As a strong analgesic with a significantly lower risk of stomach pain, rofecoxib (Vioxx) was a wildly successful painkiller with a worldwide annual revenue of 2.5 billion USD. However, following mounting evidence and public discovery that Vioxx doubles the risk of myocardial infarction and stroke, Merck & Co. withdrew the drug from the market on September 30, 2004 (Berkrot 2008; Karha & Eric Topol 2004). With millions of prescriptions in 80 countries at the time, this marked one of the most prominent prescription drug withdrawals in history (The Lancet 2004).
Vioxx is a non-steroidal anti-inflammatory drug (NSAID) that counteracts a multitude of conditions including arthritis, migraines and dysmenorrhea. The mechanism of most NSAIDs can be attributed to the inhibition of cyclooxygenase, which serves as a catalyst for the bisoxygenation of arachidonic acid to prostaglandin, a messenger molecule (see Fig. 1). Cyclooxygenase exists in two isoforms, COX-1 and COX-2. COX-1 works to produce prostaglandins involved in kidney function regulation, platelet function and stomach protection; while COX-2 is responsible for the production of prostaglandins involved in inflammation (Botting 2006). Although many NSAIDs are non-specific and target both COX isoforms, Vioxx falls within the category of specific COX-2 inhibitors, allowing it to treat inflammation without causing adverse gastrointestinal effects (Chan et al. 1999).
From the cardiovascular perspective however, the effects of Vioxx take a different turn. While COX-1 is a source of vasoconstrictor thromboxane A2, COX-2 produces vasodilator prostacyclin. Upon the inhibition of COX-2, the equilibrium between thromboxane A2 and prostacyclin is shifted and as a result, thrombosis (blood clots) and artherogenesis (formation of plaque) can occur (Bresalier et al. 2005). This is reflected in several epidemiological studies, where Vioxx use was found to increase the risk of heart disease compared to other NSAIDs (Graham et al. 2005). From these mechanisms, it is important to note that non-specific COX inhibitors and selective COX-2 inhibitors both possess beneficial and detrimental effects. On one side of the spectrum, there is a tradeoff between gastrointestinal protection and greater risk of cardiovascular disease when using COX-2 inhibitors; while non-specific COX inhibitors present gastrointestinal toxicity but a lower chance of cardiovascular disease (Mukherjee et al. 2001). Given the distinctions between each individual patient, it is essential that healthcare professionals must take this tradeoff into consideration when prescribing painkillers.
Unfortunately, information regarding the cardiovascular risk associated with Vioxx failed to emerge before it was too late. By September 2004, Vioxx was estimated to have caused between 80 000 to 138 000 heart attacks and cardiac deaths in the US (US Senate 2004). Following its withdrawal, it became clear to the scientific community and the general public that Merck and the FDA were both aware of the increased risks years before Vioxx was withdrawn (Canadian Medical Association 2005). This influx of controversial information brought attention to the heavy influence of drug companies, and cast a doubt on the ability of current national agencies to protect the public. In a society that trusts implicitly in national agencies, this serves as a reminder that flaws do exist in the current systems and that we should work to question information that has been given to us.
References
Berkrot, B., 2008. Merck confident will meet Vioxx settlement goals . Reuters. Available at: http://www.reuters.com/article/2008/01/17/idUSN1655298220080117 [Accessed 5 October 2013].
Botting, R., 2006. Inhibitors of Cyclooxygenases: Mechanisms, Selectivity and Uses. Journal of Physiology and Pharmacology, 57(5), pp.113–124.
Bresalier, R. et al., 2005. Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial. The New England Journal of Medicine, 352(11), pp.1092–1102.
Canadian Medical Association, 2005. Vioxx: lessons for Health Canada and the FDA. Canadian Medical Association Journal, 172(1).
Chan, C. et al., 1999. Rofecoxib [Vioxx, MK-0966; 4-(4. The Journal of Pharmacology and Experimental Therapeutics, 290(2), pp.551–560.
Graham, D. et al., 2005. 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. The Lancet, 365(9458), pp.475–481.
Karha, J. & Topol, Eric, 2004. The sad story of Vioxx, and what we should learn from it. Cleveland Clinic Journal of Medicine, 71(12), pp.933–939.
Mukherjee, D., Nissen, S. & Topol, E, 2001. Risk of Cardiovascular Events Associated With Selective COX-2 Inhibitors. The Journal of the American Medical Association, 286(8), pp.954–959.
The Lancet, 2004. Vioxx: an unequal partnership between safety and efficacy. The Lancet, 364(9442), pp.1287–1288.
Olympics Blog, 2008. How NSAIDs block protective prostaglandins. [electronic print] Available at: http://www.pponline.co.uk/encyc/drugs-and-recovery-pain-relief-medication-may-not-be-the-answer-to-a-speedy-recovery-1048 [Accessed 6 October 2013].
US Senate, 2004. Testimony of David J. Graham, MD, MPH. Available at: http://www.senate.gov [Accessed 6 October 2013].