Profile and prevalence of aspirin resistance in patients with cardiovascular disease

We determined the prevalence and clinical predictors of aspirin resistance by prospectively studying 325 patients with stable cardiovascular disease who were receiving aspirin (325 mg/day for > or =7 days) but no other antiplatelet agents. We also compared the detection of aspirin resistance with optical platelet aggregation, a widely accepted method, with a newer, more rapid method, the platelet function analyzer (PFA)-100, a whole blood test that measures platelet adhesion and aggregation ex vivo. Blood samples were analyzed in a blinded fashion for aspirin resistance by optical aggregation using adenosine diphosphate (ADP) and arachidonic acid, and by PFA-100 using collagen and/or epinephrine and collagen and/or ADP cartridges to measure aperture closure time. Aspirin resistance was defined as a mean aggregation of > or =70% with 10 microM ADP and a mean aggregation of > or =20% with 0.5 mg/ml arachidonic acid. Aspirin semiresponders were defined as meeting one, but not both of the above criteria. Aspirin resistance by PFA-100 was defined as having a normal collagen and/or epinephrine closure time (< or =193 seconds). By optical aggregation, 5.5% of the patients were aspirin resistant and 23.8% were aspirin semiresponders. By PFA-100, 9.5% of patients were aspirin resistant. Of the 18 patients who were aspirin resistant by aggregation, 4 were also aspirin resistant by PFA-100. Patients who were either aspirin resistant or aspirin semiresponders were more likely to be women (34.4% vs 17.3%, p = 0.001) and less likely to be smokers (0% vs 8.3%, p = 0.004) compared with aspirin-sensitive patients. There was a trend toward increased age in patients with aspirin resistance or aspirin semiresponders (65.7 vs 61.3 years, p = 0.06). There were no differences in aspirin sensitivity by race, diabetes, platelet count, renal disease, or liver disease.     

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.     

Comparison of increased aspirin dose versus combined aspirin plus clopidogrel therapy in patients with diabetes mellitus and coronary heart disease and impaired antiplatelet response to low-dose aspirin

The effects of therapy with aspirin 300 mg/day and with combined aspirin 100 mg/day plus clopidogrel 75 mg/day on platelet function were compared in patients with diabetes mellitus and coronary artery disease and impaired antiplatelet responses to aspirin 100 mg/day. The study population consisted of 151 outpatients with type II diabetes mellitus and coronary artery disease who were taking aspirin 100 mg/day. Of the 151 patients, a subgroup of subjects with impaired aspirin response were selected on the basis of the results of platelet aggregometry. Nonresponsiveness to aspirin was defined as mean aggregation > or =69% with 3 micromol/L adenosine diphosphate and mean aggregation > or =70% with 2 micromol/L collagen. Aspirin semiresponders were defined as meeting 1 but not both of these criteria. Nonresponders and semiresponders were randomized equally to aspirin 300 mg/day and aspirin 100 mg/day plus clopidogrel 75 mg/day, and aggregation tests were repeated after 2 weeks. Sixty of the 151 patients with diabetes (40%) were found to respond to aspirin inadequately. Platelet aggregation induced by adenosine diphosphate and collagen decreased significantly after aspirin 300 mg/day or combined therapy. Combined treatment was found to have a stronger inhibitory effect on platelet aggregation induced by adenosine diphosphate than aspirin 300 mg/day (p = 0.002). Impaired aspirin response was resolved by increasing the aspirin dose or adding clopidogrel to aspirin (p <0.0001 for each). However, desired platelet inhibition was achieved in significantly more patients by combined treatment than by aspirin 300 mg/day (p <0.05). In conclusion, aspirin 100 mg/day does not inhibit platelet function adequately in a significant number of patients with diabetes mellitus and coronary artery disease. Increasing the aspirin dose to 300 mg/day or adding clopidogrel to aspirin can provide adequate platelet inhibition in a significant number of those patients with impaired responses to low-dose aspirin.     

Measuring aspirin resistance, clopidogrel responsiveness, and postprocedural markers of myonecrosis in patients undergoing percutaneous coronary intervention

Aspirin and clopidogrel are proven to prevent thromboembolic events during percutaneous coronary intervention (PCI). Enzyme release of creatine kinase-MB (CK-MB) enzyme during PCI has been associated with an increased risk of future adverse cardiac events. This study examined the correlation between measurements of aspirin resistance and the level of inhibition of the thienopyridine-specific P2Y12 platelet receptor and CK-MB release after PCI. We prospectively studied 330 patients with elective PCI treated with drug-eluting stents. Patients were pretreated with aspirin and clopidogrel. Patients with positive CK-MB or acute coronary syndrome and those on glycoprotein IIb/IIIa inhibitors were excluded. Serum assays of aspirin resistance (Ultegra Rapid Platelet Function Assay-ASA, Accumetrics) and clopidogrel resistance (Rapid Platelet Function Assay P2Y12, Accumetrics) were performed before PCI. Serum troponinI and CK-MB levels were measured at 8, 16, and 24 hours after PCI. Aspirin resistance unit (ARU) measurement > or =550 was detected in 12 patients (3.7%). Mean platelet reactivity unit (PRU; measurement of inhibition of P2Y12 activity) was 192.2 +/- 95.4 (lower PRU, more inhibition of P2Y12 receptor). There was no correlation between level of ARU or PRU and troponin I or CK-MB release after PCI at any time point. Only multivessel coronary disease was found to be a predictor of any increase in CK-MB in a multivariate analysis (odds ratio 2.2, 95% confidence interval 1.4 to 3.3, p = 0.0003). A positive correlation was found between levels of ARU and PRU. Target vessel revascularization/major adverse cardiac event rate at 6 months was 8.2% with no correlation between ARU or PRU and release of cardiac enzymes or occurrence of adverse cardiac events. In conclusion, this study does not support routine measurements of aspirin and clopidogrel resistance in stable patients undergoing PCI.     

Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials

Purpose

We performed a systematic review to define the relative and absolute risk of clinically relevant adverse events with the antiplatelet agents, aspirin and clopidogrel.

Materials and methods

Databases were searched for randomized controlled trials of low-dose aspirin (75-325 mg/dayay) or clopidogrel administered for cardiovascular prophylaxis. Relative risks (RR) were determined by meta-analysis of 22 trials for aspirin versus placebo and from single studies for aspirin versus clopidogrel, aspirin versus aspirin/clopidogrel, and clopidogrel versus aspirin/clopidogrel. Absolute risk increase was calculated by multiplying RR increase by the pooled weighted incidence of the control.

Results

Aspirin increased the risk of major bleeding (RR = 1.71; 95% confidence interval [CI], 1.41-2.08), major gastrointestinal (GI) bleeding (RR = 2.07; 95% CI, 1.61-2.66), and intracranial bleeding (RR = 1.65; 95% CI, 1.06-5.99) versus placebo. No difference between 75-162.5 mg/day and >162.5-325 mg/day aspirin versus placebo was seen. The absolute annual increases attributable to aspirin were major bleeding: 0.13% (95% CI, 0.08-0.20); major GI bleeding: 0.12% (95% CI, 0.07-0.19), intracranial bleeding: 0.03% (95% CI, 0.01-0.08). No study compared clopidogrel with placebo. One study showed increased major GI bleeding (but not non-GI bleeding endpoints) with aspirin versus clopidogrel (RR = 1.45; 95% CI, 1.00-2.10). The absolute annual increase was 0.12% (95% CI, 0.00-0.28).

Conclusions

Low-dose aspirin increases the risk of major bleeding by ∼70%, but the absolute increase is modest: 769 patients (95% CI, 500-1250) need to be treated with aspirin to cause one additional major bleeding episode annually. Compared with clopidogrel, aspirin increases the risk of GI bleeding but not other bleeding; however, 883 patients (95% CI, 357-∞) would need to be treated with clopidogrel versus aspirin to prevent one major GI bleeding episode annually at a cost of over 1 million dollars.     

Low-dose aspirin increases aspirin resistance in patients with coronary artery disease

PURPOSE: We sought to investigate the association of aspirin dose and aspirin resistance in stable coronary artery disease patients measured by a point-of-care assay. METHODS: We studied 468 consecutive stable coronary artery disease patients in a referral cardiac center who were taking aspirin 80 to 325 mg daily for > or =4 weeks. The VerifyNow Aspirin (Ultegra RPFA-ASA, Accumetrics Inc, San Diego, Calif) was used to determine aspirin responsiveness. An aspirin reaction unit (ARU) > or =550 indicates the absence of aspirin-induced platelet dysfunction, based on correlation with epinephrine-induced light transmission aggregometry. Demographic and clinical data were collected to analyze the predictors of aspirin resistance. RESULTS: Aspirin resistance was noted in 128 (27.4%) patients. Univariate predictors of aspirin resistance include elderly (P = 0.002), women (P <0.001), anemia (P <0.001), renal insufficiency (P = 0.009) and aspirin dose < or =100 mg (P = 0.004). Multivariate analysis revealed hemoglobin (odds ratio [OR] 0.6; 95% confidence interval [CI] 0.51 to 0.69; P <0.001) and aspirin dose < or =100 mg (OR 2.23; 95% CI 1.12 to 4.44; P = 0.022) to be independent predictors of aspirin resistance. Daily aspirin dose < or = 100 mg was associated with increased prevalence of aspirin resistance compared with 150 mg and 300 mg daily (30.2% vs 16.7% vs 0%, P = 0.0062). CONCLUSION: A 100 mg or less daily dose of aspirin, which may have lower side effects, is associated with a higher incidence of aspirin resistance in patients with coronary artery disease. Prospective randomized studies are warranted to elucidate the optimal aspirin dosage for preventing ischemic complications of atherothrombotic disease.     

Comparative effect of aspirin and clopidogrel on arterial function in CHF

BACKGROUND: By inhibiting prostaglandins, aspirin may be deleterious in congestive heart failure (CHF) and/or partially counteract the efficacy of angiotensin-converting enzyme inhibitors (ACEI). Conversely, clopidogrel has no effect on prostaglandin metabolism. The aim of this study was to prospectively investigate the effect of aspirin and clopidogrel on arterial functional properties in CHF patients treated with ACEI. METHODS: Forty-five patients with stable NYHA class II-IV CHF (64.0+/-15.5 years), ejection fraction <40%, were included in this prospective double-blind study and randomized to receive aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days. Reflected wave assessed by radial applanation tonometry and pulse wave velocity (PWV) were measured at day 0 and day 14. RESULTS: Aspirin resulted in an increase in the augmentation index of the reflected wave (Delta=+3.5+/-5.2%, p=0.005) and the height above the shoulder of the reflected wave (Delta=+1.7+/-3.1 mm Hg, p=0.023), without statistically variation in PWV. Conversely, clopidogrel had no effect on the same parameters (p=0.512, p=0.677 and 0.801, respectively). Overall, variations in the augmentation index of reflected wave significantly differed when compared aspirin with clopidogrel (p=0.0261). CONCLUSION: This study demonstrates the existence of a negative effect of aspirin 325 mg/day when compared to clopidogrel 75 mg/day on arterial functional properties in CHF patients treated with ACEI.     

心血管病患者中的阿司匹林抵抗

目的　前瞻性地评价心血管病患者发生阿司匹林抵抗 (AR)的流行病学概况 ,并探讨其预测因子。方法　 35 2例病情稳定的心血管病住院患者 ,每日服用阿司匹林 10 0mg ,连服 7天 ,服用最后一剂后 2 4h内抽取的空腹静脉血为血样 ,分别用二磷酸腺苷 (ADP)、花生四烯酸 (AA)诱导血小板凝集试验 (PAgT) ,检测血小板聚集率。结果　患者中AR发生率为 3.98% ,阿司匹林半敏感 (ASR)者占 2 5 .9% ,且AR或ASR患者中的女性较AS者多(35 .2 %vs 18.2 % ,P =0 .0 0 1) ,而AS者中吸烟者较AR或ASR者多 (0 %vs 9.5 % ,P =0 .0 0 2 )。结论　阿司匹林用于抗血小板治疗及预防动脉硬化事件的心血管病患者 ,若有AR存在可选择其他安全有效的抗血小板制剂长期服用 ,预测AR及抗血小板治疗个体化 ,将是抗血小板治疗未来的方向     

冠心病患者阿司匹林抵抗的相关因素

目的观察冠心病患者发生阿司匹林抵抗的发生率,并探讨冠心病患者出现阿司匹林抵抗现象的相关因素。方法60例病情稳定的冠心病住院患者,每日口服拜阿司匹林100 mg,连服7 d,分别以二磷酸腺苷（ADP）和花生四烯酸（AA）为诱导剂,检测血小板聚集功能。结果阿司匹林抵抗（AR）发生率为20%;阿司匹林半敏感（ASR）者占13%。与阿司匹林敏感（AS）者相比,伴有高脂血症、糖尿病的冠心病患者AR较多（50%vs15%,P<0.05）,两组年龄、性别、吸烟和并发高血压病统计无显著性差异。结论伴有高脂血症、糖尿病的冠心病患者发生阿司匹林抵抗较多,阿司匹林抵抗与年龄、性别、吸烟和并发高血压病等因素无关。     

A prospective,blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease

OBJECTIVES: This study was designed to determine if aspirin resistance is associated with clinical events. BACKGROUND: Aspirin resistance, defined by platelet function testing and presumed clinical unresponsiveness to aspirin, has been previously reported by our group and others. However, little information exists linking the laboratory documentation of aspirin resistance and long-term clinical events. METHODS: We prospectively enrolled 326 stable cardiovascular patients from 1997 to 1999 on aspirin (325 mg/day for > or =7 days) and no other antiplatelet agents. We tested for aspirin sensitivity by optical platelet aggregation using adenosine diphosphate (ADP) and arachidonic acid (AA). The primary outcome was the composite of death, myocardial infarction (MI), or cerebrovascular accident (CVA). Mean follow-up was 679 +/- 185 days. Aspirin resistance was defined as a mean aggregation of > or =70% with 10 microM ADP and > or =20% with 0.5 mg/ml AA. RESULTS: Of the patients studied, 17 (5.2%) were aspirin resistant and 309 (94.8%) were not aspirin resistant. During follow-up, aspirin resistance was associated with an increased risk of death, MI, or CVA compared with patients who were aspirin sensitive (24% vs. 10%, hazard ratio [HR] 3.12, 95% confidence interval [CI] 1.10 to 8.90, p = 0.03). Stratified multivariate analyses identified platelet count, age, heart failure, and aspirin resistance to be independently associated with major adverse long-term outcomes (HR for aspirin resistance 4.14, 95% CI 1.42 to 12.06, p = 0.009). CONCLUSIONS: This study demonstrates the natural history of aspirin resistance in a stable population, documenting a greater than threefold increase in the risk of major adverse events associated with aspirin resistance.     

Measurement of platelet aggregation during antiplatelet therapy in ischemic stroke

Aspirin, ticlopidine and clopidogrel are used as a pharmacological means to efficiently decrease the number of reoccurrence of ischemic stroke (100-325 mg/d). This antiplatelet treatment could prevent the secondary stroke by approximately 22%. Laboratory effective platelet inhibition for the clinician, and methods for routine screening evaluation for the laboratory were studied. (1) For the standardisation of platelet aggregation technology blood samples of 150 healthy persons were studied in 5 centres. CARAT TX computerised optical aggregometer was used for measuring with collagen (2 microg/ml), epinephrine (10 microM), arachidonic acid 0.5 mM and ADP 5 microM as inductors. (2) Laboratory tests were compared in each centres performed in platelet-rich plasma of ischemic cardiovascular and stroke patients (n=823) taking 100-325 mg aspirin/d. (3) Blood samples of 555 ischemic stroke patients treated with aspirin (100-325 mg/d), 96 patients treated with ticlopidine (500 mg/d), and 67 patients treated with clopidogrel (75 mg/d) were evaluated, respectively.(1) The mean of maximal aggregation (%) - 2SD of untreated controls (n=150) were detected for collagen with 64%, epinephrine 59% and ADP 62%. (2) In 823 aspirin treated patients were found similar inhibition in different centres with same methods for standardisation. The mean inhibition level was in case of collagen 38%, epinephrine 37% and ADP 61%. (3) The distribution of ineffective platelet inhibition was detected in 17% of aspirin group (collagen and epinephrine), 4% of ticlopidine and 18% of clopidogrel group with ADP, respectively. Our findings were in the stroke cohort: effective inhibition levels: 36% in aspirin group, 73% in ticlopidine and 25% treated with clopidogrel. Platelet aggregation tests could help to find the optimal, and "custom taylored" dose of antiaggregating drugs in the secondary prevention of ischemic stroke.     

Response to aspirin and clopidogrel in patients scheduled to undergo cardiovascular surgery

Background Recent data indicate that among patients undergoing percutaneous coronary intervention low platelet response to aspirin is associated with clopidogrel low response. It is unclear whether these findings extend to other patient populations. We, therefore, aimed to evaluate the relation between response to aspirin and clopidogrel among patients scheduled to undergo cardiac or vascular surgery. Methods Patients who were scheduled for cardiac or vascular surgery and had taken aspirin 81–325 mg daily for at least a week and clopidogrel 75 mg daily for at least 3 days underwent blood testing for platelet function. One hundred patients were included in the current analysis. Platelet function was evaluated by the modified TEG platelet mapping assay with addition of ADP or arachidonic acid (AA), and by the PFA-100 assay with collagen-epinephrine (CEPI) or collagen-ADP (CADP) cartridges. Low response to aspirin or clopidogrel was defined as inhibition ≤20% for TEG-AA or TEG-ADP, respectively. Results Thirteen patients (13%) were low responders to aspirin and 34 (34%) were low responders to clopidogrel. Eight patients were low responders to both drugs. There were no differences in clinical characteristics between drug low responders versus sensitive patients. Aspirin low responders had lower TEG-ADP inhibition (19.5 ± 6 vs. 35.8 ± 3%, P = 0.03) and tended to have lower PFA-CADP time (84.7 ± 7 vs. 105.6 ± 5 s, P = 0.1) than aspirin sensitive patients. Clopidogrel low responders had lower TEG-AA inhibition (58 ± 6 vs. 75.1 ± 4%, P = 0.01) and PFA-CEPI time (168 ± 13 vs. 200.4 ± 10 s, P = 0.07) than clopidogrel sensitive patients. Conclusions In patients scheduled to undergo cardiovascular surgery low response to aspirin is associated with low response to clopidogrel.     

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

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

Aspirin and clopidogrel in acute coronary syndromes: therapeutic insights from the CURE study

Platelet adhesion, activation, and aggregation are central to thrombus formation, which follows atherosclerotic plaque disruption and causes acute coronary syndromes. Aspirin and clopidogrel exert their antiplatelet effects by inhibiting thromboxane A2 production and adenosine diphosphate-induced platelet aggregation pathways, respectively. Aspirin has proven benefits in primary and secondary prevention of coronary artery disease. Clopidogrel, an alternative antiplatelet agent used in patients with aspirin intolerance, is especially useful in combination with aspirin after coronary stent procedures. The CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) study demonstrates for the first time the benefit of adding clopidogrel to aspirin rather than using aspirin alone in patients having acute coronary syndromes without ST-segment elevation myocardial infarction. Patients who are resistant to aspirin (up to 10%) have higher rates of cardiovascular events and may derive special benefit from the combination therapy. Aspirin resistance can be assessed through platelet aggregometry testing, measurement of urinary thromboxane metabolites, and, possibly, genomic testing in the future.     

Effects of aspirin and clopidogrel on plasma brain natriuretic peptide in patients with heart failure receiving ACE inhibitors

BACKGROUND: By inhibiting prostaglandins, aspirin may be deleterious in heart failure (HF) and/or may counteract angiotensin-converting enzyme (ACE) inhibitor efficacy. Conversely, clopidogrel has no effect on prostaglandin metabolism. AIM: To investigate the effect of aspirin and clopidogrel on brain natriuretic peptide (BNP) levels in HF patients treated with ACE inhibitors. METHODS: 36 patients with stable HF (65+/-13 years, 24 males/12 females, NYHA class II to IV, ejection fraction <40%, 13 with coronary disease, all treated with ACE inhibitors) were enrolled in this prospective, double-blind study and randomised to aspirin 325 mg/day or clopidogrel 75 mg/day for 14 days. BNP was determined at day 0 and day 14. RESULTS: 19 patients were randomised to aspirin and 17 to clopidogrel. Baseline characteristics were similar in both groups. BNP levels increased in the aspirin group from day 0 to day 14 (107+/-103 to 144+/-149 pg/ml, p=0.04) whereas clopidogrel had no effect (104+/-107 and 97+/-99 pg/ml respectively, p=0.61). CONCLUSION: This study demonstrates an adverse effect of aspirin 325 mg/day on BNP plasma levels in HF patients treated with ACE inhibitors. In contrast clopidogrel 75 mg/day had no effect.     

Gastroduodenal tolerance of 75 mg clopidogrel versus 325 mg aspirin in healthy volunteers. A gastroscopic study

BACKGROUND: Clopidogrel is a new antiplatelet agent that offers increased protection over aspirin in preventing vascular ischaemic events in patients with symptomatic atherosclerosis. In a large, randomized, international study of clopidogrel and aspirin (n = 19,185 patients) clopidogrel was associated with a lower incidence of gastrointestinal adverse events, including gastrointestinal haemorrhage and hospitalizations because of gastrointestinal haemorrhage. The aim of the study was to determine whether macroscopic differences in the gastric mucosa between aspirin- and clopidogrel-treated subjects could be detected by gastroscopy after short-term treatment. METHODS: Thirty-six healthy volunteers were randomized in a double-blind, double-dummy, parallel design, to 75 mg/day of clopidogrel or 325 mg/day of aspirin for 8 days. Gastroscopy was performed at base line before administration of study drug and directly after treatment completion. Gastroduodenal effects were measured in accordance with a modified Lanza scale. RESULTS: At base line no difference between the groups was detected (median Lanza score, 0.0 in both groups). At the end of treatment the aspirin group showed a median score of 7.5, and the clopidogrel group showed an unchanged median score of 0.0 (P < 0.001). In the aspirin group 13 individuals reported 19 adverse events versus 8 individuals and 13 adverse events for clopidogrel, with approximately half of the adverse events being gastrointestinal in each group. No serious adverse events were reported. CONCLUSION: In contrast to aspirin, short-term treatment with clopidogrel does not induce macroscopic changes in the gastroduodenal mucosa. The study results show that in patients without gastroduodenal disease clopidogrel, but not aspirin, does not induce any gastroscopically evident erosions during short-term treatment.     

Gastroduodenal Tolerance of 75 mg Clopidogrel versus 325 mg Aspirin in Healthy Volunteers: A Gastroscopic Study

Background: Clopidogrel is a new antiplatelet agent that offers increased protection over aspirin in preventing vascular ischaemic events in patients with symptomatic atherosclerosis. In a large, randomized, international study of clopidogrel and aspirin (n = 19,185 patients) clopidogrel was associated with a lower incidence of gastrointestinal adverse events, including gastrointestinal haemorrhage and hospitalizations because of gastrointestinal haemorrhage. The aim of the study was to determine whether macroscopic differences in the gastric mucosa between aspirin- and clopidogrel-treated subjects could be detected by gastroscopy after short-term treatment. Methods: Thirty-six healthy volunteers were randomized in a double-blind, double-dummy, parallel design, to 75 mg/day of clopidogrel or 325 mg/day of aspirin for 8 days. Gastroscopy was performed at base line before administration of study drug and directly after treatment completion. Gastroduodenal effects were measured in accordance with a modified Lanza scale. Results: At base line no difference between the groups was detected (median Lanza score, 0.0 in both groups). At the end of treatment the aspirin group showed a median score of 7.5, and the clopidogrel group showed an unchanged median score of 0.0 (P &lt; 0.001). In the aspirin group 13 individuals reported 19 adverse events versus 8 individuals and 13 adverse events for clopidogrel, with approximately half of the adverse events being gastrointestinal in each group. No serious adverse events were reported. Conclusion: In contrast to aspirin, short-term treatment with clopidogrel does not induce macroscopic changes in the gastroduodenal mucosa. The study results show that in patients without gastroduodenal disease clopidogrel, but not aspirin, does not induce any gastroscopically evident erosions during short-term treatment.     

Resistance in vitro to low-dose aspirin is associated with platelet PlA1 (GP IIIa) polymorphism but not with C807T(GP Ia/IIa) and C-5T Kozak (GP Ibalpha) polymorphisms

OBJECTIVES: We investigated whether three platelet gene polymorphisms, Pl(A1/A2), C807T, and C-5T Kozak (encoding, respectively, for platelet membrane glycoproteins (GP) IIIa, GP Ia/IIa, GP Ibalpha), could contribute to the resistance to a low dose of aspirin (160 mg/day). BACKGROUND: Aspirin antiplatelet effect is not uniform in all patients, and the mechanism by which some patients are in vitro resistant to aspirin remains to be determined. However, it has been suggested that polymorphisms of platelet membrane glycoproteins might contribute to aspirin resistance. METHODS: Ninety-eight patients on aspirin (160 mg/day) for at least one month were enrolled. Aspirin resistance was measured by the platelet function analyzer (PFA)-100 analyzer; genotyping of the three polymorphisms was performed using a polymerase chain reaction-based restriction fragment-length polymorphism analysis. RESULTS: Using a collagen/epinephrine-coated cartridge on the PFA-100, the prevalence of aspirin resistance was 29.6% (n = 29). Aspirin-resistant patients were significantly more often Pl(A1/A1) (86.2%; n = 25) than sensitive patients (59.4%; n = 41; p = 0.01). Of the 29 patients, 25 were reevaluated after having taken 300 mg/day aspirin for at least one month. Only 11 patients still have nonprolonged collagen epinephrine closure time, and these were all Pl(A1/A1). No relation was found between resistance status and C-5T Kozak or C807T genotypes. CONCLUSIONS: Platelets homozygous for the Pl(A1) allele appear to be less sensitive to inhibitory action of low-dose aspirin. This differential sensitivity to aspirin may have potential clinical implications whereby specific antiplatelet therapy may be best tailored according to the patient's Pl(A) genotype.     

The effect of long-term clopidogrel use on neointimal formation after percutaneous coronary intervention

OBJECTIVE: The purpose of this study was to evaluate the long term effect of clopidogrel-based antiplatelet therapy on neointimal formation. METHODS: This study comprised 78 patients with typical stable angina pectoris or documented myocardial ischaemia, and with only one angiographic lesion in one native coronary artery undergoing successful stent implantation without predilatation with C-reactive protein levels < or =5 mg/l at 72 h after the procedure. All patients received dual antiplatelet therapy with 75 mg/day clopidogrel and 300 mg/day aspirin for four weeks. Clopidogrel was switched to isochronous placebo in half of the patients (n=39) at the end of the fourth week. This allocation was maintained for 20 weeks, and at week 24 of the study, coronary angiography and intravascular ultrasound imaging were performed again in all cases in order to evaluate the changes that had occurred in the in-stent neointimal formation; rates of restenosis were also recorded RESULTS: At the end of the follow-up period, angiographic stenosis diameter and restenosis rates were smaller in the clopidogrel group than in the placebo group (23.3% versus 35.6%, p=0.05 and 5.12% versus 10.25%; p=0.03 respectively); the intravascular ultrasonographic neointimal cross sectional area was also smaller in the clopidogrel group (3.6 +/- 2.7 mm(2) versus 5.2 +/- 2.5 mm(2), p=0.03). CONCLUSIONS: Long-term clopidogrel administration significantly reduced neointimal formation at the stent site as well as reducing major clinical events in patients who did not develop high-risk systemic inflammatory response after percutaneous coronary intervention.     

Comparison of platelet P2Y(12) ADP receptor-mediated pathway inhibition in triple versus dual antiplatelet therapy as assessed by VASP-phosphorylation in Japanese patients undergoing coronary stenting

Despite wide interindividual variability in response to clopidogrel, platelet P2Y(12) ADP receptor inhibition in Japanese patients has not been fully studied using specific methodology. This study compared platelet P2Y(12) ADP receptor inhibition during treatment with clopidogrel versus clopidogrel plus cilostazol in patients undergoing coronary stenting. Forty-two patients in whom platelet function was measured within 2 months after coronary stenting were enrolled. All patients were treated with aspirin 100 or 200 mg/day, and were divided into a dual therapy group (aspirin plus clopidogrel 75 mg/day; n = 34) and a triple therapy group (aspirin plus clopidogrel 75 mg/day plus cilostazol 200 mg/day; n = 8). Vasodilator-stimulated phosphoprotein (VASP) phosphorylation analysis and 5 and 20 μmol/L-induced maximal platelet aggregation were assessed. No differences were found in baseline characteristics except for a higher incidence of diabetes mellitus (DM) in the triple therapy group. Although there were no differences in platelet aggregation between the 2 groups, VASP index was significantly lower in the triple therapy group than in the dual therapy group (23.1 ± 15.3% versus 51.2 ± 19.9%; P = 0.001). The rate of low responsiveness to clopidogrel, defined by VASP index > 50%, was lower in the triple therapy group than in the dual therapy group (12.5% versus 55.9%; P = 0.047). Similarly, in DM patients the triple therapy group had a lower VASP index compared with the dual therapy group (23.1 ± 15.3% versus 47.0 ± 23.5%; P = 0.015).Clopidogrel plus cilostazol is more effective in inhibiting the platelet P2Y(12) ADP receptor pathway than clopidogrel alone. This may be useful for reducing clopidogrel resistance in Japanese patients.