An Aspirin a Day May Actually Keep the Doctor Away

Aspirin, as we know it today, is one of the cheapest and oldest painkillers on the market. It is estimated that 100 billion tablets are consumed each year.¹

Before it was a mass-produced, synthetic derivative, aspirin was used as salicylic acid found in the willow tree. In 400 BC, Hippocrates used brewed willow leaves for labor pains, and he recommended chewing willow bark for pain relief. The use of the willow bark continued in 1763 when Reverend Edward Stone described the benefits of giving it for rheumatic fever. Reverend Stone also noted the relief in pain and fever associated with malaria. It was printed in the journal Philosophical Transaction of the Royal Society as an inexpensive substitute to Peruvian bark, the treatment for malaria at the time.

In 1897, acetylsalicylic was derived as the synthetic form of salicylic acid by Felix Hoffman, a German scientist of Bayer Pharmaceutical company. Acetylsalicylic was a less irritating and less acidic form of its predecessor. Hoffman developed it as a more tolerable formulation to help ease his father’s arthritis pain. In 1900, Bayer received patent in the United States for aspirin. Bayer Pharmaceuticals kept the patent on aspirin through the 1930s, keeping it as brand aspirin or Bayer aspirin.¹ Aspirin was never approved by the US FDA, it was grandfathered in as an existing drug under the 1938 Food, Drug, and Cosmetic Act.²

Interestingly, the mechanism of action of aspirin as an analgesic was unknown until Professor John Vane won a Nobel Prize in Medicine for the discovery. In 1982, he proposed aspirin’s mechanism of action as blocking prostaglandin, an enzyme needed to produce natural hormones that caused pain.

Today, aspirin is still used as an analgesic for muscle pain, menstrual pain, arthritis, toothaches, but the popular consumption may be attributed more to its other uses.³

Stroke, Heart Attack

In 1950, Dr. Craven recommended his tonsillectomy patients chew aspergum (aspirin chewing gum). Eventually, he noticed that many of his patients who used a very high amount of aspergum had to be hospitalized for severe bleeding. He then began recommending daily aspirin to all of his patients, claiming it prevented a clot from forming. Unfortunately, he was ignored by the medical community because a placebo-controlled study had not been done.

Aspirin was not looked at again as an antithrombotic agent until the 1960s, when Harvey Weiss found that aspirin prevented platelets from adhering to each other. A couple of years later, John O’Brien and Peter Elwood used Weiss’s findings to study aspirin’s antithrombotic effects. In the Elwood Trial, heart attack survivors were enlisted in a double-blind controlled study, but it did not show a statistically significant reduction in heart attacks in the group taking aspirin. Over the years, several other studies came out that showed aspirin’s modest effectiveness for heart attacks, but the evidence was not overwhelming. This uncertainty in aspirin’s benefit changed in the 1980s when statistician Richard Peto used the newly discovered technique of meta-analysis to show the FDA and medical community that all of these aspirin studies combined showed aspirin caused a statistically significant decrease in major cardiovascular events such as heart attack and stroke. In the end, this caused the widespread use of aspirin as a preventive drug for heart attacks.⁴

Aspirin can be used for the treatment of patients with acute myocardial infarction (MI), during percutaneous coronary interventions (PCI) and during coronary artery bypass grafts (CABG), and for the primary prevention of cardiovascular disease.

Aspirin can also be used for prevention/treatment of stroke or transient ischemic attacks (TIA), and for primary prevention in atrial fibrillation patients with a low CHA2DS2-VASc (<1) score. Some of the important

studies that support aspirin’s benefits in MI and stroke include the International Study of Infarct Survival (ISIS-2) trial and the Antithrombotic Trialist’ Collaboration. In 1988, ISIS-2 trial showed that aspirin use in patients who had a suspected MI in the last 24 hours resulted in reduction in non-fatal reinfarction, stroke, 5-week vascular mortality, and all-cause mortality.⁵ In 2002, the Antithrombotic Trialist’ Collaboration analyzed 16 trials of long-term aspirin use with doses ranging from 50 to 1500 mg/day for secondary prevention of CV events. They found that aspirin use resulted in significant reductions in stroke/coronary events and that low doses (75-100 mg/day) were as effective as higher doses.

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What Next?

In addition to the traditional uses of aspirin, there are many new uses that have been discovered and are still in the process of validation through continued research. Aspirin in breast cancer, for example, has shown promising results for certain subtypes. Studies have shown that women who took 3 or more doses of low-dose aspirin per week had a decreased risk of developing breast cancer, specifically the hormone receptor-positive, HER2 negative subtype. This decrease was not seen in other subtypes of breast cancer and nor with other NSAIDs, such as ibuprofen, or with the 325 mg dose of aspirin. The mechanism by which the risk reduction occurs is unknown, but it is hypothesized that lowering of COX-2 and prostaglandin activity could results in inhibition of cancer DNA formation, inhibiting angiogenesis, or promoting apoptosis.⁷

Other types of cancer research have started to tap into aspirin’s benefits as well. A fairly recent meta-analysis showed that aspirin use was associated with a decreased risk of colorectal cancer. Taking 325 mg of aspirin a day reduced risk by 20% compared to taking 75 mg of aspirin a day, which reduced risk by 10%. These studies also revealed that taking aspirin 7 days per week reduced risk by 18% compared to taking aspirin 2 times per week, which showed a reduction of only 8%. When aspirin was taken for 5 years, it further reduced risk by 10%. Risk reduction almost doubled when aspirin was taken for 10 years. Again, the mechanism is not fully understood, but it has been suggested that aspirin may accomplish these effects by enhancing apoptosis in early cancer cells.

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Furthermore, recent studies have shown that aspirin reduced the risk of posterior subcapsular cataracts, which is particularly disabling type of cataracts. Aspirin 81 mg with 325 mg on alternate days showed a significant reduction in risk of developing this category of cataracts. Aspirin did not reduce risk of developing all types of cataracts. Researchers believe the mechanism could be due to inhibition of enzymes within the lens.

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Finally, research has shown some modest benefit in pregnant women who are at significantly increased risk for preterm delivery due to preeclampsia. In a large multicenter study, aspirin 60 mg daily was shown to significantly reduce the risk of preterm delivery due to early-onset (before 32 weeks) preeclampsia in women who are at significant risk. Women who received aspirin were 14% less likely to deliver their babies before 37 weeks. For women who have a history of early-onset preeclampsia, this research may be especially important.

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With so much potential in ongoing research with aspirin, it is clear that aspirin is a drug of many uses and benefits, possibly some we have not even discovered yet.

What Can Aspirin Not Do?

It is clear how aspirin benefits many patient populations, however, there are many rumors of uses that are simply myths. We may see patients that have been told aspirin can be used for things that it cannot. For example, patients may have heard that is can be used for toothaches. Directly applying aspirin to a toothache may seem like a good idea to block pain, but it must be absorbed in the bloodstream to be effective. Topical application can also cause gum irritation. Some patients believe that chewing aspirin gum can relieve a sore throat, when in actuality, aspirin does not have local soothing effects.¹¹

Some patients have been reported to crush aspirin and use as treatment for acne. Although, it may be similar to salicylic acid, aspirin directly applied to the face, like the gums, can be irritating. Other topical salicylic acid products should be encouraged for use instead.

Conclusion

An internet search of aspirin reveals several articles varying from medical journals to blog discussions. Aspirin has been noted to be used historically as pain control, but research has widened its use to cardioprotection to possible prevention of cancers. The use is so variable that space shuttles even carry vials of aspirin. As extensive as its use may be, we must remember the risks that accompany aspirin: nausea or vomiting, gastrointestinal ulcerations, headache, and bleeding. Thus, its use should be patient specific. It has had a promising future since its use as willow bark, and it seems to have a promising future today.

Written with Zain Cheikhali, Morgan Lee, and Lindsey Hamrick - all PharmD Candidates 2018 Harrison School of Pharmacy Auburn University

References:

1.

Increasing the knowledge & understanding of aspirin. The Aspirin Foundation. http://www.aspirin-foundation.com/history-of-aspirin/100-years-of-aspirin/.

2.

Wittick C, Burkle C, Lanier W. Ten common questions (and their answers) about off-label drug use. Mayo Clin Proc. 2012 Oct; 87(10): 982—990.

3.

Aspirin - Surprisingly Versatile. Bayer. May 2017. https://www.bayer.com/en/aspirin.aspx.

4.

Ittaman SV, VanWormer, JJ, Rezkalla, SH. The role of aspirin in the prevention of cardiovascular disease. Clin Med Res. 2014; 12(3-4), 147—154.

http://doi.org/10.3121/cmr.2013.1197

5.

Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R. ISIS-2: 10-year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ (Clinical Research Ed ) 1998;316(7141):1337—1343.

6.

Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71—86.

7.

Clarke, CA. et al. Regular and low-dose aspirin, other non-steroidal anti-inflammatory medications and prospective risk of HER2-defined breast cancer: the California Teachers Study. Breast Cancer Res. May 2017; 19:52.

8.

Ye X, Fu J, Yang Y, Chen S (2013) Dose—Risk and Duration–Risk Relationships between Aspirin and Colorectal Cancer: A Meta-Analysis of Published Cohort Studies. PLOS ONE. 8(2): e57578.

https://doi.org/10.1371/journal.pone.0057578

9.

Christen WG, Manson JE, Glynn RJ, Ajani UA, Schaumberg DA, Sperduto RD, et al. Low-dose aspirin and risk of cataract and subtypes in a randomised trial of US physicians. Ophthal Epidem. 1998;5:133-142.

10.

CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-Dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343:619-29.

11.

Graedon’s guide to key aspirin information. The People’s Pharmacy.

http://www.healthcentral.com/static/pp/pdf_guides/aspirin.pdf