| The Magazine of the CALIFORNIA ACADEMY OF SCIENCES |
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Counterpoints in Science The Spin on Aspirin Aspirin use decreases the incidence of breast cancer, according to an article in the Journal of the American Medical Association in 2003. The authors found that women who had taken aspirin at least once a week for six months had a 20 percent lower risk of developing breast cancer than women who had not. I wasn't surprised at this finding: it seems there's hardly any medical condition aspirin can't alleviate. Given my own family history of male coronary artery disease, I might very well have died from a heart attack by now if I hadn't chewed a baby aspirin every morning for the past 16 years. In 1983, Charles Hennekens of Harvard recruited 22,000 American doctors, including me, to study whether aspirin prevents heart attacks in healthy men. Aspirin had already proved useful in preventing recurrent heart attacks, so men with known cardiac disease were not included. Half of us received an aspirin tablet every other day, half received an identical-looking placebo with no active ingredients. By the end of 1988 the control group had experienced 189 heart attacks, the aspirin group only 104-a difference of more than 40 percent. The trial was stopped and Hennekens recommended we all take aspirin. Aspirin's beneficial effect on the heart is particularly ironic. When it was first introduced to medical practice at the end of the nineteenth century, some doctors vigorously opposed its use because they thought it was bad for the heart. The bark of the white willow tree, Salix alba, has been used for thousands of years to treat fever. It appears in Egyptian hieroglyphics and was recommended by Hippocrates, the father of Western medicine. The Reverend Edward Stone of Chipping Norton in Oxfordshire rediscovered it in 1763 and the Royal Society of London published his article, "Account of the Success of the Bark of the Willow in the cure of Agues." The active ingredient of willow bark turned out to be a bitter-tasting yellow crystal now called salicilin. French chemists synthesized a simpler version, salicylic acid. Both salicilin and salicylic acid reduced fever and pain but caused unpleasant side effects such as nausea and ringing in the ears. Working at Bayer, a small German chemical company that specialized in dyes, chemists Friedrich Duisberg and Felix Hoffmann sought to find a version of salicylic acid with fewer side effects. They came up with acetylsalicylic acid (ASA) in 1897. Doctors in Berlin tested it on their patients and were enthusiastic about its relief of pain, inflammation, and fever. Bayer named the drug Aspirin after Spiraea, the meadowsweet plant, which contains high concentrations of salicylates. By 1902, 160 scientific studies had appeared, almost universally favorable. Aspirin relieved tenor Enrico Caruso's headaches and eased writer Franz Kafka's suffering from tuberculosis. Then as now, most aspirin was consumed by people with inflammatory diseases or arthritis. Aspirin became the world's most popular medicine and made the Bayer Company's fortune. The United States was the only country in which Bayer was able to obtain both a patent and a trademark on Aspirin. The patent gave it control over production for 17 years. The trademark imprinted the name Bayer Aspirin on the minds of people with headaches, fevers, and other maladies long after the patent expired, as reported by C.C. Mann and M.L. Plummer in their book, The Aspirin Wars: Money, Medicine, and 100 Years of Rampant Competition (Knopf, 1991). In 1918, when the United States was at war with Germany, the government sold all Bayer's U.S. assets to the highest bidder. That turned out to be Sterling Products, Inc., a patent medicine outfit that advertised laxatives and impotence cures. The brand name Bayer Aspirin continued to prosper until the 1930s; by that time, drugstore shelves were groaning with competitive aspirin products. Now, more than 80 million aspirin tablets are consumed each day in the United States. Aspirin's mechanism of action was not understood until the early 1970s, when British researcher John Vane found it blocked the synthesis of prostaglandins. Prostaglandins are molecules that were first found in the prostate gland, but it happens that practically every cell in the body can make them. When cells are damaged or affected by disease, they release these hormone-like molecules into the circulation, causing pain and fever. Aspirin relieves these symptoms by inhibiting cyclooxygenases (COXes), enzymes needed to make prostaglandins. For this discovery, Vane was awarded a Nobel Prize in 1982. There are many kinds of prostaglandins, and some of them promote blood clotting. Billions of tiny disc-shaped platelets circulate in the bloodstream and clump together to initiate a clot. By muting prostaglandin action, aspirin prevents clots from forming. How aspirin reduces some kinds of cancer-particularly colon cancer and, according to a recent report, breast cancer-is not known, but several thousand researchers are trying to find out. Prostaglandin inhibition is also the source of aspirin's major side effects, such as gastric distress. Prostaglandins manufactured by the stomach help maintain the mucus coating that protects the lining from acid. Aspirin, as well as some of the other non-steroidal anti-inflammatory drugs (NSAIDS) like acetaminophen (Tylenol), ibuprofen (Motrin), and naproxen (Nap-rosyn, Aleve), can cause an upset stomach or even an ulcer. Some of these drugs cause less stomach discomfort than aspirin, but the trade-off is that they're less effective in preventing heart attacks. In medical practice aspirin is prescribed at three different dosage levels. Ordinary over-the-counter doses relieve pain and fever. In high prescription doses, aspirin reduces the redness, swelling, heat, and pain of inflammation. Victims of arthritis and other inflammatory conditions often take more than ten tablets a day for years. Aspirin's third mode of action, interfering with the clumping of platelets, requires only the smallest doses. One aspirin researcher quoted in The Aspirin Wars joked that you could prevent heart attacks by licking a baby aspirin every other morning. Aspirin is one of the safest drugs known, yet it is not entirely benign in younger patients. It increases the risk of Reye's syndrome, a rare but serious illness that may strike children in the aftermath of a viral infection such as flu or chickenpox, damaging the brain and liver. Though only one in a million children gets Reye's syndrome, publicity surrounding the condition has effectively destroyed the children's market for aspirin. One out of five Americans swallows aspirin every day. Worldwide, 100 billion pounds of aspirin go down human gullets annually. Even so, it is probably the most underutilized lifesaver in the medical pharmacopoeia. It's one of those rare "miracle cures" that actually works, preventing untold thousands of cardiovascular and cancer deaths each year. Millions more could be spared if all the people who could benefit from aspirin were taking it. But most people won't take medicine unless they're feeling sick, even if they're at high risk for cancers, coronaries, and strokes as are most adult Americans. Instead of taking full advantage of this panacea, this willow-bark gift of the gods, we spend enormous sums on the pharmaceutical industry's latest exorbitantly expensive and extravagantly advertised products. Most are inferior to dirt-cheap acetylsalicylic acid. If the drug companies could still make big money out of aspirin as Bayer did a century ago, full-page ads for aspirin would be right up there with those for Viagra and Lipitor, and a lot more people would enjoy better health. The Vioxx story is a perfect example. Six years ago, drug giant Merck began testing its own COX inhibitor, rofecoxib, which it trade-named Vioxx. When patients with rheumatoid arthritis were given Vioxx, they suffered fewer gastrointestinal problems than patients taking naproxen. Those taking Vioxx also had more heart attacks than those on naproxen. But Merck was so eager to make money with an aspirin competitor that it minimized and covered up these results-putting millions of consumers at risk. Aspirin was not included in the test. In 1999, the Food and Drug Administration (FDA) granted Merck approval to market Vioxx. The FDA's Arthritis Advisory Committee strongly recommended a further trial to assess the additional heart attack risk. The FDA, now led by industry-friendly bureaucrats, ignored this advice from its own experts. So Merck aggressively marketed the drug. Its 2001 press release was titled "Merck reconfirms Favorable Cardiovascular Safety of Vioxx." Meanwhile, numerous controlled studies found Vioxx-takers experiencing more heart attacks and strokes than those taking placebos. Merck routinely declared these studies flawed and spent more than $100 million per year in consumer advertising. Finally, on September 30, 2004, the evidence that Vioxx actually increased the risk of heart attacks and strokes was so overwhelming that Merck was forced to withdraw Vioxx from the market. By that time, more than 80 million patients had taken the drug and annual sales had topped $2.5 billion. In the respected New England Journal of Medicine (October 21, 2004), Eric J. Topol, a member of the FDA's Arthritis Advisory Committee, writes that Merck valued sales over safety and that the FDA failed in its primary mission of protecting the public. As a result, "there may be tens of thousands of patients who have had major adverse events attributable to rofecoxib." If these 80 million patients had taken aspirin, they would have had a few more upset stomachs, but would have saved a lot of money and thousands more would still be alive. Vioxx doubles or triples the risk of heart attacks, aspirin halves the risk. After more than a century of use, aspirin is still the closest thing we have to an ideal medication. It is effective against a broad array of common disorders, safe in a wide range of dosages, available over the counter in every drugstore and grocery, and affordable for everyone who needs it. Breast cancer is the latest, but almost certainly not the last, disease to be added to the lengthy list of conditions aspirin ameliorates. The phrase "aspirin: the miracle drug" has become a cliché in medical news headlines; a new book by that name is being published even as I write these words. I suspect The New Yorker cartoonist had aspirin in mind when he showed God handing Moses the Ten Commandments on Mount Sinai and saying, "Take these two tablets and call me in the morning." Jerold M. Lowenstein is professor of medicine at the University of California, San Francisco. jlowen@itsa.ucsf.edu |