CLINICAL RESEARCH: INTERVENTIONAL CARDIOLOGY
Optimal suppression of thromboxane a2 formation by aspirin during percutaneous transluminal coronary angioplasty: no additional effect of a selective cyclooxygenase-2 inhibitor
Dermot Kearney, MD*,
Anthony Byrne, MD*,
Peter Crean, MD, FRCPI ,
Dermot Cox, PhD* and
Desmond J. Fitzgerald, MD, FRCPI*,*
* Department of Clinical Pharmacology, RCSI, Dublin, Ireland
Department of Cardiology, St. James' Hospital, Dublin, Ireland
Manuscript received January 19, 2003;
revised manuscript received September 22, 2003,
accepted September 26, 2003.
* Reprint requests and correspondence: Prof. Desmond J. Fitzgerald, Dept. of Clinical Pharmacology, Royal College of Surgeons in Ireland, 123, St. Stephen's Green, Dublin 2, Ireland.
dfitzgerald{at}rcsi.ie
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Abstract
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OBJECTIVES: We examined the contribution of cyclooxygenase (COX)-1 and -2 to the generation of prostacyclin, thromboxane (Tx) A2, and 8-epi prostaglandin (PG) F2 during percutaneous transluminal coronary angioplasty (PTCA).
BACKGROUND: Both TxA2 and 8-epi PGF2 activate platelets and are mitogenic, whereas prostacyclin is a platelet inhibitor, and therefore may influence the outcome of PTCA.
METHODS: Twenty-one patients undergoing PTCA while receiving aspirin 300 mg daily or aspirin plus the selective COX-2 inhibitor nimesulide were compared with 13 patients treated only with fradafiban, a glycoprotein IIb/IIIa antagonist. Urine was analyzed for the metabolites of TxA2 (Tx-M) and prostacyclin (PGI-M) and for the isoprostane, 8-epi PGF2.
RESULTS: In the fradafiban group, there was a marked increase in Tx-M during PTCA (mean, 1,973; 95% confidence interval [CI] 112 to 3,834 rising to mean 7,645; 95% CI 2,009 to 13,281 pg/mg creatinine, p = 0.018). The Tx-M excretion was similarly reduced by aspirin and the combination of aspirin and nimesulide. In contrast, the combination of nimesulide and aspirin inhibited PGI-M excretion to a greater extent than aspirin (p = 0.001). Urinary 8-epi PGF2 excretion was elevated following PTCA compared with normal subjects (p = 0.002) and appeared to be unaffected by any of the treatments.
CONCLUSIONS: The increase in TxA2 during PTCA is primarily COX-1 dependent, and aspirin alone is effective in suppressing its formation. In contrast, prostacyclin generation is both COX-1 and COX-2 dependent. The inhibition of COX-1 and COX-2 did not prevent the production of 8-epi PGF2, suggesting that this is not enzymatically derived. The persistent generation of 8-epi PGF2 may contribute to the thrombosis and restenosis that complicate PTCA.
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Abbreviations and Acronyms
| | COX | = cyclooxygenase | | GP | = glycoprotein | | MI | = myocardial infarction | | NSAID | = non-steroidal anti-inflammatory drug | | PG | = prostaglandin | | PGI2 | = prostacyclin | | PGI-M | = 2,3 dinor-6-keto-PGF1 | | PTCA | = percutaneous transluminal coronary angioplasty | | Tx | = thromboxane | | Tx-M | = 11-dehydro-TxB2 |
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Prostaglandins (PGs) and isoprostanes are products of arachidonic acid that are important regulators of platelet and vascular function (1,2). The principal platelet product, thromboxane A2 (TxA2), is a potent vasoconstrictor and smooth muscle cell mitogen that promotes platelet aggregation (3–6). Prostacyclin (PGI2), the main product ofvascular endothelium, prevents platelet aggregation and is a potent vasodilator (7). Formation of these products is regulated by the enzyme cyclooxygenase (COX) of which there are two isoforms: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) (8,9). The COX-1 isoform is found in all tissues and is the "constitutive" form of the enzyme (9). Thromboxane formation is largely derived from COX-1 expressed in platelets (10). The COX-2 isoform is largely absent from most tissues, but is induced by free radicals, growth factors, and cytokines (11–14); COX-2 is expressed in a variety of conditions, including the synovial tissues of acutely inflamed joints (15) and in the majority of patients with colonic carcinoma (16). Curiously, studies with selective COX-2 inhibitors suggest that PGI2 is generated largely through COX-2 in normal subjects (17,18). Isoprostanes are analogues of PGs formed largely by free radical attack on arachidonic acid (2,19), although they are also generated in vitro by both COX isoforms (20,21). Some of these compounds, such as the isoprostane 8-epi PGF2 (also known as iPF2-III), have biological activity similar to TxA2 (2).
Generation of prostaglandins and isoprostanes is enhanced in human atherosclerosis (10,22–24). In particular, there is a marked rise in both TxA2 (25,26) and 8-epi PGF2 (27) in patients undergoing coronary angioplasty that could contribute to the risk of thrombosis and restenosis. It is assumed that most of the TxA2 formed is generated by platelet COX-1 and therefore sensitive to aspirin, which is more selective for COX-1 (28). Indeed, aspirin has proved effective in reducing the risk of coronary thrombosis during percutaneous transluminal coronary angioplasty (PTCA) (29). However, previous studies have suggested that COX-2 may contribute to the generation of TxA2 in patients with unstable angina (10); COX-2 is expressed in atherosclerotic tissue, where it is localized to inflammatory and vascular smooth muscle cells (30), both of which are capable of generating TxA2. Moreover, vascular COX-2 may generate prostaglandin endoperoxides that are then metabolized by adhering platelets to TxA2, bypassing the need for platelet COX-1 (31).
In this study, we explored the effects of selective COX-2 inhibition on TxA2 and 8-epi-PGF2 formation in 21 patients undergoing PTCA. Each of these patients was treated with aspirin 300 mg once daily before the procedure. The patients were randomized to receive nimesulide in addition to aspirin, at a dose that is highly selective for inhibition of COX-2 (17). In this way, the contribution of COX-2 to any residual TxA2 would be detected. The results were compared with those from a separate group of patients undergoing PTCA who were receiving neither aspirin nor nimesulide. The patients in this group had PTCA performed while on fradafiban, a glycoprotein (GP) IIb/IIIa receptor antagonist (25). These patients were randomized to either fradafiban or aspirin as part of a concurrent study exploring the effects of these agents on TxA2 formation (25). For ethical reasons, no control group undergoing PTCA without an anti-platelet treatment could be considered for the study.
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Methods
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Patients.
The study was approved by the Ethics Committee of St. James' Hospital, Dublin. Each patient gave written informed consent prior to randomization. Twenty-one patients undergoing elective PTCA, who were already receiving aspirin 300 mg daily, were randomized to either continue on this treatment alone or to receive, in addition, nimesulide 100 mg twice daily. Patients who had received any other non-steroidal anti-inflammatory drug (NSAID) or systemic steroid therapy within the previous 10 days were excluded from the study. Other exclusion criteria were a history of either unstable angina or myocardial infarction (MI) within the previous 14 days, significantly abnormal baseline renal or hepatic function, or any contraindication to anti-platelet or NSAID therapy. All patients were allowed to continue all other prescribed medications, including calcium-channel receptor antagonists, nitrates, beta-adrenergic blockers, HMG Co-A reductase inhibitors, and angiotensin-converting enzyme inhibitors, which were not disallowed by the study protocol. Eleven patients received aspirin alone, and 10 patients received the combined therapy. Nimesulide was commenced on the day before the PTCA, with two doses given prior to the procedure and continued for 48 hours (four additional doses) after the procedure.
Biochemical analysis.
Spot urine samples were collected from each patient prior to PTCA. After PTCA, total urine collections from each patient were performed over the following time intervals: 0 to 6 h, 6 to 12 h, 12 to 24 h, and 24 to 36 h postintervention. The collected urine samples were divided into aliquots and stored at –20° C until analyzed. Each urine specimen was tested for levels of the stable metabolites of TxA2 and PGI2, namely 11-dehydro TxB2 (Tx-M) and 2,3 dinor-6-keto-PGF1 (PGI-M), respectively (22). All specimens were also analyzed for 8-epi PGF2 (27). Quantitation was by gas chromatography/mass spectrometry, as previously described (25,27). Briefly, samples were labeled with known amounts of deuterated internal standard for each of these three compounds. After solid-phase extraction, the samples were dried and re-suspended in 50 µl of methoxyamine overnight at room temperature. Following successive thin-layer chromatography, the samples were derivatized to the pentafluorobenzyl (PFB) ester, tri-methylsilyl- (Tx-M and PGI-M) or t-butyldimethylsilyl- (8-epi PGF2) ethers. The samples were analyzed by gas chromatography, negative-ion, chemical ionization, mass spectrometry using a Varian 1077 gas chromatograph coupled to a Finnegan Mat INCOS XL mass spectrometer. The values were expressed as pg/mg creatinine to correct for the volume of urine collected.
Patients in the fradafiban group (n = 13) also underwent coronary angioplasty. These patients had not received aspirin or any other NSAID for at least 10 days prior to the initial urine sample collection. None of these patients received nimesulide. Their PTCA was performed under cover of fradafiban, a GP IIb/IIIa receptor antagonist (25). Based on the findings of a previous dose-ranging study, each of these patients received a bolus intravenous dose of 15 mg over 30 min, followed by a continuous infusion rate of 2.09 mg/h for 23.5 h. Infusion of drug commenced at least 1 h before PTCA. Urine samples were collected from these patients at the same intervals as for the patients in the aspirin and aspirin plus nimesulide groups, and samples were stored and analyzed for the same products (with the exception of PGI-M).
A control group (n = 11) consisting of normal individuals with no history of atherosclerosis was also studied. None of these subjects had taken any steroids, aspirin, or other NSAID medications for at least 10 days prior to giving a single (spot) urine sample. These urine collections were also analyzed for Tx-M, PGI-M, and 8-epi PGF2.
Statistical analysis.
The data are expressed as the mean with the 95% confidence interval. Data were analyzed with Stata release 8, using a generalized linear models approach in which a log link function was used to take into account the log normal distribution of the dependent variables. Dummy terms were used for each time point with the baseline being the omitted category. Dummy terms were likewise used for the fradafiban and nimesulide plus aspirin data, with aspirin alone being the omitted category. Robust standard errors were calculated using Huber-White sandwich estimators to account for the lack of independence of values within patients (32).
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Results
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The patient and control groups are described in Table 1.
Thromboxane biosynthesis.
Urinary Tx-M was elevated in the fradafiban group not treated with aspirin prior to the procedure compared with normal controls (mean 1,973; 95% confidence interval [CI] 112 to 3,834 vs. mean 552; 95% CI 454 to 650 pg/mg creatinine, p < 0.05). There was a marked rise in Tx-M after PTCA to a peak of mean 7,645; 95% CI 2,009 to 13,281 pg/mg creatinine at 6 to 12 h after the procedure in comparison with aspirin (p < 0.0001). Subsequently, Tx-M levels returned toward the pre-PTCA value. The excretion of Tx-M was markedly reduced in the aspirin group relative to the patients treated with fradafiban (overall comparison p < 0.0001). In the aspirin-alone group, urinary Tx-M was reduced prior to PTCA, less than the levels that are seen in non-cardiac patients (mean 291; 95% CI 221 to 361 vs. mean 552; 95% CI 454 to 650 pg/mg creatinine, p < 0.0001) and there was no rise in Tx-M following PTCA. In the patients who received both nimesulide and aspirin, urinary Tx-M was similar to that seen in the aspirin-alone group before PTCA (mean 354; 95% CI 177 to 885 pg/mg creatinine, p = 0.318) and no further increase was seen as a result of the procedure (Fig. 1).
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Figure 1 Urinary excretion of 11-dehydro thromboxane B2 (Tx-M) in patients on fradafiban alone, aspirin alone, or aspirin plus nimesulide prior to and at selected intervals during and following percutaneous transluminal coronary angioplasty (PTCA). Urinary Tx-M was higher in the fradafiban group prior to PTCA than in normal subjects (p < 0.05) and increased markedly during the procedure compared with aspirin alone (p < 0.0001).
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Urinary 8-epi PGF2.
Urinary 8-epi PGF2 was similar in all three patient groups before coronary angioplasty and marginally, but not significantly higher than in the normal subjects (mean 255; 95% CI 203 to 307 pg/mg creatinine). After the procedure, there was a small (although not significant) rise in all treatment groups. In the fradafiban group, which did not receive aspirin, urinary 8-epi PGF2 reached a peak of mean 719; 95% CI 230 to 1,668 pg/mg creatinine at 6 to 12 h after PTCA (p = 0.21). In the aspirin-alone group, the peak observed in the first 6 h was mean 503; 95% CI 361 to 645 pg/mg creatinine, and in the aspirin plus nimesulide group, the peak was mean 852; 95% CI 269 to 1,099 pg/mg creatinine. Although there was no significant change in the groups individually, when all three groups were considered together the level of urinary 8-epi PGF2 was elevated following PTCA compared to normal subjects (p = 0.002) (Fig. 2).
PGI2 biosynthesis.
Previous studies have shown that PGI2 is largely generated by COX-2 in man (17,18). In this study, PGI2 biosynthesis was used to assess the biological effect of adding nimesulide to aspirin. In the normal control group the level of urinary PGI-M excretion was mean 132; 95% CI 84 to 180 pg/mg creatinine. The addition of nimesulide caused a significant drop in PGI2 formation compared with aspirin alone prior to PTCA (mean 96; 95% CI 83 to 109 vs. mean 25; 95% CI 2 to 48 pg/mg creatinine, p = 0.018). Overall, urinary 2,3 dinor-6-keto-PGF1 excretion was lower in patients receiving aspirin plus nimesulide compared to aspirin alone over the period of sampling following PTCA (p = 0.001) (Fig. 3).
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Figure 3 Urinary excretion of 2,3 dinor-6-keto-PGF1 (PGI-M) in patients on aspirin or aspirin and nimesulide prior to and at selected intervals during and following percutaneous transluminal coronary angioplasty (PTCA). The addition of nimesulide caused a significant drop in PGI-M formation compared to aspirin alone prior to (p = 0.018) and over the period of sampling after PTCA (p = 0.001).
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Discussion
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Several studies have reported an increase in TxA2 and 8-epi PGF2 in cardiovascular diseases, including atherosclerosis and in patients undergoing PTCA (10,22–27,30). The increase in TxA2 formation has been attributed to platelet COX-1 on the basis of the response to low-dose aspirin. However, in a study of patients with unstable angina (10), aspirin suppressed incompletely the excretion of 11-dehydro-TxB2. Addition of indobufen, which is both a COX-1 and a COX-2 inhibitor, suppressed the generation of TxA2 further. The investigators suggested that a component of the TxA2 generated in these patients may have been generated by COX-2 (10). Consistent with this hypothesis, COX-2 is expressed in atherosclerotic plaque (33). Moreover, we have recently demonstrated that COX-2 is induced in the proliferating smooth muscle cells of rat carotid arteries after balloon angioplasty has been performed (34). In this model, there is an increase in TxA2 formation, much of which is suppressed by a selective COX-2 inhibitor.
The COX-2-derived TxA2 may explain the failure of aspirin to prevent thrombosis in many patients with coronary artery disease. Although it inhibits both COX isoforms, aspirin is more selective for COX-1 (28). Indeed, at low doses, aspirin primarily inhibits platelets, where the predominant isoform is COX-1 (9,35). We explored whether there was COX-2–dependent TxA2 formation in patients undergoing PTCA where aspirin has proved to be effective (29), but where thrombosis and restenosis are still significant problems. As it would not be possible to withhold antithrombotics during PTCA, all patients were treated with aspirin, and half of them also received nimesulide. We have previously shown that nimesulide is a potent inhibitor of COX-2 (17), inducing >90% inhibition of endotoxin-induced COX-2 activity in whole blood. In vivo, nimesulide is highly selective for COX-2 at the dose used in the present study, with little effect on prostaglandins generated by platelets or in gastric biopsies, where COX-1 predominates (36).
In our study, the increase in PGI2 formation reported to occur during coronary angioplasty (26) was inhibited by aspirin alone. The inhibition of PGI2 formation was accentuated by the addition of nimesulide, suggesting that COX-2 plays a role in the generation of PGI2 following PTCA. This is not surprising as PGI2 is largely generated by COX-2 in normal subjects (17,18) and in patients with atherosclerosis (35). Despite the inhibition of COX-2 by nimesulide, there was no additional effect on TxA2 formation compared to aspirin alone. Thus, COX-2 does not contribute to the formation of TxA2 in patients undergoing coronary angioplasty.
Urinary 8-epi PGF2 excretion is increased in atherosclerosis (37,38) and increases following coronary angioplasty in patients with MI, where reperfusion injury may contribute to its biosynthesis (27). Studies in a transgenic mouse model where atherosclerosis occurs following disruption of the apo-E gene showed a marked increase in the level of 8-epi PGF2 in atherosclerotic plaque (37). In this model, the generation of isoprostanes was suppressed by the anti-oxidant vitamin E. The results are consistent with the original description of isoprostanes as free-radical-derived products of arachidonic acid (2,19). However, several groups have reported that 8-epi PGF2 can also be generated by both isoforms of COX (20,21).
In the current study, urinary 8-epi PGF2 was elevated throughout the sampling period compared to that seen in normal subjects, although this was highly variable. No temporally distinct rise was seen as reported in patients undergoing PTCA for acute MI (27), where there was an abrupt increase at 6 h, possibly as a consequence of a more extensive reperfusion injury. Nevertheless, the persistent generation of 8-epi PGF2 in patients undergoing coronary angioplasty is potentially important, as 8-epi PGF2 is biologically active (2,19), yet may not be susceptible to inhibition by aspirin. Indeed, in our study, a combination of aspirin and nimesulide that potently inhibited both COX-1 and COX-2, as demonstrated by the suppression of TxA2 and PGI2 formation, failed to inhibit the generation of 8-epi PGF2. The findings suggest that 8-epi PGF2 is formed largely in a non-enzymatic fashion in these patients, consistent with the hypothesis that isoprostanes are primarily free-radical-derived products. However, given the small sample size and large individual variation in the data, and the tendency for 8-epi PGF2 to rise in the numesulide plus aspirin group, we cannot exclude an enzymatic component to the generation of this product, as previously suggested (20,21).
Study limitations.
A number of limitations in this study should be noted. As can be seen in Table 1, the number of stents deployed in the aspirin-alone and combination therapy groups was similar at 6 of 11 and 4 of 10, respectively. No stents were deployed in the control fradafiban group (n = 13). Whether stenting, either elective or "bailout," and balloon angioplasty differ in their effects on eicosanoid generation is unknown. Furthermore, although there were no serious complications such as failed procedure, acute or subacute vessel occlusion, or major adverse cardiovascular events reported, other post-intervention complications, including minor bleeding events, hematoma formation at the site of sheath insertion, or creatine kinase elevations, were not recorded. The exact locations of treated lesions were not recorded, although, in each case, only one lesion was treated. It is possible that such events and clinical circumstances could influence eicosanoid generation and contribute to differences in the product levels among the different groups. Nevertheless, the levels of the measured products post-PTCA and the effect of aspirin on PGI2 and TxA2 levels are consistent with findings in similar studies (25–27).
Conclusions.
First, optimal suppression of TxA2 is achieved with the use of aspirin alone during PTCA. The addition of a selective COX-2 inhibitor does not result in any additional suppression of TxA2 generation. Indeed, this has the potentially negative effect of suppressing PGI2 generation. Second, formation of 8-epi PGF2 persists even with potent COX inhibitors, and this may contribute to the thrombosis and restenosis that can complicate PTCA.
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Footnotes
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Supported by grants from the Health Research Board (HRB) and Higher Education Authority of Ireland. Dr. Kearney was an HRB Clinical Postdoctoral Fellow during the performance of this work.
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