Comparison of thromboembolic events in patients treated with Celecoxib, a Cyclooxygenase-2 specific inhibitor, versus Ibuprofen or Diclofenac

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Abstract

It has been hypothesized that cyclooxgenase 2 specific inhibitors may increase the risk of cardiovascular (CV) thromboembolic events because of their inhibition of vascular prostacyclin synthesis and lack of an effect on platelet thromboxane A2 production and aggregation. Thus, we analyzed the data for celecoxib and nonsteroidal anti-inflammatory drugs (NSAIDs) from the Celecoxib Long-term Arthritis Safety Study to determine the incidences of serious CV thromboembolic events. This trial included 3,987 persons randomized to celecoxib 400 mg twice daily (2,320 person-years of exposure) and 3,981 persons randomized to either ibuprofen 800 mg 3 times daily or diclofenac 75 mg twice daily (2,203 person-years). Because acetylsalicylic acid (ASA) use for CV risk prophylaxis (≤325 mg/day) was permitted, separate analyses were performed for all patients and those not taking ASA. The incidences of serious CV thromboembolic events (myocardial infarction, stroke, CV deaths, and peripheral events) were similar, and not significantly different, between celecoxib and NSAID comparators (combined or individually) for all patients as well as the subgroup of patients not taking ASA. This observation was true both for all serious CV thromboembolic events, as well as for individual events. No increase in myocardial infarction was apparent, even in patients not taking ASA who were candidates for secondary prophylaxis for myocardial infarction. The relative risks for celecoxib versus NSAIDs for serious CV thromboembolic events were 1.1 for all patients and 1.1 for the subgroup of patients not taking ASA (95% confidence interval 0.7 to 1.6 and 0.6 to 1.9, respectively). In addition, the incidences of adverse CV events such as hypertension, edema, and congestive heart failure were similar to, or significantly lower than, NSAID comparators regardless of the use of ASA. Thus, these analyses demonstrate no increased risk of serious CV thromboembolic events associated with celecoxib compared with conventional NSAIDs and therefore do not support the hypothesis of a class adverse effect of cyclooxgenase 2 specific inhibitors on the CV system.

Section snippets

Study population and protocol:

The details of the study population and protocol have been published previously.8 In brief, outpatients aged ≥18 years were eligible to participate in the study if upon screening they were diagnosed with rheumatoid arthritis or osteoarthritis evident for ≥3 months and were expected to require continuous treatment with an NSAID for the duration of the trial. Other inclusion and exclusion criteria were derived from the product labels of the study drugs so as to mirror clinical practice. The trial

Patient disposition and baseline treatment group characteristics:

Patient disposition is outlined in Figure 1. Reasons for randomized patients not receiving the study drug have been outlined previously.3 Number of patients, average exposure, total exposure, baseline demographics, blood pressure, ASA use, and CV risk factors for the study groups are shown in Table 1. There were 3,987 persons randomized to celecoxib (2,320 person-years of exposure) and 3,981 exposed to either ibuprofen or diclofenac (2,203 person-years). The average age of the study population

Discussion

Clinical evidence from the CLASS data does not support the assertion that celecoxib is associated with an increased risk of serious CV thromboembolic events compared with NSAIDs in the aggregate or to the individual NSAID comparators, ibuprofen or diclofenac. This conclusion is supported by analyses of serious CV thromboembolic events among patients not taking ASA as well as by an analysis of other CV adverse events (e.g., hypertension) related to serious CV thromboembolic events (e.g.,

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