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Perry T, editor. Therapeutics Letter. Vancouver (BC): Therapeutics Initiative; 1994-.
Therapeutics Letter 43 provides an update on COX-2 inhibitors. Conclusions: Based on FDA data from the CLASS and VIGOR studies, COX-2 selective inhibitors are associated with an increased incidence of serious adverse events as compared to non-selective NSAIDs. Published versions of the CLASS and VIGOR trials focused on GI events and failed to report other serious adverse events fully. In the interests of public safety, serious adverse event rates from all trials must be published.
The COX-2 inhibitors have been successfully marketed based on the presumption that the main mechanism by which non-selective NSAIDs cause gastrointestinal (GI) ulcers is inhibition of COX-1. Based on this hypothesis, drugs that selectively inhibit COX-2 enzymes will have similar anti-inflammatory activity with less GI toxicity. Short-term RCTs, in which all patients underwent endoscopy, showed fewer cumulative gastroduodenal erosions and ulcers with the COX-2 inhibitors (9–15%) than with non-selective NSAIDs (41–46%).2,3 Regulatory authorities judged this surrogate outcome insufficient to prove that COX-2 selective inhibitors were better than non-selective NSAIDs in terms of the life-threatening complications of NSAIDs, ulcers complicated by GI bleeds, perforations and obstructions. Thus the monographs of celecoxib, rofecoxib (Vioxx®) and meloxicam (Mobicox)® include the same warnings of the risk of GI toxicity as all other NSAIDs.
With the objective to demonstrate a reduced incidence of complicated ulcers with COX-2 inhibitors, the manufacturers of celecoxib and rofecoxib conducted two large RCTs, the CLASS and VIGOR trials, respectively. The major findings of these trials were published in JAMA4 and N Engl J Med5 in 2000. In February 2001, Therapeutics Letter #39 summarized the most important outcome data from the published reports. Shortly after circulation of Letter #39, the FDA published on their website a complete review of the same CLASS and VIGOR trials6–8, leading to a different interpretation of the overall safety of this class of drugs.9
The FDA data reveal that the CLASS study as published in JAMA, and summarized in Letter #39, reported only the first six months of data from two trials of longer duration. One of the trials was a 15-month trial comparing celecoxib with ibuprofen and the other was a 12-month trial comparing celecoxib with diclofenac. Both the six-month and full trial data are provided in the FDA review.6,7 The published VIGOR trial duration and GI outcome data are the same as that found on the FDA website, but the FDA report is more complete and provides overall serious adverse event data.8
As pointed out in Letter #42, total serious adverse events (SAEs) provide essential information about both harm and benefit. SAEs include death, hospitalization or extension of hospitalization and any life-threatening event or serious disability. In the case of NSAIDs, complicated ulcers represent one of the SAEs.
The Table presents the percentage of total patients who had one or more SAE and a breakdown of those events into mortality, complicated ulcers and other SAEs.
Patients with one or more Serious Adverse Event (FDA data)
The reason for the increased incidence of serious adverse events with the COX-2 selective inhibitors can not be completely answered from the available FDA data. SAEs are more completely reported in the FDA VIGOR report than the FDA CLASS report. Myocardial infarction (RR 4.9 [1.7–14.3], ARI 0.4%, NNH 250) and adjudicated thrombotic cardiovascular events (RR 2.38 [1.39–4.00], ARI 0.6%, NNH 167) are increased with rofecoxib as compared to naproxen.1,8 The reason why COX-2 inhibitors might increase thrombosis is discussed by Mukherjee et al.1 However, none of the reported individual or combined outcomes explain the overall 1.0–1.9% absolute risk increase of other serious adverse events associated with either celecoxib or rofecoxib.
Before making a claim of a safety benefit over a comparator, the total % SAEs should be less than that observed with the comparator. For example, rofecoxib as compared to naproxen reduced complicated ulcers (ARR 0.5%) leading to a claim of a safety benefit, but the magnitude of this benefit is outweighed by the harm associated with rofecoxib in terms of other SAEs (ARI 1.9%).
In the VIGOR trial, symptomatic ulcers were reduced with rofecoxib as compared to naproxen, and withdrawals due to adverse events were the same in both groups (see Table, Letter #39). The complete data for symptomatic ulcers in the CLASS trial are as follows: 0.65% of patients treated with celecoxib and 1.0% of patients on other NSAIDs had symptomatic ulcers (RR 0.63 [0.39–1.03]). Interpretation of this trend is complicated by the fact that fewer patients in the celecoxib group (3.4%) underwent endoscopies as compared to patients treated with the other NSAIDs (4.9%; RR 0.70 [0.57–0.87]). The decrease in withdrawals due to adverse events with celecoxib at 6 months4 (Letter #39) was also seen in the full trial: 22.4% of celecoxib patients and 24.6% of patients on other NSAIDs withdrew due to adverse events (RR 0.91 [0.84–0.98], ARR 2.4%, NNT = 42). This finding predominantly reflects a higher incidence of withdrawals due to GI symptoms and increase in hepatic enzymes in patients treated with diclofenac.
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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