Effects of low-dose aspirin on serum C-reactive protein and thromboxane B2 concentrations: a placebo-controlled study using a highly sensitive C-reactive protein assay.

OBJECTIVES

We performed a placebo-controlled study to evaluate the effect of low-dose aspirin on serum C-reactive protein (CRP) levels.

BACKGROUND

Elevated circulating concentrations of CRP, an inflammatory marker, increase the risk of thrombotic cardiovascular diseases such as myocardial infarction (MI). Moreover, low-dose aspirin therapy has been reported to be more effective in preventing MI in men with higher CRP levels than it is in those with lower levels, raising the possibility that aspirin prevents thrombosis by reducing vascular inflammation. The effect of low-dose aspirin therapy on serum CRP levels in men has been addressed recently, but the results of the two studies conflict.

METHODS

Effects of aspirin (81 mg every day or 325, 81 or 40 mg every-third-day given for 31 days) on serum CRP, using a highly-sensitive assay, and on serum platelet-cyclo-oxygenase (COX)-1-derived thromboxane (Tx) B₂ concentrations were studied simultaneously in 57 healthy volunteers (30 men and 27 women).

RESULTS

Trough platelet COX-1-derived serum Tx B₂ concentrations decreased by 100% with daily aspirin and by 90%, 84% and 78% with 325, 81 and 40 mg aspirin every-third-day (p < 0.001). However, there were no significant changes in serum CRP levels from baseline with daily low-dose aspirin therapy, with any of the every-third-day aspirin regimens or with placebo treatment.

CONCLUSIONS

Low doses of aspirin that markedly inhibit platelet COX-1 activity, as manifested by a profound decline in platelet-derived serum Tx B₂ concentrations, have no detectable effect on serum CRP levels in healthy men and women.     

Platelet inhibition by aspirin 81 and 325 mg/day in men versus women without clinically apparent cardiovascular disease

Compared with men, women have greater platelet aggregation before and after low-dose aspirin. It is not known whether high-dose aspirin therapy brings residual platelet aggregation in women closer to that in men. Our objective was to compare inhibition of platelet aggregation in women and men after low- and high-dose aspirin. We enrolled healthy subjects (n=106) in a trial of 14 days of aspirin 81 mg/day followed by 14 days of 325 mg/day. Platelet function was measured at baseline and after the 2 aspirin doses. Women had greater baseline platelet activation measurements. After the 2 aspirin doses, men and women had near complete suppression of platelet aggregation to arachidonic acid in whole blood and in platelet-rich plasma (PRP), the direct cyclo-oxygenase-1 pathway affected by aspirin. For indirect pathways, women had significantly greater residual platelet activation to collagen and adenosine diphosphate (ADP) in whole blood after the 2 aspirin doses and in response to collagen and ADP in PRP after aspirin 325 mg/day only. After aspirin 325 mg/day, women continued to have greater residual platelet aggregation compared with men after aspirin 81 mg/day in response to collagen (p=0.016 in whole blood, p=0.037 in PRP), ADP (p<0.001 in whole blood, p=0.012 in PRP), and epinephrine (p=0.03 in PRP). Excretion of urinary thromboxane metabolite (urinary 11-dehydrothromboxane B2) decreased after aspirin to a similar extent in men and women. In conclusion, women continue to have greater residual platelet activity after high-dose aspirin compared with men treated with a lower dose of aspirin.     

C-reactive protein levels increase after exercise testing in patients with increased platelet reactivity

Aspirin has the potential to influence C-reactive protein (CRP) levels, an inflammatory marker, by its anti-inflammatory activity. Persistently increased platelet reactivity, however, can be detected with different laboratory methods despite aspirin therapy in some patients. The aim of this study was to investigate the effects of increased platelet reactivity on CRP levels at rest and after exercise in patients with documented or suspected coronary artery disease. Blood samples were collected from 100 patients (age, 58.1+/-8.5 years; 63.0% men) who were treated with 100 or 300 mg/day enteric-coated aspirin for at least 7 days, before and immediately after treadmill test for CRP analyses. Platelet reactivity was measured by the standardized platelet function analyzer-100, and increased platelet reactivity was defined as a normal collagen/epinephrine closure time (<165 s). Of the 100 patients, 82 had normal platelet reactivity (group A) and 18 had increased platelet reactivity (group B). The CRP levels increase was statistically significant after exercise in patients with increased platelet reactivity [group A: 2.3 (1.4-4.3) to 2.8 (1.6-4.9) mg/l, P=0.09; group B: 3.3 (2.0-4.5) to 4.7 (2.9-8.5) mg/l, P=0.02]. Detecting increased platelet reactivity is associated with an increase in CRP levels. The clinical significance of this finding needs to be further investigated.     

Projected life-expectancy gains with statin therapy for individuals with elevated C-reactive protein levels

OBJECTIVES: We sought to estimate the potential gains in life expectancy achieved with statin therapy for individuals without overt hyperlipidemia but with elevated C-reactive protein (CRP) levels. BACKGROUND: Persons with low-density lipoprotein (LDL) cholesterol levels below current treatment guidelines and elevated CRP levels are at increased risk of cardiovascular disease and may benefit from statin therapy. METHODS: We constructed a decision-analytic model to estimate the gains in life expectancy with statin therapy for individuals without overt hyperlipidemia but with elevated CRP levels. The annual risks of myocardial infarction (MI) and stroke, as well as the efficacy of statin therapy, were based on evidence from randomized trials. Estimates of prognosis after MI or stroke were derived from population-based studies. RESULTS: We estimated that 58-year-old men and women with CRP levels >or=0.16 mg/dl but LDL cholesterol <149 mg/dl would gain 6.6 months and 6.4 months of life expectancy, respectively, with statin therapy. These gains were similar to those for patients with LDL cholesterol >or=149 mg/dl (6.7 months for men and 6.6 months for women). In sensitivity analyses, we identified the baseline risk of MI and the efficacy of statin therapy for preventing MI as the most important factors in determining the magnitude of benefit with statin therapy. CONCLUSIONS: Our results suggest that individuals with elevated CRP levels, many of whom do not meet current National Cholesterol Education Program guidelines for drug treatment, may receive a substantial benefit from statin therapy. This analysis supports a crucial need for direct intervention trials aimed at subjects with elevated CRP levels.     

Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans.

BACKGROUND & AIMS: The safety of low-dose daily aspirin therapy in the gastrointestinal tract is uncertain. Our objectives were to evaluate the long-term effects of very low daily aspirin doses in the gastrointestinal tract and effects on platelet-derived serum thromboxane levels in volunteers. METHODS: Subjects were randomized to receive 10 mg (n = 8), 81 mg (n = 11), or 325 mg (n = 10) aspirin daily for 3 months. Before administration of aspirin, all subjects underwent gastroduodenoscopy, and most underwent proctoscopy for assessment of mucosal injury and prostaglandin content. After 1.5 and 3 months, subjects again underwent gastroduodenoscopy and, at 3 months, another proctoscopy. RESULTS: Each aspirin dose (even 10 mg) significantly reduced gastric mucosal prostaglandin levels, to approximately 40% of the baseline value. All three doses also induced significant gastric injury, and 325 mg caused duodenal injury. Three subjects developed gastric ulcers, 1 while taking 10 mg/day of aspirin. Furthermore, aspirin at 81 mg/day and 325 mg/day (but not 10 mg/day) significantly reduced duodenal mucosal prostaglandin levels to approximately 40% of the baseline value. Only 325 mg of aspirin per day significantly reduced rectal mucosal prostaglandin levels to approximately 60% of the baseline value. Serum thromboxane levels were inhibited 62%, 90%, and 98% with 10, 81, and 325 mg of aspirin. CONCLUSIONS: The findings explain aspirin's predominant gastric toxicity and question the safety of even 10 mg of aspirin daily.     

Lack of significant effect of low doses of aspirin on the concentrations of C-reactive protein in a group of individuals with atherothrombotic risk factors and vascular events.

Atherothrombosis is associated with the presence of a microinflammatory response, usually monitored by the use of C-reactive protein (CRP) measurements. In the Physician Health Study it was suggested that individuals who benefit most from the treatment are those who have enhanced concentrations of this biomarker. The possibility was suggested that one of the mechanisms of action of aspirin in thrombotic prevention is through its anti-inflammatory properties in terms of reducing the concentration of CRP. We conducted a regression analysis in a cohort of 3888 apparently healthy individuals and those with atherothrombotic risk factors and vascular events, 370 of whom were under the treatment of low doses (相似文献   

Medicare Coverage Policies: A Macro and Micro Analysis

Markers of inflammation, such as C-reactive protein (CRP) and fibrinogen, have been shown to be predictive of cardiovascular disease. In the Physicians Health Study, the magnitude of reduction in the risk of myocardial infarction with aspirin therapy was related to baseline CRP levels, raising the possibility that the protective effect of aspirin may be due to antiinflammatory properties in addition to its antiplatelet effect. We therefore investigated whether aspirin therapy lowers CRP levels. Because heavy physical exertion is a well-known trigger of myocardial infarction, we also investigated the effect of aspirin on CRP levels before and after strenuous exercise. Thirty-two healthy men, aged 29 ± 6 years, were enrolled in a randomized, double-blind, parallel study. Blood samples were obtained immediately before and after maximal treadmill exercise at baseline and following 7 days of aspirin therapy (81 or 325 mg). The levels of CRP, as measured by ELISA, increased by 13% following exercise (P < 0.0001). However, aspirin did not significantly alter CRP levels, either at rest (0.81 ± 0.13 mg/L before aspirin vs. 0.78 ± 0.13 mg/L on aspirin) or following exercise (0.92 ± 0.13 mg/L before aspirin vs. 0.86 ± 0.13 mg/L on aspirin), P = 0.73. When the resting and postexercise data were combined, the levels were 0.87 ± 0.13 mg/L before aspirin and 0.82 ± 0.13 mg/L on aspirin (a nonsignificant 6% reduction, P = 0.20). In conclusion, in healthy male subjects CRP levels were not significantly reduced by short-term aspirin therapy. Our data, taking together with other reports, suggest that aspirin may not affect the levels of inflammatory markers. However, further studies are needed with a longer duration of therapy, among subjects with coronary heart disease, and using additional markers of inflammation besides CRP to determine the long-term effects of aspirin use.     

Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.

OBJECTIVES: We investigated whether use of low-dose enteric-coated (EC) aspirin for secondary prevention of cardiovascular events has sufficient bioavailability to achieve complete platelet cyclooxygenase (COX) inhibition in all individuals. BACKGROUND: Aspirin reduces cardiovascular morbidity and mortality in patients with pre-existing vascular disease; however, there is variability in the way individuals respond. Persistent normal platelet function despite therapy, referred to as "aspirin resistance," is associated with an increased risk of major cardiovascular events. METHODS: We studied 131 stable cardiovascular patients between March and September 2002 who were taking 75 mg EC aspirin. Serum thromboxane (TX) B2 levels were assayed as a measure of COX activity. Mean arachidonic acid (AA)-induced platelet aggregation > or =20% was deemed evidence of persistent platelet activity and an incomplete aspirin response. RESULTS: Patients of median age 63 years (61% men) were enrolled. Forty-four percent of patients had elevated serum TX B2 levels (>2.2 ng/ml). Arachidonic acid-induced platelet aggregation occurred more frequently in these patients (21% vs. 3%; p = 0.004). In all cases addition of exogenous aspirin during the assay abolished platelet aggregation. Patient weight and age were significant independent predictors of an incomplete response to EC aspirin (p = 0.025 and p < 0.001, respectively). These patients were also more likely to have a history of myocardial infarction (MI) (p = 0.038). CONCLUSIONS: Many patients who are prescribed low-dose EC aspirin for secondary prevention of cardiovascular events have persistent uninhibited platelet COX activity. Younger and heavier patients and those with a previous MI are most likely to have an inadequate response to treatment.     

心肌梗死发作期与血清C反应蛋白关系的探讨

目的探讨血清C反应蛋白(CRP)水平与心肌梗死(MI)发作期的相关性及其与不良心血管事件之间的关系。方法用全自动生化分析仪对40例体检正常者和50例MI发作期(14d内)患者进行血清CRP水平检测,并及时随访不良心血管事件的发生情况。结果入院时MI发作期患者CRP水平为(23.83±6.25)mg/L显著高于正常人的(6.53±3.25)mg/L,差异有统计学意义(P<0.05);MI发作期患者不同时间血清CRP水平与对照组比较,差异均有统计学意义(P<0.05);CRP与不良心血管事件之间的相关系数(r)=0.933。结论 MI发作期患者血清CRP水平明显高于正常对照组,其升高与MI的发作明显相关,可作为急性心肌梗死发作期危险性的一种敏感和可靠的预测因子,另外在临床上血清CRP水平作为MI及心血管意外事件的预报因子也有其敏感性和可靠性。     

Pharmacodynamic interaction of naproxen with low-dose aspirin in healthy subjects

OBJECTIVES: We investigated the occurrence of pharmacodynamic interaction between low-dose aspirin and naproxen. BACKGROUND: The uncertainty of cardioprotection by naproxen has encouraged its combination with aspirin in patients with arthritis and cardiovascular disease. METHODS: The incubation of washed platelets with naproxen for 5 min before the addition of aspirin reduced the irreversible inhibition of thromboxane (TX)B(2) production by aspirin. The pharmacodynamic interaction between the two drugs was then investigated in four healthy volunteers who received aspirin (100 mg daily) for 6 days and then the combination of aspirin and naproxen for further 6 days: aspirin 2 h before naproxen (500 mg, twice-daily dosing). After 14 days of washout, naproxen was given 2 h before aspirin for further 6 days. RESULTS: The inhibition of serum TXB(2) production (index of platelet cyclooxygenase [COX]-1 activity) and platelet aggregation ex vivo and urinary 11-dehydro-TXB(2) levels (index of TXB(2) biosynthesis in vivo) by aspirin alone (99 +/- 0.2%, 95 +/- 0.6%, and 81 +/- 4%, respectively) was not significantly altered by the co-administration of naproxen, given either 2 h after aspirin or in reverse order. In a second study, the concurrent administration of a single dose of aspirin and naproxen did not affect platelet TXB(2) production and aggregation at 1 h after dosing, when aspirin alone causes maximal inhibitory effect. Moreover, the rapid recovery of platelet COX-1 activity and function supports the occurrence of a pharmacodynamic interaction between naproxen and aspirin. CONCLUSIONS: Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin's cardioprotective effects.     

Frequency of aspirin resistance in a community hospital

Aspirin resistance and its predictors were studied in community hospital patients who required antiplatelet therapy for thrombotic event prophylaxis. Demographic and antiplatelet medication data were collected and medication response followed. Aspirin resistance was assayed with the VerifyNow System with > or = 550 aspirin reaction units (ARUs) used as a dichotomous indicator of aspirin resistance. Patients (n = 123) were 21 to 95 years old; 49.6% were women, 77.2% were black, 95.1% were hypertensive, 85.4% had coronary disease, and 30.1% were smokers. ARU score for 325 versus 81 mg/day was 435.2 +/- 93.7 versus 401.9 +/- 83.9 ARU (p = 0.04), with a 12.1% (8 of 66 patients) nonresponse rate to 81 mg/day. Of the 8 patients who were unresponsive to 81 mg/day of aspirin, 7 responded to 325 mg/day. The 5.3% (3 of 57 patients) who were resistant to 325 mg/day received clopidogrel; 2 became responders. Multivariate analysis demonstrated significant associations of aspirin resistance with smoking (risk ratio 11.47, 95% confidence interval 6.69 to 18.63, p < 0.0001), including a significant interaction between smoking and aspirin resistance. In conclusion, this study estimates aspirin resistance prevalence and shows a strong association of smoking with platelet hyperactivity in a diverse community hospital population. Nonresponders to 81 mg/day frequently responded to 325 mg/day or to the addition of clopidogrel.     

Anti-inflammatory effects of simvastatin in subjects with hypercholesterolemia

AIMS: Beneficial effects of statins in preventing cardiovascular events may depend, at least in part, on their anti-inflammatory action. The aim of the study was to assess the influence of simvastatin and aspirin on serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in hypercholesterolemic subjects. METHODS AND RESULTS: In 33 asymptomatic men with total cholesterol (TC) >6.5 mmol l(-1) and in 25 men with coronary heart disease and borderline-high cholesterol levels (between 5.2 and 6.5 mmol l(-1)) chronically treated with low-dose aspirin (75 mg/d), serum levels of CRP, TNF-alpha, IL-6, and IL-8 were determined before and after a 3-month simvastatin therapy (20-40 mg daily). In the former group, these markers of inflammation were also measured before and after a 2-week treatment with aspirin (300 mg/d), implemented prior to and in combination with simvastatin. A distinct reduction of CRP and TNF-alpha was found in both groups; IL-6 levels were decreased only in subjects with marked hypercholesterolemia. Aspirin had no effect on the anti-inflammatory action of simvastatin. CONCLUSIONS: In men with hypercholesterolemia simvastatin treatment lowers serum levels of CRP and proinflammatory cytokines. Low-dose aspirin does not add to the anti-inflammatory action of simvastatin.     

Patterns of aspirin dosing in non-ST-elevation acute coronary syndromes in the CRUSADE Quality Improvement Initiative

Recent studies have suggested that low-dose aspirin has preserved benefit with less bleeding compared with standard-dose aspirin when given with or without clopidogrel in patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACSs). We evaluated 22,618 patients with NSTE ACSs and high-risk features (ischemic ST-segment changes and/or positive cardiac markers) from 369 hospitals included in the CRUSADE initiative from May 4, 2003 to September 30, 2004. We analyzed acute (<24 hours of admission) and discharge aspirin doses in relation to concomitant clopidogrel use and other clinical predictors. Dosing of aspirin in the first 24 hours was as follows: 17.3% of patients (n = 3,911) received 81 mg, 13.5% (n = 3,062) received 162 mg, 67.4% (n = 15,247) received 325 mg, and 1.8% (n = 398) received >325 mg. Use of lower dose aspirin increased at discharge: 40.2% (n = 7,524) received 81 mg, 3.1% (n = 579) received 162 mg, and 55.7% (n = 10,423) received 325 mg. In patients who received concomitant clopidogrel at discharge (n = 12,635), 37.6% received aspirin 81 mg and 58.5% received 325 mg. Compared with patients who did not receive concomitant discharge clopidogrel (n = 4,772), 44.0% received aspirin 81 mg and 51.2% received 325 mg. Use of aspirin 81 mg was significantly lower in patients undergoing percutaneous coronary intervention (31.5% vs 46.2%, p <0.0001). In conclusion, most patients with high-risk NSTE ACSs in the United States continue to be treated with aspirin 325 mg at discharge with and without concomitant clopidogrel, despite recent studies that have shown a better safety profile with low-dose aspirin.     

Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial

There is increasing evidence that aspirin initiates biosynthesis of novel antiinflammatory mediators by means of interactions between endothelial cells and leukocytes. These mediators are classified as aspirin-triggered 15-epi-lipoxins. Such compounds may account at least in part for aspirin's clinical benefits, which are distinct from the well appreciated action of aspirin as a platelet inhibitor. Here, we addressed whether aspirin-triggered 15-epilipoxinA4 (ATL) formation is aspirin-dependent in humans and its relationship to aspirin's antiplatelet activity. We conducted a randomized clinical trial among 128 healthy subjects allocated to placebo or to 81-, 325-, or 650-mg daily doses of aspirin for 8 weeks. Plasma thromboxane (TX)B2, an indicator of platelet reactivity, and ATL were assessed from blood collected at baseline and at 8 weeks. Plasma ATL levels significantly increased in the 81-mg aspirin group (0.25 +/- 0.63 ng/ml, P = 0.04), with borderline increases in the 325-mg group (0.16 +/- 0.71 ng/ml) and no apparent significant changes in the 650-mg group (0.01 +/- 0.75 ng/ml, P = 0.96). When ATL and TXB2 were compared, levels changed in a statistically significant and opposite direction (P < 0.01) for all three aspirin doses. These results demonstrated that low-dose aspirin (81 mg daily) initiates production of antiinflammatory ATL opposite to the inhibition of TX. Monitoring ATL may represent a simple clinical parameter to verify an individual's vascular leukocyte antiinflammatory response with low-dose aspirin treatment. These results also emphasize the importance of cell-cell interactions in the modulation of hemostatic, thrombotic, and inflammatory processes.     

Rofecoxib, a COX-2 inhibitor, lowers C-reactive protein and interleukin-6 levels in patients with acute coronary syndromes

BACKGROUND: Patients with acute coronary syndromes (ACS) have high levels of inflammatory mediators such as C-reactive protein (CRP) and interleukin (IL)-6. AIM: To evaluate whether patients with ACS treated with rofecoxib, a COX-2 inhibitor, will have reduced CRP, IL-6, and soluble tumor necrotic factor receptor-1 (sTNF-R1) levels and improved endothelial function. METHODS AND RESULTS: Thirty-four patients hospitalized with ACS were randomized to receive rofecoxib, 25 mg/d plus aspirin 100 mg/d, or placebo plus aspirin, 100 mg/d, for a period of 3 months. Blood samples for CRP, IL-6, and sTNF-R1 levels were drawn prior to randomization, and after 1 month and 3 months. CRP levels in the rofecoxib group (n = 18) were significantly lower both at 1 month and 3 months compared to the baseline levels (p < 0.02). IL-6 levels were significantly lower at 1 month (p < 0.02) in the rofecoxib group, but not at 3 months. There was no change in endothelial function or sTNF-R1 levels. CONCLUSION: Patients recovering from ACS had lower levels of CRP and IL-6 at 1 month and lower CRP levels at 3 months when treated with rofecoxib plus aspirin. Suppression of inflammatory processes may lead to retardation of coronary atherosclerosis and coronary events.     

Once- versus twice-daily aspirin treatment in patients with essential thrombocytosis

Insufficient platelet inhibition has been reported in up to 40% of aspirin-treated patients, including patients with essential thrombocytosis. To maintain sufficient platelet inhibition, a shorter dosing interval with aspirin has been suggested. We aimed to investigate the antiplatelet effect of low-dose aspirin given twice-daily compared to standard once-daily dosing in patients with essential thrombocytosis. We included 22 patients, who were treated for 7 days with standard once-daily aspirin (75 mg once-daily) followed by 7 days treatment of twice-daily aspirin (37.5 mg twice-daily). The two regimens were separated by 14 days aspirin washout. Blood samples were obtained 1h and 24h/12h after the last pill intake in each regimen. The effect of aspirin was evaluated by: (1) platelet aggregation measured by whole blood impedance aggregometry (Multiplate® Analyser) using arachidonic acid (ASPItest 0.5 mM) as agonist and (2) serum thromboxane B₂ levels determined using an enzyme-linked immunosorbent assay. The difference in platelet aggregation from 1h to the end of the dosing interval (24h/12h) was used to compare the two regimens. We demonstrated a significantly smaller difference in platelet aggregation in the twice-daily regimen compared to the once-daily: mean of difference = 228 AU*min (95% confidence interval (CI): 92–363, p < 0.01). In addition, a significantly smaller difference in thromboxane B₂ was demonstrated in the twice-daily regimen compared to the once-daily regimen: mean of difference = 16.3 ng/mL (95% CI: 9.9–22.7, p < 0.01). In conclusion, twice-daily dosing with low-dose aspirin provides a more consistent platelet inhibition compared with standard once-daily dosing in patients with essential thrombocytosis.     

Ulcer formation with low-dose enteric-coated aspirin and the effect of COX-2 selective inhibition: a double-blind trial

BACKGROUND & AIMS: We assessed the risk of ulcers with low-dose aspirin and the interaction of low-dose aspirin with a COX-2 selective inhibitor in a double-blind trial that compared placebo, low-dose aspirin, rofecoxib + low-dose aspirin, and ibuprofen. METHODS: Osteoarthritis patients > or =50 years of age without ulcers or erosive esophagitis at baseline endoscopy were assigned randomly to placebo, enteric-coated aspirin 81 mg/day, rofecoxib 25 mg combined with aspirin 81 mg/day, or ibuprofen 800 mg 3 times a day. Repeat endoscopies were performed at 6 and 12 weeks. RESULTS: The 12-week cumulative incidence of ulcers was placebo (N = 381) 5.8%, aspirin (N = 387) 7.3%, rofecoxib combined with aspirin (N = 377) 16.1%, and ibuprofen (N = 374) 17.1% (P < 0.001 for rofecoxib combined with aspirin and for ibuprofen vs. each of placebo and aspirin). Over 12 weeks, mean increases in the number of erosions were placebo 0.17, aspirin 0.85 (P = 0.002 vs. placebo), rofecoxib combined with aspirin 1.67, and ibuprofen 1.91 (both P < 0.001 vs. aspirin and placebo). CONCLUSIONS: Low-dose aspirin alone did not significantly increase ulcer incidence. Addition of a cyclooxygenase-2 (COX-2) selective inhibitor to low-dose aspirin increased ulcer incidence, to a rate not significantly less than a nonselective nonsteroidal anti-inflammatory drug (NSAID) alone. Determining the relative impact of COX-2 selective inhibitors and nonselective NSAIDs on gastrointestinal mucosal injury in low-dose aspirin users will require further study.     

The effect of aspirin on C-reactive protein as a marker of risk in unstable angina

OBJECTIVES: This study was designed to assess the interaction between aspirin and C-reactive protein (CRP) release in unstable angina. BACKGROUND: C-reactive protein release in acute coronary syndromes may be a response to myocardial necrosis or may reflect the inflammatory process that drives atherogenesis. Aspirin has the potential to influence CRP release, either by its anti-inflammatory activity or by reducing myocardial necrosis. The clinical significance of this potential interaction has not previously been tested. METHODS: We conducted a prospective cohort study of 304 consecutive patients admitted with non-ST-elevation acute coronary syndromes. Serial blood samples were obtained for CRP and troponin I assay. End points were cardiac death and nonfatal myocardial infarction during follow-up for 12 months. RESULTS: A total of 174 patients (57%) were taking aspirin before admission. Patients taking aspirin had lower troponin I concentrations throughout the sampling period, only 45 (26.0%) having concentrations >0.1 mg/l compared with 48 (37.8%) patients not taking aspirin (p = 0.03). Maximum CRP concentrations were also lower in patients taking aspirin (8.16 mg/l [3.24 to 24.5]) than in patients not taking aspirin (11.3 mg/l [4.15 to 26.1]), although the difference was not significant. However, there was significant interaction (p = 0.04) between prior aspirin therapy and the predictive value of CRP concentrations for death and myocardial infarction at 12 months. Thus, odds ratios (95% confidence intervals) for events associated with an increase of 1 standard deviation in maximum CRP concentration were 2.64 (1.22-5.72) in patients not pretreated with aspirin compared with 0.98 (0.60-1.62) in patients pretreated with aspirin. CONCLUSIONS: The association between CRP and cardiac events in patients with unstable angina is influenced by pretreatment with aspirin. Modification of the acute-phase inflammatory responses to myocardial injury is the major mechanism of this interaction.     

Platelet Activation Is Associated With Myocardial Infarction in Patients With Pneumonia

Background

Troponins may be elevated in patients with pneumonia, but associations with myocardial infarction (MI) and with platelet activation are still undefined.

Objectives

The aim of this study was to investigate the relationship between troponin elevation and in vivo markers of platelet activation in the early phase of hospitalization of patients affected by community-acquired pneumonia.

Methods

A total of 278 consecutive patients hospitalized for community-acquired pneumonia, who were followed up until discharge, were included. At admission, platelet activation markers such as plasma soluble P-selectin, soluble CD40 ligand, and serum thromboxane B₂ (TxB₂) were measured. Serum high-sensitivity cardiac troponin T levels and electrocardiograms were obtained every 12 and 24 h, respectively.

Results

Among 144 patients with elevated high-sensitivity cardiac troponin T, 31 had signs of MI and 113 did not. Baseline plasma levels of soluble P-selectin and soluble CD40 ligand and serum TxB₂ were significantly higher in patients who developed signs of MI. Logistic regression analysis showed plasma soluble CD40 ligand (p < 0.001) and soluble P-selectin (p < 0.001), serum TxB₂ (p = 0.030), mean platelet volume (p = 0.037), Pneumonia Severity Index score (p = 0.030), and ejection fraction (p = 0.001) to be independent predictors of MI. There were no significant differences in MI rate between the 123 patients (45%) taking aspirin (100 mg/day) and those who were not aspirin treated (12% vs. 10%; p = 0.649). Aspirin-treated patients with MIs had higher serum TxB₂ compared with those without MIs (p = 0.005).

Conclusions

MI is an early complication of pneumonia and is associated with in vivo platelet activation and serum TxB₂ overproduction; aspirin 100 mg/day seems insufficient to inhibit thromboxane biosynthesis. (MACCE in Hospitalized Patients With Community-acquired Pneumonia; NCT01773863)     

Rapid platelet inhibition after a single capsule of Aggrenox®: Challenging a conventional full‐dose aspirin antiplatelet advantage?

Aggrenox is a novel combination of 25 mg of aspirin with 200 mg of sustained release dipyridamole. In a recent large trial (ESPS-2), Aggrenox was twice as effective for secondary stroke prevention as either aspirin or dipyridamole alone, suggesting superior platelet inhibition for combination therapy. We sought to compare the time course of platelet inhibition with Aggrenox compared with escalating doses of non-enteric coated aspirin. Data from 10 healthy volunteers were analyzed. Fasting subjects sequentially ingested aspirin in the following order: 325 mg, 81 mg, 25 mg, and then one pill of Aggrenox after a 3-week interval for aspirin washout. Platelet function was assessed at baseline, 15, 30, 60, and 120 min post-medication with 5 microM epinephrine and 5 microM ADP using conventional aggregometry. Aspirin provided significant (P < 0.01) reduction of platelet aggregation at 15 min post 325 mg, 30 min post 81 mg, and unexpectedly within 60 min after taking 25 mg of aspirin. A single pill of Aggrenox also inhibited platelet aggregation within 1 hr after administration. Aspirin inhibits platelets remarkably fast. Both Aggrenox and a matching dose of aspirin (25 mg) exhibit significant antiplatelet properties within 60 min after ingestion. These findings could be relevant for the optimal balance between the reduction of vascular events via sufficient and rapid platelet inhibition and low risk of bleeding complications associated with the Aggrenox therapy.