Vioxx

Vioxx, what is Rofecoxib?

Rofecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that was used in the treatment of osteoarthritis, acute pain conditions, and dysmenorrhoea. Formerly marketed by Merck & Co. under the trade names Vioxx, Ceoxx and Ceeoxx, it was voluntarily withdrawn from the market in 2004 because of concerns about increased risk of heart attack and stroke.

Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. Worldwide, over two million people were prescribed Vioxx at the time. In the year before withdrawal, Merck had a sales revenue of US$2.5 billion from Vioxx.

Rofecoxib was available on prescription as tablets and as an oral suspension.

Vioxx, COX-2 selective inhibitor.

Rofecoxib belongs to the group of NSAIDs known as COX-2 selective inhibitors or coxibs (CycloOXygenase-2 Inhibitors). Being COX-2 selective means that these drugs act specifically on one form of the cyclooxygenase (COX) enzyme, namely the COX-2, whereas previous NSAIDs inhibited both COX-1 and COX-2. This specificity allows rofecoxib and other COX-2 inhibitors to reduce inflammation and pain while minimizing undesired gastrointestinal adverse effects - peptic ulcers - that are common with non-selective NSAIDs such as aspirin, naproxen, and ibuprofen.

Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. (Bombardier et al., 2000).

Vioxx, adverse drug reactions.

Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs.

Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects - they reduce pain, fever and inflammation. The term "non-steroidal" is used to distinguish these drugs from steroids, which (amongst a broad range of other effects) have a similar eicosanoid depressing anti-inflammatory action. NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs). The most prominent members of this group of drugs are aspirin and ibuprofen. Paracetamol, or acetaminophen, has little anti-inflammatory activity, and is not an NSAID.

Beginning in 1829, with the isolation of salicylic acid from the folk remedy willow bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Part of the popularity of NSAIDs is that, unlike opioids, they do not produce sedation, respiratory depression, or addiction. NSAIDs, however, are not without their own problems (see below). Certain NSAIDs have become accepted as relatively safe, resulting in the rescheduling of these agents, e.g. ibuprofen, to allow availability over-the-counter.

Vioxx, market withdrawal.

VIGOR study

The VIGOR study, published in 2000, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. There was no significant difference in the mortality from cardiovascular events between the two groups. Nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was accounted for by the patients meeting the criteria for low-dose aspirin prophyalxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, angioplasty, or coronary bypass), but who were excluded from taking low-dose aspirin in the initial design study. Once this risk was noted, Merck notified investigators in other rofecoxib studies to modify allow high-risk patients to take low-dose aspirin. (Bombardier et al., 2000)

Merck's scientists interpreted the finding as a protective effect of naproxen in reducing the risk of MI in high cardiovascular risk patients by 80 percent (which some commentators have noted would make naproxen three times as effective as aspirin). The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001, which led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke).

In sum, the VIGOR study suggested that medium-term use of rofecoxib resulted in nearly four-times the risk of suffering a heart attack or stroke in patients already at high risk of adverse cardiovascuar events compared to patients receiving a placebo. There was no difference in risk for patients with normal cardiovascular risk.

APPROVe study

In 2001, Merck commenced the APPROVe (Adenomatous Polyp Prevention on Vioxx) study, a three year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib.

The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. (Bresalier et al., 2005) Previous Phase III clinical trials had also not shown this trend. (Swan, 2004)

In sum, the APPROVe study suggested that long-term use of of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo.

Withdrawal

Merck publicly announced the withdrawal of the drug from the market worldwide on September 30, 2004.

In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.

On November 5 the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis (Merck & Co., 2004).

Other COX-2 inhibitors

It is currently unknown whether the increased risk of adverse cardiovascular events is common to all COX-2 inhibitors. Recent studies have demonstrated the increased risk of cardiovascular events associated with the use of celecoxib, valdecoxib and parecoxib. (Solomon et al., 2005; Nussmeier et al., 2005)

Newer and more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), are currently undergoing Phase III/IV clinical trials. It is likely that these trials will be extended in order to supply additional evidence of cardiovascular safety.

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