In my last column (Pharmacy Practice News, November, page 50), I walked through the data on selective serotonin reuptake inhibitors (SSRIs) in children. The immediate lesson there was that Prozac (fluoxetine, Lilly) seemed to show some benefit against depression, and no clear evidence of harm, and that the rest of the members of the class either lacked good evidence of benefit or demonstrated some increased risk of suicide.

The bigger-picture lesson, however, was that decisions shouldn’t be made on drug approvals or withdrawals if the evidence isn’t available to everyone who needs to make those decisions. With that in mind, let’s turn to cyclooxygenase-2 (COX-2) inhibitors and cardiovascular disease.

Whither Vioxx?

This is the other story that doesn’t seem to go away. As I write this, Merck, the maker of Vioxx (rofecoxib) is one-for-two in the courtroom, losing a $253 million jury award in Texas but winning its next product liability case in New Jersey in early November. The story has been a big one since Merck announced it would withdraw rofecoxib in September 2004, and I doubt we’ll hear the end of it for years to come.

Let’s start from the beginning: What made anyone think that a new painkiller—designed, of course, to lack the ulcers and other gastrointestinal side effects of their nonspecific nonsteroidal anti-inflammatory drug (NSAID) COX inhibitor ancestors, but more on that later—would have cardiovascular side effects? Well, for one thing, results from the VIGOR (Vioxx Gastrointestinal Outcomes Research) study, published in 2000 (N Engl J Med 2000;343:1520-1528). That study, comparing naproxen and rofecoxib, found that the rate of myocardial infarction among patients taking naproxen (0.1%) was lower than that rate among patients taking rofecoxib (0.4%), with a relative risk of 0.2 and a 95% confidence interval (CI) of 0.1 to 0.7—statistically significant. Overall mortality and rate of death from cardiovascular causes were similar in both groups, however, and careful readers will note the lack of a control group that left open the question of whether this was a protective effect of naproxen, or some characteristic of people with rheumatoid arthritis, or something else entirely.

Still, it was cause for concern, and it gave credence to a yet-unproven preclinical idea that rofecoxib, by reducing the production of the antithrombotic protein, prostacyclin, altered the balance of prostacyclin and the prothrombotic product thromboxane, leading to more clots. These concerns led researchers to include monitoring of cardiovascular events in trials that were ongoing to study whether the COX-2 inhibitors prevented recurrent colon polyps. The results of these studies, one by Nussmeier and colleagues, the other under the auspices of the National Cancer Institute, were eventually published in The New England Journal of Medicine (2005;352:1092-1102 and 2005;352:1071-1080).

Both studies were halted when it became clear that the COX-2 inhibitors did in fact increase the risk of cardiovascular events. As soon as that happened, Merck withdrew Vioxx, and the rest, as they say, is FDA history. But the data on which these actions was taken—just as in the case of the SSRIs in children—were not generally available. Report after report said that the drugs doubled the risk of cardiovascular events, but didn’t say what the absolute risk before and after was. Was it the difference between 0.1% and 0.2%, which is a doubling but a remarkably small absolute risk? Or was it the difference between 25% and 50%?

NEJM Data Yield New Clues

Let’s look at the data to find out—something that was impossible to do until February 15, 2005, when The New England Journal published it online. What one of the polyp studies found was that 46 patients taking 25 mg of rofecoxib per day "had a confirmed thrombotic event during 3059 patient-years of follow-up (1.50 events per 100 patient-years), as compared with 26 patients in the placebo group during 3327 patient-years of follow-up (0.78 event per 100 patient-years); the corresponding relative risk was 1.92 (95% CI, 1.19-3.11; P=0.008)." Most of this increased risk was due to myocardial infarctions and ischemic cerebrovascular events in the rofecoxib group. That doubling (1.92 times, to be precise) was statistically significant. Your baseline risk of a cardiovascular event over a 20-year period, say, would be one fifth of 0.78, or about 0.16—a 16% chance of an event. If you took Vioxx for those 20 years, your risk would be one fifth of 1.5, or 0.3—a 30% chance of an event.

The NCI study had similar results for celecoxib (Celebrex, Pfizer)—seven of 679 patients in the placebo group (1%) had cardiovascular events during the study, while 23 of 671 patients receiving 400 mg of celecoxib twice daily (3.4%) did. That’s a hazard ratio of 3.4, with a 95% CI of 1.4 to 7.8, so the result is statistically significant. At lower doses—200 mg twice a day—16 of 685 patients (2.3%) suffered cardiovascular events, but the 95% CI was 0.9 to 5.5, which falls short of statistical significance.

And another trial of whether two COX-2 inhibitors were effective in managing pain following coronary artery bypass graft (N Engl J Med 2005;352:1081-1091) randomly assigned 1,671 patients to either intravenous parecoxib—a prodrug of valdecoxib (Bextra, Pfizer)—for at least 3 days, followed by oral valdecoxib through day 10; intravenous placebo followed by oral valdecoxib; or placebo for 10 days. The groups given parecoxib and valdecoxib had a higher proportion of patients with cardiovascular events among the patients given parecoxib and valdecoxib than among those given placebo (2.0% vs. 0.5%; risk ratio, 3.7; 95% CI, 1.0-13.5). These findings speak to the idea that the increased cardiovascular risk of the COX-2 inhibitors aren’t limited to a particular agent—it’s more than likely a class effect.

It perhaps goes without saying that with millions of people taking these medications, any small effect—even on the order of an absolute risk change of 1% to 2%—could mean thousands of additional cardiovascular events. Still, without the actual data, relative risk data—such as "doubling"—don’t tell you all that much. I’ll leave the withdrawals and approvals to the FDA, and the liability issues to the courts, but I’ll let the data speak for themselves.

The Case for COX-2 GI Protection

By the way, raise your hand if you think the makers of COX-2 inhibitors ever proved that their drugs caused fewer GI side effects than older NSAIDs. Put down your hand. The FDA didn’t think so, and wouldn’t let such claims be part of the marketing campaigns for the class of drugs when it began approving them in 1999. CLASS (the Celecoxib Long-Term Arthritis Safety Study), which compared celecoxib to various NSAIDs, found a GI-protective effect at a six-month analysis, but not at 12 months. The VIGOR study did find such an effect for rofecoxib over naproxen.