基于FDA不良事件数据库对5种他汀类药物肌肉不良事件性别差异的数据挖掘和分析

目的：评估阿托伐他汀等5种常用他汀类药物肌肉相关不良事件（adverse drug events，ADEs）在男女性别方面的差异，为临床个体化用药提供参考。方法：从美国食品药品监督管理局（Food and Drug Administration，FDA）不良事件公开数据库（FAERS）中提取2004-2016年上报的洛伐他汀、辛伐他汀、普伐他汀、阿托伐他汀、瑞舒伐他汀肌肉相关ADEs报告（包括肌肉骨骼僵硬，肌肉无力，肌肉痉挛，纤维肌痛，肌痛，肌炎，横纹肌溶解等）。采用报告比值比法（ROR）检测以上5种他汀类药物肌肉相关ADEs在男女性别方面的差异并对其进行分析。结果：FAERS在2004年1月-2016年12月共收录以上5种他汀类药物为首要怀疑对象肌肉相关的ADEs报告54 472例（女性28 310例，51.97%；男性26 162例，48.03%），阿托伐他汀女性报告最高（10 520例，37.16%）、辛伐他汀男性报告最高（10 611例，40.56%），洛伐他汀报告最低（女性754例，2.66%；男性516例，1.97%）。经ROR法分析表明，肌肉痉挛（洛伐他汀ROR=1.93，辛伐他汀ROR=1.38，普伐他汀ROR=1.41，阿托伐他汀ROR=1.30，瑞舒伐他汀ROR=1.76）女性的报告均高于男性；纤维肌痛（洛伐他汀ROR=2.37，辛伐他汀ROR=7.10，普伐他汀ROR=7.56，阿托伐他汀ROR=6.93，瑞舒伐他汀ROR=6.16）女性的报告亦均高于男性；男性在横纹肌溶解（洛伐他汀ROR=0.49，辛伐他汀ROR=0.55，普伐他汀ROR=0.50，阿托伐他汀ROR=0.59，瑞舒伐他汀ROR=0.54）以及血肌酸磷酸激酶升高（洛伐他汀ROR=0.14，辛伐他汀ROR=0.56，普伐他汀ROR=0.30，阿托伐他汀ROR=0.49，瑞舒伐他汀ROR=0.50） ADEs报告高于女性。结论：运用ROR法检测表明常用他汀类药物中，女性大多发生肌无力、肌肉痉挛、纤维肌痛等轻度ADEs，男性更容易发生横纹肌溶解等严重ADEs。     

Assessment of ADRs associated with lipid-lowering agents recorded in the Department of Internal Medicine, University Hospital, Jena

Drug-related illness is an important cause of admission to hospital. Little information is available regarding the frequency of ADRs caused by antilipidemic agents classified as HMG-CoA reductase inhibitors (statins). Treatment with statins has been associated with the occurrence of myopathy or liver toxicity in case reports. Recent lipid intervention studies have involved the implementation of lipid lowering therapy with HMG-CoA reductase inhibitors in cardiovascular risk management. Since January 1997 we have been involved in a study, the aim of which was to improve the spontaneous drug information reporting system in Germany. The study was supported by the German Federal Institute for Drugs and Medical Devices, the "Bundesinstitut für Arzneimittel und Medizinprodukte", Berlin BfArM. Between early 1997 and late 2000, as a result of this monitoring of ADRs, we analyzed all patient histories concerning therapy with statins. A total of 550 ADR patients were evaluated, (209 male, 341 female) with a mean age of 66.4 years. 27 (4.9%) of all patients had received statins (atorvastatin = 12, fluvastatin = 7, simvastatin as well as pravastatin = 3, lovastatin = 2). Only 2 of the 27 patients admitted to hospital for typical ADRs of statins such as skeletal muscle toxicity (e.g. myalgia, rhabdomyolysis) or disorders involving hepatic structure or function were receiving statins (atorvastatin). An increased risk of rhabdomyolysis has been reported in the case of several statins, following concomitant use with erythromycin, cyclosporine or itraconazole, all of which are potent inhibitors of CYP3A4 enzyme. But only 1 atorvastatin patient had received cyclosporine as a CYP3A4 inhibitor. After discontinuing medication, signs of intoxication disappeared. The antihyperlipidemic drugs available are generally safe and effective, and rate of ADRs is low if concomitant intake of other drugs and the differing pharmacokinetic profiles of the statins are considered.     

A systematic review of the drug–drug interaction between statins and colchicine: Patient characteristics,etiologies, and clinical management strategies

Colchicine and statins are frequently co-prescribed for prevention and treatment of cardiovascular diseases, auto-inflammatory diseases, and gout. Both are substrates and inhibitors of the cytochrome P-450 (CYP) 3A4 isozyme and P-glycoprotein so that taken together, they represent a clinically significant interaction. Data suggest the interaction may be associated with potentially life-threatening myopathies and rhabdomyolysis. The purposes of this systematic review (SR) were to gather and appraise evidence surrounding the statin-colchicine drug interaction and discuss related risk-mitigation strategies. An electronic literature search was performed. Twenty-one articles met the protocol to be included in the qualitative analysis: 18 case reports/series, 2 retrospective observational cohort studies, and 1 retrospective case-control study. Thirty-eight patients developed an adverse drug event (ADE) receiving statin-colchicine combination therapy; 25 (66%) patients developed myopathy; 10 (26%) patients developed rhabdomyolysis, and three (8%) patients developed neuromyopathy. Over 70% of patients developed ADEs on simvastatin or atorvastatin, and 80% of studies reported moderate-to-high intensity statins. Colchicine dosing varied but ranged between 0.5 to 1.5 mg daily. Sixty-two percent of patients in the case reports/series had comorbid renal disease. Seven studies (33% of all included studies) reported patients taking concomitant interacting medications at the CYP3A4 and/or P-glycoprotein efflux pump. Seventeen studies (81% of all included studies) reported ADEs leading to hospitalization. A multivariate analysis from one case-control study identified risk factors prognosticating myopathy ADEs in patients taking statin-colchicine therapy: comorbid renal disease and/or cirrhosis, colchicine doses 1.2 mg daily or greater, and concomitant interacting medications. Clinicians must be cognizant that the statin-colchicine drug interaction may lead to patient harm and thus should employ risk-mitigation strategies for statin-associated muscle symptoms. Future studies are warranted to validate clinically relevant risk factors that are strongly associated with the complications owing to the statin-colchicine drug interaction.     

Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction

AIMS

In a systematic screening of the World Health Organization Adverse Drug Reaction database, VigiBase, in July 2008, a measure of association used to detect interactions (Omega) highlighted azithromycin with the individual statins atorvastatin, lovastatin and simvastatin and rhabdomyolysis. The aim was to examine all reports including rhabdomyolysis-azithromycin and statins in VigiBase to assess if the data were suggestive of an interaction.

METHODS

The individual case reports in VigiBase and the original files were reviewed. In order to investigate the reporting over time for rhabdomyolysis with azithromycin and statins to VigiBase, Omega values were generated retrospectively.

RESULTS

The reporting over time showed that rhabdomyolysis under concomitant use of azithromycin and statins was reported more often than expected from 2000 and onwards in Vigibase. After exclusion of possible duplicates and follow-up reports, 53 cases from five countries remained. Rhabdomyolysis occurred shortly after initiation of azithromycin in 23% of cases. In 11 patients an interaction had been suggested by the reporter. With the exception of one patient, the statin doses reported were within the recommended daily doses.

CONCLUSIONS

Case reports in VigiBase are suggestive that interactions between azithromycin and statins resulting in rhabdomyolysis may occur. This analysis showed the potential of the newly developed disproportionality measure, Omega, which can help to identify drug interactions in VigiBase in the future. The results also showed that reviewing spontaneous reports can add information to drug interactions not established previously.     

Genetic marker of statin-induced rhabdomyolysis

This review summarizes genetic factors predisposed to statin-induced rhabdomyolysis. The first genetic risk factor of statin myopathy uncovered by genome-wide analysis of single nucleotide polymorphisms was the common variant of SLCO1B1 gene. Analysis of 30000 genetic markers in 85 patients with myopathy induced by high-dose simvastatin showed a strong association with 521T>C polymorphism of SLCO1B1. Another study also showed that this variant of SLCO1B1 has a significant association with myopathy in patients taking pravastatin or atorvastatin although the number of patients analyzed was limited. In addition to SLCO1B1, recent studies suggested that variants of genes encoding transporters (ABCG2 and ABCB1) and metabolic enzymes (CYP2C8 and UGT1A3) involved in the disposition of statins, and those involved in the metabolic muscle disease (glycogen storage disorders, carnitine palmitoyl-2 deficiency and myoadenylate deaminase deficiency) are also risk factors of statin-induced myopathy. These genetic factors may provide predisposition testing for statin-induced rhabdomyolysis.     

Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients

Two men, aged 83 and 78 years, who received stable therapy with simvastatin 80 mg/day were hospitalized 1-2 weeks after completion of short-term treatment with erythromycin and clarithromycin, respectively. Both patients were admitted with myalgia, muscle weakness, functional disability (inability to raise arms and legs), and serum creatine kinase levels more than 60 times the upper limit of normal (ULN). Substantial elevations in aspartate aminotransferase (> 30 times the ULN) and alanine aminotransferase (> 7 times the ULN) levels were also observed. Rhabdomyolysis was diagnosed in both patients. Both recovered, but the combined events resulted in almost 40 days of hospitalization, the cost of which is considerable. According to the Naranjo adverse drug reaction probability scale, the likelihood that the rhabdomyolysis was secondary to a simvastatin-macrolide interaction was probable. Four cases of rhabdomyolysis after therapy with combined simvastatin and clarithromycin have been reported previously, but this is apparently the first report of rhabdomyolysis after coadministration of erythromycin. The interacting mechanism likely was inhibited cytochrome P450 (CYP) 3A4 metabolism and possibly P-glycoprotein transport of simvastatin as well. Previous reports of simvastatin-clarithromycin-related events involved additional drugs that inhibited CYP3A4 and P-glycoprotein. However, this was not the situation with our two patients. To prevent future events, it is crucial that clinicians recognize the interaction risk associated with concurrent use of simvastatin and clarithromycin or erythromycin. The risk could be managed by temporary interruption of simvastatin treatment or administration of a noninteracting antimicrobial agent.     

Atorvastatin: a safety and tolerability profile

Extensive data are available on the safety of atorvastatin from randomised clinical trials, postmarketing analyses and reports to regulatory agencies. Atorvastatin is generally well tolerated across the range of therapeutic dosages, with the exception of a slightly higher rate of liver enzyme elevations with atorvastatin 80 mg/day which does not appear to confer an increased risk of clinically important adverse events. Unlike simvastatin, atorvastatin is associated with a low incidence of muscular toxicity. It is not associated with neurological, cognitive or renal adverse effects and does not require dosage adjustment in patients with renal dysfunction, due to its favourable pharmacokinetic profile, which is unique among the statins. In patients aged > or =65 years, atorvastatin is well tolerated with no dose-dependent increase in adverse events up to the maximum daily dosage of 80 mg/day. Thus, atorvastatin is a safe and well tolerated statin for use in a wide range of patients.     

Interaction potential between clarithromycin and individual statins—A systematic review

The high prevalence of statin and clarithromycin utilization creates potential for overlapping use. The objectives of this MiniReview were to investigate the evidence base for drug‐drug interactions between clarithromycin and currently marketed statins and to present management strategies for these drug combinations. We conducted a systematic literature review following PRISMA guidelines with English language studies retrieved from PubMed and EMBASE (from inception through March 2019). We included 29 articles (16 case reports, 5 observational, 5 clinical pharmacokinetic and 3 in vitro studies). Based on mechanistic/clinical studies involving clarithromycin or the related macrolide erythromycin (both strong inhibitors of CYP3A4 and of hepatic statin uptake transporters OATP1B1 and OATP1B3), clarithromycin is expected to substantially increase systemic exposure to simvastatin and lovastatin (>5‐fold increase in area under the plasma concentration‐time curve (AUC)), moderately increase AUCs of atorvastatin and pitavastatin (2‐ to 4‐fold AUC increase) and slightly increase pravastatin exposure (≈2‐fold AUC increase) while having little effect on fluvastatin or rosuvastatin. The 16 cases of statin‐clarithromycin adverse drug reactions (rhabdomyolysis (n = 14) or less severe clinical myopathy) involved a CYP3A4‐metabolized statin (simvastatin, lovastatin or atorvastatin). In line, a cohort study found concurrent use of clarithromycin and CYP3A4‐metabolized statins to be associated with a doubled risk of hospitalization with rhabdomyolysis or other statin‐related adverse events as compared with azithromycin‐statin co‐administration. If clarithromycin is necessary, we recommend (a) avoiding co‐administration with simvastatin, lovastatin or atorvastatin; (b) withholding or dose‐reducing pitavastatin; (c) continuing pravastatin therapy with caution, limiting pravastatin dose to 40 mg daily; and (d) continuing fluvastatin or rosuvastatin with caution.     

Adverse reactions of HMG—CoA reductase inhibitors as a consequence of drug—drug interaction

Use of HMG-CoA reductase inhibitors in treating hypercholesterolemia is a well-established therapy.Presently,atorvastatin,fluvastatin,lovastatin,simvastatin and pravastatin are used clinically.Cerivastatin was pulled from the market in 2001 due to its higher risk of inducing rhabdomyolysis than all other drugs.Hepatotoxicity and rhabdomyolysis are the known adverse reactions by these drugs.However,the hepatotoxicity has been regarded to be mild,and is now referred to as transaminitis.Rhadomyolysis occurs in rare instances but is sometimes life threatening as a result of renal failure caused by myoglobinemia.The mechanism leading to rhabdomyolysis is unknown but in many of the reported cases,increased plasma concentratinos of thes drugs have been observed,most likely as a consequence of drug interaction.Inhibition of CYP 3A4 and UGT is believed to be the reason for this interaction.     

A pharmacoeconomic evaluation of statins in the treatment of hypercholesterolaemia in the primary care setting in Spain

BACKGROUND: Cardiovascular disease is one of the leading causes of death and it has been shown that primary prevention with the HMG-CoA reductase inhibitor (statin) lipid-lowering drugs can reduce cardiovascular events. Acquisition costs vary between statins and this may be an important consideration in the overall cost effectiveness (CE) of different options. OBJECTIVE: To perform a CE study of the main statins used in Spain for primary prevention of cardiovascular disease in patients with high cholesterol levels [corrected] STUDY DESIGN: The CE analysis was based on an open-label, prospective, naturalistic, randomised intervention study under usual care conditions in primary care settings in patients with high cholesterol levels (total cholesterol [TC] >240 mg/dL, low-density lipoprotein cholesterol [LDL-C] >160 mg/dL) and one or more cardiovascular risk factors. The analysis was conducted from the perspective of the Spanish National Health System; the year of costing was 2001. PATIENTS: A total of 161 patients (49.7% males), mean age 65 +/- 10.3 years, without evidence of cardiovascular disease were included in the study. Of those, 82.1% were hypertensive, 37.1% had diabetes mellitus and 17.9% were smokers. INTERVENTIONS: Forty-eight patients received oral atorvastatin 10 mg/day, 32 received fluvastatin 40 mg/day, 44 received simvastatin 20 mg/day and 37 patients received pravastatin 20 mg/day for 6 months. MAIN MEASUREMENTS AND RESULTS: After 6 months, the therapeutic goals of LDL-C control, according to the recommendations of the Spanish Society of Arteriosclerosis--Consensus-2000, were reached in 62.5%, 43.8%, 45.5% and 40.5% of patients treated with atorvastatin, fluvastatin, simvastatin and pravastatin, respectively. The average CE ratio, expressed as the cost in euros (euro) per patient achieving the therapeutic goals, was euros 424.3 for atorvastatin, euros 503.5 for fluvastatin, euros 527.0 for simvastatin and euros 683.4 for pravastatin. The incremental CE ratios for atorvastatin versus fluvastatin and simvastatin were euros 238.9 and euros 149.5, respectively, per additional patient reaching therapeutic goals. Atorvastatin, fluvastatin and simvastatin all dominated pravastatin. CONCLUSIONS: All the statins studied have been shown to be effective for reducing both TC and LDL-C levels. In this study, atorvastatin was the most efficient drug, with the best CE ratio (cost per patient reaching therapeutic goals). Atorvastatin was more effective and less costly than pravastatin, and when compared with fluvastatin or simvastatin the additional cost per additional patient achieving therapeutic goals was 相似文献   

Effect of Atorvastatin versus Simvastatin on Lipid Profile and Plasma Fibrinogen in Patients with Hypercholesterolaemia: A Pilot, Randomised, Double-Blind, Dose-Titrating Study

OBJECTIVE: To investigate the effect of atorvastatin vs simvastatin on lipid profile and plasma fibrinogen in patients with hypercholesterolaemia. PATIENTS: 30 outpatients (25 men), with a median age of 51 years were studied. Eight patients had established coronary artery disease (CAD) and four had diabetes mellitus at baseline. 11 patients presented a Frederickson's IIb phenotype and 19 a IIa phenotype at baseline. STUDY DESIGN: After a 6-week placebo period, patients were randomly assigned to simvastatin (10 mg/day, n = 15) or atorvastatin (10 mg/day, n = 15). Lipid profile, apolipoproteins B and A-I and plasma fibrinogen were measured for a 16-week period, at 4-week intervals. Thereafter, the dose of each drug was doubled only in patients with low density lipoprotein cholesterol (LDL-C) levels above 130 mg/dl for a further 16-week period. RESULTS: Ten of 15 patients on atorvastatin 10mg (66%) and four of 15 on simvastatin 10mg (27%) achieved the LDL-C <130 mg/dl goal. Apolipoprotein B was reduced by both drugs (-33%, p < 0.001 for atorvastatin and -18%, p < 0.05 for simvastatin), but plasma fibrinogen and triglyceride were reduced only by atorvastatin (-20%, p < 0.01; -36%, p < 0.001, respectively). During the second 16-week period seven of 11 patients receiving the simvastatin 20mg dose (64%) achieved the LDL-C <130 mg/dl goal. The comparison of atorvastatin 10mg with simvastatin 20mg showed that the drugs appear to be equipotent in terms of LDL-C lowering. CONCLUSIONS: Atorvastatin in equipotent doses to simvastatin appeared to be more effective than the latter in reducing triglyceride and plasma fibrinogen in patients with hypercholesterolaemia, mainly in those with Frederickson's phenotype Iib.     

Safety considerations with fenofibrate/simvastatin combination

Introduction: Fenofibrate/simvastatin combination is useful for patients with mixed dyslipidemia. Aim of this review is to critically present the safety aspects of the fenofibrate/simvastatin combination.

Areas covered: Current evidence regarding the adverse effects of fenofibrate/simvastatin combination is critically presented based on the results of large randomized controlled trials and other relevant studies. Additionally, clinical pharmacology, drug interactions and the effects of fenofibrate and simvastatin on metabolic variables and cardiovascular risk are briefly described.

Expert opinion: Large randomized clinical trials show that the combined administration of fenofibrate with simvastatin is not associated with significantly increased incidence of serious adverse events compared with simvastatin monotherapy. The incidence of rhabdomyolysis is slightly increased with fibrate/statin combination compared with monotherapy but the actual risk is very low. Although fenofibrate increases creatinine and homocysteine serum levels, the incidence of diabetic nephropathy and thrombotic events was not significantly increased with fenofibrate/simvastatin combination compared with simvastatin monotherapy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial. Furthermore, a decrease in albuminuria was observed with fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and ACCORD Lipid trials. Overall, the combined administration of fenofibrate with simvastatin appears to be safe, unless clinicians give fenofibrate/simvastatin combination to patients with predisposing risk factors for the occurrence of adverse events.     

Risk factors for statin-associated rhabdomyolysis

PURPOSE: To identify and characterize risk factors for rhabdomyolysis in patients prescribed statin monotherapy or statin plus fibrate therapy. METHODS: A nested case-control study was conducted within a cohort of 252,460 new users of lipid-lowering medications across 11 geographically dispersed U.S. health plans. Twenty-one cases of rhabdomyolysis confirmed by medical record review were compared to 200 individually matched controls without rhabdomyolysis. A conditional logistic regression model was applied to evaluate the effects of age, gender, comorbidities, concurrent medication use, dosage, and duration of statin use on the development of rhabdomyolysis. RESULTS: Statin users 65 years of age and older have four times the risk of hospitalization for rhabdomyolysis than those under age 65 (odds ratio (OR) = 4.36, 95% confidence interval (CI): 1.5,14.1). We also observed a joint effect of high statin dosage and renal disease (p = 0.022). When these two variables were added to the model with age, we obtained an OR of 5.73 for dosage (95%CI: 0.63, 52.6) and 6.26 for renal disease (95%CI: 0.46, 63.38). Although not statistically significant, we did observe a greater than twofold increase in risk for rhabdomyolysis among females (OR = 2.53, 95%CI: 0.91, 7.32). CONCLUSIONS: Findings of this study indicate that older age is a risk factor for rhabdomyolysis among statin users. Although the evidence is not as strong, high statin dosage, renal disease, and female gender may be additional risk factors. Patients at higher risk of developing rhabdomyolysis should be closely monitored for signs and symptoms of the disease.     

Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.

Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. CONCLUSION: Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.     

阿托伐他汀和辛伐他汀调脂疗效的成本-效果分析

目的 比较阿托伐他汀与辛伐他汀片治疗高脂血症的成本与效果.方法 将110例确诊为冠心病的患者,随机分成两组:A组57例口服阿托伐他汀片(商品名:立普妥);B组53例口服辛伐他汀片(商品名:舒降之),同治疗8周.利用药物经济学的原理,采用成本-效果分析方法对阿托伐他汀与辛伐他汀治疗冠心病高脂血症的临床疗效进行评价.结果 阿托伐他汀和辛伐他汀的成本分别为752.80元和733.35元,辛伐他汀组降低总胆固醇和低密度脂蛋白的效果优于阿托伐他汀组,治疗成本-效果比也低于阿托伐他汀组.结论 辛伐他汀治疗冠心病高脂血症的经济效率优于阿托伐他汀.