Introduction
The effects of aspirin and other substances having the same effect as aspirin have been known since the ancient Greeks recorded the use of the willow bark as a fever fighter thousands of years ago. It was discovered that the leaves and bark of the willow tree contain a substance called salicin, a naturally occurring compound similar to acetylsalicylic acid, the chemical name for aspirin and which was used to reduce pain and heal fever. But the continued use of aspirin has led to aspirin resistance, a common term related to the use of aspirin and its response to patients.
The origin of aspirin is known to have come about through research. In 1899 Bayer distributed aspirin powder to physicians to give to their patients. By this time, aspirin was considered the number one drug worldwide for almost all the then known diseases. Even though aspirin was dependent entirely on the cure of many diseases, it had to be obtained through a doctor’s prescription. The year 1915 marked the change of this state when aspirin was allowed to be sold without a prescription. It is in this same year that aspirin was manufactured in tablet form.
A few years later aspirin began to be used in the treatment of pains related to rheumatism, lumbago, and neuralgia.
As the use of aspirin was recommended for almost all diseases, Dr. Lawrence Craven, a California general practitioner took up this chance and prescribed aspirin to his patients. When he did a follow-up, he noticed that the 400 men he had prescribed aspirin to had not suffered any heart attacks. This prompted him to make regular recommendations to all patients and colleagues that “an aspirin a day” could reduce the risk of a heart attack. More research and developments led to the introduction of aspirin for children. This form of aspirin was chewable. Perhaps it would be interesting to note that even the astronauts of the Apollo airship had a kit of medication containing aspirin.
The more the years went by the more the use of aspirin expanded beyond pain relief and began to be used as a potential lifesaver, tolerated micro coating (clear coat) was added to Genuine Bayer aspirin to make the tablets easier to swallow. More and more research in the components and working mechanism of aspirin led to the FDA’s proposing the use of aspirin for reducing the risk of recurrent MI (myocardial infarction) or heart attack and also for preventing first MI in patients with unstable angina (Mueller MR, Salat A, Stangl P, 1997 pp 1008). Moreover, the FDA approved the use of aspirin for the prevention of recurrent transient-ischemic attacks or “mini-strokes” in men and made aspirin a standard therapy for previous strokes in men. In addition to its role in heart attack and stroke prevention, research continues to explore aspirin’s possible role in the prevention of colon, esophageal cancer, and other diseases. Indeed the use of aspirin can be demonstrated, even if there are no other means, by the statistics which showed that in 1996, twice as many people chose aspirin over the personal computer as an invention they couldn’t live without in a national survey on inventions conducted by MIT.
It is important to note that aspirin, also known as acetylsalicylic acid is a drug that for many days has been used the relieve minor pains and aches and also to reduce fever and as an anti-inflammatory. Later there were more and more experiments and research by other researchers and authors leading to developments in the structure and contents of the drug which came hand in hand with the discovery of aspirin components. Since then, the uses of aspirin have been multiplying day in day out. It was discovered that aspirin had an anti-clotting effect which is also referred to as antiplatelet and as such was to be used in low doses to prevent cardiovascular events and blood clot formation in people at high risk of developing blood clots.
Another use of aspirin which turned to be very common is the usage of high dose aspirin especially immediately after a heart attack to inhibit the synthesis of prothrombin and as such providing a second and differentiated anti-coagulant effect. However, this second usage is yet to be fully understood and discussed.
No drug has been found to be very perfect in treatment without having any side effects to all individuals that are using it. This means that besides having numerous positive results, aspirin-like many other drugs can have or can pose dangerous effects to patients who use it. For instance, one negative effect of aspirin is gastrointestinal distress (stomach bleeding) and Tinnitus. In addition, aspirin increases bleeding in women who are menstruating. This is because aspirin has an anti-coagulant property. Lastly, aspirin has been associated with Reyes syndrome especially in children under the age of 12 years when used in the treatment of fever, flu, or even chickenpox.
Aspirin can be grouped into a class of drugs. It falls in the class of non-steroid anti-inflammatory drugs (NSAIDs) which is a class of drugs that mostly contains salicylic acid. The drugs in this group work under the nonselective inhibition of the enzyme cyclooxygenase mechanism.
For a long time now, the use of aspirin has been applied to several minor treatments. Some historical aspect of the origins and development of aspirin suggests that French chemist Charles Frederic Gerhardt was the first doctor or medical researcher to come up with acetylsalicylic acid in 1853. This is what later came to be named aspirin in 1899. In this experiment, Gerhardt mixed acetyl chloride with the sodium salt of salicylic acid and called the resulting compound (salicylic acetic).
Later in 1859, another researcher Von Gilm reacted salicylic acid and acetyl chloride to get acetylated salicylic acid. In 1869, Schroeder, Prinzhorn, and Kraut did both Gergadt’s and Von’s experiments and proved that both the experiments produced the same compound, that is acetylsalicylic acid.
In 1897, Felix Hoffmann, a chemist, and employee of Bayer & company reacted salicylic acid and acetic anhydrite and obtained acetylsalicylic acid. It can be noticed that Hoffmann simply repeated Gilm / Krauts procedure but substituted acetic anhydride for acetyl chloride. Since then, the Hoffman procedure has been purported to be the basis of Bayer’s claims to discover aspirin (Vermeer F, Vahanian A, Fels P.W, 2000 pp 233).
It follows that according to the publications from Bayer and company, Hoffmann’s father was suffering from the pain of arthritis and could not stand the side effects of salicylic acid. This forced Hoffmann to substitute the chemicals when he made a formula to give to his father. (Vermeer F, et al. 2000 pp 236). Later it came to be known that the active ingredient in aspirin that is the acetylsalicylic acid was synthesized for the first time in a chemically pure and stable form by Dr. Felix Hoffmann in 1897 (Vermeer F, et al. 2000 pp. 240)
Though there are many theories and claims of the discovery of aspirin, of importance is its medical value and ability to treat/cure. This means no matter the direction the history of aspirin is taking, it is a rather fact that aspirin is a very important drug that has been used in various therapeutic cases. For example, aspirin has been used in the treatment of mild and moderate pain such as migraines and fever. In addition, aspirin has been used together with other non-steroidal anti-inflammatory drugs and opioid analgesics in the treatment of cancer-related pain.
On the other hand, high doses of aspirin have been used in the treatment of acute cases of rheumatic fever, rheumatic arthritis, and other inflammatory joint conditions. It is also used in low doses as an inhibitor of platelet aggregation. Moreover, studies have shown that aspirin can be used to reduce the incidences of transient ischemic attack and unstable angina in men.
Like heart disease and stroke, recent years have witnessed an increased report of cases of bowel cancer which had become one of the biggest causes of death in Western Europe. Studies have shown that, around one in every 35 people will contract the disease and around one in every 50 will die unless more effective treatments are found.
Researchers have suggested that aspirin may be part of the answer to this problem. A study that examined the health of nearly 90,000 American nurses from 1976 to 1995 showed that in those who regularly took aspirin the risk of getting colon cancer dropped by a half (Helgason CM, Tortorice KL, Winkler SR, Penney DW, Schuler JJ, McClelland TJ, Brace L.D, 1993 pp 346). Doctors don’t yet know how aspirin works here although it is possible that the drug affects the growth of small polyps on the bowel wall. Prostaglandins seem to be involved in this process. The growths may turn malignant in some forms of the disease and aspirin appears to prevent this (Helgason et al 1993 pp 349).
Other uses of aspirin include the treatment of pericarditis, coronary artery disease, and acute myocardial infarction (MI). In addition, doctors have recommended the use of a low dose of aspirin for the prevention of stroke and myocardial infarction in patients who have been diagnosed with coronary artery disease or high-risk cardiovascular disease (Helgason et al 1993 pp 350).
In the veterinary section, aspirin has several applications. For example, for a long time, aspirin has been used in the treatment of animals such as cats and dogs having either pain or those suffering from arthritis. Aspirin has also been used to relieve pain in horses though this use is not common because it has relatively short-lived analgesic effects on them.
Aspirin also has a protective effect in diseases affecting both ends of the age scale. Two of the most important causes of complications during pregnancy – fetal growth retardation and pre-eclampsia – are thought to be caused by blood clots in the arteries serving the placenta. Recent research has shown that regular doses of aspirin may help keep those blood vessels open allowing the fetus to receive the nutrients it needs to grow and preventing the rise in maternal blood pressure which occurs in pre-eclampsia and which can cause kidney damage, convulsions
Moreover, in some aged individuals, some forms of dementia are caused by blockages of the blood vessels in the brain. There is some preliminary evidence that aspirin may reduce the severity of brain damage in individuals suffering from dementia allowing sufferers to lead longer and fuller lives. However, it is also advisable to note that just like the other new therapeutic applications of aspirin the evidence is incomplete. Further trials are in progress.
Though the use of aspirin can be applied to several therapies, it has met numerous contradictions concerning its use and the side effects it has on the users. One of such contradictions is the warning against the use of aspirin by children under the age of 12 years. This is because it has been argued that the use of aspirin by children under the age of 12 years has been linked with cases of Reyes syndrome. Moreover, patients who have been diagnosed with bleeding conditions and hemophilia are advised against the use of salicylates which is a component of aspirin.
Aspirin has also been known to have some serious side effects / negative effects on some individual patients. Several studies undertaken have shown that aspirin can cause blood to lose. One of the medical and scientific researchers Delaney argues that “when aspirin is combined with other anticoagulants has a high probability of leading to a great risk of gastrointestinal bleeding.” In this study, Delaney shows the relationship between aspirin and the undetected loss of blood which leads to chronic anemia. The study proved that patients, who reported cases of blood loss, reported ceasing when aspirin use is stopped and anemia reoccurring when aspirin use is continued.
Aspirin has also been associated with abdominal pain such as dyspepsia. Elsen (a medical researcher) proved that incidences of abdominal pain were caused by anti-inflammatory drugs in which aspirin is a member. Another side-effect of aspirin is heartburn. This side effect though came to be solved by the usage of aspirin in coated enteric form/tablets (Gan R, Teleg RA, Florento L, Bitanga E. S, 2002 pp 255).
Moreover, high doses of aspirin have been associated with hearing loss in human beings. It has been argued that large doses of salicylates or salicylic acid in the body, block the pristine causing hearing problems (Gan R, et al 2002 pp 256) This effect is not commonly experienced because in most cases high levels of salicylic acid are not reached in the human bodies. Aspirin has also been related to prolonged bleeding up to ten days after an operation (Gan R, et al 2002 pp 256).
Many people are curious to know about the reasons why aspirin is the most commonly used ant-platelet drug especially in the prevention of acute diseases such as coronary artery disease (CAD). Aspirin is most appropriate because it has the ability to produce irreversible acetylation of the hydroxyl group of a single series residue of position 530 within the polypeptide chain of platelet prostaglandin G/H synthase-1 (Cox-1 D) resulting in the decreased synthesis of thromboxane A2 (TxA2), potent vasoconstriction and a platelet aggregator.
Since platelets lack the biosynthesis machinery to synthesize fresh enzymes, the inhibition of COX-1 induced by aspirin persists during their lifespan which is about eight to ten days. The plasma half-life of aspirin is about 20 minutes because aspirin is rapidly deacetylated to salicylate in the liver (Valles J, Santos M.T, Aznar J, 1998 pp350). After a single dose of aspirin, platelet cell activity recovers by 10% per day in parallel with the entry of new platelet into the circulation.
Though sanmuganation et al showed that a low dose of aspirin therapy has a significant reduction of cardiovascular events, myocardial infarction, or stroke in most patients, there are some individuals or cases whereby there was a witnessed failure of anticipated anti-platelet response from low dose aspirin therapy (Valles J, In addition, various laboratory parameters that aim to measure platelet aggregation have shown that there is variability among a score of individuals, in terms of response to the anti-platelet action of conventional doses of aspirin.
Various individual researchers and research groups have been working steadily in the recent past in an effort to demystify aspirin resistance. One such group is a Canadian-based research group that has been doing some research and came up with the following (Steinhubl SR, Varanasi JS, Goldberg L, et al 2003 pp 1336).
In their study which they published on January 18th, 2008 online of the British medical journal (BMJ) and accessed on 26 February 2008, they tried to further establish the concept of aspirin resistance. In this study, there was a suggestion that about 25 percent of all patients that take or use aspirin showed non-responsiveness to the drug (Mehta SR, Yusuf S, Peters R.J, 2001 527). This report is according to Douglass Simpson, Corgenix president, and chief executive officer.
In speaking about the products of Asprirnworks® in relation to aspirin resistance and testing, he strongly advocated that “we have done the research and now have an idea of how aspirin works which equips us with a better knowledge to produce aspirin work products which are perfectly positioned to assist the medical community in quickly, easily and accurately determining the effect of aspirin in patients.”
The study which was called “aspirin ‘resistance’ and risk of cardiovascular morbidity; systematic overview and meta-analysis” sought and combined information from a total of 20 studies totaling almost 3000 patients with cardiovascular disease. The resultant outcome showed that “based on the available data and with compliance accurately accounted for, aspirin non-responsive is real and is clinically relevant and leads to adverse cardiovascular outcomes.
The data also proposes that there is clinically significant variability in the aspirin effect which is well established and thus patients need to be informed of this possibility. The report also emphasized the need to establish a standardized protocol for treating patient populations who are non-responsive to the effect of aspirin.
But before one can say more about the issue of aspirin resistance, one has to look at the definitions of aspirin resistance, the evidence and underlying factors about the phenomenon, and how widely accepted the phenomenon is. The question of whether or not aspirin resistance is an existing medical condition thus arises. If one adopts one of the definitions of aspirin resistance that is, “the inability of aspirin to produce an anticipated effect on one or more tests of platelet function, for example, inhibiting the biosynthesis of thromboxane or inhibiting platelet aggregation and causing a prolongation of the bleeding time, ” such a definition provides a context within which this failure resembles other treatment failures of other drugs such as satins β blockers, and ACE inhibitors.
Testing of the clinical effectiveness of aspirin in secondary prevention has been clearly demonstrated and therefore can be termed as comparable to those of other agents in that all of them reduce non-fatal cardiovascular disease events by approximately 25 – 35 percent and also reduce fatal events by between 15- 20 percent in randomized trials. However, the study suggests that 70 – 75 percent of non-fatal and 80 – 85 percent of fatal events are not prevented by these drugs. These events which have been taken into consideration in the formulation of the above-cited definition of aspirin resistance show that to some, this inability can be termed as drugs resistance.
As a result, there has been the employment of several mechanical approaches which have been geared towards demystifying the aspirin resistance factor or ideology. Some of these approaches rely heavily on ex vivo evaluations of platelet function. The approach also considers other factors such as vascular function, interaction with other blood cells for instance monocytes and others as probable causes despite the fact that thrombosis is the proximate cause of nearly all occlusive vascular events.
It is however still unknown precisely how the impact of aspirin on the ex vivo response to selected concentrations of single aggregating agonists, might model its efficacy in preventing clinical events in vivo. This is because there is a possibility of multiple factors which are prone to confound platelets aggregometry such as; time of the day, smoking exercise, and blood cholesterol.
It is important to note that sometimes platelet aggregometry may recover despite the sustainable inhibition of thromboxane in the case of administration of chronic doses with aspirin. This, therefore, leads to a conclusion that the term aspirin resistance is insufficiently precise to offer a credible basis for clinical decision making (Gan R, et al 2002. pp 257)
Another research aimed at finding out whether aspirin resistance exists or not came up with the following conclusion after an extensive study. The report says that “it is incontrovertible that inter-individual variability in platelet responsiveness to oral antiplatelet drugs exists. Analogous to biological responses to other Pharmacological agents, the response to clopidogrel has been shown to display a continuous distribution while a similar response to aspirin may exist. On the basis of the aforementioned studies, there is substantial evidence illustrating hypo- or non-responsiveness to aspirin measured in the laboratory (i.e. resistance) is associated with adverse spontaneous (cardiovascular death, acute coronary syndromes, stroke or peripheral arterial occlusion) or procedure-related (myocardial necrosis after PCI or reocclusion after peripheral angioplasty) clinical events in diverse populations of patients with atherothrombotic disease in stable or unstable phase.” The report goes on to say that nevertheless, the currently available data are flawed by some major limitations. For instance, it points out some examples such as; “samples size of these reports is small; Confounding variables are not adequately controlled by the study designs; different definitions of aspirin resistance are used; Variable aspirin dosage; uncertain treatment compliance; and lack of pretreatment platelet activity assessment are noted in aspirin studies” (Steinhubl et al 2003 pp 1331).
Suggestions given are that “clinical application of aspirin resistance will require studies on larger populations that define aspirin resistance using consistent and reproducible assays, and correlate the measurements with clinical outcomes which can be improved by alterations in antiplatelet strategy (e.g., increasing dose of antiplatelet agent, and or adding or substituting second antiplatelet agent).” Such prospective randomized trials are currently underway. For instance, recent reports say that Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management, and Avoidance (CHARISMA) trial has been employed to compare clopidogrel and aspirin versus placebo and aspirin for high-risk primary or secondary prevention. This is done through the test of Urinary 11- dehydrothromboxane B2 levels which were checked in a substudy, enabling prospective.
In the recent past, aspirin resistance has relied heavily on the quantitative interpretation of the impact of aspirin on platelet aggregation ex vivo. This has been through thromboxane B2 and urinary – 11 dehydrothromboxine B2 excretion. The two approaches have been very useful in the explanation of the clinical pharmacology of aspirin. However, none of them has had a relative qualitative aspect to clinical outcomes in individuals.
The above observation may lead us to the conclusion that as per the results of the experiments approaches, the inference that a quantitative response in one of these variables to aspirin demonstration, might predict the efficacy of aspirin in preventing a heart attack or stroke in that particular individual is unsubstantiated.
A report from science daily as accessed on February 26 2008 says that up to 20 percent of patients taking aspirin to lower the risk of suffering a second cerebrovascular event do not have an antiplatelet response from aspirin, the effect thought to produce the protective effect. This statement is believed to have been published after the report given by researchers at the University at Buffalo. Dr. Francis M. Gengo, Pharm.D., the lead researcher on the study, went on to say that “Millions of people use low-dose aspirin either for prevention of a second stroke, second heart attack or second episode of peripheral artery disease, but we have known for years that in some stroke and heart attack patients, aspirin has no preventive effect.” Here Dr. Francis seems to suggest that there is some aspect of aspirin in relation to the response effect it has on the treated diseases as compared to several years back, which puts doubt on its effectiveness nowadays especially in regard to treatment to cardiovascular diseases and stroke. Though he does not mention the word aspirin resistance, DR. Francis gives a notion that such a phenomenon is bound to exist.
Dr. Francis rather poses some important questions regarding the relationship between aspirin failure and aspirin resistance. He says that “We’ve known about clinical aspirin failure for many years, we’re just beginning to understand clinical aspirin resistance.” He goes on to ask that “If you are aspirin resistant, does that mean you are more likely to be a clinical aspirin failure? Is one related to the other?’ The answer is, likely, yes,” he concludes.
Perhaps before discussing more on aspirin resistance, we should look at the possible causes of aspirin resistance. Taking one of the definitions of aspirin resistance that is, the inability of aspirin to reduce platelet production of thromboxane A2 production and thereby allowing platelet activation and aggregation, the measure of aspirin effectiveness in patients can be measured and detected by various ways inclusive laboratory tests of platelet thromboxane A2 production, or platelet function that depend on platelet thromboxane production (Gan R, Teleg RA, Florento L, Bitanga E. S. 2002 pp 253). This way various causes both non-genetic and genetic can be said to be the cause of aspirin resistance.
Non-genetic potential causes of aspirin resistance include inadequate doses, drug interactions, up-regulation of non-platelet sources of thromboxane biosynthesis, and increased platelet turnover. Inadequate doses of aspirin mean that there is not enough dose of aspirin, which is usually 75mg – 150mg a day in a patients body which means that the available aspirin in the body gets overwhelmed by the platelet production resulting in continued platelet production and subsequently platelet production of thromboxane A2. Non- platelet sources of thromboxane mean that thromboxane is produced by other pathways which are not the target of aspirin, therefore, rendering aspirin ineffective against the stoppage of thromboxane production.
Another cause of aspirin resistance can be said to be high levels of blood cholesterol which promotes coagulation events in the bloodstream. This means that aspirin in normal doses has minimal or hardly any anti-clotting effect in patients with high cholesterol levels whereas on the other hand treatment with a statin (inhibition of cholesterol) reduces significantly blood clotting.
Aspirin resistance can also be related to numerous other causes. One of these causes is the fact that the body’s response to aspirin may change over time. In addition, some people may have trouble absorbing aspirin from the digestive tract. Moreover, it is important to note that smoking and being overweight blunts / inhibit to some degree the effect of aspirin on platelets. Besides, extensive studies have indicated that non-steroidal anti-inflammatory drugs (NSAIDs), and ibuprofen may block aspirins’ protective effects.
Moreover, there is the possibility of an occurrence of increased sensitivity to collagen and adenosine diphosphate. This means that there might be an occurrence of platelet activation that won’t be detected by aspirin. Indeed, there are occurrences, though in rare cases an increased production of platelets by the bone marrow in response to certain situations such as stress which may be caused by for example the aftermath of coronary artery bypass surgery. This particular process introduces a string of newly formed platelets into the bloodstream and these platelets were not exposed to aspirin during the 24 hours dose interval.
Apart from non-genetic causes, there are also some genetic causes. But to know the genetic causes of aspirin resistance more perhaps we can start by discussing how aspirin works, aspirin works by irreversibly inhibiting the cyclooxygenase-1(COX-1) enzyme through acetylating the serine residue at position 529. The CoX enzyme catalyzes the conversion of arachidonic acid (AA) to prostaglandins G1 / G2 which are subsequently converted by thromboxane synthesize to thromboxane A2 (TXA2). TXA2 is a potent vasoconstrictor that activates platelet aggregation through specific binding to the TXA2 hypertrophy and proliferation of vascular smooth muscle cells and regulates the constriction of vascular and bronchiolar smooth muscles (Goodman et al 2007).
The antiplatelet effects of aspirin sometimes fail to be equal in all patients causing a certain proportion of patients prescribed aspirin to suffer recurrent thromboembolic vascular events. This phenomenon has given rise to the term “aspirin resistance.” However, it can be argued that because there are a number of reasons as to why patients might not respond to aspirin, the term is seen to be misleading especially bearing in mind that there are other pathways within which the platelets are activated for instance by agonists such as adenosine diphosphate (ADP), collagen or even thrombin of which are not affected by the action of aspirin.
As a result of the above observations, the underlying causes of aspirin resistance are not yet well understood although certain mechanisms may be involved. There have been suggestions that platelet heterogeneity might contribute to variations in aspirin response between different individuals. However, the evidence and support of these claims are at present lacking.
Besides, the possibility of a genetic contribution to aspirin resistance has been a topic of discussion in the recent past, and as such a genetic contribution would be expected to act at the level of megakaryocyte during the process of platelet development. A number of studies have examined the association of aspirin resistance with polymorphism in the COX-1 enzyme and some evidence reached for the genetic basis of aspirin resistance. One of these studies is the Cox enzyme the gene for the COX-1 enzyme and COX-1 enzyme is located on chromosome 9. Both contain approximately 600 amino acids with 62 sequence homology. The COX-1 gene is 22kb and is constitutively expressed in the endoplasmic reticulum of most cells. COX-2 on the other hand is relatively smaller at 8.3kb and is expressed at low levels in most cells. It is induced in response to stimuli including pro-inflammatory cytokines and growth factors (Helgason CM, Tortorice KL, Winkler SR, Penney DW, Schuler JJ, McClelland TJ, Brace L. D, 1993 pp 345). The expression on both COX-1 and COX-2 is very low within platelets or even sometimes undetectable especially in healthy patients. On the contrary, expression is very high in patients with an increased rate of platelet turnover seen in inflammatory and ineffective disorders and also in recent surgery (.Helgason et al 1993 pp 347).
The COX-2 enzyme is known to produce TXA2 from AA in monocytes, macrophages, and vascular endothelial cells. Aspirin is compared with the Cox-2 Isoform. Recently a new splice variation of COX-1 was cloned in a dog brain and named Cox-3. Cox-3 is a specific target for paracetamols in the brain. This may explain, though not extensively, the pharmacological action of paracetamols and other antipyretic analgesic drugs which are weak inhibitors of COX-1 and COX-2.
Even so, the COX-3 enzyme is not known to be expressed in platelets or to be a target of aspirin which rules out any argument against its involvement in aspirin resistance. This means that COX-1 is the area of interest I any attempt to identify single nucleotide polymorphisms (SNP’s) which may cause aspirin resistance at a genetic level, especially after bearing in mind that COX-2 is much less sensitive to aspirin.
Cyclooxygenase-1 gene polymorphisms are of potential importance because individual SNPS’s or their haplotypes may affect enzyme action as well as its interaction with aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs). Moreover, certain SNPs in the enzyme could inhibit the action of COX-1 thereby suppressing TAX2 production viaCOX-1 independent mechanisms. Conversely, other SNPs with COX-1 may increase their activity again contributing to aspirin resistance. O date more than 20 variants of the COX-1 and platelet sensitivity to aspirin were investigated by Marce et al, patients with the cardiovascular disease treated with aspirin (75- 300mg) for at least two weeks were genotyped for the five most common SNP. There were A842G (located in the promoter region), C22T (exon2), G128A (exon3), C644A (exon6), and C714A (exon70.The A 842G GSND has been shown to be a complete linkage disequilibrium with another variant, C150T in Caucasians. Platelet function studies were performed in relation to the four most common haplotypes. A significant increase was detected in AA-induced platelet aggregation and in serum thromboxane B2 (TXB2, a breakdown product of TXA1), in patients with the haplotype containing the mutant – 842. These results suggest that patients carrying the mutant -842G allele are less sensitive to aspirin treatment and may indeed be classified as aspirin resistors.
Regular treatment with aspirin and other NSAIDs has also been associated with a reduced risk of colorectal adenomas. A study by Ulrich et al investigated whether the effect of aspirin or other NSAIDs differs depending on the COX-1 genotype. Four SNPs were investigated, one of them being the –C50T genotype found to be a complete linkage disequilibrium with the A -842G polymorphism. The C50T allele is present in the signal peptide at the position. The investigators found that patients homozygous for the wild type C50T allele who were on aspirin were significantly less likely to develop colorectal adenomas compared with the patients not on aspirin treatment. In patients with the mutant -50T allele, no effect of aspirin was seen on colorectal adenoma development.
A small study by Gonzalez Conejero et.al found out that healthy subjects carrying the mutant – 50T allele in the COX-1 gene had higher levels of 11 dihydro TXb2, both before and after treatment with 100mg of aspirin. These investigators found no relationship between decreased sensitivity to aspirin and the -50T polymorphisms when assessed by AA-induced aggregometry or using a platelet function analyzer -100 (PFA 100) with collagen adrenaline cartridges. The findings from the study of Marce et al., Ulrich et al, and Gonzales Conejero et al are generally consistent because patients with the -842G allele in the promoter will carry the – 50T allele in the signal peptide and both have been found to confer reduced sensitivity to aspirin.
Hepantalo et al did some recent studies and supported the above findings. In this study, the investigators recommitted 1010 patients undergoing elective parallels coronary intervention treated with aspirin was measured through both AA-induced platelet aggregation and using a (PFA-100) analysis containing a collagen adrenaline cartridge in the basis of the AA-induced platelet aggregation, 60% of the patients labeled as non-responsive to aspirin carried the mutant-842G allele, and only 17% of those carrying this allele were aspirin respondents. When aspirin resistant was measured using (PFA-100) method, only 32% of the patients carrying the mutant-842G allele were classified as aspirin non respondents as compared with 19% of the patients homozygous for the common -842G polymorphism in determining response to aspirin.
Another generic cause of aspirin resistance can be demonstrated through the examination of the role of platelet receptors Glycoprotein 11b / 111a. Glycoprotein11b / 111a receptors are polymorphic and have two common variants that are; PIA1 and PIA2. Undas et al undertook a study of 10 healthy men treated with 75mg of aspirin daily for seven days with thrombin generation being measured pre and post-intervention. He found out that thrombin was similar between the two groups at baseline. After aspirin treatment, 23 of the 25 individuals homozygous for PIa1 had depressed thrombin levels as expected. However, by contrast only nine of the fifteen of the patients possessing the PIA2 allele showed any depression of thrombin generation. On examining the effect of aspirin on bleeding time on healthy men with PIA2 polymorphisms by the same group of investigators, they found out that the patients with PIA2 had a shorter bleeding time as compared with those homozygous for PIA1. The data above collectively suggests that PIA1 confers resistance to aspirin as compared with type PIA2 (Macchi L, Christiaens L, Brabant S, et al 2003. pp 1115)
It is of great importance to note that, all the above examples try to link the phenomenon of aspirin resistance to genetic causes. Indeed many polymorphisms in the COX- gene and in platelet receptors have been identified with many implicated reducing the antithrombotic properties of aspirin (Macchi et al 2003 pp 1118). However, as to date, the data for the extent of the genetic contribution to aspirin resistance is not conclusive with investigators’ reports having conflicting results. Therefore this situation calls for extensive genetic association studies in conjunction with well-validated indices of platelet function so as to establish the genetic influence, if any, in aspirin resistance.
Clinical implications
Emerging as an area of research and further debate with respect to chronic aspirin therapy is the concept of aspirin resistance. This phenomenon has been widely defined by various researchers and research groups. In some cases, the definition has been derived from patients who have experienced chronic events while using the drug aspirin. This has led to a general condition commonly known as treatment failure especially as applied to patients whose aspirin therapy fails to achieve the expected effects/feedback; that is the reduction in the measured level of platelet activation or aggregation.
Indeed aspirin response has been characterized in a variety of ways including measurement of urinary metabolites of thromboxane flow cytometric determination of platelet membrane molecule expression or even by employing one of the multiple ex vivo platelet aggregation assays (Macchi et al 2003 pp 1118).
Even though it has been difficult to demonstrate the clinical relevance of the various assays of platelet function convincingly and no test has yet emerged as a clear gold standard for identifying patients resistant to aspirin. As a result, it is not surprising that the reported incidence of aspirin resistance varies widely i.e. from 5% to as large as 75%. This is despite the fact that most recent studies have involved a relatively similar stable population.
The very first study aimed at demonstrating the interpatient variability in response to aspirin was first published nearly 50 years ago. Since then, there have been numerous trials evaluating responsiveness to aspirin in a variety of different settings. Despite all those attempts it can be noted that up to date, there has been no known uniform response to aspirin despite using a wide range of techniques. These techniques include platelet aggregometry, classical platelet aggregometry, flow cytometric analyses of markers of platelet activation, and bleeding time. Recent innovations and inventions have led to the establishment of several points– on care assays of platelet function. These developments have been geared towards overcoming the limitations of the more technically demanding laboratory-based assays initially utilized.
Another milestone is the lack of clear-cut answers to a relatively but critically important question of whether patients’ responsiveness to aspirin might change in relation to clinical status or overtime. There have been some studies that have yielded some significant variability to the response of aspirin over time, however, these variabilities are not uniform. In one study of over 300 patients with a history of Ischemic stroke who were treated with between 325 mg and 1300mg of aspirin, there was the only achievement of complete inhibition in 151 patients and even so, this effect was durable for only over six months I a limited 104 (70%) patients. In another much recent study during a 24months period of aspirin treatment, patients exhibited a gradual decline in the level of inhibition achieved, and by the end of the study period; the effects of aspirin appeared negligible (Macchi et al 2003 pp 1118).
More study has shown that there is an increasing body of literature that establishes a link between the variability in response to aspirin and adverse clinical events. One of the literature reports that “Grotemeyer et al, in a study of 180 patients admitted with stroke used in a vitro measurement of placemats reactivity performed 12 hours following administration of 500 mgs of aspirin and found that 33% of the patients have platelets that were active despite aspirin therapy. Patients were discharged on 500 mgs of aspirin three-time on-responsive years of following up, patients who were initially non responsive were more likely to suffer an adverse event including recurrent stroke or even death.” (Gum PA, Kottke-Marchant K, Poggio E.D, 2001 pp:230).
The study continues to state that Muller et al, evaluated the response to aspirin using whole blood platelet aggregometry in 100 patients with intermittent claudication treated with 100mg per day of aspirin. Here the author reports that there was considerable variation in the response of aspirin in the course of the year during which platelet aggregometry was performed four times. Moreover, patients found not fully responding to aspirin therapy had an increase in adverse events as manifested by re-occurrence of vascular gratis (Gum P.A, et al 2001 pp230).
On November 6th, 2004, an international panel convened for a round table meeting in New Orleans. This meeting was held a few weeks prior to the American heart association scientific sessions. The meeting’s main agenda was the discussion of critical issues of which aspirin resistance was mentioned. The panel members representing a range of disciplines including cardiology, clinical pharmacology, hematology, and gastroenterology examined the current literature along with a number of case studies and provided an insight into the concept of aspirin resistance and its implication in clinical practice.
One of the areas reviewed was the taste of platelet function. This is because studies in the past few years have reported a potential association between tastes of platelet function and clinical outcomes. There was a cited example whereby a study of 326 stable cardiovascular patients taking aspirin which was published in 2003, Gum and colleagues reported that aspirin resistance, as defined by optical platelet aggregation testing, was associated with an increased risk of the combined endpoint of death, myocardial infarction, or cerebrovascular accident (Buchanan MR, Brister S.J, 1995 pp 224).
Moreover, another milestone facing the study of the implication of aspirin resistance is that, though this and other studies have been linked laboratory measurement of platelet function with clinical outcomes is that there is no relevant evidence suggesting that any changes in aspirin administration therapy for instance increasing the dose of aspirin, has any likelihood of positively improving outcomes in the patients.
According to Eikelboon, a clinical hematologist and lead author of the 2002 circulation study he argues that “we know that aspirin has dose-dependent effects on some measures of anti-platelet function but the corresponding clinical benefits are uncertain.” (Eikelboom JW, Hirsch J, Weitz JI, Johnston M, Yi Q, Yusuf S, 2002 PP 967). In this publication, Eikelboon tries to review some possible mechanisms that have been proposed to try and explain why patients have abnormal test results and vascular events while undertaking aspirin therapy. He suggests some causes such as alternative pathways for platelet activation not affected by low dose aspirin; insufficient doses of the drug; polymorphism of aspirins target that is the glucooxygenase-1 (COX-1) gene; and patient no-adherence. Dr, Eikelboon suggests that perhaps understanding the mechanisms of aspirin resistance might lead to the identification of new therapeutic target and subsequently lead to the development of new laboratory measures and the creation of more customized therapies (Hankey GJ, Eikelboom J.W, 2004. pp 377)
I this round table meeting the panelists in addition discussed and agreed that aspirin resistance which has been widely referred to as the inability of aspirin to inhibit platelet thromboxane formation or the phenomenon which is the ability of the drug to cause prolonged bleeding time or the most familiar definition which is “the occurrence of serious vascular events despite the use of a recommended dose of aspirin” as imprecise because they tend to talk more about treatment failure rather than resistance. They supported this argument by saying that “the definitions are flawed because they imply that the drug is not doing its pharmacological job.” (Hankey et al 2004 pp 377). According to one of the panelists Dr. John Oaks, the term aspirin resistance does not clearly differentiate the failure of aspirin to inhibit COX-1 dependent (i.e. resistance to the action of aspirin in its molecular target) and resistance that is the responsiveness of platelet ion which COC-1 is maximally inhibited by aspirin.
Moreover, there are numerous tests of platelet aggregation such as turbidimetric aggregometry (the historical “gold standard” for evaluating platelet function), impedance aggregometry, PFA-100 verify now, and various flow cytometric tests which vary in complexity. Moreover, there are thromboxane tests which include serum thromboxane B2 and urinary-11 dehydrothromboxane B2 (Hankey et al 2004 pp 377). Even so, the clinical importance of these tests is still unknown. Another member of the panel Dr. Michelson said that the importance myth which needs to be demystified is whether all these clinical tests of aspirin resistance can predict clinical outcomes. He even went ahead and cited various platelet function laboratory tests that have been done in regard to cardiovascular disease as a means of predicting clinical outcomes and to monitor antiplatelet drugs, but was equally quick to mention that, none of these tests so far has sufficiently been studied in large clinical trials so that it becomes part of standard clinical care. He argued that until there is substantiated evidence, clinicians should not test their patients for aspirin resistance or neither differ their patients’ treatment on the basis of these tests (Hankey et al 2004 pp 379).
Another point of debate in the medical implications of aspirin resistance is the question of whether the patient should be given the option for testing. Dr. Eikelboon however brings forth the argument that bearing in mind that there is no evidence of increased dose benefits to patients, it would appear unethical to confuse patients by advising them to choose to be tested or not for aspirin resistance.
As per the present, various medical researchers seem to agree that changing aspirin therapy in response to platelet function test results may not only be appropriate but might as well have dangerous consequences. This is especially true after the evidence of increased risk of gastrointestinal (GD ulceration) after the administration of higher doses of aspirin. Indeed it has been noted that aspirin even at lower doses may lead to asthma in some patients or even cause GI bleeding and other serious complications. In his conclusion, Dr. Feldman says that “it worries me as a gastroenterologist to see aspirin does being pushed higher and higher without clear evidence that it is beneficiary for patients (Hankey et al 2004 pp 380).
The aspirin resistance phenomenon has led to suggestions of countermeasures and also measures to ensure that patients using aspirin have an alternative treatment that is more effective. This has led to the ideology of substituting aspirin with alternative antiplatelet agents such as clopidogrel (Plavix). Though clopidogrel is more expensive than aspirin, it has however been shown to be at least as effective in reducing the risk of serious cardiovascular events. There have been suggestions that there should be adoption or the use of other drugs such as clopidogrel or even the addition of clopidogrel to aspirin as this is beneficial in some clinical circumstances. Even so, there is a need for more research and more strategies particularly in regard to serious side effects such as bleeding.
The issue of aspirin resistance has made several researchers try out various experiments in an attempt to come up with an alternative treatment of aspirin resistance. For instance, one study says that patients undergoing coronary artery bypass surgery exhibited a 15-fold increase of COX-2 protein, which was associated with a marked increase in thromboxane formation. Moreover, this increase in thromboxane formation was not prevented by conventional aspirin treatment (100 mg/day), suggesting that this aspirin resistance might be due to the enhanced expression of the less –aspirin-sensitive COX-2 Isoform (Zimmermann N., Kienzle P., Weber A.-A., Gams E., Hohlfeld T., Schror K,1999. Circulation pp 327). In this essay, it is argued that”Platelet aspirin resistance is associated with an increased content of cyclooxygenase-2.” In trying to find the authenticity of this observation the following study was undertaken.
In this study, there was the use of ‘Terbogrel’ which is a pyridine derivative of formula EMI2.1 and is disclosed by US patent US 5,482,948. It is an equipotent inhibitor of thromboxane synthase and antagonist of thromboxane receptors, being effective at low nanomolar concentrations (Muck S., Weber A.-A., Schr·or K. (1998 pp 32)., Muck et al, 1998, says that, in addition to blocking thromboxane-mediated actions, “terbogrel” as an inhibitor of thromboxane synthase and was shown to redirect the arachidonic acid metabolism via the COX-pathway from thromboxane A2 towards prostacyclin (PGI2). This might result in the generation of a highly cardioprotective compound in myocardial ischemia, as demonstrated by stimulation of its endogenous biosynthesis (Hohlfeld et al. 1993 pp 264 /397). This study however failed to find any hint that this compound can be applied in order to treat or prevent thromboembolic disorders in a patient, who suffers from aspirin resistance. The study however agrees that “the problem underlying the present invention is the provision of a method to treat or prevent thromboembolic disorders in a patient, who suffers from aspirin resistance. (Hohlfeld et al. 1993 pp 390).
Now that there is the knowledge that over 16 million people use aspirin daily in America alone, and the phenomenon of aspirin resistance is emerging, it means that there is a call to the finding of a possible treatment either of aspirin resistance or even to those patients who depend entirely on aspirin for treatment of various diseases such as cardiovascular disease. Unfortunately as per the p[resent, there is no clear-cut treatment against aspirin resistance. Recent studies have shown that there are superior clinical benefits of clopidogrel and also the combination of clopidogrel with aspirin (Vermeer F, Vahanian A, Fels P.W, 2000. pp 233). These findings suggest that alternative antiplatelet agents are likely to play a significant role in the treatment of acute events of cardiovascular disease and other acute diseases like arthritis. It is possible that the clinical benefits of alternative antiplatelet such as clopidogrel and other agents similar to it are likely to be even more profound in patients who have been termed as aspirin resistant and therefore said to be not benefiting from adequate antiplatelet inhibition. It can be argued that indeed, future treatment of aspirin resistance with additional antiplatelet agents may significantly improve the poor prognosis associated with the diagnosis (Vermeer et al 2000 pp 237).
There is still a lack of a widely accepted definition of aspirin resistance. This has worked in negative favor towards the efforts geared towards finding the strategy of dealing with the treatment of aspirin patients and also a barrier to determining the true extent of the problem. It has been widely noticed that depending on the assay used, the effect of aspirin non-responsiveness ranges between zero percent to 27 percent. This means that one can pony determine the aspirin resistance depending on that particular essay and also the definition of aspirin resistance that you start out with.
The concept of aspirin resistance is still poorly understood and many who work in cardiovascular health, suspect that the matter is more complicated than just the fact of having resistance or not. Experts have suggested that there should be a better understanding of this phenomenon especially because there are so many people who are in secondary preventive regimens and still have events.
In addition, the fact that those who exhibit aspirin resistance are at a higher risk of cardiovascular events means that there is a need to develop and work on a large prospective randomized ad clinical trials aimed at a better assessment of aspirin resistance testing. There should also be a determination of the stability of this phenomenon over time and also measurement of the effect of changing medication regimens in response to it (Vermeer et al 2000 pp 238).
It has generally been agreed that “doctors should continue with their current practice in prescribing aspirin for chronic therapy to prevent adverse cardiovascular events as the overall risk reduction is well reported.”
Another strategy towards dealing with aspirin resistance saw the launching of aspirin works tests in the united states of America in June 20007 following an FDA 510k clearance. This test is now available in the European major medical reference laboratories. This test measures the effect of aspirin in the platelet through direct measurement of thromboxane production (aspirin target). The less it stickles to the blood platelets, the less effect the aspirin is having.
The aspirin works test kit is an enzyme-linked immunoassay (Elisa) to determine levels of II-Dehydro thromboxane B2 (IIdhTxB2) in human urine, which aids in both the qualitative and quantitative detection of aspirin effect in apparently healthy individuals post-ingestion. This test is most appropriate and most preferred because unlike other platelet aggregation tests, which require freshly drawn blood that must be evaluated within at least four hours, the aspirin works test requires a urine sample that is easy to be obtained in any doctor’s office.
In most cases, aspirin resistance has been widely used to refer to or describe the inability of aspirin to protect patients from ischemic vascular events. This particular inability of aspirin is also referred to as clinical aspirin resistance. However, this definition is so broad and general in that it is non-specific and could apply to many other various conditions.
Bearing in mind that not all vascular conditions can be prevented by any style of preventive strategy,( including the use of aspirin) it is unrealistic to describe the inability of aspirin to protect patients as resistance.
Aspirin resistance has also been used to describe “the inability of aspirin to produce an anticipated effect on one or more tests of platelet function, for example, inhibiting the biosynthesis of thromboxane or inhibiting platelet aggregation and causing a prolongation of the bleeding time. This particular inability has been called biochemical aspirin resistance.
However, it is of great importance to note that the precise quantitative and qualitative abnormalities related to platelet function which for the basis of the definition of biochemical resistance has not been established, and on that same note, their clinical relevance has yet to be determined (Schror K. 1997, pp 345).
As a result of the above scenario, there are several different laboratory tests of platelet function that are being done which aim at diagnosing “biochemical” aspirin resistance (Schror K. 1997, pp 356). The above procedure has numerous milestones and the greatest being that each of these diagnostic tests has its own limitations, for instance, the aggregate test which uses the optical platelet aggregation method is widely available but however, it is not very specific.
Another limitation facing the definition and determination of the resistance of aspirin is the requirements and procedure to be taken while testing resistance. For instance, there are several requirements and procedures when one is for example adopting a laboratory measure for biochemical utility. This type of test or measure for biochemical resistance has to be associated consistently and independently with the occurrence of recurrent vascular events in patients taking the drug aspirin.
In addition, the procedure must be valid and very standardized. Moreover, clinical management should be altered and the alteration is in line with the results. Lastly, the overall benefits of testing should outweigh any adverse consequences and costs (Nosca L, 2002 pp 576).
A study was done while paying attention to the above-mentioned procedure and criterion showed that there was an independent and significant association between the failure of aspirin to suppress agonistic induced platelet aggregation and an increased risk of serious vascular events in 326 patients with coronary or cerebral vascular who were treated with aspirin. In this study, one major method of testing was used as the optical platelet aggregometry (Nosca L, 2002 pp 578).
The study also showed that there is a probability of up to 28 percent of future serious vascular events in high-risk vascular patients that will be attributed to the failure of aspirin to suppress Thromboxane production or platelet aggregation. The general observation of this study is that it tends to prove that there is a possibility of the existence of aspirin resistance or (aspirin non-responsiveness) (Nosca L, 2002 pp 578).
However, before aspirin resistance can be accepted as a valid clinical entity worth screening and treatment, all the steps in the criterion mentioned above must be followed or met. Even so, there has been a tendency in the recent past for medical researchers and authors to define aspirin resistance as “ the lack of anticipated response to a therapeutic dose of aspirin(75 – 150mgs per day for at least five days for a compliant patient) that can be demonstrated by a specific, valid and viable laboratory measures of the antiplatelet effects of aspirin and which co-relates significantly and consistently with an increased incidence of antithrombotic vascular events” (Gum P.A, Kottke-Marchant K, Poggio 2001 pp 237).
Lastly, it can be noted that most of the drugs which would have been found alongside aspirin in most pharmacies have long since disappeared, and have been replaced by newer and more effective drugs (Gum P. et al 2001 pp 240). But aspirin goes from strength to strength. And given the pace of current research into new uses for the drug, it seems likely that it will still be available long into the next century.
In conclusion, we first start by saying that there is no generally agreed definition of the phenomenon currently referred to as aspirin resistance. This is aspirin failure to produce expected results in a predefined test can not be referred to as resistance, but rather aspirin failure.
Secondly, many tests have been performed by various groups concerning the genetic and non-genetic causes of aspirin and also its clinical importance, so far there is yet to be found, any direct relationship between the genes processes and aspirin resistance. In addition, the clinical relevance of all the tests of aspirin resistance is yet to be backed up by evidence of its clinical importance.
Thirdly, many doctors and researchers have agreed that increasing aspirin doses to patients is more unethical and dangerous especially now that its benefits in the patient have not yet been established. In addition, many doctors recommend that patients using aspirin should not be subjected to the option of choosing to be tested for aspirin resistance as this may only increase their panic, or even make them believe lies in the effectiveness of aspirin. They, therefore, recommend that doctors should continue to give normal prescriptions of aspirin to their patients or gauge the benefits of recommending alternative drugs.
Lastly, general observation shows that aspirin will remain the commonly and widely used drug especially for the primary and secondary treatment of patients with cardiovascular disease and other diseases like arthritis in the foreseeable future. There is, therefore, a need for increased efforts in research in terms of increased manpower, resources, and time towards dealing with aspirin resistance.
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