Feature

What have we learnt from Vioxx?

BMJ 2007; 334 doi: http://dx.doi.org/10.1136/bmj.39024.487720.68 (Published 18 January 2007) Cite this as: BMJ 2007;334:120
  1. Harlan M Krumholz, Harold H Hines Junior professor of medicine and epidemiology and public health1,
  2. Joseph S Ross, instructor2,
  3. Amos H Presler, research associate3,
  4. David S Egilman, clinical associate professor4
  1. 1Department of Medicine, Yale University School of Medicine, 333 Cedar Street, PO Box 208088, New Haven, CT 06520-8088, USA
  2. 2Department of Geriatrics and Adult Development, Mount Sinai School of Medicine, New York, USA
  3. 3Never Again Consulting, Attleboro, MA, USA
  4. 4Department of Bio Med Community Health, Brown University, Providence, RI, USA
  1. Correspondence to: H M Krumholz harlan.krumholz{at}yale.edu

    In October UK patients who had cardiovascular events while taking rofecoxib lost the right to fight Merck in the US for compensation. But researchers and journals can still benefit from this case if they learn from the mistakes, write Harlan Krumholz and colleagues

    Rofecoxib (Vioxx) was introduced by Merck in 1999 as an effective, safer alternative to non-steroidal anti-inflammatory drugs for the treatment of pain associated with osteoarthritis. It was subsequently found to increase the risk of cardiovascular disease and withdrawn from the worldwide market. Merck now faces legal claims from nearly 30 000 people who had cardiovascular events while taking the drug.1 The company has stated that it will fight each case, denying liability.2 Our recent participation in litigation at the request of plaintiffs provided a unique opportunity to thoroughly examine and reflect on much of the accumulated court documents, research, and other evidence. This story offers important lessons about how best to promote constructive collaboration between academic medicine and industry.

    Early suspicion of cardiovascular risk

    Since the early development of rofecoxib, some scientists at Merck were concerned that the drug might adversely affect the cardiovascular system by altering the ratio of prostacyclin to thromboxane, which act in opposition, balancing blood flow and clotting.w1 A study sponsored by Merck during 1996-7 reported that rofecoxib reduced urinary metabolites of prostacyclin in healthy volunteers by about half.w2 In internal emails made public through litigation,3 Merck officials sought to soften the academic authors' interpretation that cyclo-oxygenase-2 (COX 2) inhibition within the vascular endothelium may increase the propensity for thrombus formation, the basis of what became known as the FitzGerald hypothesis.w3 The academic authors changed the manuscript at Merck's request—for example, they changed “systemic biosynthesis of prostacyclin ... was decreased by [rofecoxib]” to “Cox-2 may play a role in the systematic biosynthesis of …

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