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Anesth Analg 2007; 105:1793-1804
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000286229.05723.50
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ANALGESIA

Cardiovascular Thromboembolic Adverse Effects Associated with Cyclooxygenase-2 Selective Inhibitors and Nonselective Antiinflammatory Drugs

Girish P. Joshi, MBBS, MD, FFARCSI*, Ralph Gertler, MD{dagger}, and Ruth Fricker, MD{ddagger}

From the *Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, Dallas, Texas; {dagger}Institute of Anesthesiology and Intensive Care, German Heart Centre of the State of Bavaria and the Technical University Munich; and {ddagger}Pfizer GmbH, Karlsruhe, Germany.

Address correspondence and reprint requests to Girish P. Joshi, MBBS, MD, FFARCSI, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9068. Address e-mail to girish.joshi{at}utsouthwestern.edu.

Abstract

BACKGROUND: Concerns of increased cardiovascular (CV) thromboembolic adverse effects from nonsteroidal antiinflammatory drugs (NSAIDs, both nonselective [NS]-NSAIDs and cyclooxygenase [COX]-2 selective inhibitors) have prevented their use despite numerous benefits.

METHODS: In this descriptive review, we critically examine the randomized, active- and placebo-controlled studies, observational trials, and meta-analyses evaluating the CV adverse effects associated with long-term and short-term use of COX-2 selective inhibitors and NS-NSAIDs. The potential mechanisms for these CV effects are also presented.

RESULTS: Although the studies evaluating the CV risks have limitations, there appears to be an increased CV risk with both COX-2 selective inhibitors and NS-NSAIDs, particularly in high-risk patients. Therefore, the United States Food and Drug Administration has given a similar "boxed" warning highlighting the potential for increased risk of CV events associated with their use. Nevertheless, there are differences in the CV risks between COX-2 selective inhibitors (e.g., higher CV risk with rofecoxib than celecoxib) as well as differences in the CV risks between individual NS-NSAIDs (e.g., higher CV risks with diclofenac than naproxen).

CONCLUSIONS: Until long-term, prospective, randomized, adequately powered, clinical studies in relevant patient populations have been completed, the CV risks associated with the use of NSAIDs, especially in high-risk patients, will likely continue to be controversial. Nevertheless, the benefits of their short-term (e.g., perioperative) use in patients without CV risks probably outweigh their potential CV adverse effects. Finally, careful risk/benefit assessment should be undertaken and both COX-2 selective inhibitors and NS-NSAIDs should be used with caution in patients with CV risk factors.

Pain is a complex and multifactorial phenomenon, and therefore, requires multimodal therapy (1). The potential advantages of nonsteroidal antiinflammatory drugs (NSAIDs, both nonselective [NS]-NSAIDs and cyclooxygenase [COX]-2 selective inhibitors) include attenuation of the inflammatory pain response and prevention of peripheral and central sensitization, improved analgesia, opioid sparing, and a reduction of opioid-related side effects (1,2). However, the concerns of the cardiovascular (CV) thromboembolic effects (i.e., myocardial infarction [MI] and stroke) of NSAIDs have prevented their use even when they would be indicated (1–3). This descriptive review examines the potential CV thromboembolic adverse effects associated with long-term and short-term use of NS-NSAIDs and COX-2 selective inhibitors, and discusses the potential mechanisms for these CV effects.

CV THROMBOEMBOLIC EVENTS WITH LONG-TERM USE

Long-Term, Randomized, Active-Controlled, Arthritis Studies
Concern regarding the increased risk of CV thromboembolic events associated with COX-2 selective inhibitors was originally hypothesized by FitzGerald et al. (4) who suggested that selective blockade of the COX-2 enzyme might predispose patients to increased CV risk. These concerns were further compounded when a secondary post hoc analysis of the vioxx gastrointestinal outcomes research (VIGOR) study (5) showed the incidence of CV thromboembolic events to be significantly higher in the rofecoxib 50 mg daily group compared with the naproxen 500 mg bid group after 9 mo of treatment in patients with rheumatoid arthritis (RA) (Table 1). However, the celecoxib long-term arthritis safety study (CLASS) found that celecoxib 400 mg bid was not associated with a significant increase in CV thromboembolic events compared with NS-NSAIDs (diclofenac 75 mg bid or ibuprofen 800 mg tid) in patients with osteoarthritis (OA) or RA (6). In contrast to the VIGOR study, in which aspirin use was prohibited, approximately 22% patients in each treatment group in the CLASS received small-dose aspirin (≤325 mg daily). An analysis of data from the nonaspirin-user population in the CLASS (6) showed there was also no significant difference in CV thromboembolic events with celecoxib use compared with NS-NSAID use. A large randomized study, the therapeutic arthritis research and gastrointestinal event trial (TARGET) study, also demonstrated no statistically significant increased risk of CV thromboembolic events with lumiracoxib (a new COX-2 selective inhibitor) use compared with NS-NSAID use (7,8). In the TARGET study, 24% of patients in both the lumiracoxib and NS-NSAID treatment groups used small-dose aspirin (≤325 mg daily).


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  		Table 1. COX-2 Selective Inhibitor Use and Risk of CV Events in Large Randomized Studies in Patients with OA and RA

 

These studies are limited because they were not designed or adequately powered to evaluate CV risk, and because the CV thromboembolic events were evaluated as secondary end points. Furthermore, the majority of the patients included in these studies was not considered to be at high risk for CV events.

Retrospective Observational Studies
A number of retrospective observational studies have evaluated the CV profile of COX-2 selective inhibitors and NS-NSAIDs in a setting more akin to the "real-world." However, these studies have provided varying results, with a decrease in risk observed in some studies and an increase in risk observed in others (Table 2). In a nested case-control study involving more than 1.4 million controls and NSAID users aged 18 to 84 yr enrolled in the Kaiser Permanente managed care organization in California, rofecoxib >25 mg/d was associated with a threefold higher increase in the incidence of acute MI and sudden cardiac death compared with celecoxib users or NSAID nonusers (9). However, in a population-based, retrospective cohort study in more than 166,000 cases and controls aged ≥66 yr using administrative health care databases in Ontario, Canada, rofecoxib, celecoxib, and NS-NSAIDs did not increase the short-term risk of acute MI compared with nonuse of NSAIDs controls (10).


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  		Table 2. COX-2 Selective Inhibitor Use and Risk of CV Events in Observational and Case-Control Studies

 


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  		Table 2. Continued

 
A large, matched case-control study evaluated the relative risk (RR) of acute MI among users of celecoxib, rofecoxib, and NS-NSAIDs in Medicare beneficiaries with a comprehensive drug benefit (11). This study, which included 54,475 patients aged ≥65 yr, found that use of rofecoxib was associated with an increased RR of acute MI compared with celecoxib (RR, 1.24 [95% CI, 1.05–1.46]; P = 0.001). In addition, naproxen and indomethacin were associated with an increased risk of severe CV events. In a further retrospective cohort study of the Tennessee Medicaid program, the RR of hospital admission for acute MI or cardiac death in nonusers of antiinflammatory drugs was similar to those taking NS-NSAIDs, celecoxib, or rofecoxib (≤25 mg) (12). However, rofecoxib at doses of >25 mg was associated with an increased incidence of acute MI or cardiac death (12).

Further, in a population-based, nested case-control study of elderly patients (mean age 62 yr) in Canada showed that compared with nonuse of NSAIDs, rofecoxib use was associated with an increased risk of acute MI that was more pronounced at higher doses; however, no increased risk of MI was observed with celecoxib or other NS-NSAIDs (13). In another nested case-control study in the United Kingdom, a significantly increased risk of MI was associated with use of rofecoxib, diclofenac, ibuprofen, and naproxen, but not celecoxib (14). A case-control study showed that the odds of nonfatal MI were greater in patients receiving rofecoxib than in those receiving celecoxib (15).

Thus, almost all observational studies have found a higher incidence of CV thromboembolic events with the use of rofecoxib (particularly at doses >25 mg) compared with celecoxib and NS-NSAIDs.

Although many observational studies have not shown an increase in the risk of CV events with celecoxib use, others have. For example, Johnsen et al. (16) used hospital discharge registries to demonstrate that the risk of hospitalization for an MI was higher in celecoxib users than nonusers of NSAIDs in a population-based, case-control study in Denmark. Of note, rofecoxib and other nonaspirin NSAIDs were also found to be associated with an increase in risk of MI (16). In a nested case-control study in a cohort of more than 486,378 patients registered in the United Kingdom General Practice Research Database with at least one prescription of a NS-NSAID, Andersohn et al. (17) showed that celecoxib, rofecoxib, etoricoxib, valdecoxib, and diclofenac all had an increased risk of acute MI compared with nonuse of NSAIDs. Of note, these studies indicate that NS-NSAIDs are also associated with a potential increase in CV risk.

The interaction between aspirin and COX-2 selective inhibitor use with respect to MI risk has only been evaluated in a few studies. In one study, the RR of MI for rofecoxib, compared with no NS-NSAID use, was similar for users and nonusers of aspirin (15). Another study showed that aspirin use reduced the RR of MI in small-dose rofecoxib users but not high-dose rofecoxib users, and that aspirin use did not affect the RR of MI in celecoxib users (13).

It should be noted that data from all these observational studies are subject to a number of limitations and should always be interpreted with caution. Studies are conducted in differing patient populations using a variety of different end points and study designs. In addition, they are subject to the potential problem of selection bias. Compared with randomized controlled trials, observational study data are perhaps less robust, but in the absence of information on CV risk from randomized controlled trials, these kinds of data can provide useful information to the scientific community.

Meta-Analyses and Systematic Reviews
The observations from the VIGOR and CLASS studies prompted the conduct of numerous meta-analyses of randomized controlled studies and retrospective cohort observational studies of COX-2 selective inhibitors (Table 3). Mukherjee et al. (18) compared the annualized MI rates for rofecoxib (0.74%) and celecoxib (0.8%) from the VIGOR and CLASS studies, respectively, with the placebo group (0.52%). Subsequent meta-analyses of randomized controlled trials of celecoxib found that there was no significant increase in the risk of Antiplatelet Trialists’ Collaboration (APTC) thromboembolic events (i.e., nonfatal stroke, nonfatal MI, and cardiac death) in patients receiving celecoxib (50–800 mg total daily dose) compared with those receiving NS-NSAIDs (diclofenac, naproxen, and ibuprofen) or placebo (19,20).


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  		Table 3. COX-2 Selective Inhibitor Use and Risk of CV Events in Meta-Analyses or Pooled Analyses of Studies

 

In another meta-analysis of 23 randomized controlled trials of patients with OA, RA, Alzheimer’s disease, or chronic low back pain, there was no evidence of increased risk of APTC thromboembolic events in patients receiving rofecoxib (12.5, 25, or 50 mg) compared with placebo or NS-NSAIDs (21). In contrast, a cumulative meta-analysis of 18 randomized controlled studies and 11 observational studies showed a significantly higher RR of CV adverse events with rofecoxib compared with celecoxib or NS-NSAIDs (22).

Recently, a pooled analysis of three trials of patients with OA and RA (n = 34,701), the Multinational Etoricoxib and Diclofenac Arthritis Long-Term Program, found no differences in the CV thromboembolic events in patients receiving etoricoxib 60–90 mg daily or diclofenac 150 mg twice daily (23).

A systematic review of 16 cohort and case-control studies, including many of those described earlier, evaluated the risk of MI in relation to both NS-NSAID and COX-2 selective inhibitor use (24). The pooled RR for MI was 0.98 (95% CI, 0.92–1.05) for naproxen, 1.07 (95% CI, 1.02–1.12) for ibuprofen, and 1.44 (95% CI, 1.32–1.56) for diclofenac. In addition, the pooled RR for MI was 0.96 (95% CI, 0.90–1.02) for celecoxib and 1.26 (95% CI, 1.17–1.36) for rofecoxib (all doses). However, there was a dose effect with rofecoxib use, in which a greater RR was observed with doses >25 mg/d than <25 mg/d, but dose effect was not seen with celecoxib.

A recent meta-analysis, which included 17 case-control studies and six cohort studies reporting on CV risks (predominantly MI) associated with COX-2 selective inhibitors or NS-NSAIDs, demonstrated that celecoxib was not associated with an increase of CV risk (RR, 1.06, 95% CI, 0.91–1.23) compared with nonuse whereas rofecoxib was associated with a dose-dependent increase in risk (25). Furthermore, diclofenac was also found to increase CV risk in this analysis (RR, 1.40, 95% CI, 1.16–1.70).

However, such meta-analyses and systematic reviews have been criticized because the studies included combined results from different trials, using different dose strengths, with differing patient populations, CV risk factors, study designs, study drug comparators, and duration of use, as well as differing use of concomitant medications.

Long-Term, Randomized, Placebo-Controlled Studies
The decision to withdraw rofecoxib from the market in September 2004 was based on the findings of the APPROVe trial (26), which showed that the risk of APTC thromboembolic events was significantly higher in patients receiving rofecoxib than those receiving placebo (RR, 1.92; P = 0.008) (Table 4). The APPROVe study was a 3-yr prospective, multicenter, randomized, double-blind, placebo-controlled clinical study designed to evaluate the efficacy of rofecoxib 25 mg compared with placebo in preventing recurrence of colorectal polyps in patients with a history of colorectal adenomas (26). The study was prematurely halted after investigators found that patients taking rofecoxib had twice the risk of CV thromboembolic events compared with patients receiving placebo (15 vs 7.8 per 1000 patients annually). The difference in the incidence of CV events was statistically significant after 18 mo. However, there was earlier separation, at 5 mo, between the two groups in the incidence of nonadjusted investigator-reported congestive heart failure, pulmonary edema, or cardiac failure. Overall, the CV mortality was similar in the two groups.


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  		Table 4. COX-2 Selective Inhibitor Use and Risk of CV Events in Randomized Placebo-Controlled Studies in Patients with Cancer and Alzheimer’s Disease

 

Analysis of long-term studies evaluating the efficacy of celecoxib in the prevention of colorectal adenomatous polyps and Alzheimer’s disease have also raised questions and concerns regarding its CV safety (27–31). Before the publication of results from the prevention of spontaneous adenomatous polyps (PreSAP), the adenoma prevention celecoxib (APC) study, and the Alzheimer’s disease antiinflammatory prevention trial (ADAPT), celecoxib (200 mg bid) was found to be associated with a small but nonsignificant increase in cardiac failure compared with placebo in a 52-wk, randomized, controlled study, completed in 1999, to determine the impact of celecoxib on Alzheimer’s disease progression (31).

In December 2004, a study conducted by the National Cancer Institute was also halted due to an increase in CV events in celecoxib users (27,28). The APC study was a placebo-controlled study designed to evaluate the effects of celecoxib 200 mg twice daily and 400 mg twice daily in preventing colorectal adenoma (27). This study demonstrated a dose-related increase in the composite end point of death from CV causes, MI, stroke, or heart failure. In contrast to the results of the APC study (29), the PreSAP study, which included patients taking celecoxib 400 mg daily (n = 933) or placebo (n = 628) did not show an increase in adjudicated deaths from CV causes, MI, stroke, or congestive heart failure with celecoxib when compared with placebo over an average treatment duration of 33 mo (RR, 1.30 [95% CI, 0.65–2.62]). Similarly, the ADAPT trial (30), in which elderly patients (aged >70 yr) at high risk of Alzheimer’s disease (n = 2400) received naproxen 220 mg twice daily, celecoxib 200 mg twice daily, or placebo for 3 yr, did not demonstrate a significant increase in the incidence of MI, stroke, or any cardiac/sudden death in patients taking celecoxib when compared with placebo (30). Of note, the final results of the CV safety analysis in the ADAPT are still pending.

It is possible that the differences in the dosing regimens (i.e., twice daily in the APC study compared with once daily in the PreSAP study) may have contributed to the increase in CV risk. In addition, differences in patient population, use of concomitant medications, and geographic differences may also have contributed to the disparity in the studies. Of note, these randomized placebo-controlled studies, similar to the large long-term randomized controlled trials (i.e., CLASS, VIGOR, and TARGET), were not designed to evaluate CV safety, and thus, the CV thromboembolic adverse events were recorded as secondary end points. Furthermore, patients were not considered to be at high risk for CV events, except in the Alzheimer’s disease study (due to patients’ ages).

CV THROMBOEMBOLIC EVENTS AFTER SHORT-TERM PERIOPERATIVE USE

There is also controversy and concern regarding the CV safety of COX-2 selective inhibitors in the perioperative setting. Findings from previous short-term studies of noncardiac surgical patients receiving COX-2 selective inhibitors have not revealed any serious CV adverse effects (2). However, two placebo-controlled studies in patients undergoing coronary artery bypass grafting (CABG) surgery reported a higher rate of postoperative CV thromboembolic events with the use of COX-2 selective inhibitors (parecoxib [an IV prodrug of valdecoxib] and valdecoxib) (Tables 5 and 6). In the first CABG study (32), the adverse events were investigator-reported, whereas in the second CABG study (33), they were predefined and adjudicated. Interestingly, in the second CABG study, 35% of the CV thromboembolic events occurred at least 2 days after all study medications had been discontinued (33). The authors concluded that in patients undergoing CABG surgery with cardiopulmonary bypass, the increased incidence of serious adverse events clearly outweighed any analgesic benefit of the COX-2 selective inhibitors. These studies led to the label change for both COX-2 selective inhibitors and NS-NSAIDs, indicating a contraindication in patients undergoing CABG surgery.


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  		Table 5. COX-2 Selective Inhibitor Use and Risk of CV Events Randomized Placebo-Controlled Studies in Postoperative Patients

 


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  		Table 6. Incidence of and Relative Risks for CV Adverse Events in Patients After CABG and Major General Noncardiac Surgery

 
In a subsequent large randomized study of patients undergoing major noncardiac surgical procedures (orthopedic, gynecologic, cancer resection, and noncardiac thoracic) that evaluated the safety of parecoxib/valdecoxib compared with placebo plus standard of care (34), the overall incidence of predefined adjudicated adverse events, including CV thromboembolic events, was similar among patients who received parecoxib/valdecoxib and placebo (Table 6). Furthermore, in contrast to the CABG studies that reported a higher incidence of sternal wound infections and healing complications in the parecoxib and valdecoxib group (32,33), the noncardiac surgery study found no differences in the incidence of wound infections. Although 33% of patients were hypertensive and 33% had hyperlipidemia, the majority of patients in the noncardiac surgery study were not at high risk for underlying atherosclerotic disease (<3% had a previous MI, <7% had a history of coronary artery disease, and <5% had a history of angina).

A post hoc pooled analysis of CV safety data from all randomized, placebo-controlled parecoxib studies in surgery (n = 19), which included the two CABG studies and 17 noncardiac surgery studies was performed to achieve the greatest statistical power (35). The data indicated that the incidence of CV adverse events after short-term (≤10 days) use of parecoxib 20–80 mg (0.44%) was similar to that with placebo (0.37%). However, patients included in the noncardiac surgery studies had a low CV risk. Therefore, further study is required to determine the safety CV profile in patients with high CV risk (e.g., previous MI, unstable angina, cardiac failure, and known or suspected atherosclerotic disease).

The differences in the observed CV adverse events between noncardiac and cardiac (i.e., CABG) surgical patients may have been due to differences in the baseline risk of patients as well as differences in the risks of surgical procedures (i.e., the risks of cardiopulmonary bypass). Patients undergoing CABG surgery have significant CV risks including preexisting generalized atherosclerotic disease, which might predispose them to CV thromboembolic adverse events. Furthermore, CABG patients are exposed to additional risks of cardiopulmonary bypass such as its effects on platelets and endothelium. In addition, the potential resistance of platelets to aspirin occurs after CABG surgery (36,37), which may explain the increased incidence of CV thromboembolic events despite co-administration of aspirin (75–325 mg daily).

The lack of observed CV adverse events with the use of COX-2 selective inhibitors in the noncardiac surgical procedures might suggest that the CV risks with their short-term use may differ from those with long-term use. In addition to the risks and benefits of NS-NSAIDs and COX-2 selective inhibitor, it is important that the risks and benefits of alternate analgesics (e.g., opioids) are also considered. Although opioids are effective in the perioperative period, they are limited by their dose-related adverse effects including nausea, vomiting, sedation, dizziness, drowsiness, and bladder dysfunction as well as reduced gastrointestinal motility and constipation, all of which may contribute to a delayed recovery and return to daily living (1). In addition, the benefits of combining antiinflammatory drugs with other analgesics including regional analgesic techniques should also be considered (1).

POSSIBLE MECHANISMS OF CV EFFECTS

The mechanisms for the apparent increase in cardiac risk associated with COX-2 selective inhibitors and NS-NSAIDs are uncertain and controversial. No hypothesis has yet been formally tested (3,38). One hypothesis initially proposed was that an imbalance of prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) production, which have crucial roles in vascular homeostasis, leads to an increased risk of CV thrombotic events in COX-2 selective inhibitor users (38,39). This hypothesis proposes that NS-NSAIDs maintain a homeostatic balance by inhibiting both COX-1 (responsible for the production of TXA2, the predominant COX product in platelets, which is a potent inducer of vasoconstriction and platelet aggregation) and COX-2 (responsible for the production of PGI2, the predominant COX product in the endothelium, which inhibits platelet aggregation, prevents smooth muscle proliferation in vitro, and induces vascular smooth muscle relaxation) (38). However, COX-2 selective inhibitors, by blocking only the vasodilatation and platelet inhibitor properties of PGI2, may increase arterial blood pressure and accelerate atherogenesis, thereby leading to thrombosis. It is also suggested that decreased PGI2 may favor thrombosis without directly interfering with platelet function.

There is no clinical evidence to support this imbalance hypothesis and, in fact, the evidence suggests that multiple mechanisms may be involved. If the hypothesis were correct, then theoretically addition of small-dose aspirin to a COX-2 selective inhibitor should resolve any increase in CV risk, but this effect has not been observed (40). In addition, this hypothesis does not explain the differences in the CV events between celecoxib and rofecoxib, or the differences in the CV events observed with NS-NSAIDs and between individual NS-NSAIDs. Furthermore, NS-NSAIDs block COX-1 and COX-2 differentially, which suggests that the observed CV effects may not be a class effect of antiinflammatory drugs (i.e., both COX-2 selective inhibitors and NS-NSAIDs). Indeed, NS-NSAIDs such as diclofenac and nabumetone have also been shown to have a CV risk of a similar magnitude to COX-2 selective inhibitors, yet they do not affect the ratio of PGI2 to TXA2, or may even shift it in favor of prostacyclin (41).

The potential differences in the observed CV events among COX-2 selective inhibitors and also between COX-2 selective inhibitors and NS-NSAIDs may be due to differences in chemical structures, pharmacokinetics, metabolism, and pharmacodynamics. Rofecoxib is a methyl sulfone, whereas celecoxib and valdecoxib are aryl sulfonamides and thus may have differential effects. Rofecoxib has been shown to promote oxidative damage to low-density lipoprotein (LDL) and phospholipids in vitro, but the sulfonamide-type COX-2 selective inhibitors, celecoxib and valdecoxib, like NS-NSAIDs (meloxicam, diclofenac, naproxen, ibuprofen), do not (42). This prooxidant activity of rofecoxib occurs in the absence of COX-2 enzyme, is dependent on rofecoxib concentration, and is attenuated in the presence of an antioxidant. Furthermore, radiographic diffraction analysis also showed that rofecoxib interacts with membrane phospholipids in a manner likely to increase permeability to free radical ions and/or free radical diffusion, whereas celecoxib does not, suggesting that such interactions tend to disrupt membrane structure and expose phospholipids to oxidative damage. This finding supports the hypothesis that rofecoxib is unique among COX-2 selective inhibitors in its ability to promote oxidative damage to both LDL and cell membranes via interaction with the outer phospholipid boundary of each, using a mechanism that does not involve COX-2 inhibition.

According to the oxidative-modification hypothesis of atherosclerosis, oxidation alters the physical and functional properties of LDL and vascular cell membrane phospholipids in a manner that promotes atherogenesis (43,44), using a mechanism that involves inflammation of the endothelium and underlying intimal tissue (45–47). Specifically, oxidative modification of LDL and membrane lipids contributes to foam cell formation and endothelial dysfunction (48), and the presence of oxidized LDL is a marker for plaque instability (49) and acute coronary syndromes (50). These observations suggest that chemical differences between COX-2 selective inhibitors of the sulfone type and the sulfonamide type, rather than the effect of COX-2 selective inhibition on PGI2 versus TXA2 balance, may account for at least some of the differences in the CV risks among antiinflammatory drugs. There is a suggestion that antiinflammatory and antiatherogenic effects, which may not have been mediated by PGI2, may also be involved (51).

In addition to PGI2, a number of other factors contribute to the regulation of vasodilatation in opposition to the vasoconstrictive effect of TXA2. Perhaps the most important of these is nitric oxide (NO), which is produced by the endothelium in response to a variety of stimuli, including increased blood flow; in animal models, NO has also been shown to modulate the activity of COX-2 (52). In atherosclerosis, inflammation of the endothelium results in diminished capacity to produce NO, and as a result, the ability to induce vasodilatation in response to increased blood flow is also diminished; thus, flow-mediated vasodilatation can be used to evaluate endothelial function, and diminished flow-mediated vasodilatation is characteristic of patients with CV disease (53). Antiinflammatory drugs may differ in their effects on endothelial function, probably through a mechanism (e.g., effects on NO production) that does not involve COX-2 inhibition (53–55).

Another possible mechanism for the differential CV effects of antiinflammatory drugs might involve arterial blood pressure increase, as a result of modulation of renal hemodynamics and tubular function by prostaglandins. In clinical studies and epidemiologic studies, differences in systolic blood pressure of this magnitude have been associated with a significantly increased incidence of MI and stroke (56–58). Antiinflammatory drugs have been shown to have different effects on the incidence in new onset hypertension (59,60).

SUMMARY

Although the studies evaluating the CV risks of COX-2 selective inhibitors and NS-NSAIDs have significant limitations, there appears to be an increased CV risk with their use, particularly in high-risk patients. Therefore, the United States Food and Drug Administration has given NS-NSAIDs and celecoxib (the only COX-2 selective inhibitor currently available in the United States) a similar "boxed" warning highlighting the potential for increased risk of CV events associated with their use and contraindication in patients undergoing CABG surgery. Nevertheless, there are differences in the CV risks between COX-2 selective inhibitors (e.g., higher CV risk with rofecoxib than celecoxib) as well as differences in the CV risks between individual NS-NSAIDs (e.g., higher CV risks with diclofenac than naproxen).

Until long-term, prospective, randomized, adequately powered, clinical studies in relevant patient populations with clinically appropriate predefined CV end points have been completed, it is critical that both COX-2 selective inhibitors and NS-NSAIDs be used with caution in patients with CV risk factors. Although the specific CV risk factors have not yet been determined, NSAIDs should be avoided in patients with previous MI, angina, cardiac failure, hypovolemia, significant peripheral vascular disease, preexisting renal dysfunction, and significant liver dysfunction. Patients receiving long-term antiinflammatory drugs should be monitored for increase in arterial blood pressure and intravascular volume overload. Importantly, careful risk/benefit assessment of the use of other analgesics (e.g., opioids) in place of NSAIDs should also be undertaken.

Although the CV risks associated with the use of COX-2 selective inhibitors and NS-NSAIDs will likely continue to be a very controversial issue, the benefits of their perioperative use (i.e., the short-term use) in patients without CV risks probably outweigh their potential CV adverse effects. Future studies as well as postmarketing surveillance should provide more information regarding the CV safety of COX-2 selective inhibitors and NS-NSAIDs, particularly in high-risk populations.

ACKNOWLEDGMENTS

The authors thank Connie Chen, PharmD, and Juliet Fawcett, PhD, for editorial help.

Footnotes

Accepted for publication July 27, 2007.

Girish Joshi has received research grants and honorarium from Pfizer Inc. Ruth Fricker is an employee of Pfizer Inc.

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