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.     

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.     

Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial.

OBJECTIVES: Our objective was to determine the timing of benefit with intensive statin therapy after an acute coronary syndrome (ACS) in two time windows: an early window soon after an ACS and a late window in more stable patients. BACKGROUND: The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial showed that the use of intensive statin therapy improved clinical outcomes over two years in ACS patients versus standard therapy. The relative contributions of early or late effects to the overall clinical efficacy of intensive therapy are presently unclear. METHODS: A total of 4,162 patients with ACS were recruited in the PROVE IT-TIMI 22 trial. Patients were randomized to intensive statin therapy (atorvastatin, 80 mg) or standard therapy (pravastatin, 40 mg). The composite triple end point of death, MI, or rehospitalization for recurrent ACS was determined in each group at 30 days. The composite triple and primary end points were assessed in stable patients from six months to the end of study, after censoring for clinical events before six months. RESULTS: The composite end point at 30 days occurred in 3.0% of patients receiving atorvastatin 80 mg versus 4.2% of patients receiving pravastatin 40 mg (hazard ratio [HR] = 0.72; 95% confidence interval [CI], 0.52 to 0.99; p = 0.046). In stable patients, atorvastatin 80 mg was associated with a composite event rate of 9.6% versus 13.1% in the pravastatin 40 mg group (HR = 0.72; 95% CI, 0.58 to 0.89; p = 0.003). CONCLUSIONS: Intensive statin therapy early after ACS leads to a reduction in clinical events at 30 days, consistent with greater early pleiotropic effects. In stable patients, intensive statin therapy provides long-term reduction in clinical events when compared with standard therapy. Thus, ACS patients should be started in-hospital and continued long-term on intensive statin therapy.     

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.     

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.     

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。     

Intensity of lipid lowering with statins and brachial artery vascular endothelium reactivity after acute coronary syndromes (from the BRAVER trial)

The time course and differential effects of statin regimens on endothelial function after acute coronary syndromes (ACSs) are unknown and could contribute to the superiority of a more intense strategy. A subset of subjects who were enrolled in the PROVE IT-TIMI 22 trial (n = 50) underwent evaluation of vascular reactivity by high-resolution brachial ultrasound. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent sublingual nitroglycerin-mediated dilation (NMD) were measured at baseline and at 48 hours, 1 month, and 4 months after the initiation of 40 mg of pravastatin (n = 26) or 80 mg of atorvastatin (n = 24). After 4 months, low-density lipoprotein cholesterol was decreased by 32% in the atorvastatin group but was not different from baseline after ACS in the pravastatin group. C-reactive protein decreased similarly in the 2 groups. Brachial artery diameters at rest were similar in the 2 groups and at each time point of the trial. FMD and NMD increased significantly after 4 months by 27% and 24%, respectively (p <0.05), with no difference between groups. There was no correlation between the change in FMD and the change in lipids or C-reactive protein. In subjects who had received previous statin therapy (n = 15), there was no significant variation in FMD (p = 0.140) and NMD (p = 0.129). In conclusion, initiation of statin therapy soon after ACS is associated with improvements in endothelium-dependent and independent vascular reactivities after 4 months.     

Atorvastatin and pravastatin elevated pre-heparin lipoprotein lipase mass of type 2 diabetes with hypercholesterolemia

To clarify whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statin) increases lipoprotein lipase mass in preheparin plasma (preheparin LPL mass), we observed the change in preheparin LPL mass during administration of atorvastatin and pravastatin to type 2 diabetes mellitus patients with hypercholesterolemia. The subjects were randomly divided into two groups. One group was 24 patients given atorvastatin (10 mg/day), and the other was 23 patients given pravastatin (20 mg/day) for 4 months. After 4 months of administration, no significant change of HbA1c was observed. TC significantly decreased in the atorvastatin group compared to the pravastatin group. TG significantly decreased in the atorvastatin group. Low density lipoprotein cholesterol level significantly decreased in both groups (- 36.3%, p < 0.01 in atorvastatin, - 24.3%, p < 0.01 in pravastatin). Preheparin LPL mass slightly increased in both groups after 4 months of administration. Especially in patients who showed low preheparin LPL mass (less than 50 ng/ml) before statin administration, preheparin LPL mass significantly increased in both groups (+ 25.8% in the atorvastatin group, + 24.39% in the pravastatin group). These results suggested that administration of atorvastatin and pravastatin to type 2 diabetic patients with hypercholesterolemia increased serum preheparin LPL mass concentration. Especially, its effect was remarkable in patients who showed low preheparin LPL mass.     

Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial.

OBJECTIVES: This study sought to investigate potential protective effects of atorvastatin in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Randomized studies have shown that pretreatment with atorvastatin may reduce periprocedural myocardial infarction in patients with stable angina during elective PCI; however, this therapy has not been tested in patients with ACS. METHODS: A total of 171 patients with non-ST-segment elevation ACS were randomized to pretreatment with atorvastatin (80 mg 12 h before PCI, with a further 40-mg preprocedure dose [n = 86]) or placebo (n = 85). All patients were given a clopidogrel 600-mg loading dose. All patients received long-term atorvastatin treatment thereafter (40 mg/day). The main end point of the trial was a 30-day incidence of major adverse cardiac events (death, myocardial infarction, or unplanned revascularization). RESULTS: The primary end point occurred in 5% of patients in the atorvastatin arm and in 17% of those in the placebo arm (p = 0.01); this difference was mostly driven by reduction of myocardial infarction incidence (5% vs. 15%; p = 0.04). Postprocedural elevation of creatine kinase-MB and troponin-I was also significantly lower in the atorvastatin group (7% vs. 27%, p = 0.001 and 41% vs. 58%, p = 0.039, respectively). At multivariable analysis, pretreatment with atorvastatin conferred an 88% risk reduction of 30-day major adverse cardiac events (odds ratio 0.12, 95% confidence interval 0.05 to 0.50; p = 0.004). CONCLUSIONS: The ARMYDA-ACS trial indicates that even short-term pretreatment with atorvastatin may improve outcomes in patients with ACS undergoing early invasive strategy. These findings may support routine use of high-dose statins before intervention in patients with ACS.     

Comparisons of effects of statins (atorvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin) on fasting and postprandial lipoproteins in patients with coronary heart disease versus control subjects

The effects of atorvastatin at 20, 40, and 80 mg/day on plasma lipoprotein subspecies were examined in a randomized, placebo-controlled fashion over 36 weeks in 97 patients with coronary heart disease (CHD) with low-density lipoprotein (LDL) cholesterol levels of >130 mg/dl and compared directly with the effects of fluvastatin (n = 28), pravastatin (n = 22), lovastatin (n = 24), and simvastatin (n = 25). The effects of placebo and 40 mg/day of each statin were also examined in subjects with CHD with subjects in the fasting state and in the fed state 4 hours after a meal rich in saturated fat and cholesterol and compared with results in age- and gender-matched control subjects. At all doses tested in the fasting and fed states, atorvastatin was significantly (p <0.01) more effective in lowering LDL cholesterol and non-high-density lipoprotein (HDL) cholesterol than all other statins, and significantly (p <0.05) more effective than all statins, except for simvastatin, in lowering triglyceride and remnant lipoprotein (RLP) cholesterol. At 40 mg/day in the fasting state, atorvastatin was significantly (p <0.01) more effective than all statins, except for lovastatin and simvastatin, in lowering cholesterol levels in small LDL, and was significantly (p <0.05) more effective than all statins, except for simvastatin, in increasing cholesterol in large HDL and in lowering LDL particle numbers. Our data indicate that atorvastatin was the most effective statin tested in lowering cholesterol in LDL, non-HDL, and RLP in the fasting and fed states, and getting patients with CHD to established goals, with fluvastatin, pravastatin, lovastatin, and simvastatin having about 33%, 50%, 60%, and 85% of the efficacy of atorvastatin, respectively, at the same dose in the same patients.     

Adverse events with concomitant amiodarone and statin therapy

The authors reviewed adverse events (AEs) reported to the United States Food and Drug Administration to determine the percentage of statin-associated AE reports with concurrent amiodarone use for simvastatin, atorvastatin, and pravastatin. AEs affecting the following organ systems were analyzed: muscle, liver, pancreas, and bone marrow. The percentage of simvastatin reports with concurrent amiodarone use was 1.0%, compared with 0.7% of the atorvastatin-associated reports (p = not significant). The percentage of pravastatin reports with concurrent amiodarone use was 0.4% (p < 0.05 for pravastatin vs. simvastatin). Muscle toxicity was the most commonly reported statin-amiodarone AE, accounting for 77% of the reports. AEs tended to occur in older male patients (mean age, 76 years), who were on multiple other medications (mean number of other medications, five). Clinicians should be vigilant about muscle-related complaints in patients concomitantly taking amiodarone, especially in elderly patients on multiple medications. Use of a statin not metabolized through the cytochrome P450-3A4 system may be appropriate in this setting.     

Long-term effects of pravastatin and fosinopril on peripheral endothelial function in albuminuric subjects

The purpose of this double-blind, randomized, placebo-controlled trial was to determine the long-term effects of pravastatin and fosinopril treatment on peripheral endothelial function in subjects with albuminuria. Subjects (mean age 51 years, 63% male) were randomized to pravastatin 40 mg or matching placebo and to fosinopril 20mg or matching placebo. Using high resolution ultrasound, flow-mediated dilation (FMD) and nitroglycerin-induced dilation (NID) was assessed at baseline and after 4 years of treatment in a total of 276 subjects. At baseline, mean+/-standard error FMD was 4.73+/-0.49% and NID was 10.86+/-0.67%. Pravastatin significantly reduced total cholesterol and LDL cholesterol (p<0.01) and randomization to pravastatin was associated with a non-significant improvement of 18.9% in FMD (+0.80+/-0.95, p=0.09), without a significant change in NID. Interestingly, pravastatin significantly increased FMD by 34.9% in men (+1.23, p=0.04), but only 1.1% in women (+0.06, p=0.95). Fosinopril was not associated with a change in FMD or NID despite significantly decreasing urinary albumin excretion, systolic and diastolic blood pressure (all p<0.01). In conclusion, after 4 years of follow-up, pravastatin treatment tended to increase FMD and this effect was predominantly present in men. Fosinopril treatment did not modify FMD during long-term follow-up.     

Effects of colesevelam hydrochloride on low-density lipoprotein cholesterol and high-sensitivity C-reactive protein when added to statins in patients with hypercholesterolemia

Elevated high-sensitivity C-reactive protein (hs-CRP) levels are associated with an increased risk of atherosclerotic coronary heart disease (CHD). The addition of the bile acid sequestrants, such as colesevelam hydrochloride (HCl), to statins further reduces low-density lipoprotein (LDL) cholesterol levels. However, the effects of approved cholesterol-lowering bile acid sequestrants on hs-CRP have not previously been reported. Three randomized, double-blind, placebo-controlled, parallel, 6-week clinical trials of similar design investigated the efficacy of adding colesevelam HCl to stable simvastatin, atorvastatin, or pravastatin treatment in 204 patients with primary hypercholesterolemia. The primary end point was the mean percent change in the LDL cholesterol levels. Secondary end points included the effects on other lipid parameters and hs-CRP levels. A pooled analysis showed that adding colesevelam HCl to statin therapy significantly lowered LDL cholesterol levels (21 mg/dl or 16% mean reduction from baseline, p = 0.0013, and 11 mg/dl or 9% mean reduction compared with placebo, p = 0.0003). Four times as many patients receiving colesevelam HCl plus a statin achieved a LDL cholesterol target of <100 mg/dl compared with patients receiving a statin plus placebo (39% vs 10%, respectively, p <0.0001). The incidence of mild gastrointestinal adverse effects was slightly higher in the colesevelam HCl plus statin group than in the placebo plus statin group. Finally, the differences in the change in hs-CRP levels with colesevelam HCl plus statin therapy were significant compared with the changes with placebo plus statin (median change -23%, p = 0.0069). In conclusion, this is the first report suggesting that an approved cholesterol-lowering bile acid sequestrant, specifically colesevelam HCl, decreases hs-CRP levels when added to statin therapy.     

Comparative pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with cytochrome P450 inhibitors

Three-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) are first-line treatments for hypercholesterolemia. Although exceedingly well tolerated, treatment with statins incurs a small risk of myopathy or potentially fatal rhabdomyolysis, particularly when coadministered with medications that increase their systemic exposure. Studies compared the multiple-dose pharmacokinetic interaction profiles of pravastatin, simvastatin, and atorvastatin when coadministered with 4 inhibitors of cytochrome P450-3A4 isoenzymes in healthy subjects. Compared with pravastatin alone, coadministration of verapamil, mibefradil, or itraconazole with pravastatin was associated with no significant changes in pravastatin pharmacokinetics. However, concomitant verapamil increased the simvastatin area under the concentration:time curve (AUC) approximately fourfold, the maximum serum concentration (C(max)) fivefold, and the active metabolite simvastatin acid AUC and C(max) approximately four- and threefold, respectively (all comparisons p <0.001). Similar (greater than fourfold) important increases in these parameters and a >60% increase in the serum half-life (p = 0.03) of atorvastatin were observed when coadministered with mibefradil. The half-life of atorvastatin also increased by approximately 60% (p = 0.052) when coadministered with itraconazole, which elicited a 2.4-fold increase in the C(max) of atorvastatin and a 47% increase in the AUC (p <0.001 for C(max) and AUC). Clarithromycin significantly (p <0.001) increased the AUC (and C(max)) of all 3 statins, most markedly simvastatin ( approximately 10-fold increase in AUC) and simvastatin acid (12-fold), followed by atorvastatin (greater than fourfold) and then pravastatin (almost twofold). Pravastatin has a neutral drug interaction profile relative to cytochrome P450-3A4 inhibitors, but these substrates markedly increase systemic exposure to simvastatin and atorvastatin.     

Pravastatin reduces restenosis after coronary angioplasty of high grade stenotic lesions: Results of SHIPS (SHIga Pravastatin Study)

Summary We conducted a multicenter prospective, randomized, double-blind, placebo-controlled trial to test whether pravastatin, a hydroxymethyl glutaryl coenzyme A reductase inhibitor, can decrease restenosis after percutaneous transluminal coronary angioplasty (PTCA). Pravastatin 10 mg twice daily was begun at least 10 days prior to elective PTCA in patients with total cholesterol less than 280 mg/dl. The end-point was a between-group comparison of the frequency of restenosis defined as a more than 50% loss of the initial gain in diameter stenosis at the PTCA site at 3 months during follow-up by automated quantitative coronary arteriography. Of 207 patients randomly assigned to study groups, 139 patients underwent PTCA; 133 procedures were successful, and 124 patients underwent follow-up angiography at 3 months, and 179 lesions (85 pravastatin, 94 placebo) in 124 patients (62 pravastatin, 62 placebo) were analyzed. The two groups were comparable for baseline characteristics. Total cholesterol decreased by 19.6% in the pravastatin group (p<0.001) but not in the placebo group. Although the restenosis rate was not different in the two groups (29.4% in pravastatin vs. 39.4% in placebo, p=0.215) as a whole, it was reduced to about one fifth (8.8%) in the pravastatin group compared with 14.8% in the placebo group (p=0.0011) when the comparison was restricted to high grade lesions (75% diameter stenosis, 34 lesions in pravastatin, 29 lesions in placebo). Pravastatin thus reduces restenosis after PTCA of high grade lesions.     

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.     

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。     

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.     

Effect of two-day atorvastatin pretreatment on long-term outcome of patients with stable angina pectoris undergoing elective percutaneous coronary intervention

Several randomized studies and meta-analyses have suggested that pretreatment with statins may decrease periprocedural myocardial infarction (MI) in patients undergoing percutaneous coronary intervention (PCI). The purpose of this randomized study was to investigate the effect of a 2-day atorvastatin therapy before PCI on long-term clinical outcome. Two hundred statin-naive patients with stable angina pectoris referred for PCI were enrolled and randomized (ratio 1:1) to 2-day pretreatment with atorvastatin 80 mg/day and subsequent PCI (atorvastatin group), or immediate PCI (control group). The registry group comprised 182 consecutive patients on long-term statin therapy referred for immediate PCI during the same period as randomized patients. We compared the first occurrence of MI or death during long-term follow-up. There were no significant differences in most clinical characteristics and early results among the 3 groups. Median follow-up was 45 months (1 to 59). Incidences of death/MI were 11.4%, 12.9%, and 13.8% in the atorvastatin, control, and registry groups, respectively. In the same groups, age-adjusted estimated 4-year freedom from death/MI was 0.78 versus 0.75 versus 0.80, respectively (p=0.882, log-rank test). In multivariate analysis, only age of patients (odds ratio 1.04, 95% confidence interval 1.02 to 1.07, p<0.001) was identified as a significant predictor of death or MI during follow-up. In conclusion, these results suggest that 2-day therapy with high-dose atorvastatin before PCI did not influence occurrence of periprocedural MI or long-term clinical outcomes.