Aspirin is also used long-term to help prevent furtherheart attacks,ischaemic strokes, andblood clots in people at high risk.[11] For pain or fever, effects typically begin within 30 minutes.[11] Aspirin works similarly to other NSAIDs but also suppresses the normal functioning ofplatelets.[11]
Aprecursor to aspirin found in the bark of thewillow tree (genusSalix),salicin, is metabolized in the human gut into the medicinally active compoundsalicylic acid[12] and has been used for its health effects for at least 2,400 years.[13][14]Pharmacology sought asynthetic alternative. In 1853, the chemistCharles Frédéric Gerhardt treated the medicinesodium salicylate withacetyl chloride to produce acetylsalicylic acid for the first time.[15] Over the next 50 years, other chemists, mostly of the German companyBayer, established the chemical structure and devised more efficient production methods.[15]: 69–75 Felix Hoffmann (or perhapsArthur Eichengrün) of Bayer was the first to produce acetylsalicylic acid in a pure, stable form in 1897.[16] By 1899, Bayer had dubbed this drug Aspirin and was selling it globally.[17]: 27
In 1897, scientists at theBayer company began studying acetylsalicylic acid as a less-irritating replacement medication for common salicylate medicines.[15]: 69–75 [22] By 1899, Bayer had named it "Aspirin" and was selling it around the world.[17]
Aspirin's popularity grew over the first half of the 20th century, leading to competition between many brands and formulations.[23] The wordAspirin was Bayer's brand name; however, its rights to thetrademark werelost or sold in many countries.[23] The name is ultimately a blend of the prefixa(cetyl) +spir, fromSpirsäure, German for meadowsweet, the plant genus from which the aspirin precursor salicylic acid was first isolated (originallySpiraea, nowFilipendula) +-in, the common suffix for drugs near the end of the 19th century.[24]
The synthesis of aspirin is classified as anesterification reaction.Salicylic acid is treated withacetic anhydride, an acid derivative, causing a chemical reaction that turns salicylic acid'shydroxyl group into anester group (R-OH → R-OCOCH3). This process yields aspirin andacetic acid, which is considered abyproduct of this reaction. Small amounts ofsulfuric acid (and occasionallyphosphoric acid) are almost always used as acatalyst. This method is commonly demonstrated in undergraduate teaching labs.[28]
Aspirin synthesis
Reaction between acetic acid and salicylic acid can also form aspirin but this esterification reaction is reversible and the presence of water can lead to hydrolysis of the aspirin. So, an anhydrous reagent is preferred.[29]
Formulations containing high concentrations of aspirin often smell likevinegar[30] because aspirin can decompose through hydrolysis in moist conditions, yielding salicylic and acetic acids.[31]
Aspirin, anacetyl derivative of salicylic acid, is a white, crystalline, weakly acidic substance that melts at 136 °C (277 °F),[9] and decomposes around 140 °C (284 °F).[32] Itsacid dissociation constant (pKa) is 3.5 at 25 °C (77 °F).[33]
Polymorphism is the ability of a substance to form more than onecrystal structure. Until 2005, there was only one proven polymorph of aspirin (form I), though the existence of another polymorph was debated since the 1960s, and one report from 1981 reported that when crystallized in the presence of aspirin anhydride, thediffractogram of aspirin has weak additional peaks. Though at the time it was dismissed as mere impurity, it was, in retrospect, form II aspirin.[34]
Form II was reported in 2005,[35][36] found after attempted co-crystallization of aspirin andlevetiracetam from hotacetonitrile. Pure form II aspirin can be prepared by seeding the batch with aspirin anhydrate in 15% weight.[34]
In form I, pairs of aspirin molecules form centrosymmetricdimers through theacetyl groups with the (acidic)methyl proton tocarbonylhydrogen bonds. In form II, each aspirin molecule forms the same hydrogen bonds, but with two neighbouring molecules instead of one. With respect to the hydrogen bonds formed by thecarboxylic acid groups, both polymorphs form identical dimer structures. The aspirin polymorphs contain identical 2-dimensional sections and are therefore more precisely described as polytypes.[37]
Form III was reported in 2015 by compressing Form I above 2 GPa, but it reverts to form I when pressure is removed.[38] Form IV was reported in 2017, which is stable at ambient conditions.[39]
Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of thecyclooxygenase (COX; officially known as prostaglandin-endoperoxide synthase, PTGS) enzyme required for prostaglandin and thromboxane synthesis.[43] Aspirin acts as an acetylating agent where an acetyl group is covalently attached to aserine residue in the active site of the COX enzyme (suicide inhibition).[44] This makes aspirin different from other NSAIDs (such asdiclofenac andibuprofen), which are reversible inhibitors.[44]
Low-dose aspirin use irreversibly blocks the formation ofthromboxane A2 in platelets, which inhibits platelet aggregation during the lifetime of the affected platelet (8–9 days). This antithrombotic property makes aspirin useful for reducing the incidence of heart attacks in people who have had a heart attack, unstable angina, ischemic stroke or transient ischemic attack.[45] 40mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.[46]
Prostaglandins, a type ofhormone, have diverse effects, including the transmission of pain information to the brain, modulation of thehypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that formblood clots. Heart attacks are caused primarily by blood clots, and low doses of aspirin are seen as an effective medical intervention to prevent a second acute myocardial infarction.[47]
At least two different types ofcyclooxygenases,COX-1 andCOX-2, are acted on by aspirin. Aspirin irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2. COX-2 normally producesprostanoids, most of which are proinflammatory. Aspirin-modified COX-2 (akaprostaglandin-endoperoxide synthase 2 or PTGS2) producesepi-lipoxins, most of which are anti-inflammatory.[48] Newer NSAID drugs,COX-2 inhibitors (coxibs), have been developed to inhibit only COX-2, with the intent to reduce the incidence of gastrointestinal side effects.[18]
Several COX-2 inhibitors, such asrofecoxib (Vioxx), have been withdrawn from the market, after evidence emerged that COX-2 inhibitors increase the risk of heart attack and stroke.[49][50] Endothelial cells lining the microvasculature in the body are proposed to express COX-2, and, by selectively inhibiting COX-2, prostaglandin production (specifically, PGI2; prostacyclin) is downregulated with respect to thromboxane levels, as COX-1 in platelets is unaffected. Thus, the protective anticoagulative effect ofPGI2 is removed, increasing the risk of thrombus and associated heart attacks and other circulatory problems.[51]
Furthermore, aspirin, while inhibiting the ability of COX-2 to form pro-inflammatory products such as theprostaglandins, converts this enzyme's activity from a prostaglandin-forming cyclooxygenase to alipoxygenase-like enzyme: aspirin-treated COX-2 metabolizes a variety ofpolyunsaturated fatty acids to hydroperoxy products which are then further metabolized tospecialized proresolving mediators such as theaspirin-triggered lipoxins(15-epilipoxin-A4/B4), aspirin-triggeredresolvins, and aspirin-triggeredmaresins. These mediators possess potent anti-inflammatory activity. It is proposed that this aspirin-triggered transition of COX-2 from cyclooxygenase to lipoxygenase activity and the consequential formation of specialized proresolving mediators contributes to the anti-inflammatory effects of aspirin.[52][53][54]
Aspirin has been shown to have at least three additional modes of action. It uncouplesoxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from the inner membrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once again to release protons.[55] Aspirin buffers and transports the protons. When high doses are given, it may actually cause fever, owing to the heat released from the electron transport chain, as opposed to the antipyretic action of aspirin seen with lower doses. In addition, aspirin induces the formation of NO-radicals in the body, which have been shown in mice to have an independent mechanism of reducing inflammation. This reduced leukocyte adhesion is an important step in the immune response to infection; however, evidence is insufficient to show that aspirin helps to fight infection.[56] More recent data also suggest salicylic acid and its derivatives modulate signalling throughNF-κB.[57] NF-κB, atranscription factor complex, plays a central role in many biological processes, including inflammation.[58][59][60]
Aspirin is readily broken down in the body to salicylic acid, which itself has anti-inflammatory, antipyretic, and analgesic effects. In 2012, salicylic acid was found to activateAMP-activated protein kinase, which has been suggested as a possible explanation for some of the effects of both salicylic acid and aspirin.[61][62] The acetyl portion of the aspirin molecule has its own targets. Acetylation of cellular proteins is a well-established phenomenon in the regulation of protein function at the post-translational level. Aspirin is able to acetylate several other targets in addition to COX isoenzymes.[63][64] These acetylation reactions may explain many hitherto unexplained effects of aspirin.[65]
Aspirin is available in a variety ofpharmaceutical formulations, each with distinct pharmacological and safety profiles.[66][67][68] A key concern in aspirin therapy is the risk ofgastrointestinal bleeding, prompting the development of formulations aimed at maintaining efficacy while minimizing gastrointestinal harm.[69][70][68] Some formulations are also combined, for example, buffered aspirin withvitamin C. Formulation examples include:
Immediate-release tablets (IR-ASA): Commonly contain 75–100 mg or 300–320 mg of aspirin and are rapidly absorbed in the stomach.[66][68]
Enteric-coated tablets (EC-ASA): Designed to dissolve in the higher pH environment of the small intestine, reducing gastric irritation but sometimes leading to erratic absorption.[66][71]
Buffered formulations: Contain aspirin with buffering agents to reduce GI irritation; studies show similar mucosal injury rates to plain aspirin.[66]
Aspirin combined with vitamin C (ASA-VitC): Reduces gastric damage and blood loss compared to plain aspirin.[72]
Effervescent tablets are a specialized oral dosage form containing aspirin and an effervescent base—typically a combination ofcitric acid,tartaric acid, andsodium bicarbonate. When dissolved in water, these tablets produce a fizzy reaction that rapidly disperses the drug throughout the solution.[73][74]
Phospholipid-aspirin complex liquid formulation (PL-ASA): Novel, FDA-approved and under further investigation for its ability to reduce GI injury while maintaining reliable platelet inhibition.[71]
Aspirin formulations differ significantly in terms ofpharmacokinetics, efficacy, and gastrointestinal safety. Enteric-coated (EC) aspirin, developed to reduce gastric irritation by delaying release until thesmall intestine, exhibits erratic absorption and reduced bioavailability, particularly in individuals with body weight over 70 kg. This can lead to suboptimalthromboxane A2 inhibition and decreasedantiplatelet efficacy compared to plain aspirin.[66] This diminishedpharmacodynamic effect has been associated with reduced cardiovascular protection in heavier individuals.[66] Although EC aspirin is associated with fewer gastric erosions inendoscopic studies, it does not significantly reduce gastrointestinal bleeding orulceration,[66] and may increase the risk of small bowel mucosal injury due to local topical effects[75][69][76]
Buffered aspirin, which includes agents to neutralize gastric acid, similarly offers no clear safety advantage over plain aspirin.[66]
Novel formulations such as the phospholipid-aspirin complex (PL-ASA) attempt to overcome these limitations by pre-associating aspirin with lipidexcipients. PL-ASA has been shown to reduce acute gastric injury while providing predictable absorption and bioequivalence to plain aspirin, with no significant food effect.[68] This formulation achieves consistent platelet inhibition with reduced interindividual variability in pharmacodynamic response compared to EC aspirin.[68]
For long-term prevention, anetwork meta-analysis suggests that a daily dose of 100 mg of coated aspirin may provide optimal protection against all-cause mortality and cancer, while higher doses are more effective in reducing cardiovascular events and lower doses may be better tolerated.[77] Nonetheless, plain aspirin remains the preferred formulation for cardiovascular prevention due to its superior and consistent pharmacokinetic properties.[66]
Acetylsalicylic acid is aweak acid, and very little of it isionized in thestomach after oral administration. Acetylsalicylic acid is quickly absorbed through the cell membrane in theacidic conditions of the stomach. The higherpH and larger surface area of thesmall intestine cause aspirin to be absorbed more slowly there, as more of it is ionized. Owing to the formation of concretions, aspirin is absorbed much more slowly during overdose, andblood plasma concentrations can continue to rise for up to 24 hours after ingestion.[78][79][80]
About 50–80% of salicylate in the blood is bound tohuman serum albumin, while the rest remains in the active, ionized state; protein binding is concentration-dependent. Saturation of binding sites leads to more free salicylate and increased toxicity. The volume of distribution is 0.1–0.2 L/kg. Acidosis increases the volume of distribution because of enhancement of tissue penetration of salicylates.[80]
As much as 80% of therapeutic doses of salicylic acid ismetabolized in theliver.Conjugation withglycine formssalicyluric acid, and withglucuronic acid to form two different glucuronide esters. The conjugate with the acetyl group intact is referred to as theacyl glucuronide; the deacetylated conjugate is thephenolic glucuronide. These metabolic pathways have only a limited capacity. Small amounts of salicylic acid are also hydroxylated togentisic acid. With large salicylate doses, the kinetics switch from first-order to zero-order, asmetabolic pathways become saturated andrenal excretion becomes increasingly important.[80]
Salicylates are excreted mainly by the kidneys as salicyluric acid (75%), free salicylic acid (10%), salicylic phenol (10%), acyl glucuronides (5%),gentisic acid (< 1%), and2,3-dihydroxybenzoic acid.[81] When small doses (less than 250mg in an adult) are ingested, all pathways proceed by first-order kinetics, with an elimination half-life of about 2.0 h to 4.5 h.[82][83] When higher doses of salicylate are ingested (more than 4 g), the half-life becomes much longer (15 h to 30 h),[84] because the biotransformation pathways concerned with the formation of salicyluric acid and salicyl phenolic glucuronide become saturated.[85] Renal excretion of salicylic acid becomes increasingly important as the metabolic pathways become saturated, because it is extremely sensitive to changes inurinary pH. A 10- to 20-fold increase in renal clearance occurs when urine pH is increased from 5 to 8. The use of urinary alkalinization exploits this particular aspect of salicylate elimination.[86] It was found that short-term aspirin use in therapeutic doses might precipitate reversibleacute kidney injury when the patient was ill withglomerulonephritis orcirrhosis.[87] Aspirin for some patients withchronic kidney disease and some children with congestive heart failure was contraindicated.[87]
Medicines made fromwillow and othersalicylate-rich plants appear in clay tablets from ancientSumer as well as theEbers Papyrus from ancient Egypt.[15]: 8–13 [23][24] Hippocrates referred to the use of salicylic tea to reduce fevers around 400 BC, and willow bark preparations were part of the pharmacopoeia of Western medicine inclassical antiquity and theMiddle Ages.[23] Willow bark extract became recognized for its specific effects on fever, pain, and inflammation in the mid-eighteenth century[88] after the Rev Edward Stone ofChipping Norton, Oxfordshire, noticed that the bitter taste of willow bark resembled the taste of the bark of thecinchona tree, known as "Peruvian bark", which was used successfully inPeru to treat a variety of ailments. Stone experimented with preparations of powdered willow bark on people in Chipping Norton for five years and found it to be as effective as Peruvian bark and a cheaper domestic version. In 1763, he sent a report of his findings to theRoyal Society in London.[89] By the nineteenth century, pharmacists were experimenting with and prescribing a variety of chemicals related tosalicylic acid, the active component of willow extract.[15]: 46–55
Old package. "Export from Germany is prohibited"
In 1853, the chemistCharles Frédéric Gerhardt treatedsodium salicylate withacetyl chloride to produce acetylsalicylic acid for the first time;[15]: 46–48 in the second half of the 19th century, other academic chemists established the compound's chemical structure and devised more efficient methods of synthesis. In 1897, scientists at the drug and dye firmBayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines, and identified a new way to synthesize it.[15]: 69–75 That year,Felix Hoffmann (orArthur Eichengrün) of Bayer was the first to produce acetylsalicylic acid in a pure, stable form.[16][24]
Salicylic acid had been extracted in 1839 from the herbmeadowsweet, whose German name,Spirsäure, was the basis for naming the newly synthesized drug, which, by 1899, Bayer was selling globally.[15]: 46–55 [17]: 27 The wordAspirin was Bayer's brand name, rather than the generic name of the drug; however, Bayer's rights to the trademark were lost or sold in many countries. Aspirin's popularity grew over the first half of the 20th century, leading to fierce competition with the proliferation of aspirin brands and products.[23]
Aspirin's popularity declined after the development ofacetaminophen/paracetamol in 1956 andibuprofen in 1962. In the 1960s and 1970s,John Vane and others discovered the basic mechanism of aspirin's effects,[15]: 226–231 while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anti-clotting agent that reduces the risk of clotting diseases.[15]: 247–257 The initial large studies on the use of low-dose aspirin to prevent heart attacks that were published in the 1970s and 1980s helped spur reform inclinical research ethics andguidelines for human subject research and US federal law, and are often cited as examples of clinical trials that included only men, but from which people drew general conclusions that did not hold true for women.[90][91][92]
Aspirin sales revived considerably in the last decades of the 20th century, and remain strong in the 21st century with widespread use as a preventive treatment forheart attacks andstrokes.[15]: 267–269
In Canada and many other countries, "Aspirin" remains a trademark, so generic aspirin is sold as "ASA" (acetylsalicylicacid).
In the US, "aspirin" is a generic name.
Bayer lost its trademark for aspirin in the United States and some other countries in actions taken between 1918 and 1921, because it had failed to use the name for its own product correctly and had for years allowed the use of "Aspirin" by other manufacturers without defending the intellectual property rights.[93] Aspirin is ageneric trademark in many countries.[94][95] Aspirin, with a capital "A", remains a registered trademark of Bayer in Germany, Canada, Mexico, and in over 80 other countries, for acetylsalicylic acid in all markets, but using different packaging and physical aspects for each.[96][97]
Aspirin is used in the treatment of a number of conditions, including fever, pain,rheumatic fever, and inflammatory conditions, such asrheumatoid arthritis,pericarditis, andKawasaki disease.[11] Lower doses of aspirin have also been shown to reduce the risk of death from aheart attack, or the risk ofstroke in people who are at high risk or who have cardiovascular disease, but not in elderly people who are otherwise healthy.[100][101][102][103][104] There is evidence that aspirin is effective at preventingcolorectal cancer, though the mechanisms of this effect are unclear.[105] There is also evidence that aspirin can treat 80% ofED cases.[106]
Aspirin is an effective analgesic for acute pain, although it is generally considered inferior toibuprofen because aspirin is more likely to causegastrointestinal bleeding.[107] Aspirin is generally ineffective for those pains caused by musclecramps,bloating,gastric distension, or acute skin irritation.[108] As with other NSAIDs,combinations of aspirin andcaffeine provide slightly greater pain relief than aspirin alone.[109]Effervescent formulations of aspirin relieve pain faster than aspirin in tablets,[110] which makes them useful for the treatment ofmigraines.[111]Topical aspirin may be effective for treating some types ofneuropathic pain.[112]
Aspirin, either by itself or in a combined formulation, effectively treats certaintypes of a headache, but its efficacy may be questionable for others. Secondary headaches, meaning those caused by another disorder or trauma, should be promptly treated by a medical provider. Among primary headaches, theInternational Classification of Headache Disorders distinguishes betweentension headache (the most common), migraine, andcluster headache. Aspirin or other over-the-counter analgesics are widely recognized as effective for the treatment of tension headaches.[113] Aspirin, especially as a component of anaspirin/paracetamol/caffeinecombination, is considered a first-line therapy in the treatment of migraine, and comparable to lower doses ofsumatriptan. It is most effective at stopping migraines when they are first beginning.[114]
Like its ability to control pain, aspirin's ability to controlfever is due to its action on theprostaglandin system through its irreversible inhibition ofCOX.[115] Although aspirin's use as anantipyretic in adults is well established, many medical societies and regulatory agencies, including theAmerican Academy of Family Physicians, theAmerican Academy of Pediatrics, and theFood and Drug Administration, strongly advise against using aspirin for the treatment of fever in children because of the risk ofReye syndrome, a rare but often fatal illness associated with the use of aspirin or other salicylates in children during episodes of viral or bacterial infection.[116][117][118] Because of the risk of Reye syndrome in children, in 1986, the USFood and Drug Administration (FDA) requiredprescribing information on all aspirin-containing medications advising against its use in children and teenagers.[119][120]
Aspirin is an important part of the treatment of those who have had aheart attack.[122] It is generally not recommended for routine use by people with no other health problems, including those over the age of 70.[123]
The 2009 Antithrombotic Trialists' Collaboration published in Lancet evaluated the efficacy and safety of low dose aspirin in secondary prevention.[124] In those with prior ischaemic stroke or acute myocardial infarction, daily low dose aspirin was associated with a 19% relative risk reduction of serious cardiovascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death). This did come at the expense of a 0.19% absolute risk increase in gastrointestinal bleeding; however, the benefits outweigh the hazard risk in this case.[124] Data from previous trials have suggested that weight-based dosing of aspirin has greater benefits in primary prevention of cardiovascular outcomes.[125] However, more recent trials were not able to replicate similar outcomes using low dose aspirin in low body weight (<70 kg) in specific subset of population studied i.e. elderly and diabetic population, and more evidence is required to study the effect of high dose aspirin in high body weight (≥70 kg).[126][127][128]
Afterpercutaneous coronary interventions (PCIs), such as the placement of acoronary arterystent, a U.S.Agency for Healthcare Research and Quality guideline recommends that aspirin be taken indefinitely.[129] Frequently, aspirin is combined with anADP receptor inhibitor, such asclopidogrel,prasugrel, orticagrelor to preventblood clots. This is called dual antiplatelet therapy (DAPT). Duration of DAPT was advised in the United States and European Union guidelines after the CURE[130] and PRODIGY[131] studies. In 2020, the systematic review and network meta-analysis from Khan et al.[132] showed promising benefits of short-term (< 6 months) DAPT followed by P2Y12 inhibitors in selected patients, as well as the benefits of extended-term (> 12 months) DAPT in high risk patients. In conclusion, the optimal duration of DAPT after PCIs should be personalized after outweighing each patient's risks of ischemic events and risks of bleeding events with consideration of multiple patient-related and procedure-related factors. Moreover, aspirin should be continued indefinitely after DAPT is complete.[133][134][135]
The status of the use of aspirin for the primary prevention in cardiovascular disease is conflicting and inconsistent, with recent changes from previously recommending it widely decades ago, and that some referenced newer trials in clinical guidelines show less of benefit of adding aspirin alongside other anti-hypertensive and cholesterol lowering therapies.[123][136] The ASCEND study demonstrated that in high-bleeding risk diabetics with no prior cardiovascular disease, there is no overall clinical benefit (12% decrease in risk of ischaemic events v/s 29% increase in GI bleeding) of low dose aspirin in preventing the serious vascular events over a period of 7.4 years. Similarly, the results of the ARRIVE study also showed no benefit of same dose of aspirin in reducing the time to first cardiovascular outcome in patients with moderate risk of cardiovascular disease over a period of five years. Aspirin has also been suggested as a component of apolypill for prevention of cardiovascular disease.[137][138] Complicating the use of aspirin for prevention is the phenomenon of aspirin resistance.[139][140] For people who are resistant, aspirin's efficacy is reduced.[141] Some authors have suggested testing regimens to identify people who are resistant to aspirin.[142]
As of April 2022[update], theUnited States Preventive Services Task Force (USPSTF) determined that there was a "small net benefit" for patients aged 40–59 with a 10% or greater 10-year cardiovascular disease (CVD) risk, and "no net benefit" for patients aged over 60.[143][144][145] Determining the net benefit was based on balancing the risk reduction of taking aspirin for heart attacks and ischaemic strokes, with the increased risk ofgastrointestinal bleeding,intracranial bleeding, andhemorrhagic strokes. Their recommendations state that age changes the risk of the medicine, with the magnitude of the benefit of aspirin coming from starting at a younger age, while the risk of bleeding, while small, increases with age, particular for adults over 60, and can be compounded by other risk factors such asdiabetes and a history of gastrointestinal bleeding. As a result, the USPSTF suggests that "people ages 40 to 59 who are at higher risk for CVD should decide with their clinician whether to start taking aspirin; people 60 or older should not start taking aspirin to prevent a first heart attack or stroke." Primary prevention guidelines from September 2019[update] made by theAmerican College of Cardiology and theAmerican Heart Association state they might consider aspirin for patients aged 40–69 with a higher risk of atherosclerotic CVD, without an increased bleeding risk, while stating they would not recommend aspirin for patients aged over 70 or adults of any age with an increased bleeding risk.[123] They state a CVD risk estimation and a risk discussion should be done before starting on aspirin, while stating aspirin should be used "infrequently in the routine primary prevention of (atherosclerotic CVD) because of lack of net benefit". As of August 2021[update], theEuropean Society of Cardiology made similar recommendations; considering aspirin specifically to patients aged less than 70 at high or very high CVD risk, without any clear contraindications, on a case-by-case basis considering both ischemic risk and bleeding risk.[136]
Some conclude the benefits are greater than the risks due to bleeding in those at average risk.[146] Others are unclear if the benefits are greater than the risk.[154][155] Given this uncertainty, the 2007United States Preventive Services Task Force (USPSTF) guidelines on this topic recommended against the use of aspirin for prevention of CRC in people with average risk.[156] Nine years later however, the USPSTF issued a grade B recommendation for the use of low-dose aspirin (75 to 100mg/day) "for the primary prevention of CVD [cardiovascular disease] and CRC in adults 50 to 59 years of age who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years".[157]
A meta-analysis through 2019 said that there was an association between taking aspirin and lower risk of cancer of the colorectum, esophagus, and stomach.[158]
In 2021, theUnited States Preventive Services Task Force raised questions about the use of aspirin in cancer prevention. It notes the results of the 2018 ASPREE (Aspirin in Reducing Events in the Elderly) Trial, in which the risk of cancer-related death was higher in the aspirin-treated group than in the placebo group.[159]
In 2025, a group of scientists at theUniversity of Cambridge found that aspirin stimulates the immune system to reducecancer metastasis. They found that a protein calledARHGEF1 suppressesT cells, that are required for attacking metastatic cancer cells. Aspirin appeared to counteract this suppression by targeting a clotting factor calledthromboxane A2 (TXA2), which activates ARHGEF1, thus preventing it from suppressing the T cells.[160] The researchers called the discovery a "Eureka moment".[161] It was reported that the findings could lead to a more targeted use for aspirin in cancer research.[162] It was also said that self-medicating with aspirin should not be done yet due to its potentialside effects until clinical trials were held.[163]
Aspirin, along with several other agents with anti-inflammatory properties, has been repurposed as an add-on treatment for depressive episodes in subjects withbipolar disorder in light of the possible role of inflammation in the pathogenesis of severe mental disorders.[164] A 2022 systematic review concluded that aspirin exposure reduced the risk of depression in a pooled cohort of three studies (HR 0.624, 95% CI: 0.0503, 1.198, P=0.033). However, further high-quality, longer-duration, double-blind randomized controlled trials (RCTs) are needed to determine whether aspirin is an effective add-on treatment for bipolar depression.[165][166][167] Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain.[164]
Although cohort and longitudinal studies have shown low-dose aspirin has a greater likelihood of reducing the incidence of dementia, numerous randomized controlled trials have not validated this.[168][169] Some researchers have speculated the anti-inflammatory effects of aspirin may be beneficial for schizophrenia. Small trials have been conducted but evidence remains lacking.[170][171]
Aspirin is a first-line treatment for the fever and joint-pain symptoms ofacute rheumatic fever. The therapy often lasts for one to two weeks, and is rarely indicated for longer periods. After fever and pain have subsided, the aspirin is no longer necessary, since it does not decrease the incidence of heart complications and residual rheumatic heart disease.[172][173]Naproxen has been shown to be as effective as aspirin and less toxic, but due to the limited clinical experience, naproxen is recommended only as a second-line treatment.[172][174]
Along with rheumatic fever,Kawasaki disease remains one of the few indications for aspirin use in children[175] in spite of a lack of high quality evidence for its effectiveness.[176] Low-dose aspirin supplementation has moderate benefits when used for prevention ofpre-eclampsia.[177][178] This benefit is greater when started in early pregnancy.[179] Aspirin has also demonstratedanti-tumoral effects, via inhibition of thePTTG1 gene, which is often overexpressed in tumors.[180]
For some people, aspirin does not have as strong an effect on platelets as for others, an effect known as aspirin-resistance or insensitivity. One study has suggested women are more likely to be resistant than men,[181] and a different, aggregate study of 2,930 people found 28% were resistant.[182]A study in 100 Italian people found, of the apparent 31% aspirin-resistant subjects, only 5% were truly resistant, and the others werenoncompliant.[183]Another study of 400 healthy volunteers found no subjects who were truly resistant, but some had "pseudoresistance, reflecting delayed and reduced drug absorption".[184]
Meta-analysis and systematic reviews have concluded that laboratory confirmed aspirin resistance confers increased rates of poorer outcomes in cardiovascular and neurovascular diseases.[185][182][186][187][188][189] Although the majority of research conducted has surrounded cardiovascular and neurovascular, there is emerging research into the risk of aspirin resistance after orthopaedic surgery where aspirin is used for venous thromboembolism prophylaxis.[190] Aspirin resistance in orthopaedic surgery, specifically after total hip and knee arthroplasties, is of interest as risk factors for aspirin resistance are also risk factors for venous thromboembolisms and osteoarthritis; the sequelae of requiring a total hip or knee arthroplasty. Some of these risk factors include obesity, advancing age, diabetes mellitus, dyslipidemia and inflammatory diseases.[190]
Adult aspirin tablets are produced in standardised sizes, which vary slightly from country to country, for example 300mg in Britain and 325mg in the United States. Smaller doses are based on these standards,e.g., 75mg and 81mg tablets. The 81 mg tablets are commonly called "baby aspirin" or "baby-strength", because they were originally – but no longer – intended to be administered to infants and children.[191] No medical significance occurs due to the slight difference in dosage between the 75mg and the 81mg tablets. The dose required for benefit appears to depend on a person's weight.[125] For those weighing less than 70 kilograms (154 lb), low dose is effective for preventing cardiovascular disease; for patients above this weight, higher doses are required.[125]
In general, for adults, doses are taken four times a day for fever or arthritis,[192] with doses near the maximal daily dose used historically for the treatment ofrheumatic fever.[193] For the prevention ofmyocardial infarction (MI) in someone with documented or suspectedcoronary artery disease, much lower doses are taken once daily.[192]
April 2022 recommendations from theUnited States Preventive Services Task Force (USPSTF) states that for adults aged 40 to 59 years with a 10% or greater 10-year risk of cardiovascular disease (CVD), the decision to initiate low-dose aspirin for primary prevention should be individualized, as the net benefit is small and must be balanced against bleeding risk.[144] For adults aged 60 years or older, the USPSTF recommends against starting low-dose aspirin for primary prevention of CVD, as potential harms outweigh the benefits. These recommendations apply to adults without established CVD or increased bleeding risk, and emphasize shared decision-making between patients and clinicians.[144] Compared to the 2009 update,[194] the 2022 update narrows the eligible population, raises the threshold for benefit, and places greater importance on bleeding risks, especially in older adults.[195][196]
The WHI study of postmenopausal women found that aspirin resulted in a 25% lower risk of death from cardiovascular disease and a 14% lower risk of death from any cause, though there was no significant difference between 81mg and 325mg aspirin doses.[197] The 2021 ADAPTABLE study also showed no significant difference in cardiovascular events or major bleeding between 81mg and 325mg doses of aspirin in patients (both men and women) with established cardiovascular disease.[198]
Low-dose aspirin use was also associated with a trend toward lower risk of cardiovascular events, and lower aspirin doses (75 or 81mg/day) may optimize efficacy and safety for people requiring aspirin for long-term prevention.[199]
In children with Kawasaki disease, aspirin is taken at dosages based on body weight, initially four times a day for up to two weeks and then at a lower dose once daily for a further six to eight weeks.[200]
In October 2020, the USFood and Drug Administration (FDA) required theprescribing information to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.[201][202] They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.[201][202] One exception to the recommendation is the use of low-dose 81mg aspirin at any point in pregnancy under the direction of a health care professional.[202]
Aspirin should not be taken by people who are allergic toibuprofen ornaproxen,[203] or who havesalicylate intolerance[204][205] or a more generalizeddrug intolerance to NSAIDs, and caution should be exercised in those withasthma or NSAID-precipitatedbronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people withpeptic ulcers, mild diabetes, orgastritis seek medical advice before using aspirin.[203][206] Even if none of these conditions is present, the risk ofstomach bleeding is still increased when aspirin is taken withalcohol orwarfarin.[203] People withhemophilia or other bleeding tendencies should not take aspirin or other salicylates.[203][206] Aspirin is known to causehemolytic anemia in people who have the genetic diseaseglucose-6-phosphate dehydrogenase deficiency, particularly in large doses and depending on the severity of the disease.[207] Use of aspirin duringdengue fever is not recommended owing to increased bleeding tendency.[208] Aspirin taken at doses of ≤325 mg and ≤100 mg per day for ≥2 days can increase the odds of suffering a gout attack by 81% and 91% respectively. This effect may potentially be worsened by high purine diets, diuretics, and kidney disease, but is eliminated by the urate lowering drug allopurinol.[209] Daily low dose aspirin does not appear to worsen kidney function.[210] Aspirin may reduce cardiovascular risk in those without established cardiovascular disease in people with moderate CKD, without significantly increasing the risk of bleeding.[211] Aspirin should not be given to children or adolescents under the age of 16 to control cold or influenza symptoms, as this has been linked withReye syndrome.[212]
Aspirin increases the risk ofupper gastrointestinal bleeding.[213] Enteric coating on aspirin may be used in manufacturing to prevent release of aspirin into the stomach to reduce gastric harm, but enteric coating does not reduce gastrointestinal bleeding risk.[213][214] Enteric-coated aspirin may not be as effective at reducing blood clot risk.[215][216] Combining aspirin with otherNSAIDs has been shown to further increase the risk of gastrointestinal bleeding.[213] Using aspirin in combination with clopidogrel or warfarin also increases the risk of upper gastrointestinal bleeding.[217]
The blockade of COX-1 by aspirin apparently results in the upregulation of COX-2 as part of a gastric defense.[218] There is no clear evidence that simultaneous use of a COX-2 inhibitor with aspirin may increase the risk of gastrointestinal injury.[219]
"Buffering" is an additional method used with the intent to mitigate gastrointestinal bleeding, such as by preventing aspirin from concentrating in the walls of the stomach, although the benefits of buffered aspirin are disputed.[66] Almost any buffering agent used in antacids can be used; Bufferin, for example, usesmagnesium oxide. Other preparations usecalcium carbonate.[220] Gas-forming agents ineffervescent tablet and powder formulations can also double as a buffering agent, one example beingsodium bicarbonate, used inAlka-Seltzer.[221]
Taking vitamin C with aspirin has been investigated as a method of protecting the stomach lining. In trials, vitamin C-releasing aspirin (ASA-VitC) or a buffered aspirin formulation containing vitamin C was found to cause less stomach damage than aspirin alone.[222][223]
It is a widespread habit among eye specialists (ophthalmologists) to prescribe aspirin as an add-on medication for patients with retinal vein occlusion (RVO), such ascentral retinal vein occlusion (CRVO) andbranch retinal vein occlusion (BRVO).[224] The reason of this widespread use is the evidence of its proven effectiveness in major systemic venousthrombotic disorders, and it has been assumed that may be similarly beneficial in various types of retinal vein occlusion.[225]
However, a large-scale investigation based on data of nearly 700 patients showed "that aspirin or other antiplatelet aggregating agents or anticoagulants adversely influence the visual outcome in patients with CRVO and hemi-CRVO, without any evidence of protective or beneficial effect".[226] Several expert groups, including theRoyal College of Ophthalmologists, recommended against the use of antithrombotic drugs (incl. aspirin) for patients with RVO.[227]
Reye syndrome, a rare but severe illness characterized by acuteencephalopathy andfatty liver, can occur when children or adolescents are given aspirin for a fever or other illness or infection. From 1981 to 1997, 1207 cases of Reye syndrome in people younger than 18 were reported to the USCenters for Disease Control and Prevention (CDC). Of these, 93% reported being ill in the three weeks preceding the onset of Reye syndrome, most commonly with arespiratory infection,chickenpox, ordiarrhea. Salicylates were detectable in 81.9% of children for whom test results were reported.[229] After the association between Reye syndrome and aspirin was reported, and safety measures to prevent it (including aSurgeon General's warning, and changes to theprescribing information of aspirin-containing drugs) were implemented, aspirin taken by children declined considerably in the United States, as did the number of reported cases of Reye syndrome; a similar decline was found in the United Kingdom after warnings against pediatric aspirin use were issued.[229] The USFood and Drug Administration recommends aspirin (or aspirin-containing products) should not be given to anyone under the age of 12 who has a fever,[212] and the UKNational Health Service recommends children who are under 16 years of age should not be given aspirin, except on the advice of a doctor.[230]
For a small number of people, taking aspirin can result in symptoms includinghives, swelling, and headache.[231] Aspirin can exacerbate symptoms among those with chronic hives, or create acute symptoms of hives.[232] These responses can be due to allergic reactions to aspirin, or more often due to its effect of inhibiting the COX-1 enzyme.[232][233] Skin reactions may also tie to systemic contraindications, seen with NSAID-precipitatedbronchospasm,[232][233] or those withatopy.[234]
Aspirin and other NSAIDs, such as ibuprofen, may delay the healing of skin wounds.[235] Earlier findings from two small, low-quality trials suggested a benefit with aspirin (alongside compression therapy) on venous leg ulcer healing time and leg ulcer size,[236][237][238] however, larger, more recent studies of higher quality have been unable to corroborate these outcomes.[239][240]
Aspirin can induceswelling of skin tissues in some people. In one study,angioedema appeared one to six hours after ingesting aspirin in some of the people. However, when the aspirin was taken alone, it did not cause angioedema in these people; the aspirin had been taken in combination with another NSAID-induced drug when angioedema appeared.[241]
Aspirin causes an increased risk of cerebral microbleeds, having the appearance onMRI scans of 5 to 10mm or smaller, hypointense (dark holes) patches.[242][243]
A study of a group with a mean dosage of aspirin of 270mg per day estimated an average absolute risk increase inintracerebral hemorrhage (ICH) of 12 events per 10,000 persons.[244] In comparison, the estimated absolute risk reduction in myocardial infarction was 137 events per 10,000 persons, and a reduction of 39 events per 10,000 persons in ischemic stroke.[244] In cases where ICH already has occurred, aspirin use results in higher mortality, with a dose of about 250mg per day resulting in arelative risk of death within three months after the ICH around 2.5 (95%confidence interval 1.3 to 4.6).[245]
Use of low-dose aspirin before a surgical procedure has been associated with an increased risk of bleeding events in some patients, however, ceasing aspirin prior to surgery has also been associated with an increase in major adverse cardiac events. An analysis of multiple studies found a three-fold increase in adverse events such asmyocardial infarction in patients who ceased aspirin prior to surgery. The analysis found that the risk is dependent on the type of surgery being performed and the patient indication for aspirin use.[247]
Aspirin overdose can be acute or chronic. In acute poisoning, a single large dose is taken; in chronic poisoning, higher than normal doses are taken over a period of time. Acute overdose has amortality rate of 2%. Chronic overdose is more commonly lethal, with a mortality rate of 25%;[249] chronic overdose may be especially severe in children.[250] Toxicity is managed with a number of potential treatments, includingactivated charcoal, intravenous dextrose and normal saline,sodium bicarbonate, anddialysis.[251] The diagnosis of poisoning usually involves measurement of plasma salicylate, the active metabolite of aspirin, by automated spectrophotometric methods. Plasma salicylate levels in general range from 30 to 100mg/L after usual therapeutic doses, 50–300mg/L in people taking high doses and 700–1400mg/L following acute overdose. Salicylate is also produced as a result of exposure tobismuth subsalicylate,methyl salicylate, andsodium salicylate.[252][253]
Aspirin is known tointeract with other drugs. For example,acetazolamide andammonium chloride are known to enhance the intoxicating effect of salicylates, and alcohol also increases the gastrointestinal bleeding associated with these types of drugs.[203] Aspirin is known to displace a number of drugs from protein-binding sites in the blood, including theantidiabetic drugstolbutamide andchlorpropamide,warfarin,methotrexate,phenytoin,probenecid,valproic acid (as well as interfering withbeta oxidation, an important part of valproate metabolism), and other NSAIDs. Corticosteroids may also reduce the concentration of aspirin. Other NSAIDs, such as ibuprofen and naproxen, may reduce the antiplatelet effect of aspirin.[254][255] Although limited evidence suggests this may not result in a reduced cardioprotective effect of aspirin.[254] Analgesic doses of aspirin decrease sodium loss induced by spironolactone in the urine, however this does not reduce the antihypertensive effects of spironolactone.[256] Furthermore, antiplatelet doses of aspirin are deemed too small to produce an interaction with spironolactone.[257] Aspirin is known to compete withpenicillin G for renal tubular secretion.[258] Aspirin may also inhibit the absorption of vitamin C.[259][260][unreliable medical source?][261]
The ISIS-2 trial demonstrated that aspirin at doses of 160mg daily for one month, decreased the mortality by 21% of participants with a suspected myocardial infarction in the first five weeks.[262] A single daily dose of 324mg of aspirin for 12 weeks has a highly protective effect against acute myocardial infarction and death in men with unstable angina.[263]
Aspirin has been repurposed as an add-on treatment for depressive episodes in subjects withbipolar disorder. However, meta-analytic evidence is based on very few studies and does not suggest any efficacy of aspirin in the treatment of bipolar depression. Thus, notwithstanding the biological rationale, the clinical perspectives of aspirin and anti-inflammatory agents in the treatment of bipolar depression remain uncertain.[164]
Several studies investigated the anti-infective properties of aspirin for bacterial, viral and parasitic infections. Aspirin was demonstrated to limit platelet activation induced byStaphylococcus aureus andEnterococcus faecalis and to reduce streptococcal adhesion to heart valves. In patients with tuberculous meningitis, the addition of aspirin reduced the risk of new cerebral infarction [RR = 0.52 (0.29-0.92)]. A role of aspirin on bacterial and fungal biofilm is also being supported by growing evidence.[264]
Evidence from observational studies was conflicting on the effect of aspirin in breast cancer prevention;[265] a randomized controlled trial showed that aspirin had no significant effect in reducing breast cancer,[266] thus further studies are needed to clarify the effect of aspirin in cancer prevention.[267]
There are anecdotal reports that aspirin can improve the growth and resistance of plants,[268][269] though most research has involvedsalicylic acid instead of aspirin.[270]
Aspirin is sometimes used inveterinary medicine as ananticoagulant or torelieve pain associated with musculoskeletal inflammation orosteoarthritis. Aspirin should be given to animals only under the direct supervision of aveterinarian, as adverse effects—including gastrointestinal issues—are common. An aspirin overdose in any species may result insalicylate poisoning, characterized byhemorrhaging, seizures, coma, and even death.[271]
Dogs are better able to tolerate aspirin than cats are.[272] Cats metabolize aspirin slowly because they lack theglucuronide conjugates that aid in the excretion of aspirin, making it potentially toxic if dosing is not spaced out properly.[271][273] No clinical signs of toxicosis occurred when cats were given 25mg/kg of aspirin every 48 hours for 4 weeks,[272] but the recommended dose for relief of pain and fever and for treatingblood clotting diseases in cats is 10mg/kg every 48 hours to allow for metabolization.[271][274]
^McTavish J (Fall 1987). "What's in a Name? Aspirin and the American Medical Association".Bulletin of the History of Medicine.61 (3):343–366.JSTOR44442097.PMID3311247.
^World Health Organization (2023).The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Carstensen JT, Attarchi F (April 1988). "Decomposition of aspirin in the solid state in the presence of limited amounts of moisture III: Effect of temperature and a possible mechanism".Journal of Pharmaceutical Sciences.77 (4):318–21.Bibcode:1988JPhmS..77..318C.doi:10.1002/jps.2600770407.PMID3379589.
^"Acetylsalicylic acid". Jinno Laboratory, School of Materials Science, Toyohashi University of Technology. 4 March 1996. Archived fromthe original on 20 January 2012. Retrieved12 April 2014.
^Vishweshwar P, McMahon JA, Oliveira M, Peterson ML, Zaworotko MJ (December 2005). "The predictably elusive form II of aspirin".Journal of the American Chemical Society.127 (48):16802–16803.Bibcode:2005JAChS.12716802V.doi:10.1021/ja056455b.PMID16316223.
^Vane JR (June 1971). "Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs".Nature.231 (25):232–5.doi:10.1038/newbio231232a0.PMID5284360.
^Patrignani P, Patrono C (April 2015). "Cyclooxygenase inhibitors: From pharmacology to clinical read-outs".Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids.1851 (4):422–32.doi:10.1016/j.bbalip.2014.09.016.PMID25263946.
^Martínez-González J, Badimon L (2007). "Mechanisms underlying the cardiovascular effects of COX-inhibition: benefits and risks".Current Pharmaceutical Design.13 (22):2215–27.doi:10.2174/138161207781368774.PMID17691994.
^Romano M, Cianci E, Simiele F, Recchiuti A (August 2015). "Lipoxins and aspirin-triggered lipoxins in resolution of inflammation".European Journal of Pharmacology.760:49–63.doi:10.1016/j.ejphar.2015.03.083.PMID25895638.
^Weylandt KH (August 2016). "Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell".European Journal of Pharmacology.785:108–115.doi:10.1016/j.ejphar.2015.11.002.PMID26546723.
^Silva Caldas AP, Chaves LO, Linhares Da Silva L, De Castro Morais D, Gonçalves Alfenas RD (29 December 2017)."Mechanisms involved in the cardioprotective effect of avocado consumption: A systematic review".International Journal of Food Properties.20 (sup2):1675–1685.doi:10.1080/10942912.2017.1352601.ISSN1094-2912....there was postprandial reduction on the plasma concentration of IL-6 and IkBα preservation, followed by the lower activation of NFκB, considered the main transcription factor capable of inducing inflammatory response by stimulating the expression of proinflammatory cytokines, chemokines, and adhesion molecules.
^Patel V, Fisher M, Voelker M, Gessner U (July 2012). "Gastrointestinal effects of the addition of ascorbic acid to aspirin".Pain Practice.12 (6):476–84.doi:10.1111/j.1533-2500.2011.00517.x.PMID22151399.
^Lotrionte M, Biasucci LM, Peruzzi M, Frati G, Giordano A, Biondi-Zoccai G (2016). "Which Aspirin Dose and Preparation Is Best for the Long-Term Prevention of Cardiovascular Disease and Cancer? Evidence From a Systematic Review and Network Meta-Analysis".Progress in Cardiovascular Diseases.58 (5):495–504.doi:10.1016/j.pcad.2016.02.001.PMID26851562.
^Grootveld M, Halliwell B (January 1988). "2,3-Dihydroxybenzoic acid is a product of human aspirin metabolism".Biochemical Pharmacology.37 (2):271–80.doi:10.1016/0006-2952(88)90729-0.PMID3342084.
^Hartwig-Otto H (November 1983). "Pharmacokinetic considerations of common analgesics and antipyretics".The American Journal of Medicine.75 (5A):30–7.doi:10.1016/0002-9343(83)90230-9.PMID6606362.
^Done AK (November 1960). "Salicylate intoxication. Significance of measurements of salicylate in blood in cases of acute ingestion".Pediatrics.26:800–7.doi:10.1542/peds.26.5.800.PMID13723722.S2CID245036862.
^abD'Agati V (July 1996). "Does aspirin cause acute or chronic renal failure in experimental animals and in humans?".American Journal of Kidney Diseases.28 (1 Suppl 1): S24-9.doi:10.1016/s0272-6386(96)90565-x.PMID8669425.
^abAlgra AM, Rothwell PM (May 2012). "Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials".The Lancet. Oncology.13 (5):518–27.doi:10.1016/S1470-2045(12)70112-2 (inactive 18 November 2025).PMID22440112.There is good evidence from randomised trials that daily aspirin [use] prevents colorectal polyps [type of tumor] and reduces the long-term risk of sporadic colorectal cancer and colorectal cancer in Lynch syndrome. [...] We have now shown that [data from] case–control studies [estimates similar] effect of aspirin on risk of colorectal cancer. [... Furthermore,] case–control and cohort studies yielded associations [of aspirin] with reductions in risk of biliary, oesophageal, and gastric cancer.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Hersh EV, Moore PA, Ross GL (May 2000). "Over-the-counter analgesics and antipyretics: a critical assessment".Clinical Therapeutics.22 (5):500–48.doi:10.1016/S0149-2918(00)80043-0.PMID10868553.
^Beutler AI, Chesnut GT, Mattingly JC, Jamieson B (December 2009). "FPIN's Clinical Inquiries. Aspirin use in children for fever or viral syndromes".American Family Physician.80 (12): 1472.PMID20000310.
^National Clinical Guideline Centre (UK) (July 2013)."Adjunctive pharmacotherapy and associated NICE guidance".Myocardial infarction with ST-segment elevation: the acute management of myocardial infarction with ST-segment elevation [Internet]. NICE Clinical Guidelines. Royal College of Physicians (UK). 17.2 Aspirin.PMID25340241.Archived from the original on 31 December 2015.
^Norris JW (September 2005). "Antiplatelet agents in secondary prevention of stroke: a perspective".Stroke.36 (9):2034–6.doi:10.1161/01.STR.0000177887.14339.46 (inactive 18 November 2025).PMID16100022.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Oliveira DC, Silva RF, Silva DJ, Lima VC (September 2010). "Aspirin resistance: fact or fiction?".Arquivos Brasileiros de Cardiologia.95 (3): e91-4.doi:10.1590/S0066-782X2010001300024 (inactive 18 November 2025).PMID20944898.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Ben-Dor I, Kleiman NS, Lev E (July 2009). "Assessment, mechanisms, and clinical implication of variability in platelet response to aspirin and clopidogrel therapy".The American Journal of Cardiology.104 (2):227–33.doi:10.1016/j.amjcard.2009.03.022 (inactive 18 November 2025).PMID19576352.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^abcDavidson KW, Barry MJ, Mangione CM, Cabana M, Chelmow D, Coker TR, et al. (((US Preventive Services Task Force))) (April 2022). "Aspirin Use to Prevent Cardiovascular Disease: US Preventive Services Task Force Recommendation Statement".JAMA.327 (16):1577–1584.doi:10.1001/jama.2022.4983 (inactive 18 November 2025).PMID35471505.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^abCuzick J, Thorat MA, Bosetti C, Brown PH, Burn J, Cook NR, et al. (January 2015)."Estimates of benefits and harms of prophylactic use of aspirin in the general population".Annals of Oncology.26 (1):47–57.doi:10.1093/annonc/mdu225.PMC4269341.PMID25096604.There is now overwhelming evidence for a reduction in CRC [colorectal cancer] incidence and mortality from regular aspirin use. [... Data are less extensive for oesophageal cancer, but still shows] consistent reductions in mortality [,] with a 58% reduction after 5 years of follow-up in randomised trials, and a 44% reduction in cohort studies. [...] 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. [...] Higher doses do not appear to confer additional benefit but increase toxicities. Excess bleeding is the most important harm associated with aspirin use, and its [excessive bleeding's] risk and fatality rate increases with age.
^Camara Planek MI, Silver AJ, Volgman AS, Okwuosa TM (January 2020)."Exploratory Review of the Role of Statins, Colchicine, and Aspirin for the Prevention of Radiation-Associated Cardiovascular Disease and Mortality".Journal of the American Heart Association.9 (2) e014668.doi:10.1161/JAHA.119.014668 (inactive 18 November 2025).PMC7033839.PMID31960749.Clinically, aspirin has long been associated with a reduction in cancer mortality. This has largely been studied in colorectal cancer. Studies in mediastinal cancers are rarer. Fourteen smaller observational studies have reported a reduction in breast cancer mortality with use of aspirin (HR [Hazard Ratio], 0.69; 95% CI [Confidence Interval], 0.53–0.90). However, some of these studies included other anti‐inflammatory agents with aspirin, including nonsteroidal anti‐inflammatory drug anticoagulants.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Thun MJ, Jacobs EJ, Patrono C (April 2012). "The role of aspirin in cancer prevention".Nature Reviews. Clinical Oncology.9 (5):259–67.doi:10.1038/nrclinonc.2011.199.PMID22473097.S2CID3332999.Aspirin [benefits from] large randomized clinical trials that were originally conducted to study [its] cardioprotective effects but that can now [also] be combined to study cancer end points. Results from secondary analyses of these trials have recently provided the first randomized evidence that prophylactic [preventive] daily treatment with aspirin reduces incidence and death rates from all cancers combined, even at doses as low as 75 mg.
^Richman IB, Owens DK (July 2017). "Aspirin for Primary Prevention".The Medical Clinics of North America (Review).101 (4):713–724.doi:10.1016/j.mcna.2017.03.004.PMID28577622.
^Verdoodt F, Friis S, Dehlendorff C, Albieri V, Kjaer SK (February 2016). "Non-steroidal anti-inflammatory drug use and risk of endometrial cancer: A systematic review and meta-analysis of observational studies".Gynecologic Oncology.140 (2):352–8.doi:10.1016/j.ygyno.2015.12.009.PMID26701413.
^Bosetti C, Rosato V, Gallus S, Cuzick J, La Vecchia C (June 2012). "Aspirin and cancer risk: a quantitative review to 2011".Annals of Oncology.23 (6):1403–15.doi:10.1093/annonc/mds113 (inactive 18 November 2025).PMID22517822.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^United States Preventive Services Task Force (March 2007). "Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement".Annals of Internal Medicine.146 (5):361–4.doi:10.7326/0003-4819-146-5-200703060-00008 (inactive 18 November 2025).PMID17339621.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Bosetti C, Santucci C, Gallus S, Martinetti M, La Vecchia C (May 2020). "Aspirin and the risk of colorectal and other digestive tract cancers: an updated meta-analysis through 2019".Annals of Oncology.31 (5):558–568.doi:10.1016/j.annonc.2020.02.012 (inactive 18 November 2025).hdl:2434/730600.PMID32272209.The present comprehensive meta-analysis supports and further quantifies the inverse association between regular aspirin use and the risk of colorectal and other digestive tract cancers, including some rare ones. The favorable effect of aspirin increases with longer duration of use, and, for colorectal cancer, with increasing dose.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^abcBartoli F, Cavaleri D, Bachi B, Moretti F, Riboldi I, Crocamo C, et al. (November 2021). "Repurposed drugs as adjunctive treatments for mania and bipolar depression: A meta-review and critical appraisal of meta-analyses of randomized placebo-controlled trials".Journal of Psychiatric Research.143:230–238.doi:10.1016/j.jpsychires.2021.09.018.PMID34509090.S2CID237485915.
^Bauer IE, Green C, Colpo GD, Teixeira AL, Selvaraj S, Durkin K, et al. (December 2018). "A Double-Blind, Randomized, Placebo-Controlled Study of Aspirin and N-Acetylcysteine as Adjunctive Treatments for Bipolar Depression".The Journal of Clinical Psychiatry.80 (1).doi:10.4088/JCP.18m12200 (inactive 18 November 2025).PMID30549489.S2CID56483705.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Saxena A, Kumar RK, Gera RP, Radhakrishnan S, Mishra S, Ahmed Z (July 2008). "Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease".Indian Pediatrics.45 (7):565–73.PMID18695275.
^Hashkes PJ, Tauber T, Somekh E, Brik R, Barash J, Mukamel M, et al. (September 2003). "Naproxen as an alternative to aspirin for the treatment of arthritis of rheumatic fever: a randomized trial".The Journal of Pediatrics.143 (3):399–401.doi:10.1067/S0022-3476(03)00388-3 (inactive 18 November 2025).PMID14517527.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Roberge S, Villa P, Nicolaides K, Giguère Y, Vainio M, Bakthi A, et al. (2012). "Early administration of low-dose aspirin for the prevention of preterm and term preeclampsia: a systematic review and meta-analysis".Fetal Diagnosis and Therapy.31 (3):141–6.doi:10.1159/000336662 (inactive 18 November 2025).PMID22441437.S2CID26372982.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E (February 2017). "The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis".American Journal of Obstetrics and Gynecology.216 (2): 110–120.e6.doi:10.1016/j.ajog.2016.09.076 (inactive 18 November 2025).PMID27640943.S2CID3079979.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Dorsch MP, Lee JS, Lynch DR, Dunn SP, Rodgers JE, Schwartz T, et al. (May 2007). "Aspirin resistance in patients with stable coronary artery disease with and without a history of myocardial infarction".The Annals of Pharmacotherapy.41 (5):737–41.doi:10.1345/aph.1H621 (inactive 18 November 2025).PMID17456544.S2CID22245507.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Pignatelli P, Di Santo S, Barillà F, Gaudio C, Violi F (October 2008). "Multiple anti-atherosclerotic treatments impair aspirin compliance: effects on aspirin resistance".Journal of Thrombosis and Haemostasis.6 (10):1832–4.doi:10.1111/j.1538-7836.2008.03122.x (inactive 18 November 2025).PMID18680540.S2CID1776526.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Li J, Song M, Jian Z, Guo W, Chen G, Jiang G, et al. (2014). "Laboratory aspirin resistance and the risk of major adverse cardiovascular events in patients with coronary heart disease on confirmed aspirin adherence".Journal of Atherosclerosis and Thrombosis.21 (3):239–47.doi:10.5551/jat.19521 (inactive 18 November 2025).PMID24201035.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Sofi F, Marcucci R, Gori AM, Abbate R, Gensini GF (August 2008). "Residual platelet reactivity on aspirin therapy and recurrent cardiovascular events--a meta-analysis".International Journal of Cardiology.128 (2):166–71.doi:10.1016/j.ijcard.2007.12.010 (inactive 18 November 2025).hdl:2158/323452.PMID18242733.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Shim EJ, Ryu CW, Park S, Lee HN, Shin HS, Kim SB (October 2018). "Relationship between adverse events and antiplatelet drug resistance in neurovascular intervention: a meta-analysis".Journal of NeuroInterventional Surgery.10 (10):942–948.doi:10.1136/neurintsurg-2017-013632 (inactive 18 November 2025).PMID29352056.S2CID38147668.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Fiolaki A, Katsanos AH, Kyritsis AP, Papadaki S, Kosmidou M, Moschonas IC, et al. (May 2017). "High on treatment platelet reactivity to aspirin and clopidogrel in ischemic stroke: A systematic review and meta-analysis".Journal of the Neurological Sciences.376:112–116.doi:10.1016/j.jns.2017.03.010 (inactive 18 November 2025).PMID28431593.S2CID3485236.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^abvan Oosterom N, Barras M, Bird R, Nusem I, Cottrell N (December 2020). "A Narrative Review of Aspirin Resistance in VTE Prophylaxis for Orthopaedic Surgery".Drugs.80 (18):1889–1899.doi:10.1007/s40265-020-01413-w (inactive 18 November 2025).hdl:10072/401324.PMID33037568.S2CID222234431.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Slawson DC (November 2022). "USPSTF Recommends Against Initiating Aspirin for Primary Prevention of CVD in Adults 60 Years or Older".American Family Physician.106 (5): 586.PMID36379482.
^Mann JF, Joseph P, Gao P, Pais P, Tyrwhitt J, Xavier D, et al. (February 2023). "Effects of aspirin on cardiovascular outcomes in patients with chronic kidney disease".Kidney International.103 (2):403–410.doi:10.1016/j.kint.2022.09.023 (inactive 18 November 2025).PMID36341885.S2CID253194139.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^abcSørensen HT, Mellemkjaer L, Blot WJ, Nielsen GL, Steffensen FH, McLaughlin JK, et al. (September 2000). "Risk of upper gastrointestinal bleeding associated with use of low-dose aspirin".The American Journal of Gastroenterology.95 (9):2218–2224.doi:10.1016/s0002-9270(00)01040-6 (inactive 18 November 2025).PMID11007221.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Wallace JL (October 2008). "Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?".Physiological Reviews.88 (4):1547–65.doi:10.1152/physrev.00004.2008.PMID18923189.S2CID448875.
^Rostom A, Muir K, Dubé C, Jolicoeur E, Boucher M, Joyce J, et al. (July 2007). "Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review".Clinical Gastroenterology and Hepatology.5 (7):818–28, 828.e1-5, quiz 768.doi:10.1016/j.cgh.2007.03.011 (inactive 18 November 2025).PMID17556027.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Davison C, Smith BW, Smith PK (August 1962). "Effects of buffered and unbuffered acetylsalicylic acid upon the gastric acidity of normal human subjects".Journal of Pharmaceutical Sciences.51 (8):759–763.Bibcode:1962JPhmS..51..759D.doi:10.1002/jps.2600510813 (inactive 18 November 2025).PMID13883982.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Dammann HG, Saleki M, Torz M, Schulz HU, Krupp S, Schürer M, et al. (February 2004). "Effects of buffered and plain acetylsalicylic acid formulations with and without ascorbic acid on gastric mucosa in healthy subjects".Alimentary Pharmacology & Therapeutics.19 (3):367–74.doi:10.1111/j.1365-2036.2004.01742.x (inactive 18 November 2025).PMID14984384.S2CID22688422.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Konturek PC, Kania J, Hahn EG, Konturek JW (November 2006). "Ascorbic acid attenuates aspirin-induced gastric damage: role of inducible nitric oxide synthase".Journal of Physiology and Pharmacology.57 (Suppl 5):125–36.PMID17218764.
^Sánchez-Borges M, Capriles-Hulett A (January 2000). "Atopy is a risk factor for non-steroidal anti-inflammatory drug sensitivity".Annals of Allergy, Asthma & Immunology.84 (1):101–6.doi:10.1016/S1081-1206(10)62748-2 (inactive 18 November 2025).PMID10674573.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Stadelmann WK, Digenis AG, Tobin GR (August 1998). "Impediments to wound healing".American Journal of Surgery.176 (2A Suppl):39S –47S.doi:10.1016/S0002-9610(98)00184-6 (inactive 18 November 2025).PMID9777971.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Layton AM, Ibbotson SH, Davies JA, Goodfield MJ (July 1994). "Randomised trial of oral aspirin for chronic venous leg ulcers".Lancet.344 (8916):164–5.doi:10.1016/s0140-6736(94)92759-6 (inactive 18 November 2025).PMID7912767.S2CID912169.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^del Río Solá ML, Antonio J, Fajardo G, Vaquero Puerta C (July 2012). "Influence of aspirin therapy in the ulcer associated with chronic venous insufficiency".Annals of Vascular Surgery.26 (5):620–9.doi:10.1016/j.avsg.2011.02.051 (inactive 18 November 2025).hdl:10324/2904.PMID22437068.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Berges-Gimeno MP, Stevenson DD (June 2004). "Nonsteroidal anti-inflammatory drug-induced reactions and desensitization".The Journal of Asthma.41 (4):375–84.doi:10.1081/JAS-120037650 (inactive 18 November 2025).PMID15281324.S2CID29909460.{{cite journal}}: CS1 maint: DOI inactive as of November 2025 (link)
^Gorelick PB (June 2009). "Cerebral microbleeds: evidence of heightened risk associated with aspirin use".Archives of Neurology.66 (6):691–3.doi:10.1001/archneurol.2009.85.PMID19506128.
^abHe J, Whelton PK, Vu B, Klag MJ (December 1998). "Aspirin and risk of hemorrhagic stroke: a meta-analysis of randomized controlled trials".JAMA.280 (22):1930–5.doi:10.1001/jama.280.22.1930.PMID9851479.S2CID22997730.
^Medical knowledge self-assessment program for students 4, By American College of Physicians, Clerkship Directors in Internal Medicine, Nephrology 227, Item 29
^Biondi-Zoccai GG, Lotrionte M, Agostoni P, Abbate A, Fusaro M, Burzotta F, et al. (November 2006). "A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease".European Heart Journal.27 (22):2667–2674.doi:10.1093/eurheartj/ehl334.PMID17053008.
^Gaudreault P, Temple AR, Lovejoy FH (October 1982). "The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison".Pediatrics.70 (4):566–9.doi:10.1542/peds.70.4.566.PMID7122154.S2CID12738659. (primary source)
^Morra P, Bartle WR, Walker SE, Lee SN, Bowles SK, Reeves RA (September 1996). "Serum concentrations of salicylic acid following topically applied salicylate derivatives".The Annals of Pharmacotherapy.30 (9):935–40.doi:10.1177/106002809603000903.PMID8876850.S2CID9843820.
^Baselt R (2011).Disposition of toxic drugs and chemicals in man (9th ed.). Seal Beach, California: Biomedical Publications. pp. 20–23.ISBN978-0-9626523-8-7.
^Gladding PA, Webster MW, Farrell HB, Zeng IS, Park R, Ruijne N (April 2008). "The antiplatelet effect of six non-steroidal anti-inflammatory drugs and their pharmacodynamic interaction with aspirin in healthy volunteers".The American Journal of Cardiology.101 (7):1060–1063.doi:10.1016/j.amjcard.2007.11.054.PMID18359332.
^Baxter K, Preston CL (eds.)."Aspirin and Spironolactone".MedicinesComplete: Stockley's Drug Interactions. Royal Pharmaceutical Society.
^Hollifield JW (August 1976). "Failure of aspirin to antagonize the antihypertensive effect of spironolactone in low-renin hypertension".Southern Medical Journal.69 (8):1034–6.doi:10.1097/00007611-197608000-00022.PMID785608.
^Loh HS, Watters K, Wilson CW (1 November 1973). "The effects of aspirin on the metabolic availability of ascorbic acid in human beings".Journal of Clinical Pharmacology.13 (11):480–486.doi:10.1002/j.1552-4604.1973.tb00203.x.PMID4490672.
^Basu TK (1982). "Vitamin C-aspirin interactions".International Journal for Vitamin and Nutrition Research. Supplement.23:83–90.PMID6811490.
^Ioannides C, Stone AN, Breacker PJ, Basu TK (December 1982). "Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs".Biochemical Pharmacology.31 (24):4035–4038.doi:10.1016/0006-2952(82)90652-9.PMID6818974.
^Lewis HD, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE, et al. (August 1983). "Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study".New England Journal of Medicine.309 (7):396–403.doi:10.1056/NEJM198308183090703.ISSN0028-4793.PMID6135989.
^Cook NR, Lee IM, Gaziano JM, Gordon D, Ridker PM, Manson JE, et al. (July 2005). "Low-dose aspirin in the primary prevention of cancer: the Women's Health Study: a randomized controlled trial".JAMA.294 (1):47–55.doi:10.1001/jama.294.1.47.PMID15998890.
McTavish JR (1987). "What's in a name? Aspirin and the American Medical Association".Bulletin of the History of Medicine.61 (3):343–66.JSTOR44442097.PMID3311247.
Ling G (2005)."Aspirin".How Products Are Made. Vol. 1. Thomson Gale.
Jeffreys D (2004).Aspirin: the Remarkable Story of a Wonder Drug. Bloomsbury.
