Cardiac Risk With COX-2 and NSAID Drugs

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Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used medications in the world. They are effective in reducing inflammation and pain and are readily available both by prescription and over the counter.

However, many of these drugs are now known to increase the risk of cardiovascular problems, including acute coronary syndrome (ACS), heart attack, heart failure, stroke, and possibly atrial fibrillation. 

The magnitude of the increased cardiovascular risk with NSAIDS is generally quite small. But the risk increases with chronic usage and with higher doses, and is substantially higher in people with the known cardiovascular disease. Further, the risk is higher with some NSAIDs than with others.

(Note: Aspirin is the oldest and most commonly used NSAID. However, aspirin reduces cardiovascular risk, and will not be discussed in this article. You can read about the prophylactic use of aspirin here.)

Types of NSAIDS

The non-aspirin NSAIDs work by inhibiting the cyclooxygenase (COX) enzymes, an effect the reduces the production of prostaglandins that cause pain and inflammation.

There are actually two COX enzymes — COX-1 and COX-2 — that have different effects. COX-2 is associated with pain and inflammation, while COX-1 has other functions, including protecting the stomach lining from acid.

Accordingly, NSAIDS are classified by whether they block only COX-2 (the “selective” NSAIDS), or whether they block both COX-1 and COX-2 (the “nonselective” NSAIDs).

The original NSAIDs, such as ibuprofen (Advil) and naproxen (Aleve), were all nonselective NSAIDS. Because they block COX-1 they are associated with gastric irritation. Numerous nonselective NSAIDS have now been developed and marketed, including ketoprofen, flurbiprofen,oxaprozin, tolmetin, sulindac, etodolac, indomethacin, meloxicam, ketorolac, piroxicam, meclofenamate, nabumetone, and mefanamic acid.

Drug companies worked hard to develop selective NSAIDs that block only COX-2, in order to reduce gastric complications. Eventually several several selective NSAIDs were developed, but most of these now have been withdrawn from the market. In the US, celecoxib (Celebrex) is currently the only selective NSAID available. Another selective NSAID, etoricoxib, is available in other countries.

Diclofenac (Voltarten), another “newer” NSAID, cannot be definitively classified as either selective or non-selective.

Cardiovascular Risk With NSAIDs

The increase in cardiac risk with NSAIDs was first noted with the selective NSAID rofecoxib (Vioxx), which generated great publicity and numerous lawsuits against its manufacturer, Merck. Vioxx was subsequently removed from the market. Because of the negative publicity generated by this selective NSAID, most other selective NSAIDs were also withdrawn.

However, since that time numerous clinical studies have shown that a small increase in cardiovascular risk is in fact associated with all NSAIDs, both the traditional nonselective NSAIDs and the newer COX-2 selective drugs.

With virtually all the NSAIDs, the cardiovascular risk increases with the length of usage of these drugs, with higher doses, and with the underlying cardiac risk of the person taking the drugs.

Are Some NSAIDs “Safer” Than Others?

Data comparing the magnitude of cardiac risk caused by specific NSAIDs is lacking. Because of the large number of these drugs that are available, and the small magnitude of risk involved, conducting the clinical trials necessary to tease out any differences would be prohibitively expensive.

However, a meta-analysis of the available clinical studies was published in 2013. This analysis showed that the risk of cardiovascular events was significantly increased compared to placebo with high-dose diclofenac, and with all the selective NSAIDs. An increase in risk was also seen with ibuprofen that was not statistically significant. And no increase in risk was seen with naproxen.

This meta-analysis is not considered conclusive. Most experts have formed the opinion that all the NSAIDs, of both categories, should be supposed to increase cardiovascular risk.

However, if an NSAID needs to be used in a person concerned about increasing cardiac risk, most experts would recommend naproxen. If gastrointestinal side effects are a particular concern, most experts would lean toward celecoxib.

Other Cardiac Concerns Related to NSAIDS

In addition to increasing the risk of cardiac events, both categories of NSAIDs are also associated with an increase in blood pressure when used chronically.

Further, most of the nonselective NSAIDs interfere with the beneficial effects that aspirin has on platelets, thus countering the effects of prophylactic aspirin. This interference has not been seen, however, with the nonselective NSAID diclofenac, or with the selective NSAIDs.

A Word From Tips For Healthy Living

While Vioxx got all the publicity, it turns out that all the NSAIDs appear to increase cardiac risk at roughly the same rate (with the exceptions already noted).

For people who are at increased cardiovascular risk, NSAIDs should be used at the lowest effective dose for the shortest possible period of time. If your cardiac risk is elevated, naproxen is probably your NSAID of choice.

In addition, experts recommend avoiding NSAIDs altogether, whenever possible, in people with established cardiovascular disease.

Anyone with hypertension must be aware that NSAIDs can increase blood pressure and reduce the effectiveness of antihypertensive therapy.

Anyone taking aspirin for prophylaxis against cardiovascular disease should avoid nonselective NSAIDs whenever possible. If NSAIDs are going to be used, they should be taken at least two hours after the aspirin.

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