Commentary

It seemed like a good idea at the time: drugs that selectively inhibited cyclooxygenase 2 (COX 2) would inhibit the synthesis of prostaglandins responsible for pain and inflammation, without interfering with the important “housekeeping” functions of COX 1, such as maintenance of gastric mucosal integrity.¹ It soon became apparent, however, that the COX 2 inhibitors (led by celecoxib and rofecoxib) were not wonder drugs at all. Efficacy was similar to their non-selective counterparts, but they were considerably more expensive and conferred only a slight gastrointestinal safety advantage. Nevertheless, these drugs became pharmaceutical juggernauts used by tens of millions of patients worldwide.

The possibility that COX 2 inhibitors might increase risk of CV events was first raised in a large trial of rofecoxib.² The 5 fold higher incidence of MI with rofecoxib, 50 mg/day was initially attributed to a cardioprotective effect of naproxen, the active comparator. Despite its rather thin biological plausibility, this assertion could not be refuted given the absence of a placebo group. Subsequent observational studies and other randomised trials of COX 2 inhibitors reached inconsistent conclusions, particularly on the hazards of celecoxib. However, the trials of Bresalier et al and Solomon et al provide new evidence that COX 2 inhibitors, as a class, increase risk of CV events in a dose dependent fashion.

Why? The most widely held hypothesis is that unlike traditional NSAIDs, COX 2 inhibitors selectively inhibit endothelial prostacyclin synthesis without blocking the synthesis of thromboxane A2 in platelets, resulting in platelet aggregation and vasoconstriction. If this is the case, it is reasonable to ask why low dose aspirin did not seem protective in the APPROVE trial. In fact, it probably was. By virtue of being treated with aspirin, these patients (who were initially excluded from the trial) were almost certainly at increased risk of CV events a priori, and the concomitant use of aspirin probably attenuated the observed association between rofecoxib and CV events.

Other more meaningful questions arise naturally from these 2 studies. Why did it take so long to clearly establish this association? Part of the answer rests in the high background incidence and “expectedness” of CV events, especially in older patients treated with COX 2 inhibitors, and the complex “web of causation” that makes it virtually impossible to definitively attribute even a single CV event to these drugs. Another explanation stems from the challenges of observational epidemiology. Foremost among these is the fact that patients treated with COX 2 inhibitors were often older and “sicker” than patients given traditional NSAIDs, making it difficult to ferret out the modifying influences of bias and confounding on CV outcomes.

A more difficult and sensitive question relates to the toll exacted by COX 2 inhibitors at the population level. The true magnitude is unknowable, but given the popularity of these drugs and the absolute risk estimates of Bresalier et al and Solomon et al (notably, estimates derived from relatively “well” patients), it is likely that COX 2 inhibitors have caused many excess deaths from MI, heart failure, and stroke.

While science and the courts look into the rearview mirror, clinicians and patients wonder how best to use these drugs in the future. Rofecoxib has been removed from the market, but celecoxib and other COX 2 inhibitors remain available. Although a considerable body of evidence suggests that celecoxib may be safer than rofecoxib, it is clearly not risk free. In light of celecoxib’s mediocre track record as an anti-inflammatory, it seems reasonable to ask whether it or COX 2 inhibitors should be used at all. Clinicians may have differing opinions on this. Recognising that no drug is completely free of risk, it seems sensible to restrict the use of COX 2 inhibitors to a small minority of patients without overt vascular disease who require an anti-inflammatory but are at high risk of gastrointestinal haemorrhage or are intolerant of other NSAIDs. These patients should be apprised of the possible risks and if they consent to treatment, both the dose and duration of therapy should be minimised.