Aspirin: 4,000 years and still learning

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Aspirin (acetylsalicylic acid) and its progenitors are valuable medications with a history spanning at least 4 millennia. An enormous number of patients take aspirin for a variety of reasons, and managing their therapy around the time of surgery can be challenging, as Drs. Prabhakaran and Whinney discuss in this issue.1 Even after 4,000 years, we are still learning about these remarkable drugs.

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Figure 1.

Figure 1.

Medicines made from the bark of willow trees (genus Salix) and other salicylate-rich plants have been used as analgesics since at least 2000 bce. References exist on the Ebers Papyrus from Egypt (circa 1550 bce) as well as on ancient Sumerian tablets.2 It was not until the 18th century, however, that Edmund Stone identified salicin, a glycoside of salicylic acid and the active compound in willow bark extract. Searching for a way to reduce the burning throat and dyspepsia caused by salicylic acid, chemists at Friedrich Bayer & Company—the same group that popularized heroin as a “nonaddictive” form of morphine—eventually produced acetylsalicylic acid. Bayer gave the compound the brand name “Aspirin,” using “A” for acetylation, “-spir-“ for Spirea (another common source of salicylic acid), and “-in” as a conventional drug-name ending (Figure 1).3


In the 1940s, a general practitioner in California named Lawrence Craven recognized that many of his post-tonsillectomy patients had to be hospitalized for bleeding after he started recommending they use aspirin-containing chewing gum for pain relief.4 Under the then-debated hypothesis that myocardial infarction (MI) involves thrombosis, he recommended that adult men should take aspirin daily. He believed that women had lower rates of MI because they were more likely to take aspirin, something that men did not view as a “masculine” thing to do.

In a series of letters in journals such as the Mississippi Valley Medical Journal,5 Craven reported his observations of very low rates of MI and no strokes in aspirin users. Given the nonrigorous nature of his research and the obscure journals in which he published, his findings languished for many years. Ironically, he died of an MI in 1957.


The history of aspirin research illustrates how the fields of hemostasis and inflammation are now linked.

In the late 1960s, Weiss et al6 reported that aspirin rapidly and irreversibly inhibits platelet aggregation. In parallel, using biological assays in work that eventually led to the Nobel Prize, Vane7 discovered that inflammation involves the de novo synthesis of prostaglandins and that aspirin directly inhibits this synthesis. Further work connecting these lines of investigation led us to understand that platelet aggregation is enhanced by the prostaglandin derivative thromboxane A2, produced by cyclooxygenase-1, and that aspirin irreversibly inhibits this enzyme by acetylation.


After decades of research ranging from the Physicians’ Health Study to well-named trials such as ARRIVE, ASCEND, and ASPREE, we now know that taking daily low doses of aspirin for primary prevention can reduce the risk of cardiovascular events and may reduce the risk of colorectal cancer—but at the cost of an increased risk of bleeding.8

Which patients will gain the most benefit and incur the least risk is still debated. What is certain, however, is that aspirin has an important role in acute coronary syndromes, secondary prevention of MI and stroke, and prevention of thrombosis after coronary stent placement. In the perioperative setting, we are learning that aspirin may benefit patients with myocardial injury after noncardiac surgery, a recently described clinical entity associated with surprisingly high mortality rates.9,10

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