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Arthritis after Vioxx®

February 2005

By Richard P. Huemer, MD

Last fall, doctors and patients were stunned by Merck’s voluntary worldwide withdrawal of its arthritis drug Vioxx® (rofecoxib) from the market, the largest prescription drug withdrawal in history. Vioxx® and other COX-2 (cyclooxygenase-2) inhibitors had been promoted as “wonder drugs” because of their ability to relieve arthritis pain without causing the stomach problems associated with other pain medications.

This startling decision to abandon Vioxx®

followed the report of a significant increase in heart attacks and strokes among long-term users of the drug.1,2 An estimated 80 million people had taken Vioxx® by the time it was withdrawn, and annual sales of the drug exceeded $2.5 billion. The news media speculated on which drugs might fill the gap left by Vioxx®, while devoting curiously little attention to natural arthritis remedies.3

Although Merck’s announcement came as a surprise to many, doubts about the drug had surfaced years earlier. In early 2001—less two years after the FDA approved Vioxx®—the FDA’s Advisory Committee on Arthritis met to discuss potential cardiovascular risks associated with Vioxx®.

Critics Blast FDA, Merck

Commenting on the 2001 FDA Advisory Committee meeting, Eric J. Topol, MD, wrote a stinging editorial in the October 21, 2004, issue of the New England Journal of Medicine, titled “Failing the Public Health—Rofecoxib, Merck, and the FDA.” Dr. Topol charged that the FDA never exercised its initiative to mandate a trial of rofecoxib (Vioxx®) and a similar drug, celecoxib (Celebrex®), in relation to their cardiovascular risks or benefits, despite evidence suggesting a correlation. Nor did Merck embrace the idea of conducting a trial to assess cardiovascular risk or benefit associated with Vioxx®. Instead, Merck sponsored educational symposia and commissioned medical articles to debunk the cardiovascular concerns associated with Vioxx®, while spending more than $100 million a year to promote the drug with direct-to-consumer advertising.4

In November 2004, Dr. David Graham, associate director for science at the FDA’s Office of Drug Safety and a 20-year FDA scientist, testified before Congress about the FDA’s failure to protect the public health, calling the agency’s oversight of the drug “a profound regulatory failure.” Although concerns about the safety of Vioxx® had been building for several years, the FDA maintained that the drug’s benefits of providing pain relief with minimal gastrointestinal side effects warranted keeping it on the market, albeit with a warning about heart risks. Vioxx® was finally taken off the market on September 30, 2004, following the release of a study showing that the drug doubled the risk of heart attack and stroke in long-term users.

By this time, millions of Americans had used the drug, and Dr. Graham estimated that Vioxx® had caused 88,000-139,000 excess cases of heart attack and stroke. “I would argue the FDA as currently configured is incapable of protecting America against another Vioxx®. We are virtually defenseless,” said Dr. Graham. During his testimony, Dr. Graham noted that he felt pressured by supervisors to water down his findings from a study of patient insurance records indicating that Vioxx® increased heart attack risk. US Senate Finance Committee Chairman Charles Grassley, an Iowa Republican, said he worried that the FDA was “far too cozy” with drug companies, noting that an independent drug safety office might be needed.

Lethal Dangers of Blocking Only COX-2

If you read the July 2000 issue of Life Extension, you would have learned how COX-2 inhibitor drugs can damage your body. Our article described the specific destructive mechanisms that occur when the COX-2 enzyme is inhibited in the body.

The problem with inhibiting only the COX-2 enzyme is that metabolic imbalances occur, resulting in an overproduction of byproducts that damage the arterial wall and induce arterial blood clotting.5 This excess production of toxic byproducts results in increased incidence of heart attack and stroke,6 as evidenced by the higher rates of adverse cardiovascular events in those who took Vioxx®.

Enzymes are proteins that speed up chemical reactions in the body. In the case of the COX-2 enzyme, that hastened chemical reaction is the conversion of arachidonic acid into a pro-inflammatory agent called prostaglandin E2. When COX-2 is inhibited, less prost-aglandin E2 is converted from arachidonic acid, and most people experience a corresponding reduction in arthritis pain and inflam-mation. Unfortunately, when arachidonic acid is blocked from conversion to prostaglandin E2, other enzymes can still convert arachidonic acid into dangerous substances such as leukotriene B4 and thromboxane A2.7,8

Leukotriene B4 is a pro-inflammatory agent8 that is especially destructive to the arterial lining and joints.9,10 Numerous studies document the atherosclerosis-inducing effects of leukotriene B4.9 The enzyme that facilitates the conversion of arachidonic acid to leukotriene B4 is called 5-lipooxygenase (5-LOX). If a person takes a drug that inhibits only COX-2 but does not interfere with 5-LOX, the result can be accelerated atherosclerosis, as more substrate (arachidonic acid) is available for conversion to toxic leukotriene B4.9

Thromboxane A2 induces blood platelet aggregation and promotes abnormal blood clotting within the arteries, which causes many types of heart attacks and strokes.5,11 The enzyme responsible for converting arachidonic acid into thromboxane A2 is called cyclooxygenase-1 (COX-1).12 Aspirin inhibits the COX-1 enzyme and is known to dramatically reduce heart attack and ischemic stroke risk.11 Unfortunately, many patients prescribed COX-2 inhibitors are told to avoid even low-dose aspirin to guard against stomach ulceration. The fatal result can be excess amounts of clot-inducing thromboxane A2 being manufactured from the excess arachidonic acid produced as a result of a COX-2 inhibitor drug.

These destructive mechanisms are illustrated in the sidebar below (“Arachidonic Acid’s Destructive Cascade”), which shows how blocking only the COX-2 enzyme can result in metabolic imbalances that can cause dangerously high levels of leukotriene B4 and thomboxane A2. Leukotriene B4 damages arterial walls, while thromboxane A2 increases the risk of abnormal arterial blood clotting.5,9


Abnormalities of arachidonic acid metabolism have been implicated in spasm and thrombosis of coronary arteries. Scientists in Japan investigated levels of arachidonic acid metabolites in patients with acute myocardial infarction.46 Plasma levels of thromboxane B2 and leukotriene B4 in systemic artery blood were significantly elevated during the acute stage of heart attack. These findings suggest that abnormalities of arachidonic acid metabolism accompany and may play a role in the pathogenesis of acute myocardial infarction.

A Cardiovascular Benefit of COX-2

There are many reasons why one would want to suppress excess COX-2. Not only does it speed up the conversion of arachidonic acid into pro-inflammatory prostaglan-din E2, but the COX-2 enzyme itself has been shown to facilitate the development and progression of certain cancers.13

Life Extension first recommend-ed inhibiting COX-2 as an adjuvant cancer therapy in 1996, and major cancer centers are prescribing COX-2 inhibitors such as Celebrex®14,15 to most of their cancer patients. The (albeit limited) effect of aspirin and ibuprofen in inhibiting COX-2 is one mechanism that researchers speculate to be responsible for lower incidences of certain cancers in those who regularly take aspirin or ibuprofen.16

The one benefit of COX-2 is that it facilitates the formation of prostacyclin, also called prostaglandin I2, which has favorable effects on the vascular system by inhibiting platelet aggregation, inducing healthy arterial dilation, and preventing the proliferation of smooth muscle cells in the arterial wall.5,11 Excess proliferation of smooth muscle cells from the middle layer of the artery into the endothelium is a key mechanism in the formation of atherosclerotic plaque. Prostacyclin is formed from arachidonic acid primarily by the COX-2 enzyme.11 When a powerful COX-2 inhibitor drug is taken, less beneficial prostacyclin is available to protect against heart attack and stroke.11

How Dangerous Are COX-2 Inhibitors?

We have just defined three mechanisms by which COX-2 inhibitor drugs may cause atherosclerosis, thrombosis, and the ensuing in-creased incidence of heart attack and stroke. Based on the number of published studies documenting these pathological mechanisms, it is surprising that there are not even greater numbers of adverse cardiovascular events.

Some researchers fear that the clinical studies that were used to obtain approval of these drugs were not of sufficient duration to gather statistically significant data. Other researchers believe that the drug companies and FDA ignored early warnings of cardiovascular risks in this class of drug.

What follows is a summary of what happens when one takes only a COX-2 inhibitor while ignoring the effects of other enzymes on arachidonic acid metabolism:

  • By not suppressing the COX-1 enzyme, higher levels of thromboxane A2 can accumulate, causing an acute heart attack or stoke by inducing abnormal platelet aggregation.11
  • By not suppressing the 5-lipooxgenase enzyme, higher levels of leukotriene B4 can accumulate, damaging the arterial wall and accelerating atherosclerosis.9
  • By excessively blocking COX-2, the formation of artery-protecting prostacyclin (prostaglandin I2) is suppressed.5

These three mechanisms were long ago established, yet the FDA did not even consider them and allowed potent COX-2 inhibitors to be marketed because they caused less gastric ulceration.

As you have read, the precursor of most inflammatory problems is arachidonic acid, which is the substrate for the enzymatic formation of prostaglandin E2, leukotriene B4, and thromboxane A2.

Most Americans produce too much arachidonic acid because they consume too many foods that are high in omega-6 fatty acids. The best way of reducing arachidonic acid is to reduce meat consumption and eat more fish or take fish oil supplements. Substituting healthy foods rich in omega-3 fatty acids for dangerous omega-6 fats will mitigate a significant underlying cause of arthritis, heart attack, stroke, and other chronic inflammatory-related diseases.17