VIENNA, Austria-High doses of selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) increase risk for myocardial infarction (MI) in arthritis patients, according to a large-scale, nested, case-control study presented Friday at the Annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR) in Vienna, Austria.

"This [increased cardiovascular risk] is definitely and decidedly not limited to COX-2 inhibitors," says study author Gurkirpal Singh, MD, professor of medicine, immunology and rheumatology at Stanford University Medical School in Palo Alto, California. "An increased risk of heart attack is a common phenomenon with a large number of NSAIDs."

In fact, the two NSAIDs in the new study were indomethacin and sulindac, which increased risk of acute MI by 71% and 41%, respectively. In the study, meloxicam users faced a 37% increase risk of heart attack, while rofecoxib use was associated with a 32% increased risk, the study showed. Ibuprofen conferred an 11% increased risk, celecoxib had a 9% increased risk, and valdecoxib users had no increased risk of heart attack, the study showed. Naproxen did not have a cardioprotectoive effect in this study.1 In the study, there was a strong dose response across the board for all NSAIDs, Dr. Singh says.

 

Individual risk factors key to prescribing NSAIDs

"It does appear to be a class effect of all NSAIDs," Dr. Singh notes. "Since these drugs have similar efficacy, the choice in a particular patient should depend on the relative gastrointestinal or cardiovascular safety."

Currently, Dr. Singh is looking at subgroup analysis to see if aspirin mitigates these risks in about 300,000 patients who were taking concomitant aspirin.

To arrive at these findings, Dr. Singh and colleagues culled data from Medi-Cal, California's Medicaid program. They identified all adult arthritis patients treated with an NSAID between 1999 and 2004. Of this population, more than 15,000 had suffered an acute MI. After matching these patients with four control groups (for age, gender, and date of acute MI), study investigators looked at current exposure to selective and nonselective NSAIDs with remote exposure. They adjusted for 38 possible confounding risk factors, as well as concomitant aspirin therapy.

As a whole, all nonselective NSAIDs raised risk of heart attack by about 12%. Compared with nonselective agents, only rofecoxib increased risk of MI.

"Rofecoxib does stand out, but lower doses of rofecoxib versus higher doses of other agents may not show [such a big increase]," Dr Singh says.

There was a strong relationship between the risk of acute MI with increasing dose of rofecoxib, with the risk increasing from 1.16 at daily doses of 12.5 mg to 2.4 at daily doses over 50 mg. An increased risk with higher doses was also seen with many nonselective NSAIDs: diclofenac 1.02 at <e;150 mg and 1.37 at >e;150 mg; naproxen 1.07 at <e;1 g and 1.16 at >1 g; and celecoxib 1.01 <e;200 mg and 1.24 at >200 mg.

In this study, there was no correlation between risk and selectivity. "The risks were all over the place, so there is not an obvious correlation between selectively and CV risk," Dr. Singh notes.

 

More evidence accrues

In this week's British Medical Journal,2 researchers found that for patients prescribed NSAIDs in the 3 months before the MI, the risk increased compared with those who had not taken these drugs in the previous 3 years. Specifically, the risk increased by 24% for ibuprofen and 55% for diclofenac.

In a related study presented at EULAR on Friday, Chris J. Hawkey, MD, codirector of the Institute of Clinical Research and head of the Wolfson Digestive Disease Center, Institute of Clinical Research, University Hospital, Nottingham, UK, confirmed that NSAID use is associated with an increased risk of MI as the first indication of ischemic heart disease.3

Unlike Dr. Singh's paper, this study did not elucidate specific drugs. Patients taking NSAIDs had a 77% increase in odds ratio compared with community-based controls, the study showed.

In an interview with CIAOMed, Dr. Hawkey says that he feels the excitement over coxibs may have been "premature, given that nonselective NSAIDs have the capacity to have similar effects [as coxibs]," he says. "The data coming out show that the increased risk of heart attack is at least the same with nonselective NSAIDs."

While questions remain about how these drugs actually increase risk of heart attack and whether risk abates when use is ceased, "we need to be firm about the size of the risk and which individual NSAIDs confer risks," Dr. Hawkey urges. "That's the critical question. We need to look at individual drugs because we don't prescribe drugs as a class."

The new studies "add important information" to the discussion of NSAIDs and cardiovascular risk, says Tore K. Kvein, MD, incoming president of EULAR, professor at the University if Oslo, and head of the department of rheumatology at Diakonhjemmet Hospital in Norway.

References:

1. Singh G, Mithal A, Triadafilopoulos G. Both selective COX-2 inhibitors and non-selective NSAIDs increase the risk of acute myocardial infarction in patients with arthritis: selectivity is with the patient, not the drug class. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract OP0091.
2. Hippisley-Cox J, Coupland C. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ. 2005;330:1366-1369.
3. Hawkey CJ, Hawkey GM, Everitt SJ, et al. Increased risk of MI as the first manifestation of alchemic heart disease. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract OP0092.