Although there remains much to be skeptical about in the world of medicine, there is also the occasional study that promises optimism. So every now and again I will mix things up and talk about a drug, a device, or a treatment where there is strong evidence of value.

Once, long ago, at an otherwise forgotten cocktail party someone ventured to ask me, “If you were stranded on a desert island and could only take 3 medicines with you, what would they be?” After a brief period of thought, I came up with the following: morphine, penicillin, and aspirin. People might be surprised to learn that I didn’t name some fancy new antibiotic or “miracle drug” for cancer or heart disease, but my answer today would remain the same. There are few things in life that these medicines can’t treat or, at least, palliate. For the remainder of this post, my comments will be restricted to the wonder drug known as aspirin.

 

 

The medicinal effects of aspirin compounds date back more than 3,500 years to the Elbers Papyrus, a 110 page-long Egyptian medical text noting the pain-relieving properties of tonics derived from parts of salix (willow) trees. Descriptions of trade in willow tree bark go back to 216 AD, but it wasn’t until 1897 that Felix Hoffman, working for the Friedrich Bayer Company, first synthesized the compound we know today as aspirin. Less than a decade later the drug was in widespread commercial use in the form of a simple stamped tablet. Bayer, who knew a thing or two about marketing, soon had spokesmen like opera singer Enrico Caruso and author Franz Kafka shilling his product, with the latter noting that aspirin helped him ease “the unbearable pain of being.” According to the Aspirin Foundation, the current annual worldwide consumption equates to 35,000 metric tons. But unlike almost all the other drugs I will be discussing in this blog, aspirin is a drug that we should probably be taking even more of.

I remember once listening to a neurologist say that it was his goal for his patients to “go home and die of cancer” rather than dying from a stroke. It sounded strange and provoked a laugh, but for the neurologist it is certainly the truth. Meanwhile, the opposite is true for the oncologist. Other doctors have other goals; the infectious disease specialist wants to spare her patients a death from sepsis while the cardiologist wishes to avert death by heart attack. The sad truth is that we are all going to die of something. The goal isn’t to live forever, but rather to live as long and as well as possible. For people older than 40-years, 2 of 3 men can expect the grim reaper to visit in the form of cardiovascular disease, while 1 in 2 women can expect the same. So if we can’t eliminate death, can we at least forestall it? Fortunately, the answer is “yes.”

A single aspirin at the time of a heart attack lowers mortality by about 25%, nearly as much as all other interventions combined, including heart catheterization and stent placement. Not only is aspirin the cheapest, most effective treatment for an active heart attack, long term use can prevent heart attacks from occurring. The data here is well established and not controversial.

Here’s the breakdown:

• Long-term aspirin use reduces the relative number of both heart attacks and strokes by 14%, and all-cause mortality by 6%.
• In men, aspirin primarily reduces heart attack, while in women, it primarily reduces stroke.
• Unfortunately, long-term use of aspirin is also associated with a 55% relative increase in the number of bleeding events, primarily along the GI tract (e.g. gastritis, ulcer). This translates into 1 to 2 extra GI bleeds for every 100 people taking the drug for 10 years and 1 to 2 extra brain bleeds for every 1,000 people taking the drug for 10 years.
• The best dose of aspirin to achieve benefit, while minimizing harm, is 81 mg (i.e. one “baby aspirin” or ¼ of a normal aspirin tablet—not much at all).
• The number of patients needed to treat over a 6.8 year follow up to prevent 1 serious cardiovascular event is 284, while the number needed to treat to induce a major bleeding event is 299.

This last bullet is important because it suggests that the benefit of aspirin is roughly equal to the harm when taken by a large population. But aspirin’s benefits are far greater in folks with known cardiovascular disease or those with risk factors for it—high blood pressure, diabetes, elevated cholesterol, smoking, and/or a family history of heart attack. Here, aspirin’s potential benefits outweigh its potential harms, and the sicker you are the greater the benefit which is why aspirin is recommended for all patients after a first heart attack or stroke.

To calculate your risk of cardiovascular disease, see http://cvrisk.nhlbi.nih.gov/. Although there are problems associated with the calculator (see my post on statins), it’s okay for a ballpark estimate. For example, in men between the ages of 45 and 59 with a 10% 10-year cardiovascular risk, daily aspirin use in 1,000 men for 10 years can be expected to prevent 32 heart attacks while causing 8 extra GI bleeds and 1 extra bleeding stroke—a benefit well worth the risk. The numbers reach a break-even point in men with a calculated 10-year risk of 3%, and aspirin is not recommended for men at a lower risk than this.

To calculate your stroke risk, see http://stroke.ucla.edu/body.cfm?id=66. For example, in women between the ages of 55 and 59 with a calculated 10-year stroke risk of 10%, daily aspirin use in 1,000 women for 10 years can expect to prevent 17 ischemic strokes while causing 4 extra GI bleeds. That is a pretty significant risk reduction and far greater than other, more expensive, treatments.

In 2009, the USPSTF (United States Preventative Services Task Force), an independent collaboration of doctors, gave an “A” recommendation for daily aspirin use in men, aged 45-79, for heart attack prevention and a similar “A” recommendation for women, aged 55-79, for stroke prevention where the calculated potential benefit is greater than the potential harm. The committee felt the evidence insufficient to make a recommendation in either men or women over age 80.

This is pretty powerful, but we’re not done yet. While it’s clear that aspirin relieves pain, reduces fever, limits inflammation, and prevents heart attack and stroke, it turns out that long-term aspirin use likely prevents certain cancers, most notably colon cancer. The association is not new—a study published in the New England Journal of Medicine way back in 1991 noted a 40% reduction in colon cancer deaths in aspirin-takers. Unfortunately, that same increase in bleeding that kept creeping into the cardiovascular trials also reared its ugly head in the cancer trials. This, along with negative results in colon cancer prevention from 2 large trials in patients who took aspirin every other day prompted the USPSTF to give aspirin for colorectal cancer prevention a “D” grade (meaning that doctors should discourage it) in 2007.

Since then there have been multiple additional trials looking at long term daily aspirin use where the results have been far more positive: a 35% reduction in the incidence of colorectal cancer, a 40% reduction in colorectal cancer death, a 30% reduction in the incidence of both esophageal and stomach cancers, a 10% reduction in the incidence of breast and prostate cancers, an 18% reduction in heart attack and 5% reduction in stroke. Overall, daily aspirin use for 10 years can be expected to result in a 9% reduction in the number of cancers, heart attacks, and/or strokes in men and a 7% reduction in women with most of the benefit coming in the form of reduced cancers. This is pretty phenomenal and far better than any other medicine to date.

Some final notes on aspirin and cancer:

• The benefit of aspirin in reducing cancer was only seen after 5 years or more of daily use.
• Aspirin’s cancer-reducing effect applies only to certain cancers, primarily adenocarcinomas, but the effect appears to persist for up to 2 decades after at least 5 years of therapy.
• The benefit increases with age and duration of aspirin use.
• Side effects primarily related to GI bleeding and stomach irritation will preclude the use of aspirin in many. In the trials noted above, the dropout rate was as high as 40% due to noncompliance and/or side effects.
• You should discuss aspirin use with your doctor before beginning a daily regimen. Aspirin should be used cautiously—if at all—when taking blood thinners like Coumadin, Xarelto, and Eliquis. The concomitant use of alcohol, NSAIDs (e.g. Motrin and Aleve), antiplatelet drugs like Plavix, and SSRI-antidepressants (Paxil, Zoloft, Celexa, Lexapro and Luvox) increase the risk the risk of bleeding.

Be careful! Be safe! Be healthy!

 

References:

1. Valentin Fuster and Joseph Sweeny, “Aspirin: A Historical and Contemporary Overview,” Circulation 2011; 123: 768-78.
2. Manling Xie et al., “Aspirin for Primary Prevention of Cardiovascular Events: Meta-Analysis of Randomized Controlled Trails and Subgroup Analysis by Sex and Diabetes Status,” PLoS ONE 2014; 9 (10): e90286. doi: 10.1371.
3. Final Recommendation Statement, “Aspirin for the Prevention of Cardiovascular Disease: Preventative Medication, March 2009,” US Preventative Services Task Force 2009; uspreventativeservicestaskforce.org/
4. Antithrombotic Trialists (ATT) Collaboration, “Aspirin in the Primary and Secondary Prevention of Vascular Disease: Collaborative Meta-Analysis of Individual Participant Data from Randomised Trials,” Lancet 2009; 373: 1849-60.
5. Final Recommendation Statement, “Aspirin/NSAIDs for Prevention of Colorectal Cancer: Preventative Medication, March 2007,” US Preventative Services Task Force 2007; uspreventativeservicestaskforce.org/
6. Peter Rothwell et al., “Long-Term Effect of Aspirin on Colorectal Cancer Incidence and Mortality: 20-Year Follow-Up of Five Randomised Trails,” Lancet 2010; 376: 1741-50.
7. Peter Rothwell et al., “Effect of Daily Aspirin on Long-Term Risk of Death Due to Cancer: Analysis of Individual Patient Data from Randomised Trials,” Lancet 2011: 377: 31-41.
8. Garcia-Albeniz and A.T. Chan, “Aspirin for the Prevention of Colorectal Cancer,” Best Pract Clin Gastroenterol 2011; 25 (0): 461-72.
9. Soren Frils et al., “Low-Dose Aspirin or Nonsteroidal Anti-Inflammatory Drug Use and Colorectal Cancer Risk,” Ann Int Med 2015; 163: 347-55.
10. Cuzick et al., “Estimates of Benefits and Harms of Prophylactic Use of Aspirin in the General Population,” Ann Oncol 2015; 26: 47-57. *Best Review*