COX-2 InhibitorsStudy Populations

In evaluating randomized, controlled trials, we find a diversity of patient populations, with a wide range of risks for CV events at the baseline evaluation (from 4% to 100%) (Table 2). Even though the impact of the degree of baseline CV risk on the results is still debatable, the use of valdecoxib in CABG trials involved very-high-risk patients, and an increased CV risk was found.

Rofecoxib has demonstrated an increased CV risk in patients with RA and in patients with a history of colorectal adenomas. It has also shown an increased CV risk in patients with colorectal adenomas. However, no large, long-term, controlled trials have been done to evaluate the efficacy and safety of valdecoxib, lumiracoxib, and canadian etoricoxib in patients with RA or colorectal adenomas.

This raises an interesting question regarding specific study populations. It appears that patients with RA and a history of colorectal adenoma are at an increased risk of CV disease when they use coxibs for a long duration (more than nine months), whereas patients with OA or Alzheimer’s disease are not at an elevated risk.

RA is a significant risk factor in the development of CV disease, independent of other patient factors. Vascular endo-thelial growth factor (VEGF) can be detected in the serum, syn-ovial tissue, and fluids of patients with RA. In these patients, VEGF is a marker for angiogenesis, which allows for the formation of new blood vessels and permits a supply of nutrients and oxygen that helps with the perpetuation of synovitis. In several reports, VEGF concentrations were elevated in the serum of RA patients compared with healthy controls and OA patients. VEGF concentrations appear to be higher in patients with early RA and correlate well with disease activity and severity.

Similar findings have been published regarding patients with colorectal cancer. As normal tissue progresses to become an adenoma, to nonmetastatic cancer, and then to metastatic cancer, the concentration of VEGF continues to increase. In patients with only colorectal adenomas, however, there is debate about the significance of VEGF concentrations.

Although increased VEGF levels are observed in patients with RA and colorectal adenomas, these levels are not significantly elevated in uncomplicated cases of either OA or Alzheimer’s disease. Therefore, VEGF may play an important role in the development of CV consequences, as observed with coxib use. silagra tablets

Ideally, when coxibs are used, the level of COX-2 enzyme expression is increased; this is directly related to the inflammatory component of the disease state studied. In cancer patients, COX-2 has been recognized as an upstream stimulator of VEGF production and is beneficial for maintaining endothelial cell integrity (Figure 3).

Figure 3 The COX-2 enzyme stimulates tumor

Figure 3 The COX-2 enzyme stimulates tumor angiogenesis by activating multiple pathways. It is responsible for converting arachidonic acid to prostaglandin H2 (PGH2), which is later converted to PGE2, PGI2,and thromboxane A2 (TXA2).PGE2 leads to the production or activation of vascular endothelial growth factor (VEGF), survival signal pathway (Akt), anti-apoptotic pathway (BcI-2), vascular integrin (avp3), matrix metalloproteinase (MMP-2 and MMP-9), interleukin-12 (IL-12), IL-8, and epidermal growth factor-receptor (EGF-R). PGI2 leads to an increase in endothelial cell (EC) sprouting and vascular permeability.TXA2 production leads to an increase in endothelial cell migration. (Adapted with permission from Gately S, et al. Semin Oncol 2004;3l[Suppl 7]:2-ll. © 2004,Elsevier.)

Thus, if COX-2 activity is blocked with a coxib, VEGF concentrations may decrease, making endothelial cells prone to apoptotic cell death. Cell death would result in damage to the basement membrane, thereby leading to the initiation of the coagulation cascade, resulting in platelet activation, aggregation, and finally thrombus formation.

Studies have shown conflicting results on the effects of COX-2 inhibition and the effects on endothelial cell activity. It seems reasonable that the risk of these events might be even greater in patients with cells that have been exposed to stress or previous damage.
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It is interesting that in randomized, active-controlled studies, the incidence of arterial thromboembolic events was increased with the use of a VEGF antagonist, bevacizumab (Avastin, Genentech), when combined with chemotherapy for the treatment of colon cancer. The incidence of both overall arterial thromboembolic events and CV arterial events was higher in patients receiving bevacizumab (4.4% vs. 1.9%) than in the active controls (2.1% vs. 1.0%).

The increased risk of CV disease, as seen with rofecoxib and celecoxib in the APPROVe and APC trials, may be related to the underlying disease process. In both studies, all patients had a history of colorectal adenomas and had undergone a previous colonoscopy to remove any adenomas that were present before they were enrolled in the study. Therefore, the enrolled patients did not have any adenomas and would not have been expected to have increased levels of VEGF at baseline; however, patients with a history of colorectal adenomas or polyp removal, such as these study populations, generally have a col-orectal adenoma recurrence rate of approximately 20% per year. Given this assumption, then, about 60% of patients could have developed an adenoma by the third year during these clinical trials. Patients with recurrent adenomas would have the potential to have increased VEGF concentrations and to be at an increased risk of CV events when given coxibs.
This theory is further supported by the observed delay in CV events in both the rofecoxib and celecoxib randomized clinical trials. As was noted, the risk with rofecoxib was not seen until 18 months of therapy, whereas this risk with celecoxib was seen after 2.5 to three years of therapy. Hence, for the first 18 months, patients may not have had an increased CV risk, because they were adenoma-free at the time of their inclusion in the study. However, more patients may have developed adenomas as the study progressed and, as a consequence, could have experienced an increased number of CV events.

Unfortunately, because the data on cancer prevention from these studies are not yet available, this explanation is merely a theory. Yet it suggests that effects on vascular and inflammation markers such as VEGF may contribute to the increased CV risk seen with the coxibs.

Conclusion

Currently, only celecoxib is available in the U.S.; lumiracoxib are under investigation. Rofecoxib was removed from the market in September 2004 because of its increased risk of CV events, and valdecoxib was removed in April 2005 as a result of a combination of increased risk of CV eventsand severe dermatologic conditions.

It is clear that drugs within this class of medications have shown an increased risk of CV toxicity, but it is not yet possible to affirm that this is a class effect. One concern related to the current data is that the TARGET trial—the only study powered to detect an increased risk of CV events—did not show an increased risk with lumiracoxib compared with other NSAIDs.

Another matter for debate is that the nonselective NSAIDS that were used as comparator agents in these trials also lacked data on CV safety; however, results from randomized controlled trials, observational studies, case-control studies, and meta-analyses have all demonstrated some increased risk with canadian celecoxib, rofecoxib, and valdecoxib.

It is also difficult to attribute the risks to a specific entity; that is, higher doses and a duration of therapy of more than nine months appear to pose the greatest risk, but the effects of COX-2 selectivity, the half-lives of the drugs, the effects of ASA, and other factors still need to be defined.

In addition, the baseline CV risk has not clearly been shown to be a factor in the development of CV events, although underlying disease states—specifically, RA and colorectal adenomas—may play a role. We will be able to gain a further understanding of the role of these conditions on CV outcomes after all of the data on cancer prevention have been released.

To date, the question of safety with coxibs is still unanswered. In view of the undefined risks of thrombosis with coxibs, only patients who meet defined criteria for their use should receive them at the lowest possible dose for the shortest period of time.