In people with pre-existing cardiovascular disease, it has long been well documented that long-term use of aspirin is an effective anti-platelet treatment that significantly reduces the risk of serious cardiovascular events (such as heart attacks and strokes) by 30% and cardiovascular death by 15%.[1, 2]
This benefit greatly exceeds the potential risk of increased bleeding events, which is a side effect of aspirin. Therefore clinical guidelines recommend that people with cardiovascular disease take low dose aspirin (75 to 162 mg) daily to prevent recurrence of cardiovascular events.[4-6]
More recently, the use of aspirin in healthy people for prevention of cardiovascular disease, as well as cancer, has been getting more and more attention. However, research on prophylactic use of aspirin conflicting and clinical guidelines are contradictory. Here I will shed some light on new research to help you make an informed decision whether aspirin may protect you…
Aspirin as a prophylaxis in primary prevention (i.e. to keep healthy people healthy)
Discussions about prophylactic use of aspirin revolve around cardiovascular disease, and more recently cancer. Here I will be dealing with them separately. But first, let’s get a perspective on bleeding caused by aspirin.
Bleeding – the notorious side effect of aspirin
Aspirin is well known for increasing bleeding risk, especially gastro-intestinal (GI) bleeding. Despite common concerns over GI and cerebral bleeding caused by aspirin, evidence from randomized trials and large population studies of people using aspirin prophylactically for many years suggest those concerns are blown out of proportion.
A large meta-analysis of 18 studies using aspirin doses of 75 to 375 mg found that the mean number of extra upper gastrointestinal bleeding cases associated with low-dose aspirin use is 1.2 per 1000 patients per year. However, when evaluating the relationship between aspirin use and bleeds, it is important to distinguish between bleeding in relation to short-term use of aspirin, as reported in most of the published trials, and bleeding in relation to long-term use.[7, 9] Shortly after start of prophylactic aspirin use, the risk of a GI bleeding is high but decreases thereafter. An analysis of 17 randomized studies found that the risk of a bleed in the first month of aspirin use was increased by 4-fold, but fell thereafter. Data from long-term studies shown that after 5 years of aspirin use there is no significant excess risk of bleeding.
Although gastric and intestinal mucosal damage can be seen on endoscopic examination after short-term aspirin administration, this appears to improve during continuous aspirin use and can be explained by a gastric adaptation to continuous low-dose aspirin. In contrast to ibuprofen and rofecoxib, low-dose aspirin (80 mg), when compared to placebo, appears not to cause stomach ulceration in people with a healthy GI system. On the other hand, aspirin use in people with untreated stomach ulcer can increase bleeding risk 15-fold.
The most serious bleeds are those that lead to death, and despite frequent comments to the contrary, there appears to be no valid evidence that fatal GI bleeds are increased by low-dose aspirin. Support for this comes from the landmark Antithrombotic Trialists’ meta-analysis, where there were 9 fatal GI bleeds in patients on aspirin and 20 in those on placebo. Deaths due to bleeding were 3.9 per 100,000 patients per year in in patients using aspirin vs. 5.1 per 100,000 per year in those on placebo. In line with this, a recent analysis concluded that major bleeding events that are comparable in severity to cardiovascular disease or cancer, are infrequent in people using aspirin prophylactically.
Aspirin for prevention of cardiovascular disease
Most people who use aspirin as a prophylaxis do so for cardiovascular disease prevention. In contrast to the consistent evidence supporting the use of aspirin in secondary prevention, aspirin prophylaxis for cardiovascular disease prevention is debated among researchers. This is reflected in the contradictory guidelines, as shown in table 1.
Table 1: Overview of current guidelines on the use of aspirin in primary prevention for cardiovascular disease.
United States Preventive Services Task Force (USPSTF) 2009
Encourage men aged 45–79 years to use aspirin when the potential benefit of a reduction in heart attack outweighs the potential harm.
Encourage women aged 55–79 years to use aspirin when the potential benefit of a reduction of ischemic stroke outweighs the potential harm.
European Society of Cardiology (ESC) 2012
In patients without overt CVD, aspirin cannot be recommended in primary prevention because of increased risk of major bleeding.
Antiplatelet therapy may be considered in hypertensive patients without a history of CVD.
Antiplatelet therapy with aspirin is not recommended for people with diabetes who do not have clinical evidence of atherosclerosis.
American College of Chest Physicians (ACCP) 2012
Persons aged 50 years or older without symptomatic CVD: low-dose aspirin 75–100 mg daily.
American Heart Association/American Stroke Association (AHA/ASA) 2011
Use of aspirin CV prophylaxis is recommended for persons whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment (i.e., 10-year risk of CV
event = 6–10 %).
Aspirin can be useful for the prevention of a first stroke among women whose risk is sufficiently high for the benefits to outweigh the risks associated with treatment.
Aspirin is not useful for preventing a first stroke in persons at low risk.
Aspirin is not useful for preventing a first stroke in persons with diabetes or diabetes plus asymptomatic peripheral artery disease in the absence of any other CVD.
American Diabetes Association (ADA) 2014
Consider aspirin therapy (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk 10% or more).
This includes most men aged 50 years or above and women aged 60 years or above, who have at least one additional major risk factor (family history of CVD, hypertension,
smoking, dyslipidemia, or albuminuria).
Aspirin should not be recommended for CVD prevention for
adults with diabetes at low CVD risk (10-year CVD risk below 5%, such as in men below 50 years and women below 60 years with no major additional CVD risk factors), since the potential adverse effects from bleeding likely offset the potential benefits.
CV = cardiovascular; CVD = cardiovascular disease
Older meta-analyses of studies on prophylactic aspirin use concluded that despite important reductions in heart-attacks and ischemic stroke, the benefits are in large part offset by increases in hemorrhagic stroke and major bleeding event.[23-27]
In contrast to this previously perceived uncertain net value, a more recent meta-analysis, which also specifically analyzed the benefit-risk ratio in men vs. women, and in diabetics, concluded:
“The use of low-dose aspirin was beneficial for primary prevention of cardiovascular disease and the decision regarding an aspirin regimen should be made on an individual patient basis. The effects of aspirin therapy varied by sex and diabetes status. A clear benefit of aspirin in the primary prevention of cardiovascular disease in people with diabetes needs more trials.”
This meta-analysis found we found significant benefits of aspirin use vs. placebo; major cardiovascular event, heart attack and ischemic stroke were reduced by of 10, 14, and 14% in the overall population who used aspirin. The effects of aspirin may vary by sex and diabetes status. Aspirin use was associated with a significant reduction in the risk of cardiovascular events in both sexes but different specific types of benefits; a reduction in heart attack among men and a reduction in ischemic stroke
among women. Aspirin had no significant effect on cardiovascular disease in the overall diabetic population, but was associated with a reduction in heart attack among men with diabetes.
The range of aspirin dose varied from 75 to 650 mg/day in the studies included in this meta-analysis.
Notably, it was found that risk reductions achieved with low aspirin doses (75 mg/day) were similar to those obtained with higher doses (650 mg/day). It was also pointed out that although there was an increase in bleeding events, it is not sensible to conclude that the benefit of aspirin is always offset by the risk of bleeding; in fact, the results suggest that the benefit of reducing risk of ischemic stroke outweigh the harm hemorrhagic stroke.
Also, it is important to underscore that the current guidelines listed in table 1 are based on clinical trials of aspirin use in primary prevention of cardiovascular disease, and thus only consider the benefits of a reduction in cardiovascular risk versus potential harms from bleeding.[17, 29] Aspirin’s potential as an anti-cancer prophylaxis is not taken into consideration.
Aspirin for prevention of cancer
Accumulating research supports use of aspirin for cancer prevention.[9, 30-35] The evidence for an anti-cancer effect of aspirin is strongest for colorectal cancer, but rapidly accumulating data supports that aspirin also offers protection against development and/or progression/severity (i.e. incidence and mortality) of other common cancers , such as breast cancer [37-41] and prostate cancer.[42-45]
Cancer is the second most common cause of premature death worldwide, after heart disease, and its prevalence is increasing because of the aging population, as well as an increasing prevalence of risk factors such as obesity and physical inactivity. Every year, there are 1.5 million new cancer cases and 560 000 cancer deaths in the US.[47, 48] During a lifespan, 41% of the US population will develop cancer and 21% will die from cancer.
In light of the high and rising burden of cancer, aspirin’s potential anti-cancer effects need to be taken into consideration when evaluating the risk-benefit of aspirin use. Daily low dose aspirin (as low as75 mg) reduces deaths due to several common cancers, both during and after the study completion, and benefit increases with duration of aspirin use. Specifically, in long-term studies (4 years or more) investigating the use of aspirin for primary and secondary prevention of cardiovascular disease, when compared to placebo, aspirin reduced 20-year cancer mortality by 20-30%, due mainly to fewer deaths after completion of the trials. This suggest that aspirin has a long-term carryover effect and that it may take a long time to see the full benefits of aspirin on cancer related outcomes.
Amore recent analysis of cancer outcomes included 77,549 patients (40,269 randomly assigned to aspirin and 3, 280 to placebo) from previous studies of aspirin use and prevention of cardiovascular disease. After a minimum of 5 years of follow-up, it was found that aspirin groups had 12% fewer cancer deaths compared with placebo groups. In studies of daily low-dose aspirin in primary prevention (i.e. healthy people) aspirin reduced cancer incidence from 3 years onwards by 25%, in both men and women.
Net benefit of aspirin when considering prevention of both cardiovascular disease and cancer
In light of the new research on aspirin and cancer, the latest risk-benefit analyses are more favorable than the ones that only consider cardiovascular disease.[17, 49] A recent study assessed the benefits and harms of prophylactic use of aspirin in the general population by summarizing data from the most recent systematic reviews on the effect of aspirin on site-specific cancer incidence and mortality, cardiovascular events and side effects. It was found that the effects of aspirin on cancer are not apparent until at least 3 years after the start of use, and some benefits are sustained for several years after cessation in long-term users. No differences between low and standard doses of aspirin are observed, but there were no direct comparisons. Excess bleeding is the most important harm associated with aspirin use, and its risk and fatality rate increases with age. For average-risk individuals aged 50-65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, heart attack or stroke events over a 15-year period and an overall 4% reduction in all deaths over a 20-year period. It was concluded that prophylactic aspirin use for a minimum of 5 years at doses between 75 and 325 mg/day appears to have a favorable benefit-harm profile and that longer use is likely to have greater benefits.
A benefit and cost-effectiveness analysis investigated whether including a cancer mortality-reducing effect influences which men would benefit from aspirin for primary prevention. It was demonstrated that when this potential effect of aspirin on cancer mortality is included, aspirin becomes beneficial (and cost-effective) for a large group of middle-aged men at low heart disease risk who otherwise might not receive net benefit from taking aspirin. This suggests that guidelines on aspiring use should include the cancer effect and reconsider their recommendations for primary prevention based on all beneficial effects of aspirin.
Another study analyzed the overall balance of risk and benefit of low-dose daily aspirin in primary prevention, by looking at the major cardiovascular events, incident cancer, and major extra-cranial bleeds, as well as the time course of onset of respective effect of aspirin. Aspirin reduced the risk of the composite outcome of major vascular events, cancer, or fatal extra-cranial bleeds by 12% after a follow-up of up to 8 years. Surprisingly, the proportion of major extra-cranial bleeds that were fatal was lower in patients taken aspirin versus those taking placebo (3.9% vs. 11.3%). Notably, the reduced risk of major cardiovascular events on aspirin was initially offset by an increased risk of major bleeding, but effects on both of these two outcomes diminished with increasing follow-up, leaving only the reduced risk of cancer from 3 years onwards.
This study is notable because it assessed how effects on all major outcomes (cardiovascular disease, cancer and bleeding) evolve with time after 5 years of follow-up, which has never been done before. Previous systematic reviews and analyses of the risks and benefits of aspirin have not considered effects of aspirin on cancer incidence, mortality, or non-vascular death together, and have assumed that the effects of aspirin on major cardiovascular and bleeding events will be independent of duration of aspirin use. This study, together with the previous study showing that aspirin reduces 20-year cancer mortality by 20-30% , suggest that extended use of aspirin is be safer than previously supposed and of value in prevention of cancer development and cancer deaths in the general population.
It should be underscored that when evaluating the risk-benefit balance with aspirin use, one needs to not only consider the incidence of benefits and harms, but also take into account their respective consequences. Any fatality is fatal, but it is quite clear that a non-fatal stroke or heart attack is more likely to result in long-term disability than a non-fatal bleed.
When should you NOT take aspirin?
Several prevalent conditions are potential contraindications for low-dose aspirin use. People who have or have had stomach ulcers should also be careful with aspirin (even low-dose regimens) because of aspirin’s potential negative gastric effects.[3, 8, 14, 52-54] Other factors the increase risk of upper gastrointestinal bleeding in people taking low-dose aspirin are Helicobacter pylori infection, alcohol, calcium channel blockers, older age and male sex (incidence of serious upper gastrointestinal bleeding/perforation is twice as high in men than in women).[14, 55, 56]
Those with arthritis, who are likely to take non-steroidal anti-inflammatory drugs (NSAIDs) for their condition, should not take aspirin due to potential harmful medication interactions.[57, 58] For example, compared with those who used aspirin alone, patients taking aspirin plus ibuprofen had a 73% increased risk of cardiovascular mortality and an almost 2-fold increased risk of all-cause mortality. Likewise, another study in healthy people found that use of prophylactic aspirin together with frequent use of non-aspirin NSAIDs (4 times/week, including ibuprofen), was associated with a 2-fold increase risk of a first heart attack. Thus, NSAIDs may counteract the cardio-protective effects of aspirin. In addition, risk of bleeding and/or stomach ulcer is particularly high in people who take non-aspirin NSAID together with aspirin.[10, 13, 52, 59]
What aspirin dose and form should you take?
Low-dose aspirin is in range of 75 mg/day to 150 mg/day, and is commonly the dose that is used for primary prevention of cardiovascular disease. Notably, the cardiovascular disease risk reduction achieved with low aspirin doses (75 mg/day) are similar to those obtained with higher doses (650 mg/day). This may be because the successive daily administration of only 30 mg of aspirin is sufficient to result in virtually inactivation of platelet COX-1, and thus blockade of platelet thromboxane production (the substance made by platelets that causes blood clotting and constriction of blood vessels). However, there is no study using the 30 mg dose.
For cancer prevention, daily aspirin doses as low as 75 mg have been demonstrated to be protective [30, 33, 60], but a larger dose between 300 to 650 mg per day may confer greater cancer protection.[17, 61-63] People who have a family history of cancer may want to try a minimum daily aspirin dose of 325 mg. However, it should be noted that the protective gastric adaptation to aspirin is delayed and/or less effective when higher aspirin doses are taken (such as those doses used for anti-inflammatory purposes).
When it comes to cancer prevention, duration of use may be more important than the actual dose.[9, 33, 63]. This is not surprising, as for most cancers, the time from carcinogenesis to clinically detected disease is at least 10 years.
What form of aspirin should you take? It is commonly believed that enteric-coated and buffered (effervescent) forms of aspirin are less likely to cause GI bleeding than plain aspirin tablets. A study that investigated this found that the risk for GI bleeding plain, enteric-coated, and buffered aspirin at average daily doses of 325 mg or less were comparable. At doses greater than 325 mg, the relative risk was – counterintuitively - larger for buffered aspirin than plain aspirin (there were insufficient data to evaluate enteric-coated aspirin at this dose level). Another study that compared enteric-coated aspirin and plain aspirin found that the risk of stomach bleeding and/or perforation was the same for both. When comparing buffered aspirin with plain aspirin, buffered aspirin does not cause less gastrointestinal symptoms compared with plain aspirin.
The latest research does support the use of low-dose aspirin for primary prevention of both cardiovascular disease and cancer, in both men and women. When seen in a long-term perspective, the benefits of aspirin prophylaxis does outweigh the potential harm from bleeding/stomach ulceration in the large majority of the general population. This can be summarized with the following bullet points:
* For every 1666 treated with aspirin for 1 year for primary prevention of heart disease there would be one less cardiovascular event.
* For every 3333 people treated with aspirin for a year there would be one extra significant bleed.
* For every 29 people taking aspirin for around 5 years, 20 years later one death from cancer would be prevented.
Use the lowest effective daily dose of 75-150 mg for cardiovascular disease prevention, or if you have cancer running in your family, you may want to opt for at least 300 mg. Stick with plain aspirin, as enteric-coated and buffered form of aspirin – contrary to common belief – don’t seem to reduce gastrointestinal symptoms. And plain aspirin is cheaper.
In an upcoming article I will cover the issue of taking aspirin together with fish oil. Stay tuned…
1. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ, 1994. 308(6921): p. 81-106.
2. Antithrombotic Trialists, C., 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): p. 71-86.
3. Huang, E.S., et al., Long-term use of aspirin and the risk of gastrointestinal bleeding. Am J Med, 2011. 124(5): p. 426-33.
4. Smith, S.C., Jr., et al., AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation, 2011. 124(22): p. 2458-73.
5. Kernan, W.N., et al., Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2014. 45(7): p. 2160-236.
6. Eikelboom, J.W., et al., Antiplatelet drugs: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. e89S-119S.
7. Critical views in gastroenterology & hepatology: aspirin prophylaxis: putting gut bleeds into perspective. Gastroenterol Hepatol (N Y), 2014. 10(1): p. 61-3.
8. Valkhoff, V.E., et al., Low-dose acetylsalicylic acid use and the risk of upper gastrointestinal bleeding: a meta-analysis of randomized clinical trials and observational studies. Can J Gastroenterol, 2013. 27(3): p. 159-67.
9. Rothwell, P.M., et al., 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. Lancet, 2012. 379(9826): p. 1602-12.
10. de Abajo, F.J. and L.A. Garcia Rodriguez, Risk of upper gastrointestinal bleeding and perforation associated with low-dose aspirin as plain and enteric-coated formulations. BMC Clin Pharmacol, 2001. 1: p. 1.
11. Garcia Rodriguez, L.A., S. Hernandez-Diaz, and F.J. de Abajo, Association between aspirin and upper gastrointestinal complications: systematic review of epidemiologic studies. Br J Clin Pharmacol, 2001. 52(5): p. 563-71.
12. Olivero, J.J. and D.Y. Graham, Gastric adaptation to nonsteroidal anti-inflammatory drugs in man. Scand J Gastroenterol Suppl, 1992. 193: p. 53-8.
13. Laine, L., et al., Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial. Gastroenterology, 2004. 127(2): p. 395-402.
14. Lanas, A., et al., Helicobacter pylori increases the risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther, 2002. 16(4): p. 779-86.
15. Morgan, G., Aspirin for the primary prevention of vascular events? Public Health, 2009. 123(12): p. 787-8.
16. Thorat, M.A. and J. Cuzick, Prophylactic use of aspirin: systematic review of harms and approaches to mitigation in the general population. Eur J Epidemiol, 2015. 30(1): p. 5-18.
17. Brotons, C., et al., A systematic review of aspirin in primary prevention: is it time for a new approach? Am J Cardiovasc Drugs, 2015. 15(2): p. 113-33.
18. Force, U.S.P.S.T., Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med, 2009. 150(6): p. 396-404.
19. Perk, J., et al., European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). Eur Heart J, 2012. 33(13): p. 1635-701.
20. Vandvik, P.O., et al., Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 2012. 141(2 Suppl): p. e637S-68S.
21. Goldstein, L.B., et al., Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke, 2011. 42(2): p. 517-84.
22. American Diabetes, A., Standards of medical care in diabetes--2014. Diabetes Care, 2014. 37 Suppl 1: p. S14-80.
23. Antithrombotic Trialists, C., et al., Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet, 2009. 373(9678): p. 1849-60.
24. Bartolucci, A.A., M. Tendera, and G. Howard, Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol, 2011. 107(12): p. 1796-801.
25. Raju, N., et al., Effect of aspirin on mortality in the primary prevention of cardiovascular disease. Am J Med, 2011. 124(7): p. 621-9.
26. Seshasai, S.R., et al., Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med, 2012. 172(3): p. 209-16.
27. Berger, J.S., et al., Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials. Am Heart J, 2011. 162(1): p. 115-24 e2.
28. Xie, M., et al., Aspirin for primary prevention of cardiovascular events: meta-analysis of randomized controlled trials and subgroup analysis by sex and diabetes status. PLoS One, 2014. 9(10): p. e90286.
29. Patrono, C., Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither? Eur Heart J, 2013. 34(44): p. 3403-11.
30. Rothwell, P.M., 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(9759): p. 31-41.
31. Rothwell, P.M., et al., Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet, 2012. 379(9826): p. 1591-601.
32. Algra, A.M. and P.M. Rothwell, Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials. Lancet Oncol, 2012. 13(5): p. 518-27.
33. Rothwell, P.M., et al., Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet, 2010. 376(9754): p. 1741-50.
34. Bosetti, C., et al., Aspirin and cancer risk: a quantitative review to 2011. Ann Oncol, 2012. 23(6): p. 1403-15.
35. Jacobs, E.J., et al., Daily aspirin use and cancer mortality in a large US cohort. J Natl Cancer Inst, 2012. 104(16): p. 1208-17.
36. Farag, M., Can Aspirin and Cancer Prevention be Ageless Companions? J Clin Diagn Res, 2015. 9(1): p. XE01-XE03.
37. Zhong, S., et al., Association between aspirin use and mortality in breast cancer patients: a meta-analysis of observational studies. Breast Cancer Res Treat, 2015. 150(1): p. 199-207.
38. Huang, X.Z., et al., Aspirin and nonsteroidal anti-inflammatory drugs after but not before diagnosis are associated with improved breast cancer survival: a meta-analysis. Cancer Causes Control, 2015. 26(4): p. 589-600.
39. Fraser, D.M., et al., Aspirin use and survival after the diagnosis of breast cancer: a population-based cohort study. Br J Cancer, 2014. 111(3): p. 623-7.
40. Barron, T.I., et al., Recent prediagnostic aspirin use, lymph node involvement, and 5-year mortality in women with stage I-III breast cancer: a nationwide population-based cohort study. Cancer Res, 2014. 74(15): p. 4065-77.
41. Jacobo-Herrera, N.J., et al., Clinical evidence of the relationship between aspirin and breast cancer risk (review). Oncol Rep, 2014. 32(2): p. 451.
42. Liu, Y., et al., Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis. BMC Med, 2014. 12: p. 55.
43. Vidal, A.C., et al., Aspirin, NSAIDs, and risk of prostate cancer: results from the REDUCE study. Clin Cancer Res, 2015. 21(4): p. 756-62.
44. Huang, T.B., et al., Aspirin use and the risk of prostate cancer: a meta-analysis of 24 epidemiologic studies. Int Urol Nephrol, 2014. 46(9): p. 1715-28.
45. Dhillon, P.K., et al., Long-term aspirin use and the risk of total, high-grade, regionally advanced and lethal prostate cancer in a prospective cohort of health professionals, 1988-2006. Int J Cancer, 2011. 128(10): p. 2444-52.
46. Torre, L.A., et al., Global cancer statistics, 2012. CA Cancer J Clin, 2015. 65(2): p. 87-108.
47. Preventable cancer in the USA. Lancet, 2010. 375(9727): p. 1665.
48. Siegel, R.L., K.D. Miller, and A. Jemal, Cancer statistics, 2015. CA Cancer J Clin, 2015. 65(1): p. 5-29.
49. Halvorsen, S., et al., Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology working group on thrombosis. J Am Coll Cardiol, 2014. 64(3): p. 319-27.
50. Cuzick, J., et al., Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol, 2015. 26(1): p. 47-57.
51. Pignone, M., et al., Effect of including cancer mortality on the cost-effectiveness of aspirin for primary prevention in men. J Gen Intern Med, 2013. 28(11): p. 1483-91.
52. Weil, J., et al., Prophylactic aspirin and risk of peptic ulcer bleeding. BMJ, 1995. 310(6983): p. 827-30.
53. Cryer, B. and K.W. Mahaffey, Gastrointestinal ulcers, role of aspirin, and clinical outcomes: pathobiology, diagnosis, and treatment. J Multidiscip Healthc, 2014. 7: p. 137-46.
54. Iwamoto, J., et al., Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy. World J Gastroenterol, 2013. 19(11): p. 1673-82.
55. Hernandez-Diaz, S. and L.A. Rodriguez, Incidence of serious upper gastrointestinal bleeding/perforation in the general population: review of epidemiologic studies. J Clin Epidemiol, 2002. 55(2): p. 157-63.
56. Algra, A. and J.P. Greving, Aspirin in primary prevention: sex and baseline risk matter. Lancet, 2009. 373(9678): p. 1821-2.
57. MacDonald, T.M. and L. Wei, Effect of ibuprofen on cardioprotective effect of aspirin. Lancet, 2003. 361(9357): p. 573-4.
58. Kimmel, S.E., et al., The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. J Am Coll Cardiol, 2004. 43(6): p. 985-90.
59. Sorensen, H.T., et al., Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin. Am J Gastroenterol, 2000. 95(9): p. 2218-24.
60. Thun, M.J., E.J. Jacobs, and C. Patrono, The role of aspirin in cancer prevention. Nat Rev Clin Oncol, 2012. 9(5): p. 259-67.
61. Garcia Rodriguez, L.A. and C. Huerta-Alvarez, Reduced incidence of colorectal adenoma among long-term users of nonsteroidal antiinflammatory drugs: a pooled analysis of published studies and a new population-based study. Epidemiology, 2000. 11(4): p. 376-81.
62. Flossmann, E., et al., Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet, 2007. 369(9573): p. 1603-13.
63. Elwood, P.C., et al., Aspirin, salicylates, and cancer. Lancet, 2009. 373(9671): p. 1301-9.
64. Kelly, J.P., et al., Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product. Lancet, 1996. 348(9039): p. 1413-6.
65. Jaspers Focks, J., et al., Gastrointestinal symptoms in low-dose aspirin users: a comparison between plain and buffered aspirin. Neth Heart J, 2014. 22(3): p. 107-12.
66. Rose, P.W., E.K. Watson, and L.S. Jenkins, Aspirin for prevention of cancer and cardiovascular disease. Br J Gen Pract, 2011. 61(587): p. 412-5.