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PubMed2003

Low-temperature (180 K) crystal structure, electron paramagnetic resonance spectroscopy, and propitious anticonvulsant activities of CuII2(aspirinate)4(DMF)2 and other CuII2(aspirinate)4 chelates.

The purpose of this research was to characterize by X-ray crystallography the ternary dimethylformamide (DMF) Cu(II) complex of acetylsalicylic acid (aspirin), in an effort to compare the structure-activity relationships for the anticonvulsant activity of this and other Cu(II)aspirinate chelates. The ternary DMF Cu(II) complex of aspirin was synthesized and crystals grown from a DMF solution were characterized by single crystal X-ray diffraction. This crystalline material was analyzed for anticonvulsant activity in the Maximal Electroshock (MES) Grand Mal and subcutaneous Metrazol (scMET) Petit Mal models of seizure used to detect anticonvulsant activity. The ternary DMF complex was found to be a monomolecular binuclear complex, tetrakis-mu-(acetylsalicylato)bis(dimethylformamido)dicopper(II) [Cu(II)(2)(aspirinate)(4)(DMF)(2)] with the following parameters: monoclinic, space group P2(1)/n, a=12.259 (1), b=10.228 (1), c=16.987 (1) A, beta=92.07 (1) degrees; V=2128.5 (3) A(3); Z=2. The structure was determined at 180 K from 2903 unique reflections (I>1sigma(I)) to the final values of R=0.030 and wR=0.033 using F. This binuclear complex contains four acetylsalicylate bridging ligands which are related to each other in a two by two symmetry center. The four nearest O atoms around each Cu atom form a closely square planar arrangement with the square pyramidal coordination completed by the dimethylformamide oxygen atom occupying an apical position at a distance of 2.154 (1) A. Each Cu atom is displaced towards the DMF ligand by 0.187 A from the plane of the four O atoms. Electron paramagnetic resonance (EPR) spectra of [Cu(II)(2)(aspirinate)(4)(DMF)(2)] crystals show a strong antiferromagnetic coupling of the copper atoms, similar to that observed with other binuclear copper(II)salicylate compounds. Studies used to detect anticonvulsant activity revealed that [Cu(II)(2)(aspirinate)(4)(DMF)(2)] was an effective anticonvulsant in the MES model of seizure but ineffective against scMET-induced seizures. The monomolecular ternary binuclear [Cu(II)(2)(aspirinate)(4)(DMF)(2)] complex is more effective in inhibiting MES-induced seizures than other binuclear or mononuclear Cu(II) chelates of aspirin including: binuclear polymeric [Cu(II)(2)(aspirinate)(4)], [Cu(II)(2)(aspirinate)(4)(H(2)O)], which is anticipated to be less polymeric, and monomolecular ternary [Cu(II)(2)(aspirinate)(4)(DMSO)(2)] and [Cu(II)(aspirinate)(2)(Pyr)(2)]. These and other chelates appear to be more effective in the scMET model of seizure than [Cu(II)(2)(aspirinate)(4)(DMF)(2)]. These structure-activity relationships support the potential efficacy of Cu chelates of aspirin in treating epilepsies.

Animals↗
PubMed2002

Uncoupled regulation of leukotriene C4 synthase in platelets from aspirin-intolerant asthmatics and healthy volunteers after aspirin treatment.

BACKGROUND: We have reported that thromboxane A2 induces suppression of leukotriene (LT) C4 synthase activity in human platelets. AIM: In the present study, we describe a mechanism whereby aspirin treatment can lead to increased formation of LTC4, which is a potent bronchoconstrictor and inflammatory mediator. This mechanism is also demonstrated to be present in platelets from aspirin-intolerant asthmatics (AIA). METHODS: The effect of arachidonic acid or platelet agonists on LTC4 synthase activity was investigated in platelets obtained from healthy volunteers, aspirin-intolerant asthmatics or aspirin-tolerant asthmatics after in vivo treatment or in vitro pre-incubation with aspirin. RESULTS: Incubation of normal platelets with arachidonic acid or collagen provoked approximately 50% reduction of platelet LTC4 synthase activity, as determined by the conversion of LTA4 to LTC4. However, the inhibitory effect of arachidonic acid or collagen was not observed after oral administration of aspirin prior to collection of the platelets. Arachidonic acid-induced inhibition of LTC4 synthase activity was totally abolished in platelets collected from peripheral blood already 30 min after aspirin ingestion but was fully restored in platelets collected 3 to 7 days after the administration of aspirin. Treatment of platelet suspensions with aspirin in vitro dose-dependently counteracted the suppressive effect of arachidonic acid on LTC4 formation, with total reversal at approximately 40 microm. In contrast, the major aspirin metabolite, salicylic acid did not alter arachidonic acid-induced reduction of LTC4 synthase activity. Similarly, LTC4 synthase activity in platelets from AIA and aspirin-tolerant asthmatics (ATA) was reduced by approximately 50% after pre-treatment with arachidonic acid in vitro. Again the inhibitory effect was abolished when platelets were pre-incubated in the presence of aspirin. CONCLUSION: The results indicate that oral aspirin administration can lead to uncoupling of thromboxane A2-dependent negative feedback mechanisms, which may normally restrict the production of cysteinyl leukotrienes. This mechanism can be of potential interest in aspirin-induced asthma.

Adult↗
PubMed2002

Aspirin use and counseling about aspirin among patients with diabetes.

OBJECTIVE: Despite being a safe, effective therapy for lowering cardiovascular risk, only 20% of diabetic patients were using aspirin in the early 1990s. This study examines current physician practices and the use of aspirin therapy by individuals with diabetes. RESEARCH DESIGN AND METHODS: A random sample of diabetic patients receiving care in the Department of Veterans Affairs health care system were surveyed during January-March 2000. The association between aspirin counseling, aspirin use, and reported coronary vascular disease (CVD) and classical CVD risk factors were examined using logistic regression. The effect of increasing aspirin use on risk of myocardial infarction (MI) and cardiovascular mortality was demonstrated by simulation. RESULTS: Seventy-one percent of respondents reported being counseled about aspirin use, and 66% were taking daily aspirin. Individuals with known CVD were more likely to be counseled (odds ratio [OR] 4.9, 95% CI 2.9-8.1) and to use aspirin (2.1, 1.2-3.7). The factor most strongly associated with aspirin use was having been counseled about aspirin therapy by a doctor. We estimate that for this population, increasing daily aspirin use to 90% could prevent an additional 11,000 MIs and potentially save >8,000 lives. CONCLUSIONS: Compared with previous reports, a substantial proportion of these diabetic patients have been counseled about and use aspirin. Most clinicians recognize aspirin as an important treatment for patients with preexisting coronary disease. However, since diabetes is now considered a CVD equivalent, it is imperative that clinicians include counseling about aspirin therapy as a care priority for all their diabetic patients, as this simple intervention may prevent many cardiovascular events and deaths.

Aged↗
PubMed2004

Magnitude and time course of platelet inhibition with Aggrenox and Aspirin in patients after ischemic stroke: the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial.

The European Stroke Prevention Study showed greater stroke prevention for Aggrenox than either for aspirin or dipyridamole alone. To test whether Aggrenox has superior antiplatelet properties to aspirin alone we conducted the AGgrenox versus Aspirin Therapy Evaluation (AGATE) trial. Forty patients with prior ischemic stroke not taking aspirin for at least 30 days were randomized to Aggrenox (2 pills/daily) or aspirin (81 mg plus matching placebo/daily) for 30 days. Platelet function was assessed at baseline, 24 h, and days 3, 7, 15, and 30 by aggregometry, flow cytometry and cartridge-based analyzers. Both Aggrenox and aspirin provided fast and sustained platelet inhibition. Aggrenox(R), however, especially after 15 days, showed significant prolongation of the closure time (P=0.04), diminished expression of platelet/endothelial cell adhesion molecule-1 (PECAM-1) (P=0.01), glycoprotein IIb (GPIIb) antigen (P=0.02), and GPIIb/IIIa activity (P=0.01) by PAC-1 C antibody, CD63 (P=0.03), as well as inhibition of Protease Activated Receptors (PAR-1) associated with intact (SPAN12, P=0.01) and cleaved (WEDE15, P=0.01) thrombin receptors as compared with aspirin. Surprisingly, GPIb expression increased, especially after aspirin. In the randomized trial of small sample size, aspirin and Aggrenox produced fast and sustained platelet inhibition. In 25 of 90 direct comparisons, Aggrenox was superior to aspirin, whereas in 4 of 90, aspirin was superior to Aggrenox. In 61 of 90 direct comparisons, aspirin and Aggrenox were equivalent. Aggrenox was associated with a profound reduction of PAR-1 receptors, an observation that may be related to the greater clinical benefit of Aggrenox compared with Aspirin in preventing recurrent stroke.

Aged↗
PubMed2005

Failure of tacrolimus to prevent aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease.

BACKGROUND: In patients with aspirin-exacerbated respiratory disease (AERD), pretreatment with asthma controller medications (leukotriene modifiers, inhaled or systemic corticosteroids, and salmeterol) partially modifies the severity of aspirin-induced asthmatic reactions. OBJECTIVE: A recent study showed that pretreatment with tacrolimus completely prevented aspirin-induced respiratory reactions and might allow silent aspirin desensitization. METHODS: Ten patients with rhinosinusitis, nasal polyps, and asthma had a history of asthma attacks after ingesting aspirin and nonsteroidal anti-inflammatory drugs. All underwent baseline oral aspirin challenges and had typical respiratory reactions. They were then randomized to receive tacrolimus (0.1 mg/kg weight; 8 patients) or placebo (2 patients) in a double-blind protocol before rechallenge with aspirin using the previous provoking dose of aspirin. In addition, respiratory reactions sustained by 50 consecutive patients with AERD during 2004 were recorded, analyzed, and compared with the tacrolimus/placebo-treated patients to determine whether there were any differences. RESULTS: Tacrolimus pretreatment failed to block respiratory reactions to provoking doses of aspirin in 5 of 8 patients with AERD, and in the other 3 patients did not block higher doses of aspirin. The results of oral aspirin challenges in the control population of 50 patients were compared with either the baseline or postchallenge data from the tacrolimus-pretreated or placebo-pretreated patients with AERD, and there were no significant differences. CONCLUSIONS: Use of tacrolimus as add-on pretreatment to prevent reactions to aspirin in patients with AERD or to achieve the goal of silent aspirin desensitization could not be accomplished.

Administration, Oral↗
PubMed2006

Recombinant factor VIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel on in vitro thrombin generation.

BACKGROUND: Antiplatelet drugs constitute the therapy of choice for acute coronary syndromes, but bleeding can be a side-effect requiring treatment. Restoration of normal platelet activity is also mandatory before urgent surgery. This study investigated: (a) whether a regimen of aspirin or clopidogrel plus aspirin significantly inhibited platelet thrombin generation (TG); and (b) the reversal of this inhibition by recombinant activated factor VII (rFVIIa). METHODS AND RESULTS: TG was evaluated by the lag time, time to peak, peak of TG, and area under the curve after 35 min of assay (AUC(0 --> 35 min)). These measures were examined by the calibrated automated thrombography method in 22 healthy volunteers, 22 volunteers after a 100 mg day(-1) aspirin intake (200 mg first day) for 5-7 days, and 22 healthy volunteers after aspirin 100 mg day(-1) (200 mg first day) plus clopidogrel 75 mg day(-1) (300 mg first day) for 4-7 days. The TG parameters were measured under basal conditions and after platelet stimulation by sodium arachidonate (AA), adenosine 5'-diphosphate (ADP), collagen and rFVIIa in normal non-aspirinated as well as in vivo aspirinated platelet-rich plasma (PRP) or aspirin plus clopidogrel PRP. Lag time was shorter (P < 0.05), and peak of TG and AUC(0 --> 35 min) were significantly greater (P < 0.01 for both), in PRP activated with ADP, collagen, AA or FVIIa than in non-activated PRP from normal subjects. Both non-activated PRP and activated PRP prepared from platelets obtained from volunteers after aspirin intake showed significant prolongation of the time parameters but there was less effect on peak of TG and AUC(0 --> 35 min). For most parameters, aspirin plus clopidogrel administration showed to be more effective compared with the effect obtained by aspirin alone. When rFVIIa was added to ASA-PRP or ASA + Clop PRP, lag time (P < 0.001 for all) and time to peak (P < 0.001-0.017) were significantly shortened, indicating that rFVIIa reverses the inhibitory effect of these anti-aggregating agents. CONCLUSION: Platelets activated by AA, ADP, collagen or FVIIa triggered TG. This effect was inhibited by aspirin plus clopidogrel, suggesting an additional benefit of this drug combination for preventing thrombosis. rFVIIa reverses the inhibitory effect of aspirin or aspirin plus clopidogrel, and could be useful for bleeding complications or when acute surgery is needed during treatment with these antiplatelet drugs.

Adult↗
PubMed1995

Aspirin enhances the benefits of late reperfusion on infarct shape. A possible mechanism of the beneficial effects of aspirin on survival after acute myocardial infarction.

BACKGROUND: The time window of the benefits of late reperfusion on infarct shape is limited. In rats, these benefits diminish in a wave front over time, with minimal benefits when reperfusion follows 16 hours of coronary occlusion. The mechanism of the benefits of aspirin on survival after acute myocardial infarction is unknown. The purpose of this study was to test the ability of aspirin to enhance the benefits of late coronary artery reperfusion on infarct shape and to examine the mechanism of the benefits of aspirin on infarct shape. METHODS AND RESULTS: Rats were entered into two different protocols, the morphometric and the histological protocols. In the morphometric protocol, rats were randomized into two groups: the aspirin group, in which rats underwent left coronary artery occlusion followed by treatment with aspirin (12 mg/kg i.v.), and the control group, in which rats underwent left coronary artery occlusion followed by treatment with placebo. Rats in both groups were reperfused 8 hours after coronary occlusion. Rats in the aspirin group received aspirin in the drinking water (12 +/- 2 mg/kg daily). Morphometric analysis was performed 2 weeks after acute myocardial infarction. In the histological protocol, rats underwent the same randomization, coronary occlusion, and reperfusion protocols. Hearts were removed 24 hours after coronary occlusion, and microvessels were assessed for patency. Infarct size expressed as a percent of circumference was similar in the aspirin and placebo treatment groups (28 +/- 2% versus 33 +/- 3%, P = NS). Septal thickness was also similar in both groups (1.8 +/- 0.1 versus 2.1 +/- 0.1 mm, P = NS for aspirin versus placebo). The aspirin-treated group had thicker infarcts compared with the placebo-treated group (0.8 +/- 0.1 versus 0.5 +/- 0.1 mm, P < .05) and less expanded infarcts (expansion index, 1.2 +/- 0.1 versus 2.0 +/- 0.2, P < .05). Aspirin was associated with increased patency of the microvessels in the infarcted area compared with the placebo group (96% versus 64% of microvessels patent, P < .001). CONCLUSIONS: Aspirin enhances the benefit of late coronary artery reperfusion on infarct shape after 8 hours of coronary occlusion. The benefits of aspirin on infarct shape after late reperfusion are related to increased patency of the microvessels in the infarcted area.

Animals↗
PubMed2003

Warfarin and aspirin give more benefit than aspirin alone but also more bleeding after myocardial infarction.

The anticoagulant, warfarin, and the antiplatelet agent, aspirin, have been shown to have similar benefits after myocardial infarction. As these agents have different mechanisms of action, the beneficial effects of warfarin and aspirin may be additive after myocardial infarction. In the Warfarin, Aspirin, Reinfarction Study (WARIS II), the main outcome was a composite of death, non-fatal reinfarction or thromboembolic stroke, whichever came first over 4 years. Compared to aspirin alone (160 mg/day), the risk reduction was 19% (p = 0.03) with warfarin alone (INR of 2.8 IU) and 29% (p = 0.001) with the combination of aspirin and warfarin (aspirin, 75 mg/day; warfarin, INR of 2.2 IU). This difference in the first event with warfarin alone or the combination, represented a reduction in reinfarction and thromboembolic stroke rather than death. For reinfarction, compared to aspirin alone (117 of 1206), there was a reduction with warfarin alone (90 of 1216) and a further reduction with the combination (69 of 1208). For thromboembolic stroke, compared to aspirin (32 of 1206), there were similar reductions with warfarin and the combination. There were more major and minor bleeding in the warfarin groups than the aspirin group, with major bleeding occurring in 8, 33 and 28 patients taking aspirin, warfarin and aspirin and warfarin, respectively. In conclusion, as compared with aspirin alone, therapy with moderate-intensity warfarin combined with aspirin and high-intensity warfarin alone, resulted in a reduced risk of reinfarction and ischemic stroke but a higher risk of bleeding.

Aged↗
PubMed1996

Prophylaxis against deep venous thrombosis after total knee arthroplasty. Pneumatic plantar compression and aspirin compared with aspirin alone.

A prospective, randomized study was conducted to assess the efficacy of pulsatile pneumatic plantar compression for prophylaxis against deep venous thrombosis after total knee arthroplasty performed with use of regional anesthesia. One hundred and twenty-two patients (164 knees) who were scheduled to have a unilateral or a one-stage bilateral total knee arthroplasty were separately randomized to be managed with either aspirin alone or the pulsatile pneumatic plantar-compression device and aspirin. The prevalence of deep venous thrombosis was 27 per cent (twenty-two of eighty-one knees) in the group treated with pneumatic plantar compression compared with 59 per cent (forty-nine of eighty-three knees) in the patients managed with aspirin alone (the control group) (p < 0.001). A significant difference was also noted in the group that had had a unilateral arthroplasty (a prevalence of 27 per cent [eleven of forty-one knees] in the group treated with pneumatic plantar compression, compared with 67 per cent [twenty-six of thirty-nine knees] in that treated with aspirin alone; p < 0.006) and in the group that had had a one-stage bilateral procedure (a prevalence of 28 per cent [eleven of forty knees] in the group treated with pneumatic plantar compression, compared with 52 per cent [twenty-three of forty-four knees] in that treated with aspirin alone; p < 0.03). No proximal thrombi were noted in any patient who used the pulsatile pneumatic plantar-compression device, while the prevalence of proximal thrombosis in the popliteal or femoral veins was 14 per cent (twelve of eighty-three knees) in the group treated with aspirin alone (p < 0.0003). In the group treated with a unilateral procedure and aspirin alone the prevalence of proximal thrombosis was 13 per cent (five of thirty-nine knees; p < 0.02), while in the group treated with a bilateral procedure and aspirin alone it was 16 per cent (seven of forty-four knees; p < 0.01). Only in the patients who had had a unilateral procedure was use of the compression device associated with significantly less edema postoperatively than was use of aspirin alone. The change between the preoperative and postoperative circumferences of the thigh and leg was significantly less (9 +/- 4.1 millimeters [mean and standard deviation] less for the thigh [p < 0.01] and 6 +/- 3.9 millimeters less for the leg [p < 0.049]) with the compression device than with aspirin alone. In addition, there was significantly less mean drainage (98 +/- 61.1 milliliters) in the group treated with a unilateral procedure and pneumatic compression, compared with that treated with a unilateral procedure and aspirin alone (p < 0.041). An internal timer of the compression device was used to assess the compliance of the patient with use of the device, and a relationship between deep venous thrombosis and the total duration of treatment with the device was found. The patients in whom deep venous thrombosis did not develop used the device for a mean of 96 +/- 23.4 hours (range, sixty to 164 hours) postoperatively, or 19.2 +/- 5.1 hours a day, while those in whom thrombosis developed used it for a mean of 67 +/- 21.1 hours (range, twenty-six to 101 hours), or 13.4 +/- 4.3 hours a day (p < 0.001). No untoward effects were noted in any patient who used the device. This study confirms the safety and efficacy of pulsatile pneumatic plantar compression and aspirin compared with aspirin alone and supports the use of mechanical compression for prophylaxis against deep venous thrombosis and for reduction of edema in patients who have had a total knee arthroplasty. In addition, we found a direct relationship between compliance with the use of this device and its efficacy in reducing deep venous thrombosis.

Arthritis, Rheumatoid↗
PubMed1992

ISIS-3: a randomised comparison of streptokinase vs tissue plasminogen activator vs anistreplase and of aspirin plus heparin vs aspirin alone among 41,299 cases of suspected acute myocardial infarction. ISIS-3 (Third International Study of Infarct Survival) Collaborative Group.

41,299 patients entering 914 hospitals up to 24 h (median 4 h) after the onset of suspected acute myocardial infarction were randomised between streptokinase (SK: 1.5 MU infused over about 1 h), tissue plasminogen activator (tPA, duteplase: 0.60 MU/kg infused over about 4 h), or anisoylated plasminogen-streptokinase activator complex (APSAC), anistreplase: 30 U over about 3 min). All patients were to receive aspirin (162 mg/day enteric-coated), with the first tablet chewed for rapid and full antiplatelet effect. Half of all patients were randomly allocated subcutaneous calcium heparin (12,500 IU starting at 4 h and given twice daily for 7 days or until prior discharge) in addition to aspirin, and the other half were to receive aspirin alone. ASPIRIN PLUS HEPARIN VERSUS ASPIRIN ALONE--The addition of heparin to aspirin was associated with an excess of transfused or other major non-cerebral bleeds (1.0% aspirin plus heparin vs 0.8% aspirin alone; 2p < 0.01) and of definite or probable cerebral haemorrhage (0.56% vs 0.40%; 2p < 0.05), but with no significnat differences in total stroke (1.28% vs 1.18%). Reinfarctions were slightly less common among those allocated aspirin plus heparin (3.16% vs 3.47%; 2p = 0.09). There was no signficant difference in the pre-specified endpoint of 35-day mortality (2132 [10.3%] aspirin plus heparin vs 2189 [10.6%] aspirin alone). During the scheduled heparin treatment period there were slightly fewer deaths in the aspirin plus heparin group (days 0-7 in hospital: 1534 [7.4%] vs 1633 [7.9%]; 2 p = 0.06), with a slight convergence by day 35 (598 further deaths [3.1% of survivors] vs 556 [2.9%]). The pattern was similar to that observed in the GISSI-2 trial, so that in both trials combined there was a significant reduction in mortality during the scheduled treatment period (2071 [6.8%] vs 2239 [7.3%]; 2p < 0.01). This indicates avoidance of 5 deaths (SD 2) per 1000 patients allocated this high-dose subcutaneous heparin regimen in addition to aspirin, but some of any early benefit may be lost after heparin ceases, with no significant mortality advantage in days 0-35 (both trials: 3100 [10.0%] vs 3172 [10.2%]) or during follow-up to 6 months. SK VERSUS APSAC--APSAC was associated with significantly more reports of allergy causing persistent symptoms and of non-cerebral bleeds, but not of transfused bleeds or of reinfarctions. There was a slight excess of strokes with APSAC (1.04% SK vs 1.26% APSAC; 2p = 0.08), much of it appearing soon after treatment started (strokes during days 0-1: 0.50% SK vs 0.73% APSAC; 2p < 0.02) and being attributed to cerebral haemorrhage (0.24% SK vs 0.55% APSAC; 2p < 0.0001). No significant difference was observed in reinfarction (3.47% SK vs 3.55% APSAC). There was no significant mortality difference during days 0-35, either among all randomised patients (1455 [10.6%] SK vs 1448 [10.5%] APSAC) or among the pre-specified subset presenting within 0-6 h of pain onset and with ST elevation on the electrocardiogram in whom fibrinolytic treatment may have most to offer (861 [10.0%] SK vs 855 [9.9%] APSAC). No significant difference in 6-month survival was apparent overall or in the subset.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMed1993

Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: a comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.

Aspirin, alone or in combination with dipyridamole, is known to prevent occlusion of aortocoronary vein grafts. The benefit of dipyridamole in addition to aspirin remains controversial, and the efficacy and safety of oral anticoagulants for prevention of vein-graft occlusion have not been established. We assessed one-year angiographic vein-graft patency after aortocoronary-bypass surgery in 948 patients assigned to receive aspirin, aspirin plus dipyridamole, or oral anticoagulants in a prospective, randomised trial. The design was double-blind and placebo-controlled for the aspirin groups, but open for oral anticoagulant treatment. Dipyridamole (5 mg/kg per 24 h intravenously for 28 h, followed by 200 mg twice daily) and oral anticoagulants (desired prothrombin time range 2.8-4.8 international normalised ratio) were started before surgery, and aspirin (50 mg per day) was started after surgery. Clinical outcome was assessed by the incidence of myocardial infarction, thrombosis, major bleeding, or death. Occlusion rate of distal anastomoses was 11% in the aspirin plus dipyridamole group versus 15% in the aspirin group (relative risk 0.76, 95% CI 0.54-1.05) and 13% in the oral anticoagulants group. Clinical events occurred in 20.3% of patients receiving aspirin plus dipyridamole compared with 13.9% of the aspirin group (relative risk 1.46, 95% CI 1.02-2.08) and 16.9% of the oral anticoagulants group. Our data provide no convincing evidence that addition of dipyridamole to 50 mg aspirin per day improves aortocoronary vein-graft patency. Moreover, there is evidence that the combination increases the overall clinical-event rate. Compared with aspirin, oral anticoagulants provided no benefit.

Acenocoumarol↗
PubMed2003

Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa.

In addition to inhibiting cyclooxygenase (COX)-1-derived prostanoid biosynthesis, aspirin acetylates COX-2, enabling the conversion of arachidonic acid to 15(R)-epi lipoxin A4, or aspirin-triggered lipoxin (ATL). Selective COX-2 inhibitors block ATL formation and exacerbate mucosal injury in rats treated with aspirin. In the present study, we have examined whether inhibition of COX-2 activity in healthy volunteers taking aspirin exacerbates gastric mucosal injury and if such an effect would be prevented by NCX-4016, a NO-releasing derivative of aspirin. Thirty-two volunteers were randomized to receive 2 wk of treatment with NCX-4016 (800 mg twice a day) or aspirin (100 mg once a day) alone or in combination with 200 mg of celecoxib twice a day. Mucosal damage was assessed by endoscopy. The mean mucosal injury score was 5.8 +/- 1.8 in subjects treated with aspirin and 2.4 +/- 0.7 (P < 0.01 vs. aspirin) in subjects treated with NCX-4016. Administration of celecoxib increased the injury score in volunteers treated with aspirin (9.9 +/- 1.9) but not in subjects taking NCX-4016 (1.5 +/- 0.8). Aspirin and NCX-4016 caused a comparable suppression of serum thromboxane B2 levels and increased urinary excretion of ATL. Celecoxib inhibited endotoxin-induced prostaglandin E2 generation in whole blood by approximately 80% and abolished ATL formation. These findings suggests that (i) aspirin and NCX-4016 trigger ATL formation in humans, (ii) celecoxib inhibits ATL formation and exacerbates the mucosal injury caused by low doses of aspirin, and (iii) the NO-donating moiety of NCX-4016 protects the gastric mucosa even in the presence of suppression of COX-1 and COX-2.

Adult↗
PubMed2006

Aspirin desensitization in aspirin intolerance: update on current standards and recent improvements.

PURPOSE OF REVIEW: This review provides an overview of sensitivity to aspirin (acetylsalicylic acid) and its management. In particular, it focuses on current standards and recent improvements in aspirin desensitization. Recent publications on various desensitization protocols and routes of administration are discussed. RECENT FINDINGS: The incidence of aspirin hypersensitivity in the general population ranges from 0.6-2.5%, but that in adult asthmatics ranges from 4.3-11%. Carefully controlled challenge tests with aspirin or other non-steroidal anti-inflammatory drugs are performed as the diagnostic tool of choice. Aspirin desensitization therapy has demonstrated therapeutic effects. Various protocols and routes of administration have been elaborated in the last two decades. Oral administration by means of an initial desensitization with incremental doses of aspirin, followed by daily high-dose therapy, has proven clinical efficacy and safety. Immunological mechanisms of aspirin desensitization therapy are also discussed. SUMMARY: The full clinical picture of aspirin intolerance--the association of aspirin-induced bronchial asthma (with severe acute asthma attacks), aspirin sensitivity and nasal polyps--is commonly summarized as the 'Samter triad'. This condition is related to the abnormal metabolism of arachidonic acid, implicating both the lipoxygenase and the cyclooxygenase pathways. Knowledge concerning mechanisms and clinical features of aspirin intolerance has grown rapidly in recent years. Research has focused on new strategies of aspirin desensitization therapy, especially oral administration using high-dosage protocols.

Aspirin↗
PubMed2004

Clopidogrel plus omeprazole compared with aspirin plus omeprazole for aspirin-induced symptomatic peptic ulcers/erosions with low to moderate bleeding/re-bleeding risk -- a single-blind, randomized controlled study.

BACKGROUND: Clopidogrel causes significantly less symptomatic peptic ulcer disease and gastrointestinal bleeding than low-dose aspirin in average-risk patients. The gastrotoxicity of clopidogrel in patients with active peptic ulcer disease is unknown. AIM: To compare the incidence of unhealed ulcers in patients receiving clopidogrel or aspirin. METHODS: Patients with aspirin-induced peptic ulcer disease treated with omeprazole (20 mg/day) were randomized to receive clopidogrel (75 mg/day) or to continue with low-dose aspirin. Success was defined as ulcer/erosion healing at the eighth week. RESULTS: One hundred and twenty-nine patients were recruited (69 received clopidogrel and 60 continued with aspirin). Thirty-one (45%) in the clopidogrel group and 25 (42%) in the aspirin group had a minor gastrointestinal bleed. No ulcer showed an adherent clot or visible vessel. The distributions of peptic ulcer disease were similar in the clopidogrel and aspirin groups (gastric ulcer: 41% vs. 40%; duodenal ulcer: 10% vs. 12%; gastric ulcer + duodenal ulcer: 6% vs. 3%; gastritis: 32% vs. 37%; duodenitis: 4% vs. 7%; gastritis + duodenitis: 0% vs. 2%). Clopidogrel and aspirin were re-started after 0.86 +/- 1.79 and 0.44 +/- 1.60 days, respectively (P = 0.170). Three (4%) patients stopped clopidogrel due to drug rash. Using per protocol analysis, the treatment success rates of clopidogrel and aspirin were 94% (62/66) and 95% (57/60), respectively. CONCLUSIONS: In patients with aspirin-associated peptic ulcer disease of low to moderate grade, both early conversion from aspirin to clopidogrel and continuation of aspirin are safe.

Adolescent↗
PubMed1994

Plasma acetylsalicylic acid and salicylic acid levels during aspirin provocation in aspirin-sensitive subjects.

The ability of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit the cyclo-oxygenase which catalyzes formation of prostaglandins appears to be central to the mechanisms involved in aspirin sensitivity. We have investigated whether the plasma levels of acetylsalicylic acid (ASA) and its main metabolite salicylic acid (SA) at the time of intolerance reactions correspond with the concentrations required for enzyme inhibition in vitro. Twelve aspirin-sensitive and 15 aspirin-tolerant subjects were followed during provocation with aspirin. ASA and SA concentrations in plasma were determined by HPLC. After oral provocation (up to 460 mg cumulative dose), the levels of ASA and SA in plasma were equivalent in aspirin-sensitive and aspirin-tolerant subjects. For the aspirin-sensitive subjects, at the time of adverse reaction, the concentration range was 2.9-33.3 microM for ASA and 18.1-245 microM for SA. Oral provocation with sodium salicylate yielding 10-fold higher SA levels did not elicit intolerance reactions. Statistically significantly lower levels of ASA and SA (P < or = 0.01) evoked airway obstruction, as compared with merely extrapulmonary symptoms. Bronchial absorption of aspirin was found after inhalation of lysine-aspirin and was comparable in asthmatic and nonasthmatic subjects. In three aspirin-sensitive subjects who developed airway obstruction, the plasma levels for ASA and SA were 0.9-2.6 microM and 0.0-6.7 microM, respectively. In conclusion, the plasma levels of ASA reached at the time of a positive reaction are of the magnitude known to inhibit cyclo-oxygenases. Neither differences in bioavailability of ASA nor the formation of SA seems to contribute to the aspirin-elicited reactions.

Administration, Oral↗
PubMed2002

Department of Veterans Affairs Cooperative Studies Program Clinical Trial comparing combined warfarin and aspirin with aspirin alone in survivors of acute myocardial infarction: primary results of the CHAMP study.

BACKGROUND: Both aspirin and warfarin when used alone are effective in the secondary prevention of vascular events and death after acute myocardial infarction. We tested the hypothesis that aspirin and warfarin therapy, when combined, would be more effective than aspirin monotherapy. Methods and Results- We conducted a randomized open-label study to compare the efficacy of warfarin (target international normalized ratio 1.5 to 2.5 IU) plus aspirin (81 mg daily) with the efficacy of aspirin monotherapy (162 mg daily) in reducing the total mortality in 5059 patients enrolled within 14 days of infarction and followed for a median of 2.7 years. Secondary end points included recurrent myocardial infarction, stroke, and major hemorrhage. Four hundred thirty-eight (17.3%) of 2537 patients assigned to the aspirin group and 444 (17.6%) of 2522 patients assigned to the combination group died (log-rank P=0.76). Recurrent myocardial infarction occurred in 333 patients (13.1%) taking aspirin and in 336 patients (13.3%) taking combination therapy (log-rank P=0.78). Stroke occurred in 89 patients (3.5%) taking aspirin and in 79 patients (3.1%) taking combination therapy (log-rank P=0.52). Major bleeding occurred more frequently in the combination therapy group than in the aspirin group (1.28 versus 0.72 events per 100 person years of follow-up, respectively; P<0.001). There were 14 individuals with intracranial bleeds in both the aspirin and combination therapy groups. CONCLUSIONS: In post-myocardial infarction patients, warfarin therapy (at a mean international normalized ratio of 1.8) combined with low-dose aspirin did not provide a clinical benefit beyond that achievable with aspirin monotherapy.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

A cost-effectiveness analysis of combination antiplatelet therapy for high-risk acute coronary syndromes: clopidogrel plus aspirin versus aspirin alone.

BACKGROUND: Although clopidogrel plus aspirin is more effective than aspirin alone in preventing subsequent vascular events in patients with unstable angina, the cost-effectiveness of this combination has yet to be examined in this high-risk population. OBJECTIVE: To determine the cost-effectiveness of clopidogrel plus aspirin compared with aspirin alone. DESIGN: Cost-utility analysis. DATA SOURCES: Published literature. TARGET POPULATION: Patients with unstable angina and electrocardiographic changes or non-Q-wave myocardial infarction. time horizon: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Combination therapy with clopidogrel, 75 mg/d, plus aspirin, 325 mg/d, for 1 year, followed by aspirin monotherapy, was compared with lifelong aspirin therapy, 325 mg/d. OUTCOME MEASURES: Lifetime costs, life expectancy in quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio. RESULTS OF BASE-CASE ANALYSIS: Patients treated with aspirin alone lived 9.51 QALYs after their initial event and incurred expenses of 127,700 dollars; the addition of clopidogrel increased life expectancy to 9.61 QALYs and costs to 129,300 dollars. The incremental cost-effectiveness ratio for clopidogrel plus aspirin compared with aspirin alone was 15,400 dollars per QALY. RESULTS OF SENSITIVITY ANALYSES: The analysis of 1 year of therapy was robust to all sensitivity analyses. In the probabilistic sensitivity analysis, fewer than 3% of simulations resulted in cost-effectiveness ratios over 50,000 dollars per QALY. The cost-effectiveness of longer combination therapy depends critically on the balance of thrombotic event rates, durable efficacy, and the increased bleeding rate in patients taking clopidogrel. LIMITATIONS: This analysis may not apply to patients with severe heart failure, those undergoing long-term anticoagulant therapy, those recently managed with revascularization, or those undergoing short-term treatment with glycoprotein IIb/IIIa inhibitors. CONCLUSIONS: In patients with high-risk acute coronary syndromes, 1 year of therapy with clopidogrel plus aspirin results in greater life expectancy than aspirin alone, at a cost within the traditional limits of cost-effectiveness. The durable efficacy of clopidogrel relative to the risk for hemorrhage should be further explored before more protracted therapy can be recommended.

Angina, Unstable↗
PubMed1983

Comparison of aspirin and copper aspirinate with respect to gastric mucosal damage in the rat.

The copper salt of aspirin has been compared with aspirin in terms of damage to mucosal tissue. Using a protein-bound dye to highlight erosions, it has been found that copper aspirinate is at least as damaging as aspirin itself. This finding is not in agreement with previously published claims. Copper aspirinate produced more widespread superficial erosions and slightly less deep erosions than aspirin alone. Mixtures of the copper(II) ion and aspirin produced results similar to copper aspirinate, suggesting that the hydrolysis products of copper aspirinate, copper(II) ion and aspirin, together may be especially damaging to the mucosa. Copper alone was not damaging, but aspirin alone yielded intermediate results. Short incubation times produced only erosions (no ulcers), which were clearly differentiated into two classes by depth of color. Histological examination verified this classification into superficial and deep erosions.

Animals↗