American Heart Association revision stresses stepped care for pain

Additional data from trials of COX-2 inhibitors have reinforced the link between the CV events and the drugs. In addition, several reports have identified an increased risk of CV events even with the nonselective NSAIDs. Thirdly, other countries have introduced similar warning statements and advisories to both healthcare professionals and the lay public about the use of NSAIDs.

"The new scientific advisory is important, as it reemphasizes the step-wise approach for pain management that has been around for decades-although, in this case, it has been tailored for CV patients or patients at risk for CV disease," said Tien M. H. Ng, Pharm.D., BCPS, assistant professor of clinical pharmacy at the University of Southern California School of Pharmacy. Specifically, the new guide recommends that physicians start with nonpharmacologic treatments such as exercise, physical therapy, weight loss, and heat or cold therapy. If there is no relief of pain, physicians should consider acetaminophen, aspirin, and even short-term use of narcotic analgesics as a first step, taking the patient's medical history into account. If more pain relief is needed, non-COX-2 NSAIDs should be considered first, with a move toward the least selective COX-2 inhibitors, and eventually more selective COX-2 inhibitors, only if necessary. In each case, the lowest dose possible should be used to control symptoms and for the shortest duration.

Naproxen appears to be the preferred choice, although clinical trials to date have had limitations. Next, in increasing degrees of selectivity for COX-2, and increased cardiovascular risk, are ibuprofen, diclofenac, celecoxib (Celebrex, Pfizer), valdecoxib (Bextra, Searle), rofecoxib (Vioxx, Merck-no longer marketed), and etoricoxib (Arcoxia, Merck-not yet Food & Drug Administration-approved). Once a decision is made to prescribe an NSAID, additional concerns come into play.

For instance, patients should be monitored for increased blood pressure, edema, worsening renal function, and gastrointestinal bleeding. The new statement also suggests adding a proton pump inhibitor to patients who require low-dose aspirin, to diminish the risk of bleeding.

"The data clearly indicate that non-COX-2 NSAIDs and selective COX-2 inhibitors are associated with an increased risk of CV events," said Ng. "The risk appears to be accentuated in patients with underlying CV risk factors or documented CAD [coronary artery disease], although the exact magnitude of increased risk is poorly defined." Ng explained that there are numerous potential mechanisms that have been postulated to cause the increased risk, but the most commonly cited include inhibition of endothelial prostacyclin, which increased prothrombotic potential and raised blood pressure. "The risk also appears to be dose-dependent," Ng explained.

One other issue highlighted in the new statement involves whether patients using aspirin for cardioprotection can also use NSAIDs or selective COX-2 inhibitors for pain relief. According to the authors, evidence indicates that ibuprofen, but not rofecoxib, acetaminophen, or diclofenac, interferes with aspirin's ability to irreversibly acetylate the platelet COX-1 enzyme, and could, although it has never been proven, reduce the protective effect of aspirin on thrombosis. The FDA has also said that patients taking low-dose aspirin and ibuprofen 400 mg should take the ibuprofen at least 30 minutes after aspirin ingestion, or at least eight hours before aspirin ingestion to avoid any potential interaction.

"It is important for both healthcare practitioners and the lay public to recognize that the concomitant use of aspirin with ibuprofen is not recommended for patients with CV disease. In many instances, acetaminophen can be substituted for ibuprofen or other NSAIDs," Ng said.