NSAIDS and CAD: Risks vs. Benefits

General (including evidence of efficacy)

Various nonsteroidal antiinflammatory drugs (NSAIDS) are on the market worldwide. In general, the drugs are classified as traditional NSAIDS (i.e., naproxen, ibuprofen) versus cyclooxygenase-2 (COX-2) inhibitors (i.e., celecoxib). At doses tailored to equivalent pain relief, the different NSAIDS have very unique dosages. For example, for patients with osteoarthritis who often have concomitant CAD, the WOMAC (Western Ontario McMaster) score is quite comparable for naproxen 500 mg BID as for celecoxib 200 once daily.

For patients with coronary artery disease (CAD), naproxen is the only drug to demonstrate safety from a cardiovascular perspective. The other NSAIDS have some modest excess of cardiovascular events.

Differences between drugs within the class

The primary difference between the NSAIDs can be broken down to 5 important variables:

The degree of COX-2 selectivity. In their most recent scientific statement, the American Heart Association has put a lot of weight on this variable. The more COX-2 selective an agent, the greater its cardiotoxicity. This of course is only 1 variable. Rofecoxib (Vioxx) is highly COX-2 selective.
The effect on blood pressure. In clinical trials, agents that raise systolic blood pressure by 3 mm or greater are associated with greater cardiovascular (CV) events. Most NSAIDs, by their effect on the renal system, raise blood pressure to some degree. Naproxen and celecoxib are relatively safe in this regard.
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The half-life of a NSAID. In general the longer the half-life, the greater the CV toxicity.
The interaction with aspirin. Fairly detailed observations from registries and clinical trials have uncovered an interaction between ibuprofen and aspirin. Since patients with CAD are on aspirin, this interaction is of public health importance such that the FDA has issued a warning that aspirin and ibuprofen should be given 2 hours apart.
The dosing of a drug. Rofecoxib was found to be associated with increased CV events at doses of 50 mg daily and not at 25 mg daily.

Administration

The NSAID compounds are for the most part administered orally. Diclofenac has a transdermal preparation, and there are parenteral preparations of NSAIDs such as ketorolac.

Pharmacologic action

NSAIDs raise the risk of CV events through the following actions:

By selective inhibition of cyclooxygenase-2, there is an inhibition of prostacyclin production leading to a prothrombotic state (the Fitzgerald hypothesis).
By promoting sodium and water retention, there is a predisposition for worsening hypertension and fluid retention (including congestive heart failure [CHF]) in CAD patients.

Indications and contraindications

In general, the major contraindications fall into 3 categories: CV, gastrointestinal, and hepatic.

NSAIDs are contraindicated for patients with:

Overt CHF and recent MI or stroke within 6 months
Active GI bleeding (upper or lower) within 6 months
Jaundice with elevated transaminases

Undesirable effects

The primary CV side effects of NSAIDs in CAD patients include:

A trend toward higher rates of CV death, MI, and stroke in nonnaproxen NSAIDs
A raising of systolic and diastolic blood pressure. Remember, even elevations of 3 mm Hg can be associated with a 25% increase in CV events.
Renal dysfunction, including fluid overload and CHF

Alternative approaches

The American Heart Association has proposed a number of alternatives for patients with CAD taking NSAIDs. In general, the following recommendation holds true: use as little at the least frequency as tolerated. I would avoid ibuprofen. Be sure to monitor your patient’s use of over-the-counter preparations (ibuprofen, naproxen).

In general acetaminophen can be used up to 4 g/day. The problem with high doses of acetaminophen is liver toxicity.

I would stay clear of any narcotic medications, although the AHA recommends them in place of NSAIDs. The use of physiotherapy and nonpharmacologic approaches is widely recommended.

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