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.     

A comparison of dual vs. triple antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndrome: results of the ELISA-2 trial.

AIMS: To compare dual vs. triple antiplatelet pre-treatment in patients with non-ST-elevation acute coronary syndrome (NSTE ACS) who were planned for early catheterization. METHODS AND RESULTS: A total of 328 consecutive patients with NSTE ACS were included and were randomized to pre-treatment with dual (n = 166, aspirin, clopidogrel 600 mg) or triple antiplatelet therapy (n = 162, aspirin, clopidogrel 300 mg, and Tirofiban). The primary endpoint was enzymatic infarct size, defined as cumulative LDH release (LDHQ(48)). Initial TIMI flow of the culprit vessel was a pre-specified secondary endpoint. Angiography was performed in 98% of patients at a median of 23 h after admission. Enzymatic infarct size (median, 25-75%) was 166 (60-349) IU/L in the triple group compared with 193 (75-466) IU/L in the dual group (P = 0.2). Initial TIMI 3 flow of the culprit vessel was significantly more often observed after triple antiplatelet therapy (67 vs. 47%, P = 0.002). At 30 days follow-up, myocardial infarction (MI) occurred in 46% of patients in the triple antiplatelet group, compared with 57% in the dual antiplatelet group, P = 0.052. No significant difference in bleeding was present. CONCLUSION: This study showed that in patients with NSTE ACS, triple antiplatelet pre-treatment was associated with a non-significant reduction in enzymatic infarct size, a significantly better initial perfusion of the culprit vessel, and a trend towards a better survival without death or MI. Further, large-scale studies should be performed to find whether the beneficial trend in favour of triple antiplatelet pre-treatment can be reproduced.     

Relationship between risk stratification by cardiac troponin level and adherence to guidelines for non-ST-segment elevation acute coronary syndromes

BACKGROUND: The threshold of troponin elevation that stimulates changes in clinical decision making for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACSs) has not been previously evaluated. METHODS: A total of 23 298 patients with NSTE ACSs from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) initiative were separated into categories of maximum troponin ratios (ratio of the highest recorded troponin value in the first 24 hours to the local laboratory troponin assay upper limit of normalization [ULN]). RESULTS: Unadjusted rates of in-hospital mortality increased from the group with troponin levels below the reference limit (maximum troponin ratio 0-1 x ULN; n = 5291) to those with minor (1-2 x ULN; n = 2499), intermediate (2-5 x ULN; n = 3825), and major (>5 x ULN; n = 11 683) elevations (-2.8% vs 4.6% vs 4.7% vs 6.0%). The use of early (<24 hours) aspirin, heparin, glycoprotein IIb/IIIa inhibitors, and beta-blockers was similar for the group with troponin levels below the reference limit compared with those with minor troponin elevations, and greater use of medications was demonstrated in patients with intermediate and major troponin elevations. Use of cardiac catheterization and percutaneous coronary intervention was higher in patients with troponin levels below the reference limit compared with those with minor troponin elevations, and procedures were used most frequently in patients with major troponin elevations. Similar patterns of care were demonstrated after excluding patients with chronic renal insufficiency. CONCLUSIONS: Any degree of troponin elevation is associated with a higher risk of mortality for patients with NSTE ACSs, but guideline-recommended medical therapies are used more commonly only in patients with intermediate and major troponin elevations, whereas patients with troponin levels below the reference limit underwent invasive procedures more frequently than those with mild troponin elevations.     

Heart failure with preserved left ventricular systolic function among patients with non-ST-segment elevation acute coronary syndromes

Previous studies of non-ST-segment elevation acute coronary syndromes (NSTE ACSs) complicated by heart failure (HF) have focused primarily on patients with left ventricular systolic dysfunction defined by an ejection fraction (EF) <40%. Little is known about HF with preserved systolic function (EF > or =40%) in the NSTE ACS population. We identified high-risk patients with NSTE ACS (ischemic electrocardiographic changes and/or positive cardiac markers) from the CRUSADE quality improvement initiative who had an EF recorded and who had information on HF status. Management and outcomes were analyzed and compared based on the presence or absence of HF and whether left ventricular EF was > or =40%. Of 94,558 patients with NSTE ACS, 21,561 (22.8%) presented with signs of HF, and most had HF with preserved systolic function (n = 11,860, 55%). Mortality rates were 10.7% for HF/systolic dysfunction, 5.8% for HF/preserved systolic function, 5.7% for no HF/systolic dysfunction, and 1.5% for no HF/preserved systolic function. Use of guideline-recommended medical therapies and interventions was frequently significantly lower in those with HF regardless of EF compared with those without HF, except for use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In conclusion, NSTE ACS complicated by HF with preserved systolic function is common and associated with a 2.3-fold higher mortality compared with NSTE ACS without HF or systolic dysfunction. Guideline-recommended therapies and interventions are under-utilized in patients with NSTE ACS and HF, with and without preserved systolic function, compared with those without HF.     

国产替罗非班对老年急性冠脉综合征介入治疗患者近期预后的影响

目的 评价国产替罗非班对老年（≥60岁）急性冠脉综合征（ACS）接受冠状动脉介入治疗（PCI）患者近期预后的影响。方法325例患者根据是否使用替罗非班分为替罗非班组（n=210）和对照组（n=115）,所有患者术中均植入了药物洗脱支架;替罗非班组在口服阿司匹林＋氯吡格雷基础上加用替罗非班,对照组仅口服阿司匹林＋氯吡格雷;比较两组基线资料、支架植入即刻心肌梗死溶栓治疗（TIMI）血流3级比率、支架内血栓发生率、轻微出血、大出血和血小板减少发生率、术后30d死亡、心肌梗死（MI）和靶血管血运重建（TVR）率。结果替罗非班组PCI后即刻TIMI血流3级比率高于对照组（99．05％VS94．78％,P〈0．05）;支架内血栓发生率明显低于对照组（0．47％vs3．47％,P〈0．01）;术后30d,替罗非班组死亡、MI和TVR率明显低于对照组（分别为0．00％VS2．61％、0．47％VS3．47％和0．47％vs1．73％,P〈0．01）;替罗非班组轻微出血发生率高于对照组,但无统计学差异（7．14％VS4．35％,P〉0．05）,两组大出血发生率和血小板减少发生率均无显著差异（分别为0．00％12S0．00％和0．95％vs0．87％,P〉0．05）。结论国产替罗非班可明显改善老年ACS患者PCI术后即刻TIMI血流状况;有效降低支架内血栓发生率;减少术后30d死亡、MI和TVR发生率,且不增加大出血和血小板减少的发生,从而改善患者的近期预后。     

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.     

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.     

Management of non-ST-segment-elevation acute coronary syndromes in Spain. The DESCARTES (Descripción del Estado de los Síndromes Coronarios Agudos en un Registro Temporal ESpañol) study

INTRODUCTION AND OBJECTIVES: There is little information regarding the management of non-ST segment elevation acute coronary syndromes (NSTE ACS) in Spain from a population-based perspective. Our objective was to study the status of clinical care in patients with NSTE ACS in Spain from a representative perspective of the situation on a national level. PATIENTS AND METHOD: A prospective registry was used for consecutive patients with NSTE ACS admitted to 52 Spanish hospitals with different cardiological facilities. Centers that fulfilled the quality control criteria for the study were randomly selected for inclusion. RESULTS: Between April and May, 2002, 1877 patients were recruited. Median age was 69 years, 93% had at least one risk factor and 73% had antecedents of cardiovascular disease. The electrocardiogram on admission was abnormal in 76% of the cases, and troponin levels were elevated in 53%. Twenty-seven percent of the patients were admitted to a cardiac care unit or intensive care unit. The rates of use of diagnostic techniques were: echocardiography 56%; non-invasive test for detection of ischemia 39%; coronary angiography 41%. During hospitalization, 24% underwent coronary revascularization, 88% received aspirin, 81% heparin, 37% clopidogrel, 12% glycoprotein IIb/IIIa inhibitors, 63% ss-blockers, 46% angiotensin-converting enzyme inhibitors, and 52% statins. The final diagnosis was angina in 54%, myocardial infarction in 28%, and other in 18%. Mortality was 3.7% at 28 days and 7.8% at 6 months. CONCLUSIONS: DESCARTES is the first representative registry of NSTE ACS management in Spain. It shows that despite their high-risk profile, these patients receive suboptimal medical care according to current clinical recommendations.     

Effect of clopidogrel on 1-year mortality in hospital survivors of acute ST-segment elevation myocardial infarction in clinical practice.

AIMS: We sought to assess the effect of clopidogrel on clinical events 1 year after discharge in survivors of ST-elevation myocardial infarction (STEMI) in clinical practice. METHODS AND RESULTS: We analysed data of consecutive survivors of acute STEMI and either concomitant therapy with aspirin or aspirin plus clopidogrel at discharge, who were prospectively enrolled in the Acute Coronary Syndromes (ACOS) registry between July 2000 and November 2002. A total of 5886 (3795 with and 2091 without clopidogrel) patients were included into this analysis. Patients were divided into three groups according to the initial reperfusion therapy: no reperfusion therapy (n=1445), fibrinolysis (n=1734), or primary PCI (n=2707). The multivariable analysis for 12+2 month mortality after discharge using the propenstiy score with adjustment for baseline characteristics and treatments (age, sex, diabetes mellitus, hypertension, prior MI, hyperlipidaemia, renal insufficiency, cardiogenic shock, heart rate, systolic blood pressure, anterior infarct location, reduced left ventricular function, elective revascularization, beta-blockers, statins, ACE-inhibitors) showed that mortality was significantly lower in the aspirin plus clopidogrel group compared with the aspirin group in the total group and patients with reperfusion therapy [total group odds ratio (OR) 0.48, 95% confidence interval (CI) 0.48-0.61; no reperfusion therapy OR 0.96, 95% CI 0.65-1.45; fibrinolysis OR 0.53, 95% CI 0.32-0.87; primary percutaneous coronary intervention OR 0.38, 95% CI 0.23-0.62]. CONCLUSION: In clinical practice, adjunctive therapy with clopidogrel, in addition to aspirin, in survivors after STEMI is associated with a reduction in 1-year mortality in patients treated with early reperfusion therapy.     

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.     

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.     

Prolonged application of clopidogrel reduces inflammation after percutaneous coronary intervention in the porcine model

OBJECTIVE: We determined the effect of prolonged treatment with clopidogrel on C-reactive protein (CRP) concentrations and blood thrombogenicity after percutaneous transluminal coronary angioplasty followed by intracoronary brachytherapy in the porcine model. ANIMAL MODEL: All 48 pigs received antiplatelet therapy, including aspirin (325 mg, daily) and clopidogrel (300 mg, loading dose) 1 day before PCI, followed by a daily dose of clopidogrel (75 mg/day) in addition to aspirin. During PCI, one of two balloon-injured arteries was randomly assigned to receive immediate radiation treatment. Animals were sacrificed after 24 h, 1 month, and 3 months post-PCI. The pigs, which were sacrificed 3 months post-PCI, were divided into two groups. The first group received clopidogrel in addition to aspirin for 3 months, and the second group received clopidogrel in addition to aspirin for only 1 month after PCI and then aspirin alone. METHODS: Blood was taken from all pigs before intervention, immediately after intervention, and before sacrifice. Serum CRP was measured by enzyme-linked immunosorbent assay. To analyze the procoagulant effects of PCI on blood thrombogenicity, a one-stage clotting assay was performed. RESULTS: Clopidogrel treatment for 3 months reduced CRP levels more than did clopidogrel therapy for 1 month only at 3 months post-PCI (27.9+/-3.9 vs. 56.6+/-11.3 microg/ml; P=.019). Baseline CRP levels were found to be 50.4+/-4.8 microg/ml. Plasma clotting was not affected by prolonged clopidogrel therapy (322.8+/-59.3 s vs. 295.2+/-52.5 s; P=ns). CONCLUSIONS: Prolonged treatment with clopidogrel reduced CRP levels post-PCI.     

ACS患者PCI术后不同剂量氯吡格雷应用效果观察

目的 探讨PCI术后双剂量氯吡格雷对急性冠脉综合征患者血浆超敏C反应蛋白（hs-CRP）和脂蛋白相关性磷脂酶A2 （Lp-PLA2）的影响.方法 将162例行PCI手术的急性冠脉综合征患者随机分为观察组和对照组,各81例.所有患者PCI术前均予阿司匹林300 mg,氯吡格雷负荷剂量300 mg治疗,术后观察组口服氯吡格雷150mg/d,对照组口服氯吡格雷75 mg/d,30 d后两组患者均以75 mg/d维持治疗.术前及术后30 d测定并比较两组血浆hs-CRP和Lp-PLA2.随访1 a,观察两组发生心血管不良事件及出血情况.结果 观察组不良心血管事件发生率为3.7％,对照组为9.9％,两组比较,P ＜0.05.两组患者均未发生颅内出血和消化道出血,观察组总出血事件发生率为9.9％,对照组为7.4％,两组比较差异无统计学意义.两组术后30 d时血浆hs-CRP和Lp-PLA2均降低（P＜0.05或＜0.01）,且观察组治疗后比对照组降低更明显（P均＜0.05）.结论 PCI术后双剂量氯吡格雷可以更明显减轻急性冠脉综合征患者的炎症情况,且未见严重不良反应.     

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.     

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.     

Absence of interaction between atorvastatin or other statins and clopidogrel: results from the interaction study

BACKGROUND: Some, but not all, post hoc analyses have suggested that the antiplatelet effects of clopidogrel are inhibited by atorvastatin. We sought to address this issue prospectively by performing serial measurements of 19 platelet characteristics using conventional aggregometry, rapid analyzers, and flow cytometry. METHODS: The Interaction of Atorvastatin and Clopidogrel Study (Interaction Study) was designed for patients undergoing coronary stenting. All patients (n = 75) received 325 mg of aspirin daily for at least 1 week and 300 mg of clopidogrel immediately prior to stent implantation. They had been taking atorvastatin (n = 25), any other statin (n = 25), or no statin (n = 25) for at least 30 days prior to stenting. The main outcome measure was comparison of platelet biomarkers 4 and 24 hours after clopidogrel administration between study groups. RESULTS: At baseline, patients from both statin groups exhibited diminished platelet aggregation and reduced platelet expression of G-protein-coupled protease-activated thrombin receptor (PAR)-1. There were no significant differences in measured platelet characteristics among the study groups 4 and 24 hours after clopidogrel intake, with the exception of a lower collagen-induced aggregation at 24 hours and a constantly diminished expression of PAR-1 in patients treated with any statin. CONCLUSIONS: Statins in general, and atorvastatin in particular, do not affect the ability of clopidogrel to inhibit platelet function in patients undergoing coronary stenting. These prospective data also suggest that statins may inhibit platelets directly via yet unknown mechanism(s) possibly related to the regulation of the PAR-1 thrombin receptors.     

Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery.

OBJECTIVES: We sought to characterize patterns of clopidogrel use before coronary artery bypass grafting (CABG) and examine the drug's impact on risks for postoperative transfusions among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). BACKGROUND: Adherence in community practice to American College of Cardiology/American Heart Association guidelines for clopidogrel use among NSTE ACS patients has not been previously characterized. METHODS: We evaluated 2,858 NSTE ACS patients undergoing CABG at 264 hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Initiative. We examined the patterns of acute clopidogrel therapy and its association with bleeding risks among those having "early" CABG < or =5 days and again among those having "late" surgery >5 days after catheterization. RESULTS: Within 24 h of admission, 852 patients (30%) received clopidogrel. In contrast to national guidelines, 87% of clopidogrel-treated patients underwent CABG < or =5 days after treatment. Among those receiving CABG within < or =5 days of last treatment, the use of clopidogrel was associated with a significant increase in blood transfusions (65.0% vs. 56.9%, adjusted odds ratio [OR] 1.36, 95% confidence interval [CI] 1.10 to 1.68) as well as the need for transfusion of > or =4 U of blood (27.7% vs. 18.4%, OR 1.70, 95% CI 1.32 to 2.19). In contrast, acute clopidogrel therapy was not associated with higher bleeding risks if CABG was delayed >5 days (adjusted OR 1.18, 95% CI 0.54 to 2.58). CONCLUSIONS: Despite guideline recommendations, the overwhelming majority of NSTE ACS patients treated with acute clopidogrel needing CABG have their surgery within < or =5 days of treatment. A failure to delay surgery is associated with increased blood transfusion requirements that must be weighed against the potential clinical and economic impacts of such delays.     

Beneficial effect of a loading dose of 600 mg of clopidogrel on platelet parameters in patients admitted for acute coronary syndrome

INTRODUCTION: Despite the beneficial effect of an aspirin-clopidogrel combination in acute coronary syndrome, the incidence of ischaemic recurrences remains significant and very probably implicates a variability in the response to anti-platelet agents. OBJECTIVE: We sought to demonstrate the evidence for a beneficial effect, in terms of anti-platelet effect, of a higher loading dose of 600 mg of clopidogrel compared to the usual 300 mg in patients admitted to our centre with acute coronary syndrome. MATERIALS AND METHODS: Platelet reactivity was evaluated with the ADP 10_mol test and the degree of platelet activation by the expression of P-selectin. 178 consecutive patients admitted for acute coronary syndrome received 250 mg of intravenous aspirin together with either a loading dose of 300 mg of clopidogrel (n = 104) or 600 mg (n = 74) administered 12 to 24 hours prior to coronary angiography. RESULTS: The patients who received 600 mg of clopidogrel had an average aggregation intensity to ADP and a rate of platelet high reactivity post treatment that was significantly lower [48+20 vs 58+18, p = 0.0011 and 11 patients (15%) vs 26 patients (25%), p = 0.0003 respectively]. The degree of platelet activation evaluated with P-selectin was significantly lower in patients receiving 600mg [0.33 + 0.17 vs 0.50+0.29, p < 0.001]. CONCLUSION: Our study provides evidence for a beneficial effect of a loading dose of 600mg of clopidogrel compared to the usual 300 mg in terms of platelet reactivity and platelet activation post treatment.     

Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications.

BACKGROUND AND AIMS: The role of clopidogrel in patients at risk for gastrointestinal complications is uncertain, although it has been recommended for patients who have gastrointestinal intolerance to aspirin. We tested the hypothesis that clopidogrel is as effective as esomeprazole and aspirin in preventing recurrences of ulcer complications. METHODS: This was a prospective, double-blind, randomized, controlled study of 170 patients who developed ulcer bleeding after the use of low-dose aspirin between November 2002 and January 2005. After healing of ulcers and eradication of Helicobacter pylori, if present, patients were assigned randomly to treatment with esomeprazole 20 mg/day and aspirin 100 mg/day (n = 86) or clopidogrel 75 mg/day (n = 84) for 52 weeks. The primary end point was recurrent ulcer complications. RESULTS: During a median follow-up period of 52 weeks, no patient in the esomeprazole group, as compared with 9 patients in the clopidogrel group, developed recurrent ulcer complications. The cumulative incidences of recurrent ulcer complications were 0% in patients receiving esomeprazole and aspirin and 13.6% in patients receiving clopidogrel (absolute difference, 13.6%; 95% confidence interval for the difference, 6.3-20.9; log-rank test, P = .0019). CONCLUSIONS: The combination of esomeprazole and aspirin is superior to clopidogrel in preventing ulcer complications in patients who have a past history of aspirin-related peptic ulcer bleeding.