Aspirin: A New Look at an Old Drug by Ken Flieger In purses and backpacks, in briefcases and medicine chests the world over, millions of people keep close at hand a drug that has both a long past and a fascinating future. Its past reaches at least to the fifth century B.C., when Hippocrates used a bitter powder obtained from willow bark to ease aches and pains and reduce fever. Its future is being shaped today in laboratories and clinics where scientists are exploring some intriguing new uses for an interesting old drug. The substance in willow bark that made ancient Greeks feel better, salicin, is the pharmacological ancestor of a family of drugs called salicylates, the best known of which is the world's most widely used drug--aspirin. Americans consume an estimated 80 billion aspirin tablets a year. The Physicians' Desk Reference lists more than 50 over-the- counter drugs in which aspirin is the principal active ingredient. Yet, despite aspirin's having been in routine use for nearly a century, both scientific journals and the popular media are full of reports and speculation about new uses for this old remedy. The National Library of Medicine's main computerized catalog includes more than 2,700 scientific articles about aspirin. And those are only the English language publications that have appeared in the last five years. Yet aspirin's beginnings were rather unspectacular. Nearly 100 years ago, a German industrial chemist, Felix Hoffmann, set about to find a drug to ease his father's arthritis without causing the severe stomach irritation associated with sodium salicylate, the standard anti-arthritis drug of the time. In the forms then available, the large doses of salicylates used to treat arthritis--6 to 8 grams a day--commonly irritated the stomach lining, and many patients, like Hoffmann's father, simply could not tolerate them. Figuring that acidity made salicylates hard on the stomach, Hoffmann started looking for a less acidic formulation. His search led him to synthesize acetylsalicylic acid (ASA), a compound that appeared to share the therapeutic properties of other salicylates and might cause less stomach irritation. ASA reduced fever, relieved moderate pain, and, at substantially higher doses, alleviated rheumatic and arthritic conditions. Hoffmann was confidant that ASA would prove more effective than salicylates then in use. His superiors, however, did not share his enthusiasm. They doubted that ASA would ever become a valuable, commercially successful drug because at large doses salicylates commonly produced shortness of breath and an alarmingly rapid heart rate. It was taken for granted--incorrectly as it turns out--that ASA would weaken the heart and that physicians would be reluctant to prescribe it in preference to sodium salicylate, a drug they at least knew. Hoffmann's employer, Friedrich Bayer & Company, gave ASA the now- familiar name aspirin, but in 1897 Bayer didn't think aspirin had much of a future. It could not have foreseen that almost a century after its development aspirin would be the focus of extensive laboratory research and some of the largest clinical trials ever carried out in conditions ranging from cardiovascular disease and cancer to migraine headache and high blood pressure in pregnancy. How Does It Work? The mushrooming interest in aspirin has come about largely because of fairly recent advances in understanding how it works. What is it about this drug that, at small doses, interferes with blood clotting, at somewhat higher doses reduces fever and eases minor aches and pains, and at comparatively large doses combats pain and inflammation in rheumatoid arthritis and several other related diseases? The answer is not yet fully known, but most authorities agree that aspirin achieves some of its effects by inhibiting the production of prostaglandins. Prostaglandins are hormone-like substances that influence the elasticity of blood vessels, control uterine contractions, direct the functioning of blood platelets that help stop bleeding, and regulate numerous other activities in the body. In the 1970s, a British pharmacologist, John Vane, Ph.D., noted that many forms of tissue injury were followed by the release of prostaglandins. In laboratory studies, he found that two groups of prostaglandins caused redness and fever, common signs of inflammation. Vane and his co-workers also showed that, by blocking the synthesis of prostaglandins, aspirin prevented blood platelets from aggregating, one of the initial steps in the formation of blood clots. This explanation of how aspirin and other nonsteroidal anti- inflammatory drugs (NSAIDs) produce their intriguing array of effects prompted laboratory and clinical scientists to form and test new ideas about aspirin's possible value in treating or preventing conditions in which prostaglandins play a role. Interest quickly focused on learning whether aspirin might prevent the blood clots responsible for heart attacks. A heart attack or myocardial infarction (MI) results from the blockage of blood flow not through the heart, but to heart muscle. Without an adequate blood supply, the affected area of muscle dies and the heart's pumping action is either impaired or stopped altogether. The most common sequence of events leading to an MI begins with the gradual build-up of plaque (atherosclerosis) in the coronary arteries. Circulation through these narrowed arteries is restricted, often causing the chest pain known as angina pectoris. An acute heart attack is believed to happen when a tear in plaque inside a narrowed coronary artery causes platelets to aggregate, forming a clot that blocks the flow of blood. About 1,250,000 persons suffer heart attacks each year in the United States, and some 500,000 of them die. Those who survive a first heart attack are at greatly increased risk of having another. Could Aspirin Help? To learn whether aspirin could be helpful in preventing or treating cardiovascular disease, scientists have carried out numerous large randomized controlled clinical trials. In these studies, similar groups of hundreds or thousands of people are randomly assigned to receive either aspirin or a placebo, an inactive, look- alike tablet. The participants--and in double-blind trials the investigators, as well--do not know who is taking aspirin and who is swallowing a placebo. Over the last two decades, aspirin studies have been conducted in three kinds of individuals: persons with a history of coronary artery or cerebral vascular disease, patients in the immediate, acute phases of a heart attack, and healthy men with no indication of current or previous cardiovascular illness. The results of studies of people with a history of coronary artery disease and those in the immediate phases of a heart attack have proven to be of tremendous importance in the prevention and treatment of cardiovascular disease. The studies showed that aspirin substantially reduces the risk of death and/or non-fatal heart attacks in patients with a previous MI or unstable angina pectoris, which often occurs before a heart attack. On the basis of such studies, these uses for aspirin (unstable angina, acute MI, and survivors of an MI) are described in the professional labeling of aspirin products, information provided to physicians and other health professionals. Aspirin labeling intended for the general public does not discuss its use in arthritis or cardiovascular disease because treatment of these serious conditions- -even with a common over-the-counter drug--has to be medically supervised. The consumer labeling contains a general warning about excessive or inappropriate use of aspirin, and specifically warns against using aspirin to treat children and teenagers who have chickenpox or the flu because of the risk of Reye syndrome, a rare but sometimes fatal condition. Aspirin for Healthy People? Once aspirin's benefits for patients with cardiovascular disease were established, scientists sought to learn whether regular aspirin use would prevent a first heart attack in healthy individuals. The findings regarding that critical question have thus far been equivocal. The major American study designed to find out if aspirin can prevent cardiovascular deaths in healthy individuals was a randomized, placebo-controlled trial involving just over 22,000 male physicians between 40 and 84 with no prior history of heart disease. Half took one 325-milligram aspirin tablet every other day, and half took a placebo. The trial was halted early, after about four-and-a-half years, and the findings quickly made public in 1988 when investigators found that the group taking aspirin had a substantial reduction in the rate of fatal and non-fatal heart attacks compared with the placebo group. There was, however, no significant difference between the aspirin and placebo groups in number of strokes (aspirin-treated patients did slightly worse) or in overall deaths from cardiovascular disease. A similar study in British male physicians with no previous heart disease found no significant effect nor even a favorable trend for aspirin on cardiovascular disease rates. The British study of 5,100 physicians, while considerably smaller than the American study, reported three-quarters as many vascular "events." FDA scientists believe the results of the two studies are inconsistent. The U.S. Preventive Services Task Force, a panel of medical- scientific authorities in health promotion and disease prevention, is one of many groups looking at new information on the role of aspirin in cardiovascular disease. In its Guide to Clinical Preventive Services, issued in 1989, the task force recommended that low-dose aspirin therapy "should be considered for men aged 40 and over who are at significantly increased risk for myocardial infarction and who lack contraindications" to aspirin use. A revised Guide, scheduled for publication in the fall of 1994, is expected to include a slightly revised recommendation concerning aspirin and cardiovascular disease but no major change in advice to physicians about aspirin's possible role in preventing heart attacks. Better understanding of aspirin's myriad effects in the body has led to clinical trials and other studies to assess a variety of possible uses: preventing the severity of migraine headaches, improving circulation to the gums thereby arresting periodontal disease, preventing certain types of cataracts, lowering the risk of recurrence of colorectal cancer, and controlling the dangerously high blood pressure (preeclampsia) that occurs in 5 to 15 percent of pregnancies. None of these uses for aspirin has been shown conclusively to be safe and effective, and there is concern that people may be misusing aspirin on the basis of unproven notions about its effectiveness. Last October, FDA proposed a new labeling statement for aspirin products advising consumers to consult a doctor before taking aspirin for new and long-term uses. The proposed statement would read, "IMPORTANT: See your doctor before taking this product for your heart or for other new uses of aspirin because serious side effects could occur with self treatment." The Other Side of the Coin While examining new possibilities for aspirin in disease treatment and prevention, scientists do not lose sight of the fact that even at low doses aspirin is not harmless. A small subset of the population is hypersensitive to aspirin and cannot tolerate even small amounts of the drug. Gastrointestinal distress--nausea, heartburn, pain--is a well-recognized adverse effect and is related to dosage. Persons being treated for rheumatoid arthritis who take large daily doses of aspirin are especially likely to experience gastrointestinal side effects. Aspirin's antiplatelet activity apparently accounts for hemorrhagic strokes, caused by bleeding into the brain, in a small but significant percentage of persons who use the drug regularly. For the great majority of occasional aspirin users, internal bleeding is not a problem. But aspirin may be unsuitable for people with uncontrolled high blood pressure, liver or kidney disease, peptic ulcer, or other conditions that might increase the risk of cerebral hemorrhage or other internal bleeding. New understanding of how aspirin works and what it can do leaves no doubt that the drug has a far broader range of uses than Felix Hoffmann and his colleagues imagined. The jury is still out, however, on a number of key questions about the best and safest ways to use aspirin. And until some critical verdicts are handed down, consumers are well-advised to regard aspirin with appropriate caution. n Ken Flieger is a writer in Washington, D.C.