[Prevention of cardiovascular events with antiplatelet drugs: aspirin (and others)?].
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Aspirin↗
Biomedical subjects
C Patrono
Publications and source records attributed to C Patrono.
Prevention of myocardial infarction and stroke by aspirin: different mechanisms? Different dosage?
More than 50 randomized trials have documented the efficacy and safety of aspirin as an antiplatelet agent and a cardiovascular drug. However, the optimal dose for preventing coronary and cerebral thrombosis has long been a cause of debate. For patients with ischaemic heart disease the range recommended for the prevention of a secondary event, based on strong clinical evidence, is 75-160 mg aspirin/day. For patients with cerebrovascular disease, recommendations range from 30-1300 mg/day. If these patients require a higher dose of aspirin it suggests that a different mechanism of action is involved. This paper considers hypotheses and reports the findings of recent clinical trials. The SALT study compared aspirin with placebo in 1360 patients with TIA or minor ischaemic stroke. It showed an 18% reduction in the risk of stroke or death in patients receiving 75 mg aspirin/day. Five other trials of 55,000 patients with ischaemic cerebrovascular disease compared the protective effect of aspirin (range 30-300 mg/day) with placebo, clopidogrel, or oral anticoagulants. Aspirin was better than placebo, safer than oral anticoagulants, and no different from clopidogrel. The implications of these findings are discussed. Mechanistic studies and randomized clinical trials strongly suggest that the mechanism of action and dose requirement of the antithrombotic effect of aspirin in patients with cerebrovascular disease is the same as that for ischaemic heart disease.
Aspirin↗
Effects of nimesulide on constitutive and inducible prostanoid biosynthesis in human beings.
BACKGROUND: The aim of this study was to test the hypothesis that nimesulide, a nonsteroidal antiinflammatory drug, or its principal metabolite 4-hydroxynimesulide, is a selective inhibitor of prostaglandin H synthase-2 in human beings. METHODS: Heparinized whole blood samples obtained from healthy subjects were incubated with lipopolysaccharide (10 micrograms/ml) for 24 hours at 37 degrees C and prostaglandin E2 was measured in plasma as an index of monocyte prostaglandin H synthase-2 activity. The production of thromboxane B2 in whole blood allowed to clot at 37 degrees C for 60 minutes was assessed as an index of platelet prostaglandin H synthase-1 activity. We also measured the urinary excretion of 11-dehydrothromboxane B2, prostaglandin E2, 6-ketoprostaglandin F1 alpha, and thromboxane B2 as in vivo indexes of cyclooxygenase activity. All prostanoids were measured by previously validated radioimmunoassay techniques. RESULTS: In the whole blood assays in vitro, nimesulide was twentyfold more potent than 4-hydroxynimesulide toward the two isozymes and both compounds displayed a twentyfold preference for prostaglandin H synthase-2 versus prostaglandin H synthase-1. The administration of a single oral dose of 100 mg nimesulide to six healthy subjects significantly (p < 0.01) reduced monocyte prostaglandin H synthase-2 and prostaglandin H synthase-1 activity ex vivo by more than 90% and 50%, respectively, up to 6 hours. At 24 hours, prostaglandin H synthase-2 but not prostaglandin H synthase-1 activity was significantly reduced by 49% (p < 0.05). Nimesulide significantly (p < 0.05) reduced the urinary excretion of 11-dehydrothromboxane B2 and 6-ketoprostaglandin F1 alpha by approximately 30% and 25%, respectively, while not affecting that of prostaglandin E2 and thromboxane B2. CONCLUSIONS: Nimesulide is a potent inhibitor of human monocyte prostaglandin H synthase-2. However, despite a twentyfold selectivity ratio, therapeutic plasma levels of nimesulide are sufficiently high to cause detectable inhibition of platelet prostaglandin H synthase-1.
Adult↗
Platelet-active drugs: the relationships among dose, effectiveness, and side effects.
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Aspirin↗
Eicosanoids and iso-eicosanoids: constitutive, inducible and transcellular biosynthesis in vascular disease.
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Animals↗
Platelet activation and inhibition in unstable coronary syndromes.
Platelet activation occurs episodically in unstable angina, as reflected by enhanced thromboxane metabolite excretion, and most episodes can be suppressed by low-dose aspirin. Biochemical evidence of platelet activation and electrocardiographic evidence of myocardial ischemia are often temporally dissociated, thus suggesting the likely involvement of different triggers. Aspirin is effective in reducing the short-term and long-term risks of myocardial infarction and death by 40-60%, in a dose-independent fashion consistent with the saturability of platelet cyclo-oxygenase inhibition at low doses. Suppression of platelet thromboxane synthesis by aspirin and the blockade of platelet adenosine diphosphate receptors by ticlopidine or clopidogrel appear to have a similar impact on limiting the risk of a thrombotic outcome of plaque fissuring, thereby suggesting combined strategies for future studies.
Angina, Unstable↗
Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina.
BACKGROUND: We have previously reported aspirin failure in suppressing enhanced thromboxane (TX) biosynthesis in a subset of episodes of platelet activation during the acute phase of unstable angina. The recent discovery of a second prostaglandin H synthase (PGHS-2), inducible in response to inflammatory or mitogenic stimuli, prompted us to reexamine TXA2 biosynthesis in unstable angina as modified by two cyclooxygenase inhibitors differentially affecting PGHS-2 despite a comparable impact on platelet PGHS-1. METHODS AND RESULTS: We randomized 20 patients (15 men and 5 women aged 59+/-10 years) with unstable angina to short-term treatment with aspirin (320 mg/d) or indobufen (200 mg BID) and collected 6 to 18 consecutive urine samples. Urinary 11-dehydro-TXB2 was extracted and measured by a previously validated radioimmunoassay as a reflection of in vivo TXA2 biosynthesis. Metabolite excretion averaged 102 pg/mg creatinine (median value; n=76) in the aspirin group and 55 pg/mg creatinine (median value; n=99) in the indobufen group (P<.001). There were 16 samples (21%) with 11-dehydro-TXB2 excretion >200 pg/mg creatinine among patients treated with aspirin versus 6 such samples (6%) among those treated with indobufen (P<.001). In vitro and ex vivo studies in healthy subjects demonstrated the capacity of indobufen to largely suppress monocyte PGHS-2 activity at therapeutic plasma concentrations. In contrast, aspirin could only inhibit monocyte PGHS-2 transiently at very high concentrations. CONCLUSIONS: We conclude that in unstable angina, episodes of aspirin-insensitive TXA2 biosynthesis may reflect extraplatelet sources, possibly expressing the inducible PGHS in response to a local inflammatory milieu, and a selective PGHS-2 inhibitor would be an ideal tool to test the clinical relevance of this novel pathway of arachidonic acid metabolism in this setting.
Aged↗
Diabetes mellitus, hypercholesterolemia, and hypertension but not vascular disease per se are associated with persistent platelet activation in vivo. Evidence derived from the study of peripheral arterial disease.
BACKGROUND: Previous studies relating increased thromboxane (TX) biosynthesis to cardiovascular risk factors do not answer the question whether platelet activation is merely a consequence of more prevalent atherosclerotic lesions or reflects the influence of metabolic and hemodynamic disturbances on platelet biochemistry and function. METHODS AND RESULTS: We examined 64 patients with large-vessel peripheral arterial disease and 64 age- and sex-matched control subjects. TXA2 biosynthesis was investigated in relation to cardiovascular risk factors by repeated measurements of the urinary excretion of its major enzymatic metabolite, 11-dehydro-TXB2, by radioimmunoassay. Urinary 11-dehydro-TXB2 was significantly (P = .0001) higher in patients with peripheral arterial disease (57 +/- 26 ng/h) than in control subjects (26 +/- 7 ng/h). Seventy percent of patients had metabolite excretion > 2 SD above the normal mean. However, 11-dehydro-TXB2 excretion was enhanced only in association with cardiovascular risk factors. Multivariate analysis showed that diabetes, hypercholesterolemia, and hypertension were independently related to 11-dehydro-TXB2 excretion. During a median follow-up of 48 months, 8 patients experienced major vascular events. These patients had significantly (P = .001) higher 11-dehydro-TXB2 excretion at baseline than patients who remained event free. CONCLUSIONS: The occurrence of large-vessel peripheral arterial disease per se is not a trigger of platelet activation in vivo. Rather, the rate of TXA2 biosynthesis appears to reflect the influence of coexisting disorders such as diabetes mellitus, hypercholesterolemia, and hypertension on platelet biochemistry and function. Enhanced TXA2 biosynthesis may represent a common link between such diverse risk factors and the thrombotic complications of peripheral arterial disease.
Adult↗
Unstable coronary artery disease: need for long-term antithrombotic treatment? Aspirin alone may not be the ideal antithrombotic strategy, but that's what we have adequate trial data for.
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Anticoagulants↗
Isoprostanes: potential markers of oxidant stress in atherothrombotic disease.
Isoprostanes are emerging as a new class of biologically active products of arachidonic acid metabolism of potential relevance to human vascular disease. Their formation in vivo seems to reflect primarily, if not exclusively, a nonenzymatic process of lipid peroxidation. Enhanced urinary excretion of 8-iso-PGF2 alpha has been described in association with cardiac reperfusion injury and with cardiovascular risk factors, including cigarette smoking, diabetes mellitus, and hypercholesterolemia. Besides providing a likely noninvasive index of lipid peroxidation in these settings, measurements of specific F2 isoprostanes in urine may provide a sensitive biochemical end point for dose-finding studies of natural and synthetic inhibitors of lipid peroxidation. Although the biological effects of 8-iso-PGF2 alpha in vitro suggest that it and other isoeicosanoids may modulate the functional consequences of lipid peroxidation, evidence that this is likely in vivo remains inadequate at this time.
Antioxidants↗
In vivo formation of 8-Epi-prostaglandin F2 alpha is increased in hypercholesterolemia.
F2-isoprostanes are bioactive prostaglandin (PG)-like compounds that are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF2 alpha may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formation of 8-epi-PGF2 alpha is altered in patients with hypercholesterolemia and contributes to platelet activation in this setting. Urine samples were obtained from 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects for measurement of immunoreactive 8-epi-PGF2 alpha. Urinary excretion of 11-dehydro-thromboxane (TX) B2, a major metabolite of TXA2, was measured as an in vivo index of platelet activation. Low-dose aspirin, indobufen, and vitamin E were used to investigate the mechanism of formation and effects of 8-epi-PGF2 alpha on platelet activation. Urinary 8-epi-PGF2 alpha was significantly (P = .0001) higher in hypercholesterolemic patients than in control subjects: 473 +/- 305 versus 205 +/- 95 pg/mg creatinine. Its rate of excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8-epi-PGF2 alpha was unchanged after 2-week dosing with aspirin and indobufen despite complete suppression of TX metabolite excretion. Vitamin E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF2 alpha and 11-dehydro-TXB2 by 34% to 36% and 47% to 58% at 100 and 600 mg daily, respectively. We conclude that the in vivo formation of the F2-isoprostane 8-epi-PGF2 alpha is enhanced in the vast majority of patients with hypercholesterolemia. This provides an aspirin-insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation in the setting of hypercholesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF2 alpha formation by vitamin E supplementation may contribute to the beneficial effects of antioxidant treatment.
Antioxidants↗
Platelet activation and lipid peroxidation in patients with acute ischemic stroke.
BACKGROUND AND PURPOSE: Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, thromboxane (TX) A2, or by free radical-catalyzed peroxidation of arachidonic acid, ie, isoprostanes. We investigated the biosynthesis of TXA2 and F2-isoprostanes, as reflected by the urinary excretion of 11-dehydro-TXB2 and 8-epi-prostaglandin (PG) F2 alpha respectively, in 62 consecutive patients (30 men, 32 women; mean age, 67 +/- 14 years) with acute ischemic stroke. METHODS: At least two consecutive 6-hour urine samples were obtained during the first 72 hours after onset of symptoms. Urinary eicosanoids were measured by previously described radioimmunoassays. RESULTS: Repeated periods of enhanced thromboxane biosynthesis were found in 52% of patients. Urinary 11-dehydro-TXB2 averaged 221 +/- 207 (mean +/- SD; n = 197; range, 13 to 967) pmol/mmol creatinine in 30 patients treated with cyclooxygenase inhibitors (mostly aspirin) at the time of study versus 392 +/- 392 (n = 186; range, 26 to 2533) in 32 untreated patients (P < .001). The corresponding values for 8-epi-PGF2 alpha excretion were 74 +/- 42 (range, 14 to 206) and 83 +/- 65 (range, 24 to 570) pmol/mmol creatinine (P > .05). The correlation between the two metabolites was moderate in both untreated patients (r = .41, P < .001) and patients with cyclooxygenase inhibitors (r = .31, P < .001). In a multiple regression analysis, increased thromboxane production was independently associated with severity of stroke on admission, atrial fibrillation, and treatment with cyclooxygenase-inhibiting drugs. CONCLUSIONS: We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.
Acute Disease↗
Mechanisms of bleeding and thrombosis in myeloproliferative disorders.
Arterial and venous thromboses and microcirculatory disturbances such as erythromelalgia and neurologic and visual symptoms are the thrombotic manifestations occurring in Polycythaemia Vera and Essential Thrombocythaemia. The increased in vivo thromboxane A2 generation existing in these patients and the selective sensitivity of erythromelalgia to aspirin suggest that platelet PGG/H synthase products may be involved in transducing the increased thrombotic risk. The relationship between Thromboxane A2 production and thrombotic accidents will be investigated by the European Collaboration on Low-Dose Aspirin in Polycythaemia Vera (ECLAP) which will test the efficacy of low-dose aspirin by a randomised clinical trial. The haemorrhagic diathesis of polycythaemic and thrombocythaemic subjects is generally mild and spontaneous bleeding usually manifests in patients with very high platelet count. Its mechanism may be related to quantitative as well as to qualitative platelet changes. Possible mechanisms linking the high grade thrombocytosis to bleeding are consumption of von Willebrand factor and clot fragility due to a mechanical effect of the high platelet count or to inhibition of fibrin polymerization by platelet Glycoprotein Ib.
Blood Platelets↗
Differential inhibition of human prostaglandin endoperoxide synthase-1 and -2 by nonsteroidal anti-inflammatory drugs.
We have evaluated the selectivity in vitro of various conventional nonsteroidal anti-inflammatory drugs (NSAIDs) and new anti-inflammatory compounds (NS-398, L-745,337 and SC58125) in inhibiting the cyclooxygenase activity of platelet prostaglandin endoperoxide synthase (PGHS)-1 and monocyte PGHS-2 in a human whole blood assay. The effects of the compounds towards the cyclooxygenase activity of monocyte PGHS-2 induced in response to lipopolysaccharide (LPS) was evaluated by measuring the levels of PGE2 produced in plasma. The effects of the same inhibitors on platelet PGHS-1 activity were assessed by allowing 1-ml whole blood samples to clot at 37 degrees C for 1 h in the presence of the compounds and measuring immunoreactive TXB2 levels in serum. Under these experimental conditions, most compounds resulted equipotent towards the two isozymes. Differently, meloxicam, nimesulide and diclofenac were approximately 10- to 20-fold more potent in inhibiting the cyclooxygenase activity of monocyte PGHS-2 than platelet PGHS-1. L-745,337, NS-398 and SC58125 achieved selective inhibition of monocyte PGHS-2 (IC50, PGHS-1/IC50, PGHS-2: < 100) and may provide adequate tools to test the contribution of this novel pathway of arachidonate metabolism to human inflammatory disease and to verify the hypothesis that the common side-effects of NSAIDs are due primarily to their ability to affect the activity of PGHS-1.
Anti-Inflammatory Agents, Non-Steroidal↗
Induction of prostaglandin endoperoxide synthase-2 in human monocytes associated with cyclo-oxygenase-dependent F2-isoprostane formation.
1. The isoprostane 8-epi-prostaglandin (PG)F2 alpha is produced by free radical-catalyzed peroxidation of arachidonic acid. It may also be formed as a minor product of the cyclo-oxygenase activity of platelet PGH synthase (PGHS)-1. We investigated 8-epi-PGF2 alpha production associated with induction of the human monocyte PGHS-2 and its pharmacological modulation. 2. Heparinized whole blood samples were drawn from healthy volunteers, 48 h following oral dosing with aspirin 300 mg to suppress platelet cyclo-oxygenase activity. One ml aliquots were incubated with lipopolysaccharide (LPS: 0.1-50 micrograms ml-1) for 0-24 h at 37 degrees C. PGE2 and 8-epi-PGF2 alpha were measured in separated plasma by radioimmunoassay and enzyme immunoassay techniques. 3. Levels of both eicosanoids were undetectable (i.e. < 60 pg ml-1) at time 0. LPS induced the formation of PGE2 and 8-epi-PGF2 alpha in a time- and concentration-dependent fashion, coincident with the induction of PGHS-2 detected by Western blot analysis of monocyte lysates. After 24 h at 10 micrograms ml-1 LPS, immunoreactive PGE2 and 8-epi-PGF2 alpha averaged 10,480 +/- 4,643 and 295 +/- 140 pg ml-1 (mean +/- s.d., n = 6), respectively. 4. Dexamethasone and 5-methanesulphonamido-6-(2,4-difluorothiophenyl)-1-indano ne (L-745,337), a selective inhibitor of the cyclo-oxygenase activity of PGHS-2, reduced PGE2 and 8-epi-PGF2 alpha production in response to LPS. 5. Isolated monocytes produced PGE2 and 8-epi-PGE2 alpha in response to LPS (10 micrograms ml-1) in a time-dependent fashion. Monocyte PGE2 and 8-epi-PGF2 alpha production was largely prevented by dexamethasone (2 microM) and cycloheximide (10 micrograms ml-1) in association with suppression of PGHS-2 but not of PGHS-1 expression. 6. We conclude that the induction of PGHS-2 in human monocytes is associated with cyclo-oxygenase-dependent generation of the vasoconstrictor and platelet-agonist 8-epi-PGF2 alpha.
Adult↗
Aspirin in ischemic cerebrovascular disease. How strong is the case for a different dosing regimen?
BACKGROUND: A vast consensus exists in defining a narrow range of recommended daily doses of aspirin, ie, 75 to 160 mg, for the prevention of myocardial infarction, stroke, and vascular death in patients with different manifestations of coronary hearth disease. In contrast, for patients with cerebrovascular disease, a much larger degree of uncertainty still exists, with recommendations ranging from 30 to 1300 mg daily. SUMMARY OF COMMENT: The contention that higher doses of aspirin (650 to 1300 mg) are more effective than lower doses in stroke prevention is based on indirect and selective comparisons of different trial data, mini-meta-analyses, or subgroup analyses of individual trials. In the absence of definitive evidence from direct randomized comparisons of low-dose versus high-dose aspirin in trials of adequate size to detect a moderate difference between the two, the biological hypotheses that underpin the suggestion of greater efficacy of higher aspirin doses in cerebrovascular disease patients are reviewed and disputed. Practical implications of the use of higher doses of aspirin are also assessed on the basis of theoretical calculations of absolute benefits and risks. CONCLUSIONS: Until additional information from ongoing trials is available, good clinical practice should dictate the use of the lowest dose of aspirin shown effective in the prevention of stroke and death in patients with ischemic cerebrovascular disease, ie, 75 mg daily.
Aspirin↗
Aspirin in polycythemia vera and essential thrombocythemia: current facts and perspectives.
The role of aspirin in the antithrombotic strategy of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is highly controversial. Long considered unsafe on the basis of a single clinical trial testing very high doses in PV patients, aspirin is being increasingly used at lower dosage. The rationale for the use of aspirin in patients with PV and ET is provided by the efficacy of this agent in the treatment of microcirculatory disturbances of thrombocythemic states associated with myeloproliferative disorders and by recent evidence that asymptomatic PV and ET patients have persistently increased thromboxane (TX) A2-biosynthesis. This increase, which most likely reflects enhanced platelet activation in vivo, is independent of the platelet mass and blood viscosity and largely supressed by a short term low-dose aspirin regimen (50 mg/day for 7 days). Since enhanced TXA2 biosynthesis may play a role in transducing the increased thrombotic risk associated with PV and ET, long-term low-dose aspirin administration has been proposed as a possible antithombotic strategy in these subjects. The safety of this treatment in PV patients has been recently reassessed by the Gruppo Italiano per lo Studio della Policitemia Vera (GISP) which has followed for over one year 112 patients randomized to receive 40 mg/day aspirin or placebo. In the same study, serum TXB2 measurements provided evidence that the low-dose aspirin regimen tested was fully effective in inhibiting platelet cyclooxygenase activity. On this basis, a large scale trial aimed at assessing the antithrombotic efficacy of this approach is currently being organized. In patients with ET both the minimal aspirin dose required for complete inhibition of platelet cyclooxygenase and the safety of long-term aspirin administration need to be established prior to extensive clinical evaluation of this strategy.
Adult↗
Effects of nabumetone on prostanoid biosynthesis in humans.
BACKGROUND: The active metabolite of the anti-inflammatory drug nabumetone has been characterized as a selective inhibitor of the inducible prostaglandin H synthase (PGHS). The aim of this study was to investigate the rate of eicosanoid biosynthesis after oral dosing with nabumetone in nine healthy subjects. METHODS: We measured the urinary excretion of products of platelet (11-dehydro-thromboxane B2 [TXB2]) and renal (prostaglandin IF2 alpha [PGF2 alpha]) arachidonate metabolism as in vivo indexes of the constitutive PGHS-1 pathway. Moreover, the production of TXB2 during whole blood clotting was assessed as an index of the cyclooxygenase activity of platelet PGHS-1 ex vivo. RESULTS: At steady state, nabumetone (500 and 1000 mg daily for 7 days) was associated with statistically significant dose-dependent reduction in the urinary excretion of 11-dehydro-TXB2 and serum TXB2 levels by approximately 50% to 70%. However, the drug did not significantly affect the urinary excretion of PGF2 alpha. After discontinuation of nabumetone, urinary 11-dehydro-TXB2 excretion and whole blood TXB2 production returned to predrug levels with a similar timecourse that was consistent with the elimination half-life of its active metabolite. The daily administration of low-dose aspirin (40 mg), a selective inhibitor of platelet PGHS-1, caused a cumulative inhibition of urinary 11-dehydro-TXB2 and whole blood TXB2 production that recovered with a timecourse consistent with platelet turnover. CONCLUSIONS: Nabumetone does dose-dependently inhibit the cyclooxygenase activity of platelet PGHS-1 of healthy subjects both in vivo and ex vivo. Thus it is unlikely that its safety profile in patients may be related to selective inhibition of the inducible PGHS-2.
Administration, Oral↗