ASPIRIN

Dr Arlene Goldman MB, BCh, MRCP(UK) MACP

Contents

 

Aspirin has been established as an important prophylactic drug in high-risk cardiovascular groups. However many people in all age groups who are not at high risk are taking aspirin prophylactically against myocardial infarction and stroke and this review will seek to define current recommendations as to efficacy and dose with due regard to serious side effects. The indications for aspirin as secondary prevention appear to be clearly defined but primary prevention poses more problems. and the question of healthy people with no known risk factors taking aspirin must be seriously considered. The indications appear to be different for men compared to women and for the ages below and above 50.

Mechanism of action

Aspirin inhibits the cyclo-oxygenase enzyme in platelets leading to reduced formation of prostaglandin,the precursor of thromboxanes.The role of platelet activating factor must be addressed.Membrane phospholipid breaks down and lysophospholipid is formed.Lysophospholipid is the precursor of platelet activating factor. The authors state that an effective antiplatelet drug should inhibit the formation and/or action of platelet activating factor in order to prevent platelet aggregation. 1

In platelets ,aspirin prevents the formation of thromboxane A2.which induces platelet aggregation. Moncada et al have demonstrated that in vascular endothelium cells aspirin prevents the synthesis of prostacyclin,which inhibits platelet aggregation. Clinical evidence is overwhelming that the antithrombotic effects predominate. 2

Aspirin irreversibly inhibits cyclooxygenase (prostaglandin H synthase) which is the first enzyme of prostaglandin synthesis.Prostaglandin H2 is processed from platelets and vascular endothelium and produces thromboxane A2 (TXA2) and prostacyclin.Thromboxane A2 induces platelet aggregation and vasoconstriction and prostacyclin (PGI2) inhibits platelet aggregation and produces vasodilation. 3

Myocardial infarction and Stroke

Clear benefits have been found in the use of aspirin for nonfatal myocardial infarction,evolving myocardial infarction in the acute phase,unstable angina and stroke. In primary prevention there is a clear reduction in myocardial infarction in men over 50. 27 However it must be noted that other authors state that although aspirin should be considered in men over the age of 50 years with uncontrolled risk factors for the development of coronary events and should be used cautiously if at all if poorly controlled hypertension is present. 2

The primary drugs used in the treatment of angina pectoris include organic nitrates,beta-adrenoreceptor antagonists,calcium antagonists and the antithrombotic agents aspirin and heparin.In unstable angina aspirin and heparin reduce the risk of myocardial infarction and aspirin increases survival. 4

Aspirin reduced the occurrence of strokes categorised as noncardioembolic significantly more than those categorised as cardioembolic. 71 patients with ischaemic stroke were studied. 65% were cardioembolic,18% noncardioembolic and 17% uncertain cause. Left ventricular wall motion abnormalities were more likely in noncardioembolic strokes and were more commonly men. They concluded that aspirin may have a differential effect depending on mechanism of stroke. 5

Two major trials Isis-2 and PHS have demonstrated that aspirin significantly lowers thromboxane synthesis even in doses as low as 1 mg.Low dose aspirin 160 mgs or one aspirin every other day were administered and both groups had a significant reduction in fatal and nonfatal cardiovascular events. It was concluded that low dose aspirin should be the prophylactic of choice aimed at reducing platelet cyclo-oxygenase activity.At least 100mgs of aspirin daily are essential to completely inhibit steady state thromboxane synthesis. Full strength aspirin daily had no beneficial effect in reducing mortality of patients with cardiovascular or cerebrovascular disease. 6

The most widely tested antiplatelet regimen was "medium dose"(75-325mgs/day) aspirin.In an acute emergency it may be better to use an initial dose of 160-325mgs/day rather than 75mgs.The optimal duration of treatment for patients with a past history of myocardial infarction,stroke or transient ischaemic attack could not be determined directly as most trials lasted on an average about 2 years.There was a suggestion that longer treatment might be more effective. 7

Stroke and Ticlopidine

Antiplatelet therapy with aspirin or ticlopidine (a platelet function inhibitor with a different mechanism of action than aspirin) reduces stroke by about 25% in many patients with transient ischaemic attack or initial stroke.Warfarin should not be used routinely for primary cerebrovascular disease but is useful to prevent cardioembolic stroke. Patients with nonvalvular atrial fibrillation have a substantial risk for stroke and most should be treated with warfarin.Risk-factor management such as control of hypertension,cessation of smoking and treatment of hyperlipidaemia is as important as antithrombotic or surgical therapies for most patients with threatened stroke.Treating isolated systolic hypertension in elderly patients reduces stroke risk. 26

Myocardial Infarction Trials

Three large scale randomised trials compare directly the risks and benefits of thrombolytic agents in acute myocardial infarction

 

GISSI -2 Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico
ISIS-3 Third International Study of Infarct Survival (International Extension of GISSI 2)
GUSTO-1 Global Utilisation of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries

 

It was generally agreed that t-PA Tissue type plasminogen activator APSAC Streptokinase and anisoylated plasminogen streptokinase activator complex all reduce mortality when given to patients with acute evolving myocardial infarction.

Thrombolytic therapy given to such patients presenting up to 12 hours after onset of symptoms reduces mortality by approx 20% and that aspirin therapy for patients presenting up to 24 hours reduces the mortality rate by approx 23% and the benefits are additive.The earlier administration and more widespread use of thrombolytic therapy and aspirin would save many lives. 8

New Anti-Platelet Agents

Ticlopidine

Inhibits platelet aggregation possibly by altering the platelet membrane and and blocking the interaction between fibrinogen and its membrane glycoprotein receptor,GP11b/111a Ticlopidine may not be beneficial when a rapid antiplatelet effect is needed.The most serious side-effect is reversible neutropenia. Where aspirin has failed or is contraindicated Ticlopidine has been approved for use in cerebral ischaemia. 3

Two North American Trials involving more than 4000 patients showed Ticlopidine to be significantly more effective in reducing the incidence of fatal or nonfatal stroke and death than aspirin in patients with TIA or minor stroke.9

Clopidogrel which is closely related to Ticlopidine is an antiplatelet agent with fewer side effects and is being investigated.3

Indobufen

A reversible inhibitor of platelet cyclooxygenase. Indobufen is associated with less GIT side effects than aspirin. Indobufen has proved to be an effective antithrombotic agent. 23 One trial was on various forms of heart disease ref 11and two were on coronary bypass grafting. 3

Platelet Glycoprotein GP11b/111a Inhibition

A new class of agents that are under investigation that act by inhibiting fibrinogen binding to the platelet glycoprotein 11b/111a receptor.The 7E3 antibody directed against this complex has been studied in patients and shown a reduced incidence of complications following percutaneous transluminal coronary angioplasty. 3

Atrial fibrillation

The incidence of atrial fibrillation increases with each decade of life.Congestive cardiac failure,coronary artery disease and hypertension are the most important causes as rheumatic heart disease has decreased.Non rheumatic atrial fibrillation is associated with an increase in the risk of ischaemic stroke. Atrial fibrillation is associated with an increase in the incidence of silent cerebral infarction and increased mortality.It is contentious as to whether atrial fibrillation is independently associated with the risk of stroke or is a marker of underlying cardiac disease.Data from four prospective randomised studies clearly support the use of warfarin prophylaxis in non rheumatic atrial fibrillation.The role of aspirin for prophylaxis in non rheumatic atrial fibrillation remains unclear. 10

Data from five prospective placebo-controlled studies in patients with non rheumatic atrial fibrillation treated with anticoagulation showed a reduction of thromboembolism ranging from 37-87% in patients on warfarin.There was a relatively low incidence of intracerebral and/or fatal bleeding complications.High intensity anticoagulation with an INR of 2.8-4.2 (International Normalised Ratio) was comparable with low dose anticoagulation INR 1.5-2.7.Intracerebral and/or fatal bleeding only occurred with INR > or = 2.6. Independent clinical predictors of increased risk for thromboembolism were recent congestive cardiac failure, arterial hypertension and previous stroke or arterial thromboembolism.Results in patients with chronic and intermittent atrial fibrillation were comparable. Lone atrial fibrillation does not seem to carry an increased risk for stroke when strict criteria for diagnosis of lone atrial fibrillation are applied. In two of the five studies aspirin was additionally randomised and contradictory findings resulted.The authors concluded that the role of aspirin prophylaxis still needs to be determined. 11

Bleeding and Side Effects

Inhibition of platelet function is noted one hour after ingestion of aspirin. Enteric coated aspirin may take 3-4hours to reach peak plasma levels.The gastric side effects appear to be dose dependent. The exact cause of aspirin induced gastric injury has not been elucidated. Inhibition of prostaglandin synthesis in the gastric mucosa has been proposed.Adaptation occurs after a period of 2-8 weeks continuous ingestion as assessed by endoscopy.There is evidence that longterm ingestion is associated with an increased incidence of gastric ulcer but not duodenal ulcer. 3

The British Doctors Study in which the aspirin dose was 500mgs/day had a significant increase in peptic ulceration and a trend towards an increase in GIT bleeding as against the US Physician's Health Study in which 325mgs every 2nd day showed no convincing evidence of gastric side effects. 3

Many animal and human studies have shown aspirin to cause gastric and mucosal erosions and enhanced spontaneous microbleeding.A broken mucosa and inhibition of thromboxane synthesis both appear to be necessary for bleeding to occur.The risk attached to aspirin consumption needs to be kept in perspective and it can be calculated that aspirin use is associated with aproximately 700 bleeds per annum in the UK.The relative risk for upper GIT bleeding is roughly similar to that for non- aspirin non- steroidal anti inflammatory drugs but those affected are generally younger and in an age group where death from upper GIT bleeding is very uncommon. In - contrast to non- aspirin non- steroidal anti inflammatory drugs no study has shown increased mortality from aspirin-related upper GIT complications. 12

Iron Deficiency anaemia

Chronic aspirin use is an important cause. Serum transferrin receptor measurements are usually elevated.24

Allergy

May aggravate chronic urticaria.

Gastro-Intestinal

The bleeding potential of even 75mgs aspirin has been established.The author assessed the results of low dose aspirin in GIT bleeding by combining the results of nine studies dealing with the prevention of ischaemic,thromboembolic or cerebrovascular events. The occurrence of bleeding was 1.5 times higher with low dose aspirin 75-325mgs/day as compared with placebo.The monthly probability of GIT bleeding per 1000 patients treated with low dose aspirin ranged between 0 and 2.1. 23

Co-existing risk factors It must be absolutely recognised that aspirin or any antiplatelet agent does not in any way substitute for the removal or treatment of coexisting risk factors such as tobacco, obesity, hyperlipidaemia,as well as hypercholesterolaemia, hypertension and metabolic disease. Control of these risk factors has been established as beneficial. 13

All patients should be encouraged to exercise regularly and to strive to attain ideal body weight. Diets should be low in cholesterol and high in dietary fibre and antioxidant vitamins. They should consume more fish but not fish oil supplements.Therapeutic doses of Niacin must be under medical supervision.Chromium and other nutritional supplements may merit consideration.With appropriate screening and precautions low dose aspirin prophylaxis may benefit selected individuals. 14

The Elderly

Advanced age is one of the strongest risk factors for coronary artery disease.A prospective randomised study of US male physicians without a history of myocardial infarction resulted in a 44% reduction in myocardial infarction in those treated with aspirin 325 mgs every other day. The treatment was only effective in those aged over 50. A prospective study of US nurses aged 34-65 without a history of diagnosed coronary artery disease showed a 32% decrease in those who took one to six aspirin per week. This effect was only seen in those aged over 50. 15

Many patients with stroke are not prescribed secondary preventive treatment.The use of aspirin in secondary preventive treatment in 96 frail elderly people older than 75 years was examined by Gerard McGonigal a consultant geriatrician in the UK. The patients were in sinus rhythm and had survived for at least 4 weeks after the stroke. In 43 of the 96 aspirin was not prescribed because of coexistent terminal illness or contraindications to the drug. such as cerebral haemorrhage and active peptic ulceration. Aspirin does have important side effects even in small doses. It is therefore ethical to withhold treatment in certain elderly people after a stroke but it is important to have an effective clinical audit to determine which patients would benefit from prophylactic aspirin therapy. 16

High risk patients - secondary prophylaxis and education

There is an increased use of low dose aspirin in secondary prevention of cardiovascular disease.(KING R) 3 audits were carried out on patients in a general practice in a market town in England. 531 patients were identified with cardiovascular disease - myocardial infarction,angina,transient ischaemic attack,cerebrovascular accident,peripheral vascular disease and more than one vascular disease.Initially more men than women were taking aspirin prophylactically but by the third audit and after receiving advice from their GP the difference between the sexes had disappeared. Women were more likely to complain that aspirin upset their stomach.It appeared that media coverage about stopping smoking,exercise,reducing cholesterol had been seen by the vast majority but they had not seen or heard about aspirin prophylaxis. 25

Aspirin and pre-eclampsia

Clasp-(collaborative low dose aspirin study in pregnancy) showed that aspirin is not sufficiently effective to recommend its widespread use for the prevention of pre-eclampsia.It may be effective in reducing the risk of recurrent early onset pre-eclampsia(starting before 32 weeks gestation) Prostaglandin thromboxane is elevated in pre-eclampsia and the rationale of treatment is inhibition of prostaglandin thromboxane synthesis.Low dose aspirin 60mgs per day is safe for pregnant mothers and foetuses. 17

Primary Prevention

Low dose aspirin prophylaxis has been associated with relatively small numbers of serious haemorrhagic complications.These complications are outweighed by the benefits of therapy in secondary prevention in high risk groups with underlying vascular disease who have already experienced an event or symptoms. There is less to gain and more to lose when low dose aspirin prophylaxis is given to large numbers of asymptomatic people. The author concludes that based on the available evidence primary prophylaxis should be reserved for those with the highest estimated risk. 18

Among low risk recipients of "primary prevention" a significant reduction of one third in non-fatal myocardial infarction was accompanied by a non-significant increase in stroke. The absolute reduction in vascular events was much smaller than for high risk patients despite a much longer treatment period. 7

The question of whether healthy people should be taking aspirin prophylactically has been discussed by various authors. V. Fuster and J.H. Chesebro believe the answer is two Primary prevention studies one in Britain and one in America both showed a low prevalence of cardiovascular events. There was an absolute reduction of less than two events per thousand per year.There was a significant increase in gastrointestinal haemorrhage requiring transfusion in the aspirin group compared with placebo and in the American study there was a slight increase in disabling strokes in those taking aspirin. The authors concluded that based on these studies the use if aspirin in an overall healthy population for primary prevention of coronary events is not justified. 2

For primary prevention aspirin should be considered in men over the age of 50 years with uncontrolled risk factors for the development of coronary events and should be used cautiously if at all if poorly controlled hypertension is present. A possible benefit in women is awaiting recommendations from the Womens Health Study. 19 There is a suggestion that asymptomatic women aged 50-65 may benefit. 3

Aspirin and Colon Cancer

It has been suggested that aspirin may reduce the risk of cancer of the colon. A prospective cohort study was done by mail questionnaire on 47,900 male health professionals aged 40-75years in the United States. The questionnaire was mailed in 1986,1988 and 1990 about the use of aspirin and other variables including the occurrence of cancer. Regular uses of aspirin had a lower risk for total colorectal cancer after controlling for age,history of polyp,previous endoscopy,parental history of colorectal cancer, smoking, body mass, physical activity, and intakes of red meat, vitamin E and alcohol. 19

A case-control study done over 4 years in Atlanta showed a reduced risk of cancer of the colon and rectum in patients on aspirin. The risk decreased with increasing doses of aspirin.20

Treatment costs

A study was done to determine the cost-effectiveness of prescribing warfarin in patients with non valvular atrial fibrillation with or without additional stroke risk factors eg a prior stroke or transient ischaemic attack, diabetes,hypertension or heart disease.Interventions with warfarin, aspirin or no therapy were analysed.

For patients with non valvular atrial fibrillation and additional risk factors for stroke, there was a greater quality-adjusted survival and cost savings with warfarin therapy.For patients who were not prescribed warfarin aspirin was preferred to no therapy on the basis of quality-adjusted survival and cost in all patients,regardless of number of risk factors present.The authors concluded that in patients with non valvular atrial fibrillation and one or more additional risk factors for stroke treatment with warfarin was cost-effective but in 65 year old patients with non valvular atrial fibrillation but no other risk-factors for stroke warfarin minimally affects quality-adjusted survival and increases costs significantly. 21

 

Summary of Reviews

Risk factor control remains of paramount importance.and it must be absolutely recognised that aspirin or any antiplatelet agent does not in any way substitute for the removal or treatment of coexisting risk factors such as tobacco, obesity, hyperlipidaemia, as well as hypercholesterolaemia, hypertension and metabolic disease. Control of these risk factors has been established as beneficial.

The use of aspirin prophylaxis for nonvalvular atrial fibrillation is unclear although it appears to have efficacy in preventing stroke.Warfarin is more effective but more expensive. Combinations of Aspirin and Warfarin increase the risk of GIT bleeding. 3

Bleeding may occur even with 75mgs but there do not appear to be reports of increased mortality with lowdose aspirin prophylaxis.

The recommended dose is 160-325mgs/day in the acute phase and 75-100mgs/day for long term use. 3

There appears to be a definite advantage for men aged over 50 with risk factors and results are awaited from The Women's Health Study. There is a suggestion that asymptomatic women aged 50-65 may benefit.

More patient education is required from Doctors and the media as regards aspirin prophylaxis..

The prophylactic use of aspirin appears to provide clear benefit for non fatal myocardial infarction,evolving myocardial infarction in the acute phase,unstable angina and stroke especially noncardioembolic.In the latter LV wall motion abnormalities predominate and are commoner in men.Aspirin therefore appears to have a differential effect depending on mechanism.

Healthy asymptomatic people with no known risk factors or well controlled risk factors are not recommended to be on aspirin prophylaxis. Healthy men over age 50 with uncontrolled risk factors for the development of coronary events may benefit but caution must be exercised if poorly controlled hypertension is present.

References

1 Ghooi RB. Thatte SM. Joshi PS The mechanism of action of aspirin-is there anything beyond cyclo-oxygenase? Medical hypotheses 44(2) (1995 Feb):77-80

2 Fuster V. Chesebro JH. Aspirin for primary prevention of coronary disease.European Heart Journal (1995)16(Supplement E),16-20

3 Hirsh J. Dalen J.Fuster V. Harker LB. Patrono C. Roth G. Aspirin and other platelet-active drugs. The relationship among dose effectiveness and side effects.Chest./108/4/OCT 1995/Supplement 247S

4 Zavecz JH. Bueno O. Pharmacologic therapy of angina pectoris. Journal of the Louisiana State Medical Society.147(5) (1995 May):208-10

5 Miller VT. Rothrock JF.Pearce LA. Feinberg WM.Hart RG.Anderson DC.Ischemic stroke in patients with atrial fibrillation:effect of aspirin according to stroke mechanism.Stroke prevention in atrial fibrillation investigators. Neurology 43(1) (1993 Jan):32-6

6 Rao GH. Rao AS. White JG. Aspirin in ischemic heart disease-an overview. Indian Heart Journal.45(2) (1993 Mar-April):73-9

7 Authors Anonymous. Collaborative overview of randomised trials of antiplatelet therapy--1:Prevention of death,myocardial infarction,and stroke by prolonged antiplatelet therapy in various categories of patients.Antiplatelet Trialists'Collaboration. BMJ 308(6921):81-106,1994 Jan 8

8 Hennekens CH.O'Donnell.Ridker PM.Marder VJ.Current issues concerning thrombolytic therapy for acute myocardial infarction.Journal of the American College of Cardiology. 25(suppl):18S-22S,1995 Jun

9 Verry M .Panak E. Cazenave JP. Antiplatelet therapy in the prevention of ischaemic stroke. Nouvelle Revue Frangaise d'Hematologie.36(3):213-28,1994 Jun

10 Kalman JM. Tonkin AM. Atrial fibrillation:epidemiology and the risk and prevention of stroke. Pacing and Clinical Electrophysiology.15(9) (1992 Sep):1332-46

11 Kottkamp H.Willems S.Hindricks G.Chen X.Haverkamp W.Hasfeld M.Borggrefe M.Breithardt G.Oral anticoagulation for prevention of thromboembolism in non-rheumatic atrial fibrillation:indications,effectiveness and risk. [German] |Zeitschrift fur Kardiologie 82(11) (1993 Nov):667-73

12 Hawkey CJ. Review article:aspirin and gastrointestinal bleeding.Alimentary Pharmacology and Therapeutics.8(2) (1994 Apr):141-6

13 Lekstrom JA. Bell WR. Aspirin in the prevention of thrombosis. Medicine.70(3);161-78, 1991 May

14 Simon HB.Patient-directed,nonprescription approaches to cardiovascular disease. Archives of Internal Medicine.154(20):2283-96,1994 Oct 24

15 Dalen JE.Goldberg RJ. Prophylactic aspirin and the elderly population.Clinics in Geriatric Medicine 8(1):119-26,1992 Feb

16 Patrono CP.McGonigal G. Letters to the editor.Journal of the Royal Colleged of Physicians of London Vol 30 No.2 Mar/April 1996

17 de Swiet M. Pre-eclampsia.111:The role of aspirin in prevention.Modern Midwife.4(12):20-2,1994 Dec

18 Kelly R. Selections from current literature:using aspirin for primary or secondary prevention. Family Practice.10(2):88-92,1993 Mar

19 Giovannucci E. Rimm EB. Stampfer MJ.Coldits GA. Ascherio A. Willett WC. Aspirin use and the risk for colorectal cancer and adenoma in male health professionals. Annals of Internal Medicine.121(4):241-6.1994 Aug 15

20 Peleg II.Maibach HT.Brown SH.Wilcox CM. Aspirin and nonsteroidal anti-inflammatory drug use and the risk of subsequent colorectal cancer. Archives of Internal Medicine.154(4):394-9,1994 Feb 28

21 Gage BF. Cardinalli AB.Albers GW.Owens DK. Cost-effectiveness of warfarin and aspirin for prophylaxis of stroke in patients with nonvalvular atrial fibrillation.JAMA.274(23):1839-45,1995 Dec 20

22 Hirschowitz BL. Nonsteroidal anti-inflammatory drugs and the gastrointestinal tract. Gastroenterologist 2(3):207-23,1994 Sep

23 Stalnikowicz-Darvasi R. Gastrointestinal bleeding during low-dose aspirin administration for prevention of arterial occlusive events. A critical analysis. Journal of Clinical Gastroenterology.21(1) (1995 Jul):13-6

24 Cook JD. Iron-deficiency anaemia. Bailleres Clinical Haematology .7(4):787-804.1994 Dec

25 Carney AJ. Carney TA. Use of aspirin in secondary prevention of coronary heart disease is rising. BMJ letter. vol 312 (1996 Mar30th):846

26 Hart RG. Rohack JJ.Solomon D. Feinberg WM. What's new in stroke?Texas Medicine.91(5):46-55,1995 May

27 Hennekens CH. Buring JE. Aspirin in the primary prevention of cardiovascular disease. Cardiology Clinics. 12(3) (1994 Aug):443-5

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