Proceedings
aspirin is more than a hundred years old, yet new uses are still being found for it. The 16th Annual Scientific Conference on aspirin held at the Royal College of Surgeons in Ireland covered not only its well-known use in heart disease, but recently discovered uses against thromboses in veins, to prevent and treat stroke, in healthy people at high risk of heart attacks, in colon cancer, and in women with 'Hughes syndrome' which combines gynaecological with blood vessel problems.

Chaired by Professor Desmond Fitzgerald, of the College's Department of Clinical Pharmacology, speakers included Colin Prentice, Professor of Medicine of the University of Leeds; Dr Raymond Johnston of the Civil Aviation Authority; Dr Anne MacGregor, Clinical Research Director, the City of London Migraine Clinic; Dr Katherine Sheehan, Registrar in Pathology at the Beaumont Hospital, Dublin; Professor Giovanni de Gaetano, President of the European Thrombosis Research Organisation; Dr Norman Delanty, consultant neurologist in the Beaumont Hospital, Dublin; and Dr Graham Hughes, of the Rayne Institute, St Thomas's Hospital, London.

Professor Prentice reported on the Pulmonary Embolism Prevention (PEP) trial, which studied 13,356 patients having fractured hip surgery randomised to aspirin 162mg daily or matching placebo for 5 weeks. PEP showed that aspirin reduced post-operative symptomatic deep vein thrombosis (DVT) by 29%, total post-operative DVT by 36% and pulmonary embolism by 43 per cent, all the differences being statistically and clinically significant. Of greater importance, the most feared complication of fatal pulmonary embolism was reduced by 58%. The expected downside, deaths due to bleeding, did not differ between the aspirin and control group. aspirin prevented 8 pulmonary emboli, 4 fatal, per 1,000 patients treated. The benefit lasted beyond the time of hospital discharge (12 days) until at least 35 days.

Professor Prentice concluded from these results that aspirin should be considered routinely in all surgical and medical groups at a high risk of venous thromboembolism. The clinical data supporting aspirin, he said, 'is more secure than the data for other antithrombotic agents including heparin and warfarin'. For major surgery, the benefits of aspirin outweigh its costs. It is the best researched thromboprophylactic agent. The PEP study, said Professor Prentice, is a challenge to heparin makers to perform a similar trial to prove its effects are better.

Dr Johnston continued with the theme of aspirin prevention of DVT. The role of stasis in venous thrombosis was highlighted in 1940, when it was noted as a common complication of sleeping in deck chairs in underground stations during the blitz. However, until now air travel has not been highlighted as a major cause of DVT. A review in 1999 listing risk factors for DVT, for example, did not mention air travel. Yet the evidence is there. Eklof et al in 1996 showed that of 253 patients with DVT and PE 44 developed symptoms after flights of 5-17 hours. Ferrari in 1999 reported a case control study of 160 people with DVT. There was a history of travel for more than 4 hours at a time in the previous 4 weeks in 24.5% of those with DVT and in 7.5% of those without it. Twenty eight of the DVT patients had travelled by car and 9 by aircraft.

The most obvious factors linking DVT to air travel are dehydration, alcohol (which increases dehydration), immobility, a medical history of previous deep venous thrombosis or surgery, possible venous compression due to seating, the oral contraceptive pill and hormone replacement therapy.

Seat pitch in economy in scheduled aircraft has shortened from 33 to 34 inches in 1992 to 31 to 32 inches in 1999. In chartered airlines it may be 28 or 29 inches. This may have implications on a narrow bodied aircraft which may operate flights more than 5 hours long.

To avoid DVT in high risk travellers the top priority is to keep hydrated and mobile. Anti-embolism stockings and perhaps low molecular weight heparin may be useful in people at very high risk. It is reasonable to take aspirin before long haul flights, but there should be some medical guidance and a bar to people who have had a previous peptic haemorrhage. Buying first class tickets may be worthwhile, but DVTs also occur in seats in first class – and even in Air Force One, as the case of President Nixon proves.

Interestingly there have been no DVTs in UK pilots even though they are less mobile than cabin staff. There has not been a reported incidence of DVT on Concorde which one might expect as the flight time is always less than 4 hours.

Migraine
Dr MacGregor spoke about the more routine use of aspirin in headache, and specifically migraine. In most developed countries about a third of people identified as having migraine do not bother consulting their doctors. In Japan the figure is as high as 69% because it carries a huge social stigma.

aspirin is very effective for headache, and, said Dr MacGregor, for migraine, in which there is also disturbance in appetite, alertness, tolerance to light, noises and smells and fluid imbalance. aspirin helps in all these changes by being more than a painkiller. It is anti-inflammatory, inhibits platelet aggregation and subsequent serotonin release, and has central effects. Achieving high blood levels of aspirin quickly gives good pain relief before the delayed gastric emptying that occurs in the attack impairs its absorption of oral medication. The correct dose is 900 to 1000mg (three standard UK pills) preferably of a soluble formulation as this achieves high levels more rapidly than solid tablets.

Dr MacGregor's double blind cross over study in 4 migraine centres randomised patients to a new formulation of aspirin mouth dispersible 900 mg versus placebo. 80 per cent of the trial patients were using triptan prescriptions and a similar percentage described their usual attacks as severe. After 30 minutes there was a statistical difference between the two treatments that remained for at least 2 hours (48% had complete relief on aspirin vs 19% on placebo). Mouth dispersible aspirin also relieved the symptoms of dislike of light and sound and speeded up return to normal function.

Other studies have shown that combining aspirin with oral metoclopramide is as effective as a sumatriptan, is better tolerated and much cheaper. People taking aspirin and/or metoclopramide can repeat the doses for incomplete effect: they cannot do so with most triptans.

The British Association for Study of Headache advises that people with migraine take aspirin 900mg in soluble formulation early in the attack, and to add metoclopramide 10mg or domperidone 20 mg if needed. Mouth dispersible aspirin produces similar absorption to soluble formulations with the advantage that it can be taken without water. Dr MacGregor preferred domperidone to metoclopramide, as she felt that it was less likely to give extrapyramidal side effects.

The Italian General Practice Thrombosis Prevention Trial
Professor de Gaetano described the primary prevention of thrombosis trial of low dose aspirin and vitamin E in general practice in Italy, shortly to be published in the Lancet. Healthy patients with risk factors for thrombosis were randomly allocated to 100mg enteric-coated aspirin and/or 300mg vitamin E or placebo in a 2 x 2 factorial study by 315 GPs in all regions of Italy. In summer 1998 the good results of the British thrombosis prevention trial and the Hypertension Optimal Treatment (HOT) trial caused the Italian trial to be ended prematurely after 4,495 people had been enrolled. The follow up is complete for 92% of the subjects, there being data for 16,390 person years.

Risk factors were age >50 years, with at least one of the following risk factors: age >65, hypertension >160/95, hypercholesterolaemia TBC>6.4mmol/l, diabetes, obesity or family history of MI. Fifty seven per cent were female, 24% were ex smokers and 14.9% current smokers. aspirin reduced major cardiovascular events by around 30%. Total cardiovascular diseases or events were reduced by 23% and cardiovascular death by 44%, so that aspirin significantly reduced cardiovascular mortality and morbidity.

On the other hand vitamin E had no effect on any cardiovascular parameter. aspirin was linked to a slight increase in non-fatal bleeding episodes. There were five fatal cases of bleeding, but four patients had not taken aspirin. Haemorrhagic strokes were very few: three in the non-aspirin group and two on aspirin.

To avoid one cardiovascular event or death, 48 patients would need to take aspirin daily for 4 years. This is hugely cost-beneficial.

The British thrombosis prevention trial was effective in men at particularly high coronary risk: this trial showed it did so in females and males. Professor de Gaetano concluded that aspirin can transform the usual GP care for patients at cardiovascular risk into a simple and effective preventive strategy.

Aspirin and Stroke – a neurologist's viewpoint
Dr Delanty explained that stroke is the third leading cause of death in the developed world. It is the commonest neurological disorder causing permanent disability in adults. He classified them as ischaemic, haemorrhagic, or due to subarachnoid haemorrhage and venous infarction. However, they are not always easily demarcated. Ischaemic strokes can undergo haemorrhagic transformation.

About 90% of strokes are ischaemic. They can be embolic or thrombotic, due to arterial thrombo-occlusive disease. Cardiac embolic stroke is linked to significant atheroma in the aortic arch and carotid arteries. Patients with atrial fibrillation at risk of stroke should have warfarin as their treatment of choice.

The aim of aspirin in avoiding stroke is to prevent platelet aggregation. Arterial thrombotic or embolic mechanisms are secondary to endothelial failure: aspirin inhibits platelet aggregation and should help prevent stroke.

The many secondary prevention trials of aspirin in stroke have had many designs and many doses, and meta-analysis has confirmed the benefit of aspirin 75mg to 325mg per day.

Two studies, TASS (ticlopidine-aspirin,) and CAPRIE (clopidogrel-aspirin) have shown a true treatment effect of aspirin. aspirin reduced myocardial infarctions, strokes, and vascular deaths by approximately 25% in all the high risk patients. TASS showed significant falls in cumulative death and non-fatal strokes in patients with prior transient ischaemic attacks or minor strokes taking either drug. However, ticlopidine is no longer recommended because of its significant risk of neutropenia needing monitoring, and of diarrhoea. It is also, of course, much more expensive.

In CAPRIE, with nearly 20,000 patients, there was a very marginal benefit of clopidogrel over aspirin. Among 1000 patients taking aspirin for a year 19 cardiovascular events would be avoided. The figure for clopidrogel was 24. However, clopidrogel is much more expensive than aspirin, and it has been since linked with platelet problems. There is some controversy about the result of the combined aspirin-dipyridamole study: the relative risk reduction of stroke is better on the two together.

The big concern now, said Dr Delanty was not whether aspirin works – that has been proved. It was that it is greatly under-used. In the Scandinavian 4S trial, only 37% of the patients who should have been taking aspirin actually were being prescribed it. He pleaded with doctors to give aspirin to those at high risk of cardiovascular events – those with hypertension, hyperlipidaemia, smokers, with diabetes, etc.

He also recommended its use in acute non-haemorrhagic stroke. The CAST/IST/MAST-I trials enrolled >40,000 patients to 160mg or 300mg aspirin. One death or stroke was prevented by giving aspirin to each 100 patients with acute stroke. It is recognised as part of the standard care of acute stroke. If given to every acute stroke patient in Ireland, with about 3,000 strokes per year, aspirin would prevent 30 deaths annually. In the United States, with an estimated 750,000 to 1 million strokes per year, the numbers saved would be huge. However, it is important that the aspirin used is not enteric coated, as absorption is too slow and may even be incomplete.

Aspirin against Cancer – colorectal and elsewhere
Dr Sheehan has an interest in colorectal cancer, the second most common cancer in Ireland. aspirin is of interest to her because it is a cyclo-oxygenase (COX) inhibitor.

COX (which has two forms, COX-1 and COX-2) is one step in the conversion of arachidonic acid to prostaglandins. COX-2 is highly inducible and upregulated in colorectal cancer, 70-80% of which exhibit a 2-50 fold increase in COX-2 expression. It is also expressed in stomach, oesophageal, breast, ovary and skin cancers.

More than 30 published studies provide data on aspirin use in colorectal cancer. Among them are reports of a 40% lower risk of colorectal cancer among regular users of aspirin. In a prospective study, aspirin use 16 times per month reduced the risk of fatal colon cancer by 42%. Giovannucci et al found that 5-9 years of regular use could prevent colorectal cancer in women. Sulindac treatment of patients with familial polyposis (FAP) reduced the number and size of polyps within 9 months. In a familial polyposis mouse model, knock out of the COX-2 gene resulted in significant inhibition in colonic polyp growth. Furthermore, more than 25 animal studies have shown prevention or inhibition of chemically induced adenomas and carcinomas in the colon following treatment with aspirin or NSAIDs.

Several clinical trials are underway to investigate the effects of treating colorectal cancer patients with aspirin. One of the larger studies, funded by the National Cancer Institute in the US, has recruited 900 patients over 4 years. They will investigate whether or not treating patients with 325mgs of aspirin will improve disease free survival. Others are investigating the effects of aspirin and NSAIDs on oesophageal, gastric and lung cancers. The effect of aspirin may be multifactorial, on various growth and pro-angiogenic factors, rather than just on COX.

Dr Sheehan investigated tumours from 76 patients with colorectal cancer diagnosed between 1988 and 1990, were graded for the percentage of cells staining for COX-2. They were subdivided into four subsets - <1%, 1-19%, 20-50%, >50%.

There was a significant association between advanced Dukes stage (a clinical measure of severity of the cancer), lymph node involvement and maximum tumour diameter and COX-2 expression. Patients with tumours in which there was <1% COX-2 staining had much better survival than those with more COX-2 staining.

Dr Sheehan concluded that there was ample evidence to suggest that aspirin reduces the risk of developing colorectal cancer. Selective COX-2 inhibitors are on trial, but it is not known whether they are better than aspirin. It is also possible that aspirin or NSAIDs may be used to treat patients who develop this cancer. The dose and duration of aspirin that is required for treatment remains unclear but the results of clinical trials now underway should provide these answers in the near future.

Hughes Syndrome – Sticky Blood, Obstetrics and the GP
Dr Hughes first became interested in the syndrome that now bears his name in the early 1970s, when studying systemic lupus erythematosus (SLE). In 1983, he gave the Prosser-White Oration, in which he described women with multiple thromboses, neurological disease, thrombocytopenia, livedo reticularis, headaches, migraine, epilepsy, chorea, multiple abortions, peripheral thrombosis, Budd Chiari syndrome and early death from stroke. Many were thought to have 'lupus' but had negative antinuclear antibody tests. The diagnosis was changed to anti-phospholipid syndrome when it was found they had anti-phospholipid antibodies, then was renamed Hughes syndrome when Dr Hughes' part in discovering it was recognised.

It is often unrecognised. Of 146 women with primary stroke, 7% had anti-PL antibody. In 55 Italian people under 45 years old with strokes, 20% had anti-PL syndrome: four of the ten went on to have further strokes.

Dr Hughes has a weekly clinic of 800 patients, many of whom complain of memory loss. Many know precisely when their INR has fallen, because their dysarthria or headache returns when it falls from 3.2 to 2.9. One sufferer, an author, needs an INR of 3.4: if it falls to 3.1 she writes nonsense.

Some patients develop myelopathy from thromboses in the spinal cord, and are labelled as having multiple sclerosis. Of 27 patients originally diagnosed as MS half had had previous APS-related symptoms: when given warfarin 14 of the 16 primary APS patients had no further symptoms

Common features include teenage migraine, memory loss, accelerated atheroma, impotence (it affects men too), skin ulcers, mitral valve disease, monocular vision loss, and necrosis of the hip with steroids. Potentiating factors in APL and thrombosis are the oral contraceptive and smoking.

Much of the data comes from pregnancy, in which abortion and miscarriage are associated. A British Medical Journal review (1997; 314: 244) of pregnancy in Hughes syndrome patients concluded that aspirin was a big advance. Of 47 APS patients in whom the previous 60 pregnancies had a live birth rate of 29%, it became 70% when treated with aspirin and/or heparin.

Anti-phospholipid syndrome (APLS), said Dr Hughes, is the most common preventable cause of recurrent miscarriage. Women with it should take aspirin alone when they have no previous thrombosis, and aspirin with heparin when they have a previous miscarriage history. It causes up to 1 in 5 of all strokes in under 45s: with aspirin they are all potentially preventable. Some people with diagnoses of Alzheimer's, multiple sclerosis or rheumatic disorders may have APLS, and be treatable.

APLS has revolutionised the management of lupus. Some women with multiple infarctions can be taken off their high dose steroids with multiple infarctions. In fact if the treatment could have been given to Queen Anne, who had 17 miscarriages and no surviving heir, and had several other symptoms of APLS, she might have had an heir. That would have kept the Stuarts on the throne, and the House of Hanover would not have taken over. Our history would have been very different – George III might never have become King and we might still have America as a British Colony!