 50 mg (10 mL) of ROF oral suspension or 10 mL of placebo suspension (PLAC), based on a randomized, double-blinded assignment. Randomization was achieved by computer-generated assignment of sequential patients. The 50 mg dose was selected to be consistent with recommended doses of ROF for acute pain9,10 and premedication.11–13
One hour after ROF or PLAC administration, anesthesia was initiated. One hour later – approximately two hours after administration of the study drug – a postdrug sample was obtained. The time interval for blood sampling was selected based upon documentation of analgesic efficacy within 45 min of oral ingestion of ROF 50 mg in patients experiencing dental pain9 and within 75 min in patients receiving analgesia and sedation for nasal surgery,13 as well as documentation of significant plasma levels by two hours after ingestion (with virtual bioequivalence of ROF in oral suspension and tablets).14
The baseline (pre-study drug) and intraoperative (post-study drug) blood samples were prepared identically to generate platelet-rich plasma, which was adjusted to a platelet count of 250 x 109•L-1 as previously described.8 Aggregometry was performed on separate aliquots of platelet-rich plasma stimulated with ADP 10 µM or AA 1.66 µM; the maximum amplitude of each response was recorded. For a positive control, a separate plasma aliquot was incubated with 500 µM aspirin;8 then aggregometry was repeated with ADP or AA as above.
Based on previous studies of the effects of NSAIDs on intraoperative aggregometry,15 it was determined that 20 patients would be sufficient to detect a difference between treatment groups with a power > 0.80 and an alpha of < 0.05. The data from each subject were normalized to the baseline preoperative aggregation response to ADP or AA alone. Inter-group differences were assessed using an unpaired t test; P < 0.05 was considered statistically significant. Patients who failed at baseline (prior to study drug ingestion) to aggregate in response to ADP or AA (< 10% aggregation) were excluded from analysis.
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Results |
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All 20 patients completed the study. One subject in the ROF group was excluded from analysis because of failure to aggregate in response to AA at baseline (i.e., predrug). There was no evidence of increased bleeding in any of the patients. None of the subjects required administration of blood products.
When compared to patients treated with PLAC, those receiving ROF had similar intraoperative platelet aggregation (Figures 1
and 2; P = NS for intergroup differences). A decline from baseline ADP- and AA-induced aggregation was noted in samples taken intraoperatively in both PLAC and ROF-treated groups (P = NS for difference in relative declines in ROF and PLAC groups).
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Discussion |
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Although there is evidence as to the high platelet safety profile of selective COX-2 inhibitors,1,2 many clinicians remain concerned about these drugs in the perioperative setting. The aforementioned studies did not include the variables associated with surgical trauma or the potential effects of anesthesia. Such factors theoretically could uncover and/or lead to potential interactions with COX-2 inhibitors that might impair platelet function. Specifically, the declines in sympathoadrenal activity and stress hormone levels associated with anesthesia can affect platelet aggregation.8,24,25 Furthermore, it has been noted that inhalational agents such as halothane and sevoflurane suppress platelet aggregation and increase bleeding times by a variety of interacting mechanisms; and, by seemingly different mechanisms, midazolam and propofol also inhibit platelet aggregation.7,16–19 Our data are consistent with these findings in that the PLAC and ROF groups both had declines in aggregation intraoperatively. The similar declines after PLAC and ROF confirm that ROF does not compromise platelet aggregation in the context of "routine" anesthesia such as that employed in the present series; however, in that we sought to perform our assessments in the context of routine anesthetics, we did not focus on high doses of specific anesthetic agents.
Incubation of platelet-rich plasma with aspirin in the present study has provided additional evidence as to the lack of an effect of ROF on platelet function. First, aspirin incubation served as a positive control to confirm the sensitivity of the present tests of aggregation to abrogated COX-1 activity.8,26 AA induces aggregation entirely via the aspirin-sensitive COX pathway; hence, aspirin eliminated the aggregation response to this stimulus. By contrast, ADP induces aggregation by the combined effects of direct binding to platelet ADP receptors, dense granule-derived serotonin and thromboxane A, of which only the last is inhibited by aspirin.8 Second, the normal response to aspirin in the present study in samples from ROF and PLAC patients indicated that the use of ROF would not compromise the cardioprotective effect of aspirin therapy. This finding supports the clinical practice of restarting daily aspirin during the postoperative period without concern for decreased cardioprotective effects due to concurrent use of ROF. Conversely, pretreatment with a nonspecific NSAID causes patients to become "aspirin nonresponders" by rendering the active site of platelet COX-1 inaccessible to the aspirin during significant NSAID levels.27
It should be noted that, while the present study supports the perioperative safety of COX-2 inhibitors, it did not include patients with known alterations of platelet or endothelial function. Thus, conclusions as to the lack of an effect of selective COX-2 inhibition may not be wholly applicable to those patients. COX inhibitors affect hematological, endothelial, inflammatory, and algesic pathways. Such alterations of the counterbalancing roles of the products of COX-1 and COX-2 mediated processes (e.g., thromboxane and prostacyclin, respectively) may have greater impact on patients with preexisting abnormalities, especially when long-term therapy is employed.22,28
In conclusion, the present data confirm the lack of an effect of ROF on intraoperative platelet function in patients undergoing typical anesthetics for lower abdominal and pelvic surgery. There was no suggestion of ROF-induced potentiation of anti-platelet effects or alteration of the effects of subsequent aspirin. The delineation of such safety with aggregometry should mitigate concerns about potential perioperative platelet dysfunction in patients receiving a brief course of a COX-2 inhibitor.
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Footnotes |
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Accepted for publication March 13, 2003. Revision accepted September 3, 2003.
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References |
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2 Rinder HM, Tracey JB, Souhrada M, Wang C, Gagnier RP, Wood CC. Effects of meloxicam on platelet function in healthy adults: a randomized, double-blind, placebo-controlled trial. J Clin Pharmacol 2002; 42: 881–6.[Abstract]
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9 Chang DJ, Fricke JR Jr, Bird SR, Bohidar NR, Dobbins TW, Geba GP. Rofecoxib versus codeine/acetaminophen in postoperative dental pain: a double-blind, randomized, placebo- and active comparator-controlled clinical trial. Clin Ther 2001; 23: 1446–55.[Medline]
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14 Vioxx (rofecoxib tablets and oral suspension) product information. West Point, PA. Merck and Co., Inc, May 1999.
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21 Ehrich EW, Dallob A, De Lepeleire I, et al. Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model. Clin Pharmacol Ther 1999; 65: 336–47.[Medline]
22 FitzGerald GA, Patrono C. Drug therapy: the coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345: 433–42.
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24 Naesh O, Haedersdal C, Hindberg I, Trap-Jensen J. Platelet activation in mental stress. Clin Physiol 1993; 13: 299–307.[Medline]
25 Rosenfeld BA, Faraday N, Campbell D, Dise K, Bell W, Goldschmidt P. Hemostatic effects of stress hormone infusion. Anesthesiology 1994; 81: 1116–26.[Medline]
26 Patrignani P, Filabozzi P, Patrono C. Selective cumulative inhibition of platelet thromboxane production by low-dose aspirin in healthy subjects. J Clin Invest 1982; 69: 1366–72.
27 Catella-Lawson F, Reilly MP, Kapoor SC, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med 2001; 345: 1809–17.
28 Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001; 286: 954–9.
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