Vioxx Blamed for up to 140,000 Cases of Heart Disease in USA and Hints of a Government Cover-up
By Dr John Reggars

No doubt most of you will be aware that Vioxx (rofecoxib), a commonly prescribed Cox-2 inhibitor, was recently withdrawn from sales in Australia and the rest of the world. The withdrawal was a “voluntary” one by the pharmaceutical company Merck & Co. (see www.vioxx.com), due to the revelation that it caused an increased rate of cardiovascular events. A fascinating story has developed that goes behind the scenes of the processes of pharmaceutical regulation.

A recent study published in The Lancet¹ was led by Dr. David Graham, Associate Director for Science at the US Food and Drug Administration’s Office of Drug Safety. Graham has been a longstanding critic of Vioxx and in their study he and his colleagues compared Vioxx with another Cox-2 inhibitor, Celebrex, and with one of the older NSAID’s, naproxen. Overall they found those taking Vioxx had, depending on the dose, between 47% and 360% higher risk of coronary heart disease than those taking Celebrex. While there was no increased risk of coronary disease in the Celebrex group those taking naproxen had a 14% increased risk, which is contrary to previous studies that suggested naproxen protected against heart disease.

Amazingly, in the US alone, 106.7 million prescriptions were written for Vioxx between 1999 and September 2004. With such a vast amount of money involved is it any wonder that Merck & Co., the manufacturer of Vioxx, has apparently tried to suppress or discredit the adverse research findings? But it does not stop there. The FDA has also been charged with a cover-up. According to Graham, the FDA threatened him with serious consequences and did everything in its power to suppress the findings when he first submitted his study for publication. According to a different editorial², Merck forced another researcher, who was an employee, to remove her name from an earlier Merck funded study linking Vioxx to heart disease. Furthermore, although Merck funded the study and agreed to its design they publicly discredited the findings because of what they stated were “serious limitations to the analysis”.

While it is understandable that Merck would attempt to protect its interests by attacking any adverse publicity, the implication that the omnipotent FDA would deliberately deceive or gag adverse research findings is most disturbing. In a recent editorial, published in the Archives of Internal Medicine³, the authors claim that there was sufficient evidence to link Vioxx with an increased cardiovascular risk as early as 2000, the year after the drug’s approval. In 2002 the FDA did raise concerns about Vioxx’s cardiovascular safety but the only action taken was to have an additional statement included in the packaging cautioning patients with a history of ischemic heart disease.

At the heart of the concerns of many involved in this debate is the FDA’s 1990’s revamped review process, which permits drug manufacturers to pay the FDA a fee in return for shorter approval time. As a trade off for this shorter approval time the FDA requires post marketing surveillance but, according to some researchers², the agency’s capacity to demand such studies be done in a timely way has been far weaker than its authority over pre-approval requirements. Since the mid 1990’s the proportion of drugs for which the FDA requires post marketing surveillance has grown to one third of all approvals and, using the Vioxx example, it appears that the revamped system is not working. World renowned epidemiologist, Richard Deyo, in a recent paper noted that there are significant holes in the FDA’s regulatory safety net.³ According to Deyo about 3% of all drugs approved by the FDA from 1975 to 1999 were withdrawn for safety reasons and another 8% required a “black box” warning about potential serious side effects on the information leaflet. Deyo reckons that as many as one in five drugs may eventually be withdrawn or require “black box” warnings.

To further add fuel to the fire there have also been reports of conflicts of interest among researchers.⁴ Dr. Eric Topol, an outspoken cardiologist and chief academic officer of the Cleveland Clinic Foundation has been accused of a potential conflict of interest over his rigorous public criticism of Vioxx. The Cleveland Clinic is one of the most entrepreneurial and prestigious medical institutions in the US and it was revealed that Dr. Topol was a paid consultant to a hedge fund that had made money betting that shares in Merck would fall.

As mentioned above in the trial that found that Vioxx increased the risk of cardiovascular disease¹ no increased risk was found with Celebrex. However, another study on Celebrex and Alzheimer’s disease did find an increased risk of heart attack and stroke in patients taking this popular Cox-2 inhibitor.⁵ In fact one consumer group, Public Citizen, accused Pfizer of burying the results of this study and filed a petition urging the FDA to withdraw its approval and pull it from the market because of links to dangerous heart complications.

Finally, a recent Australian study has found that good ol’ paracetamol was as good if not better than ibuprofen or the newer Cox-2 inhibitor drugs in controlling pain.⁶ Nikles et al and colleagues from the University of Queensland conducted a small Double Blind Crossover Placebo RCT comparing paracetamol to ibuprofen and Cox-2 inhibitors in patients with osteoarthritis. The researchers found that 2/3 of patients in the trial considered paracetamol to be as effective as or more effective than the anti-inflammatory drugs in controlling their pain and that, after the trial, over half the patients in the trial, who had been using the newer drugs, decided to take paracetamol instead.

1. Graham DJ. The risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365(9458):475-81.
2. Solomon DH, Avorn J. Coxibs, Science, and the Public Trust. Arch Intern Med 2005; 165:158-60.
3. Deyo RA. Gaps, tensions and conflicts in the FDA approval process: Impications for clinical practice. J American Board Fam Pract 2004; 17(2):142-9.
4. Abelson R, Pollack A. Ethics: Clevaland Clinic reviews possible conflict of interest with business. New York Times January 25, 2005.
5. Pfizer Inc. A Placebo-Controlled Evaluation of the Long-Term Efficacy and Safety of Celecoxib (SC-58635) in Alzheimer’s Disease. Unpublished; 1999.
6. Nikles CJ, Yelland M, Glasziou PP, Del Mar C. Do Individualized Medication Effectiveness Tests (N-of-1 Trials) Change Clinical Decisions About Which Drugs to Use for Osteoarthritis and Chronic Pain? Am J Ther. 2005; 12(1):92-7.