Ischemic heart disease and stroke are the number 1 and 2 causes of death in the world [1]. Any well-tested, generic, and low-cost option utilized for primary and secondary prevention in the area of cardiovascular disease (CVD) should also receive attention in the area of breast cancer prevention and as an ancillary method to reduce the risk of recurrence. S.A.M. (Statins, Aspirin, and/or Metformin) helps to discern the true evidence-based off-label products from those without the evidence and reemphasizes the need to reduce the risk of CVD is as close to zero as possible in all patients via lifestyle and some medications [2]. Reducing the risk of CVD allows patients to not only reduce their risk of all-cause morbidity and mortality (and arguably the number 2 or number 1 cause of death in breast cancer patients) but the exact same recommendations that allow patients to reduce CVD risk are identical to the recommendations to reduce the risk of breast cancer or the recurrence of this disease. In this chapter, the “A” in S.A.M. or aspirin is discussed.

Extracts of some plants, such as white willow ( Salix alba ), myrtle, meadowsweet (Filipendula ulmaria), and poplar have a high concentration of “salicylates” and have been used throughout history to treat a variety of human medical conditions [3–6]. Medicinal recipes from the third Millennium BC in E gypt discussed the infusion of dried myrtle leaves for reducing the pain of rheumatism and back problems. The use of willow tree bark and leaves for medicinal reasons were also referenced by the Assyrians, Babylonians, and Chinese. Hippocrates in the fifth century BC utilized the bark and leaves of the willow tree (“salicin”—a precursor to aspirin) to treat fever and reduce pain. The Reverend Edward Stone in 1763 informed the Royal Society that willow bark contained compounds the reduced the symptoms of “ague,” which was probably malarial fever.

“Salicylic acid ,” the active ingredient from willow and meadowsweet was isolated and purified in the first half of the nineteenth century, and in 1860 was chemically synthesized by the carboxylation of sodium phenoxide. Salicylic acid was deemed the overall better salicin derivative. Salicin is really a prodrug that experiences hydrolysis in the gastrointestinal tract and is converted to saligenin and glucose. Next, saligenin is oxidized to salicylic acid. Now, back to the story.

Dr. Thomas John MacLagan, a physician from Dundee, Scotland, completed arguably the first documented controlled trial of salicylic acid and suggested in 1876 that this compound had antipyretic, analgesic, and anti-inflammatory properties [3–6]. Salicylic acid , although bitter tasting, was then routinely used to treat fever, pain. and inflammation. However, in an attempt to reduce the bitter taste and serious side effect of vomiting and ulceration of the stomach, salicylic acid was acetylated. Arguably, this new synthesized compound was derived from the meadowsweet (the old botanical name was “ Spiraea ulmaria ”—member of the rose family) and not the white willow. Regardless, this compound was clinically introduced in 1899, under the trademark Aspirin or “acetylsalicylic acid ” and it is the most commonly used drug in the world.

In one of the most fascinating medical historical observations this author has ever come across, it was the acetylation of aspirin with the purpose of reducing its bitterness and improve palatability, which was actually responsible for its unique antiplatelet or blood thinning effect [3–6]! The acetyl group could now be transferred to the serine residue (position 529) in the active site of the enzyme cyclooxygenase (COX) , which then irreversibly blocks its function (permanently in platelets because they have no nucleus) and prevents the production of key prostaglandins. In other words, without the acetylation there is no effective blood thinning potential! A truly remarkable moment of serendipity! Regardless of the acetylation, aspirin is also really a prodrug because it is rapidly deacetylated after it is absorbed from the stomach and small intestine and much of its activity, except for antiplatelet effects, are due to the salicylic acid.

Salicylic acid (2-hydroxybenzoic acid) is widely produced and found throughout the plant kingdom, and it appears that it has many functions especially as part of the plant defense system against pathogen invasion and attack, and even from environmental stress [7, 8]. However, because fruits and vegetables contain “salicylic acid” there is the thought that this may be one of the mechanisms whereby these and other foods lower disease risk. There is also the thought that salicylic acid should be called “Vitamin S ” because it is arguably an essential vitamin, and that salicylic acid deficiency should be a recognized health problem.

The first published or noted estimate of the salicylic content of a food is documented as a letter in the journal Lancet in 1903 [9]. It was an anonymous contribution and suggested salicylic acid can be found in strawberries and other fruits in small amounts. Today it is known that salicylic acid is found in a diversity of foods [7, 8]. The content varies though based on the testing method, growing conditions, time of the year, storage, and cooking method. For example, the salicylate concentration of five brands of orange juice tested ranged from 0.47 to 3.02 mg/l. A variety of studies suggest in a moderately health diet a daily salicylic acid intake of anywhere from less than 1 to approximately 4 mg/day. Interestingly, some of the major dietary sources of salicylates are:

Herbs and spices can contain a large amount of salicylates [7, 8]. As an example, a standard South Indian vegetarian diet (mint chutney, vada, sambar/lentil based vegetable stew, …) can contain over 10 mg of salicylic acid per day. Table 5.1 is a brief summary of some of the median amounts of total salicylates found in some common fruits, vegetables, spices, and juices [7, 8]. It should be kept in mind that this is based on preliminary findings of accepted testing methods and arguably these levels vary widely over time and with further research, changing environmental conditions and geographic areas and seasons.

It is interesting that fruits and vegetables appear to account for 25 % of the total intake of salicylates [7, 8]. And fruits and vegetables are also good sources of fiber and nutrients including potassium (low in sodium) and a variety of vitamins and minerals. Spices appear to also be responsible for 10–15 % of the total salicylate intake in men and women. This has led some to theorize that lower rates of colorectal cancer incidence in some Indian populations could be partially due to the higher intake of food salicylates from spices. On the other hand, populations that consume more alcohol, a known carcinogen, could be offsetting the positive effect of salicylates from food. It also appears that total serum and urinary salicylate concentrations of vegetarians are greater than omnivores and in some rare cases could compare with individuals that use low dose aspirin regularly. However, more research is needed in this area because in aspirin users of 75 mg/day the median concentration of salicylic acid is 10.03 μmol/L (range 0.23–25) versus South Indian and vegetarians, which are 0.26 μmol/L (range 0.05–0.64) and 0.11 μmol/L (range 0.04–2.47) from preliminary clinical studies.

The prolonged anticoagulant effect of aspirin actually occurs for several days, even after one dose, and until sufficient numbers of new platelets are produced [10]. Regardless, the use of aspirin for CVD prevention is a matter of the individualized benefit-to-risk scenario. Although aspirin reduces the risk of myocardial infarction and stroke, and potentially venous thrombotic events and cancer, the risk of serious gastrointestinal bleeding and hemorrhagic stroke suggests the greater the risk of vascular events the greater the benefit of aspirin. It is for this reason it is well accepted to utilize aspirin in a secondary prevention setting [10, 11]. The ISIS-2 trial found daily aspirin in the setting of acute myocardial infarction reduced the risk of vascular death by over 20 % [12], and it has also been shown to be effective with acute ischemic stroke, thus it is a primary early therapy with acute coronary syndromes and stroke. Pooled data of approximately 200 clinical trials again demonstrates a risk reduction of more than 20 % with higher dosages but without additional benefit and an increased risk of bleeding events [10, 11]. Currently, the standard practice is to recommend 75–100 mg/day of aspirin for long-term secondary prevention of cardiovascular events, and it is now being utilized to reduce the risk of restenosis after percutaneous coronary procedures [10]. Therefore, with this type of background the next logical step was to determine the impact of aspirin on the primary prevention of CVD.

In the early 1980s multiple large-scale trials were initiated to address the primary prevention question from the British Doctors Trial and the Physicians Health Study have demonstrated modest reductions versus the secondary prevention trials (12 % versus 22 %) [10]. However, the overall the risk of CVD events were extremely low in many of these trials. Additionally, primary prevention trials are not easy to complete or even initiate because of the greater use of multiple prevention measures in subjects today from diet and exercise to blood pressure, cholesterol-lowering and even glucose controlling medication such as metformin with some inherent cardiovascular or metabolic parameter benefits. Additionally, as blood pressure and lipids are improved, along with some inflammatory markers such as hs-CRP, the need for aspirin is reduced based on risk calculators such as Framingham risk score or Reynolds Risk score (this risk score also utilizes hs-CRP).

Again, most populations studied for primary prevention of cardiovascular events have had very low risk [10]. Thus, this has clouded the picture of the best candidate for aspirin in this setting. Therefore, individuals at higher than average risk are being studied in three ongoing clinical trials of aspirin in primary prevention and include the following:

The upregulation of cyclooxygenase-2 (COX-2) in the stomach with aspirin increases the risk of dyspepsia, gastrointestinal ulcers and bleeding [3]. Aspirin induced gastrointestinal injury is dose-dependent, so in an attempt to reduce the risk of gastrointestinal damage causes by regular aspirin, there were two other types developed, buffered and enteric-coated aspirin. Buffered aspirin contains calcium carbonate, magnesium oxide, magnesium carbonate, or other compounds, which reduce the hydrogen ion concentration of aspirin [16]. And the reduced hydrogen ion concentration increases the gastric solubility of aspirin, which further reduces the contact time between the gastric mucosa and aspirin. Enteric-coated aspirin was designed to pass through the stomach before dissolving thus also potentially reducing gastric damage. Despite the agreement that higher dosages of aspirin have less gastrointestinal toxicity when using alternative forms of aspirin this has not been demonstrated at the low-dose level. For example, enteric-coated aspirin dissolves in the small bowel and could pose a higher risk of small bowel ulcers compared to other types of aspirin including uncoated and buffered aspirin. Although the initial time to antiplatelet response is more rapid with a full dose aspirin (325 mg/day) versus low-dose (81 mg/day) in an emergent setting, prophylactically low-dose aspirin appears as effective.

Small past studies have consistently demonstrated the benefit of uncoated aspirin on bleeding times compared to enteric-coated aspirin and some experts have recommended that uncoated aspirin should be the primary recommended form in the setting of acute MI, unstable angina, or after angioplasty [17]. One small study found that 80 % of the uncoated aspirin group developed abnormal bleeding times versus only 10 % of the enteric-coated group (p < 0.01).

In a recent large cohort comparing buffered aspirin (100 mg) to plain aspirin there was no difference found in the reported rates of gastrointestinal symptoms (27 % in both groups) [18, 19]. And the authors suggested plain aspirin as the first choice because of the considerable cost savings compared to other forms of aspirin and the use of a proton pump inhibitor (PPI) if gastrointestinal symptoms occur, and if this does not work then shift to a buffered option. It is important to note that in some countries the cost of these specialty aspirins such as buffered can be twice as much plain aspirin.

The Japanese Primary Prevention Project (JPPP) was an open-label, multicenter, randomized parallel-group trial of 14,464 participants aged 60–85 years with hypertension, dyslipidemia, or diabetes recruited by primary physicians at over 1000 clinics in Japan [20]. Patients were randomized to 100 mg/day enteric-coated aspirin or no aspirin. The study was terminated after a median follow-up of 5 years because of futility or unlikely it would reach a significant reduction, which was death from cardiovascular causes (at the time of termination 56 fatal events occurred in both groups) and nonfatal myocardial infarction and nonfatal stroke (composite outcome). Although aspirin significantly reduced the incidence of nonfatal myocardial infarction and transient ischemic attack, it also significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization.

There is a suggestion that the reason some enteric-coated aspirin studies have failed including the JPPP could be due to what is known as “pseudoresistance ” [21]. In other words, this was highlighted in a recent study of healthy volunteers screened for their response to a single dose of 325-mg immediate release or enteric-coated aspirin [22]. No case of aspirin resistance was noted, but a delayed and reduced drug absorption was found in up to 49 % of the enteric-coated group but 0 % with plain aspirin. Thus, the term “pseudoresistance” with enteric-coated aspirin is a potential possibility that needs further investigation.

It is interesting that preliminary small human and laboratory studies of probiotics to prevent gastrointestinal toxicity of aspirin, or NSAIDs for example Lactobacillus casei has shown some initial promise [23]. Perhaps the anti-inflammatory effects of lactic acid may be a future option. However, more well-done trials are needed because in the past for example vitamin C was preliminarily investigated to reduce aspirin toxicity but this seems to have stalled from the lack of long-term data [24].

The ultimate question is that the true benefits and limitations of the different forms of aspirin is not sufficiently lucid, including which ones, if any, have more substantial anticancer effects. Again it should be reiterated that most of the cardiovascular clinical trials have utilized plain aspirin for efficacy and the secondary anticancer end points also appear to be primarily from plain aspirin. Still, the question remains.

On a fairly regular basis a patient may inquire about a dietary supplement that appears to be reducing a painful condition better than any other product on the market. For example, I have found this to be true especially in the area of osteoarthritis. However, these miracle-like products appear to cost patients an excessive amount of money in many circumstances (50 or more dollars a month). When I peruse the bottle label I am often surprised to find that one of the primary ingredients is “salicin .” It should be reiterated that salicin was derived from white willow bark and leaves to help create or synthetically produce aspirin. In my opinion, many of these patients are simply paying 50 dollars a month for aspirin and do not know it. This would explain the satisfactory pain relief but it does not of course explain the exorbitant price, and thus I warn patients about this on a regular basis.

It needs to be reiterated that research has suggested that upon ingestion, a large percentage of the salicin in willow bark is absorbed and is metabolized via intestinal flora to saligenin, which is then absorbed and metabolized by the liver to produce salicylic acid [3]. This is exactly what acetylsalicylic acid is converted to with metabolism (salicylic acid), thus unless someone can prove in a head-to-head comparison that salicin is superior to aspirin then there is some skepticism. Still, if any benefit I can theoretically surmise from salicin occurs over aspirin it may be in a minority of individuals that simply do not want the blood thinning effects of aspirin to occur, but still desire the analgesic, antipyretic, and anti-inflammatory effects.

Minimal research has been completed on the safest dosage or percentage (15 %, 20 %, 50 %?) of salicin in a dietary supplement. Further information on salicin can be found from some recent reviews of the subject that provide good background or foundational knowledge [25]. Interestingly, a Cochrane review of herbal treatments of acute low back pain found some evidence that 120 or 240 mg salicin is probably greater than placebo for short-term improvements in pain (two trials with 261 participants and moderate quality evidence) [26]. Again, no head-to-head quality trial against low cost or comparable aspirin dosages has been conducted.

There are two broad mechanisms of anticancer action in aspirin [27–30]:

One of the largest reviews of data from randomized trials of daily aspirin versus no aspirin for the prevention of vascular events (51 randomized trials) has only increased the interest in the anticancer effects of aspirin [31]. Aspirin appeared to reduce the risk of cancer deaths by 15 % (p = 0.008; 34 trials, 69,224 participants) especially when utilized for 5 or more years (37 % reduction; p = 0.0005). In six trials of daily low-dose aspirin in primary prevention utilizing 35,535 participants, aspirin reduced cancer incidence from 3 years onward by 24 % (p = 0.0003) and this significant reduction occurred in women and men. The researchers also found that fatality cases from major extracranial bleeds was significantly lower on aspirin compared to controls (68 % reduction, 8 of 203 and 15 of 132; p = 0.009).

Researchers have also analyzed observational studies and the overall estimates of the impact of aspirin on individual cancers in case-control studies were closely correlated with randomized data (r(2) = 0.71, p = 0.0006) [32]. For example, not just for colorectal cancer but consistent reductions in the risk of esophageal, gastric, biliary and breast cancer was found. Additionally, aspirin appeared to significantly reduce the risk of finding cancers with distant metastasis, which is again consistent with randomized data.

Regardless, it should be kept in mind that gastrointestinal cancer risk reduction and potentially death from this cancer has the most consistent data when it comes to aspirin utilization. Data from over 150 case-control studies and 50 cohort studies have published consistent correlations between regular use of aspirin and a reduced risk of colorectal, esophageal, and stomach cancer.

Aspirin shows even potential greater impacts in those at high-risk of colorectal cancer [33–35]. For example, the in the Colorectal Adenoma/Carcinoma Prevention Programme 1 (CAPP1) 600 mg/day in 200 adolescent FAP (familial adenomatous polyposis) carriers reduced polyp number and a significant reduction in polyp size occurred for those patients utilizing aspirin for more than 1 year. The same intervention was utilized in CAPP2, which was a randomized trial of 600 mg aspirin daily in Lynch syndrome carriers (n = 937) and a 63 % reduction (p = 0.008) in incidence was found for those completing at least 2 years of treatment. However, patients with shorter follow-up there were no significant difference [33, 34]. It appears that currently individuals at high risk for colorectal cancer are now potential candidates for aspirin prophylaxis [35]. Gastrointestinal toxicity and compliance was similar between groups during the trial but was not accessed during full follow-up. CAPP3 is an ongoing double-blind trial of 100, 300, or 600 mg daily aspirin in 3000 high-risk patients.

The Women’s Health Study (WHS) could be a game changer but not because of its primary endpoint, but because of the impact on colorectal cancer and perhaps advanced cancers. This was a randomized trial of approximately 10 years of treatment with 100 mg of every other day aspirin versus placebo in middle-aged women to prevent vascular events and cancer was a pre-study outcome [36]. This is arguably the first reliable data in women of aspirin and cancer risk. A total of 19,934 women at least 45 years of age and without previous cardiovascular disease were randomized to aspirin and 19,942 were given placebo. There was no significant reduction in the risk of major cardiovascular events, or death from cardiovascular causes (primary endpoint), but there was a reduction in stroke with aspirin (RR = 0.83; p = 0.02) with an average use of 10.1 years. Subgroup analysis demonstrated a significant reduction in major cardiovascular events, ischemic stroke, and myocardial infarction for women 65 years and older. Overall gastrointestinal bleeding requiring transfusion was also 40 % significantly higher in the aspirin group compared to placebo arm (p = 0.02).