The study, reported at the American Heart Association Scientific Sessions 2005 today, showed the highest risk of death with high doses of the COX-2 inhibitors. But high doses of regular NSAIDs, including ibuprofen, and lower doses of COX-2 inhibitors were also associated with increased death rates.

Lead author of the study, Dr Gunnar Gislason (Bispebjerg University Hospital, Copenhagen, Denmark), told heartwire: "This is more evidence showing that COX-2 inhibitors are harmful for MI patients. The take-home message from this study is that COX-2 inhibitors and also regular NSAIDs should be avoided in patients with heart disease." The FDA has already made this recommendation following several studies showing an increase in risk of MI with these drugs, and Gislason noted that his results supported that action.

Gislason explained to heartwire: "We know COX-2 inhibitors and probably also regular NSAIDs increase MI risk, but no studies have been done specifically in patients with cardiovascular disease." He and his colleagues therefore set out to analyze the effect of these drugs in MI patients. They did this by examining the records in the Danish National Patients Registry to identify patients discharged from the hospital after a first MI. And they also tracked prescriptions of selective COX-2 inhibitors and other NSAIDs after discharge, their dosages, and for how long they were prescribed.

They found 58 432 patients who suffered a first MI between 1995 and 2002, of whom a substantial number had received at least one prescription for a COX-2 inhibitor or an NSAID at some point after discharge.

The researchers analyzed the risk of a second MI or death from any cause during the time patients were taking a COX-2 inhibitor or NSAID compared with patients who were not taking these drugs.

After adjustment for age, year of MI, gender, social status, other medical conditions, and concomitant medications, they found that patients taking high doses of COX-2 inhibitors or other NSAIDs were at a "strikingly higher" risk of death compared with patients not taking these drugs.

Lower doses of the COX-2 inhibitors rofecoxib (Vioxx, Merck) and celecoxib (Celebrex, Pfizer) were also associated with a significantly higher risk of death, but lower doses of regular NSAIDs were not.

"We showed a clear dose-related increase in risk of death with both COX-2 inhibitors and regular NSAIDs. The higher the dose, the higher the risk of death," Gislason commented to heartwire.

But the association with recurrent MI was not so clear. "We found a weak association—about a 50% increased risk—but this was not significant," Gislason noted. He said this was surprising, as he would have expected that the increased death rates seen in the patients receiving COX-2 inhibitors/NSAIDs would have been due to higher rates of second MIs.

However, he pointed out that recurrent MIs recorded in this study were found by scanning the register of hospitalizations, but that if patients had a fatal MI and died before reaching the hospital, this would not have been recorded as a hospitalization and therefore would not have been included in these results. "As 50% of the deaths in this study did occur outside the hospital, this could be a reasonable explanation, but we are now examining the death certificates to establish exact cause of death, which should give us more information," he said.

Noting that this was an observational study and the results are therefore not as reliable as those from a randomized trial, Gislason commented: "We will probably never have a randomized trial of these drugs in cardiac patients, so this is going to be the best data we are going to get."