Aspirin: Past, Present and Future
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n COLLEGE LECTURES Aspirin: past, present and future Peter C Elwood ABSTRACT – Many folk remedies used since pre- white willow tree, dried ‘upon the outside of a baker’s historic times have depended upon salicylates for oven for more than three months’. He described the their effect. One hundred years ago aspirin was effective treatment with this powder of ‘fever in over formulated from salicylic and acetic acids. It was 50 patients suffering from various agues’. the first drug to be synthesised and its formula- Salicylic acid seems to have been first synthesised tion is regarded as the foundation of the modern from carbolic acid around 1859 by a German chemist pharmaceutical industry. and it came to be widely used for the relief of pain The benefit of low-dose aspirin as a prophy- and fever. Because of its irritant action on the This article is lactic after a thrombotic event was first reported stomach, efforts were then made by chemists to find based on the 25 years ago. Its use after coronary or cerebral a form or a derivative of salicylic acid which could be Milroy Lecture thrombosis is virtually mandatory, unless there better tolerated. In 1897 Felix Hoffman, a chemist given at the Royal College of are signs of intolerance. A ‘loading dose’ of working in a laboratory owned by Friedrich Bayer in Physicians on 26 soluble aspirin should be given on first contact Elberfeld, Germany, and stimulated by earlier work June 2000 by with a patient who may be suffering from on acetylation, formulated a pure and stable form of Peter C Elwood myocardial infarction. Patients considered to be acetyl salicylic acid simply by mixing acetic and sali- MD FRCP FFPHM , at increased risk of a vascular event should also cylic acids 2. Hoffman was motivated by the suffering Honorary be advised to carry their own aspirin and, if they of his father, who had severe arthritis, and could not Professor, experience sudden severe chest pain, to chew tolerate salicylic acid. University of Wales and swallow a 300mg tablet or a soluble Bayer gave the name A-spirin to the new prepara- College of preparation immediately. tion, from acetylation ( A-), together with spirin, part Medicine, Cardiff The current phase of the aspirin story is, how- of the name for meadowsweet ( Spiraea ulmaria ), a ever, not over, and its possible value in a variety plant rich in salicylates. Bayer patented the name and of conditions, including dementia and certain commenced to market the product in 1899. It was Clin Med JRCPL cancers, seems likely to ensure that it will long a huge success and sales grew rapidly. In fact, the 2001;1:132–37 continue to play a remarkable part in clinical company set up by Friedrich Bayer & Company is practice. reckoned to have been the first pharmaceutical company, and the production of aspirin is generally accepted to have laid the foundation of the modern The medicinal use of salicylates pharmaceutical industry. Aspirin was accepted widely with great enthu- Salicylates are widely distributed in plants and many siasm, and it was soon recommended in the medical herbal remedies probably depend for their effect on press for use with fever, migraine, the pain of the presence of a salicylate. Around 400 BCE inoperable cancer, rheumatoid arthritis, gout, Hippocrates recommended a brew of leaves from rheumatic fever, acute tonsillitis, corns and warts 3. In the willow tree ( Cortex salicis ), a rich source of 1997, the National Library of Medicine listed over salicylates, for the relief of pain in childbirth. 23,000 papers on aspirin, and it has been estimated The attention of chemists seems to have been first that currently a paper on aspirin is published on drawn to salicylates after the Reverend Edward Stone average every two hours! of Chipping Norton wrote, in 1763, to the President of the Royal Society in London, the most prestigious Platelets and vascular disease scientific body in the world at that time 1. In common with many physicians, Stone believed in the so-called The early microscopists saw platelets, but they dis- Doctrine of Signatures, namely that alongside many missed them as either cell debris, or dirt on the maladies providence had provided the means for slides. Donné, a French physiologist, seems to have their cure. He was therefore attracted to the willow been the first, in 1842, to describe platelets 4. He tree because it flourishes in moist and wet soils and it called them ‘globulins du chyle ’ and believed they was in such situations that fevers were then common. coalesced to form white blood cells. Osler, the Stone reported how he had used increasing doses of Regius Professor of Physic in Oxford, recognised a powder prepared from the bark of the common that platelets play a part in thrombosis, and in 1874 132 Clinical Medicine Vol 1No 2March/April 2001 Aspirin: past, present and future he described pseudo-podia and the adherence of platelets to Table 1. The reduction in vascular events by long-term low- fibrin when stimulated 5. dose aspirin prophylaxis. ( Based on the combined results of Nevertheless, the role of platelets and their part in thrombosis 145 randomised controlled trials as reported in ref 13) was long debated and it was not until perhaps the late 1950s that Reduction in various clinical groups : there was general agreement about their role in coronary and Patients with prior MI 11 trials25% reduction other thrombotic processes. Since then a vast amount of work has Patients with an acute MI 9 trials29% reduction led to the present understanding of platelet function. Early papers Patients with a prior stroke or TIA 18 trials22% reduction of particular relevance were published in 1974 by Haerem 6, who Other high risk groups of patients 104 trials32% reduction showed that tiny platelet emboli could often be found in the coro- Reduction in the separate outcomes : nary micro-circulation in cases of sudden death in which there Reduction in non-fatal MIs 122 trials34% reduction was no major coronary thrombus, and in 1984 by Michael Davies, Reduction in non-fatal strokes124 trials25% reduction who showed that a platelet plug could be found at the head of Reduction in all vascular deaths 144 trials17% reduction Reduction in all-cause deaths 144 trials16% reduction almost every thrombus in the coronary vessels 7. Relative reduction in different patient groups : Males and females similar reduction Aspirin and platelet activity Older and younger similar reduction Hypertensive and normotensivesimilar reduction An effect of aspirin on platelets was first described by Morris in Diabetic and non-diabetic similar reduction 19678. O’Brien and others immediately took this up and showed that reductions in the dose of aspirin down to quite low levels lost none of the platelet anti-aggregant effects, and that the effect of a single dose of aspirin is detectable on platelet aggre- The results of these trials have been examined in a number of gation for about ten days – that is, until all the affected platelets overviews. These show a remarkable consistency and indicate have been replaced 9,10. that aspirin reduces the incidence of non-fatal vascular events by Aspirin, even at very low doses, affects platelet function between 30 and 40% and reduces deaths from all causes by primarily by inhibiting platelet cyclo-oxygenase, an enzyme around 20% (Table 1). The consistency in the results offers no involved in the formation of the aggregating agent thromboxane evidence of any important differences in the proportionate A2. In fact, aspirin has other effects on haemostatic mechanisms, benefit for patients with a variety of previous clinical conditions some of which are due to interference with vitamin K in the such as unstable angina, previous MI or stroke, peripheral hepatic synthesis of the coagulation factors VII, IX and X 11. vascular disease and artery and valve surgery (Table 2). Nor is These may add to its protective effect. there any evidence of significant heterogeneity in the reduction achieved by aspirin in different groups of patients such as male Aspirin and coronary thrombosis and female, older and younger, diabetic and non-diabetic etc. Of course there are failures and some patients experience a The first randomised controlled trial of aspirin in the prevention vascular event despite aspirin prophylaxis. Some of these failures of vascular events was reported in 1974 12, and to date over 145 are undoubtedly due to poor compliance. Compliance was randomised controlled trials of aspirin in vascular disease have assessed in the Physicians’ Health Study, in which aspirin was to been reported in the medical press. These have involved a total be taken on alternate days. Subjects who took aspirin on every of over 100,000 patients, amongst whom there were almost recommended day experienced a 51% reduction in vascular 11,000 heart attacks and strokes 13. These trials have established events, whereas those who took aspirin on less than half the days aspirin, used in cardiovascular disease, as the most thoroughly recommended showed only a 17% reduction 14. Furthermore, an tested drug and have shown it to be probably the most cost- MI which occurs in a patient taking aspirin is likely to be of the effective of all drugs used in clinical practice today. small, non Q-wave variety 15. Table 2: Risks and benefits in aspirin prophylaxis. (Based on the combined results of 145 trials (ref 13 and others)) Prior Prior First month Other high-risk Low risk In every 1,000 patients, per year: MI stroke after stroke* subjects patients – the likely saving of clinical events 38 35 8 22 2–3 – major bleeds possibly due to aspirin 1.0 0.8 0.7 0.5 1.0 – intra-cranial bleeds possibly due to aspirin 0.5** 0.1** 2.0** 0.1** 0.5** * The figures in this column are the additional savings during the first month after a stroke.