Dallas, TX - The American Heart Association (AHA) has issued new guidance discouraging the use of both COX-2 inhibitors and regular nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with known heart disease or those thought to be at high risk of getting heart disease [1]. Not all experts, however, agree with the order of treatment recommended.

The statement, published online February 26, 2007, in Circulation, recommends a new stepwise approach to the treatment of musculoskeletal pain in such patients, starting with nonpharmacological treatments, such as physical therapy and exercise, weight loss to reduce stress on joints, and heat or cold therapy. If this does not provide enough pain relief, acetaminophen, aspirin, and even short-term use of narcotic analgesics are recommended as first-line drugs; NSAIDs with the lowest COX-2 selectivity should be used next; and the more-selective COX-2 inhibitors are at the bottom of the list, to be used only as a last resort.

The statement says that all drugs should be used at the lowest dose necessary to control symptoms and prescribed for the shortest time possible.

Lead author of the AHA statement, Dr Elliott Antman (Brigham and Women's Hospital, Boston, MA), told heartwire that when using an NSAID, physicians should start with naproxen, as this is one of the least-COX-2-selective agents. He said that the available data suggest that naproxen has a neutral effect on the heart. "There haven't been that many trials with naproxen, so we don't know for sure, but the previous view—that naproxen may be cardioprotective as it was associated with a lower rate of cardiac events than COX-2 inhibitors—is now known to be wrong. We now know that COX-2 inhibitors definitely increase risk, and it appears that naproxen is neutral in this regard."

Once the decision is made to prescribe an NSAID, the statement says that several additional points should be considered. These include:

• In patients at increased risk of thrombotic events, low-dose aspirin plus a proton-pump inhibitor could be added.
• COX-2 inhibitors can lead to impaired renal perfusion, sodium retention, and increases in blood pressure, which may contribute to their adverse cardiovascular effects. Therefore, renal function and blood pressure should be monitored in subjects taking COX-2 inhibitors, and extra caution should be exerted when these drugs are given to subjects with preexisting hypertension, renal disease, and heart failure.

The statement says that more data are also needed on the cardiovascular safety of conventional NSAIDs. But until such data are available, the use of any COX inhibitor, including over-the-counter NSAIDs, for long periods of time should be considered only in consultation with a physician.

There is confusion in the minds of both doctors and patients on how to treat musculoskeletal pain in heart-disease patients.

Antman told heartwire that the AHA statement has been issued at the current time as it was felt that there is now enough evidence to make some firm recommendations on the use of COX-2 inhibitors and NSAIDs in patients with or at risk of heart disease. "There have been several 'advisories' and notes of caution issued on this subject over the past few years, but there have been numerous different reports on this issue, and there is confusion in the minds of both doctors and patients on how to treat musculoskeletal pain in heart-disease patients. The AHA feels it is important to have very clear guidance for doctors on this, and now is a good time to issue this guidance, as we now have incontrovertible evidence that COX-2 inhibitors increase the risk of MI, and there is also now strong evidence to suggest that this is also a problem with regular NSAIDs," he commented.

Antman said that while the advice in this AHA statement is aimed particularly at the treatment of musculoskeletal pain in patients with or at high risk of heart disease and that patients at a low risk of heart disease can probably be treated a bit more liberally, he would still recommend that this stepped-care strategy is a reasonable approach for all patients, as the exact risk of heart disease is often unclear.

Another study published this week suggests that acetaminophen and aspirin, as well as NSAIDs, may increase the risk of hypertension [2]. Referring to this paper, published February 26, 2007 in the Archives of Internal Medicine, Antman told heartwire that this is a separate concern, which may be related to the inhibition of vasodilatory prostaglandins. "We know that NSAIDs can increase blood pressure. This is in addition to their prothrombotic effects. They have a double negative. While aspirin and acetaminophen may also have an effect on blood pressure, aspirin is known to be cardioprotective and acetaminophen appears to have neutral thrombotic effect."

heartwire asked a few cardiologists with an interest in this field and some rheumatologists for their thoughts on the AHA statement, and while all appear to support the recommendation that COX-2 inhibitors should be last on the list, some experts have questioned the advice to give a narcotic before a non-COX-2-selective NSAID, particularly naproxen.

I will be surprised if the rheumatology community will concur with this.

One to voice this opinion was cardiologist Dr Scott Solomon (Brigham and Women's Hospital). "I think the recommendation of using narcotics in the short term prior to using non-COX-2-selective NSAIDS will be quite controversial, and I will be surprised if the rheumatology community will concur with this. Overall there are very little data on cardiovascular risk with nonselective NSAIDS, although that is not the same as saying there is no risk. Physicians need to weigh any potential cardiovascular risks of nonselective NSAIDs together with the clear increased risk of GI bleeding against risk of abuse with narcotics," he commented to heartwire.

Rheumatologist Dr Michael Weinblatt (Brigham and Women's Hospital) concurred. "I totally agree with Dr Solomon's concerns about initial use of narcotics. It should also be noted that multiple different diseases are grouped in the musculoskeletal family, including rheumatoid arthritis [RA], which is a systemic inflammatory disease with increased morbidity and mortality. I would not agree with the recommendations that initial therapy of that disease focus on nonpharmacologic approaches. In fact, the initial approach of RA is institution of therapeutic doses of anti-inflammatory drugs and disease-modifying therapies. The use of narcotics as an initial therapy for rheumatoid arthritis is not supported by the extensive rheumatology literature," he said.

Antman responds that it is important that clinicians read the entire scientific statement to appreciate the context in which the recommendations are being made. He notes that the statement makes it clear that both safety and efficacy should be considered and the least risky medication should be tried first. "Clearly, if a physician felt that even a short course of narcotic analgesics posed an unacceptable risk of abuse in a given patient, that would not be an appropriate option to consider in the first line of the stepped-care approach. On the other hand, it can be argued that a short course of narcotic analgesics in the appropriately chosen patient with known heart disease or who is at risk for heart disease may well be a more desirable early option to try rather than jumping quickly to riskier drugs such as those with more COX-2 selectivity," he said.

Addressing Weinblatt's comments, Antman says: "The focus of our statement was on the selection of oral drugs from a cardiovascular-risk perspective rather than to provide guidelines for disease management to rheumatologists. Our statement is not at all inconsistent with the rheumatology guidelines that recommend topical agents and oral therapy for tendonitis/bursitis, topical and intra-articular agents and oral agents for noninflammatory conditions, and disease-modifying therapies followed by oral agents in inflammatory conditions."

 The data indicting all NSAIDs is over the top, in my opinion.

Dr Eric Topol (Scripps Clinic, La Jolla, CA), who was one of the first to identify the cardiac problems with COX-2 inhibitors, also feels strongly that narcotics should not be given before naproxen. "I use naproxen as the first-line agent, since it has never been invoked as having cardiovascular toxicity. The data [in the AHA statement] indicting all NSAIDs is over the top, in my opinion."

Antman responds: "The AHA statement provides a compilation of the latest available data on the more traditional NSAIDs and clearly shows an increased risk of CV events, whether one is looking at randomized trials, observational studies, or registries. Most of the data as summarized in the table in the statement indicate a risk with ibuprofen or diclofenac. The available data on naproxen, a non-COX-2-selective NSAID, suggest it is probably neutral with respect to cardiovascular risk and therefore, as per our recommendations, indeed it should be tried prior to NSAIDs with some COX-2 activity and certainly before the COX-2-selective NSAIDs."

Other cardiologists contacted by heartwire were supportive of the AHA statement, even the recommendation for early use of narcotics. Dr Harlan Krumholz (Yale University, New Haven, CT) described the statement as "an important distillation of the published literature," and Dr Debabrata Mukherjee (University of Lexington, KY) said he thought the stepwise approach advocated was "very reasonable." Mukherjee added: "We still have concerns about coxibs, and they should be used only as a last resort in patients with or at risk of heart disease. I think short-term use of tramadol or narcotics before even naproxen is reasonable, as we now understand the risks of even nonselective NSAIDs and the concern about an aspirin-NSAID interaction. However, one must be judicious in using narcotics in individuals with prior history of drug or substance abuse, and they should not be used for more than few weeks."