Effects of colchicine on platelet aggregation in patients on dual antiplatelet therapy with aspirin and clopidogrel

Journal of Thrombosis and Thrombolysis - Platelets aggregation leading to thrombosis plays a pivotal role in the pathophysiology of acute coronary syndrome (ACS) and of stent thrombosis....     

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.     

Effect of aspirin treatment in patients with peripheral arterial disease monitored with the platelet function analyzer PFA-100.

We have used the platelet analyzer PFA-100TM to assess the effect of aspirin (ASA) in patients with documented peripheral arterial disease (PAD). Thirty-one previously untreated patients were recruited. Laboratory investigations, including the collagen and adenosine diphosphate closure time (CADP-CT) and the collagen and epinephrine closure time (CEPI-CT) were performed before and 7 days after treatment with 100 mg ASA per day. Five patients were excluded from the final analysis: one patient did not appear for second examination, in one patient type I von Willebrand disease was diagnosed, and three patients with prolonged CEPI-CT admitted the intake of non-steroidal anti-inflammatory drugs. Prior to ASA treatment, CADP-CT was 90 +/- 15 s (range, 67-124 s) and CEPI-CT was 116 +/- 27 s (range, 78-164 s). There was a significant negative correlation between CADP-CT and von Willebrand factor antigen (r = -0.57, P = 0.001). After treatment with 100 mg ASA per day, CADP-CT was not significantly different (96 +/- 22 s; range, 65-158 s). CEPI-CT, however, was prolonged in all patients, compared with pre-ASA values (226 +/- 82 s; range, 89 to > 300 s). In 12 of 26 patients, CEPI-CT was > 300 s and in another four of 26 patients CEPI-CT was prolonged to more than the upper normal range ('responders'). In the remaining 10 patients, CEPI-CT values did not exceed the upper limit of the normal range ('non-responders'). Five non-responders were re-investigated after intake of 300 mg ASA per day for 3 weeks; in none of these was a CEPI-CT > 165 s recorded. We conclude that 40% of PAD patients have an inadequate response to ASA, as determined by the PFA-100TM CEPI-CT. Whether these patients have a reduced benefit from this treatment remains to be investigated.     

2型糖尿病对阿司匹林和氯吡格雷双联抗血小板药物治疗效应的分析

目的:本研究通过前瞻性连续入选在我院因稳定性冠心病行经皮冠状动脉介入治疗(PCI)的患者,分析探讨糖尿病对阿司匹林和氯吡格雷双联抗血小板药物效应的影响。方法:2008年8月至2011年11月前瞻性连续入选稳定性冠心病患者。入院后服用氯吡格雷前测定花生四烯酸(AA)诱导的血小板聚集率和基线二磷酸腺苷(ADP)诱导的血小板聚集率,之后给予氯吡格雷300 mg负荷量口服,继续服用氯吡格雷75 mg/d至1 d后,再次测定服用氯吡格雷后ADP诱导的血小板聚集率。结果:入选了355例稳定性冠心病患者,其中合并2型糖尿病103例,非糖尿病252例。阿司匹林抵抗的发生率18.6%,糖尿病组与非糖尿病组阿司匹林抵抗的发生率未见明显差异(20.4%vs.17.9%,P=0.578),将患者基线特征纳入Logistic回归模型进行校正后结果显示,糖尿病并未增高阿司匹林抵抗的风险(OR=1.3,95%CI=0.7～2.7,P=0.439)。氯吡格雷抵抗的发生率为20.8%;糖尿病组氯吡格雷抵抗的发生率明显高于非糖尿病组(33.0%vs.15.9%,P<0.001);Logistic回归校正后结果显示,糖尿病是氯吡格雷抵抗的独立危险因素(OR=5.7,95%CI=2.9～11.1,P<0.001)。结论:双联抗血小板药物基础上,糖尿病未增高阿司匹林抵抗的风险;但是糖尿病明显增高了氯吡格雷抵抗的风险。     

The effect of short-term treatment with simvastatin on renal function in patients with peripheral arterial disease

The objective of this study was to investigate the effects of lipid-lowering treatment on renal function in patients with peripheral arterial disease (PAD). This was a retrospective study of hyperlipidemic claudicants referred to a vascular surgery and risk modification clinic. Serum creatinine and urate concentrations and the fasting lipid profile were measured pretreatment and after 3-4 months of treatment with 20 mg/day simvastatin. In 103 consecutive patients with PAD (57 men; 46 women), median age 67 years (range: 51 to 83) there was a significant decrease in serum creatinine from a mean (SD) of 87 (12) micromol/L pretreatment to 84 (12) micromol/L post-treatment (p<0.0001). This difference was more marked in the tertile of patients with the highest baseline creatinine levels. There was also a significant reduction in serum urate from 0.37 (0.07) mmol/L to 0.35 (0.07) mmol/L (p<0.0001). Both these effects were independent of the degree of total cholesterol (TC) or low-density lipoprotein (LDL) cholesterol reduction. There was a significant reduction in TC from 6.6 (1.0) to 5.2 (0.8) mmol/L and LDL cholesterol from 4.3 (1.0) to 2.8 (0.7) mmol/L; both p<0.0001. Significant improvement also occurred in the high-density lipoprotein cholesterol and triglyceride levels. Cholesterol lowering with simvastatin 20 mg/day improved indices of renal function after 3-4 months of treatment in hyperlipidemic patients with PAD. Further studies are needed to establish and define the clinical relevance of these findings, especially in patients with different degrees of renal failure.     

Response to aspirin and clopidogrel monitored with different platelet function methods

Laboratory non-response to aspirin or clopidogrel is defined as an inability to cause in vitro detectable platelet function inhibition. It would be beneficial to monitor response to aspirin or clopidogrel with widely available and routinely used platelet function methods, like the platelet function analyzer (PFA-100) or the fully automated coagulation analyzer BCT. The aim of this study was to assess the potential of the coagulation analyzer BCT and the platelet function analyzer PFA-100 in monitoring the response of aspirin and clopidogrel. A group of 125 consecutive patients with arterial occlusive disease treated either with aspirin 100 mg/day (82 patients) or clopidogrel 75 mg/day (43 patients) as only antiplatelet drug were investigated. For the first time platelet-enriched plasma (PRP), not adjusted to a fixed predetermined concentration of platelets, was used for aggregation studies and the effect of clopidogrel alone without combination of aspirin treatment on platelet function was investigated. Response to aspirin was observed in 85% (70/82) of patients using PFA-100, while performing the arachidonic acid-induced aggregation on the BCT showed an inhibitory effect to aspirin in 91% (75/82) of patients. Non-response to aspirin was assessed with both platelet function methods in 7% (6/82) of patients. Clopidogrel response was observed in 58% (25/43) of patients when performing ADP-induced aggregation on the BCT. On the PFA-100 the antiplatelet effect of clopidogrel could not be detected. In conclusion, measurement of platelet aggregation on the BCT using native platelet-enriched plasma allows the quantification of individual inhibitory effects to aspirin as well as to clopidogrel, while the PFA-100 seems only suitable to investigate the degree of platelet inhibition induced by aspirin but not by clopidogrel.     

Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention

Increased platelet inhibition is achieved when clopidogrel is added to aspirin (acetylsalicylic acid [ASA]). A broad variability in platelet inhibition profiles during the early phases of treatment has been demonstrated and may be attributed to ASA resistance. However, the influence of ASA sensitivity on platelet function profiles of patients on long-term dual antiplatelet therapy has yet to be explored. A total of 135 patients who had previously undergone percutaneous coronary intervention on long-term (>1 month) ASA and clopidogrel therapy was included. The PFA-100 system was used to define ASA resistance. Platelet aggregation, after adenosine diphosphate (6 and 20 micromol/L) and collagen (6 microg/ml) stimuli, and platelet activation (glycoprotein IIb/IIIa activation and P-selectin expression), after adenosine diphosphate (2 micromol/L) and thrombin receptor-activating peptide (50 micromol/L) stimuli, were assessed by light transmittance aggregometry and flow cytometry, respectively. Patient variability in response to treatment was defined by the coefficient of variability. ASA resistance was found in 60 of 135 patients (44%). Patients with diabetes were more frequently ASA resistant. Collagen/epinephrine- and collagen/adenosine diphosphate-coated cartridges on the PFA-100 had shorter closure times in the ASA-resistant population compared with ASA-sensitive patients. Platelet aggregation and activation were significantly higher in ASA-resistant patients. A broad variability (coefficient of variation >0.25) in patient response to treatment was observed in ASA-resistant and -sensitive patients. In conclusion, ASA resistance is associated with increased platelet reactivity in patients on long-term dual antiplatelet treatment.     

高龄老年应用氯吡格雷与阿司匹林抗血小板治疗的临床研究

目的对比研究高龄老年应用氯吡格雷与阿司匹林抗血小板治疗的效果及安全性。方法91例高龄老年冠心病患者随机分为氯吡格雷组(50 mg/d)、阿司匹林组(100 mg/d)及对照组(复方丹参滴丸10粒3次/d),药物治疗8周后,观察实验前后血小板聚集率改变、胃黏膜出血、对中性粒细胞及血小板的影响以及凝血三项的改变。结果与对照组比较,氯吡格雷组与阿司匹林组对血小板聚集率均有确切的抑制作用;在血小板聚集率抑制方面,氯吡格雷组优于阿司匹林组;各组实验前后均未出现中性粒细胞及血小板的显著变化;在胃黏膜损伤方面,虽然阿司匹林组发生例数较多,但各组均无显著差异;阿司匹林组及对照组实验前后凝血指标未发生变化,氯吡格雷组用药后活化部分凝血酶时间延长,与对照组比较有显著差异,而用药前两组无显著差异。结论高龄老年应用氯吡格雷与阿司匹林均能获得确切的抗血小板聚集效果,且较安全,其中氯吡格雷效果优于阿司匹林。     

Limited early antiplatelet effect of 300 mg clopidogrel in patients with aspirin therapy undergoing percutaneous coronary interventions

Aim Our aim was to evaluate the early efficacy and variabilityof the platelet inhibition exerted by 300 mg clopidogrel forthe purpose of acute percutaneous coronary interventions usingplatelet function tests. Methods and results Elective percutaneous coronary interventionwas used as a timely model in which clopidogrel was added toongoing acetylsalicylic acid (aspirin) (100 mg/day) at 2.5 hprior to procedure. Blood samples were collected before administrationof clopidogrel and immediately before the intervention from50 patients. Platelet functions were assessed with traditionalaggregation and PFA-100^®. At baseline, 14 (28%) patients were poor responders to aspirinaccording to PFA and 9 (18%) continued to show arachidonic acid-inducedaggregation. After clopidogrel ADP-triggered aggregation wasonly modestly inhibited in 40% of the patients. Eight percentof the study population was left without any measurable antiplateleteffect. The patients with modest response to clopidogrel hadhigher levels of c-peptide (1.5 nmol/L) than the ones respondingwell (0.9 nmol/L, ). Conclusion Neither ongoing aspirin treatment nor added clopidogreldid reach an expected extent of platelet inhibition. This studyshows that aspirin-treated patients undergoing PCI gain highlyvariable levels of platelet inhibition with short-term clopidogrel300 mg. At 2 h after adding clopidogrel it failed to enhance platelet inhibition in 40% of the patients.In future, targeted platelet function tests may be helpful toindividually select an effective antiplatelet medication forthese patients. This study suggests that for acute PTCA clopidogreldoes not reach the optimal antithrombotic efficacy in all patients.     

Platelet response to aspirin and clopidogrel in patients with peripheral atherosclerosis

Aspirin and clopidogrel are important drugs in the secondary prevention of ischemic events. A considerable individual variation in platelet response to these drugs has, however, been reported, and high residual platelet reactivity despite treatment may be an independent risk factor for ischemic events. Most studies have been undertaken in patients with coronary heart disease, but patients with peripheral artery disease (PAD) may exhibit greater residual platelet reactivity, possibly because of platelet activation by a larger area of diseased endothelium. It is yet unsettled which method that best measures platelet reactivity and an eventual lack of response to aspirin. Several instruments are promoted to measure platelet response and low-response to platelet inhibitors, but it is questionable if they measure this in comparable ways. We studied the comparability of three tests of platelet reactivity for the assessment of low-response to aspirin and clopidogrel in patients with PAD. In 263 patients, platelet function was assessed twice, 3 months apart, by the Platelet Function Analyzer-100 (PFA), light transmission aggregometry (LTA), and whole blood impedance aggregometry (IA). In a subgroup of 43 patients, we studied the effect of a single dose of 600 mg clopidogrel on platelet function. Low-response to aspirin assessed by analyses targeting cyclooxygenase-1 activity (LTA, IA) was rare (≤ 8.1%). With the PFA, we found 17% with low response at both visits, and 60% who were consistently responsive, whereas 23% were categorized differently at the two visits. Low response to clopidogrel, occurred in 0-23%, depending on the method and the criteria used. A low-response to aspirin, defined by lack of COX-1 inhibition, is a rare phenomenon whereas high residual platelet reactivity as determined by PFA may be a rather frequent finding but is not consistent over time in all patients. A low-response to clopidogrel depends very much on the method and definition used.     

Effect on platelet function of cilostazol, clopidogrel, and aspirin, each alone or in combination

Management of peripheral arterial disease (PAD) requires standard atherosclerotic risk management interventions. However, PAD is often complicated by walking pain (intermittent claudication [IC]), which requires symptom-specific therapies as well. Thus, all PAD patients are encouraged to take antiplatelet agents to reduce the associated risks of major cardiovascular events, and those with IC may also require treatment with cilostazol, an agent proven to increase exercise capacity and enhance quality of life in these patients. Although it was initially thought that cilostazol's antiplatelet properties might render it unsafe to use in combination with other platelet inhibitors because of possible additive effects, a recent study has dispelled such concerns. There is evidence that in a crossover trial of 21 patients with PAD and IC, aspirin alone, or clopidogrel alone, significantly increased bleeding times, but cilostazol alone did not. The combination of aspirin and clopidogrel had a greater effect on increasing bleeding time than either monotherapy, and no further bleeding time prolongation was observed, when cilostazol was added to any aspirin/clopidogrel regimen. These findings suggest that PAD patients with IC may be safely managed with both cilostazol and standard antiplatelet therapy, without increasing the risk of adverse bleeding effects.     

国产和进口氯吡格雷对不稳定性心绞痛患者血小板功能的影响

目的　观察国产氯吡格雷和进口氯吡格雷对不稳定性心绞痛 (UAP)患者血小板功能的影响 ,比较两药抗血小板作用的优劣及其安全性。方法　 4 0例UAP患者随机分为 2组 ,其中国产氯吡格雷组 2 0例 ,进口氯吡格雷组 2 0例。另选健康对照组 10例。两治疗组分别于服用氯吡格雷前、服用氯吡格雷 30 0mg 2h后及服用氯吡格雷 75mg1次 d 1周后抽血查血小板聚集率及血小板活化指标。结果　UAP患者血小板聚集率及血小板活化状态较健康对照组明显增高。治疗前国产和进口氯吡格雷组的血小板聚集率及血小板活化指标无显著差异。治疗后两治疗组之间无显著差异。结论　血小板的活化在UAP的发生、发展过程中起着重要的作用。国产和进口氯吡格雷均有良好的抗血小板作用 ,两者抗血小板聚集和活化的作用相似 ,且无明显的不良反应。     

The effect of doubling the dose of clopidogrel on platelet aggregation in patients with clopidogrel resistance

Antiplatelet drugs play a pivotal role in the management of patients with acute coronary syndrome. Clopidogrel is an important antiplatelet drug commonly used in the treatment of those patients. However, the variability in patient response to clopidogrel is worrisome because a decreased response may lead to unfavorable clinical outcomes. Thus, it is crucial to study possible ways to overcome this problem. In the current study, we measured platelet aggregation in vitro to identify patients with clopidogrel resistance. Those patients were given double the standard maintenance dose of clopidogrel and platelet aggregation was reassessed. It was found that there was a significant increase in clopidogrel response (p < 0.001). Therefore, we recommend that using double the standard maintenance dose of clopidogrel should be considered in those patients.     

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.     

Effects of triple antiplatelet therapy (aspirin, clopidogrel, and cilostazol) on platelet aggregation and P-selectin expression in patients undergoing coronary artery stent implantation

The purpose of this study was to determine the effect of the addition of cilostazol to aspirin plus clopidogrel on platelet aggregation after intracoronary stent implantation. Twenty patients who underwent coronary stent placement were randomly assigned to therapy with aspirin plus clopidogrel (dual-therapy group, n = 10) or aspirin plus clopidogrel plus cilostazol (triple-therapy group, n = 10). A loading dose of clopidogrel (300 mg) and cilostazol (200 mg) was administered immediately after stent placement, and clopidogrel (75 mg/day) and cilostazol (100 mg twice daily) were given for 1 month. Platelet aggregation in response to adenosine diphosphate (ADP; 5 and 20 micromol/L) or collagen and P-selectin (CD-62P) expression was assayed at baseline, 2 hours, 24 hours, 1 week, and 1 month after stent placement. Inhibition of ADP-induced platelet aggregation was significantly higher in patients receiving triple therapy than those receiving dual therapy from 24 hours after stent placement, and inhibition of collagen-induced platelet aggregation was significantly higher in the triple-therapy group beginning 1 week after stent placement. P-Selectin expression was significantly lower in the triple-therapy than dual-therapy group at 1 week and 30 days. In conclusion, compared with dual antiplatelet therapy, triple therapy after coronary stent placement resulted in more potent inhibition of platelet aggregation induced by ADP and collagen. These findings suggest that triple therapy may be used clinically to prevent thrombotic complications after coronary stent placement.