Randomized Clinical Trials

A summary of randomized trials of coxib therapy is presented in Table 2.


In the VIGOR trial, rofecoxib (Vioxx) was compared with canadian naproxen in 8,076 patients with rheumatoid arthritis (RA) over a median of nine months.4 The dose of rofecoxib in this trial (50 mg daily) was twice the FDA-approved dose recommended for chronic RA analgesia and anti-inflammatory use. Similar efficacy was found between treatments, with rofecoxib causing significantly fewer GI events; however, rofecoxib demonstrated an increased risk of CV events over naproxen.

Patients receiving rofecoxib were 2.4 times more likely to experience a major CV event, such as myocardial infarction (MI), unstable angina, cardiac thrombus, resuscitated cardiac arrest, sudden or unexplained death, an ischemic stroke, or transient ischemic attacks. The incidence of MI was also five times greater with rofecoxib (0.5%) than with naproxen (0.1%). The reported differences in CV events could not be explained by any of the baseline patient characteristics measured.

Table 2 Review of Multicenter, Randomized, Double-Blind Trials of the Coxibs



Treatment Groups

Patients Using Aspirin (%) CV Risk (Percent)




VIGOR(2000) Rofecoxib 50 mg q.d. (n = 4,047) b.i.d. (n = 4,029)

ASA not allowed


RA ~ 9 months
APPROVe(2005) Rofecoxib 25 mg q.d. (n = I,287)Placebo (n = I,299)



Colorectal adenomas ~ 3 years
CLASS(20 00) Canadian Celecoxib 400 mg b.i.d. (n = 3,987) 800 mg t.i.d. (n = 1,985) b.i.d. (n = 1,996)



OA (73%), RA (27%) ~ 6 months
APC(2005) Celecoxib 200 mg b.i.d. (n = 685) Celecoxib 400 mg b.i.d. (n = 67I)Placebo (n = 679)



Colorectal adenomas ~ 33 months
PreSAP(2005) Celecoxib 400 mg q.d. (n = 933)Placebo (n = 628)



Colorectal adenomas ~ 33 months
ADAPT(2005) Celecoxib 200 mg b.i.d. Naproxen 250 mg b.i.d. Placebo (n = unknown)



Alzheimer’s disease N/A
CABG No.I(2003) Parecoxib 40 mg IV every 12 days for 3 days, followed by valdecoxib 40 mg every 12 days (n = 311)Control group (n = I5I)



CABGpatients I4 days
CABG No. 2(2005) Parecoxib 40 mg IV for 1 day, followed by 20 mg every I2 days for 3 days, then valdecoxib 20 mg every I2 days (n = 555)IV placebo for 3 days, followed by valdecoxib 20 mg every I2 days (n = 556);placebo (n = 560)



CABGpatients I0 days
TARGET(2004) Lumiracoxib 400 mg q.d. (n = 9,II7) Naproxen 500 mg b.i.d. (n = 4,730) Canadian Ibuprofen 800 mg t.i.d. (n = 4,397)

~ 24%

~ I0% (vascu­lar disease);~ 45% (hyper­tension) OA ~ I2 months
EDGE(2005) Etoricoxib 90 mg QD (n = 2,789)TID (n = 2,607)

~ 30%

~ 35%

OA ~ 9 months
* CV events included fatal/nonfatal myocardial infarction,unstable angina,sudden death from cardiac causes,cerebrovascular events,and peripheral vascular events.b.i.d. = twice daily; CABG = coronary artery bypass graft; CI = confidence interval; CV = cardiovascular; MI = myocardial infarction; N/A = not available; NNH = number [of patients] needed to harm; OA = osteoarthritis; q.d. = once daily; RA = rheumatoid arthritis; RR = relative risk.

Acetylsalicylic acid (ASA) was not allowed in this trial, although 4% of patients did meet the FDA’s criteria for using ASA to prevent a CV event. Of the MIs experienced by patients, 38% of them occurred within this small group of patients who were not taking ASA but who should have been. In both subgroups (for whom aspirin was indicated and not indicated), the naproxen group revealed a lower risk of stroke and MI, a lower risk of serious thrombotic events, and lower rates of adjudicated events compared with the rofecoxib group.

The VIGOR trial was the first to raise concerns about CV ADEs with rofecoxib. At the time, the differences in CV events were considered to be a result of a cardioprotective effect of naproxen rather than an increased risk from rofecoxib.

After many observational studies and meta-analy-ses revealing conflicting results of CV risk, safety data from the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial were released. Over a period of three years, rofecoxib 25 mg daily was compared with placebo in 2,586 patients with a history of colorectal adenomas to assess the ability of rofecoxib to prevent the recurrence of colorectal polyps. The rofecoxib patients had a greater risk of developing a confirmed throm-botic event compared with the patients receiving placebo (relative risk [RR], 1.92; 95% confidence interval [CI], 1.19-3.11; P = .008).
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Differences in cardiac events (MI, unstable angina, and sudden death from cardiac causes) were also reported. Rofecoxib was associated with a 2.8 times greater risk of a CV event. These observed differences did not occur until 18 months after the start of the trial, and they continued to grow as treatment continued. Unlike patients in the VIGOR trial, patients in the APPROVe trial were allowed to take ASA, although only 20% of patients reported taking it. ASA use did not demonstrate a lower risk of either thrombotic or CV events.

A history of symptomatic atherosclerotic CV disease and diabetes were the only two baseline characteristics that appeared to affect the results; each showed a higher relative risk for the rofecoxib patients than for the placebo patients. With the APPROVe results, rofecoxib had shown an increase in CV risk when compared with both naproxen and placebo. As a result, Merck voluntarily withdrew rofecoxib from the U.S. marketplace on September 30, 2004.


In the Celecoxib Long-term Arthritis Safety Study (CLASS), celecoxib was compared with conventional NSAIDs (ibuprofen and diclofenac) in 8,059 patients with a history of osteoarthritis (OA) and RA. This study was designed to determine the GI safety benefit of celecoxib (Celebrex) versus the comparator. As with the VIGOR trial,4 higher doses of celecoxib (400 mg twice daily) were used in this study.

After a six-month treatment period, the incidence of serious thrombotic effects did not differ significantly in the celecoxib patients (1.3°%) from that of the NSAID group (1.2%). Even though 20% of patients used ASA, no impact on the frequency of CV events was noted.

The results of the Adenoma Prevention with Celecoxib (APC) trial revealed an increased risk of CV events with twice daily and 400 mg twice daily when compared with placebo in 2,035 patients. Patients were treated for approximately 33 months. Forty-six CV events were reported with celecoxib, in a dose-dependent manner. Patients taking 400 mg/day had a 2.3 times higher incidence of a CV event compared with placebo, and patients taking 800 mg/day had a 3.4 times greater incidence of a CV event compared with those taking placebo.

Approximately 30% of patients took ASA during the study, but ASA had no impact on the frequency of CV events in any of the three groups.

A similar trial, Prevention of Sporadic Adenomatous Polyps (PreSAP), compared celecoxib 400 mg daily to placebo in reducing the occurrence of adenomatous polyps in the colon and rectum. After more than 1,500 patients were treated for 33 months, the incidence of CV events did not differ between groups (RR, 1.1; 95% CI, 0.6-2.3). About 15% of the study’s patients took ASA, but this did not affect the frequency of CV events in either group.

Although the reasons for the conflicting results between the PreSAP and APC trials cannot be easily explained, the cele-coxib dosing differed in the trials. Celecoxib 400 mg once daily (in PreSAP) does not provide the same consistent exposure to the drug during a 24-hour period as celecoxib 200 mg twice daily (in APC). A more consistent concentration of drug may have contributed to the increased risk of CV events noted in the APC trial over the PreSAP trial, even with the same 400-mg total daily dose.

The Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) compared celecoxib 200 mg twice daily with naproxen 220 mg twice daily and placebo. The purpose was to evaluate a potential decrease in the incidence of Alzheimer’s disease with NSAID therapy. Although the projected accrual was 2,625 patients, a preliminary safety review demonstrated no increase in cerebrovascular or CV events in the celecoxib arm. However, patients receiving naproxen showed an increased risk of CV events over placebo. In late December 2004, as a result of the naproxen results, the trial was stopped early.

Despite the conflicting results of these trials involving celecoxib, the FDA required that a warning of a potential increased CV risk be added to package labeling on the basis of the APC findings.