Wednesday, September 13, 2006

Merck - Vioxx: Dr David Graham - "The seduction of common sense"

PharmaGossip's favourite FDA person Dr David Graham has an editorial in JAMA. It's about Vioxx (rofecoxib) and the other coxibs:

What does this all mean? First, rofecoxib increases the risk of acute MI at low and high doses. This risk begins early in therapy, probably with the first dose. There is no initial 18-month period of immunity from risk.17-19,21, 26 Celecoxib also increases risk at doses higher than 200 mg/d; at lower doses, the potential risk is less clear. Several other NSAIDs increase risk, including the COX-2 selective NSAIDs diclofenac and meloxicam, and the nonselective NSAID indomethacin, and probably ibuprofen. Meta-analyses of randomized clinical trials and observational studies agree that naproxen is neutral for MI risk.

It ends looking at the latest Merck coxib, etoricoxib and the MEDAL study:

By inference, therefore, etoricoxib also must increase cardiovascular risk, but that inference is not immediately apparent because of the way MEDAL was designed, and by the way it appears that the findings are being interpreted and positioned.

This veiled and misleading ambiguity has much in common with the stratagems used for VIGOR and APPROVe, where the true results were opposite to those claimed and promoted. From the perspective of patient safety and rational therapeutics, naproxen, not diclofenac, should have been the reference drug in MEDAL.33 Had that been so, it is highly likely that etoricoxib would have been shown to be no different than its first-cousin rofecoxib with respect to cardiovascular risk. From a business perspective, were etoricoxib to be exposed as another "naked emperor," its US approval might be difficult, even by the FDA's apparently industry-friendly standards. If the lessons of recent history have been learned, the FDA's concerns will now be squarely focused on patient safety rather than corporate profitability, and, ultimately, common sense will prevail.

Bravo, Dr Graham!


Anonymous said...

The editorial by David J. Graham, M.D., M.P.H (1) is incorrect in stating that “ Traditional nonsteroidal anti-inflammatory drugs (NSAIDs) inhibited both isoforms of the enzyme cyclooxygenase responsible for the first step in the conversion of arachidonic acid into a variety of prostaglandins, thromboxanes, and leukotrienes throughout the body.”
Dr. Graham overlooked that arachidonic acid, which is cleaved by phospholipases A2, can be oxidized either by cyclo-oxygenases, or by lipoxygenases which are iron metallo-enzymes, at the origin of the formation of anandamide. The lipoxygenase pathway leads to the formation of leukotrienes and lipoxins, whereas the COX pathway leads to formation of prostaglandins and thromboxanes.

1. Graham DJ. COX-2 Inhibitors, Other NSAIDs, and Cardiovascular Risk: The Seduction of Common Sense. JAMA. 2006 Sep 12; [Epub ahead of print]

Michal R. Pijak, M.D., Consultant and Assistant Professor of Medicine, Rheumatology, Allergy and Clinical Immunology, Division of Clinical Immunology, Department of Internal Medicine, University Hospital Bratislava, Slovakia.

insider said...

Thank you for your comment.

Are you going to write to the journal as well?