Hellerup, Denmark - Further evidence that all nonsteroidal anti-inflammatory drugs (NSAIDs) could be harmful to patients with established cardiovascular disease has come from a new Danish study [1].

The observational study, published online in Circulation on June 19, 2006, found that selective COX-2 inhibitors in all dosages and nonselective NSAIDs in high dosages were associated with increased mortality in patients with previous MI.

Taking these drugs if you have heart disease is like putting a gun to your head.

The authors, led by Dr Gunnar Gislason (Gentofte University Hospital, Hellerup, Denmark), calculate that the number of post-MI patients that need to be treated to cause one death is as low as 13 or 14 for rofecoxib and celecoxib and just 24 for diclofenac and 45 for ibuprofen. They point out that this is the first study to address the risk of all NSAIDs specifically in post-MI patients, and it shows that the harmful effects of these drugs appear much more severe in such patients.

"People with a vulnerable cardiac system seem to be even more at risk from the cardiovascular side effects of these drugs," Gislason commented to heartwire. "In addition, the average time of treatment in our study was just one month, so it appears that even short courses of these drugs are dangerous in patients with known heart disease. This is not just a problem associated with chronic treatment," he added.

"This study for me is confirmation that people with heart disease should not take COX-2 inhibitors or high doses of regular NSAIDS. Taking these drugs if you have heart disease is like putting a gun to your head," Gislason said.

The researchers used the Danish National Patient Registry, which details all hospital admissions in Denmark, to identify patients with a first MI between 1995 and 2002. They then used the national prescription registry, which keeps records of every prescription dispensed from pharmacies in Denmark, to identify patients who had been prescribed an NSAID or COX-2 inhibitor after their discharge from the hospital following their MI. They analyzed these data to find the risk of rehospitalization for MI or death related to the use of NSAIDs/ COX-2 inhibitors using two statistical methods (multivariable proportional hazards models and case-crossover analysis).

They found a total of 58 432 patients who were discharged alive following an MI, 9773 who were subsequently rehospitalized for MI and 16 573 who died during the follow-up period. Of the patients, 5.2% had been prescribed rofecoxib, 4.3% celecoxib, 17.5% ibuprofen, 10.6% diclofenac, and 12.7% other NSAIDs.

Results showed that the risk of death more than doubled with any use of rofecoxib or celecoxib, and both drugs had a strong dose-response relationship. There was also an increased risk for MI with these two COX-2 inhibitors, which did not appear to be influenced by dose.

The nonselective NSAIDs were also associated with substantial risk, with a strong dose-response relationship. Lower daily doses of ibuprofen (<1200 mg/day) and diclofenac (<100 mg/day) were not associated with excess mortality risk, while higher doses were. But like the COX-2 inhibitors, both ibuprofen and diclofenac were associated with excess risk of MI at both low and high dose.

In an accompanying editorial [2], Drs Judith Hochman and Nirav Shah (New York University School of Medicine, NY) say that this study "contributes to the growing body of evidence suggesting that we temper our use of all NSAIDs, weighing risk vs benefit." They point out that the average duration of therapy was short in this study—approximately one month, which supports a prothrombotic mechanism.

They continue: "If even short-term use is associated with relatively large risk for death and reinfarction in those with prior MI, then widespread use of such agents may be resulting in substantial morbidity. While these risks have not been as well established for patients without prior evidence of cardiovascular disease, the use of NSAIDs must be viewed with caution among high-risk patients.

"When pain demands treatment, a conversation that elicits patient preferences should help guide the first agents of choice. High-dose aspirin (up to 1500 mg/day) is associated with protection from cardiovascular events but also with gastrointestinal toxicity. Used with proton pump inhibitors, it is probably the safest choice for post-MI patients. When NSAIDs are used for patients at risk for or with established cardiovascular disease, they should be used at the lowest effective dose, for the shortest necessary duration, with concomitant low-dose aspirin and proton pump inhibitors as indicated," they write.

They note that this study, as with any observational study, has a number of limitations—for example, information on the use of aspirin was not available. They explain that if most patients were taking aspirin, which could be expected as it is guideline-recommended in post-MI patients, and as aspirin may mitigate the excess risk of NSAIDs, the reported excess risk of death and recurrent MI for the use of NSAIDs alone may be substantially underestimated. But patients may have discontinued aspirin while they took NSAIDs to reduce the risk of gastrointestinal adverse effects or because they thought the NSAID had similar cardioprotective effects, and this would have increased the risk of recurrent cardiovascular events. .

Hochman and Shah also point out that the pain-eliciting condition that initially led to COX-2 or NSAID use may have itself increased the risk of events, and this would inflate the apparent NSAID risk.

They note that Pfizer will soon be starting a randomized noninferiority study comparing naproxen, ibuprofen, and celecoxib in 21 000 patients, with cardiovascular events as the main end point. Patients enrolled will have arthritis and either established cardiac disease or high cardiovascular risk, and about two thirds will be taking aspirin.

The editorialists say there is a critical need for large simple clinical trials to test the safety as well as the real-world effectiveness of widely used NSAIDS. They add that these trials must include high-risk populations, including those with cardiovascular disease, and to establish the absolute cardiovascular risk of these agents, a placebo or high-dose aspirin group should be included.

We have seen a large number of observational studies on NSAIDs, and the results are very different for each of them. We cannot make decisions based upon this type of . . . data. In fact, observational data have a long history of resulting in misleading conclusions.

But in an interview with heartwire, Gislason expressed concern about including heart-disease patients in studies of these agents. "Yes, a large randomized study will be the final evidence, but if I had heart disease, I certainly wouldn't volunteer for such a trial," he said.

But Dr Steven Nissen (Cleveland Clinic, OH), who is coordinating the Pfizer trial, says a randomized trial is the only way to answer the question of the cardiovascular risks of NSAIDs and COX-2 inhibitors.

Nissen says Gislason's study provides very little useful information. "We have seen a large number of observational studies on NSAIDs, and the results are very different for each of them. We cannot make decisions based upon this type of post hoc observational data. In fact, observational data have a long history of resulting in misleading conclusions. Not too long ago, every observational study showed that estrogen reduced the risk of heart disease. The randomized trial showed exactly the opposite. Observational studies must contend with many known and unknown confounders. It's time to do a definitive trial, and that is exactly what is planned," he told heartwire.