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Anesth Analg 2004;98:1082-1085 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000105866.99259.94
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Abstract |
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Nonsteroidal antiinflammatory drugs are routinely administered in the perioperative period. Because of the absence of cyclooxygenase-2 in platelets, cyclooxygenase-2-selective drugs are thought not to cause platelet inhibition. Because platelets play an important role in the coagulation process, the absence of platelet function inhibition may lead to fewer bleeding complications after surgery. We studied the influence of aspirin, diclofenac, lornoxicam, and rofecoxib on arachidonic acid and collagen-induced CD 62 P (P selectin) expression by using flow cytometry. Blood from 68 volunteers was obtained before and 1, 3, and 12 h after the oral ingestion of 1 of the randomly assigned study medications. Aspirin, diclofenac, and lornoxicam had a significant effect on arachidonic acid and collagen-induced CD 62 P expression in platelets, whereas rofecoxib did not show this effect. We conclude that rofecoxib is safe to use perioperatively with respect to inhibition of platelet function.
IMPLICATIONS: We compared the effect of rofecoxib and three nonselective nonsteroidal antiinflammatory drugs on platelet function, measured by CD 62 P expression. Platelet function was not altered by rofecoxib, but it was inhibited by aspirin, diclofenac, and lornoxicam. Rofecoxib may be safer than classic NSAIDs with respect to platelet function during the perioperative period.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in clinical practice and have beneficial antiinflammatory, analgesic, and antipyretic effects by inhibiting cyclooxygenase (COX). COX is the rate-limiting enzyme for prostaglandin (PG) synthesis and exists as two isoenzymes: COX-1 and COX-2. The common side effects of classic NSAIDs, such as gastrointestinal toxicity and decreased platelet function, are considered to result from inhibition of COX -1. Because platelets do not express the COX-2 isoenzyme, the influence of COX-2-selective inhibitors on platelet function should be less (1).
Rofecoxib is the most selective COX-2 inhibitor currently on the market (2). Recently, however, concerns have been expressed about the possible side effects of rofecoxib because of decreased prostacyclin production and a possible effect of platelet activation (3). However, Homoncik et al. (4) found that even large doses of rofecoxib had no influence on platelet function, as assessed by in vitro bleeding time. Greenberg et al. (5) compared 4 days of treatment with rofecoxib or placebo in healthy volunteers co-medicated with small-dose aspirin. Rofecoxib caused no changes in thromboxane (TX) B2 serum levels or platelet aggregation induced by arachidonic acid (AA). In contrast to ibuprofen, diclofenac and rofecoxib do not impair the irreversible inhibition of platelets caused by aspirin (6).
Because rofecoxib has recently been approved for acute pain management, it is important to have information about any potential influence on platelet function (7). We therefore compared rofecoxib with three nonselective NSAIDs with regard to platelet function, measured with CD 62 P expression, a marker of platelet function.
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Methods |
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After we obtained local ethics committee approval and informed, written consent, 68 volunteers (24 men and 44 women, ASA physical status I) were studied in a double-blinded randomized trial. By using sequentially ordered opaque envelopes containing computer-generated codes, subjects were randomly assigned to receive orally one of the four study drugs (500 mg of acetylsalicylic acid [Aspirin®; Bayer AG, Leverkusen, Germany], 75 mg of diclofenac [Voltaren®; Novartis Pharma, Vienna, Austria], 8 mg of lornoxicam [Xefo®; Nycomed Austria, Linz, Austria], or 25 mg of rofecoxib [Vioxx®; MSD, Vienna, Austria]). These doses represent those used in clinical practice according to the manufacturers’ recommendations. Exclusion criteria included a predisposition to abnormal bleeding, pathologic blood cell count, the use of any drug 2 wk before the study, and a Broca index [(body weight in kilograms)/(height in centimeters - 100)] <0.8 or >1.2.
The investigators were divided into three groups. The first team did the prestudy evaluation, enrolled the volunteers, and sampled blood. The second team randomized the population and handed out the study medication and was not involved in any other part of the study. The third team, blinded to the study medication, performed the platelet investigation by using flow cytometry.
Blood samples were obtained by antecubital vein puncture before and 1, 3, and 12 h after drug intake. After the first 5 mL were discarded, samples of 4.5 mL of whole blood were collected in silicone-coated glass tubes containing 0.5 mL of 0.129 M buffered sodium citrate (Vacutainer System®; Becton Dickinson, Meylan Cedex, France) by using a 19-gauge needle.
Blood cell count was measured with a Coulter counter (Celldyn 3500 R; Abbott, Chicago, IL). After dilution (1:10) with phosphate-buffered saline (GIBCO Invitrogen Corp., Scotland, UK), the samples were stimulated with normal saline (control), 0.8 µg of AA (Sigma-Aldrich Corp., St. Louis, MO), or 2 µg of collagen (Kollagen Horn; Nycomed Pharma GmbH, Munich, Germany) for 5 min at room temperature.
After stimulation for 20 min, blood samples were stained with 5 µL of fluorescein isothiocyanate-conjugated anti-CD61 (ß3-chain of glycoprotein IIb/IIIa on the surface of platelets [Becton Dickinson, San Jose, CA]) and 5 µL of phycoerythrin-conjugated anti-CD62P (P selectin) on the surface of activated platelets (Becton Dickinson, San Jose, CA). All procedures were carefully performed, and we avoided stirring and activating platelets. The samples were then fixed at 4°C with 1% p-formaldehyde (pH 7.35; VWR International, West Chester, PA).
Flow cytometric analysis was performed on a FACSCalibur flow cytometer and analyzed with CellQuest 3.1 software (Becton Dickinson, San Jose, CA). The flow cytometer was calibrated daily with fluorescence microbeads (Calibrite Beads; Becton Dickinson, San Jose, CA).
After 10,000 events were measured, a gate was set around the platelet population identified by forward and side-scatter characteristics. Platelets were identified as anti-CD61 positive, and the presence of the monoclonal antibody against P selectin (anti-CD62P) was used to determine the percentage of platelets expressing P selectin.
In the a priori study plan, our intention was to detect a 30% difference in activation at the P = 0.05 level with a power of 80%. The calculated sample size required 17 probands per group. Data were tested for normal distribution by using the Kolmogorov-Smirnov test. Then analysis of variance with Bonferroni’s correction was used to detect statistical significance (P < 0.05).
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Results |
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All volunteers had normal blood cell counts (Table 1). Results are presented in Figures 1 and 2. There was a significant decrease in CD 62 P-positive events after ingestion of aspirin, diclofenac, and lornoxicam when platelets were activated with AA or collagen. In contrast, rofecoxib had no influence on CD 62 P expression. There was no CD 62 P expression response irrespective of the study drug when samples were activated with normal saline (control group).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this study we compared the effect of the three nonselective NSAIDs—acetylsalicylic acid, diclofenac, and lornoxicam—and the COX-2-selective NSAID, rofecoxib, on AA and collagen-activated CD 62 P expression in 68 healthy volunteers. The drugs were administered orally, and CD 62 P expression was measured with flow cytometry. The results confirmed our hypothesis that nonselective NSAIDs have a significant effect on AA and collagen-induced CD 62 P expression in platelets in healthy volunteers. In contrast, rofecoxib, a COX-2-selective inhibitor, did not show this effect.
Diseases requiring surgical intervention are often accompanied by preoperative pain requiring treatment until surgery. However, the two COX isoforms, COX-1 and COX-2 (8), are inhibited differently by different NSAIDs (9). Although nonaspirin NSAIDs also increase bleeding times, the effects of these drugs on clinical bleeding are less clear (10). NSAIDs exert their antiplatelet actions by inhibiting COX-1, thereby blocking the formation of platelet-activating TXA2. However, the new COX-2-specific inhibitors still retain some platelet TXA2-inhibitory properties (11,12).
The glycoprotein P selectin (CD 62 P) is expressed exclusively on activated platelets provided that degranulation of 
granules has occurred. Increased binding of anti-CD 62 P indicates an irreversible degranulation of the platelets. Activation of platelets leads to the rapid release and surface expression of P selectin, which plays a central part in secondary hemostasis (13). P selectin also supports the docking of leukocytes on the endothelial lesion and the inflammatory reaction produced by leukocytes. Suppression of P selectin expression by NSAIDs could, therefore, have a beneficial effect on patients at risk of a systemic inflammatory response syndrome.
Here, two possibilities can be considered: First, early forms of platelets do express COX-2. Second, the affinity of COX-2-selective inhibitors such as meloxicam, celecoxib, and rofecoxib for COX-2 compared with COX-1 is 2.0-, 6.6-, and 35.5-fold, respectively (9). Thus, even rofecoxib could cause some COX-1 inhibition. Our results did not show a significant difference in AA and collagen CD 62 P expression. Nevertheless, there are no clinical trials comparing bleeding tendency after the administration of COX-2-selective drugs.
The most selective COX-2 inhibitor on the market (2) should possibly be avoided in patients with cardiovascular diseases (3). The VIGOR study group (14) found that rofecoxib was associated with fewer clinically important gastrointestinal events when compared with naproxen. However, the incidence of myocardial infarction was less frequent in patients treated with naproxen, although the mortality was similar in both groups.
Mice genetically deficient in the PGI2 receptor, when treated with TXA2 receptor antagonists, showed enhanced injury-induced vascular proliferation and platelet activation. Thus, it is thought that PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TXA2 (15). Rofecoxib may cause such an imbalance between PGI2 and TXA2. Vane (2) questioned, if the balance hypothesis is correct, why there is no evidence of a class effect involving all COX-2 inhibitors. One explanation could be differences in the physicochemical or pharmacokinetic properties among the selective COX-2 inhibitors. We found no significant change in CD 61 expression after AA and collagen activation in our subjects given rofecoxib.
The clinical effect of different NSAIDs on hemostasis in otherwise healthy patients (e.g., those undergoing knee arthroscopy) is not yet clear and needs to be well defined in respect to bleeding, thrombotic outcomes, or both. Answering this clinically relevant question is important to decide which NSAID can (should) be continued or discontinued before surgery, particularly because several anesthetics decrease adenosine diphosphate-activated CD 62 P expression (16–18). AA and collagen, however, induce CD 62 P expression through another pathway. Therefore, an additive effect of anesthetics and NSAIDs is possible. This suggests that NSAIDs should be used with caution during the intraoperative period.
We conclude that rofecoxib could be a safe drug with respect to platelet function. This is of major interest for the perioperative period.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345: 433–42.
[Free Full Text] - Vane JR. Biomedicine: back to an aspirin a day? Science 2002; 296: 474–5.
[Abstract/Free Full Text] - Mukherjee D. Selective cyclooxygenase-2 (COX-2) inhibitors and potential risk of cardiovascular events. Biochem Pharmacol 2002; 63: 817–21.[Web of Science][Medline]
- Homoncik M, Malec M, Marsik C, et al. Rofecoxib exerts no effect on platelet plug formation in healthy volunteers. Clin Exp Rheumatol 2003; 21: 229–31.[Web of Science][Medline]
- Greenberg HE, Gottesdiener K, Huntington M, et al. A new cyclooxygenase-2 inhibitor, rofecoxib (VIOXX), did not alter the antiplatelet effects of low-dose aspirin in healthy volunteers. J Clin Pharmacol 2000; 40: 1509–15.[Abstract]
- 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.
[Abstract/Free Full Text] - McCrory CR, Lindahl SG. Cyclooxygenase inhibition for postoperative analgesia. Anesth Analg 2002; 95: 169–76.
[Free Full Text] - Van Hecken A, Schwartz JI, Depre M, et al. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40: 1109–20.[Abstract]
- Chan CC, Boyce S, Brideau C, et al. Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor—pharmacological and biochemical profiles. J Pharmacol Exp Ther 1999; 290: 551–60.
[Abstract/Free Full Text] - Kenny GN. Potential renal, haematological and allergic adverse effects associated with nonsteroidal anti-inflammatory drugs. Drugs 1992; 44: 31–6.[Medline]
- Riendeau D, Percival MD, Boyce S, et al. Biochemical and pharmacological profile of a tetrasubstituted furanone as a highly selective COX-2 inhibitor. Br J Pharmacol 1997; 121: 105–17.[Web of Science][Medline]
- Klein T, Nusing RM, Pfeilschifter J, Ullrich V. Selective inhibition of cyclooxygenase 2. Biochem Pharmacol 1994; 48: 1605–10.[Web of Science][Medline]
- McEver RP. Role of selectins in leukocyte adhesion to platelets and endothelium. Ann N Y Acad Sci 1994; 714: 185–9.[Web of Science][Medline]
- Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis: VIGOR Study Group. N Engl J Med 2000; 343: 1520–8.
[Abstract/Free Full Text] - Cheng Y, Austin SC, Rocca B, et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 2002; 296: 539–41.
[Abstract/Free Full Text] - Faraday N. Platelets, perioperative hemostasis, and anesthesia. Anesthesiology 2002; 96: 1042–3.[Web of Science][Medline]
- Dogan IV, Ovali E, Eti Z, et al. The in vitro effects of isoflurane, sevoflurane, and propofol on platelet aggregation. Anesth Analg 1999; 88: 432–6.
[Abstract/Free Full Text] - de Rossi LW, Horn NA, Hecker KE, et al. Effect of halothane and isoflurane on binding of ADP- and TRAP-6-activated platelets to leukocytes in whole blood. Anesthesiology 2002; 96: 117–24.[Web of Science][Medline]
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