Aspirin

TL;DR. Aspirin is an NSAID that behaves like nothing else in the class, because it binds cyclooxygenase irreversibly. A platelet has no nucleus and cannot make new enzyme, so one low dose disables it for its entire 7 to 10 day life. That is why 75 mg does nothing for a headache and everything for a heart attack. The big change in the last decade: aspirin remains firmly established for people who have already had a cardiovascular event, and is no longer recommended for most healthy people, because three large 2018 trials found the bleeding outweighed the benefit.

1. What it is

Acetylsalicylic acid. An NSAID (Chapter 66) with a unique property: rather than competing reversibly with arachidonic acid for the COX active site, it acetylates a serine residue in the enzyme, permanently disabling it.

Two completely different drugs depending on dose:

2. Where it comes from

Willow bark, containing salicin, was used for pain and fever in Sumerian, Egyptian, Greek, and Roman medicine; Hippocrates described it. In 1763 Edward Stone reported a clinical trial of willow bark to the Royal Society. Salicylic acid was isolated in the nineteenth century and was effective and violently irritating to the stomach.

Felix Hoffmann at Bayer synthesised acetylsalicylic acid in 1897, acetylating salicylic acid to make it more tolerable, and Bayer marketed it as Aspirin from 1899. (There is a long-standing priority dispute involving Arthur Eichengrün, who claimed to have directed the work and to have been written out of the record under Nazi-era policies.) Its mechanism was not understood until 1971, when John Vane showed it inhibits prostaglandin synthesis, work that won a Nobel Prize.

Bayer lost the Aspirin trademark in several countries as part of First World War reparations, which is why "aspirin" is a generic word in the US and UK and a brand in Germany and Canada.

3. Why irreversibility changes everything

A platelet is a cell fragment with no nucleus. It cannot synthesise new protein. So when aspirin acetylates its COX-1, that platelet's ability to make thromboxane A2 is gone for its entire remaining lifespan, 7 to 10 days.

The consequences:

• A single low dose inhibits platelet function for days, even though aspirin's own half-life is about 20 minutes and it is cleared from blood within hours.
• Recovery is not by drug clearance but by platelet turnover: about 10 percent of your platelets are replaced daily, so function recovers over roughly a week.
• Low doses are selective. 75 mg is enough to acetylate platelet COX-1 as blood passes through the portal circulation, before the drug reaches the systemic circulation and other tissues, so it spares vascular COX-2 (which makes protective prostacyclin) reasonably well. Higher doses lose that selectivity and, paradoxically, may be less cardioprotective as well as more harmful.
• Before surgery, aspirin is stopped 7 to 10 days ahead where bleeding risk requires it, because that is how long new platelets take to arrive.
• Ibuprofen can block aspirin's benefit. Ibuprofen occupies the same site reversibly; if it is there first, aspirin cannot acetylate. Take aspirin at least 30 minutes before ibuprofen, or ibuprofen at least 8 hours after aspirin (Chapter 84).

4. Dose and use

Illustrative. This is a drug where the indication decides the dose and the decision is clinical.

Cardiovascular (secondary prevention): 75 to 100 mg once daily, indefinitely.

Pain and fever (adults): 300 to 900 mg every 4 to 6 hours, maximum 4 g/day. Take with or after food. Largely displaced by paracetamol and ibuprofen for routine use.

Suspected heart attack: the standard advice in the UK and US is to chew a 300 mg aspirin (US: 162 to 325 mg) while waiting for an ambulance, unless allergic. Chewing matters: it speeds absorption substantially compared with swallowing whole, and minutes count. This single intervention is one of the highest-value pieces of first aid there is, and it is why aspirin belongs in a first aid kit.

5. What it does well: the two-tier evidence

Secondary prevention: established

In people who have already had a heart attack, ischaemic stroke, transient ischaemic attack, or who have known coronary or peripheral arterial disease, low-dose aspirin clearly reduces recurrent events and death. The Antithrombotic Trialists' Collaboration meta-analyses put the reduction in serious vascular events at around 20 percent. The bleeding risk is real and clearly outweighed. This has not changed and is not seriously disputed.

Primary prevention: the reversal

For people with no established cardiovascular disease, the picture changed decisively in 2018, when three large randomised trials reported:

The result: guidelines across the US, Europe, and Australia now recommend against routine aspirin for primary prevention in most people. The 2022 US Preventive Services Task Force advises against starting it in adults 60 and over, and says the decision in those aged 40 to 59 with elevated risk should be individual and is of small net benefit.

Why the change? Partly better trials, and partly that background cardiovascular risk has fallen substantially since the older aspirin trials, because of statins, blood pressure treatment, and reduced smoking. When the baseline risk falls, the absolute benefit falls with it while the bleeding risk does not.

If you are already taking low-dose aspirin, do not stop it on the basis of this chapter. Stopping abruptly in someone with established cardiovascular disease is associated with a rebound increase in events. This is a conversation to have with your doctor, not a decision to make alone.

Colorectal cancer

An unusual and genuinely interesting finding: long-term aspirin use is associated with reduced colorectal cancer incidence and mortality, with benefit emerging after roughly 5 to 10 years of use. It is recommended for people with Lynch syndrome, where the CAPP2 trial showed substantial reductions in colorectal cancer. For the general population, the balance against bleeding is not currently judged favourable.

Pre-eclampsia

Low-dose aspirin (75 to 150 mg daily) from 12 weeks of pregnancy reduces pre-eclampsia in women at high risk, and is recommended by NICE, ACOG, and the USPSTF. This is an established use and is one of the few situations where aspirin is deliberately prescribed in pregnancy.

6. Side effects and risks

All of the NSAID class effects, plus some specific to aspirin:

• GI bleeding and ulceration. The dominant harm. Even 75 mg roughly doubles the risk of upper GI bleeding. Enteric coating reduces local irritation and does not reliably reduce bleeding risk, because the mechanism is systemic.
• Intracranial haemorrhage, less common and more serious.
• Bruising and prolonged bleeding from cuts.
• Tinnitus at higher doses, an early sign of salicylate toxicity.
• Aspirin-exacerbated respiratory disease, in around 7 to 10 percent of asthmatics (Chapter 66).
• Gout: low-dose aspirin reduces uric acid excretion and can precipitate an attack.

Reye's syndrome

Aspirin must not be given to children under 16 (under 12 in some guidance), except for specific conditions such as Kawasaki disease under specialist care.

Reye's syndrome is a rare, rapidly progressive encephalopathy with fatty liver, occurring in children given aspirin during a viral illness (particularly influenza or chickenpox). Mortality was around 30 percent. After the association was established in the early 1980s and public health warnings issued, incidence collapsed to near zero. It is one of the clearest examples of a successful pharmacovigilance intervention, and it is why children's fever is treated with paracetamol or ibuprofen.

Salicylate poisoning

Distinct from other NSAID overdoses and genuinely dangerous. It produces a characteristic mixed acid-base picture: initial respiratory alkalosis from direct stimulation of the respiratory centre, followed by metabolic acidosis.

Symptoms: tinnitus and deafness, nausea and vomiting, rapid deep breathing, sweating, fever, confusion, and in severe cases seizures, pulmonary oedema, and death. Treatment involves urinary alkalinisation with sodium bicarbonate to trap salicylate in the urine, and haemodialysis in severe cases.

Topical salicylates matter here too. Oil of wintergreen is roughly 98 percent methyl salicylate, and a single teaspoon contains the salicylate equivalent of around 7 g of aspirin, which is potentially lethal to a child. Salicylate-containing muscle rubs, wart treatments, and acne products can cause systemic toxicity, particularly in children and when applied to large areas or broken skin.

7. Interactions

8. Myths and confusions

Don't be confused: enteric-coated aspirin does not protect you from bleeding. It protects the stomach lining from direct contact, which reduces indigestion. The ulcers and bleeding come from systemic prostaglandin inhibition, which happens wherever the drug is absorbed. If you need protection, that is what a proton pump inhibitor is for.

• "Everyone over 50 should take a daily aspirin." No longer recommended for primary prevention, after ASPREE, ARRIVE, and ASCEND.
• "Aspirin thins the blood." It does not change viscosity; it stops platelets sticking together. The distinction matters when talking to clinicians.
• "Aspirin is safe because it is ancient and cheap." It is one of the more hazardous over-the-counter drugs, particularly for GI bleeding.
• "Children can have a small dose of aspirin." No. Reye's syndrome.
• "Willow bark is a natural alternative." It contains salicin, converted to salicylic acid, at variable and unstandardised doses, with the same risks and less predictability.
• "Aspirin works for a hangover." It is an NSAID on an alcohol-irritated stomach, which is a poor combination.

9. The bottom line

• Aspirin is the only NSAID that inhibits COX irreversibly, and because platelets cannot make new enzyme, one low dose disables them for their whole 7 to 10 day life.
• Established for secondary prevention: if you have had a heart attack, stroke, or have known vascular disease, low-dose aspirin reduces recurrent events by around 20 percent and the benefit clearly exceeds the bleeding risk.
• No longer recommended for most healthy people. Three large 2018 trials found the bleeding outweighed the benefit, and guidelines changed accordingly. Do not stop an existing prescription on your own.
• Chew 300 mg during a suspected heart attack while waiting for help. This is high-value first aid.
• Never give aspirin to a child under 16 because of Reye's syndrome.
• Enteric coating helps indigestion, not bleeding risk. Ibuprofen taken before aspirin blocks its cardioprotective effect.
• Oil of wintergreen and topical salicylates can cause serious systemic poisoning, especially in children.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium; US figures follow FDA labelling. Irreversible COX acetylation and platelet biology follow Roth and Majerus' original work and Patrono's reviews. The Hoffmann and Eichengrun priority dispute follows Sneader, BMJ, 2000. Vane's mechanism paper is Nature New Biology, 1971. Secondary prevention benefit follows the Antithrombotic Trialists' Collaboration meta-analyses, The Lancet, 2002 and 2009. The 2018 primary prevention reversal is ASPREE (McNeil et al., NEJM), ARRIVE (Gaziano et al., The Lancet), and ASCEND (Bowman et al., NEJM); the USPSTF's 2022 recommendation statement followed. Colorectal cancer and Lynch syndrome follows CAPP2, Burn et al., The Lancet, 2011 and 2020. Pre-eclampsia prophylaxis follows the ASPRE trial and NICE, ACOG, and USPSTF guidance. Reye's syndrome and the collapse in incidence after public health warnings follow CDC surveillance data and Belay et al., NEJM, 1999. Salicylate poisoning management follows standard toxicology and UK poisons guidance. Methyl salicylate toxicity, including the oil of wintergreen equivalence, follows paediatric toxicology case literature. Enteric coating not reducing bleeding risk follows Kelly et al., The Lancet, 1996.

Open questions. Whether any subgroup still benefits from aspirin in primary prevention, and how to identify it, is unresolved; the current answer is essentially individualised risk assessment with modest expected net benefit.

👉 Next: the stronger painkillers.