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Valdecoxib does not impair platelet function
Valdecoxib Does Not Impair Platelet Function PHILIP T. LEESE, MD,* SHEELA TALWALKER, PHD,† JEFFREY D. KENT, MD,† AND DAVID P. RECKER, MD,† The platelet effects of a supratherapeutic dose of the new cyclooxygenase (COX)-2 specific inhibitor, valdecoxib (40 mg twice a day), naproxen 500 mg twice a day, diclofenac 75 mg twice a day, and placebo were compared in 62 healthy adult subjects in this 71⁄2 day single-center, randomized, placebo-controlled trial. Platelet aggregation responses (to arachidonate [AA], collagen, and adenosine diphosphate [ADP]), bleeding time, and serum thromboxane B2 (TxB2) concentrations were measured at baseline and at regular intervals on days 1 and 8. Valdecoxib had no effect on platelet function. Naproxen and diclofenac significantly reduced the platelet aggregation response to AA and to a lesser extent collagen and ADP at most assessments compared with placebo. Naproxen significantly lowered serum TxB2 levels. In contrast to standard doses of 2 nonsteroidal antiinflammatory drugs (NSAIDs), a supratherapeutic valdecoxib dosage does not impair platelet function (COX-1). Valdecoxib may be a safer analgesic option than conventional NSAIDs in patients for whom bleeding complications are a concern. (Am J Emerg Med 2002;20:275-281. Copyright 2002, Elsevier Science (USA). All rights reserved.)
Although conventional nonsteroidal antiinflammatory drugs (NSAIDs) are regarded as the mainstay for the treatment of inflammation and pain, their use is associated with a number of significant adverse events, including gastrointestinal (GI) bleeding, impaired platelet function, and prolonged bleeding time.1-3 The analgesic and antiinflammatory properties of these agents are related to the inhibition of prostaglandin synthesis, which is mediated by the cyclooxygenase (COX) enzyme.4 Two forms of COX have been identified. COX-1 is constitutively expressed in most body tissues and plays a role in homeostasis, such as maintaining normal GI, renal, and platelet function; COX-2 is induced at sites of inflammation.5,6 Conventional NSAIDs nonselectively inhibit both COX isoforms and thus can result in considerable toxicity as well as providing antiinflammatory and analgesic activity. COX-1 mediates platelet activation by the generation of thromboxane A2 (TxA2) through the metabolism of arachidonate to prostaglandin H2, which is further metabolized to TxA2.7 Inhibition of COX-1, therefore, prevents production of TxA2, reduces platelet aggregation, and prolongs bleeding time. The clinical effects of NSAID-induced platelet
From *Quintiles Phase I Services, 11250 Corporate Ave, Lenexa, KS, and †Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL. Supported by the Pharmacia Corporation and Pfizer Inc. Manuscript received July 27, 2001, accepted August 28, 2001. Address reprint requests to David P. Recker, MD, Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL 60077. E-mail: [email protected]. Key Words: Valdecoxib, COX-2 specific inhibitor, platelets, COX-2, COX-1 sparing, supratherapeutic, NSAIDs. Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2004-0003$35.00/0 doi:10.1053/ajem.2002.32635
dysfunction consist of an increased risk of mucosal bleeding, prolonged surgical bleeding, and an additive risk of significant or life-threatening bleeding in patients taking anticoagulants.8,9 Other clinical problems associated with platelet dysfunction include increased bruising and unexplained anemia. Both surgical and nonsurgical studies have shown that conventional NSAIDs increase bleeding time and blood loss.10,11 In addition, their antiplatelet effects, combined with an NSAID-related depletion of protective GI mucosal prostaglandins, result in an increased risk of clinically significant GI bleeding. The COX-2 specific inhibitors provide analgesic and antiinflammatory efficacy similar to conventional NSAIDs, without the untoward consequences associated with inhibition of COX-1.12-15 Valdecoxib, a novel COX-2 specific inhibitor, is approximately 28,000-fold more selective against COX-2 (IC50 ⫽ 0.005 mol) than COX-1 (IC50 ⫽ 140 mol).16,17 It has been shown to be an effective analgesic anti-inflammatory agent, and appears to have an improved GI safety profile compared with conventional NSAIDs.18 Because it is COX-1 sparing, it has been hypothesized that valdecoxib will not affect platelet function. The present study tested this hypothesis by investigating the effect of valdecoxib on platelet function versus that of the conventional NSAIDs naproxen and diclofenac on normal healthy subjects. The trial described in this article compared the effects of treatment with valdecoxib 40 mg twice a day (a supratherapeutic dose), naproxen 500 mg twice a day, or diclofenac 75 mg twice a day with placebo on platelet aggregation responses to arachidonate, collagen, and adenosine diphosphate and bleeding time. The study also evaluated the effects of valdecoxib on platelet COX-1 using a sensitive ex vivo serum TxB2 assay. METHODS Subjects Healthy male and female volunteers, ranging in age from 18 to 55 years, comprised the study population. Subjects were eligible for inclusion if they weighed more than 50 kg and were within 20% of desired body weight, according to Metropolitan Life Insurance height and weight tables. All subjects were required to have a ⱖ60% platelet aggregation response to arachidonate at baseline. Normal physical examinations and clinical laboratory results were required for study eligibility. During the pretreatment screening visit, subjects must have tested negative on drug toxicology screens. Women of childbearing potential must have been using adequate contraception and have had a negative serum pregnancy test within 24 hours before receiving the first dose of study medication. Subjects were ineligible for study participation if they had had any clinically significant illness within 3 months 275
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before the study, had known hypersensitivity to NSAIDs, or used any medication within 2 weeks before receiving the first dose of study medication. A history of substance abuse or smoking, keloid formation or scarring, bleeding abnormalities (eg, frequent nosebleeds or bruising), or urinary incontinence were also grounds for study exclusion. Any subject diagnosed with or treated for esophageal, gastric, pyloric channel, or duodenal ulceration within 3 months before receiving the first dose of study medication was also excluded from the study. Written informed consent was obtained from all study subjects before study entry. The study was conducted in compliance with good clinical practices, which are consistent with the Declaration of Helsinki and its amendments. The study was approved by the Quintiles Phase I Institutional Review Board. Study Design This was a single-center, randomized, double-blind, comparator- and placebo-controlled, parallel-group, multipledose study. Subjects were randomized to receive valdecoxib 40 mg twice a day, naproxen 500 mg twice a day, diclofenac 75 mg twice a day, or placebo for 7 1⁄2 days. The doses of naproxen and diclofenac were standard doses used for analgesia whereas the valdecoxib dose was supratherapeutic. Eligible patients were randomized to receive study medication by using a previously prepared, computer-generated randomization schedule stratified by gender. All treatments were administered in tablet form. All tablets were identical in appearance. Participants were blinded to the identify of the treatments until all study data had been collated in a database. Pretreatment Period The pretreatment period was the 21-day interval before administration of the first dose of study medication and comprised the screening, admission, and baseline periods. During pretreatment screening (2 to 21 days before administration of study medication), subjects underwent physical examination and medical history within 14 days of receiving study medication. Blood and urine samples for clinical laboratory tests were obtained, and drug and alcohol toxicology screens were performed, as well as a hepatitis B surface antigen screen. During this period, written informed consent was obtained. During the admission period, subjects were admitted to the study unit. Drug/toxicology screening tests were repeated, and blood was collected for measurement of the platelet aggregation response to arachidonate. During the baseline period, blood was collected for the measurement of platelet aggregation responses to arachidonate, collagen, and adenosine diphosphate (ADP) and the determination of serum thromboxane B2 (TxB2) concentrations. Bleeding time was assessed by using the Simplate II (Organon Teknika, Boxtel, The Netherlands) method.19 Blood and urine were also collected for clinical laboratory tests (including blood urea nitrogen, creatinine, sodium, potassium, prothrombin time, and activated partial thromboplastin time). A signs-and-symptoms assessment was performed as was a serum pregnancy test for women of childbearing potential.
Treatment Period Subjects were confined to the study unit from 48 hours before receiving the first dose of study medication through the duration of the treatment period. Subjects were fed a low-fat and low-sodium diet and were prohibited from consuming alcohol or taking excluded medications. Subjects received 2 doses of study medication on days 1 through 7 and 1 dose on day 8. Doses were administered 15 minutes postprandially at 0700 hours and 1900 hours. On day 8, subjects received only 1 dose of medication at 0700. All study medication was given orally. On treatment day 1, blood was collected at 2, 4, and 8 hours after the 0700 dose and on day 8 at 30 minutes predose and 2, 4, and 8 hours postdose for platelet aggregation response measures and the serum TxB2 assays. Bleeding time was measured by the Simplate II威 method19 2, 4, and 8 hours after the 0700 dose on days 1 and 8 and also 30 minutes predose on day 8. On the last day of treatment, a physical examination, including weight and vital signs, was performed. Within 24 hours after the final dose of study medication, blood was drawn for the final clinical laboratory tests. Assessments Platelet function was assessed by baseline to final changes in platelet aggregation responses to arachidonate, collagen, and ADP by using the light transmission method of Born and Cross.20 Nine mL of blood was collected by a 19-gauge butterfly or in-dwelling catheter from a peripheral vein into a syringe containing 1 mL of 3.8% sodium citrate. The final citrate/blood volume ratio was 1:9. Platelet-rich plasma (PRP) was prepared by centrifuging the blood at 900 rpm for 10 minutes. The PRP was removed, and the remaining sample was centrifuged at 3000 rpm for an additional 10 minutes to collect the platelet-poor plasma (PPP) layer. Platelet aggregation was assessed with a dual-channel optical aggregometer, which was calibrated for maximum light transmission using 500 L PPP samples. PRP (450 L) was added to the aggregometer and left at 37°C for 3 minutes. The agonist (eg, 50 L arachidonate) was added, and maximum aggregation was calculated as the percentage of maximal light transmission achieved within 5 minutes. Bleeding time was measured by using the Simplate II威 method.19 A sphygmomanometer cuff was placed on the upper arm and inflated to 40 mm Hg. The disposable template was then placed on the forearm distal to the antecubital fossa in an area with no superficial veins. By using the template, 2 cuts (1 mm ⫻ 6 mm) were made perpendicular to the antecubital crease. Without touching the cut or disturbing the platelet plug, blood was blotted from the area at 15-second intervals by using the edge of a piece of filter paper. The time taken for blood to stop flowing was recorded, rounded to the nearest 15 seconds, and averaged for the 2 cuts. A validated enzyme immunoassay method was used to measure serum TxB2 concentrations.21 A venous catheter was used to draw a 5 ml blood sample. The sample was placed in a 7 ml Vacutainer威 and allowed to clot at 37°C for 1 hour ⫾ 5 minutes. The serum was centrifuged for 10 minutes at approximately 1100 ⫻ g at room temperature,
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FIGURE 1.
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Disposition of patients.
and serum TxB2 concentrations were measured by using an enzyme-linked immunoassay (ELISA). The lower limit of detection for this assay was 15.6 pg/mL. Statistical Analyses Nonparametric statistics were used for most analyses because of the small sample size and high variability of the data. Baseline characteristics were summarized and compared across treatment groups. Comparisons of age, height, and weight were accomplished by using the Kruskal-Wallis test, whereas gender and race/ethnic origin were compared by using the Fisher exact test. All subjects who were randomized and received at least 1 dose of study medication were included in the efficacy and safety analyses. Changes from baseline for platelet aggregation, bleeding time, and serum TxB2 concentrations were analyzed by using the Kruskal-Wallis test for comparison across treatment groups, whereas the Wilcoxon exact test was used for pairwise comparisons. Principle pairwise comparisons were valdecoxib versus the naproxen and diclofenac groups. All adverse events were coded and summarized by treatment group. Clinical laboratory values were compared within treatment groups by using a paired t test; analysis of covariance (ANCOVA) was used for between-treatment group comparisons. Vital sign changes from baseline were compared across treatment groups by using the KruskalWallis test. Based on a previous study, it was determined that 15 subjects per treatment group was the sample size needed to detect differences larger than 28.3% and 10.5% in platelet aggregation response to arachidonate and collagen, respectively, between groups at a 5% level of significance with a power of 80%.22 RESULTS Subjects Sixty-two subjects who met the inclusion criteria were entered into the study and randomized. Fifty-nine subjects completed the study. One subject in the placebo group was withdrawn because of an adverse event (urticaria), and 2
subjects in the diclofenac group were withdrawn from the study because of protocol noncompliance (family emergencies, Fig 1). The 4 treatment groups were comparable with respect to mean age, gender, and race/ethnic origin, as well as vital signs (Table 1). Subjects ranged in age from 18 to 55 years inclusive. In each treatment group, 67% to 69% of the subjects were women (Table 1). Platelet Aggregation Response to Arachidonate The median baseline aggregation responses were similar across the 4 treatment groups (range 84% to 87%, P ⫽ .597). Throughout the study period, valdecoxib had no apparent effect on arachidonate-induced platelet aggregation, with the response being similar to placebo at each time point (Fig 2). Conversely, naproxen and diclofenac resulted in a significant reduction in the median platelet aggregation response compared with placebo, which was sustained throughout the study period. Naproxen also significantly reduced the median platelet aggregation response compared with valdecoxib at each assessment throughout the study (P ⬍ .05, Fig 2). The diclofenac group also showed significant reductions in platelet aggregation compared with valdecoxib, with significant differences at 4 and 8 hours postdose on day 1 and at all postdose assessments on day 8 (P ⬍ .05, Fig 2). Response to Collagen The median baseline aggregation response to collagen was similar across the 4 treatment groups (range 82% to 86%). Treatment with valdecoxib had no significant effect on the collagen-induced platelet aggregation response compared with placebo at each time point (P ⱖ .113, Fig 3). However, treatment with naproxen resulted in a significantly greater reduction in median collageninduced aggregation relative to baseline than valdecoxib at 2 and 4 hours postdose on day 1 and 4 hours postdose on day 8 (P ⱕ .05, Fig 3). Treatment with naproxen also
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TABLE 1. Baseline Demographic Characteristics: All Randomized Subjects
Age (mean) Race/Ethnic Origin (%) White Black Asian Hispanic Other Gender (%) Female Male
Placebo (n ⫽ 16)
Valdecoxib 40 mg BID (n ⫽ 15)
Naproxen 500 mg BID (n ⫽ 16)
Diclofenac 75 mg BID (n ⫽ 16)
33.9
32.2
31.1
31.3
14 (88) 2 (13) 0 (0) 0 (0) 0 (0)
9 (60) 2 (13) 1 (7) 2 (13) 1 (7)
13 (87) 1 (7) 0 (0) 0 (0) 1 (7)
15 (94) 0 (0) 0 (0) 0 (0) 1 (6)
11 (69) 5 (31)
10 (67) 5 (33)
10 (67) 5 (33)
11 (69) 5 (31)
P 0.94* 0.28†
1.00†
Abbreviation: BID, twice a day. *Performed by using Kruskal-Wallis test. †Performed by using Fisher exact test.
reduced the platelet aggregation response significantly more than placebo at 2 and 4 hours postdose on days 1 and 8. Significant reductions from baseline were observed for diclofenac at a single time point (4 hours postdose on day 1) when compared with valdecoxib. Overall, there was a less pronounced difference between treatment groups with collagen stimulation than was noted for arachidonate-induced platelet aggregation. Response to ADP The median baseline aggregation response to ADP was comparable across all 4 treatment groups (range 81.5% to 87%). Neither valdecoxib nor placebo treatment had any effect on the platelet aggregation responses to ADP. In contrast, pairwise comparisons showed that the relative
FIGURE 2. Platelet aggregation response to arachidonate at baseline and on day 8. Statistical comparisons are based on median changes from baseline. There were no statistically significant differences between valdecoxib and placebo. Bars above and below each column represent the interquartile range. *, P ⬍ .05 for change from baseline versus naproxen; †, P ⬍ .05 for change from baseline versus diclotenac; ‡, P ⬍ .05 for change from baseline versus placebo.
reduction from baseline in aggregation response was significantly less for valdecoxib-treated subjects than for those treated with naproxen at every assessment time (P ⬍ .001). There was a single significant reduction from baseline with diclofenac as compared with valdecoxib at 4 hours on day 1 (P ⫽ .006). Bleeding Time Figure 4 shows changes from baseline in bleeding time throughout the study period. Although bleeding times were variable within each treatment group, treatment with valdecoxib did not significantly prolong bleeding time at any time point compared with placebo. However, naproxen significantly prolonged bleeding time compared with placebo, valdecoxib, and diclofenac at 8 hours postdose on day 1 (P ⱕ .05). Moreover, the magnitude of
FIGURE 3. Platelet aggregation response to collagen at baseline and on day 8. Statistical comparisons are based on median changes from baseline. There were no statistically significant differences between valdecoxib and placebo. Bars above and below each column represent the interquartile range. *, P ⬍.05 for change from baseline versus naproxen; ‡, P ⬍.05 for change from baseline versus placebo.
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FIGURE 4. Median change from baseline in bleeding time on days 1 and 8. Median baseline values were as follows (seconds): valdecoxib, 270; naproxen, 278; diclofenac, 240; and placebo, 247.5. Bars above and below each data point represent the interquartile range. *, P ⬍.05 for change from baseline versus naproxen; ‡, indicates P ⬍.05 for change from baseline versus placebo.
the prolongation was numerically greater for naproxen compared with placebo and valdecoxib, even when between-group differences were not statistically significant. The median change in bleeding time from baseline was similar for the diclofenac and placebo groups at each time point (Fig 4). Serum TxB2 Levels The median reductions from baseline in serum TxB2 concentrations correspond with the arachidonate-induced platelet aggregation results. Throughout the study, valdecoxib and placebo had similar effects on median serum TxB2 levels (Fig 5). Conversely, naproxen significantly reduced serum TxB2 compared with both valdecoxib and placebo at all time points (Fig 5). Diclofenac significantly reduced serum TxB2 levels compared with placebo at 4 hours on day 1. The rapid disappearance of serum TxB2 among naproxen-treated subjects, and the persistence of these depressed levels through day 8 are shown in Figure 5. Safety The majority of adverse events in each treatment group were mild. None of the adverse events was considered serious by the study investigators. Adverse events reported by 2 or more subjects were abdominal pain, headache, arthralgia, flushing, back pain, dizziness, flatulence, nausea, and rash. Only 2 events were judged by the investigator to be probably related to study medication. One subject, a 20-year-old woman in the placebo group who developed urticaria, was withdrawn from the study. There were statistically significant changes from baseline in clinical laboratory values in each active treatment group. In a small number of individuals, these changes were con-
sidered by the investigator to be clinically relevant. Clinically relevant changes included decreases in hematocrit and hemoglobin levels in 7% to 13% of subjects within each group and raised neutrophil and eosinophil counts in 6% of subjects receiving diclofenac. Other clinically relevant changes within each group included increases in the levels of urinary protein, creatinine, sodium, erythrocytes and white blood cells (6% to 13% of subjects), and raised serum calcium values in 6% to 7% of subjects. There were no patterns to suggest that any of the changes in clinical laboratory values were treatment related. DISCUSSION This study compared the effects of high-dose valdecoxib with standard doses of naproxen and diclofenac and with placebo on platelet function. The results indicate valdecoxib has no effect on platelet aggregation, bleeding time, or serum TxB2 levels at supratherapeutic doses. In contrast, naproxen and diclofenac produced significant decreases in platelet aggregation at recommended doses. These results are consistent with the absence of an effect of valdecoxib on platelet-associated COX-1 activity and confirm previous studies showing that conventional NSAIDs interfere with normal platelet function.3,8-10 Throughout the study period, valdecoxib had little or no effect on the platelet aggregation response to arachidonate, collagen, or ADP, whereas naproxen and diclofenac often resulted in significant reductions relative to placebo or valdecoxib. These decreases were more pronounced for naproxen than diclofenac. The increased level of inhibition observed with the arachidonate-platelet aggregation assay compared with the collagen or ADP assays is consistent with their known mechanisms of action. Arachidonate-in-
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FIGURE 5. Median change from baseline in serum TxB2 concentrations on days 1 and 8. Median baseline values were as follows (ng/mL): valdecoxib, 149; naproxen, 169; diclofenac, 119; and placebo, 139.5. *, P ⬍.05 for change from baseline versus naproxen; †, P ⬍ .05 for change from baseline v diclofenac; ‡, P ⬍.05 for change from baseline versus placebo.
duced aggregation is accomplished entirely through the production of TxA2 by COX-1, whereas collagen-induced aggregation is only partially dependent on this process, and ADP achieves platelet aggregation in a way completely unrelated to the COX-1 pathway.23 Bleeding time is a useful clinical marker of platelet aggregation but can be difficult to interpret because of high variability in the data. The lack of an observable effect of valdecoxib on the bleeding time throughout the study period is consistent with the absence of an effect of valdecoxib on platelet function. Although the marked variability in bleeding time resulted in reduced power for statistical significance being very limited, bleeding times for subjects receiving naproxen were consistently numerically higher than for valdecoxib and placebo and were significantly different at 8 hours postdose on day 1. This indicates that naproxen may have a clinically important antiplatelet effect and hence the potential to increase the risk of surgical bleeding. The lack of an effect of diclofenac on bleeding time observed in this study is consistent with the findings of other studies and its smaller effect on platelet function compared with other conventional NSAIDs, such as naproxen.24,25 In this study, TxB2 was used as a surrogate marker of platelet TxA2 because it is a stable and easily measured metabolite of TxA2.26 Median serum TxB2 showed little change in the valdecoxib and placebo groups but was significantly decreased in the naproxen group relative to both valdecoxib and placebo. The TxB2 reductions for diclofenac were less marked than for naproxen. These data, when taken together, confirm that, in contrast to conventional NSAIDs, valdecoxib is COX-1 sparing. All treatments were well tolerated, and there were no serious adverse events reported. None of the very small proportion of clinically relevant changes in hematology
(hematocrit, hemoglobin, neutrophil and eosinophil counts), urinalysis (erythrocyte and white blood cell numbers, protein, creatinine and sodium), and serum calcium laboratory values within each treatment group were considered by the investigator to be treatment related. Ideally, clinical assessments of platelet function should include both biochemical and clinical endpoints. Coordinated assessments of arachidonate-, collagen-, and ADPinduced platelet aggregation; bleeding time; and TxB2 production have become useful predictors in evaluating platelet responses to various agents. Although these surrogate markers have not been explicitly linked with a significantly increased risk of bleeding episodes, treatment with conventional NSAIDs that result in reproducible platelet dysfunction has been associated with extensive blood loss in a number of studies.7-9 Other clinical problems associated with platelet dysfunction include increased bruising, spontaneous internal bleeding, and unexplained anemia. The anemia may, in some cases, be a dual effect of conventional NSAIDs. First, NSAIDs can produce GI mucosal injury that does not manifest as an overt bleeding ulcer. Second, these GI lesions may then lead to chronic, low-grade blood loss exacerbated by NSAID-induced platelet dysfunction. In addition to its role in maintaining normal platelet function, COX-1 is responsible for the production of prostaglandins that protect the gastric mucosa by a number of interrelated mechanisms including reduction of acid secretion, stimulation of mucus secretion, and maintenance of mucosal blood flow.7 The clinical effects of NSAID-induced platelet dysfunction manifest as increased mucosal bleeding, such as from GI tract lesions, prolonged bleeding with surgery, and an additive risk of significant bleeding in patients taking anticoagulants.2,8,27 A recent endoscopy
LEESE ET AL ■ PLATELET EFFECTS OF VALDECOXIB VERSUS 2 NSAIDS
study of valdecoxib’s GI safety has shown effects similar to placebo with regard to gastric mucosal damage.18 In conclusion, this study shows that, in contrast to standard doses of the conventional NSAIDs, naproxen, and diclofenac, a supratherapeutic dose of valdecoxib does not compromise platelet function in healthy subjects. Therefore, the COX-2 specific inhibitor, valdecoxib, is potentially safer than conventional NSAIDs in the management of perisurgical pain, particularly in patients at increased risk of bleeding (ie, those with GI ulceration or those receiving anticoagulants). REFERENCES 1. Paulus HE: FDA arthritis advisory committee meeting: serious gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs, etc. Arthritis Rheum 1988;31:1450-1451 2. Garcia-Rodriguez LA, Jick H: Risk of upper gastrointestinal bleeding and perforation associated with nonsteroidal anti-inflammatory drugs. Lancet 1994;343:769-772 3. Cronberg S, Wallmark E, Soderberg I: Effect of platelet aggregation of oral administration of 10 nonsteroidal analgesics to humans. Scand J Haematol 1984;33:155-159 4. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature 1971;231:232-235 5. Kargman S, Charleson S, Cartwright M, et al: Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and human gastrointestinal tracts. Gastroenterology 1996;111:445-454 6. Grossman CJ, Wiseman J, Lucas FS, et al: Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and Cox-2 inhibitors. Inflamm Res 1995;44:253-257 7. Funk CD, Funk LB, Kennedy ME, et al: Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 1991;5:23042312 8. Gallagher JE, Blauth J, Fornadley JA: Perioperative ketorolac tromethamine and postoperative hemorrhage in cases of tonsillectomy and adenoidectomy. Laryngoscope 1995;105:606-609 9. Conrad K, Fagan T, Mackie M, et al: Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988;43:542-546 10. Spowart K, Greer A, McLaren, et al: Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers. Thromb Haemost 1988;60:382-386 11. Bashein G, Nessly ML, Rice AL, et al: Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery. Arch Intern Med 1991;151:89-93 12. Simon LS, Weaver AL, Graham DY, et al: Anti-inflammatory
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and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. A randomized controlled trial. JAMA 1999;282:1921-1928 13. 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: 1520-1528 14. Silverstein FE, Faich G, Goldstein JL, et al: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. JAMA 2000;284:1247-1255 15. Williams GW, Ettlinger RE, Ruderman EM, et al: Treatment of osteoarthritis with a once-daily dosing regimen of celecoxib. J Clin Rheum 2000;6:65-74 16. Investigational brochure for SC-65872 (valdecoxib). Pharmacia Corporation. Document No. N91-99-41-900, March 12, 1999 17. Talley J, Brown DL, Carter JS, et al: 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem 2000;43:775-7 18. Goldstein J, Fakouhi KM, Zhao W, et al: Reduced incidence of gastroduodenal ulcers with valdecoxib compared to ibuprofen and diclofenac in patients with osteoarthritis: a multicenter trial. Poster 2561 presented at Digestive Disease Week, May 22, 2001, Atlanta, GA 19. Lethagen S, Kling S: New bleeding time devices with retractable blades evaluated in children, healthy volunteers and patients with prolonged bleeding time. Thromb Haemost 1993;70:595-597 20. Born GVR, Cross MJ: The aggregation of blood platelets. J Physiol 1963;168:178-195 21. Reinke M: Monitoring thromboxane in body fluids: A specific ELISA for 11-dehydrothromboxane B2 using a monoclonal antibody. Am J Physiol 1992;262:E658-662 22. Leese PT, Hubbard RC, Karim A, et al: Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 2000;40: 124-132 23. Packham MA, Mustard JF: Normal and abnormal platelet activity. In Lasslo A, (ed). Blood Platelet Function and Medicinal Chemistry. New York, Elsevier Biomedical, 1984, pp 61-128 24. Laitinen J, Nuutinen LS, Puranen J, et al: Effect of a nonsteroidal anti-inflammatory drug, diclofenac, on haemostasis in patients undergoing total hip replacement. Acta Anaesthesiol Scand 1992;36:486-489 25. Niemi TT, Taxell C, Rosenberg PH: Comparison of the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers. Acta Anaesthesiol Scand 1997;41:1353-1358 26. Sametz W, Hummer K, Butter M, et al: Formation of 8-isoPGF(2alpha) and thromboxane A(2) by stimulation with several activators of phospholipase A(2) in the isolated human umbilical vein. Br J Pharmacol 2000;131:145-151 27. Gabriel SE, Jaakimainen L, Bombardier C: Risk for serious gastrointestinal complications related to the use of nonsteroidal anti-inflammatory drugs: A meta-analysis. Ann Intern Med 1991; 115:787-796
Although conventional nonsteroidal antiinflammatory drugs (NSAIDs) are regarded as the mainstay for the treatment of inflammation and pain, their use is associated with a number of significant adverse events, including gastrointestinal (GI) bleeding, impaired platelet function, and prolonged bleeding time.1-3 The analgesic and antiinflammatory properties of these agents are related to the inhibition of prostaglandin synthesis, which is mediated by the cyclooxygenase (COX) enzyme.4 Two forms of COX have been identified. COX-1 is constitutively expressed in most body tissues and plays a role in homeostasis, such as maintaining normal GI, renal, and platelet function; COX-2 is induced at sites of inflammation.5,6 Conventional NSAIDs nonselectively inhibit both COX isoforms and thus can result in considerable toxicity as well as providing antiinflammatory and analgesic activity. COX-1 mediates platelet activation by the generation of thromboxane A2 (TxA2) through the metabolism of arachidonate to prostaglandin H2, which is further metabolized to TxA2.7 Inhibition of COX-1, therefore, prevents production of TxA2, reduces platelet aggregation, and prolongs bleeding time. The clinical effects of NSAID-induced platelet
From *Quintiles Phase I Services, 11250 Corporate Ave, Lenexa, KS, and †Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL. Supported by the Pharmacia Corporation and Pfizer Inc. Manuscript received July 27, 2001, accepted August 28, 2001. Address reprint requests to David P. Recker, MD, Pharmacia Corporation, 5200 Old Orchard Road, Skokie, IL 60077. E-mail: [email protected]. Key Words: Valdecoxib, COX-2 specific inhibitor, platelets, COX-2, COX-1 sparing, supratherapeutic, NSAIDs. Copyright 2002, Elsevier Science (USA). All rights reserved. 0735-6757/02/2004-0003$35.00/0 doi:10.1053/ajem.2002.32635
dysfunction consist of an increased risk of mucosal bleeding, prolonged surgical bleeding, and an additive risk of significant or life-threatening bleeding in patients taking anticoagulants.8,9 Other clinical problems associated with platelet dysfunction include increased bruising and unexplained anemia. Both surgical and nonsurgical studies have shown that conventional NSAIDs increase bleeding time and blood loss.10,11 In addition, their antiplatelet effects, combined with an NSAID-related depletion of protective GI mucosal prostaglandins, result in an increased risk of clinically significant GI bleeding. The COX-2 specific inhibitors provide analgesic and antiinflammatory efficacy similar to conventional NSAIDs, without the untoward consequences associated with inhibition of COX-1.12-15 Valdecoxib, a novel COX-2 specific inhibitor, is approximately 28,000-fold more selective against COX-2 (IC50 ⫽ 0.005 mol) than COX-1 (IC50 ⫽ 140 mol).16,17 It has been shown to be an effective analgesic anti-inflammatory agent, and appears to have an improved GI safety profile compared with conventional NSAIDs.18 Because it is COX-1 sparing, it has been hypothesized that valdecoxib will not affect platelet function. The present study tested this hypothesis by investigating the effect of valdecoxib on platelet function versus that of the conventional NSAIDs naproxen and diclofenac on normal healthy subjects. The trial described in this article compared the effects of treatment with valdecoxib 40 mg twice a day (a supratherapeutic dose), naproxen 500 mg twice a day, or diclofenac 75 mg twice a day with placebo on platelet aggregation responses to arachidonate, collagen, and adenosine diphosphate and bleeding time. The study also evaluated the effects of valdecoxib on platelet COX-1 using a sensitive ex vivo serum TxB2 assay. METHODS Subjects Healthy male and female volunteers, ranging in age from 18 to 55 years, comprised the study population. Subjects were eligible for inclusion if they weighed more than 50 kg and were within 20% of desired body weight, according to Metropolitan Life Insurance height and weight tables. All subjects were required to have a ⱖ60% platelet aggregation response to arachidonate at baseline. Normal physical examinations and clinical laboratory results were required for study eligibility. During the pretreatment screening visit, subjects must have tested negative on drug toxicology screens. Women of childbearing potential must have been using adequate contraception and have had a negative serum pregnancy test within 24 hours before receiving the first dose of study medication. Subjects were ineligible for study participation if they had had any clinically significant illness within 3 months 275
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before the study, had known hypersensitivity to NSAIDs, or used any medication within 2 weeks before receiving the first dose of study medication. A history of substance abuse or smoking, keloid formation or scarring, bleeding abnormalities (eg, frequent nosebleeds or bruising), or urinary incontinence were also grounds for study exclusion. Any subject diagnosed with or treated for esophageal, gastric, pyloric channel, or duodenal ulceration within 3 months before receiving the first dose of study medication was also excluded from the study. Written informed consent was obtained from all study subjects before study entry. The study was conducted in compliance with good clinical practices, which are consistent with the Declaration of Helsinki and its amendments. The study was approved by the Quintiles Phase I Institutional Review Board. Study Design This was a single-center, randomized, double-blind, comparator- and placebo-controlled, parallel-group, multipledose study. Subjects were randomized to receive valdecoxib 40 mg twice a day, naproxen 500 mg twice a day, diclofenac 75 mg twice a day, or placebo for 7 1⁄2 days. The doses of naproxen and diclofenac were standard doses used for analgesia whereas the valdecoxib dose was supratherapeutic. Eligible patients were randomized to receive study medication by using a previously prepared, computer-generated randomization schedule stratified by gender. All treatments were administered in tablet form. All tablets were identical in appearance. Participants were blinded to the identify of the treatments until all study data had been collated in a database. Pretreatment Period The pretreatment period was the 21-day interval before administration of the first dose of study medication and comprised the screening, admission, and baseline periods. During pretreatment screening (2 to 21 days before administration of study medication), subjects underwent physical examination and medical history within 14 days of receiving study medication. Blood and urine samples for clinical laboratory tests were obtained, and drug and alcohol toxicology screens were performed, as well as a hepatitis B surface antigen screen. During this period, written informed consent was obtained. During the admission period, subjects were admitted to the study unit. Drug/toxicology screening tests were repeated, and blood was collected for measurement of the platelet aggregation response to arachidonate. During the baseline period, blood was collected for the measurement of platelet aggregation responses to arachidonate, collagen, and adenosine diphosphate (ADP) and the determination of serum thromboxane B2 (TxB2) concentrations. Bleeding time was assessed by using the Simplate II (Organon Teknika, Boxtel, The Netherlands) method.19 Blood and urine were also collected for clinical laboratory tests (including blood urea nitrogen, creatinine, sodium, potassium, prothrombin time, and activated partial thromboplastin time). A signs-and-symptoms assessment was performed as was a serum pregnancy test for women of childbearing potential.
Treatment Period Subjects were confined to the study unit from 48 hours before receiving the first dose of study medication through the duration of the treatment period. Subjects were fed a low-fat and low-sodium diet and were prohibited from consuming alcohol or taking excluded medications. Subjects received 2 doses of study medication on days 1 through 7 and 1 dose on day 8. Doses were administered 15 minutes postprandially at 0700 hours and 1900 hours. On day 8, subjects received only 1 dose of medication at 0700. All study medication was given orally. On treatment day 1, blood was collected at 2, 4, and 8 hours after the 0700 dose and on day 8 at 30 minutes predose and 2, 4, and 8 hours postdose for platelet aggregation response measures and the serum TxB2 assays. Bleeding time was measured by the Simplate II威 method19 2, 4, and 8 hours after the 0700 dose on days 1 and 8 and also 30 minutes predose on day 8. On the last day of treatment, a physical examination, including weight and vital signs, was performed. Within 24 hours after the final dose of study medication, blood was drawn for the final clinical laboratory tests. Assessments Platelet function was assessed by baseline to final changes in platelet aggregation responses to arachidonate, collagen, and ADP by using the light transmission method of Born and Cross.20 Nine mL of blood was collected by a 19-gauge butterfly or in-dwelling catheter from a peripheral vein into a syringe containing 1 mL of 3.8% sodium citrate. The final citrate/blood volume ratio was 1:9. Platelet-rich plasma (PRP) was prepared by centrifuging the blood at 900 rpm for 10 minutes. The PRP was removed, and the remaining sample was centrifuged at 3000 rpm for an additional 10 minutes to collect the platelet-poor plasma (PPP) layer. Platelet aggregation was assessed with a dual-channel optical aggregometer, which was calibrated for maximum light transmission using 500 L PPP samples. PRP (450 L) was added to the aggregometer and left at 37°C for 3 minutes. The agonist (eg, 50 L arachidonate) was added, and maximum aggregation was calculated as the percentage of maximal light transmission achieved within 5 minutes. Bleeding time was measured by using the Simplate II威 method.19 A sphygmomanometer cuff was placed on the upper arm and inflated to 40 mm Hg. The disposable template was then placed on the forearm distal to the antecubital fossa in an area with no superficial veins. By using the template, 2 cuts (1 mm ⫻ 6 mm) were made perpendicular to the antecubital crease. Without touching the cut or disturbing the platelet plug, blood was blotted from the area at 15-second intervals by using the edge of a piece of filter paper. The time taken for blood to stop flowing was recorded, rounded to the nearest 15 seconds, and averaged for the 2 cuts. A validated enzyme immunoassay method was used to measure serum TxB2 concentrations.21 A venous catheter was used to draw a 5 ml blood sample. The sample was placed in a 7 ml Vacutainer威 and allowed to clot at 37°C for 1 hour ⫾ 5 minutes. The serum was centrifuged for 10 minutes at approximately 1100 ⫻ g at room temperature,
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FIGURE 1.
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Disposition of patients.
and serum TxB2 concentrations were measured by using an enzyme-linked immunoassay (ELISA). The lower limit of detection for this assay was 15.6 pg/mL. Statistical Analyses Nonparametric statistics were used for most analyses because of the small sample size and high variability of the data. Baseline characteristics were summarized and compared across treatment groups. Comparisons of age, height, and weight were accomplished by using the Kruskal-Wallis test, whereas gender and race/ethnic origin were compared by using the Fisher exact test. All subjects who were randomized and received at least 1 dose of study medication were included in the efficacy and safety analyses. Changes from baseline for platelet aggregation, bleeding time, and serum TxB2 concentrations were analyzed by using the Kruskal-Wallis test for comparison across treatment groups, whereas the Wilcoxon exact test was used for pairwise comparisons. Principle pairwise comparisons were valdecoxib versus the naproxen and diclofenac groups. All adverse events were coded and summarized by treatment group. Clinical laboratory values were compared within treatment groups by using a paired t test; analysis of covariance (ANCOVA) was used for between-treatment group comparisons. Vital sign changes from baseline were compared across treatment groups by using the KruskalWallis test. Based on a previous study, it was determined that 15 subjects per treatment group was the sample size needed to detect differences larger than 28.3% and 10.5% in platelet aggregation response to arachidonate and collagen, respectively, between groups at a 5% level of significance with a power of 80%.22 RESULTS Subjects Sixty-two subjects who met the inclusion criteria were entered into the study and randomized. Fifty-nine subjects completed the study. One subject in the placebo group was withdrawn because of an adverse event (urticaria), and 2
subjects in the diclofenac group were withdrawn from the study because of protocol noncompliance (family emergencies, Fig 1). The 4 treatment groups were comparable with respect to mean age, gender, and race/ethnic origin, as well as vital signs (Table 1). Subjects ranged in age from 18 to 55 years inclusive. In each treatment group, 67% to 69% of the subjects were women (Table 1). Platelet Aggregation Response to Arachidonate The median baseline aggregation responses were similar across the 4 treatment groups (range 84% to 87%, P ⫽ .597). Throughout the study period, valdecoxib had no apparent effect on arachidonate-induced platelet aggregation, with the response being similar to placebo at each time point (Fig 2). Conversely, naproxen and diclofenac resulted in a significant reduction in the median platelet aggregation response compared with placebo, which was sustained throughout the study period. Naproxen also significantly reduced the median platelet aggregation response compared with valdecoxib at each assessment throughout the study (P ⬍ .05, Fig 2). The diclofenac group also showed significant reductions in platelet aggregation compared with valdecoxib, with significant differences at 4 and 8 hours postdose on day 1 and at all postdose assessments on day 8 (P ⬍ .05, Fig 2). Response to Collagen The median baseline aggregation response to collagen was similar across the 4 treatment groups (range 82% to 86%). Treatment with valdecoxib had no significant effect on the collagen-induced platelet aggregation response compared with placebo at each time point (P ⱖ .113, Fig 3). However, treatment with naproxen resulted in a significantly greater reduction in median collageninduced aggregation relative to baseline than valdecoxib at 2 and 4 hours postdose on day 1 and 4 hours postdose on day 8 (P ⱕ .05, Fig 3). Treatment with naproxen also
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TABLE 1. Baseline Demographic Characteristics: All Randomized Subjects
Age (mean) Race/Ethnic Origin (%) White Black Asian Hispanic Other Gender (%) Female Male
Placebo (n ⫽ 16)
Valdecoxib 40 mg BID (n ⫽ 15)
Naproxen 500 mg BID (n ⫽ 16)
Diclofenac 75 mg BID (n ⫽ 16)
33.9
32.2
31.1
31.3
14 (88) 2 (13) 0 (0) 0 (0) 0 (0)
9 (60) 2 (13) 1 (7) 2 (13) 1 (7)
13 (87) 1 (7) 0 (0) 0 (0) 1 (7)
15 (94) 0 (0) 0 (0) 0 (0) 1 (6)
11 (69) 5 (31)
10 (67) 5 (33)
10 (67) 5 (33)
11 (69) 5 (31)
P 0.94* 0.28†
1.00†
Abbreviation: BID, twice a day. *Performed by using Kruskal-Wallis test. †Performed by using Fisher exact test.
reduced the platelet aggregation response significantly more than placebo at 2 and 4 hours postdose on days 1 and 8. Significant reductions from baseline were observed for diclofenac at a single time point (4 hours postdose on day 1) when compared with valdecoxib. Overall, there was a less pronounced difference between treatment groups with collagen stimulation than was noted for arachidonate-induced platelet aggregation. Response to ADP The median baseline aggregation response to ADP was comparable across all 4 treatment groups (range 81.5% to 87%). Neither valdecoxib nor placebo treatment had any effect on the platelet aggregation responses to ADP. In contrast, pairwise comparisons showed that the relative
FIGURE 2. Platelet aggregation response to arachidonate at baseline and on day 8. Statistical comparisons are based on median changes from baseline. There were no statistically significant differences between valdecoxib and placebo. Bars above and below each column represent the interquartile range. *, P ⬍ .05 for change from baseline versus naproxen; †, P ⬍ .05 for change from baseline versus diclotenac; ‡, P ⬍ .05 for change from baseline versus placebo.
reduction from baseline in aggregation response was significantly less for valdecoxib-treated subjects than for those treated with naproxen at every assessment time (P ⬍ .001). There was a single significant reduction from baseline with diclofenac as compared with valdecoxib at 4 hours on day 1 (P ⫽ .006). Bleeding Time Figure 4 shows changes from baseline in bleeding time throughout the study period. Although bleeding times were variable within each treatment group, treatment with valdecoxib did not significantly prolong bleeding time at any time point compared with placebo. However, naproxen significantly prolonged bleeding time compared with placebo, valdecoxib, and diclofenac at 8 hours postdose on day 1 (P ⱕ .05). Moreover, the magnitude of
FIGURE 3. Platelet aggregation response to collagen at baseline and on day 8. Statistical comparisons are based on median changes from baseline. There were no statistically significant differences between valdecoxib and placebo. Bars above and below each column represent the interquartile range. *, P ⬍.05 for change from baseline versus naproxen; ‡, P ⬍.05 for change from baseline versus placebo.
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FIGURE 4. Median change from baseline in bleeding time on days 1 and 8. Median baseline values were as follows (seconds): valdecoxib, 270; naproxen, 278; diclofenac, 240; and placebo, 247.5. Bars above and below each data point represent the interquartile range. *, P ⬍.05 for change from baseline versus naproxen; ‡, indicates P ⬍.05 for change from baseline versus placebo.
the prolongation was numerically greater for naproxen compared with placebo and valdecoxib, even when between-group differences were not statistically significant. The median change in bleeding time from baseline was similar for the diclofenac and placebo groups at each time point (Fig 4). Serum TxB2 Levels The median reductions from baseline in serum TxB2 concentrations correspond with the arachidonate-induced platelet aggregation results. Throughout the study, valdecoxib and placebo had similar effects on median serum TxB2 levels (Fig 5). Conversely, naproxen significantly reduced serum TxB2 compared with both valdecoxib and placebo at all time points (Fig 5). Diclofenac significantly reduced serum TxB2 levels compared with placebo at 4 hours on day 1. The rapid disappearance of serum TxB2 among naproxen-treated subjects, and the persistence of these depressed levels through day 8 are shown in Figure 5. Safety The majority of adverse events in each treatment group were mild. None of the adverse events was considered serious by the study investigators. Adverse events reported by 2 or more subjects were abdominal pain, headache, arthralgia, flushing, back pain, dizziness, flatulence, nausea, and rash. Only 2 events were judged by the investigator to be probably related to study medication. One subject, a 20-year-old woman in the placebo group who developed urticaria, was withdrawn from the study. There were statistically significant changes from baseline in clinical laboratory values in each active treatment group. In a small number of individuals, these changes were con-
sidered by the investigator to be clinically relevant. Clinically relevant changes included decreases in hematocrit and hemoglobin levels in 7% to 13% of subjects within each group and raised neutrophil and eosinophil counts in 6% of subjects receiving diclofenac. Other clinically relevant changes within each group included increases in the levels of urinary protein, creatinine, sodium, erythrocytes and white blood cells (6% to 13% of subjects), and raised serum calcium values in 6% to 7% of subjects. There were no patterns to suggest that any of the changes in clinical laboratory values were treatment related. DISCUSSION This study compared the effects of high-dose valdecoxib with standard doses of naproxen and diclofenac and with placebo on platelet function. The results indicate valdecoxib has no effect on platelet aggregation, bleeding time, or serum TxB2 levels at supratherapeutic doses. In contrast, naproxen and diclofenac produced significant decreases in platelet aggregation at recommended doses. These results are consistent with the absence of an effect of valdecoxib on platelet-associated COX-1 activity and confirm previous studies showing that conventional NSAIDs interfere with normal platelet function.3,8-10 Throughout the study period, valdecoxib had little or no effect on the platelet aggregation response to arachidonate, collagen, or ADP, whereas naproxen and diclofenac often resulted in significant reductions relative to placebo or valdecoxib. These decreases were more pronounced for naproxen than diclofenac. The increased level of inhibition observed with the arachidonate-platelet aggregation assay compared with the collagen or ADP assays is consistent with their known mechanisms of action. Arachidonate-in-
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FIGURE 5. Median change from baseline in serum TxB2 concentrations on days 1 and 8. Median baseline values were as follows (ng/mL): valdecoxib, 149; naproxen, 169; diclofenac, 119; and placebo, 139.5. *, P ⬍.05 for change from baseline versus naproxen; †, P ⬍ .05 for change from baseline v diclofenac; ‡, P ⬍.05 for change from baseline versus placebo.
duced aggregation is accomplished entirely through the production of TxA2 by COX-1, whereas collagen-induced aggregation is only partially dependent on this process, and ADP achieves platelet aggregation in a way completely unrelated to the COX-1 pathway.23 Bleeding time is a useful clinical marker of platelet aggregation but can be difficult to interpret because of high variability in the data. The lack of an observable effect of valdecoxib on the bleeding time throughout the study period is consistent with the absence of an effect of valdecoxib on platelet function. Although the marked variability in bleeding time resulted in reduced power for statistical significance being very limited, bleeding times for subjects receiving naproxen were consistently numerically higher than for valdecoxib and placebo and were significantly different at 8 hours postdose on day 1. This indicates that naproxen may have a clinically important antiplatelet effect and hence the potential to increase the risk of surgical bleeding. The lack of an effect of diclofenac on bleeding time observed in this study is consistent with the findings of other studies and its smaller effect on platelet function compared with other conventional NSAIDs, such as naproxen.24,25 In this study, TxB2 was used as a surrogate marker of platelet TxA2 because it is a stable and easily measured metabolite of TxA2.26 Median serum TxB2 showed little change in the valdecoxib and placebo groups but was significantly decreased in the naproxen group relative to both valdecoxib and placebo. The TxB2 reductions for diclofenac were less marked than for naproxen. These data, when taken together, confirm that, in contrast to conventional NSAIDs, valdecoxib is COX-1 sparing. All treatments were well tolerated, and there were no serious adverse events reported. None of the very small proportion of clinically relevant changes in hematology
(hematocrit, hemoglobin, neutrophil and eosinophil counts), urinalysis (erythrocyte and white blood cell numbers, protein, creatinine and sodium), and serum calcium laboratory values within each treatment group were considered by the investigator to be treatment related. Ideally, clinical assessments of platelet function should include both biochemical and clinical endpoints. Coordinated assessments of arachidonate-, collagen-, and ADPinduced platelet aggregation; bleeding time; and TxB2 production have become useful predictors in evaluating platelet responses to various agents. Although these surrogate markers have not been explicitly linked with a significantly increased risk of bleeding episodes, treatment with conventional NSAIDs that result in reproducible platelet dysfunction has been associated with extensive blood loss in a number of studies.7-9 Other clinical problems associated with platelet dysfunction include increased bruising, spontaneous internal bleeding, and unexplained anemia. The anemia may, in some cases, be a dual effect of conventional NSAIDs. First, NSAIDs can produce GI mucosal injury that does not manifest as an overt bleeding ulcer. Second, these GI lesions may then lead to chronic, low-grade blood loss exacerbated by NSAID-induced platelet dysfunction. In addition to its role in maintaining normal platelet function, COX-1 is responsible for the production of prostaglandins that protect the gastric mucosa by a number of interrelated mechanisms including reduction of acid secretion, stimulation of mucus secretion, and maintenance of mucosal blood flow.7 The clinical effects of NSAID-induced platelet dysfunction manifest as increased mucosal bleeding, such as from GI tract lesions, prolonged bleeding with surgery, and an additive risk of significant bleeding in patients taking anticoagulants.2,8,27 A recent endoscopy
LEESE ET AL ■ PLATELET EFFECTS OF VALDECOXIB VERSUS 2 NSAIDS
study of valdecoxib’s GI safety has shown effects similar to placebo with regard to gastric mucosal damage.18 In conclusion, this study shows that, in contrast to standard doses of the conventional NSAIDs, naproxen, and diclofenac, a supratherapeutic dose of valdecoxib does not compromise platelet function in healthy subjects. Therefore, the COX-2 specific inhibitor, valdecoxib, is potentially safer than conventional NSAIDs in the management of perisurgical pain, particularly in patients at increased risk of bleeding (ie, those with GI ulceration or those receiving anticoagulants). REFERENCES 1. Paulus HE: FDA arthritis advisory committee meeting: serious gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs, etc. Arthritis Rheum 1988;31:1450-1451 2. Garcia-Rodriguez LA, Jick H: Risk of upper gastrointestinal bleeding and perforation associated with nonsteroidal anti-inflammatory drugs. Lancet 1994;343:769-772 3. Cronberg S, Wallmark E, Soderberg I: Effect of platelet aggregation of oral administration of 10 nonsteroidal analgesics to humans. Scand J Haematol 1984;33:155-159 4. Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature 1971;231:232-235 5. Kargman S, Charleson S, Cartwright M, et al: Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey and human gastrointestinal tracts. Gastroenterology 1996;111:445-454 6. Grossman CJ, Wiseman J, Lucas FS, et al: Inhibition of constitutive and inducible cyclooxygenase activity in human platelets and mononuclear cells by NSAIDs and Cox-2 inhibitors. Inflamm Res 1995;44:253-257 7. Funk CD, Funk LB, Kennedy ME, et al: Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment. FASEB J 1991;5:23042312 8. Gallagher JE, Blauth J, Fornadley JA: Perioperative ketorolac tromethamine and postoperative hemorrhage in cases of tonsillectomy and adenoidectomy. Laryngoscope 1995;105:606-609 9. Conrad K, Fagan T, Mackie M, et al: Effects of ketorolac tromethamine on hemostasis in volunteers. Clin Pharmacol Ther 1988;43:542-546 10. Spowart K, Greer A, McLaren, et al: Haemostatic effects of ketorolac with and without concomitant heparin in normal volunteers. Thromb Haemost 1988;60:382-386 11. Bashein G, Nessly ML, Rice AL, et al: Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery. Arch Intern Med 1991;151:89-93 12. Simon LS, Weaver AL, Graham DY, et al: Anti-inflammatory
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and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. A randomized controlled trial. JAMA 1999;282:1921-1928 13. 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: 1520-1528 14. Silverstein FE, Faich G, Goldstein JL, et al: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. JAMA 2000;284:1247-1255 15. Williams GW, Ettlinger RE, Ruderman EM, et al: Treatment of osteoarthritis with a once-daily dosing regimen of celecoxib. J Clin Rheum 2000;6:65-74 16. Investigational brochure for SC-65872 (valdecoxib). Pharmacia Corporation. Document No. N91-99-41-900, March 12, 1999 17. Talley J, Brown DL, Carter JS, et al: 4-[5-methyl-3-phenylisoxazol-4-yl]-benzenesulfonamide, valdecoxib: a potent and selective inhibitor of COX-2. J Med Chem 2000;43:775-7 18. Goldstein J, Fakouhi KM, Zhao W, et al: Reduced incidence of gastroduodenal ulcers with valdecoxib compared to ibuprofen and diclofenac in patients with osteoarthritis: a multicenter trial. Poster 2561 presented at Digestive Disease Week, May 22, 2001, Atlanta, GA 19. Lethagen S, Kling S: New bleeding time devices with retractable blades evaluated in children, healthy volunteers and patients with prolonged bleeding time. Thromb Haemost 1993;70:595-597 20. Born GVR, Cross MJ: The aggregation of blood platelets. J Physiol 1963;168:178-195 21. Reinke M: Monitoring thromboxane in body fluids: A specific ELISA for 11-dehydrothromboxane B2 using a monoclonal antibody. Am J Physiol 1992;262:E658-662 22. Leese PT, Hubbard RC, Karim A, et al: Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 2000;40: 124-132 23. Packham MA, Mustard JF: Normal and abnormal platelet activity. In Lasslo A, (ed). Blood Platelet Function and Medicinal Chemistry. New York, Elsevier Biomedical, 1984, pp 61-128 24. Laitinen J, Nuutinen LS, Puranen J, et al: Effect of a nonsteroidal anti-inflammatory drug, diclofenac, on haemostasis in patients undergoing total hip replacement. Acta Anaesthesiol Scand 1992;36:486-489 25. Niemi TT, Taxell C, Rosenberg PH: Comparison of the effect of intravenous ketoprofen, ketorolac and diclofenac on platelet function in volunteers. Acta Anaesthesiol Scand 1997;41:1353-1358 26. Sametz W, Hummer K, Butter M, et al: Formation of 8-isoPGF(2alpha) and thromboxane A(2) by stimulation with several activators of phospholipase A(2) in the isolated human umbilical vein. Br J Pharmacol 2000;131:145-151 27. Gabriel SE, Jaakimainen L, Bombardier C: Risk for serious gastrointestinal complications related to the use of nonsteroidal anti-inflammatory drugs: A meta-analysis. Ann Intern Med 1991; 115:787-796