Non ST elevation acute coronary syndrome: early use of pravastatin or atorvastatin is associated with divergent changes of parameters of hemostasis

PURPOSE: To find out whether pravastatin and atorvastatin rapidly (in 1-2 weeks) and similarly affect hemostasis in patients with non-ST elevation acute coronary syndrome (NSTEACS). METHODS: Ninety aspirin and heparin treated patients with NSTEACS were randomized <24 hours from pain onset to open pravastatin 40 mg/day (n=31), atorvastatin 10 mg/day (n=30) or atorvastatin 40 mg/day (n=29). At baseline, on days 7, 14 plasma thrombin-antithrombin complex (TAT), prothrombin fragments 1+2 (F1+2), D-dimer, von Willebrand factor (vWF) were measured by ELISA. Results were compared with data from controls (n=18) of another randomized study on similarly treated patients. RESULTS: In all treatment groups levels of low-density lipoprotein cholesterol (LDLCH) were lowered by days 7 (p<0,01) and 14 (p<0,01 vs. baseline and for both atorvastatin groups vs. day 7). In pravastatin group levels of TAT and F1+2 decreased, while vWF level increased. In atorvastatin groups levels of TAT and F 1+2 increased while level of vWF decreased. Contrary to pravastatin group changes in atorvastatin treated patients more resembled those in controls not receiving lipid lowering drugs. Changes of both LDLCH and TCH directly correlated only with changes of vWF (r=0.23, p=0.03 and r=0.25, p=0.02, respectively). No consistent changes of D-dimer occurred. CONCLUSION: Early use of atorvastatin and pravastatin in patients with NSTEACS was associated with rapid divergent changes of some hemostatic parameters. Except lowering of von Willebrand factor changes in atorvastatin treated patients more resembled those in controls not receiving lipid lowering drugs. Von Willebrand factor was the only parameter which changes weakly but significantly correlated with changes of CH and LDL CH levels.     

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。     

Time course of rapid C-reactive protein reduction by pravastatin in patients with stable angina

The evidence has indicated that rapid reduction of inflammatory marker, such as C-reactive protein (CRP) could be achieved by administration of a statin. However, limited information is available in evaluating the short-term time course of CRP reduction in patients with coronary artery disease by use of a statin. Forty-two patients with stable angina were randomly assigned to 20 mg/d or 40 mg/d group of pravastatin. Blood samples were drawn at days 0, 1, and 14 for measuring lipid profile, CRP levels, and hepatic enzymes in all patients. The results showed that both doses of pravastatin induced significant reductions in median CRP levels and in mean CRP levels, respectively, at day 1 (20% in the 20 mg/d group and 17.6% in the 40 mg/d group; 15% in the 20 mg/d group and 10% in the 40 mg/d group) as well as at day 14 (28.6% in the 20 mg/d group and 33.3% in the 40 mg/d group; 25% in the 20 mg/d group and 22.8% in the 40 mg/d group) compared with baseline data without a dose-dependent manner. In addition, no changes were found at day 1 regarding lipid profile; however, both doses of pravastatin induced significant reductions in total cholesterol (TC, 22% and 30%), and low-density lipoprotein (LDL) cholesterol (30% and 40%) compared with baseline at 14 days. The higher dose of pravastatin resulted in significantly greater reductions in TC and LDL cholesterol compared with the 20 mg/d dose (p = 0.05, p = 0.01, respectively). A less significant reduction was observed in triglycerides level (16% and 24%) compared with TC and LDL cholesterol. There was no significant difference in mean high-density lipoprotein (HDL) cholesterol levels compared with baseline in both groups. These data suggested that a common daily dose of pravastatin resulted in rapid reduction of CRP within 24 hours and of lipid profile within 2 weeks, and the benefit to the vascular endothelium might occur quickly by reduction of CRP levels, which may be clinically important for patients in a high-risk subgroup, such as acute coronary artery disease.     

Early use of gemfibrozil in patients with non ST Elevation acute coronary syndrome. Changes of markers of inflammation and von Willebrand factor

It is not known whether PPAR-alpha agonist gemfibrozil is able to exert rapidly its lipid modulating, potential antiinflammatory and antithrombotic effects in patients with non-ST elevation acute coronary syndrome (NSTEACS), as some other lipid lowering drugs e.g. statins do. METHODS: We randomized 44 patients with NSTEACS to open gemfibrozil (n=22, 600 mg b.i.d for 90 days) or no gemfibrozil (controls, n=22) within 24 hours after pain onset. Semiquantitative C-reactive protein (CRP) latex test was used at baseline for exclusion of patients with overt inflammation. All patients received dalteparin or enoxaparin for >48 hours and oral aspirin (125 mg/day) and were treated noninvasively. Lipids, high sensitive CRP, soluble CD40 ligand (CD40L) and von Willebrand factor (vWF) activity were assessed on days 1 (baseline), 4, 7, 14, 30 and (except CD40L) 90. RESULTS: Gemfibrozil use was associated with significant lowering of triglycerides by day 30, however it did not prevent acute significant decline of high density lipoprotein cholesterol (HDL-C), which was similar in both groups. CD40L level significantly increased while CRP levels decreased by day 30 in both groups. Moreover, selection of a subgroup with baseline HDL-C <1.0 mmol/l did not reveal any difference in changes of CRP or CD40L between gemfibrosil treated and control patients. vWF activity did not change in controls and significantly increased in gemfibrozil group by days 7, 14, but from lower baseline level. CONCLUSION: In patients with NSTEACS early administration of gemfibrozil was not associated with positive changes of CRP and CD40L levels or vWF activity compared with control group.     

阿托伐他汀或瑞舒伐他汀与氯吡格雷合用在非ST段抬高型急性冠状动脉综合征患者支架置入术后的近期疗效比较

目的比较阿托伐他汀或瑞舒伐他汀与氯吡格雷合用在非ST段抬高型急性冠状动脉综合征(NSTE-ACS)支架置入术后患者的近期疗效。方法共154例NSTE-ACS的患者接受支架置入术后,随机分为服用阿托伐他汀组(74例)及服用瑞舒伐他汀组(80例),术前服用阿司匹林(100mg)5 d、氯吡格雷(75 mg)5 d以上或术前12 h以上顿服氯吡格雷300 mg及阿司匹林片300 mg,于术前服抗血小板药前、手术当天、术后3、7 d及术后1、6个月抽取静脉血测定二磷酸腺苷(ADP)(浓度为10μmol/L)诱导的血小板聚集功能,观察住院期间及6个月的主要不良心脏事件(MACE)。结果两组患者的临床基线资料及服药情况差异无统计学意义,服用氯吡格雷(75 mg)5 d或顿服300 mg能达到明显的血小板聚集率抑制作用,血小板聚集率在阿托伐他汀组由基线的(57.2±10.3)%降至手术当日的(32.5±11.2)%,而瑞舒伐他汀组分别为(59.1±9.8)%和(30.4±10.1)%(均为P<0.01),而且这种抑制作用稳定持续至6个月之后。6个月时两组间总的MACE发生率差异无统计学意义(13.0%比15.0%,P>0.05),两组心原性死亡、非致死性心肌梗死、靶血管重建术、支架内血栓形成及出血事件差异均无统计学意义(均为P>0.05)。结论接受冠脉支架置入术的NSTE-ACS患者,服用阿托伐他汀或瑞舒伐他汀后,短期内未发现对氯吡格雷抗血小板作用产生显著影响,且两组间的近期疗效相近。     

Effect of atorvastatin and pravastatin on platelet inhibition by aspirin and clopidogrel treatment in patients with coronary stent thrombosis

We sought to determine a potential interaction between statins and antiplatelet therapy with aspirin and clopidogrel. Previous laboratory studies have shown a possible drug-drug interaction of statins metabolized by cytochrome P450 3A4 and clopidogrel (prodrug metabolized by cytochrome P450 3A4), resulting in an impaired inhibitory effect of clopidogrel on platelet aggregation. However, conclusive prospective data assessing this potentially relevant interaction are lacking. In 73 patients, 23 with previous coronary stent thrombosis (ST) (ST group) and 50 without coronary ST (control group), platelet aggregation was measured 3 times in monthly intervals using light transmission aggregometry (adenosine diphosphate [ADP] and arachidonic acid induction). Measurements were carried out with aspirin monotherapy (100 mg/day), dual antiplatelet therapy with aspirin plus clopidogrel (75 mg/day), and additional treatment of 20 mg/day of atorvastatin or 40 mg/day of pravastatin. ADP (5 and 20 micromol)-induced platelet aggregation was significantly decreased with clopidogrel (p <0.001) but remained stable under additional treatment with atorvastatin or pravastatin in the 2 groups. Patients with previous ST showed a higher ADP-induced aggregation level than control subjects. This difference was not influenced by clopidogrel or statin treatment. In conclusion, patients with previous ST show a higher aggregation level than control subjects independent of statin treatment. Atorvastatin and pravastatin do not interfere with the antiaggregatory effect of aspirin and clopidogrel. In conclusion, drug-drug interaction between dual antiplatelet therapy and atorvastatin or pravastatin seems not to be associated with ST.     

More Western hypercholesterolemic patients achieve Japan Atherosclerosis Society LDL-C goals with rosuvastatin therapy than with atorvastatin, pravastatin, or simvastatin therapy.

BACKGROUND: Data from Western comparative trials suggest that rosuvastatin is more effective than atorvastatin, simvastatin, and pravastatin in helping hypercholesterolemic patients achieve US and European lipid-lowering guidelines. The purpose of this analysis was to assess the comparative efficacy of rosuvastatin in reducing low-density lipoprotein cholesterol (LDL-C) to levels recommended by the Japan Atherosclerosis Society (JAS). METHODS AND RESULTS: A post hoc analysis of data from 6 randomized, double-blind, active-controlled trials was conducted to evaluate the relative efficacy of rosuvastatin and comparator statins in helping patients achieve the LDL-C goals established by the JAS. The first 5 trials, prospectively designed for pooling, were originally conducted to compare the effects of rosuvastatin with either atorvastatin, simvastatin, or pravastatin in reducing lipid levels and helping patients achieve the LDL-C goals established by the National Cholesterol Education Program. The 6th trial was conducted with similar objectives, but in patients with heterozygous familial hypercholesterolemia (HeFH). Data from 2,139 hypercholesterolemic patients in the first 5 trials were pooled for analysis: rosuvastatin 5 mg (n=390) or 10 mg (n=389) vs atorvastatin 10 mg (n=393); rosuvastatin 5 mg (n=240) or 10 mg (n=226) vs simvastatin 20 mg (n=249) or pravastatin 20 mg (n=252). In the studies with atorvastatin as the comparator, JAS-defined LDL-C goals were reached by 67.2% of the rosuvastatin 5-mg group, 82.3% of the rosuvastatin 10-mg group, and 58.0% of the atorvastatin 10-mg group (p<0.001 for both rosuvastatin groups vs atorvastatin) at 12 weeks. Similarly, in the trials with pravastatin and simvastatin as comparators, the JAS LDL-C goals were reached by 77.5% of the rosuvastatin 5-mg group, 86.7% of the rosuvastatin 10-mg group, 45.2% of the pravastatin 20-mg group and 65.5% of the simvastatin 20-mg group (p<0.001 for both rosuvastatin groups vs pravastatin and simvastatin). In the trial of HeFH patients (n=433 for rosuvastatin, n=187 for atorvastatin), 31.9% of patients treated with rosuvastatin 20 mg achieved JAS LDL-C goals, compared with 17.6% of patients treated with atorvastatin 20 mg (p<0.001). CONCLUSIONS: Rosuvastatin has demonstrated clinical superiority over atorvastatin, pravastatin, and simvastatin in reducing LDL-C levels and in enabling patients to reach goals established by the JAS.     

Effect of the early administration of pravastatin on C-reactive protein and interleukin-6 levels in the acute phase of myocardial infarction with ST segment elevation

INTRODUCTION AND OBJECTIVES: C-reactive protein (CRP), whose synthesis in the liver is regulated by interleukin 6 (IL-6), is related with the prognosis for ischemic heart disease. The aim of this study was to evaluate the effect of early administration of pravastatin on plasma levels of CRP and IL-6 in patients with acute myocardial infarction and ST segment elevation. PATIENTS AND METHOD: 71 patients were randomized during the first 10 hours from the onset of symptoms to receive 40 mg of pravastatin once a day or not. CRP and IL-6 were measured on admission, 48 hours and 7 days later. CRP was also measured 2 months later. RESULTS: On admission, levels of CRP and IL-6 were similar in both groups. After 7 days of treatment the administration of pravastatin was associated with a lower level of CRP (P=.002). Mean and median CRP levels decreased from 48 hours to day 7 by 48.4% and 51.9% respectively in the pravastatin group, and by 32.5% and 15.9% respectively in the control group. In contrast, no significant differences in IL-6 levels were observed between the two groups. After 2 months of follow-up, 50% of the treated patients and 25% of the control patients had CRP levels lower than 6.6 mg/L (P=.039). CONCLUSIONS: Early administration of pravastatin in the acute phase of myocardial infarction with ST segment elevation was associated with a lower level of CRP after 7 days of treatment, with no concomitant changes in IL-6 levels.     

他汀类药对氯吡格雷抗血小板作用的影响

目的 前瞻性评价普伐他汀、氟伐他汀、阿托伐他汀对氯吡格雷抗血小板作用的影响.方法 人选连续1015例急性冠状动脉综合征或稳定性心绞痛行冠状动脉造影和(或)支架术患者,分为普伐他汀组(228例)、氟伐他汀组(179例)、阿托伐他汀组(481例)和对照组(127例).比较各组术后支架内血栓发生率、不同浓度(2、5、10、20 μmol)二磷酸腺苷(ADP)诱导的1 min(ADP-1)、5 min(ADP-5)和最大血小板聚集力(ADP-M)及其影响因素.结果 4组患者基础临床情况(除年龄、高血压及冠状动脉造影复查率外)和冠状动脉病变和(或)支架术情况相似,术后支架内血栓发生率(普伐他汀组0.9%、氟伐他汀组1.1%、阿托伐他汀组1.0%、对照组0.8%,P>0.05)和ADP-1、ADP-5、ADP-M与对照组相比差异均无统计学意义(P均>0.05).多因素回归分析显示,年龄(B=0.21,P=0.001)、氯吡格雷总量(B=7.30,P=0.002)及低分子肝素的使用(OR=6.71,P=0.01)是影响氯吡格雷抗血小板作用的独立决定因素.结论 普伐他汀、氟伐他汀和阿托伐他汀对氯吡格雷的抗血小板作用无明显影响,而年龄、氯吡格雷总量及低分子肝素使用是决定氯吡格雷抗血小板作用的独立因素.     

不同调脂方案对冠心病患者C反应蛋白和CD40配体的影响

目的 观察在冠状动脉狭窄50%～70%的冠心病患者中应用阿托伐他汀和依折麦布联合治疗调脂作用和安全性,及其对C-反应蛋白(CRP)、CD40配体(CD40L)的影响. 方法选取冠状动脉狭窄50%～70%的冠心病患者42例,均未植入支架,分为他汀组19例(40 mg阿托伐他汀)和联合治疗组(10 mg阿托伐他汀+10 mg依折麦布)23例.在服药前、用药4周、用药12周测定总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、肝功能、肾功能、肌酸激酶、CRP和CD40L. 结果 (1)他汀组和联合治疗组均在4周时患者的TC、LDL-C降低,12周时他汀组的LDL-C为(1.94±0.49)mmol/L,联合治疗组为(1.92±0.54)mmol/L,两组差异无统计学意义;(2)他汀组和联合治疗组患者肝功能、肾功能、肌酸激酶用药后无明显升高;(3)两组CRP在12周时较基线均有降低,他汀组CD40L降低. 结论单用他汀治疗和联合治疗降脂疗效无差异.两种治疗均未引起患者肝、肾功能和肌酸激酶异常.40 mg阿托伐他汀治疗可降低患者CRP、CD40L.     

两种剂量阿托伐他汀对冠心病患者踝臂指数和hs CRP影响的比较

目的:观察不同剂量阿托伐他汀治疗冠心病的疗效及其对踝臂指数（ABI）和高敏C反应蛋白（hs CRP）的影响。方法: 选择冠心病患者110例,随机分为40 mg组和10 mg组,每组各55例。10 mg组予以阿托伐他汀10 mg/次,1次/晚,40 mg组予以阿托伐他汀40 mg/次,1次/晚。观察比较两组的血脂及治疗前后的ABI和hs CRP的水平。结果: 治疗后,两组的总胆固醇（TC）,三酰甘油（TG）和低密度脂蛋白胆固醇（LDL C）的水平均较治疗前显著降低（P<005或P<001）,高密度脂蛋白胆固醇（HDL C）水平较治疗前显著升高（P<005）;与10 mg组比较,40 mg组LDL C 较10mg组降低更显著（P<005）。hs CRP水平较治疗前也显著降低（P<001）;与10 mg组比较,40 mg组hs CRP水平下降更为显著(P<005)。而ABI水平治疗后较治疗前显著升高（P<001）,与10 mg组比较,40 mg组ABI的改善更为显著(P<005)。结论: 阿托伐他汀对冠心病患者的ABI和hs CRP改善明显,而且40 mg组改善更显著。     

Atorvastatin treatment decreases inflammatory and proteolytic activity in patients with hypercholesterolemia

BACKGROUND: Statins have anti-inflammatory and anti-platelet effects, which are known as non-lipid effects. Statin treatment can decrease endogenous inflammatory response. AIM: To study the effects of atorvastatin on matrix metalloproteinase-9 (MMP-9) and high sensitive C-reactive protein (hs-CRP) - markers of the proteinolytic and inflammatory activity. METHODS: In this prospective study 44 patients with hypercholesterolemia were randomly assigned into 2 groups; Group 1 (n=22) treated with atorvastatin and diet for 2 months, and Group 2 (n=22) - diet alone. MMP-9 and hs-CRP were measured at baseline and two months later. RESULTS: Groups were matched for age, sex and baseline characteristics. Lipid levels decreased by 32% (LDL from 153.9+/-26.6 to 94.5+/-20.8 mg/dl, p<0.005) in the atorvastatin group and by 9% in the diet alone group. Atorvastatin lowered plasma CRP from 5.16+/-1.9 to 2.88+/-1.06 mg/L (p<0.001) and MMP-9 activity from 64.3+/-28.1 to 35.4+/-20.0 ng/ml (p<0.0001). Atorvastatin-induced reductions in CRP and MMP-9 were greater than in the diet alone group. MMP-9 levels did not show significant changes in Group 2 after two months of diet. CONCLUSIONS: Atorvastatin treatment decreases inflammatory and proteolytic activity in patients with hypercholesterolemia.     

Effect of atorvastatin and pravastatin on serum C-reactive protein

Background Extra-lipid effects of statins, such as anti-inflammatory actions, may contribute to their clinical benefit. These effects, with important implications for the concept of a statin “class effect,” may be drug specific or may be related to the extent of lipid lowering. Methods We randomized 130 patients to treatment with either atorvastatin (80 mg daily, n = 63) or pravastatin (40 mg daily, n = 67), and measured serum lipids, C-reactive protein, and fibrinogen at baseline and after 3 months of therapy. Results Mean C-reactive protein (CRP) levels were significantly reduced in both groups, with a 36% reduction in the atorvastatin group (0.39 ± 0.36 to 0.25 ± 0.27, P = .001) and a 22% reduction observed in the pravastatin group (0.40 ± 0.33 to 0.31 ± 0.32, P = .003). A reduced or unchanged CRP level was seen in 67.2% of pravastatin-treated patients (45/67) and 73% of atorvastatin- treated patients (46/63) (P = .47). There was no difference between drugs in either the absolute or relative reductions in CRP levels. However, whereas the reduction of CRP with pravastatin was unrelated to the degree of low-density lipoprotein reduction (r = −.05, P = .69), atorvastatin-induced CRP reductions correlated directly to the change in low-density lipoprotein-C (r = .33, P = .009). Conclusions High-dose atorvastatin and pravastatin both reduce CRP levels. However, whereas pravastatin's effect on CRP is independent of lipid-lowering efficacy, these data suggest that lipid-dependent mechanisms are, at least in part, active in atorvastatin-treated patients. (Am Heart J 2003;145:e8.)     

Efficacy and safety of atorvastatin and pravastatin in patients with hypercholesterolemia

This 1-year, double-blind, active-controlled, multicenter study compared the efficacy and safety of atorvastatin to pravastatin and evaluated their ability to achieve target low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. Patients were stratified to risk factor groups based upon European Atherosclerosis Society (EAS) guidelines before randomization to atorvastatin 10 or 20 mg or pravastatin 20 or 40 mg once daily. Target LDL-C levels for patients with mild/moderate risk and severe risk were <130 mg/dl (3.4 mmol/l) and <115 mg/dl (3.0 mmol/l), respectively. If needed to achieve target levels both drugs were uptitrated within the approved dose range. Mean changes from LDL-C levels were 39% for atorvastatin patients compared to 29% for pravastatin-treated patients (p<0.0001). The number of patient responders (those reaching LDL-C goals) was higher (p<0.0001) for atorvastatin patients (91% at any study visit and 51% at the last study visit) than for pravastatin patients (48% and 20%, respectively). The daily atorvastatin dose used by most patients after the titration phase was 10 mg and the respective pravastatin dose was 40 mg. Both drugs were well-tolerated and had similar adverse event profiles. Atorvastatin, in the approved dose range, will allow a greater number of patients to reach established LDL-C treatment goals with single drug therapy.     

Treatment with ezetimibe plus low-dose atorvastatin compared with higher-dose atorvastatin alone: is sufficient cholesterol-lowering enough to inhibit platelets?

OBJECTIVES: We sought to test the platelet inhibitory and anti-inflammatory effects of a higher statin dosage compared with combined treatment with ezetimibe plus a low statin dose. BACKGROUND: Reducing the level of low-density lipoprotein cholesterol (LDL-C) with statins induces important pleiotropic effects such as platelet inhibition. An insufficient LDL-C reduction often is treated with ezetimibe, an intestinal cholesterol absorption inhibitor, in combination with a low statin dose. It is not known whether this combination therapy has the same pleiotropic effects as a statin monotherapy. METHODS: Fifty-six patients with coronary artery disease were assigned randomly to receive either 40 mg/day of atorvastatin or 10 mg/day of ezetimibe plus 10 mg/day of atorvastatin for 4 weeks. The levels of LDL-C, platelet activation markers after stimulation, platelet aggregation, and plasma chemokine levels (i.e., regulated on activation normally T-cell expressed and secreted [RANTES]) were measured before and after changing lipid-lowering medication. RESULTS: Platelet activation markers (P-selectin) after stimulation (adenosine diphosphate) were reduced by 40 mg/day of atorvastatin (-5.2 +/- 1.6 arbitrary units) but not by ezetimibe plus low-dose atorvastatin (2.1 +/- 1.8 arbitrary units; p < 0.005) despite a similar reduction of LDL-C (atorvastatin -1.01 +/- 0.18 mmol/l vs. ezetimibe plus atorvastatin -1.36 +/- 0.22 mmol/l, p = NS). Thrombin receptor-activating peptide-induced platelet aggregation as well as plasma RANTES levels were reduced by 40 mg/day of atorvastatin but not by ezetimibe plus low-dose atorvastatin. CONCLUSIONS: Platelet reactivity and a proinflammatory chemokine were reduced more by the higher atorvastatin dose than by ezetimibe plus low-dose atorvastatin. In patients with coronary artery disease, it might be important to combine ezetimibe with higher statin dosages to benefit from cholesterol-independent pleiotropic effects.     

Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial

OBJECTIVES: The aim of this research was to compare relative efficacy of different statin regimens in achieving the dual goals of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) reduction. BACKGROUND: While secondary prevention guidelines for statin therapy suggest lowering LDL-C levels <70 mg/dl, we have recently shown that clinical outcomes are improved when CRP levels are also lowered <2 mg/l. METHODS: We addressed the relative efficacy of pravastatin 40 mg and atorvastatin 80 mg daily to reduce LDL-C and CRP among 3,745 acute coronary syndrome patients. RESULTS: A total of 1,018 participants (27.1%) achieved the dual goals of LDL-C <70 mg/dl and CRP <2 mg/l. After adjustment for age, gender, smoking, diabetes, hypertension, obesity, and HDL-C, these individuals had a 28% lower risk of recurrent myocardial infarction or vascular death (relative risk = 0.72; 95% confidence interval 0.52 to 0.99). Of those who achieved dual goals, 80.6% received atorvastatin 80 mg, while 19.4% received pravastatin 40 mg (p < 0.001). Only 11% allocated pravastatin and 44% allocated atorvastatin achieved the goals of LDL-C <70 mg/dl and CRP <2 mg/l, and only 5.8% allocated pravastatin 40 mg and 26.1% allocated atorvastatin 80 mg reached the even lower goals of LDL-C <70 mg/dl and CRP <1 mg/l. The correlation coefficient for CRP measured at 30 days and at end of study was 0.61 (p < 0.001), a value almost identical to that for LDL-C over the same follow-up period (r = 0.62, p < 0.001). CONCLUSIONS: While atorvastatin 80 mg was superior to pravastatin 40 mg in terms of achieving the dual goals of aggressive LDL-C and CRP reduction, neither agent brought the majority of patients below thresholds needed to maximize patient benefit.     

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.     

Effect of withdrawal of pravastatin therapy on C-reactive protein and low-density lipoprotein cholesterol

In addition to lowering cholesterol, statins effectively lower C-reactive protein (CRP) levels. The effects of withdrawal from long-term statin therapy on CRP are unknown. This study examined the effect of withdrawal from 4 years of statin treatment on CRP. We prospectively evaluated the effects of withdrawal from pravastatin (40 mg) treatment on CRP levels in 566 subjects who participated in a randomized, placebo-controlled trial. Median (interquartile range) CRP levels before randomization were 1.29 mg/L (0.63 to 2.73) and mean low-density lipoprotein (LDL) cholesterol was 4.06 +/- 0.92 mmol/L. Four years after randomization, placebo-treated patients (n = 266) had a nonsignificant 9% increase in CRP, whereas there was a 12% decrease (p = 0.001) in the pravastatin-treated patients (n = 300). LDL cholesterol only decreased in pravastatin-treated patients (-27%; p <0.001). Withdrawal from pravastatin led to a significant increase in both CRP and LDL cholesterol to approximately pretreatment levels (p <0.05 and <0.001, respectively). Changes in CRP after withdrawal from pravastatin could not be predicted by the change in LDL cholesterol. The difference between the pravastatin and placebo groups in terms of change in CRP by withdrawal was consistent and persisted in analysis corrected for body mass index, smoking status, blood pressure, and baseline levels of total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, or triglycerides. In conclusion, withdrawal from pravastatin treatment resulted in an increase in CRP to approximately baseline levels, which is not related to the increase in LDL cholesterol.     

Strong decrease of high sensitivity C-reactive protein with high-dose atorvastatin in patients with type 2 diabetes mellitus

OBJECTIVE: Statins are known to reduce CRP concentrations, but whether high doses are more effective is not known. METHODS: In a prospective double-blind multicenter study in 186 DM2 patients without manifest coronary artery disease and with dyslipidemia, the effect of a 30-week treatment with 10 and 80 mg atorvastatin or placebo on the reduction of hs-CRP levels was measured. RESULTS: Median CRP levels increased with 6.6% in the placebo group and were reduced by 15 and 47%, respectively, with atorvastatin 10 and 80 mg (P<0.001; significantly different from 10 mg atorvastatin and from placebo (P<0.001). Variation in IL-6 and plasma lipids associated for 21 and 8%, respectively, with variation in CRP levels (P<0.001 and P=0.01). Of patients with a baseline CRP level above an arbitrary threshold of 3.0 mg/l, 56% in the 80 mg atorvastatin group reached a level of less than 3.0 mg/l, versus 23% randomized to 10 mg atorvastatin (P<0.01) and 17% in the placebo group (P<0.005). CONCLUSIONS: In DM2 patients high dose atorvastatin induced a strong reduction in CRP levels. The decrease in CRP was mainly independent of effects on lipid lowering and changes in IL-6 levels. The pleiotropic effect of high-dose atorvastatin on inflammation could add to its cardioprotective effect in high-risk patients.     

Relationship between plasma inflammatory markers and platelet aggregation in patients with clopidogrel resistance after angioplasty

We evaluated the relationship between plasma inflammation markers and clopidogrel resistance in patients after stent implantation. The plasma levels of C-reactive protein (CRP), P-selectin, platelet soluble CD40 ligand (sCD40L), interleukin 6 (IL-6) and platelet aggregation were measured in 352 patients undergoing percutaneous coronary intervention (PCI) at baseline and after 6 months. The plasma levels of CRP, P-selectin, sCD40L, IL-6 was higher in 65 (18.5%) patients with clopidogrel resistance than in those with normal responsiveness at 6 months after PCI. There was a significant positive correlation between soluble CD40L levels and platelet aggregation (r = .28, P < .05). Diabetes (DM) and sCD40L level were independent predictors for unresponsiveness after stent implantation according to stepwise multivariate analyses. The hazard ratio (HR) for sCD40L level was 3.02 (95% CI = 1.28 to 3.25; P = .036) and for DM 2.53 (95% CI = 1.28 to 6.55, P = .03). We conclude that sCD40L and DM may influence clopidogrel resistance.