How does Aspirin Work?

Low-dose daily aspirin was an idea born in the 1960s, based on the insight that aspirin prevents blood clots and blood clots are the proximate cause of heart attacks and stroke.  Millions of people were advised by their doctors to take aspirin daily, and as a result there was a large group of people available for long-term health studies.  This led to an accidental discovery that aspirin slashes risk of many kinds of cancer and may have benefit preventing Alzheimer’s Disease.  Today, the medical consensus still favors daily aspirin, but the benefit for heart health is secondary.

Back in October, I reported on an article in Science Magazine claiming that daily aspirin can lower your risk of mortality by 13%.  I calculated this might add 2 years to life expectancy – and it’s easy and essentially free.  By the time it gets to Science Magazine, this is a mainstream position, meaning that although there is dissension (also here), the pro-aspirin view is now the majority.

The benefits of aspirin come from two quite different mechanisms, and my purpose in this column is to tease them apart.  One might legitimately be called “anti-aging”.  The other is more analogous to wearing seatbelts. Seatbelts lower your risk of dying but it would be a stretch to say that they make you younger.

The first benefit of aspirin is that it “thins the blood”.  (More technically, it inhibits the chemistry that makes blood clot.)  It turns out that, though chronic damage to the arteries sets the stage for heart attacks and strokes, the precipitating incident is usually a blood clot that gets snagged in the wrong place and denies blood supply to either the heart or the brain (“ischemia”), until, after just a minute or two, they suffocate.  Blood clots in the brain are the principal reason for stroke, and blood clots in the coronary artery can cause sudden cardiac death.  To the extent that these actions are responsible for its benefits, aspirin should be described as a “safety drug” rather than an anti-aging tonic.

The second mechanism, the one that I think of as “anti-aging” is to lower inflammation.  As we get older, our bodies slowly destroy themselves, and one of the principal mechanisms is to turn the inflammation process against healthy tissue.  All the diseases of old age are linked to chronic inflammation.

  • Inflammation can turn normal cells into cancer cells.

  • Inflammation in the arteries causes the damage that leads to plaques and then strokes and heart attacks.

  • Inflammation in the joints causes arthritis.  (There was a time when osteo-arthritis was distinguished from rheumatoid arthritis, and the former was blamed on abrasion building up over a lifetime, while only the latter was attributed to inflammation.  But the modern view is that they are not so different, and that osteo-arthritis is also an inflammatory disease.)

  • Inflammation is linked to brain damage and dementia.

So just by dialing down inflammation in a dumb, non-specific way, aspirin can lower risk of all these diseases.  In the young body, inflammation is an essential part of our immune defense, and has an important role in replacing damaged tissue.  But by the time we get to be 50+, inflammation is already causing more harm than good.  In this sense, anti-inflammatory is close to anti-aging.

If aspirin’s benefit comes from reducing inflammation then if you take aspirin from age 50 to age 80, say, then you are functionally a year or two younger than you might have been at the same age had you not taken aspirin.  If you stop taking aspirin on your 80th birthday, your body is that much younger, and the benefit stays with you still.  But if the only benefit comes from preventing fatal blood clots, then if you were to stop taking aspirin at age 80, your mortality risk would jump quickly back up where it would have been had you never taken aspirin at all.  You might attribute your survival for those 30 years in part to the benefit of aspirin, but you would not be better off than if you had survived to age 80 by sheer luck.

Separating these two effects of aspirin is not so easy because there is a strong physiological connection between the them.  Inflammation is suppressed by inhibiting COX-2, and blood clots are suppressed by inhibiting COX-1.  These are abbreviations for two forms of the enzyme cyclooxygenase.  Aspirin, like most NSAID drugs act on both COX-1 and COX-2.

(Rofecoxib=Vioxx is the only one that is completely specific to COX-2, without affecting COX-1.  Vioxx worked well against inflammation, but was found to increase risk of heart attack, and was withdrawn from the market in 2004.  But why should inhibiting COX-2 without COX-1 increase risk of heart attacks?  In the infamous VIGOR study, hidden data showed 4x as many heart attacks in patients taking Vioxx.  I have found no attempts to answer this question.)

Another interesting footnote:  Ibuprofen, the second most common NSAID, inhibits clotting in the same league with aspirin.  But the anti-clotting effect of aspirin lasts 5 days, and of ibuprofen just 1.  Here’s the curious part: if you take aspirin and ibuprofen together, the effect lasts just 1 day.  Evidently, ibuprofen blocks the long-term effects of aspirin.

By my reasoning, aspirin’s action in lowering heart risk ought to be a combination of these two kinds of actions.  But the message from Vioxx suggests that this benefit comes entirely from the first benefit, COX-1 and “blood thinning”.

But to the extent that aspirin lowers risk of cancer and Alzheimer’s disease, the effect must be due to COX-2 and the anti-inflammatory action.  There is powerful evidence that aspirin lowers risk of gastro-intestinal cancers and lung cancer.  There is also evidence for a less dramatic effect on other important cancers, including breast and prostate cancers.

Daily intake of NSAIDs, primarily aspirin, produced risk reductions of 63% for colon, 39% for breast, 36% for lung, and 39% for prostate cancer. Significant risk reductions were also observed for esophageal (73%), stomach (62%), and ovarian cancer (47%). NSAID effects became apparent after five or more years of use and were stronger with longer duration. Observed protective effects were also consistently stronger for gastrointestinal malignancies (esophagus, stomach, and colon). Results for pancreatic, urinary bladder, and renal cancer were inconsistent. Initial epidemiologic studies of malignant melanoma, Hodgkin’s disease, and adult leukemia also found that NSAIDs are protective. A few studies suggest that ibuprofen has stronger anticancer effects than aspirin, particularly against breast and lung cancer. – (from  R.E. Harris et al, 2005)

There are still researchers who claim that aspirin offers no benefit at all for cancer.  Here is a study that found no reduction in cancer risk for a low dose of 1 baby aspirin every other day.

Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.

Conclusion

Aspirin’s blood-thinning and anti-inflammatory effects both contribute substantially to disease prevention.  The first is primarily associated with COX-1 and roughly 10% reduction of heart disease and stroke.  The second is assoiated with COX-2 and roughly 40% reduction in risk of cancer.

15 thoughts on “How does Aspirin Work?

  1. Aspirin use is associated with a moderate risk of severe bleeding. Better to take 1000-5000 IU/d vitamin D3 to get the supposed benefits of aspirin. There are no risks in doing so and many benefits.

    Eur Heart J. 2013 Aug 1. [Epub ahead of print]
    Is aspirin useful in primary prevention?
    Cleland JG.

    Imperial College London (Royal Brompton & Harefield Hospitals), London, UK and Department of Cardiology, Castle Hill Hospital, Hull and York Medical School, University of Hull, Kingston-upon-Hull HU6 5JQ, UK.
    Abstract

    There is no evidence that aspirin is effective for the primary prevention of cardiovascular events, although it may change the way that they present. Indeed, there is no evidence that long-term aspirin should be given to patients even with known cardiovascular disease. Theoretical arguments that aspirin can prevent cardiovascular events by reducing the propagation of thrombus are countered by evidence that plaque haemorrhage from vasa vasorum may also cause plaque growth and instability. There is evidence that aspirin causes serious bleeding into the brain and the gut. Aspirin may also detract from the benefits of drugs that have definite cardiovascular benefits, such as angiotensin-converting enzyme inhibitors. Meta-analysis is prone to multiple biases in favour of aspirin, including publication bias, bias due to trial and endpoint selection and bias due to interpretation. Meta-analysis should not be relied on in preference to adequately powered clinical trials. Unfortunately, the benefits of aspirin, if they exist, may be so small that a very large study indeed would be required to demonstrate that its benefits outweigh its risks. The evidence that aspirin might reduce cancer is intriguing but relies on data from trials conducted many decades ago using a wide range of aspirin doses. There is no reliable evidence that aspirin used in the current fashionable doses of 50-100 mg/day is of any benefit in any common clinical setting.

    • William –
      First – I thank you for commenting on this site, and I thank you for your work on Vitamin D, which I have referenced in the past, and will again: http://SunArc.org.
      I am convinced of the value of vit D supplements. The question about aspirin does not detract from the value of D in any case.
      In my review of the literature the last few days, I find support for your position that aspirin’s cardiovascular benefits are illusory. Some say that the incidence of heart attacks goes down, but that mortality from heart disease isn’t affected, for example. Some say that cerebral bleeding more than offsets the reduction in risk of stroke. I find a majority opinion favoring a small cardiovascular benefit for aspirin.
      But it seems that the benefits for cancer are more robust, larger, and better-established.
      William: Do you know if anyone has investigated whether vit D and aspirin are synergistic or antagonistic in their prevention of cancer?

    • Stan – I hadn’t heard of Nattokinase, but it looks to be worth investigating. Nattokinase is an extract of Japanese soy cheese that has anti-clotting activity and (in lab tests) seems to dissolve some of the cross-linking of proteins that are one of the ways that aging manifests.

      What epidemiological studies do you suggest?

    • These are anti-inflammatories and they don’t cause bleeding. Are they as effective as aspirin for reducing cancer risk? I think we just don’t know because the number of people taking them is small, there’s no standard dosage, and it’s hard to find a large, uniform sample of people who take (for example) curcumin supplements in order to design a study.

  2. It’s funny how many people seem to think the risk of a little stomach bleeding (which btw has never caused me harm in 10+ years of daily aspirin-taking, and I don’t take baby doses) is somehow more important than preventing death by cancer! Are one in 4 people dropping dead of aspirin-caused stomach bleeding? Until we reach that state of affairs, please let’s stop the childish nonsense about stomach bleeding. Cancer is a major public health crisis that needs immediate action.

    I wrote briefly about this subject in http://asserttrue.blogspot.com/2012/02/want-to-avoid-cancer-take-ibuprofen.html and so I think we’re on the same page. What irks me is that word simply hasn’t gotten out to the public on this. Apparently it’s more important to keep the $10 billion/yr cancer remediation industry going than to tell people about cost-effective, safe, surefire preventive measures. Since Nixon declared war on cancer, we’ve (in the U.S.) spent the equivalent of $10,000 in research dollars for every single person who has ever died of cancer in the last 40 years, and we are not appreciably closer today to anything that could (without failing the straight-face test) be called a Cure for cancer than we were in 1973. This kind of appalling return on investment is usually associated with military spending. You would think that any drug or nutrient that could produce even a 2% drop in cancer rates would be hailed as a major achievement. And yet, no one but little-guy bloggers (that’s us) are telling the tale of aspirin and NSAID anticancer effects. It’s an amazing commentary on the state of public health policy in the U.S.

    Thank you for the excellent post. Keep up the fine work.

    • Kas –
      Thanks for the link to work you’ve done on this topic. I agree with your conclusion. But to be fair, we ought to consider in addition to the inconvenience of gastrointestinal side-effects the possible increase in risk of fatal aneurisms when blood clotting is inhibited. I think the tradeoff for lower cancer rates turns out to be a substantial net plus for aspirin.

      Can other anti-inflammatories that don’t affect blood clotting offer the same benefit with lower risk? We don’t know the answer because none has been studied nearly so well as the NSAIDs.

      • While there appear to be beneficial effects of aspirin, as I’ve stated before, vitamin D is much more effective and has only health benefits, no risks.

        Ann Intern Med. 2013 Jul 16;159(2):77-85. doi: 10.7326/0003-4819-159-2-201307160-00002.
        Alternate-Day, Low-Dose Aspirin and Cancer Risk: Long-Term Observational Follow-up of a Randomized Trial.
        Cook NR, Lee IM, Zhang SM, Moorthy MV, Buring JE.
        Abstract

        Chinese translation
        BACKGROUND:

        Recent evidence suggests that daily aspirin use decreases cancer risk, particularly for colorectal cancer, but evidence for alternate-day use is scant.
        OBJECTIVE:

        To examine the association between long-term, alternate-day, low-dose aspirin and cancer in healthy women.
        DESIGN:

        Observational follow-up of a randomized trial.
        SETTING:

        Female health professionals.
        PARTICIPANTS:

        39 876 women aged 45 years or older in the Women’s Health Study (ClinicalTrials.gov: NCT00000479), 33 682 of whom continued observational follow-up.
        INTERVENTION:

        100 mg of alternate-day aspirin or placebo through March 2004, with a median 10-year follow-up. Posttrial follow-up continued through March 2012.
        MEASUREMENTS:

        Cancer incidence.
        RESULTS:

        A total of 5071 cancer cases (including 2070 breast, 451 colorectal, and 431 lung cancer cases) and 1391 cancer deaths were confirmed. Over the entire follow-up, aspirin had no association with total (hazard ratio [HR], 0.97 [95% CI, 0.92 to 1.03]; P = 0.31), breast (HR, 0.98 [CI, 0.90 to 1.07]; P = 0.65), or lung (HR, 1.04 [CI, 0.86 to 1.26]; P = 0.67) cancer. Colorectal cancer was reduced in the aspirin group (HR, 0.80 [CI, 0.67 to 0.97]; P = 0.021), primarily for proximal colon cancer (HR, 0.73 [CI, 0.55 to 0.95]; P = 0.022). The difference emerged after 10 years, with a posttrial reduction of 42% (HR, 0.58 [CI, 0.42 to 0.80]; P < 0.001). There was no extended effect on cancer deaths or colorectal polyps. More gastrointestinal bleeding (HR, 1.14 [CI, 1.06 to 1.22]; P < 0.001) and peptic ulcers (HR, 1.17 [CI, 1.09 to 1.27]; P < 0.001) occurred in the aspirin group.
        LIMITATIONS:

        Not all women received extended follow-up, and posttrial ascertainment bias cannot be ruled out. Gastrointestinal bleeding, peptic ulcers, and polyps were self-reported during extended follow-up.
        CONCLUSION:

        Long-term use of alternate-day, low-dose aspirin may reduce risk for colorectal cancer in healthy women.

        Lancet. 2012 Apr 28;379(9826):1602-12. doi: 10.1016/S0140-6736(11)61720-0. Epub 2012 Mar 21.
        Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials.
        Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JF, Wilson M, Mehta Z, Meade TW.
        Source

        Stroke Prevention Research Unit, Nuffield Department of Clinical Neuroscience, University of Oxford, UK. [email protected]
        Abstract
        BACKGROUND:

        Daily aspirin reduces the long-term risk of death due to cancer. However, the short-term effect is less certain, especially in women, effects on cancer incidence are largely unknown, and the time course of risk and benefit in primary prevention is unclear. We studied cancer deaths in all trials of daily aspirin versus control and the time course of effects of low-dose aspirin on cancer incidence and other outcomes in trials in primary prevention.
        METHODS:

        We studied individual patient data from randomised trials of daily aspirin versus no aspirin in prevention of vascular events. Death due to cancer, all non-vascular death, vascular death, and all deaths were assessed in all eligible trials. In trials of low-dose aspirin in primary prevention, we also established the time course of effects on incident cancer, major vascular events, and major extracranial bleeds, with stratification by age, sex, and smoking status.
        RESULTS:

        Allocation to aspirin reduced cancer deaths (562 vs 664 deaths; odds ratio [OR] 0·85, 95% CI 0·76-0·96, p=0·008; 34 trials, 69,224 participants), particularly from 5 years onwards (92 vs 145; OR 0·63, 95% CI 0·49-0·82, p=0·0005), resulting in fewer non-vascular deaths overall (1021 vs 1173; OR 0·88, 95% CI 0·78-0·96, p=0·003; 51 trials, 77,549 participants). In trials in primary prevention, the reduction in non-vascular deaths accounted for 87 (91%) of 96 deaths prevented. In six trials of daily low-dose aspirin in primary prevention (35,535 participants), aspirin reduced cancer incidence from 3 years onwards (324 vs 421 cases; OR 0·76, 95% CI 0·66-0·88, p=0·0003) in women (132 vs 176; OR 0·75, 95% CI 0·59-0·94, p=0·01) and in men (192 vs 245; OR 0·77, 95% CI 0·63-0·93, p=0·008). The reduced risk of major vascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer (absolute reduction 3·13 [95% CI 1·44-4·82] per 1000 patients per year) from 3 years onwards. Case-fatality from major extracranial bleeds was also lower on aspirin than on control (8/203 vs 15/132; OR 0·32, 95% CI 0·12-0·83, p=0·009).
        INTERPRETATION:

        Alongside the previously reported reduction by aspirin of the long-term risk of cancer death, the short-term reductions in cancer incidence and mortality and the decrease in risk of major extracranial bleeds with extended use, and their low case-fatality, add to the case for daily aspirin in prevention of cancer.

  3. In your extensive guide of pills and supplement you talk about an alternate intake of aspirin and ibuprofen, do you have any study that show the benefetit of a daily dose of ibuprofen ?

  4. Pingback: FDA Questions an Aspirin a Day.   I Question FDA. | Josh Mitteldorf

  5. My guess is that while Vioxx down regulates COX2, it up regulates COX1.
    While I don’t doubt that aspirin lowers risk of blood clots, it also increases the risk of hemolytic (bloody) strokes.

  6. I’m curious why no one has mentioned the possible usage of Willow Bark (which Asprin was originally based upon) instead of Asprin. Willow bark being much more natural, etc., etc.

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