Risk Factors vs. Side Effects
The risk factors of a drug are different from its side effects. While both represent unintended effects, risk factors are typically more rare and more serious than side effects. Risk factors may change with extended use of a drug; thus, sometimes a drug’s serious risk factors don’t appear until after it has been used for long-term treatment.
Major Risk Factors of Vioxx
Gastrointestinal Complications
All NSAIDs carry the risk of gastrointestinal (GI) complications, including potentially fatal bleeding ulcers in the stomach and/or intestines. Doctors have long known of these risks; in fact, stomach problems caused by NSAIDs prompted researchers to develop a new class of drugs, “super aspirins,” which promised the same pain relief with fewer GI complications. Although Vioxx caused less gastrointestinal irritation than traditional NSAIDs (like naproxen) in clinical trials, it was still associated with some risk of ulceration.
Cardiovascular Risks of Vioxx
The Vioxx GI Outcomes Research (VIGOR) study, which tested the effectiveness of Vioxx vs. naproxen in treating arthritis, found a two-fold increase in heart attacks among Vioxx patients. These results were submitted to the FDA in 2001, and in 2002, the FDA instructed Merck to add a black box warning to the Vioxx packaging concerning heart attacks. Although these results seemed to be an early warning that Vioxx carried a severe cardiovascular risk, the findings were interpreted as a positive statement about the protective effects of naproxen, rather than a statement about the dangers of Vioxx.
The APPROVe study, which tested the effectiveness of Vioxx vs. placebo on pre-cancerous colorectal adenomas, provided the first definitive evidence for the cardiovascular risks of Vioxx. After 18 months of treatment, study participants who took Vioxx had nearly twice the risk of fatal cardiovascular events, including heart attack and stroke. The Data Safety Monitoring Board overseeing the APPROVe study called for the early termination of the study; consequently, Vioxx was withdrawn from the worldwide market in 2004.
Explanation for Vioxx’s Adverse Cardiovascular Effects
As discussed in How Vioxx Works, NSAIDs work by targeting cyclooxygenase, an enzyme which facilitates the production of prostanoids in the body. There are different types of prostanoids, each with a different physical function. For example, the prostaglandin responsible for inflammation and pain is formed in response to physical triggers, such as the erosion of cartilage that occurs with arthritis.
While prostaglandin is the specific prostanoid targeted by Vioxx, the drug also suppresses other types of prostanoids, including prostacyclins. This unintended effect is the origin of Vioxx’s serious risks.
Prostacyclins act as anti-clotting agents in the blood. By interfering with the production of prostacyclin, Vioxx put patients at greater risk of blood clots, heart attacks, and strokes.
A 2005 animal study at Vanderbilt University showed that it might be possible to prevent the adverse effects of COX-2 inhibitors by using aspirin. This finding gave the community of arthritis sufferers hope that there was the potential for new drugs that lacked the risks of Vioxx.
Duration of Vioxx Treatment
In clinical trials, the incidence of heart attack increased dramatically for patients who had been using Vioxx between 12 and 18 months. Clinical research on short-term Vioxx use showed no significant elevated cardiovascular risk. However, after between 12 and 18 months of continuous treatment, study participants who received Vioxx had 2-5 times more heart attacks than those in placebo groups. This made the drug undesirable for chronic pain conditions like arthritis.
Vioxx was on the market for more than 4 years.
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