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UK Study Indicates That The Cardiovascular Risk Of Celebrex No Different From Other Pain Drugs

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An important, yet underpublicized, study among the hundreds presented at this week’s European Society of Cardiology conference held in London was “The Standard Care versus Celecoxib Outcome Trial” (SCOT). As you may recall, Merck took Vioxx, its COX-2 inhibiting pain reliever, off the market in 2004 for concerns over increased cardiovascular events such as heart attacks and strokes.  Shortly thereafter, the FDA held a three day Advisory Committee meeting in Washington, DC, to assess the potential that this was a class effect of COX-2 inhibitors and not just specific to Vioxx. A major revelation at this meeting was that ALL non-steroidal anti-inflammatory drugs (NSAIDs) – including popular drugs such as ibuprofen and diclofenac, not just COX-2 inhibitors -- have the potential of increasing cardiovascular events. As a result of these deliberations, Celebrex remained on the market, but the labels of these drugs were changed to reflect this risk.

Physicians, however, were left in a bit of a quandary. After all, most arthritic patients tend to have characteristics that make them prone to cardiovascular events: >65 years old, overweight, high blood pressure, high cholesterol, etc. Should they avoid using COX-2 inhibitors in these types of patients, even if the patients appear free of cardiovascular disease?

To answer this question, “The Standard Care versus Celecoxib Outcome Trial” (SCOT) was undertaken. This was a pragmatic trial designed to mimic the real world setting of the situations that doctors face daily in treating their patients with pain. The study was sponsored by the University of Dundee and funded via an investigator initiated research grant from Pfizer , the manufacturer of celecoxib (generic name for Celebrex). This study was required by the European Medicines Agency (EMA) as a post-approval commitment for Celebrex. Using primary care practices across the UK, Denmark, and the Netherlands, 7,297 patients were recruited for the study. They were all over 60 years old, were free of cardiovascular disease, and were already chronically taking NSAIDs (predominantly diclofenac and ibuprofen). In SCOT, half of these patients were switched to Celebrex while the other half stayed on the NSAID that they had already been taking. These patients were then followed on average for 3.2 years (the study itself took almost 10 years to run). The patients were monitored during this period with the primary endpoints being hospitalization for non-fatal MI, non-fatal stroke, or cardiovascular death. Cardiovascular events were adjudicated by an independent monitoring committee.

The first surprise was that, on treatment, there was on average about 1 primary event per 100 patient years. One might have expected more than that given the characteristics of this patient population. Furthermore, the event rate was no different between the two groups. The study also monitored adverse GI events as COX-2 inhibitors were designed to minimize this adverse effect. Here a statistically significant benefit was indeed observed as there were 38 serious adverse gastrointestinal reactions with Celebrex versus 66 with the traditional NSAIDs although here, too, there were fewer GI events than expected.

The authors of the SCOT study concluded that:

“In patients with arthritis, without known cardiovascular disease, CV event rates were low and serious ulcer-related complication rates very low, and neither outcome differed significantly between NSAIDs and celecoxib. In the study population, NSAIDs and celecoxib both appeared acceptably safe. In patients who get significant symptomatic relief from these medicines, the benefit/risk balance appears positive.”

Of course, SCOT was conducted in patients without cardiovascular disease. But what about those with heart disease who also suffer from arthritis or other chronic pain conditions? To answer that question, the “Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen and Naproxen” (PRECISION) trial was initiated in 2006 by the Cleveland Clinic. Funded by Pfizer, and likely costing upwards of $300 million, this study has been fully recruited and, according to Clinicaltrials.com (NCT00346216), should be completed next March. The results of this trial, in combination with the SCOT results, will be invaluable to physicians and patients as they seek optimal ways of controlling their pain. But for those free of cardiovascular disease, Celebrex appears to offer no increased cardiovascular risk compared to traditional NSAIDs like ibuprofen and diclofenac. Many would have bet against such an outcome 10 years ago.

(The author is a former head of Pfizer R&D, the manufacturer of Celebrex and still holds Pfizer stock.)