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PubMed2006

A new definition of aspirin non-responsiveness by platelet function analyzer-100 and its predictors.

BACKGROUND: Aspirin non-responsiveness has been described as having a normal closure time (CT) by platelet function analyzer (PFA)-100 assay despite confirmed treatment with aspirin. There is no standard definition of aspirin non-responsiveness by PFA-100, with a variety of cut-off values having been used. We proposed an alternative definition of aspirin non-responsiveness by PFA-100 assay. METHODS: One hundred eighty-four patients with diagnosis of stable coronary artery disease or diabetes mellitus were included in the study. Blood samples were drawn before and after the 7 days of aspirin therapy. An individual was labelled as aspirin non-responder if his/her post-aspirin CT was not 2SD above his/her baseline CT, where SD was calculated from the baseline CTs of the study population. Aspirin non-responsiveness was also defined as having a normal post-aspirin CT (< or =193 s) regardless of pre-aspirin CT. RESULTS: The baseline CT ranged 82-187 s (mean 129.1 +/- 27.5, median 128 s) in the study population. At the end of 1 week of aspirin administration, CT increased to a mean of 260.7 +/- 63.6 s (range 102-301). According to our definition, 28 (15.2%) of 184 patients were aspirin non-responders. Univariate analysis indicated that aspirin non-responsiveness was closely associated with gender (P = 0.012) diabetes (P = 0.006), smoking (P = 0.0496) and hypertension (P = 0.021). Multivariate analysis identified diabetes (P = 0.016) as the only significant independent predictor for the presence of aspirin non-responsiveness. Thirty-four of 184 patients (18.5%) classified as aspirin non-responders according to the second criteria. Seven patients with prolongation of post-aspirin CT more than 2SD were classified as aspirin non-responders by the second criteria. Only 1 patient without prolongation of CT more than 2SD was classified as aspirin responsive by the second criteria. CONCLUSION: Definition of aspirin non-responsiveness as post-aspirin CTs < or =193 s might overestimate the prevalence of aspirin non-responsiveness. Nevertheless, definition of aspirin non-responsiveness by PFA-100 must be standardized and its utility as a predictor of cardiovascular events needs to be further investigated.

Aspirin↗
PubMed1983

Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man.

To assess the pharmacologic effects of aspirin on endogenous prostacyclin and thromboxane biosynthesis, 2,3-dinor-6-keto PGF1 alpha (PGI-M) and 2,3-dinor-thromboxane B2 (Tx-M) were measured in urine by mass spectrometry during continuing administration of aspirin. To define the relationship of aspirin intake to endogenous prostacyclin biosynthesis, sequential urines were initially collected in individuals prior to, during, and subsequent to administration of aspirin. Despite inter- and intra-individual variations, PGI-M excretion was significantly reduced by aspirin. However, full mass spectral identification confirmed continuing prostacyclin biosynthesis during aspirin therapy. Recovery of prostacyclin biosynthesis was incomplete 5 d after drug administration was discontinued. To relate aspirin intake to indices of thromboxane biosynthesis and platelet function, volunteers received 20 mg aspirin daily followed by 2,600 mg aspirin daily, each dose for 7 d in sequential weeks. Increasing aspirin dosage inhibited Tx-M excretion from 70 to 98% of pretreatment control values; platelet TxB2 formation from 4.9 to 0.5% and further inhibited platelet function. An extended study was performed to relate aspirin intake to both thromboxane and prostacyclin generation over a wide range of doses. Aspirin, in the range of 20 to 325 mg/d, resulted in a dose-dependent decline in both Tx-M and PGI-M excretion. At doses of 325-2,600 mg/d Tx-M excretion ranged from 5 to 3% of control values while PGI-M remained at 37-23% of control. 3 d after the last dose of aspirin (2,600 mg/d) mean Tx-M excretion had returned to 85% of control, whereas mean PGI-M remained at 40% of predosing values. Although the platelet aggregation response (Tmax) to ADP ex vivo was inhibited during administration of the lower doses of aspirin the aggregation response returned to control values during the final two weeks of aspirin administration (1,300 and 2,600 mg aspirin/d) despite continued inhibition of thromboxane biosynthesis. These results suggest that although chronic administration of aspirin results in inhibition of endogenous thromboxane and prostacyclin biosynthesis over a wide dose range, inhibition of thromboxane biosynthesis is more selective at 20 than at 2,600 mg aspirin/d. However, despite this, inhibition of platelet function is not maximal at the lower aspirin dosage. Doses of aspirin in excess of 80 mg/d resulted in substantial inhibition of endogenous prostacyclin biosynthesis. Thus, it is unlikely that any dose of aspirin can maximally inhibit thromboxane generation without also reducing endogenous prostacyclin biosynthesis. These results also indicate that recovery of endogenous prostacyclin biosynthesis is delayed following aspirin administration and that the usual effects of aspirin on platelet function ex vivo may be obscured during chronic aspirin administration in man.

Adenosine Diphosphate↗
PubMed2002

Interaction between aspirin and angiotensin-converting enzyme inhibitors: should they be used together in older adults with heart failure?

PURPOSE: To determine whether the prostacyclin-inhibiting properties of aspirin counteracts the bradykinin-induced prostacyclin-stimulating effects of angiotensin-converting enzyme (ACE) inhibitors, thereby attenuating the beneficial effects of ACE inhibitors in heart failure patients. BACKGROUND: Most heart failure patients are older adults. Heart failure is the number one hospital discharge diagnosis of older Americans. The renin-angiotensin system plays a major role in the pathophysiology of heart failure, and ACE inhibitors play a pivotal role in the management of heart failure. Large-scale double-blind randomized trials have demonstrated the survival benefits of using ACE inhibitors in patients with heart failure associated with left ventricular systolic dysfunction. In addition to inhibiting the conversion of angiotensin I to angiotensin II, ACE inhibitors also decrease the breakdown of bradykinin. Bradykinin, a potent vasodilator, acts by stimulating formation of vasodilatory prostaglandins such as prostacyclin, whereas aspirin or acetyl salicylic acid inhibits the enzyme cyclooxygenase, which in turn decreases the production of the prostaglandins. Coronary artery disease and hypertension are the two major underlying causes of heart failure. Most heart failure patients are also on aspirin. There is evidence that aspirin at a daily dose of 80 to 100 mg prevents the synthesis of thromboxane A2 by platelets while relatively sparing the synthesis of prostacyclin in the vascular endothelium. Aspirin at a daily dose of 325 mg has significant inhibitory effects on the vasodilatory prostacyclin synthesis. Studies have demonstrated that, in heart failure patients, low-dose aspirin has no adverse effect on hemodynamic, neurohumoral, or renal functions. Whether the prostacyclin-inhibiting effects of aspirin attenuate some of the beneficial effects of ACE inhibitors mediated by prostacyclin stimulation in heart failure patients is currently unknown. METHODS: Data from large clinical trials investigating the interaction between aspirin and ACE inhibitors were analyzed to determine the effect of aspirin on the vasodilatory actions of ACE inhibitors in heart failure patients, and the results were analyzed on the basis of theoretical and laboratory findings. The studies included are the Studies of Left Ventricular Dysfunction (SOLVD) (N=6,797), the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II) (N=6,090), the Captopril and Thrombolysis Study (CATS) (N=296), and another study involving 317 subjects. The data from these clinical trials investigating the interaction between aspirin and ACE inhibitors included 13,470 subjects. Most of the subjects received aspirin. In the SOLVD study, subjects received aspirin or dipyridamole. Subjects were followed up for an average of about 6 years. RESULTS: In the SOLVD study, subjects were followed up for 41.1 months in the treatment trial and 37.4 months in the prevention trial. Patients who received aspirin or dipyridamole at baseline did not receive the survival benefits of enalapril, whereas patients who received enalapril did not receive the survival benefits of aspirin. In a rather small study of 317 subjects with left ventricular systolic dysfunction (ejection fraction <35%) who were followed up for a relatively longer period of time (5.7 years), the favorable long-term prognosis of patients receiving aspirin was independent of receipt of an ACE inhibitor. A retrospective subgroup analysis of data from the CONSENSUS II study demonstrated that the 6-month mortality rate of patients with acute myocardial infarction (MI) who received enalapril and aspirin was higher than the combined mortality rates of patients receiving enalapril or aspirin alone. This strong interaction between aspirin and the ACE inhibitor enalapril suggests that the survival benefit of enalapril was significantly lower in patients also taking aspirin than in those taking enalapril alone. This interaction was not associated with other nonfatal major events. In the CATS study, use of low-dose aspirin (80 or 100 mg) did not attenuate beneficial effects of captopril (immediate and 1-year follow up) after acute MI. CONCLUSION: There is a theoretical possibility that the negative interaction between ACE inhibitors and aspirin may reduce the beneficial effects of ACE inhibitors in patients with heart failure, but the information obtained from the existing databases is limited by the retrospective nature of the analyses and does not establish the association definitively. Double-blind randomized controlled trials should be conducted to determine whether such a negative interaction indeed exists.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Failure of aspirin treatment after stroke.

BACKGROUND AND PURPOSE: Despite its low efficacy, aspirin is the most widely used drug for secondary stroke prevention. The reasons why stroke recurs while patients are on aspirin are unknown. We have analyzed a series of patients who had recurrent strokes while on aspirin. METHODS: Out of 2231 consecutive patients who were admitted to the Tel Aviv Medical Center from May 1988 through December 1992 with the diagnosis of ischemic stroke, 129 admissions were due to recurrent ischemic strokes while the patients were already on aspirin, and these were defined as aspirin failures. The clinical characteristics of those patients in whom aspirin treatment failed were compared with three control groups, each comprising 129 patients who had had only a single ischemic stroke and were then taking aspirin. One control group was matched for aspirin dose and date of first stroke; another control group was matched for age, sex, and date of first stroke; and a third control group was matched for age, sex, date of first stroke, and aspirin dose. Statistical analysis was carried out by two-tailed Student's t test and chi 2 test. RESULTS: The average period until stroke was longer for patients on higher aspirin doses. Patients matched for aspirin dose and date of first stroke did not differ significantly in age (72.4 years in aspirin failures versus 74.2 years in the first control group) and sex (89 versus 94 men, respectively). Matching for age, sex, and date of first stroke but not for aspirin dose demonstrated a trend toward high frequency of aspirin failure in patients taking lower doses of aspirin (chi 2 test for trend = 3.5; P = .06). Comparison of aspirin-failure patients with a control group matched for age, sex, date of first ischemic stroke, and aspirin dose demonstrated that these patients more commonly had statistically significant hyperlipidemia (odds ratio, 2.6; 95% confidence interval, 1.0 to 6.8; P = .04) and ischemic heart disease (odds ratio, 2.3; 95% confidence interval, 1.3 to 3.9; P = .002). CONCLUSIONS: We conclude that age and sex do not influence the efficacy of aspirin. Lower aspirin dose in patients with stroke recurrence suggests that aspirin doses of 500 mg daily or more should be used in secondary stroke prevention. Hyperlipidemia and ischemic heart disease are risk factors for stroke recurrence despite aspirin treatment, which requires further clinical and laboratory evaluation.

Aged↗
PubMed2005

Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance.

UNLABELLED: We evaluated the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing elective coronary stenting. Patients (n = 150) treated with aspirin but not clopidogrel had blood samples drawn at baseline and 24 h after clopidogrel loading. Depending on the definition used, 9% to 15% were resistant to aspirin and 24% to clopidogrel. About half of the aspirin-resistant patients were also resistant to clopidogrel. As a group, aspirin-resistant patients had lower response to clopidogrel (assessed by platelet aggregation and activation markers) than aspirin-sensitive patients. Both aspirin- and clopidogrel-resistant patients had higher incidence of creatine kinase-MB elevation than the respective sensitive patients. OBJECTIVES: We sought to evaluate the response to clopidogrel among aspirin-resistant versus aspirin-sensitive patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Wide variability has been reported in response to aspirin and clopidogrel. There are limited data on the simultaneous responses to both drugs. METHODS: Elective PCI patients (n = 150) who received aspirin for > or = 1 week but not clopidogrel were included. All patients received bivalirudin during PCI. Blood samples were drawn at baseline and 20 to 24 h after a 300-mg clopidogrel dose. Aspirin resistance was defined by > or = 2 of 3 criteria: rapid platelet function analyzer-ASA score > or = 550, 5 micromol/l adenosine diphosphate (ADP)-induced aggregation > or = 70%, and 0.5 mg/ml arachidonic acid-induced aggregation > or = 20%. Clopidogrel resistance was defined as baseline minus post-treatment aggregation < or = 10% in response to 5 and 20 micromol/l ADP. RESULTS: Nineteen (12.7%) patients were resistant to aspirin and 36 (24%) to clopidogrel. Nine (47.4%) of the aspirin-resistant patients were also clopidogrel resistant. Aspirin-resistant patients were more likely to be women and have diabetes than were aspirin-sensitive patients. They also had lower response to clopidogrel, assessed by platelet aggregation and activation markers (flow cytometry-determined PAC-1 binding and P-selectin expression). Elevation of creatine kinase-myocardial band after stenting occurred more frequently in aspirin-resistant versus aspirin-sensitive patients (38.9% vs. 18.3%; p = 0.04) and in clopidogrel-resistant versus clopidogrel-sensitive patients (32.4% vs. 17.3%; p = 0.06). CONCLUSIONS: Aspirin-resistant patients as a group have reduced response to clopidogrel. Furthermore, we have identified a unique group of dual drug-resistant patients who may be at increased risk for thrombotic complications after PCI.

Aged↗
PubMed2000

[Digestive complications of aspirin].

INTRODUCTION: This review focuses on aspirin-related gastrointestinal side-effects and the mechanism by which aspirin causes gastrointestinal damage. CURRENT KNOWLEDGE AND KEY POINTS: Aspirin causes direct gastric damage by topical irritant effects and indirect damage via systemic inhibition of cyclooxygenase synthesis and microcirculation injury. The question of a possible synergistic relation between the presence of Helicobacter pylori infection and aspirin use on gastric damage is not resolved. The pathogenesis of small intestinal and colonic damage is less well understood; an increase in intestinal permeability and free radical synthesis are suggested. Gastric damage predominates. Gastroduodenal lesions from aspirin have been documented in endoscopy studies. The lesions occur rapidly, even for low-dose aspirin. The association of aspirin consumption with upper gastrointestinal bleeding has been well established. The main risk factors are advanced age, concomitant use of nonsteroidal antiinflammatory drugs and history of ulcer. Low-dose aspirin are associated with increased risk of gastrointestinal bleeding and this risk is dose-dependant. Chronic aspirin consumption can cause iron deficiency anaemia. Uncomplicated gastric ulcer (but not uncomplicated duodenal ulcer) is associated with aspirin use, with relative risk 3. Other upper gastrointestinal complications have been reported: stenosis and perforation. Aspirin can also damage other areas of the gastrointestinal tract. Oesophageal injuries (oesophagitis and stricture) have been reported. Aspirin is associated with variceal bleeding episodes in patients with cirrhosis. The adverse effects of aspirin on the small bowel are perforation, bleeding, increasing permeability. The adverse effects of aspirin on the large intestine are perforation, bleeding, collagenous colitis and anorectal stenosis with suppositories containing aspirin. Direct clinical data regarding prophylaxis with co-administration of a protective drug are not yet available for aspirin. FUTURE PROSPECTS AND PROJECTS: Patients should be made aware of adverse gastrointestinal effects due to aspirin. Further studies regarding prophylactic therapy of low-dose aspirin induced gastroduodenal lesions, which identify a subset of patients who may be at higher risk than the low-dose aspirin population as a whole, are warranted.

Aged↗