The Cardiovascular Safety of COX-2 Inhibitors

A Joint Meeting of the FDA Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee was held on February 16 through 18, 2005.  The committees discussed the overall benefit to risk considerations (including cardiovascular and gastrointestinal safety concerns) for COX-2 selective nonsteroidal anti-inflammatory drugs and related agents (see FDA Notice of COX-2 Meeting).

"Interested persons may present data, information, or views, orally or in writing, on issues pending before the committee. Written submissions may be made to the Division of Dockets Management....... FDA welcomes the attendance of the public at its advisory committee meetings...... Electronic comments should be submitted to http://www.fda.gov/dockets/ecomments."

TMT has downloaded the relevant Advisory Committee documents available on the FDA website (FDA Website - CDER Meeting Documents) as Word documents where available, and as PDF files if not, and has posted these on the TMT website to serve as a secondary download source (TMT Website - CDER Meeting Documents).

Because of its interest in the evaluation and management of chronic pain, Taylor MicroTechnology, Inc. (TMT) has been carefully following the public discussions on COX-2 safety since Vioxx was withdrawn from the market on September 30, 2004. There are very diverse views in the medical community regarding the cardiovascular safety of COX-2 inhibitors. It is TMT's considered opinion that Celebrex (celecoxib) is the most extensively studied among marketed COX-2 inhibitors and should continue to be available as one of the therapeutic options for patients with chronic pain

(see TMT Review of Cardiovascular Safety of Celebrex).

TMT Overview

• As with most chronic-use drugs, most chronic pain drugs have not been subjected to the type of study (long-term, controlled evaluation of cardiovascular endpoints) necessary for adequate assessment of cardiovascular safety.
• An exception is aspirin which has been conclusively shown to reduce cardiovascular events. However, aspirin also increases the risk of GI hemorrhage, so that for many patients aspirin therapy is not suitable for the treatment of chronic pain.
• Since the introduction of selective COX-2 inhibitors, long-term controlled studies evaluating cardiovascular safety have been performed and there is now evidence that some COX-2 inhibitors, and possibly the conventional NSAID naproxen, may increase cardiovascular risk (particularly heart attack, stroke and other thrombogenic events). Insufficient cardiovascular safety data are available for most NSAIDs. Note added 2/20/05: The above comment on naproxen was based on a December 2004 press release from the NIH on the ADAPT trial in Alzheimer's Disease which "indicated an apparent increase in cardiovascular and cerebrovascular events" among naproxen patients versus patients receiving a placebo. At the COX-2 Advisory Committee meeting in February 2005, this assertion was withdrawn and it was stated that the trial was discontinued because of the "practicalities" of continuing the trial and that "some post-hoc data composites barely reached [statistical] significance" for naproxen.
• It is not yet clear whether increased cardiovascular risk is a class effect of COX-2 inhibitors, a class effect of non-aspirin drugs for chronic pain, or a drug-specific effect confined to certain drugs in the COX-2 or non-COX-2 NSAID drug classes.
• A unifying hypothesis based on the thromboxane/prostacyclin pathways has been proposed as a basis for a class effect of COX-2 inhibitors. However, this hypothesis has not been fully supported by the actual data.
• Significant differences in molecular structure and effects on blood pressure have been shown between different COX-2 inhibitors and there is some evidence that COX-2 inhibitors that increase blood pressure may be associated with greater cardiovascular risk.
• The limited evidence suggests that increasing doses of some COX-2 inhibitors are associated with progressive increase in cardiovascular risk.

 TMT Recommendation

 The following course of action seems prudent at this time:

• Drugs for chronic pain should continue to be made available to patients with chronic arthritis or other causes of chronic pain.
• Aspirin and acetaminophen may be excellent choices for many patients.
• Dosage and duration of therapy of any drug for chronic pain should be limited to that necessary for adequate pain relief.
• Particular caution in drug selection is necessary when treating patients who also have increased cardiovascular risk or an increased risk of a GI bleed.
• Of the currently marketed COX-2 inhibitors in the United States, celecoxib (Celebrex) appears to have the most extensive safety evaluation and the most favorable safety profile. No evidence of increased cardiovascular risk has been shown at dosage of 200 mg/day or less.
• The maximum Celebrex dosage should be restricted to 200 mg/day until additional safety data become available.
• Direct marketing of Celebrex to the consumer should not be resumed, and should be discouraged for medications in general.
• Celebrex should continue to be one of the options available for the treatment of chronic pain.

Posted on www.masterdocs.com on February 5, 2005 and revised February 7, 2005.

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