Aspirin: Old and New

such asendothelialcells. overall balanceis toreduce plateletadhesiveness tocells The which lastsfor theten-day lifetime ofthe platelets. proaggregatory thromboxane (largely aCOX-1 effect) itinhibitstheformation ofthe the platelet, In prostacyclinantiaggregatory (largely a COX-2 effect). itreduces production ofthe In theendothelium, ofplateletfunction)andthevessel wall. part important exerted intheplatelet(where aggregation isan Itscardiovascular effects are Itsantipyretic effects are alsocentral. andcentrally withintheCNS. injury, inhibition ofCOX-2 formation atthe site oftissue actsasananalgesicby peripheral therefore, Aspirin, can only beachieved innucleated cells. which generation ofnew enzymetorestore function, reversible inhibitors)meansthatitrequires aspirin (incontrasttomostNSAIDswhichare irreversible nature oftheinhibitionproduced by precursor toPGE arachidonic acidtoPGH theconversion of prostanoid biosynthesis, These isoenzymescatalyse thefirststepin andproliferativein many inflammatory reactions. hasarole aninducibleform produced inresponse toexternalstimuli, andCOX-2, prostaglandins, to berelevant tothetissuehomeostaticfunctionsof COX-1 is expressed constitutively inmany tissuesandseems COX-1 andCOX-2. COX enzymes, permanently inactivatestheCOX activityofthe The principalmechanismofactionaspirinisthatit MECHANISM OF ACTION cardiovascular cyclo-oxygenase (COX), disease (CVD), system(CNS), centralnervous (CI), LIST OF ABBREVIATIONS KEYWORDS outlines someofthedeveloping areas. Thisreview looksbriefly attheestablishedusesand are stillbeingresearched. newits useshave therapeutic indications expandedconsiderably over theyears,and andantipyretic anti-inflammatory agent, Initially usedasapotentanalgesic, today. ABSTRACT oldandnew Aspirin: DECLARATION OFINTERESTS thromboxane (TX) relative risk(RR), M) oseodlat-nlmaoydus(SIS,prostaglandin H drugs (NSAIDS), nonsteroidal anti-inflammatory (MI), iepo n ragenUiest optlTut eateto hraooyadTeaetc,Uiest fLvrol Liverpoo andBroadgreenUniversityLiverpool Hospital and ofPharmacology Department University ofLiverpool, Trust, Therapeutics, 1 1 Behind theMedicalHeadlines Behind theMedicalHeadlines Specialist Registrar andGastroenterology, inClinicalPharmacology OMusumba, CO Aspirin (acetylsalicylicacid)isoneofthemostcommonly useddrugs des fet,aprn yl-xgns,therapeutic uses cyclo-oxygenase, aspirin, Adverse effects, in vitro 2 Walley T 2’ etlsto IF,gsritsia G) myocardial infarction gastrointestinal (GI), (IVF), fertilisation PGF nihshlpdsnrm AS,confidenceinterval Antiphospholipid syndrome (APS), 2á’ 2 which istheimmediate No conflictofinterests declared. PGI 2’ and TX A and TX 2’ The . 2 rfso fCiia hraooyadCnutn hsca,Royal andConsultantPhysician, Professor ofClinicalPharmacology it may causeReye’s Syndrome. but shouldnotbegiven tochildren oradolescents where Aspirin isalsoeffective inrelieving thesymptomsoffever, duetoitsbettertolerability. spondyloarthropathies, and osteoarthritis juvenile rheumatoidarthritis, treatment ofdiseasessuchasrheumatoidarthritis, aspirinstillhas asignificantrole inthe many new NSAIDs, Despitetheintroduction of forms ofsevere chronic pain. butcanalsobeusedinsome especially headaches, pain, Itisusedintreating mildtomoderate in thecommunity. prescribed ingeneralpracticeorboughtover thecounter Aspirin isahighly effective analgesicandiswidely Table 1). andeven dosesaslow as 30mgmay beeffective (see mg, is aneffective antithrombotic agentindosesof50–100 Aspirin preventionsecondary ofcardiovascular diseases. One ofaspirin’s majorusestoday and isintheprimary Use asprophylaxis for cardiovascular events (see Table 2). USES the haemorrhagic risktothepatient. andnew angina)and andstroke coronary death, stroke, developing cardiovascular disease(defined as non-fatalMI, the balancebetween theabsolutethrombotic riskof prophylaxis)dose aspirin(primary depends critically on useoflow without pre-existing occlusive vasculardisease, Inpeople by asixth. andvascularmortality by aquarter; non-fatalstroke reduces theriskofnon-fatalMIby athird; prophylaxis)occlusive vasculardisease(secondary antiphospholipid syndrome who have already hada A A s s p p i i r r i i n n

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TABLE 1 Vascular disorders for which aspirin has been shown TABLE 2 Indications for considering low-dose aspirin to to be effective and minimum effective doses.1 prevent CVD events.

Disorder Minimum effective daily dose, mg Indications for primary prevention • 50 years with a total CVD risk of 20% • Men at high cardiovascular risk 75 End organ damage from hypertension • Hypertension 75 Type II diabetes who are over 50 years • Selectively in diabetes <50 years with one of the Stable angina 75 following: Unstable angina 75 1 disease for more than 10 years Acute MI 160 2 already treated for hypertension Transient ischaemic attack & ischaemic stroke 50 3 retinopathy or nephropathy, and blood pressure Severe carotid artery stenosis 75 controlled to 150/90 Acute ischaemic stroke 160 Indications for secondary prevention GENERAL MEDICINE • Coronary heart disease (MI, stable and unstable angina) • Stroke • Transient ischaemic attack • Peripheral vascular disease

TABLE 3 Risk of stroke in atrial fibrillation if taking antithrombotic therapy.

Risk Group Risk of stroke if Risk of stroke if on Risk of stroke if on NNT untreated aspirin warfarin

Very high 12% 10% 5% 13 Previous ischaemic stroke or TIA

High 5–8% 4–6% 2–3% 22–47 > 65 years and one other risk factor from: hypertension, diabetes, heart failure or left ventricular dysfunction

Moderate 3–5% 2–4% 1–2% 47–83 > 65 years and no other risk factors < 65 years and other risk factors

Low 1–2% 1% 0·5% 200 < 65 years and no other risk factors

stroke, aspirin seems as effective as warfarin in preventing should not be given antithrombotic prophylaxis, unless recurrence of the stroke. aspirin is given for other indications. Table 3 stratifies the risk of stroke and the degree of benefit from treatment with Other cardiovascular uses either aspirin or warfarin.2 Aspirin is also used in the treatment of acute coronary syndromes, including MI, and acute stroke (once Finally, aspirin can be used in patients who have had haemorrhage has been excluded). certain revascularisation procedures, such as angioplasty and coronary bypass operations, if they have a vascular Atrial fibrillation, even in the absence of valvular heart condition for which aspirin is already indicated. It has no disease, increases the risk of thromboembolism six-fold. effect on graft survival following femoral-popliteal bypass Aspirin can reduce the risk of thromboembolic stroke by with native veins, but is beneficial, alone or with about a fifth,but is less effective than warfarin,where the risk dipyridamole, where a prosthetic bypass has been used. reduction is about two thirds. Aspirin,however,is associated with fewer serious adverse effects than warfarin. Treatment Aspirin and cancer prevention with warfarin is therefore preferred in people at high risk of stroke, unless contraindicated. But in people at moderate Several retrospective studies have shown that risk, practice is more variable, though most still use warfarin prophylactic long-term use of aspirin daily, and to a lesser in this situation. The decision on which to use for moderate extent NSAIDs, is associated with a halving in the risk of risk should ultimately be made after carefully weighing the developing colorectal cancer. overall risk of stroke compared to bleeding and taking into account the individual’s personal preference. People under Prospective research on the prevention of colorectal 65 years with no other risk factors are at low risk and cancer has often focused on colorectal adenomas,

assuming that the effects of chemopreventive agents on processing of beta amyloid-42 peptide, the principal adenomas will reflect their effects on cancer. This avoids component of amyloid plaques, an effect that has been the size and duration required for trials using colorectal shown to occur at clinically low doses of aspirin. The jury cancer itself as the outcome. Two large randomised is still out on the use of aspirin as a simple intervention prospective trials looking at adenomas in high risk against cognitive decline, and randomised prospective patients have now provided further supportive evidence. trials are needed to confirm this. Although there are as In the first study, in patients with a previous colorectal yet no such trials, most UK and Canadian specialists cancer, aspirin (325 mg) had a moderate effect in consider aspirin should be prescribed in patients with preventing recurrent adenomas at twelve months (17% in cognitive impairment and vascular risk factors.7 aspirin group vs 27% on placebo, RR 0·65, CI 95% 0·46–0·91). In the second study, patients with colonic Aspirin in pregnancy complications adenomas receiving 81 mg aspirin daily showed a 19% reduction in the risk of recurrent adenomas (CI 95% 0·69 Antiphospholipid syndrome 0·96). However, this beneficial effect was not seen at a Combined treatment with aspirin (75 mg) and GENERAL MEDICINE higher dose of 325 mg daily and it is unclear why this was unfractionated heparin in pregnant women with a history so. A third, smaller, study also showed a reduction in the of recurrent miscarriages and antiphospholipid antibodies recurrence of larger adenomas. Overall, the evidence is is standard care. encouraging but not conclusive. Other studies show that aspirin or NSAIDs may be protective against gastric Pre-eclampsia cancer, and possibly against cancers of the oesophagus, Low-dose aspirin (75 mg) reduces the risk of pre-eclampsia prostate, ovary, breast and lung.5 by around 15% for women at both low and high risk, with a similar reduction in the risk of perinatal death. Aspirin Several mechanisms by which aspirin and NSAIDs might should therefore be considered, particularly in women at prevent carcinogenesis have been postulated. The main high risk. More widespread use may be appropriate in mechanism is thought to be by inhibiting synthesis of countries with a high prevalence of pre-eclampsia.8 prostaglandins (especially PGE2) which are potent signalling molecules and have a key role in carcinogenesis. Other possible uses Lipoxygenase-mediated apotosis induced by NSAIDs in colon cancer cells has also recently been reported. Research is still ongoing but results from some studies Another hypothesis is that these drugs induce the done so far show promise in the use of aspirin for the expression of a protein, p21, that is involved in regulation following indications: of normal cell growth. There is also genetic variability in the response of individuals to the protective effects of • Migraine treatment; NSAIDs based on polymorphisms leading to variable • Prevention of cataracts; activity of their metabolising COX isoenzymes. • Improving circulation in gums; • Prevention of adult leukaemia; Cancer chemoprevention using aspirin and NSAIDs offers • Prevention of HIV replication; tantalising prospects for the future. However, detailed • Increasing success rates in IVF programmes. considerations of the total benefit in relation to toxicity, as well as the most appropriate dose, are needed before GASTROINTESTINAL SIDE EFFECTS AND aspirin can be recommended routinely for this use.6 TOLERABILITY OF ASPIRIN

Aspirin, cognitive decline and dementia Aspirin, regardless of dose or formulation, can cause gastric irritation, increased occult blood loss and Several observational studies have reported that low dose sometimes serious GI bleeding. The risk is about 1 in 200 aspirin and other NSAIDs may protect against dementia patient years overall, about twice the background risk, and of vascular and/or Alzheimer’s type. Protection against lower with lower doses though never entirely cerebral vascular disease is not surprising perhaps, but disappearing. Aspirin is safer compared to other NSAIDs, protection against Alzheimer’s disease is less obvious. which cause a five-fold increased risk of GI bleeding. Cerebrovascular disease has also been implicated in the Serious adverse GI effects are more likely in patients with clinical manifestations of Alzheimer’s. Alzheimer’s disease underlying risk factors, such as previous GI bleeding, may also, at least partially, be due to inflammatory previous peptic ulcer disease, taking concomitant drugs processes in cognitive brain centres, the microglia being of that increase the likelihood of GI bleeding (such as central importance. Aspirin and NSAIDs might attenuate corticosteroids, other NSAIDs) and advanced age. the inflammation (in which case low-dose aspirin may be Overall, the benefits of prophylactic low-dose aspirin in insufficient treatment). More likely is the hypothesis that prevention of cardiovascular events far outweigh the risks any anti-dementia effect is independent of changes in in all but low-risk patients. Studies also show no significant cyclo-oxygenase activity and occurs by influencing excess risk of intracerebral haemorrhage on aspirin.

OTHER ADVERSE EFFECTS mechanisms, and potential benefits and harms put forward for licensing today with the typical data Other adverse effects of aspirin include pseudoallergy presented for a new drug, it might well be rejected with (potentially life threatening in some), nasal polyps, Reye’s the manufacturers told to go away until they could define syndrome in children and adolescents where aspirin is no its role better and until they had better evidence! longer recommended, chronic nephritis, and, in high KEYPOINTS doses, tinnitus. Deliberate aspirin overdose is less common than paracetamol in the UK, while the reverse is • Aspirin is one of the most commonly used drugs the case in the US. worldwide. • Its main mechanism of action is by reducing ASPIRIN RESISTANCE prostaglandin biosynthesis through inhibition of the cyclooxygenase enzymes. Aspirin resistance is the inability of aspirin to inhibit • Aspirin still plays an important role as an anti- GENERAL MEDICINE platelet activation and aggregation, seen in up to 35% of inflammatory agent mainly in rheumatological individuals. The causative mechanisms are multifactorial, conditions due to its good tolerability. including non-compliance with aspirin therapy, inadequate • One of the major uses of aspirin is in the primary and dose, genetic polymorphisms of COX-1 and other genes secondary prophylaxis of cardiovascular events. involved in thromboxane biosynthesis, drug interactions, • There is growing evidence that aspirin protects against upregulation of non-platelet sources of thromboxane colorectal carcinoma and probably cancers of the biosynthesis and increased platelet turnover. Individuals stomach, oesophagus, breast, prostate, and lung, but at high risk of aspirin resistance may be treated best with more robust randomised clinical trials are needed an additional antiplatelet agent, eg clopidogrel. Research before it can be recommended for this. is ongoing into defining aspirin resistance, developing • Aspirin and NSAIDs show promise in preventing reliable tests for it, and establishing the risk of associated cognitive decline in vascular and/or Alzheimer’s cardiovascular events.9 dementia, but further randomised trials are still needed to confirm this. ASPIRIN – A DRUG FOR ALL SEASONS? • Aspirin reduces pregnancy loss in women with antiphospholid syndrome and decreases the risk of Aspirin is a valuable drug for many conditions, a fact not pre-eclampsia in women at risk. appreciated until long after its development. Indeed it • Research is still ongoing into other novel uses of could be argued that were a drug with so many aspirin.

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