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Second Consensus Report by Panel of Experts
2001

Medical Uses of Aspirin

1. Acute myocardial infarction (AMI)
2. Acute coronary syndromes (ACS)
3. Secondary prevention of Acute Myocardial Infarction (AMI)
4. Primary prevention Coronary Artery Disease (CAD)
5. Acute Ischemic Strokes
6. Transient Ischemic Attacks (TIAs)
7. Primary and secondary prevention of strokes
8. Hypertension
9. Diabetes Mellitus
10. Prophylaxis against Deep Vein Thrombosis and Pulmonary Embolism (DVT/PE)
11. Emerging Uses
      - Pregnancy
      - Phospholipid Antibody Syndrome
      - Cancer:  • Colorectal
                      • Other Cancers

Introduction

    The use of Aspirin as an analgesic, antipyretic and anti-inflammatory agent is in its second century. Its efficacy as antiplatelet agent has been confirmed in different clinical settings resulting from thrombosis in the arterial tree. The purpose of this report is to produce a consensus on different indications of this life saving drug and formulate recommendations which could be followed by the family physicians while prescribing Aspirin to patients keeping in view its safety, benefits and side effect profile.

Mechanism of action and pharmacological properties

    The antiplatelet effect is mediated through its action mainly on thromboxane A2 (TXA2). Aspirin inhibits the enzyme prostaglandin H synthesase which metabolize arachidonic acid. It irreversibly inhibits enzyme cyclo-oxygenase (Cox) thus decreasing production of TXA2 and it is responsible for antiplatelet effect. Aspirin also causes a decrease in production of prostacyclin but this is not clinically relevant because vascular endothelial cells regenerate new COX which maintains good effects of prostacyelin that is decreased platelet aggregation and vasodilation where as the effect on Thromboxane A2 inhibition in platelets is irreversible, because of the absence of muscle in the platelet.

    Plain Aspirin is rapidly absorbed through upper GIT, peak plasma levels occur 30 to 40 minutes after aspirin ingestion and inhibition of platelet function is evident within one hour. The enteric-coated aspirin may take three to four hours for its effect. A single dose of 100-mg aspirin is very effective in decreasing the production of TXA2.

1. Use of Aspirin in Acute Myocardial Infarction (AMI)

    The ISIS-2 study (table-1) and its 10 years follow-up data are the major trials confirming the usefulness of orally administered Aspirin in reducing the mortality in the setting of acute myocardial infarction. The major points of interest are:

i. As opposed to thrombolytic therapy in acute myocardial infarction Aspirin administration causes a reduction in mortality of about 25% when given during the first 24 hours of acute myocardial infarction.

ii. The reduction in the mortality by Aspirin is additive to thrombolytic therapy. Thus if both are administered in the 1st six hours a 42%          
    reduction in mortality is expected.

iii. This major reduction in mortality by Aspirin combined with Streptokinase therapy is achieved without an increase in the risk of STROKE  or major bleeds.

Recommendations

    It is recommended that all patients suspected of Acute MI whether displaying ST elevation or ST depression or Bundle Branch Block (BBB) should chew one tablet of soluble Aspirin (300 mg) immediately followed by 150mg (half a tablet) daily orally indefinitely. The concomitant use of ACE Inhibitors with Aspirin in Acute MI is safe & is recommended.

Table No. 1:   Results of 1st 5 weeks of Aspirin therapy in suspected evolving AMI
End Points	Aspirin 150mg/day (n = 8585)	Placebo 1 tab/day   (n = 8600)	Results %±SD
Non fatal reinfarction	83	170	50±9
Non fatal stroke	27	51	46±17
Fatal CV mortality	804	1,014	23±4
Any vascular event	914	1,237	23±4

2 . Use of Aspirin in Acute coronary Syndromes (ACS)

Aspirin is effective in reducing the risk of MI in patients with unstable angina. This therapy is associated with a reduced risk of Acute MI and death by 50%. This conclusion has been drawn by four large studies.

Recommendations

All patients diagnosed as unstable angina should receive 150mg of Aspirin daily for three months and then 75-100 mg/day indefinitely. Female patients may require 300 mg (one tablet) or more for this purpose.

3. Use of Aspirin for Secondary Prevention of
    Acute Myocardial Infarction (AMI)

    In a recent overview of 25 trials of Antiplatelet Agents Trials (APT) among patients with known cardiovascular disease (CVD), the use of Aspirin was associated with 32% reduction in overall MI., 27% non-fatal strokes and 15% total CVD mortality.(Table-2)

    On the basis of these studies the American and European recommendations in coronary heart disease prevention published in Feb 1998 issue of European Heart Journal (EHJ) recommends Aspirin to be given to all patients suffering from coronary artery disease and major vascular diseases.

Table No. 2 :  Aspirin for Secondary Prevention Reduction in events shown as percentage
End Point	All 4 25 Trials	MI 13 Trials	USA 2 Trials	CVA 10 Trials
Non fatal M.I	32± 5	31 ± 5	35 ± 17	35 ± 12
Non fatal stroke	27 ± 6	42 ± 11		22 ± 7
Total CV mortality	15±4	13 ± 5	37±19	15 ± 7
Important vascular events	25 ± 3	22 ± 4	36 ±13	25 ± 3

Recommendations

    All patients with clinically known vascular diseases should receive Aspirin in a dose of 75-100 mg daily for indefinite period unless specific contra-indications are present.

4. Use of Aspirin for Primary Prevention of Coronary Artery Diseases (CAD)

4. (a) Primary Prevention of acute MI

    As shown in table 3 the use of Aspirin was associated with 32% reduction in the incidence of non-fatal myocardial infarction.

Table No. 3 : Aspirin for Primary Prevention Reduction in events shown as percentage
End Point	Physician Health Study (USA)	British Doctors Trial	Overview
Non fatal M.I.	39 ±  9	3  ± 19	32 ±  8
Non-fatal stroke	19 ± 15	13 ± 24	18 ± 13
Total CV Death	2 ± 15	7 ± 14	13 ±  6
Any Vascular Event	18 ±  7	4 ± 12	13 ±  6

Recommendations

    Based on the above studies healthy male patients above the age of 35 years and having two or more risk factors should receive 75-100 mg Aspirin daily indefinitely unless specific contra-indications are present. It has been appropriately labelled as poor man’s statin when compared with studies of statins in primary prevention.

4. (b) Use of Aspirin after Angioplasty and / or Stent Implantation

    Soluble Aspirin 300 mg should be started atleast 24 hours before the intervention and continued thereafter indefinitely in a dose of 150mg daily. For the first 4 weeks Ticlopidine 250 mg twice daily or Clopidogril 75 mg once daily should be added to Aspirin.

4. (c) Use of Aspirin after Coronary Artery Bypass Graft Surgery (CABG)

    All patients undergoing CABG should be started on Aspirin 75-150mg as early as possible and continued indefinitely unless specific contra-indications are present. Combination with anticoagulants or Dipyridimol may be indicated in high risk patients.

5. Use of Aspirin in ACUTE ischaemic Stroke

    In Acute Ischaemic Stroke Aspirin is the only proven beneficial antiplatelet agent. The International Stroke Trial (IST) and Chinese Acute Stroke Trial (CAST) suggest that Aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose Aspirin gives protection in the longer term.

Recommendations

    It is recommended that patients with acute ischemic stroke be started on 300 mg Aspirin/day as early as possible and to be continued until the decision is made for secondary prevention. The dose for secondary prevention is 75-150 mg daily on long term basis.

6. Use of Aspirin in Transient Ischaemic Attack (TIAs)

    The United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin trial revealed a significant (18%) reduction in the combined rate of non-fatal stroke, non-fatal MI and death when treated with Aspirin.

Recommendations

    It is recommended that patients with TIA should receive Aspirin 300 mg/day. Dipyridimole or Ticlopidine/Clopidogril may be added in high risk patients.

7. Primary and secondary prevention of stroke

    Aspirin has been shown to reduce the relative risk of secondary stroke, TIA and death by 25 -31%, while the evidence for primary prevention is still emerging.

Recommendation

    The recommended dose for secondary prevention is 75 - 150 mg daily on long-term basis.

8. Use of Aspirin in hypertension

    Hypertension Optimal Treatment (HOT) study has shown definite effectiveness and safety of Aspirin in preventing Acute MI and Stroke in patients with hypertension. (See Table -4).

Table No. 4: Results of HOT Study
Events	Number of Events	Relative risk Reduction
Major cardiovascular events Acetylsalicylic acid Placebo	315 366	15%
Major cardiovascular events, including silent myocardial infarction Acetylsalicylic acid  Placebo	388 425	9%
All myocardial infarction Acetylsalicylic acid  Placebo	82 127	36%
All myocardial infarction including silent cases Acetylsalicylic acid  Placebo	157 184	15%
All stroke Acetylsalicylic acid  Placebo	146  148	2%
Cardiovascular mortality Acetylsalicylic acid  Placebo	133  140	5%
Total mortality Acetylsalicylic acid  Placebo	284  305	7%

Recommendations

    In addition to other measures to control Blood Pressure, 75-100 mg of Aspirin daily should be given to all patients with hypertension on long-term basis.

    In uncontrolled hypertensive patients, Aspirin should be avoided till adequate control of blood pressure is achieved.

9. Use of Aspirin in Diabetes Mellitus

    Patients with diabetes mellitus have two to three fold increase in the risk of dying from the complications of cardiovascular disease. Atherosclerosis and vascular thrombosis are major contributors. Platelets in patients with diabetes are particularly hypersensitive to platelet aggregating agents. Several trials have proved the efficacy of Aspirin as primary and secondary preventive agent in reducing the cardiovascular risk in diabetic patients.

    The use of Aspirin in early treatment of diabetic retinopathy study (ETDRS) shows no increase in the risk of retinal or vitreous bleeding even with relatively high dose of Aspirin used in diabetic patients with established retinopathy.

Recommendations

    All type-II diabetic patients (NIDDM) should receive 75-150mg of Aspirin daily and to be continued on long-term basis unless specific contra-indications are present.

10. Prophylaxis against Deep Vein Thrombosis and
Pulmonary Embolism (DVT/PE)

    The results of Pulmonary Embolism Prevention (PEP) trial have shown that patients undergoing hip replacement and other major surgery, Aspirin Therapy produced 43% reduction in Pulmonary Embolism and 36% in symptomatic Deep Vein Thrombosis. The fatal pulmonary embolism was reduced by 58%.

Recommendations

    All patients undergoing major surgery should be given Aspirin 150mg daily for 6 weeks.

11. Emerging Uses

Use of Aspirin in Pregnancy

Low dose Aspirin in Pregnancy Induced Hypertension (PIH)

    Low Dose Aspirin may prevent the onset of pre-eclampsia 15% but has no effect on established pre-eclampsia. Its role in PIH is being investigated. The drug is contraindicated after 36 weeks of pregnancy.

Cancer: Colorectal

    The evidence to-date supports that Aspirin reduces the risk of cancer in general and colorectal cancer in particular. A study in 90,000 females nurses revealed 30% reduction in colorectal cancer among those who used Aspirin regularly for 10-19 years and 44% reduction after 20 years consistent Aspirin use. Patients taking Aspirin for the risk of cardiovascular disease may also be reducing their risk of cancer specially colorectal cancer.

Other Cancers

    There is emerging evidence that low dose aspirin has a role to play in the prevention of gastric, oesophageal and prostate cancers. However, more data is needed for the consensus to develop.

Other Conditions

    Initial indications point to the beneficial effects of Aspirin in prevention of cataract and Alzheimer’s disease.

Contra-Indications to Aspirin Therapy

    As a general principle all drugs are to be avoided during the 1st trimester of pregnancy.

Absolute Contra-indications

    Aspirin should not be used in the following conditions:

1. Hypersensitivity to Aspirin and/or other salicylates
2. Haemorrhagic diathesis.
3. Documented acute gastric or duodenal ulcer.
4. Pregnancy after 36 weeks of gestation

Relative Contra-Indications

    Aspirin is to be used with caution in the following conditions:

i. G6PD deficiency
ii. Breast feeding
iii. Chronic or recurrent peptic ulcer
iv. Bronchial Asthma
v. Severe renal or hepatic damage

The causative role of Aspirin in Rye’s syndrome in children has been questioned

"Drug - Drug Interaction of Aspirin"
Many adverse drug events occur as result of drug -drug , drug disease or drug - food interactions and , therefore, are preventable. Clinicians’ awareness of the agents that commonly cause drug - induced disorders and its recognition can decrease the likelihood that an adverse event will occur.
Drug	Effect	Mechanism	Management
Acetazolamide  (Diamox)	Acidosis due to decrease   in elimination of acetazolamide	Increased acetazolamide concentration & shift of salicylates from plasma into tissue	Monitor for salicylate toxicity
Alendronate  (Fosamax)	GIT adverse effects	Unknown	Aspirin doses may need to be reduced
Antacids	Renal elimination of salicylates increases	Decreased absorption (increased urinary pH)	Monitor for reduced effectiveness upon initiation of antacid
Cortisone	GIT ulceration	Additive adverse effects	Monitor patients for excessive gastrointestinal side effects GI distress, GI bleeding ,gastric ulceration ) and for decreased effectiveness of aspirin.
Diltiazem     (Herbessr)	Diltiazem may also cause an increase in bleeding time	Inhibition of ADP induced aggregation	Monitor patients for signs or symptoms of abnormal bleeding
Frusemide  (Lasix)	Salicylate toxicity at lower aspirin doses than expected	Inhibition of proximal   tubular secretion	Avoid doses of greater than 650-mg daily of aspirin when given concurrently with Frusemide.
Ketorolac  (Toradol)	Risks of inducing NASAIDs  related adverse events	Reduced ketorolac plasma protein binding	Concomitant use of ketorolac and aspirin is contraindicated
Methotraxate	Methotrexate toxicity	Decreased methotrexate clearance	Monitor closely for toxicity, especially myelosuppression and gastrointestinal toxicity.
Spironalactone  (Aldactone)	Decrease in the effectiveness of spironolactone	Altered rennin effect	Avoid aspirin doses of greater than 650- mg daily in adults receiving spironolactone
Warfarin  (Marevan)	If warfarin and aspirin are  used concurrently, the dosage should be individualized.	Displacment of warfarain from plasma albumin	Monitor the prothrombin time or international normalized ratio (INR)

 Reference:    Micromedex computerized drug information 2001

Gastrointestinal Complications and Aspirin

    The most important and frequent side effects of Aspirin are those involving the GIT resulting from the irritation of GI mucosa producing clinical manifestations of various categories.

    These may be simple heartburn, nausea, epigastric pain, or GI bleeding of varying intensity. GI bleeding may range from microscopic blood loss to overt gastrointestinal bleeding requiring blood transfusions.

    The mechanism of mucosal irritation by Aspirin is controversial and opinions differ as to the exact mode of its production. However, the following facts have been well documented:

1. Gastrointestinal mucosal irritation or production of mucosal lesions of various severity are by and large highly dependant on the dosage and duration of Aspirin administration.

2. Smaller doses especially less than 300 mg/day are associated with a markedly lesser gastrointestinal irritation than larger doses, especially if buccal route or protective coating is used.

Safety Profile of Aspirin

    Optimal dosage of Aspirin is yet to be evaluated. However doses of 75-300 mg used in different trials appear to be similarly effective. In this range the risk of side-effect (gastric mucosal injury causing gastrointestinal haemorrhage) is reduced to placebo level. In addition there is no proven benefit of combining it with other antiplatelet agents except in a few specific conditions.

    For long term use of Aspirin smaller doses of 75-150mg are recommended. If symptoms of gastric irritation occur, physicians should be consulted before any decision is taken by the patient himself to discontinue the medication.

    As shown in Table No. 5, Aspirin as compared to the Non-Steroidal Anti-inflammatory Drugs has a much better safety profile.

The data supporting that one NSAID is safer than another or safer than Aspirin as regards gastric mucosal injury is equivocal.

Alcohol Warning:

    If a patient takes three or more alcohol drinks per day, he should contact his physician for advice as to when and how he should take pain relievers including Aspirin.

Table - 5 : Side effects of Aspirin especially compared with NSAIDs as regards bleeding
NSAIDs Toxicity Index Scores (Fries. et al, 1991)
Drug	Standardized Toxicity index Score
Aspirin	1.19
Salicylate	1.28
Ibuprofen	1.94
Naproxen	2.17
Sulindac	2.24
Piroxicam	2.52
Diclofenac Sodium	2.6
Fenoprofen	2.95
Ketoprofen	3.45
Meclofenamate	3.86
Tolmetin	3.96
Indomethacin	3.99

Key  References

Acute Myocardial Infarction
1	Antiplatelet Trialists Collaboration: secondary prevention of vascular disease by prolonged antiplatelet treatment. Br. Med. J. (Clin. Res. Ed.) 1988; 296: 320-331.
2	Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, Demots HL Protective effects of Aspirin against acute myocardial infarction and death in men with unstable angina: Results of a Verterans Administration Co-operative Study. N. Engl. J. Med. 1983: 309; 396-403.
3	Upchurch GR. Jr, Ramdev N, Walsh MT, Loscalzo J. Prothrombotic consequences of the oxidation of fibrinogen and their inhibition by aspirin. J Thromb thrombolysis. 1998;5:9-14.
4	Yusuf S, Wittes J, Friedman L: Overview of results of randomized clinical trials in heart disease: I. Treatments following myocardial infarction. JAMA 1988: 60: 2088-2093.
5	Elwood PC. Aspirin Past, Present and Future. Clinical Medicine, 2001; 1(2):132-137.
6	Krumholz HM, Chen YT, Wang Y, Radford MJ. Aspirin and angiotensin-converting enzyme inhibitors among elderly survivors of hospitalization for an acute myocardial infarction. Archives of Internal Medicine 2001;161:538-544.
Acute Coronary Syndromes
1	Willerson JT, Golino P. Specific platelet mediators and unstable coronary artery lesions. Circulation, 1989; 80: 198-205.
2	Willerson JT, Golino P, Eidt J, Campbell WB, Buja M: Specific platelet mediators and unstable coronary artery lesions: Experimental evidence and potential clinical implications. Circulation 1989; 80: 198-205.
3	Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E, Juneau M, Stasoal K. de Guise P, et al: Aspirin, heparin , or both to treat acute unstable angina. N. Engl. J. Med. 1988: 319: 1105-1111.
4	The RISC Group: Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990: 336:827-830.
5	Management of Acute Coronary Syndromes: Acute coronary syndromes without persistent elevation. Recommendation of Task Force of The European Society of Cardiology. European Heart Journals 2000;21:1406-1412.
Secondary Prevention
1	Antiplatelet Trialists. Collaboration secondary prevention by prolonged Antiplatelet treatment. Br. Med. J. 1988: 296, 320-331.
2	Steering Committee of the Physicians Health Study Research Group: Final report on the aspirin component of the ongoing Physicians Health Study. N. Engl. J. Med. 1989: 321: 129-135.
3	The SALT Collaborative Group. Swedish Aspirin Low-dose Trial (SALT) of 75 mg Aspirin as secondary prophylaxis after cerebrovascular ischemic events. Lancet. 1991;338:1345-1349.
Primary Prevention
1	Steering Committee of the Physicians Health Study Research Group: Final report on the aspirin component of the ongoing Physicians Health Study. N. Engl. J. Med. 1989: 321: 129-135.
2	Ridker PM, Cushman M, Stampfer MJ, Tracey RP, Henneknes CH. Inflammation, aspirin and the risks of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973-979.
3	Thrombosis prevention trial: Randomized trial of low intensity oral anticoagulation with warfarin and low dose aspirin in primary prevention of ischemic heart disease in men at increased risk. Medical Research Council General Practice Research Framework. LANCET 1998;351:Jan 24: 233-241.
4	Aspirin: The Poor Man’s Statin: Verheugh FWA. LANCET (Editorial)1998;351:Jan 24, 227-228.
5	David E. Risk of Aspirin may outweigh benefits in primary prevention in men with high blood pressure. BMJ 2000;320:13-17.
6	Herbert PR, Hennekens CH. Overview of four randomized trial of Aspirin in primary prevention. Archieve Int Med. 2000;160:3123-3127.
Transient Ishcemic Attack (TIA)
1	UK-TIA Study Group. United Kingdom Transient Ischemic Attack (UK-TIA) aspirin trial: interim results. BMJ. 1988;296:316-320.
2	The Dutch TIA Trial Study Group: A comparison of two doses of Aspirin (30mg versus 283mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N. Engl. J. Med. 1991; 325: 1261-1266.
3	Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European stroke Prevention study 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.
Stroke
1	Imparato AM, Riles TS, Gorstein F: The carotid bifurcation plaque: pathologic findings associated with cerebral ischemia. Stroke 1979; 10: 238-245.
2	Chen Z, Sandercock P, Pan H et al. Indications for early aspirin use in acute ischaemic stroke. A combined analysis of 40,000 randomized patients from the Chinese Acute Stroke Trial and the International stroke Trial. Stroke 2000;31:1240-9.
3	Chinese Acute Stroke Trial (CAST). Chinese Acute Stroke Collaboration Group, randomised placebo-controlled trial of early aspirin use in 20,000 patietns with acute ischaemic stroke. Lancet 1997;349:1641-67.
4	American Canadian co-operative study group: Persantine Aspirin Trial in Cerebral Ischemia: Part-II. Endpoint results. Stroke 1985; 16: 406-415.
5	Van Gijin J. Low doses of aspirin in stroke prevention. lancet. 1999;353:2172-2173.
6	The International Stroke Trial (IST): A randomized trial of aspirin, subcutaneous heparin, both or neither among 19,435 patients with acute ischaemic stroke, Lancet 1997; 349: 1569-81.
7	UK-TIA Study Group. United Kingdom Transient Ischemic Attack (UK-TIA) aspirin trial: interim results. BMJ. 1988;296:316-320.
8	Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European stroke Prevention study 2: Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.
9	Van Gijin J. Low doses of aspirin in stroke prevention. lancet. 1999;353:2172-2173.
Complications
1	Prichard PJ, Kitchingman GK, Hawkey CJ: Gastric mucosal bleeding: what dose of aspirin is safe? Gut 1987; 28: A1401.
2	Graham Dy, Smith JL: Aspirin and the stomach. Ann. Intern. Med. 1986: 104; 390-390.
3	Fries JF, William CA, Block DA, Arthritis Rheumatism, 1991;Vol. 34 No. 11:1353-61.
4	Sandler DP, Burr FR, Weinberg CR. Nonsteroidal anti-inflammatory drugs and the risk for chronic renal disease. Ann Intern Med. 1991;115:165-172.
Dose of Aspirin
1	Prichard PJ, Kitchingman GK, Hawkey CJ: Gastric mucosal bleeding: what dose of aspirin is safe? Gut 1987; 28: A1401.
2	The Dutch TIA Trial Study Group: A comparison of two doses of Aspirin (30mg versus 283mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N. Engl. J. Med. 1991; 325: 1261-1266.
3	The Use of Essential Drugs, WHO Technical Report Series 850, Sixth report of the WHO Expert Committee, Switzerland.
Angioplasty/ Stenting
1	The BARI Protocol. Circulation 1986; 73: 227-232.
2	White CV, Chaitman B, Lassar TA, Marcus ML, Chisholm RJ, Kundson M, Morton B, Roy L, Khaja F, Vondormael M, Reitman M: Antiplatelet agents are effective in reducing the immediate complications of PTCA: Results from the ticolopidine multicentre trial. (abstract) Circulation 1987: 76 (supple IV): IV-400.
3	Sharis PJ, Cannon CP, Loscalzo J. The antiplatelet effects of ticlopidine and clopidogrel. Ann Intern Med. 1998;129:394-405.
Coronary Artery Bypass Graft (CABG)
1	Brown BG, Cukingnan RA, DeRouen T, Goede LV, Wong M, Fee HJ, Roth JA, Carey JS: Improved graft patency in patients treated with platelet-inhibiting therapy after coronary bypass surgery. Circulation 1985: 72: 138-146.
2	Lorenz RL, Schacky CV, Weber M, Meister W, Kotzur J, Reichardt B, Theisen K, Weber PC: Improved aortocornary bypass patency by low dose aspirin (100mg daily) effects of platelet aggregation and thromboxane formation. Lancet 1984: 1: 1261-1264.
3	Limet R, David JL, Magotteaux P, Larock MP, Rigo P: Prevention of aorta coronary bypass graft occlusion: Beneficial effect of ticlopidine on early and late patency rates of venous coronary bypass graft. A double blind study. J. Thorac. Cardiovasc. Surg. 1987; 94: 773-783.
Diabetes mellitus
1	Clowel J.A. Use of Aspirin in diabetes mellitus, Diabetes Care 1997. Vol. 20, No. 11.
2	ETDRS investigations. Aspirin effects on mortality and morbidity in patients with diabetes mellitus JAMA 1992: 268; 1292-1300.
3	Diabetes and cardiovascular disease. A statement for healthcare professionals from American Heart Association Circulation 1999;100:1134-1146.
Pulmonary Embolism
1	Pulmonary Embolism Prevention (PEP) Trial. Collaborative Group Study Lancet 2000; 14th April;1288-1295.
Cancer
1	Giovannucchi E. The prevention of colorectal cancer by aspirin use. Biomed Pharmacother 1999; 53(7): 303-308.
2	Zaridze D., Borisova E. et al. Aspirin protects against gastric cancer Int J Cancer 1999; 82(4): 473-476.
Rye’s Syndrome
1	Smith TGC, Lessons from the 15th European Aspirin Foundation scientific meeting held at Royal College of Surgeons, Edinburgh on 26th October 1999. Pro R Col Physician Edinburg 2000;30:140-144.
Pregnancy
1	CLASP a randomized trial of low dose Aspirin for the prevention and treatment of pre-eclampsia Lancet. 1994; 343: 619-629.
2	Wallenberg HCS, Dekker G. A Makovitz; Low dose Aspirin prevents pregnancy induced hypertension in pre-eclampsia in angiotensin sensitive primigravida (Lancet-i 1986:1-3).
3	Duly I, Henderson-Smart D, Knight M, King J. Antiplatelet drugs for prevention of pre-eclampsia and its conseqeunces: systematic review. BMJ.2001 Feb 10;322:329-33.
4	Heyborne K.D. Pre-eclampsia presentation: lesson from low-dose aspirin therapy trials. Am J Obstet Gynecl 2000; 183(3):523-528.
Cataract
1	Gupta S.K., Joshi S, Relationship between aldose reductase inhibiting activity and anticataract action of various non-steroidal anti-inflammatory drugs. in Sasaki K., Hockwin O., (eds) Distribution of cataracts in the population and influencing factors and developments in ophthalmology. Basl. Karger, 1991