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Antiplatelet agents are an integral part of the treatment of patients with various presentations of atherothrombosis. Among all drugs in this group, acetylsalicylic acid has the broadest evidence base. This review is devoted to the prescription of acetylsalicylic acid for the primary prevention of vascular complications in patients without clinically apparent atherosclerosis. Current approaches to the risk stratification of ischemic events and determination of indications for such treatment are discussed. Primary prevention trials have been focused on the risk assessment scales, the prognostic value of which raises many questions. In this context, besides the traditional (classical) factors underlying these scales, it is reasonable to take into account the so-called “risk modifiers” that can affect the likelihood of CVC. The coronary artery calcium score is one of the strongest risk modifiers. The characteristics of key primary prevention trials, which included patients of different ages with various risk factors, are provided. In accordance with the current guidelines of European and Russian expert communities, the acetylsalicylic acid may be prescribed to individuals with a high risk of vascular complications, among which the best evidence base is available for patients with diabetes mellitus. The positive effects of antiplatelet treatment have been demonstrated to be maintained in the settings of modern therapy with a proven positive effect on the prognosis. A particular focus has been placed on minimizing bleeding. The correct assessment and correction of modifiable hemorrhagic risk factors, the use of drugs to protect the stomach, and the appointment of acetylsalicylic acid in the minimum effective dosage of 75 mg per day are called upon to increase the safety of treatment. A preference in favour of uncoated forms that are absorbed in the stomach for obese and diabetic patients may be discussed.
To date, a sufficient volume of clinical studies has been accumulated that have demonstrated a reduced antiplatelet effect of enteric-coated (EC) lowdose acetylsalicylic acid (ASA). Delayed and incomplete absorption from the intestinal alkaline medium, which significantly reduces the bioavailability of drug, is considered the main reason for laboratory aspirin resistance (pseudoresistance) to EC ASA. This phenomenon is of particular importance for patients with acute coronary syndrome, when a quick effect is required, as well as for patients with diabetes and obesity due to additional causes of increased platelet activity, on the one hand, and reduced bioavailability of ASA, on the other. Given the issue of efficacy, the dubious gastroprotective effect and the more pronounced damaging effect on the mucous membrane of small intestine, the use of EC ASA should be avoided, especially in patients with a multifactorial risk of insufficient response to therapy. A good alternative is buffered ASA, which quickly dissolves and is partially absorbed directly in the stomach, having antiplatelet activity comparable to simple ASA and a similar aspirin resistance, is associated with a lower risk of aspirin-induced enteropathy in comparison with ES ASA. In addition, according to a number of small studies and retrospective analyzes, buffered ASA is less likely to cause damage to gastric mucosa compared to EC ASA.
Aspirin and paracetamol (acetaminophen) are the most commonly used minor analgesics, but their effects on the gastrointestinal tract differ widely. The effects of other nonsteroidal anti-inflammatory drugs (NSAIDs), including phenylbutazone, are intermediate. Aspirin is significantly associated with major upper gastrointestinal haemorrhage, whereas paracetamol is not. Short term use of aspirin produces erythema, erosions and occasionally ulcers; paracetamol does not, while other NSAIDs do so to varying degrees. Chronic gastric ulcer is linked to aspirin intake in patients with rheumatic disease, and epidemiologically in all heavy aspirin users. In only one epidemiological study was a paradoxical significant association reported between paracetamol intake and chronic gastric ulcer. Faecal occult blood loss is increased in most regular aspirin users but not in those taking paracetamol. Although formal studies in children have apparently not been made, in isolated small clinical series it has been reported that gastrointestinal bleeding and anaemia do occur in the paediatric age group after the use of aspirin. Pathophysiologically, aspirin alters the gastric mucosal barrier to hydrogen ions and lowers gastric potential difference; paracetamol has no effect on these parameters. Such changes correlate ultrastructurally with damage in surface epithelial cells and microerosions after the use of aspirin, but not after the use of paracetamol. Aspirin and other NSAIDs cause a dramatic reduction in the ability of gastric mucosa to generate protective prostaglandins; however, paracetamol also reduces prostaglandins. Other postulated mechanisms of aspirin damage include reduction in gastric mucosal secretion, reduction in bicarbonate output, and alteration of cell turnover. Because damage to gastric mucosa by aspirin and NSAIDs is often 'silent', the clinician needs a high level of suspicion and awareness regarding this problem. In patients prone to gastric damage, or in those with a past history of aspirin-induced gastric damage, paracetamol is the drug of choice when a minor, non-inflammatory problem requires an analgesic.
Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross-over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were:
Most of the formulations yield mean residence times for ASA of 0.3–1.0h, which do not differ significantly (p > 0.05). For most of the products the first-pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first-pass effect, are about 201 and 650 ml min−1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro-intestinal absorption with pharmacokinetic model parameters, because the first-pass effect is large and often elimination of ASA is faster than absorption. The model-independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way.
No significant differences in the values of the parameters are found between most of the formulations. The ASA first-pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under ‘artificial mistakes’.
Aspirin and paracetamol (acetaminophen) are the most commonly used minor analgesics, but their effects on the gastrointestinal tract differ widely. Aspirin is significantly associated with major upper gastrointestinal hemorrhage, whereas acetaminophen is not. Short-term use of aspirin produces erythema, erosions, and occasionally ulcers; acetaminophen use does not. Chronic gastric ulcer is linked to aspirin intake in patients with rheumatic disease, and epidemiologically in all heavy aspirin users; paradoxically, in only one epidemiologic study was a significant association found between acetaminophen intake and chronic gastric ulcer. Fecal occult blood loss is increased in most regular aspirin users but not in those taking acetaminophen. Although studies in children have not apparently been made, in isolated small clinical series it has been shown that gastrointestinal bleeding and anemia do occur in the pediatric age group following the use of aspirin. Pathophysiologically, aspirin alters the gastric mucosal barrier to hydrogen ions and lowers gastric potential difference; acetaminophen has no effect on these parameters. Such changes correlate ultrastructurally with damage in surface epithelial cells and microerosions after the use of aspirin, but not after the use of acetaminophen. Aspirin causes a dramatic reduction in the ability of gastric mucosa to generate protective prostaglandins; however, acetaminophen also reduces prostaglandins. Other postulated mechanisms of aspirin damage include reduction in gastric mucosal secretion, bicarbonate output, and alteration of cell turnover. Because aspirin damage to gastric mucosa is often "silent," the clinician needs a high level of suspicion and awareness. In patients prone to gastric damage, or in those with a past history of aspirin-induced gastric damage, acetaminophen is the drug of choice when a minor, noninflammatory problem requires an analgesic.
Acetylsalicylic acid (ASA) inhibition of platelet aggregation as evaluated by collagen-induced 14C-serotonin release, has been measured in 12 healthy male subjects. Each subject received a single oral dose (650 mg) of enteric-coated ASA (ecASA) and compressed ASA tablets (cASA), or ecASA and sodium salicylate (578 mg) separated by a minimum of 5 weeks. The platelet response was related to plasma ASA and salicyclic acid determined by high-pressure liquid chromatography. Both ecASA and cASA inhibited 14C-serotonin release; no significant difference was observed in the maximum effect between these two products (p less than 0.05). No relationship was found between the maximum observed plasma ASA level and the maximum effect. Further, no correlation was found between the maximum inhibition of 14C-serotonin release in vivo and the release predicted from in vitro experiments wherein the effect was measured after incubating plasma containing specified ASA concentrations.
The effect of a saline cathartic combined with activated charcoal or activated charcoal alone on aspirin bioavailability was characterized in six healthy volunteers. Using a random, Latin-square design, subjects were given 975 mg aspirin followed by either water alone, 15 Gm activated charcoal (AC), or 15 Gm activated charcoal plus 20 Gm sodium sulfate (AC + SS) separated by one week. Both AC (44.16 +/- 16.85 microgram/ml) and AC + SS (58.61 +/- 10.63 microgram/ml) decreased (P less than 0.001) the maximal plasma salicylate concentration (Cpmax) compared to control (86.61 +/- 12.69 microgram/ml). Urinary salicylate recovery was decreased (P less than 0.01) for AC (57.88 +/- 16.26 per cent) and AC + SS (61.00 +/- 11.49 per cent) as compared to control (93.73 +/- 6.83 per cent), while for area under the plasma concentration-time curve (AUC) only AC showed a decrease (P less than 0.01) compared to control. Neither AC nor AC + SS differed from each other for Cpmax, AUC, or cumulative urinary recovery. Our findings indicate that the addition of sodium sulfate to activated charcoal has no added effect on limiting aspirin adsorption relative to activated charcoal alone.
Aspirin causes gastroduodenal erosions and/or ulcers in man when taken for prolonged periods. The effects of shorter periods of aspirin, Bufferin, or paracetamol (acetaminophen) intake as used for self-medication are unknown. In a four way, crossover, blinded endoscopic study, we compared the effects of aspirin, Bufferin, paracetamol, and placebo, two tablets four times a day for 24 hours, on the gastroduodenal mucosa of 10 normal volunteers. Both regular aspirin and bufferin produced multiple gastric (p less than 0.005) and duodenal erosions (p less than 0.05, compared with baseline and placebo studies). Paracetamol did not cause significant gastric or duodenal mucosal damage. Two subjects developed duodenal ulcer-like lesions in the course of the study. We conclude that the use of unbuffered aspirin and Bufferin, but not paracetamol, in recommended doses for one day causes significant gastroduodenal mucosal damage.
The bioavailability of aspirin gum relative to unbuffered aspirin tablets was determined in six normal volunteers. Twenty-four hours following the administration of two aspirin tablets, 91.2 +/- 1.7% (SE) of the 648-mg dose was recovered in the urine. The relative bioavailability of aspirin gum was 69.5 +/- 3.4% (SE), based on cumulative 4-hr urinary excretion of total salicylate after the chewing of three gum tablets for 15 min. The chewed gum was analyzed for total salicylate and contained an average of 37.8% of the administered dose. When added to the cumulative amount of total salicylate excreted in the urine at 24 hr after dosing, the salicylate contained in the chewed gum accounted for essentially 100% of the dose administered. Chewing aspirin gum for up to 30 min did not significantly (p greater than 0.05) reduce the amount of salicylate entrapped in the gum base when compared to chewing times of 5, 10, and 15 min. Based on the results of this study, four pieces of aspirin gum would be needed to provide the same amount of salicylate to the general circulation as two 324-mg aspirin tablets.
A graphite furnace atomic absorption spectrophotometric assay capable of accurately determining nanogram amounts of gold in biological fluids was developed. The presence of bovine serum albumin and/or phosphate in the sample reduced the method sensitivity without affecting the linear response. Binding of gold was studied by ultrafiltration using cones with a molecular weihght cutoff of 25,000. The binding of gold at various concentrations to 2 and 4% bovine serum albumin in 0.1 M phosphate buffer, pH 7.4, was independent of the gold and protein concentrations. In the 2-10 microgram/ml range, the overall binding values (mean +/- SD) of gold to 2 and 4% bovine serum albumin were 98 +/- 1.6 (n = 35) and 99 +/- 1.0% (n = 15), respectively. When ultrafiltration cones with a molecular weight cutoff of 50,000 were used, the extent of binding to 2% bovine serum albumin was 85.4 +/- 1.6% (n=11). This statistically significant difference (p less than 0.001) was due to variations in the protein retention of the two cone types. Interaction studies showed that gold was not displaced from the binding sites by salicylic acid (200 microgram/ml) or vice versa.
TIS10 is a primary response gene whose cDNA was cloned as a result of its rapid, superinducible expression in Swiss 3T3 cells in response to 12-O-Tetradecanoylphorbol-13-acetate. The 5'-untranslated region of the 3.9-kilobase TIS10 message contains only 124 nucleotides, whereas the 3'-untranslated region is almost 2 kilobases in length. Within this long 3' region, there are multiple repeats of the sequence ATTTA, a sequence often present in rapidly degraded mRNA species. Primer extension revealed that the TIS10 cDNA begins 16 base pairs downstream of the transcription start site for the TIS10 gene. The TIS10 cDNA encodes a predicted protein of 604 amino acids. A computer search identified striking similarities between the predicted TIS10 protein product and the murine, sheep, and human prostaglandin synthase/cyclooxygenase proteins. The TIS10 protein has many of the same conserved amino acids that are thought to be important for cyclooxygenase function. TIS10 mRNA is undetectable by Northern analysis in quiescent 3T3 cells. The TIS10 gene is rapidly and transiently induced by forskolin and serum, as well as by 12-O-tetradecanoylphorbol-13-acetate, in Swiss 3T3 cells. These agents elicit far more dramatic changes in TIS10 mRNA levels than in cyclooxygenase mRNA levels. The expression of the TIS10 gene appears to be highly cell type-restricted in cultured cell lines; of 12 cell lines tested under superinducing conditions, only the rodent embryonic Swiss 3T3 and Rat1 cell lines expressed TIS10 gene.
Background
Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension.
Methods
18 790 patients, from 26 countries, aged 50–80 years (mean 61·5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure ⩽90 mm Hg, 6264 to ⩽85 mm Hg, and 6262 to ⩽80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo.
Findings
Diastolic blood pressure was reduced by 20·3 mm Hg, 22·3 mm Hg, and 24·3 mm Hg, in the ⩽90 mm Hg, ⩽85 mm Hg, and ⩽80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82·6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86·5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group ⩽80 mm Hg compared with target group ⩽90 mm Hg (p for trend=0·005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0·03) and all myocardial infarction by 36% (p=0·002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0·001).
Interpretation
Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82·6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common.
Prostaglandin endoperoxide synthase-1 [prostaglandin G/H synthase-1 (PGHS-1)] and PGHS-2 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids. We refer to these isoforms as cyclooxygenase-1 (COX-1) and COX-2 in this review. This brief review focuses on recent developments in the study of these enzymes. Alterations in the expression levels of COX-2 result in distinct phenotypic changes in intestinal epithelial cells. Overexpression of COX-2 in intestinal epithelial cells results in increased adhesion to extracellular matrix proteins and inhibition of apoptosis. Disruption of the COX-2 gene in mice results in renal dysplasia, cardiac fibrosis, and defects in the ovary. Interestingly, disruption of the COX-1 gene results in distinct phenotypic changes different from those observed for COX-2. COX-1 null mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice. These two closely related enzymes must have distinct functions in the organisms, since lack of their expression causes distinct phenotypic changes for each respective isoform.
From 1979 to 1985,2435 patients thought to have had a transient ischaemic attack or minor ischaemic stroke were allocated at random to receive long term blind treatment with either aspirin 600 mg twice daily (n=815), aspirin 300 mg once daily (806), or placebo (814). Treatment continued with about 85% compliance until September 1986 (mean four years). The odds of suffering one or more of four categories of event namely, non-fatal myocardial infarction, non-fatal major stroke, vascular death, or non-vascular death-were 18% less in the two groups aliocated to receive aspirin than in the group allocated to receive placebo (2p=0.01). The more relevant but less frequent composite event of disabling stroke or vascular death was reduced by only 7%; this reduction was not significantly different from zero, but nor was it significantly different from a 25% reduction. There was no definite difference between responses to the 300 mg and 1200 mg daily doses, except that the lower dose was significantly less gastrotoxic. © 1988, British Medical Journal Publishing Group. All rights reserved.
Background.
Aspirin is known to improve the outcome of patients who have had a cerebral transient ischemic attack, but the optimal dose of aspirin remains uncertain. Experimental evidence indicates that 30 mg of aspirin daily alters platelet aggregation more favorably than the 300-mg dose currently used in patients after transient ischemic attack or minor ischemic stroke.
Methods.
We assessed the effects of two doses of a water-soluble preparation of acetylsalicylic acid, or aspirin (30 mg vs. 283 mg a day), on the occurrence of death from all vascular causes, nonfatal stroke, or nonfatal myocardial infarction in a double-blind, randomized, controlled clinical trial in patients who had had a transient ischemic attack or minor stroke. A total of 3131 patients participated in the study. The mean follow-up was 2.6 years.
Results.
In the group assigned to receive 30 mg of aspirin, the frequency of death from vascular causes, nonfatal stroke, or nonfatal myocardial infarction was 228 of 1555 (14.7 percent), as compared with 240 of 1576 (15.2 percent) in the group assigned to receive 283 mg. The age- and sex-adjusted hazard ratio for the group receiving the lower dose was 0.91 (95 percent confidence interval, 0.76 to 1.09). There were slightly fewer major bleeding complications in the 30-mg group than in the 283-mg group (40 vs. 53), and significantly fewer reports of minor bleeding (49 vs. 84). Fewer patients receiving 30 mg of aspirin reported gastrointestinal symptoms (164 vs. 179) and other adverse effects (73 vs. 90).
Conclusions.
Our data indicate that 30 mg of aspirin daily is no less effective in the prevention of vascular events than a 283-mg dose in patients with a transient ischemic attack or minor stroke, and has fewer adverse effects. (N Engl J Med 1991;325:1261–6.)
In 1988, we undertook a randomized, placebo-controlled, double-blind trial to investigate the safety and efficacy of low-dose acetylsalicylic acid (ASA), modified-release dipyridamole, and the two agents in combination for secondary prevention of ischemic stroke. Patients with prior stroke or transient ischemic attack (TIA) were randomized to treatment with ASA alone (50 mg daily), modified-release dipyridamole (400 mg daily), the two agents in a combined formulation, or placebo. Primary endpoints were stroke, death, and stroke or death together. TIA and other vascular events were secondary endpoints. Patients were followed on treatment for two years. Data from 6602 patients were analysed. Factorial analysis demonstrated a highly significant effect for ASA and for dipyridamole in reducing the risk of stroke (p ≤0.001) and stroke or death combined (p <0.01). In pairwise comparisons, stroke risk in comparison to placebo was reduced by 18% with ASA alone (p = 0.013); 16% with dipyridamole alone (p = 0.039); and 37% with combination therapy (p <0.001). Risk of stroke or death was reduced by 13% with ASA alone (p = 0.016); 15% with dipyridamole alone (p = 0.015); and 24% with the combination (p <0.001). The treatment had no statistically significant effect on the death rate alone. Factorial analysis also demonstrated a highly significant effect of ASA (p <0.001) and dipyridamole (p <0.01) for preventing TIA. The risk reduction for the combination was 36% (p <0.001) in comparison with placebo. Headache was the most common adverse event, occurring more frequently in dipyridamole-treated patients. All-site bleeding and gastrointestinal bleeding were significantly more common in patients who received ASA in comparison to placebo or dipyridamole. We conclude that 1. ASA 25 mg twice daily and dipyridamole, in a modified-release form, at a dose of 200 mg twice daily have each been shown to be equally effective for the secondary prevention of ischemic stroke and TIA; 2. When co-prescribed the protective effects are additive, the combination being significantly more effective than either agent prescribed singly; 3. low-dose ASA does not eliminate the propensity for induced bleeding.
