Thursday, March 24, 2005

Dr. Califf Summarizes Coxibs Issues at ACC
By Julie McKeel

DCRI Director Dr. Rob Califf summarized the issues related to the cardiovascular effects of the COX-2 inhibitors/nonsteroidal anti-inflammatory drugs (NSAIDs) during a session at the recent American College of Cardiology (ACC) 2005 Scientific Sessions. He also made some recommendations on how to move forward.

[COX-2 inhibitor arthritis inflammation drugs were developed to selectively block the COX-2 enzyme. Blocking this enzyme impedes the production of the chemical messengers (prostaglandins) that cause the arthritis pain and swelling. NSAIDs are commonly prescribed medications for the inflammation of arthritis and other body tissues.]

During the discussion, Califf questioned why there was so little evidence evaluating the balance of pain relief benefit and cardiovascular/gastrointestinal (GI) risk with either the COX-2 inhibitors or the regular NSAIDs. "Our system of drug development and postmarketing surveillance has failed to produce a solid estimate of the balance of risks and benefits for any patients taking chronic NSAIDs or coxibs,” Califf told the audience. “How can it be that, despite all the money spent on these drugs, we still can't tell the consumer what the balance of risks and benefits are for any of them?"

According to Califf, cardiovascular disease may be the leading cause of death in the Western world, but arthritis is the leading cause of disability. "Who among us does not have an aching joint? All of us have an interest in this." And, he continued, NSAIDs will become more important as the population ages. "I can guarantee that almost everyone over 65 takes these drugs, and not just occasionally. But these drugs do cause GI bleeding, which is a real big problem."

While it was hoped that the new COX-2-selective drugs would block the pain without causing bleeding and GI problems, they had another downside in that they appear to increase cardiovascular events. While most, if not all, treatment options include a balance of risk and benefit, Califf suggested changing the doctor's oath from "Do no harm" to "On average, do more good than harm."

In general, according to Califf, NSAIDs hold more cardiovascular risk. Naproxen is the exception due to its slightly reduced risk of forming blood clots.

Califf recommended that low-dose aspirin should be continued when indicated. When possible, alternatives to NSAIDs should be considered, such as acetaminophen and topical therapies. If an NSAID is used, naproxen plus a proton pump inhibitor should be used first. And COX-2-selective drugs should be avoided unless the above strategies fail.

Califf’s recommendations to consider naproxen plus a proton pump inhibitor (PPI) as the treatment of first choice now for patients needing an NSAID align with those made at the FDA last month.

He also recommended a large-scale study of COX-2-selective drugs with naproxen plus a proton pump inhibitor as a control arm. The patients should include a mix of aspirin takers and patients at high risk of heart disease, and clinical benefit should be the primary end point. Clinical benefit would take into account pain relief, as well as GI and cardiovascular events.

Other speakers at the COX-2 session were not sure whether a trial in patients at high risk of heart disease would be practical. Some members thought it would be difficult to recruit patients who are likely to have a cardiovascular event.

Califf disagrees with this view, saying that since many patients with known coronary disease are already taking these drugs, there should be no problem recruiting for this trial we'd have no trouble with enrollment.

But having recommended that an NSAID/PPI be the first-line choice and that coxibs should be reserved for patients who cannot take this combination or for whom it does not work, is it appropriate to then recommend randomizing between an NSAID/PPI and a coxib in a clinical trial?

Califf reminded the audience that “we have to make recommendations using judgment and the data we have.” Based on the available data, nearly all experts recommended the naproxen/PPI treatment option. However, the uncertainty [about this treatment option] should be an incentive to join a controlled to resolve the uncertainty.