瑞舒伐他汀和阿托伐他汀对氯吡格雷抗血小板活性的影响

目的观察瑞舒伐他汀和阿托伐他汀对氯吡格雷抗血小板活性的影响。方法选择60例冠心病患者接受阿司匹林100mg/d、氯吡格雷75 mg/d及低分子肝素5000 U/12 h治疗,5 d后随机分为阿托伐他汀20mg/d(阿托伐他汀组,30例)和瑞舒伐他汀10 mg/d(瑞舒伐他汀组,30例)。在服用氯吡格雷之前(基线值)、加用他汀类药物之前及服用他汀类药物3d后,用全血阻抗法分别测定不同浓度二磷酸腺苷(5、10、20μmol/L)诱导的血小板聚集率。结果与基线值比较,服用氯吡格雷5 d后和加服他汀类药物治疗3 d后,2组患者血小板聚集率明显降低,差异有统计学意义(P<0.05);与治疗前比较,阿托伐他汀组患者血小板聚集率有所升高,而瑞舒伐他汀组患者血小板聚集率有所下降,但差异无统计学意义(P>0.05)。结论经细胞色素3A4途径代谢的阿托伐他汀及不经细胞色素3A4代谢的瑞舒伐他汀,短期内对氯吡格雷抗血小板活性无影响。     

The inhibitory potency of clopidogrel on ADP-induced platelet activation is not attenuated when it is co-administered with atorvastatin (20 mg/day) for 5 weeks in patients with acute coronary syndromes

The antiplatelet potency of clopidogrel may be attenuated by short-term co-administration of lipophilic statins metabolized through the cytochrome P-450, isoform 3A4. We investigated whether the co-administration of atorvastatin (20?mg/day) for 5 weeks, in patients with acute coronary syndromes (ACS) could affect the antiplatelet activity of clopidogrel. Fifty-one patients with the first episode of an ACS were included in the study. All patients underwent percutaneous coronary intervention (PCI) and received a loading dose of 375 mg of clopidogrel, followed by 75 mg/day for at least 3 months. Twenty-six of them presented with low density lipoprotein (LDL) cholesterol levels >100?mg/dl (2.6 mmol/l) (measured within 24 h from the onset of symptoms) and received daily 20 mg/day of atorvastatin. The ADP- or TRAP-induced platelet aggregation, as well as P-selectin and CD40L surface expression, were studied at baseline (within 30 min after admission) and 5 weeks afterwards. Atorvastatin did not influence either the clopidogrel-induced inhibition of platelet aggregation initiated by 5 or 10 microM ADP or the clopidogrel-induced reduction of the membrane expression of P-selectin and CD40L induced by ADP. In conclusion, atorvastatin, even at a dose of 20 mg/day does not affect the antiplatelet efficacy of clopidogrel when co-administered for 5 weeks in ACS patients.     

Antiplatelet effects of a 600 mg loading dose of clopidogrel are not attenuated in patients receiving atorvastatin or simvastatin for at least 4 weeks prior to coronary artery stenting.

AIMS: To test prospectively whether the antiplatelet effect of a 600 mg loading dose of clopidogrel is attenuated in patients receiving atorvastatin and simvastatin for at least 4 weeks prior to coronary artery stenting. METHODS AND RESULTS: Blood samples were obtained at least 2 h after receiving 100 mg aspirin and 600 mg clopidogrel and prior to coronary stenting from 90 patients without statin therapy and 90 patients with statin (atorvastatin and simvastatin) therapy for at least 4 weeks. Maximal and residual platelet aggregation was evaluated with optical aggregometry in response to ADP (5 and 20 micromol/l). Surface expression of IIb/IIIa (CD61) and P-selectin (CD62) was assessed with whole blood flow-cytometry at baseline and following stimulation (5 and 20 micromol/l ADP). Inhibition of ADP-induced platelet aggregation was not impaired in the presence of concomitant statin therapy. Moreover, patients with and without statin therapy did not differ in respect to all flow-cytometric parameters obtained. CONCLUSION: The antiplatelet effect of a high, 600 mg loading dose of clopidogrel is not diminished in patients receiving atorvastatin and simvastatin for at least 4 weeks prior to coronary stenting.     

急性冠状动脉综合征冠状动脉支架术后应用他汀类药物对氯吡格雷抗血小板作用无影响

目的探讨急性冠状动脉综合征（ACS）患者行冠状动脉支架术后服用阿托伐他汀或普伐他汀对氯吡格雷抗血小板作用的影响。方法研究对象为150例2006年4至12月成功实施冠状动脉支架术的住院ACS患者,术后第1天起随机接受阿托伐他汀20mg／d（n=50）、普伐他汀20mg／d（／7,=50）或无他汀（n=50）治疗。围术期抗血小板治疗为阿司匹林300mg／d,当天氯吡格雷负荷量300mg,继以维持量75mg／d。观测各组患者术后第1天（基线值）及第3天的血小板膜糖蛋白P-选择素（CD62P）、血小板活化复合物（PAC-1）表达及20μmol／L二磷酸腺苷（ADP）诱导的血小板最大聚集率（MPAR）。结果三组患者临床及CD62P、PAC-1和MPAR的基线值差异均无统计学意义。各观测指标第二次测定值与基线值的差值显示,阿托伐他汀、普伐他汀和无他汀组的ACD62P[（4．69±16．78）％、（1．35±10．86）％和（2．97±10．21）％]、APAC-1[（12．78±22．07）％、（8．01±21．23）％和（10．65±21．39）％l及AMPAR[（5．44±18．68）％、（7．15±19．59）％和（3．76±23．42）％]差异均无统计学意义（P〉0．05）。急性心肌梗死患者亚组分析结果表明,ACD62P[（7．50±19．35）％、（3．24±11．18）％和（2．53±8．87）％]、APAC-1[（13．40±24．62）％、（11．28±19．90）％和（10．11±21．29）％]及AMPAR[（7．56±19．11）％、（7．87±23．60）％和（6．75±23．30）％]三组间差异亦均无统计学意义（P〉0．05）。结论接受冠状动脉支架术的ACS患者服用阿托伐他汀或普伐他汀后,短期内未发现对氯吡格雷的抗血小板作用产生显著影响。     

Multiple antiplatelet effects of clopidogrel are not modulated by statin type in patients undergoing percutaneous coronary intervention

We investigated whether statin type or dose influenced the inhibition of platelet function induced by clopidogrel in a prospective, open, parallel group study in patients undergoing elective percutaneous coronary intervention. Patients were taking CYP3A4 metabolised atorvastatin (n = 20) or simvastatin (n = 21), non-CYP3A4 metabolised pravastatin (n = 11) or fluvastatin (n = 2), or no statin therapy (n = 5). ADP and TRAP-induced platelet aggregation were measured using optical aggregometry, whole-blood single-platelet counting, and the Ultegra and Plateletworks point-of-care systems. Platelet pro-coagulant activity (annexin V binding and microparticle formation), P-selectin expression and platelet-leukocyte conjugate formation were assessed by flow cytometry. Platelet responses were measured at baseline, 4 h post clopidogrel 300 mg, and after 10 and 28 days with clopidogrel 75 mg daily. Clopidogrel significantly inhibited both ADP and TRAP-induced platelet responses over time, with steady state inhibition achieved by day 10. This was demonstrated by all techniques used. There was no significant effect of statin type or dose on platelet responses by any method at any time-point. In conclusion, statins do not influence the inhibitory effects of clopidogrel on multiple platelet responses, including aggregation, P-selectin expression, platelet-leucocyte conjugate formation and pro-coagulant responses, in patients undergoing elective PCI.     

Influence of statin treatment on platelet inhibition by clopidogrel – a randomized comparison of rosuvastatin,atorvastatin and simvastatin co‐treatment

Objectives. Possible interactions between clopidogrel and atorvastatin, simvastatin or rosuvastatin (a ‘non‐CYP3A4’ metabolized statin) were investigated in a randomized prospective study using sensitive and specific ex vivo platelet function tests. Methods. Patients with coronary artery disease participating in a double‐blind study comparing lipid‐lowering effects of atorvastatin (20–80 mg OD; n = 22) and rosuvastatin (10–40 mg OD; n = 24) were studied before and after 2 weeks treatment with clopidogrel 75 mg OD after completed statin dose titration. In addition, 23 patients were randomized to open‐label simvastatin 40 mg OD. Results. Clopidogrel inhibited 10 μmol L^?1 ADP‐induced platelet aggregation by 40 ± 27%, 57 ± 28% and 51 ± 29%, respectively, in patients on rosuvastatin, atorvastatin and simvastatin treatment. The other platelet tests yielded similar results. No dose‐dependent effects of rosuvastatin or atorvastatin co‐treatment on clopidogrel efficacy were observed. Conclusions. Treatment with CYP3A4 metabolized statins, atorvastatin or simvastatin, did not attenuate the platelet inhibitory effect of clopidogrel maintenance treatment compared with the non‐CYP3A4 metabolized, rosuvastatin.     

Accelerated platelet inhibition by switching from atorvastatin to a non-CYP3A4-metabolized statin in patients with high platelet reactivity (ACCEL-STATIN) study

Aims CYP3A4-metabolized statins can influence the pharmacodynamic effect of clopidogrel. We sought to assess the impact of switching to a non-CYP3A4-metabolized statin on platelet function among patients receiving clopidogrel and atorvastatin with high on-treatment platelet reactivity (HPR). Methods and results Percutaneous coronary intervention (PCI)-treated patients (n= 50) with HPR [20 μM adenosine diphosphate (ADP)-induced maximal platelet aggregation (MPA) >50%] were enrolled during chronic administration of atorvastatin (10 mg/day) and clopidogrel (75 mg/day) (≥6 months). They were randomly assigned to a 15-day therapy with either rosuvastatin 10 mg/day (n= 25) or pravastatin 20 mg/day (n= 25). Platelet function was assessed before and after switching by conventional aggregometry and the VerifyNow P2Y12 assay. Genotyping was performed for CYP2C19*2/*3, CYP3A5*3, and ABCB1 C3435T alleles. The primary endpoint was the absolute change in 20 μM ADP-induced MPA. After switching, MPAs after stimuli with 20 and 5 μM ADP were decreased by 6.6% (95% confidence interval: 3.2-10.1%; P < 0.001), and 6.3% (95% confidence interval: 2.5-10.2%; P = 0.002), respectively. Fifty-two P2Y12 reaction units fell (95% confidence interval: 35-70; P < 0.001) and the prevalence of HPR decreased (24%; P < 0.001). Pharmacodynamic effects were similar after rosuvastatin and pravastatin therapy. In addition to smoking status, the combination of calcium channel blocker usage and ABCB1 C3435T genotype significantly affected the change of 20 μM ADP-induced MPA. Conclusions Among PCI-treated patients with HPR during co-administration of clopidogrel and atorvastatin, switching to a non-CYP3A4-metabolized statin can significantly decrease platelet reactivity and the prevalence of HPR. This switching effect appears similar irrespective of the type of non-CYP3A4-metabolized statin.     

老年患者抗血小板治疗状况调查

目的探讨老年患者基础疾病、服用抗血小板药物类型和剂量、影响抗血小板治疗效果的药物、血小板聚集功能检查结果及出血事件的发生情况,为老年患者的抗血小板治疗提供改进和指导。方法选择规律服用抗血小板药物并定期进行血小板聚集功能测定的老年患者1404例,归类分析基础疾病、服用抗血小板药物类型和剂量、同时联用可能影响抗血小板治疗效果的药物、血小板聚集功能检查结果及出血事件的发生情况。结果与未服用抗血小板药物患者比较,服用阿司匹林或氯吡格雷以及两药联用的患者,血小板聚集功能水平明显下降(P<0.01);服用氯吡格雷同时联用质子泵抑制剂(PPI)和(或)他汀类药物的患者,二磷酸腺苷诱导血小板聚集功能水平下降幅度均低于仅服用氯吡格雷的患者(P<0.01);服用氯吡格雷同时联用PPI和(或)他汀类药物的患者,以及服用氯吡格雷+阿司匹林+PPI和(或)他汀类药物的患者,二磷酸腺苷诱导血小板聚集功能水平下降幅度均低于仅服用氯吡格雷+阿司匹林的患者(P<0.01)。结论老年患者中仍存在一定比例的阿司匹林和氯吡格雷抵抗;同时服用PPI和(或)他汀类药物,对氯吡格雷的抗血小板治疗效果有潜在不利影响;合理的药物联用原则,高度个体化的抗血小板治疗方式,以及更加精确的血小板功能检测方法,需要尽快在临床推广应用。     

Lack of evidence of a clopidogrel-statin interaction in the CHARISMA trial.

OBJECTIVES: The purpose of this study was to evaluate the potential impact of clopidogrel and statin interaction in a randomized, placebo-controlled trial with long-term follow-up. BACKGROUND: There are conflicting data regarding whether statins predominantly metabolized by CYP3A4 reduce the metabolism of clopidogrel to its active metabolite and diminish its clinical efficacy. METHODS: The CHARISMA trial was a randomized trial comparing long-term 75 mg/day clopidogrel versus placebo in patients with cardiovascular disease or multiple risk factors on aspirin. The primary end point was a composite of myocardial infarction, stroke, or cardiovascular death at median follow-up of 28 months. We performed a secondary analysis evaluating the interaction of clopidogrel versus placebo with statin administration, categorizing baseline statin use to those predominantly CYP3A4 metabolized (atorvastatin, lovastatin, simvastatin; CYP3A4-MET) or others (pravastatin, fluvastatin; non-CYP3A4-MET). RESULTS: Of 15,603 patients enrolled, 10,078 received a statin at baseline (8,245 CYP3A4-MET, 1,748 non-CYP3A4-MET) and 5,496 did not. For the overall population, the primary end point was 6.8% with clopidogrel and 7.3% with placebo (hazard ratio [HR] 0.93; p = 0.22). This was similar among patients on CYP3A4-MET (5.9% clopidogrel, 6.6% placebo, HR 0.89; p = 0.18) or non-CYP3A4-MET statin (5.7% clopidogrel, 7.2% placebo, HR 0.78; p = 0.19). There was no interaction between statin types and randomized treatment (p = 0.69). Patients on atorvastatin (n = 4,127) (5.7% clopidogrel, 7.1% placebo, HR 0.80; p = 0.06) or pravastatin (n = 1,440) (5.1% clopidogrel, 7.0% placebo, HR 0.72; p = 0.13) had similar event rates. CONCLUSIONS: Despite theoretic concerns and ex vivo testing suggesting a potential negative interaction with concomitant clopidogrel and CYP3A4-MET statin administration, there was no evidence of an interaction clinically in a large placebo-controlled trial with long-term follow-up.     

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.     

Thienopyridine-Associated Drug-Drug Interactions: Pharmacologic Mechanisms and Clinical Relevance

The thienopyridines inhibit platelet activation and aggregation by directly inhibiting the platelet P2Y12 adenosine diphosphate receptor. The available thienopyridines are prodrugs and must be converted into active forms by the cytochrome P450 (CYP) enzyme system. An important portion of the variability in platelet response to clopidogrel is explained by the variability in plasma concentrations of the clopidogrel active metabolite. Several reports have thus progressively raised concerns about potential drug interactions as a result of inhibition or induction of CYP450 enzymes. Pharmacokinetics and pharmacodynamics studies have notably shown that concomitant use of clopidogrel and some proton pump inhibitors reduces the antiplatelet effect of clopidogrel. Several other drugs (metabolized through CYP3A4 such as statins or antifungals) similarly impact the pharmacologic response to clopidogrel. Conversely, agents that induce CYP activity increase clopidogrel responsiveness. However, the data supporting the clinical relevance of such pharmacological drug interactions have been controversial. This review will provide an overview of the mechanisms underlying thienopyridine-associated drug-drug interactions, and highlight the most recent developments in the field and propose guidance for the practitioner.     

Effects of rosuvastatin on platelet inhibition by clopidogrel in cardiovascular patients

Statin interference has been suggested among the mechanisms of reduction of the antiplatelet effect of clopidogrel. We thus sought to assess the influence of rosuvastatin on clopidogrel antiplatelet action in high-risk (HR) cardiovascular patients. To set the level of platelet inhibition by combined antithrombotic treatments we retrospectively studied two populations of HR patients, one under aspirin alone, the other under aspirin plus rosuvastatin, before and after addition of clopidogrel. The effects of rosuvastatin compared with atorvastatin were then prospectively investigated in patients who underwent percutaneous coronary intervention (PCI), under clopidogrel and aspirin treatment. Light transmission platelet aggregation (LTA) was studied in response to adenosine diphosphate (ADP) (5 μM) or arachidonic acid (0.5 mM). The inhibitory effect of clopidogrel in reducing ADP-induced LTA was similar in the two HR groups of patients. No difference in ADP-induced platelet aggregation was observed in the two PCI groups of patients with either atorvastatin or rosuvastatin. In conclusion, rosuvastatin does not interfere with the antiplatelet effect of clopidogrel in patients with cardiovascular disease.     

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.     

Clopidogrel-drug interactions

Multidrug therapy increases the risk for drug-drug interactions. Clopidogrel, a prodrug, requires hepatic cytochrome P450 (CYP) metabolic activation to produce the active metabolite that inhibits the platelet P2Y?? adenosine diphosphate (ADP) receptor, decreasing platelet activation and aggregation processes. Atorvastatin, omeprazole, and several other drugs have been shown in pharmacodynamic studies to competitively inhibit CYP activation of clopidogrel, reducing clopidogrel responsiveness. Conversely, other agents increase clopidogrel responsiveness by inducing CYP activity. The clinical implications of these pharmacodynamic interactions have raised concern because many of these drugs are coadministered to patients with coronary artery disease. There are multiple challenges in proving that a pharmacodynamic drug-drug interaction is clinically significant. To date, there is no consistent evidence that clopidogrel-drug interactions impact adverse cardiovascular events. Statins and proton pump inhibitors have been shown to decrease adverse clinical event rates and should not be withheld from patients with appropriate indications for therapy because of concern about potential clopidogrel-drug interactions. Clinicians concerned about clopidogrel-drug interactions have the option of prescribing either an alternative platelet P2Y?? receptor inhibitor without known drug interactions, or statin and gastro-protective agents that do not interfere with clopidogrel metabolism.     

Prasugrel loading dose in diabetic patients with acute STEMI – Always sufficiently effective? Observation in two cases and review of current knowledge

The activation and subsequent platelet aggregation play a key role in the formation of arterial thrombosis and therefore is the key therapeutic target in the treatment of acute coronary syndromes. Dual antiplatelet therapy containing aspirin and P2Y12 ADP receptor antagonist forms currently the basis in acute ST – elevation myocardial infarction (STEMI) pharmacological treatment. Nevertheless, there is a wide variability in pharmacodynamic response to administration of clopidogrel, the most frequently used P2Y12 ADP receptor antagonist. High platelet reactivity after clopidogrel administration is associated with increased risk of stent thrombosis and points to the suitability of laboratory monitoring of antiplatelet therapy efficacy in clinical practice. Laboratory monitoring of antiplatelet therapy by ex vivo platelet function tests may help to identify individuals with poor antiplatlet response. Recently, there is a growing number of data reporting a failure in antiplatelet response following clopidogrel administration, which is specifically associated with insulin resistance and diabetes mellitus. Prasugrel, a new, potent P2Y12 ADP receptor antagonist, provides faster and more consistent inhibition of platelet function compared with clopidogrel. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance and prasugrel resistance has not yet been reliably described. We report two cases of patients with diabetes mellitus type 2 at the stage of organ complications, in whom a prasugrel loading dose of 60 mg did not reach adequate antiplatelet response in 60 min after prasugrel administration. The antiplatelet response was measured by light transmission aggregometry and by VASP protein phosphorylation assessment.     

Markers of inflammation and platelet aggregation in patients with non ST elevation acute coronary syndrome treated with atorvastatin or pravastatin

AIM: To find out whether early use of atorvastatin and pravastatin in patients with non-ST elevation acute coronary syndrome is associated with rapid changes of platelet aggregation and plasma levels of markers of inflammation. MATERIAL AND METHODS: Ninety patients (<24h from pain onset, age 64+/-10 years) treated with aspirin and heparin were randomized to open atorvastatin 10 mg/day (n=30), atorvastatin 40 mg/day (n=29) or pravastatin 40 mg/day (n=31). Spontaneous and ADP induced platelet aggregation (light transmission), plasma levels of interleukin 6 (IL-6) and C-reactive protein (CRP) (immunoassay) were assessed at baseline, on days 7 and 14. RESULTS: Baseline clinical characteristics, platelet aggregation parameters, CRP and IL-6 levels were similar in all groups. In all groups levels of total and low-density lipoprotein (LDL) cholesterol (CH) were lowered by days 7 (p<0.01) and 14 (p<0.01 vs. baseline and for both atorvastatin groups vs. day 7). Spontaneous platelet aggregation decreased by 15% from baseline, p<0.01, on day 14 in patients receiving atorvastatin 40 and was unchanged in other groups. Changes of ADP induced platelet aggregation, IL-6 and CRP levels were not significant in all groups. However combination of 2 atorvastatin groups (n=59) revealed decrease of CRP by 18% from baseline on day 14 (from 6.94+/-0.97 to 4.76+/-0.76 mg/l, p=0.028). No correlations were found between changes of LDL CH and those of other parameters. CONCLUSION: In otherwise conventionally treated patients with non-ST elevation acute coronary syndrome early use of atorvastatin was associated with rapid (in 14 days) decrease of CRP level. Higher dose of atorvastatin (40 mg/day) induced favorable changes of spontaneous platelet aggregation. There were no significant changes of parameters studied in pravastatin treated 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.     

Lipophilic statins do not affect the antiplatelet potency of clopidogrel

This letter to the editor discusses the results of the recently published study by Smith et al. which demonstrated that lipophilic statins metabolized through the cytochrome P-450 isoform 3A4 (CYP3A4) do not influence the antiplatelet effectiveness of clopidogrel in patients undergoing elective percutaneous coronary intervention. These results as well as those of other recent studies suggest that there is no adverse interaction between clopidogrel and CYP3A4-metabolized statins, during the maintenance phase of therapy (i.e., 2 or more days after the drug co-administration) either at the platelet or at the clinical level.     

Lipophilic statins interfere with the inhibitory effects of clopidogrel on platelet function--a flow cytometry study.

AIMS: Clopidogrel is a pro-drug which is converted to an active, unstable drug by cytochrome P450 (CYP). The active drug irreversibly blocks one specific platelet adenosine 5'-diphosphate (ADP) receptor (P2Y12). It has been recently suggested that the most abundant human CYP isoform, 3A4, activates clopidogrel. Since certain lipophilic statins (i.e. simvastatin, atorvastatin, lovastatin) are a substrate of CYP3A4, we were interested in potential drug interactions between clopidogrel and statins. METHODS: In patients with coronary artery disease (n=47) in whom clopidogrel treatment was initiated for balloon angioplasty and stent implantation, blood samples were taken at 0, 5 and 48 h after oral administration of clopidogrel (loading dose 300 mg, followed by 75 mg daily). ADP-stimulated (1, 10, 100 micromol/l) expression of P-selectin (CD62P) on platelets was measured by flow cytometry, and used as a marker for the antiplatelet effect of clopidogrel. RESULTS: Pre-treatment with statins (atorvastatin, simvastatin) reduced significantly (10 micromol/l ADP stimulation) the inhibitory effects of clopidogrel during the loading phase (relative reduction after 5 h 29.3%) and, to a lesser extent during the maintenance phase (relative reduction after 48 h 16.6%). In addition we found a considerable individual heterogeneity in the response and three patients (6%) were identified in whom clopidogrel exerted almost no effect. CONCLUSION:Certain statins which are substrates of the CYP3A4 isoform competitively inhibit the metabolic activation of clopidogrel. As a result the relative clopidogrel induced platelet inhibition (P-selectin-expression) is diminished--but still there is a relative clopidogrel effect of more than 80% in the maintenance phase. It may be reasonable to test the therapeutic efficacy of clopidogrel in those patients who require long-term treatment.     

Lipophilic statins do not affect the antiplatelet potency of clopidogrel

This letter to the editor discusses the results of the recently published study by Smith et al. which demonstrated that lipophilic statins metabolized through the cytochrome P--450 isoform 3A4 (CYP3A4) do not influence the antiplatelet effectiveness of clopidogrel in patients undergoing elective percutaneous coronary intervention. These results as well as those of other recent studies suggest that there is no adverse interaction between clopidogrel and CYP3A4-metabolized statins, during the maintenance phase of therapy (i.e., 2 or more days after the drug co-administration) either at the platelet or at the clinical level.