COX-2 Inhibitor Safety: HSS Physicians Reflect on the Recommendations of the FDA Advisory Panel

What was said?
What was speculated?
What are the implications for practice?

On February 16-18, 2005 a joint meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee convened to discuss the topic of COX-2 inhibitors. This was an open meeting comprised of 32 voting members, 8 of whom were rheumatologists.  In attendance were patients, patients' representatives, representatives of the FDA, and members of the pharmaceutical industry. Detailed presentations were given by FDA reviewers and pharmaceutical manufacturers on the cardiovascular safety of COX-2 inhibitors presently or previously marketed in the U.S.: rofecoxib (Vioxx®), celecoxib (Celebrex®), and valdecoxib (Bextra®); COX-2 inhibitors not presently marketed in the U.S.: etoricoxib (Arcoxia®) and lumiracoxib (Prexige®); and the non-selective non-steroidal anti-inflammatory agent naproxen (Naprosyn® and Aleve®).

With regard to the three COX-2 inhibitors presently or previously marketed in the U.S., the panel was charged with answering by vote, for each drug, the following questions after hearing the presentations:

1) Does the agent pose a significant risk for cardiovascular events?

2) Does the risk versus benefit profile of the drug  (when used for the approved indication in accord with product labeling) support its continued marketing in the U.S.?

3) If continued marketing is supported, what actions are recommended to ensure its safe use?

Confining them to voting only on the above "asked" questions, the committee's conclusions were:

1) All of the COX-2 inhibitors currently or previously available in the United States (celecoxib, valdecoxib, and rofecoxib) significantly increase the risk of cardiovascular events in users of these drugs.

2) Considering potential benefits, as well as risks and their magnitude, celecoxib, valdecoxib, and rofecoxib should be permitted to be marketed for their currently indicated uses. Although the vote was different in the case of each drug, (with celecoxib receiving the most favorable margin), the conclusion was the same for each of the three agents.

3) The committee unanimously voted that a "black box" warning should be added to the label of each of the COX-2 inhibitors, indicating potential cardiovascular risk and encouraging avoidance in high-risk individuals.

4) Committee members also favored adding a warning, rather than a "black box," to the product labels of currently marketed traditional non-selective non-steroidal anti-inflammatory agents with regard to cardiovascular risk. .

5) The committee unanimously favored educational measures in this field directed at physicians and patients.

6) Most committee members also favored restrictions on direct-to-consumer advertising of COX-2 inhibitors.

7) All committee members voted in favor of requiring the makers of future agents, both COX-2 selective agents and non-selective NSAID's, to perform cardiovascular safety studies prior to market introduction.

Although the FDA will review the above panel recommendations, it is expected that they will be expediently adopted. Clinicians will likely first see changes in product labeling, followed by patient and physician educational efforts, and, lastly, prospective safety trials of new agents.

Of note is the fact that the future availability of rofecoxib, etoricoxib, and lumiracoxib was not discussed.

Analysis and Comment from HSS Rheumatologists

We applaud the careful review and analysis of the data by the committee. We were similarly gratified and pleased to see that the view of "the patients"-- those who will reap the benefits and be exposed to the side effects -- were aired, listened to, and factored into the committee's recommendations.

The answers are neither simple nor straightforward, but nevertheless the committee evaluated the data and made, in our opinion, just, wise, and helpful initial recommendations.

We, as rheumatologists, care for patients with years of chronic disease complicated with many comorbidities.  Maintaining as near as normal activities of daily life is crucial to these individuals.  In that respect, a careful analysis of the risks (side effects) versus benefits (leading a nearly normal life) is so important. The FDA committee strongly advocated that analysis in the case of each individual patient.

We feel that this is a clear mandate for every physician to sit down, evaluate each patient's condition on an individual basis, and make an intelligent decision incorporating the patient's wishes for a normal life before withholding any therapy. COX-2 inhibitors, as well as the traditional NSAID's, offer hope of a normal life by decreasing inflammation and controlling pain, while at the same time posing some risk. Risk is not to be minimized but neither is "quality of life."  We, as educated physicians, have a responsibility to balance these often conflicting factors every time we offer any treatment to a patient.

In one respect, we may differ with the committee.  Although the lowest possible dose of any agent poses the lowest risk, in many cases of patients with lifelong arthritis, the lowest dose may not always provide the optimal risk vs. benefit ratio.  A physician may be inclined to choose a suboptimal dose with less efficacy to provide "more safety."   Unfortunately, in the case of COX-2's and traditional NSAID's, that has not been optimal in every case.  In fact, low doses may potentially cause unacceptably high risk when considering the fact that they may provide suboptimal benefit. Again, the wisdom, analysis, and opinion of the treating physician are very important here. We urge every physician to analyze each case individually and use the dose that "works" for that particular patient. 

Low dose aspirin is also indicated in cases of patients with increased cardiovascular risk for stroke and coronary artery disease. The decrease in risk obtained by low dose aspirin is not obtained with the use of traditional NSAID's or COX -2 inhibitors. Similarly, low dose aspirin does not provide the anti-inflammatory effect or pain control that provided by appropriate doses of NSAIDs or COX-2 inhibitors. Physicians should assess patients' risk for GI side effects of NSAID's (see Table 1) to identify those who need co-therapy for gastroprotection, and add appropriate proton pump inhibitors (e.g. esomeprazole, lansoprazole, or omeprazole) or prostaglandin E1analog (misoprostol) to their regimen. 

We look forward to implementation of the committee's recommendations and we will continue to analyze and comment upon on any new data or recommendations on the topic of "COX-2 inhibitor safety" as they become available.

Table 1:  Risk Factors for GI toxicity of NSAID's

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posted 3/7/2005