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PubMed2001

Does aspirin attenuate the effect of angiotensin-converting enzyme inhibitors in hypertension or heart failure?

There is a wealth of data that suggests an important interaction between aspirin and angiotensin-converting enzyme inhibitors in patients with chronic stable cardiovascular disease. The interaction is less obvious in the postinfarction setting, possibly reflecting the fact that many patients stop their aspirin therapy within a few months of such an event. An interaction is biologically plausible, because there is considerable evidence that angiotensin-converting enzyme inhibitors exert important effects through increasing the production of vasodilator prostaglandins, whereas aspirin blocks their production through inhibition of cyclooxygenase, even at low doses. There is some evidence that low-dose aspirin may raise systolic and diastolic blood pressure. There is also considerable evidence that aspirin may entirely neutralize the clinical benefits of angiotensin-converting enzyme inhibitors in patients with heart failure. In addition, aspirin may have an adverse effect on outcome in patients with heart failure that is independent of any interaction with angiotensin-converting enzyme inhibitors, possibly by blocking endogenous vasodilator prostaglandin production and enhancing the vasoconstrictor potential of endothelin. The evidence is not sufficient to justify advising long-term aspirin therapy for patients with cardiovascular disease in general, and for those with heart failure in particular. Thus, the lack of evidence of benefit with aspirin in patients with heart failure and coronary disease, along with growing evidence that aspirin is directly harmful in patients with heart failure and that aspirin may negate the benefits of angiotensin-converting enzyme inhibitors suggest that, unless there is an opportunity to randomize the patient into a study of antithrombotic strategies, then aspirin should be withdrawn or possibly substituted with an anticoagulant or an antiplatelet agent that does not block cyclooxygenase. In contrast, there is fairly robust evidence for a benefit of both aspirin and angiotensin-converting enzyme inhibitors during the first 5 weeks after a myocardial infarction, with little evidence of an interaction. The combination of aspirin and angiotensin-converting enzyme inhibitors is warranted during this period, after which discontinuation or substitution of aspirin with another agent should be considered.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Low dose aspirin: selective inhibition of rectal dialysis thromboxane B2 in healthy volunteers.

AIM: To investigate the degree and selectivity of rectal thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet thromboxane to rectal thromboxane. METHODS: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B4 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of thromboxane B2, leukotriene B4, prostaglandin E2, and serum thromboxane B2 were measured by radioimmunoassay. RESULTS: Dialysate thromboxane B2 levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95% CI: 0.79-1.43 ng/ml) on placebo, by 29% (95% CI: 11-40%) to 0.75 ng/ml (0.56-1.01 ng/ml) (P = 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E2 was 1.47 ng/ml (0.97-2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leukotriene B4 was 0.45 ng/ml (0.34-0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95% by plain aspirin 300 mg, and by 82% by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29% of the rectal thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4 is inhibited by low dose aspirin. We infer that 34% of the rectal thromboxane B2 is platelet-derived in our volunteers. CONCLUSION: Low dose aspirin will selectively inhibit a proportion of rectal thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.

Adult↗
PubMed2004

Concomitant use of buffered and enteric-coated low-dose aspirin products and antisecretory drugs.

OBJECTIVE: Buffered and enteric-coated formulations of low-dose aspirin therapy are although expected to avoid gastrointestinal complications, there are reports that these modified products are associated with such complications. One available option for preventing aspirin-induced gastrointestinal complications is the simultaneous use of the agents that inhibit acid secretion such as H(2)-receptor antagonists and proton pump inhibitors. We compared the frequency of prescriptions for antisecretory drugs between users of either buffered or enteric-coated low-dose aspirin. METHODS: Monthly prescriptions at the National Cardiovascular Center for aspirin products and antisecretory drugs were counted from January 1998 to December 2002. Counting was based on information from a prescription database file compiled from a computerized order entry system. Time-series analyses were performed to determine changes in the frequency of prescriptions for low-dose aspirin products and antisecretory drugs. In addition, the frequency of prescriptions for antisecretory drugs was compared in individuals using either buffered or enteric-coated low-dose aspirin. RESULTS: A significant reduction in the frequency of prescriptions for H(2)-receptor antagonists was observed during 2001 in users of enteric-coated low-dose aspirin compared with users of buffered low-dose aspirin users. In contrast, we observed a significant increase in the frequency of prescriptions for H(2)-receptor antagonists in users of enteric-coated low-dose aspirin during 2002. This change in prescribing H(2)-receptor antagonists in users of enteric-coated low-dose aspirin began in the latter half of 2001. Proton pump inhibitors accounted for 0.31% of prescriptions in users of buffered low-dose aspirin and 0.47% in users of enteric-coated low-dose aspirin, with this difference being statistically significant. CONCLUSION: The findings of the present study do not support the notion that enteric-coated low-dose aspirin reduces the risk of gastrointestinal complications and is safer than buffered low-dose aspirin products. However the usual caution about making inferences from observational retrospective data is appropriate.

Administration, Oral↗
PubMed1997

Effects of aspirin on nitric oxide formation and de novo protein synthesis by RINm5F cells and rat islets.

Aspirin and aspirin-like drugs are the most commonly indicated agents for the treatment of inflammation. Mechanisms of action for these drugs, however, are not clearly understood. In this study, we examined the effects of aspirin on production of nitric oxide (NO), a proinflammatory mediator, and show that aspirin inhibits NO production by transformed pancreatic beta cells (RINm5F) and rat islets in a concentration-dependent manner with an IC50 value of approximately 3 mM. Therapeutic concentrations of aspirin (1-5 mM) that block NO production affected neither nuclear factor-kappaB activation nor inducible NO synthase (iNOS) mRNA transcription but potently inhibited iNOS protein expression by both RINm5F cells and rat islets. The effects of aspirin on islet function were examined by measuring glucose-stimulated insulin secretion in the presence of various concentrations of aspirin. Aspirin (1-5 mM) did not affect insulin secretion at basal or glucose-stimulated conditions, whereas higher concentrations of aspirin (10-20 mM) significantly increased basal insulin secretion. Aspirin at high concentrations of 10 and 20 mM inhibited de novo protein synthesis as demonstrated by inhibition of [35S]methionine incorporation into total islet protein and by inhibition of rabbit reticulocyte expression by Brome mosaic virus mRNA, suggesting that inhibition of iNOS expression at these high concentrations of aspirin may be due to the impairment of the translational machinery. These findings indicate that inhibition of iNOS expression and NO production may explain, in part, the beneficial effects of aspirin as an anti-inflammatory agent at therapeutic concentrations, whereas inhibition of de novo protein synthesis may possibly explain clinical and side effects of aspirin in the inflamed tissues and organs such as stomach and kidney that may accumulate high concentrations of aspirin.

Animals↗
PubMed1991

Starting aspirin therapy after operation. Effects on early graft patency. Department of Veterans Affairs Cooperative Study Group.

BACKGROUND: Although aspirin therapy started before operation improves vein graft patency after coronary artery bypass grafting, it also causes bleeding. The objective of this prospective, centrally directed, randomized, double-blind, placebo-controlled trial was to compare the effects of aspirin therapy started before operation with aspirin started 6 hours after operation on early (7-10-day) graft patency. METHODS AND RESULTS: Patients were randomized to receive either aspirin 325 mg or placebo the night before surgery; after operation, all patients received aspirin 325 mg daily, with the first dose administered through the nasogastric tube 6 hours after operation. Angiography was performed in 72% of the analyzed patients an average of 8 days after operation, and the primary end point was saphenous vein graft patency in 351 patients. Internal mammary artery graft patency was also assessed in 246 patients because many individuals received both internal mammary artery and vein grafts. In the patients given preoperative aspirin, the vein graft occlusion rate was 7.4 +/- 1.3% compared with 7.8 +/- 1.5% in those who received preoperative placebo (p = 0.871). In the subgroup of patients receiving Y grafts, 0.0% of the grafts were occluded in the preoperative aspirin group compared with 7.0 +/- 3.6% in the preoperative placebo group (p = 0.066). The internal mammary artery occlusion rate was 0.0% (0 of 131) in the aspirin group compared with 2.4 +/- 1.4% (three of 125) in the placebo group (p = 0.081). Patients in the aspirin group received more transfusions than those in the placebo group (median, 900 versus 725 ml, p = 0.006). The reoperation rate for bleeding in the aspirin group was 6.3% compared with 2.4% in the placebo group (p = 0.036). Median chest tube drainage within the first 6 hours after operation was 500 ml in the aspirin group compared with 448 ml in the placebo group (p = 0.011). CONCLUSIONS: Thus, preoperative aspirin is associated with increased bleeding complications and offers no additional benefit in early vein graft patency compared with starting aspirin therapy 6 hours after operation. There was a trend, although not significant, toward improved early patency for Y grafts and internal mammary artery grafts with preoperative aspirin.

Aged↗
PubMed1998

Aspirin use and incident stroke in the cardiovascular health study. CHS Collaborative Research Group.

BACKGROUND AND PURPOSE: Randomized clinical trials testing aspirin in relatively low-risk, middle-aged people have consistently shown small increases in stroke associated with aspirin use. We analyzed the relationship between the regular use of aspirin and incident ischemic and hemorrhagic stroke among people aged 65 years or older participating in the Cardiovascular Health Study. METHODS: We conducted a multivariate analysis of incident stroke rates in a prospectively assessed, observational cohort of 5011 elderly people followed for a mean of 4.2 years. RESULTS: Participants had a mean age of 72 years, and 58% were women. Twenty-three percent used aspirin frequently, and 17% used aspirin infrequently at study entry. Frequent aspirin use was associated with an increased rate of ischemic stroke compared with nonusers (relative risk= 1.6; 95% confidence interval [CI], 1.2 to 2.2; P=0.001). After adjustment for other stroke risk factors, women who used aspirin frequently or infrequently at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95% CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively (P<0.01, test for trend), compared with nonusers. In men, aspirin use was not statistically significantly associated with stroke risk. Findings were similar when aspirin use in the years before the incident stroke was used in the modeling. Aspirin use at entry was also associated with a 4-fold (95% CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both infrequent and frequent users of aspirin (P=0.003). CONCLUSIONS: Aspirin use was associated with increased risks of ischemic stroke in women and hemorrhagic stroke overall in this elderly cohort, after adjustment for other stroke predictors. The possibility exists of confounding by reasons for aspirin use rather than cause and effect. Whether regular aspirin use increases stroke risk for elderly people without cardiovascular disease can only be determined by randomized clinical trials.

Aged↗
PubMed1992

Urinary leukotriene E4 after lysine-aspirin inhalation in asthmatic subjects.

The FEV1 and urinary leukotriene E4 (LTE4) concentrations were determined in six aspirin-sensitive and six non-aspirin-sensitive asthmatic subjects before and after inhalation challenge with lysine-aspirin or placebo solution. Lysine-aspirin produced a mean fall in FEV1 of 26.7 +/- 4.9% (mean +/- SEM) in subjects with aspirin sensitivity and of 8.5 +/- 6.5% (mean +/- SEM) in non-aspirin-sensitive asthmatic subjects. The mean baseline urinary LTE4 concentration of 83 pg/mg creatinine (geometric mean [GM], range 15 to 326 pg/mg creatinine) in aspirin-sensitive subjects was significantly higher than the 33.8 pg/mg creatinine (GM, range 10 to 111 pg/mg creatinine) in non-aspirin-sensitive subjects (p = 0.02). In aspirin-sensitive subjects, inhalation challenge with lysine-aspirin produced a significant increase in urinary LTE4 concentration to 240 pg/mg creatinine (GM, range 60 to 1,113 pg/mg creatine), which was not observed after placebo challenge. There was no significant change in urinary LTE4 concentration after inhalation challenge with either lysine-aspirin or placebo solution in non-aspirin-sensitive asthmatic subjects. Thus, sulfidopeptide leukotrienes are released after inhalation of lysine-aspirin in aspirin-sensitive asthmatic patients.

Administration, Inhalation↗
PubMed1999

Interaction of ACE inhibitors and aspirin in patients with congestive heart failure.

The beneficial effects of aspirin and ACE inhibitors in CHF have been well established; however, the clinical relevance of the drug interaction between these agents remains controversial. The exact mechanism of this interaction is not known, but the proposed theory involves the opposing effects of aspirin and ACE inhibitors on prostaglandins. The medical literature dose not provide a clear picture of the clinical significance of concomitant aspirin and ACE inhibitor therapy. Some studies suggest that the dose of aspirin may influence the clinical relevance of this interaction. Short-term use of aspirin > or = 300 mg was found to attenuate enalapril's effect on hemodynamic variables. However, short-term use of low-dose aspirin (236 mg) produced no effect on blood pressure. Patients with CHF who require therapy with both aspirin and ACE inhibitors may want to consider low doses of aspirin with active monitoring of hemodynamic parameters. However, chronic aspirin therapy in patients with CHF on concomitant ACE inhibitors has not been adequately studied at this time. Data concerning a possible interaction between angiotensin II receptor antagonists and aspirin are not available. However, because angiotensin II receptor antagonists do not interfere with kininase II activity, it would seem unlikely that aspirin would interact similarly with an angiotensin II receptor antagonist. Further studies are needed to examine the exact mechanism of the interaction between aspirin and ACE inhibitors. These studies should focus on the effects of different doses of aspirin given concomitantly with ACE inhibitors in patients with CHF. Prospective, randomized studies are also needed to determine the long-term effects of aspirin and ACE inhibitor therapy on mortality in patients with CHF.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Aspirin resistance: possible roles of cardiovascular risk factors, previous disease history, concomitant medications and haemorrheological variables.

BACKGROUND AND OBJECTIVE: Recent studies have described the incidence (approximately one in eight high-risk patients will experience a further atherothrombotic event over a 2-year period) of aspirin (acetylsalicylic acid) resistance and its possible background. The aim of this study was to compare the characteristics (risk profile, previous diseases, medications and haemorrheological variables) of patients in whom aspirin provided effective platelet inhibition with those in whom aspirin was not effective in providing platelet inhibition. METHODS: 599 patients with chronic cardio- and cerebrovascular diseases (355 men, mean age 64 +/- 11 years; 244 women, mean age 63 +/- 10 years) taking aspirin 100-325 mg/day were included in the study. Blood was collected between 8:00am and 9:00am from these patients after an overnight fast. The cardiovascular risk profiles, history of previous diseases, medication history and haemorrheological parameters of patients who responded to aspirin and those who did not were compared. Platelet and red blood cell (RBC) aggregation were measured by aggregometry, haematocrit by a microhaematocrit centrifuge, and plasma fibrinogen by Clauss' method. Plasma and whole blood viscosities were measured using a capillary viscosimeter. RESULTS: Compared with aspirin-resistant patients, patients who demonstrated effective aspirin inhibition had a significantly lower plasma fibrinogen level (3.3 g/L vs 3.8 g/L; p < 0.05) and significantly lower RBC aggregation values (24.3 vs 28.2; p < 0.01). In addition, significantly more patients with effective aspirin inhibition were hypertensive (80% vs 62%; p < 0.05). Patients who had effective platelet aggregation were significantly more likely to be taking beta-adrenoceptor antagonists (75% vs 55%; p < 0.05) and ACE inhibitors (70% vs 50%; p < 0.05), whereas patients with ineffective platelet aggregation were significantly more likely to be taking HMG-CoA reductase inhibitors (statins) [52% vs 38%; p < 0.05]. Use of statins remained an independent predictor of aspirin resistance even after adjustment for risk factors and medication use (odds ratio 5.92; 95% CI 1.83, 16.9; p < 0.001). CONCLUSIONS: The mechanisms underlying aspirin resistance are multifactorial. Higher fibrinogen concentrations increase RBC aggregation and can also result in increased platelet aggregation. The higher rate of hypertension in patients with effective platelet aggregation on aspirin could explain the differences in beta-adrenoceptor antagonist and ACE inhibitor use between these patients and aspirin-resistant patients. Furthermore, an additive effect of these drugs may contribute to effective antiplatelet therapy. It is also possible that drug interactions with statins might reduce aspirin bioavailability and/or activity, thereby reducing platelet inhibition in aspirin-resistant patients.

Adrenergic beta-Antagonists↗
PubMed1988

Aspirin in cardiovascular disease.

Although other mechanisms may be contributory, the antithrombotic properties of aspirin derive predominantly from its platelet-inhibitory effects. These are mediated via irreversible acetylation of platelet cyclo-oxygenase with subsequent blockade of platelet thromboxane synthesis. Long term administration of doses of aspirin as low as 20mg daily depresses platelet thromboxane formation by more than 90%; however, higher doses appear to be necessary to prevent thromboxane-dependent platelet activation in vivo. While there is evidence of biochemical selectivity with low doses of aspirin, significant reduction of the platelet-inhibitory eicosenoid, prostacyclin, occurs even at dosages ranging from 20 to 40mg daily. The ability of aspirin to prevent the occurrence or recurrence of vaso-occlusion has been extensively investigated. In the secondary prevention of myocardial infarction 7 placebo-controlled trials involving more than 15,000 patients have been completed. The dose of aspirin varied from 300 to 1500mg daily. Although none of the individual trials produced statistically significant reductions in total or coronary mortality, taken together the results are highly suggestive of a beneficial effect of aspirin. Similarly, 2 recent studies in patients with unstable angina demonstrated a protective effect of aspirin against acute myocardial infarction and death. While each study employed widely different doses of aspirin (324mg and 1250mg daily) similar reductions in mortality were reported. The effects of aspirin on the prevention of coronary artery bypass graft occlusion have been evaluated in 9 trials. Aspirin in doses of 100 to 975mg daily was shown to be of benefit in preventing early (less than 6 months) graft occlusion, particularly when therapy was started within 24 hours of operation. In patients with prosthetic vascular grafts of the lower limbs, aspirin has been shown to reduce platelet deposition, however further controlled trials will be required to establish the patient population most likely to benefit and, as in all these studies, the optimum dose of aspirin to employ. In patients with prosthetic heart valves it is clear that aspirin alone is insufficient to prevent thromboembolic complications and when administered as an adjunct to anticoagulant therapy it is associated with a high incidence of bleeding. In contrast, there is convincing evidence from several studies for the efficacy of aspirin in doses of 990 to 1300mg daily in the prevention of stroke and death in patients with transient ischaemic attacks.(ABSTRACT TRUNCATED AT 400 WORDS)

Aspirin↗
PubMed1998

Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians' Health Study.

BACKGROUND: In contrast to most observational studies, the randomized Physicians' Health Study found no association between aspirin use and colorectal cancer after 5 years. OBJECTIVE: To determine the effect of randomly assigned aspirin treatment and self-selected aspirin use on the incidence of colorectal cancer after 12 years and to identify factors influencing the self-selection of regular aspirin use. DESIGN: Randomized clinical trial and prospective cohort study. SETTING: Male physicians throughout the United States. PATIENTS: 22071 healthy male physicians who were 40 to 84 years of age in 1982. INTERVENTION: 325 mg of aspirin every other day. In 1988, the aspirin arm of the randomized trial was stopped early. Participants then chose to receive either aspirin or placebo for the rest of the study. MEASUREMENTS: Annual questionnaires asking about aspirin use and other variables, including occurrence of cancer. RESULTS: Colorectal cancer was diagnosed in 341 patients during the study period. Over 12 years of follow-up, random assignment to aspirin was associated with a relative risk for colorectal cancer of 1.03 (95% CI, 0.83 to 1.28). Various gastrointestinal symptoms and diagnoses were strong predictors of less frequent aspirin use in 1988. The relative risk for colorectal cancer in persons who used aspirin frequently after 1988 was 1.07 (CI, 0.75 to 1.53). CONCLUSIONS: In the Physicians' Health Study, both randomized and observational analyses indicate that there is no association between the use of aspirin and the incidence of colorectal cancer. The low dose of aspirin used and the short treatment period may account for the null findings. However, other characteristics associated with the use of aspirin in observational studies remain a plausible alternative explanation.

Adult↗
PubMed1979

In vivo platelet retention in human bleeding-time wounds. II. Effect of aspirin ingestion.

PRB was studied in normal human subjects before and after aspirin ingestion. Aspirin ingestion resulted in a prolongation of individual bleeding times greater than 2.4 min (greater than 2 S.D. beyond the group mean before aspirin) in 62.5% of 48 paired studies. The relationship of platelets retained vs. time was linear during the first 3 min of bleeding before and after aspirin. The mean PRB decreased from 22.1 +/- 9.2 to 9.6 +/- 8.6 (p less than 0.001) after aspirin ingestion. Subjects whose bleeding time was prolonged greater than 2.4 min had a significantly higher mean PRB before aspirin and a significantly greater mean decrease in PRB after aspirin than those whose bleeding time was prolonged less than or equal to 2.4 min. Aspirin ingestion reduced the number of EDTA-irreversible clumped platelets present in wound blood approximately 50% during the second and third minute of bleeding, but large numbers of EDTA-reversible platelet clumps were observed in wound blood before and after aspirin. Although platelet retention was significantly decreased during the first 3 min of bleeding after aspirin, the percent of venous blood platelets present in wound blood just prior to the arrest of hemorrhage was equal before and after aspirin. These observations indicate that aspirin prolongs the bleeding time by decreasing platelet clumping and slowing the rate of platelet thrombus formation in severed blood vessels. The presence of platelet clumps in wound blood after aspirin ingestion indicates that alternative mechanisms of platelet aggregation, independent of the arachidonate pathway of prostaglandin synthesis, proceed in vivo unaltered by aspirin.

Adult↗
PubMed2002

Update on aspirin in the treatment and prevention of cardiovascular disease.

Antiplatelet therapy, most notably aspirin, has been well documented to reduce risks of subsequent cardiovascular disease (CVD) in secondary prevention, acute myocardial infarction (MI), acute occlusive stroke, as well as in primary prevention. In secondary prevention, the most recent Antithrombotic Trialists' Collaboration reviewed 194 published randomized trials of antiplatelet therapy, mostly aspirin, involving more than 212 000 patients (ie, 135 000 using antiplatelet therapy or control and 77 000 using different antiplatelet regimens). In a very wide range of patients who have survived a prior occlusive vascular event-including MI, transient ischemic attacks, occlusive stroke, unstable and stable angina, percutaneous coronary interventions, and coronary artery bypass graft-aspirin prevents about 25% of serious vascular events. Among patients suffering acute Ml or acute occlusive stroke, aspirin begun promptly and continued long-term reduces risks of subsequent MI, stroke, and vascular death. In acute coronary syndromes, clopidogrel added to aspirin further reduces the risk of important vascular events, but not mortality, and causes more side effects, especially bleeding. For patients undergoing percutaneous coronary interventions, the addition of a short-term infusion of a glycoprotein IIb/IIIa receptor antagonist to aspirin prevents additional vascular events during the early in-hospital period but also increases the risk of major bleeding. Ongoing research is investigating other combinations of different antiplatelet drugs. In all these high-risk patients, there is a small excess of major bleeding among those assigned at random to aspirin, which is far outweighed by the magnitude of benefits on CVD. During an acute MI, after a loading dose of 160 mg to 325 mg aspirin, daily doses ranging from 75 to 150 mg daily are as effective as higher doses. For long-term treatment, the effects of doses < 75 mg daily are less certain. Although side effects are dose-related, especially in doses > 325 mg daily, no antiplatelet regimen is more effective than aspirin for long-term use. In primary prevention, 5 randomized trials have been published involving more than 60 000 apparently healthy men and women. Persons randomized to receive aspirin in these trials had significant reductions in risk of a first MI (32%) and important vascular events (15%). Since the numbers of strokes and vascular deaths were insufficient to distinguish between the benefits found in secondary prevention and no effect, use of aspirin in primary prevention should be weighed in light of the cardiovascular risk profile, the side effects of the drug, and its clear benefit in reducing risk of a first MI. Aspirin should be an adjunct, not an alternative, to managing other cardiovascular risk factors. Recently, the US Preventive Services Task Force and the American Heart Association recommended aspirin use for all men and women whose 10-year risks are > 6% and > or = 10%, respectively. In all these patient categories, including secondary prevention, acute MI and acute occlusive stroke, as well as primary prevention, increased and appropriate use of aspirin will prevent large numbers of premature deaths and MIs.

Aspirin↗
PubMed2005

[Study on the relationship between aspirin resistance and incidence of myonecrosis after non-emergent percutaneous coronary intervention].

OBJECTIVE: To investigate the occurrence of aspirin resistance in coronary heart disease (CHD) patients and its influence on myonecrosis among patients undergoing non-emergent percutaneous coronary intervention (PCI). METHODS: 256 CHD patients who have been on aspirin (100 mg/d) for at least 7 days were recruited based on aspirin responsiveness determination. All the patients were divided into two groups: aspirin-resistant group and aspirin-sensitive group. For all patients scheduled for non-emergent PCI, a loading dose of 300 mg of clopidogrel was given at least 12 h before PCI and a 75 mg maintenance dose was given every morning before and after PCI. The incidence of myonecrosis was evaluated by the levels of creatine kinase-myocardial band (CK-MB) and troponin I (TnI) before and after PCI. RESULTS: Aspirin resistance was found in 67 (26.2%) patients and 189 (73.8%) patients were aspirin-sensitive. There was a significantly higher proportion of female subjects in the aspirin-resistant group. The incidence of any CK-MB elevation was 38 (56.7%) in aspirin-resistant group and 42 (22.2%) in aspirin-sensitive group (P < 0.01). The elevation of TnI was observed in 41 (61.2%) of the aspirin-resistant group and in 67 (35.4%) of the aspirin-sensitive group (P < 0.05). Multivariate analysis revealed that aspirin resistance was an independent predictor for CK-MB elevation after PCI (OR = 2.5; 95% CI 1.5 to 6.5; P < 0.05). CONCLUSION: Aspirin resistance exists in some CHD patients, which increases the risk of myonecrosis following non-emergent PCI.

Aged↗
PubMed1991

Diacylglycerol overcomes aspirin inhibition of platelets: evidence for a necessary role for diacylglycerol accumulation in platelet activation.

Aspirin, an inhibitor of cyclooxygenase, inhibits platelet aggregation in response to many stimuli. Previous studies suggested an important and necessary role for protein kinase C (PKC) in platelet aggregation and secretion. Therefore, the effects of aspirin on sn-1,2-diacylglycerol (DAG), the endogenous activator of PKC, were investigated. Specifically, we sought to determine whether inhibition of DAG production is critical for aspirin action on platelets. Total DAG mass was measured using the DAG kinase assay. At low doses of gamma-thrombin (4 nM), aspirin (5 mM) completely inhibited secondary aggregation; this inhibition was associated with near-complete inhibition of DAG production. Inhibition of collagen-induced aggregation by aspirin (50 microM) was also associated with complete inhibition of collagen-stimulated DAG production and secondary aggregation. Concomitantly, aspirin reduced phosphorylation of the 40-kDa protein, a specific PKC substrate strongly suggesting inhibition of PKC in response to aspirin. To determine the physiologic significance of the inhibition of DAG production by aspirin, reconstitution studies were conducted with dioctanoylglycerol (diC8), a cell-permeable DAG. Under conditions in which aspirin completely inhibited secondary aggregation induced by gamma-thrombin, collagen, or arachidonic acid, diC8 overcame aspirin inhibition of agonist action and reconstituted secondary aggregation. DiC8 exerted these effects at low concentrations (2-3 microM), which caused minimal aggregation of control platelets. Phorbol 12,13-dibutyrate, a phorbol ester that directly activates PKC, mimicked the effects of diC8 in overcoming aspirin inhibition of collagen-induced platelet activation. However, subthreshold concentrations of the calcium ionophore ionomycin, arachidonic acid, or gamma-thrombin were unable to overcome aspirin inhibition of collagen-induced platelet aggregation, suggesting that the ability to overcome aspirin inhibition is not shared by other second messengers and is not due to nonspecific synergy. These studies constitute evidence that inhibition of DAG production and subsequent PKC activation are crucial to the antiaggregatory effects of aspirin. They also support the hypothesis that DAG production and PKC activation may be the final common pathway for induction of secondary aggregation.

Aspirin↗
PubMed1989

[Antiplatelet effects of combination therapy with low-dose aspirin and ticlopidine in cerebral ischemia].

Antiplatelet effects of combination therapy with aspirin and ticlopidine were investigated in comparison with single aspirin or ticlopidine therapy in 62 patients with cerebral thrombosis or transient ischemic attack. The 14, 21 and 27 patients were given orally daily aspirin 300mg, ticlopidine 200mg and aspirin 81mg with ticlopidine 100mg, respectively. Various platelet function tests were performed before and a week after medication. They included platelet aggregation (PA) to adenosine diphosphate (ADP), arachidonic acid (AA) and platelet activating factor (PAF) with turbidimetry, plasma beta-thromboglobulin (beta TG), platelet factor 4(PF4), thromboxane B2(TXB2) and 6keto-prostaglandin-F1 alpha(6keto PGF1 alpha) with radioimmunoassay, bleeding time with Simplate device, and platelet survival and lysis with Indium-111-tropolone-labelled platelets. Aspirin inhibited PA to ADP and AA but not to PAF, while ticlopidine inhibited PA to ADP and PAF but not to AA. In contrast, aspirin with ticlopidine inhibited PA to all of these agonists despite their smaller doses used. Aspirin reduced plasma TXB2 but not beta TG or PF4, while ticlopidine reduced beta TG and PF4 but not TXB2. On the contrary, aspirin with ticlopidine reduced TXB2 as well as beta TG and PF4. 6keto PGF1 alpha tended to be reduced by aspirin 300mg alone but not by ticlopidine with or without aspirin 81mg. Bleeding time was significantly prolonged by aspirin or ticlopidine alone, although most prolongation was produced by combination of aspirin and ticlopidine. Platelet survival and lysis remained unaltered in 4 patients treated with aspirin or ticlopidine alone, whereas platelet survival was prolonged and platelet lysis was reduced in 4 patients treated with both aspirin and ticlopidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Influence of aspirin in the management of asymptomatic carotid artery stenosis. VA Cooperative Study Group on Asymptomatic Carotid Stenosis.

PURPOSE: Aspirin therapy is recommended commonly for symptomatic extracranial carotid artery occlusive disease. However, its role in the management of asymptomatic carotid artery stenosis has not been reported previously. METHODS: In 11 clinical centers during the period 1983 to 1991, 444 adult male patients with significant asymptomatic carotid artery stenosis (> or = 50% arteriographically) were randomized to receive optimal medical management including aspirin plus carotid endarterectomy (n = 211) or optimal medical management alone (n = 233). At the conclusion of the study (mean follow-up time 47.9 months), at the time of a patient's death, or at occurrence of a neurologic end point, 16% of patients (n = 72) were not taking any aspirin, 51% (n = 226) had been converted to receiving enteric-coated aspirin, and only 33% (n = 146) were taking plain aspirin (27% at reduced dosage). Among patients from the medical group, 37 (16%) of 233 were not taking any aspirin and formed the basis for this retrospective analysis of the group for which no control population was available. RESULTS: Mortality rates in this group were not significantly different for patients not taking aspirin as compared with the rates for those taking aspirin, although patients not taking aspirin had a higher incidence of myocardial infarction (27%) as compared with patients taking aspirin (8%), p < 0.05. The incidence of ipsilateral neurologic events for patients not taking aspirin as compared with that for patients who were taking aspirin, respectively, was as follows: stroke, 13.5% and 8.7%, p > 0.05; stroke and transient ischemic attack, 37.8% and 17.3%, p < 0.05. No significant differences were observed in stroke severity scores for patients taking or not taking aspirin. CONCLUSION: These data suggest that patients with significant asymptomatic carotid artery stenosis who are intolerant of aspirin have a higher incidence of neurologic events than those patients able to tolerate the drug.

Aspirin↗
PubMed1997

The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group.

BACKGROUND: Only a few small trials have compared antithrombotic therapy (antiplatelet or anticoagulant agents) versus control in acute ischaemic stroke, and none has been large enough to provide reliable evidence on safety or efficacy. METHODS: The International Stroke Trial (IST) was a large, randomised, open trial of up to 14 days of antithrombotic therapy started as soon as possible after stroke onset. The aim was to provide reliable evidence on the safety and efficacy of aspirin and of subcutaneous heparin. Half the patients were allocated unfractionated heparin (5000 or 12,500 IU bd [twice daily]), and half were allocated "avoid heparin"; and, in a factorial design, half were allocated aspirin 300 mg daily and half "avoid aspirin". The primary outcomes were death within 14 days and death or dependency at 6 months. 19,435 patients with suspected acute ischaemic stroke entering 467 hospitals in 36 countries were randomised within 48 hours of symptom onset. RESULTS: Among heparin-allocated patients, there were non-significantly fewer deaths within 14 days (876 [9.0%] heparin vs 905 [9.3%] no heparin), corresponding to 3 (SD 4) fewer deaths per 1000 patients. At 6 months the percentage dead or dependent was identical in both groups (62.9%). Patients allocated to heparin had significantly fewer recurrent ischaemic strokes within 14 days (2.9% vs 3.8%) but this was offset by a similar-sized increase in haemorrhagic strokes (1.2% vs 0.4%), so the difference in death or non-fatal recurrent stroke (11.7% vs 12.0%) was not significant. Heparin was associated with a significant excess of 9 (SD 1) transfused or fatal extracranial bleeds per 1000. Compared with 5000 IU bd heparin, 12,500 IU bd heparin was associated with significantly more transfused or fatal extracranial bleeds, more haemorrhagic strokes, and more deaths or non-fatal strokes within 14 days (12.6% vs 10.8%). Among aspirin-allocated patients there were non-significantly fewer deaths within 14 days (872 [9.0%] vs 909 [9.4%]), corresponding to 4 (SD 4) fewer deaths per 1000 patients. At 6 months there was a non-significant trend towards a smaller percentage of the aspirin group being dead or dependent (62.2% vs 63.5%, 2p = 0.07), a difference of 13 (SD 7) per 1000; after adjustment for baseline prognosis the benefit from aspirin was significant (14 [SD 6] per 1000, 2p = 0.03). Aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within 14 days (2.8% vs 3.9%) with no significant excess of haemorrhagic strokes (0.9% vs 0.8%), so the reduction in death or non-fatal recurrent stroke with aspirin (11.3% vs 12.4%) was significant. Aspirin was associated with a significant excess of 5 (SD 1) transfused or fatal extracranial bleeds per 1000; in the absence of heparin the excess was 2 (SD 1) and was not significant. There was no interaction between aspirin and heparin in the main outcomes. INTERPRETATION: Neither heparin regimen offered any clinical advantage at 6 months. The results suggest that if heparin is given in routine clinical practice, the dose should not exceed 5000 IU subcutaneously twice daily. For aspirin, the IST suggests a small but worthwhile improvement at 6 months. Taking the IST together with the comparably large Chinese Acute Stroke Trial, aspirin produces a small but real reduction of about 10 deaths or recurrent strokes per 1000 during the first few weeks. Both trials suggest that aspirin should be started as soon as possible after the onset of ischaemic stroke; previous trials have already shown that continuation of low-dose aspirin gives protection in the longer term.

Acute Disease↗