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PubMed1999

Development and validation of a high-performance liquid chromatography tandem mass spectrometry assay for atorvastatin, ortho-hydroxy atorvastatin, and para-hydroxy atorvastatin in human, dog, and rat plasma.

A liquid chromatographic/mass spectrometric method to quantitate atorvastatin (AT) and its active metabolites ortho-hydroxy (o-AT) and para-hydroxy (p-AT) atorvastatin in human, dog, and rat plasma was validated. The method consisted of washing plasma samples at high pH with diethyl ether and subsequently extracting the analytes and two internal standards, [d5]-atorvastatin ([d5]-AT) and [d5]-ortho-hydroxy atorvastatin ([d5]-o-AT), from acidified plasma by using diethyl ether. The ether layer was evaporated to dryness and the residue reconstituted in ammonium acetate (20 mM, pH 4.0)-acetonitrile-isopropanol (60:40:1, v/v/v). Chromatographic separation of analytes was achieved by using a YMC J'Sphere H80 (C-18) 150 x 2 mm, 4 microns particle size, column with a mobile phase consisting of acetonitrile-0.1% acetic acid, (70:30, v/v). Analytes were detected by using MS/MS. Sample introduction and ionization was by electrospray ionization in the positive ion mode. The method proved suitable for routine quantitation of AT, o-AT, and p-AT over the concentration range of 0.250 to 25.0 ng/mL. Approximate retention time ranges of p-AT, o-AT, [d5]-o-AT, AT, and [d5]-AT were 2.27 +/- 0.21, 3.36 +/- 0.23, 3.54 +/- 0.46, 4.12 +/- 0.61, and 4.65 +/- 0.65 min, respectively. No peaks interfering with quantitation were observed throughout the validation processes. Mean recoveries of AT, o-AT, and p-AT from plasma ranged 100%-107%, 70.6%-104%, and 47.6%-85.6%, respectively. Mean recoveries of the [d5]-AT and [d5]-o-AT internal standards ranged 98.0%-99.9% and 97.3%, respectively. Interassay precision, based on the percent relative deviation for replicate quality controls for AT, o-AT, and p-AT, was < or = 7.19%, 8.28%, and 12.7%, respectively. Interassay accuracy for AT, o-AT, and p-AT was +/- 10.6%, 5.86%, and 15.8%, respectively. AT, o-AT, and p-AT in human, dog, and rat plasma quality controls were stable to three freeze-thaw cycles. AT, o-AT, and p-AT were stable frozen for 127, 30 and 270 days in human, dog, and rat plasma quality control samples, respectively. Human plasma quality control samples containing AT, o-AT, and p-AT were stable for at least 4 days at ambient room temperature and 37 degrees C. The lower limit of quantitation for all analytes was 0.250 ng/mL for a 1.0-mL sample aliquot.

Animals↗

PubMed2002

Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study.

BACKGROUND: Atorvastatin is very effective in reducing plasma low-density lipoprotein cholesterol (LDL-C) levels. However, there is no long-term survival study that evaluated this statin. PATIENTS-METHODS: To assess the effect of atorvastatin on morbidity and mortality (total and coronary) of patients with established coronary heart disease (CHD), 1600 consecutive patients were randomised either to atorvastatin or to 'usual' medical care. The dose of atorvastatin was titrated from 10 to 80 mg/day, in order to reach the National Cholesterol Education Program (NCEP) goal of LDL-C <100 mg/dl (2.6 mmol/l). All patients were followed up for a mean period of 3 years. MAIN OUTCOME MEASURES: Primary endpoints of the study were defined as death, non-fatal myocardial infarction, unstable angina, congestive heart failure, revascularisation (coronary morbidity) and stroke. Secondary endpoints were the safety and efficacy of the hypolipidaemic drugs as well as the cost-effectiveness of atorvastatin. RESULTS: The mean dosage of atorvastatin was 24 mg/day. This statin reduced total chlesterol by 36%, LDL-C by 46%, triglycerides by 31%, and non-high-density lipoprotein cholesterol (non-HDL-C) by 44%, while it increased HDL-C by 7%; all these changes were significant. The NCEP LDL-C and non-HDL-C treatment goals were reached by 95% (n = 759) and 97% (n = 776), respectively, of patients on atorvastatin. Only 14% of the 'usual' care patients received any hypolipidaemic drugs throughout the study and 3% of them reached the NCEP LDL-C treatment goal. The cost per quaility-adjusted life-year gained with atorvastatin was estimated at $US 8350. During this study 196 (24.5%) CHD patients on 'usual' care had a CHD recurrent event or died vs. 96 (12%) CHD patients on atorvastatin; risk ratio (RR) 0.49, confidence interval (CI) 0.27-0.73, p < 0.0001. In detail, atorvastatin reduced, in comparison to 'usual' care, total mortality (RR 0.57, CI 0.39-0.78, p = 0.0021), coronary mortality (RR 0.53, CI 0.29-0.74, p = 0.0017), coronary morbidity (RR 0.46, CI 0.25-0.71, p < 0.0001), and stroke (RR 0.53, CI 0.30-0.82, p = 0.034). All subgroups of patients (women, those with diabetes mellitus, arterial hypertension, age 60 to 75 years, congestive heart failure, recent unstable angina or prior revascularisation) benefited from treatment with atorvastatin. Withdrawal of patients because of side-effects from the atorvastatin group was low (0.75%) and similar to that of the 'usual' care group (0.4%). CONCLUSIONS: Long-term treatment of CHD patients with atorvastatin to achieve NCEP lipid targets significantly reduces total and coronary mortality, coronary morbidity and stroke, in comparison to patients receiving 'usual' medical care. Treatment with atorvastatin is well tolerated and cost-effective.

Adult↗

PubMed2006

Comparison of the efficacy and safety of rosuvastatin 10 mg and atorvastatin 20 mg in high-risk patients with hypercholesterolemia--Prospective study to evaluate the Use of Low doses of the Statins Atorvastatin and Rosuvastatin (PULSAR).

BACKGROUND: Many patients at high risk of cardiovascular disease do not achieve recommended low-density lipoprotein cholesterol (LDL-C) goals. This study compared the efficacy and safety of low doses of rosuvastatin (10 mg) and atorvastatin (20 mg) in high-risk patients with hypercholesterolemia. METHODS: A total of 996 patients with hypercholesterolemia (LDL-C > or = 3.4 and < 5.7 mmol/L [130 and 220 mg/dL]) and coronary heart disease (CHD), atherosclerosis, or a CHD-risk equivalent were randomized to once-daily rosuvastatin 10 mg or atorvastatin 20 mg. The primary endpoint was the percentage change from baseline in LDL-C levels at 6 weeks. Secondary endpoints included LDL-C goal achievement (National Cholesterol Education Program Adult Treatment Panel III [NCEP ATP III] goal < 100 mg/dL; 2003 European goal < 2.5 mmol/L for patients with atherosclerotic disease, type 2 diabetes, or at high risk of cardiovascular events, as assessed by a Systematic COronary Risk Evaluation (SCORE) risk > or = 5% or 3.0 mmol/L for all other patients), changes in other lipids and lipoproteins, cost-effectiveness, and safety. RESULTS: Rosuvastatin 10 mg reduced LDL-C levels significantly more than atorvastatin 20 mg at week 6 (44.6% vs. 42.7%, p < 0.05). Significantly more patients achieved NCEP ATP III and 2003 European LDL-C goals with rosuvastatin 10 mg compared with atorvastatin 20 mg (68.8% vs. 62.5%, p < 0.05; 68.0% vs. 63.3%, p < 0.05, respectively). High-density lipoprotein cholesterol was increased significantly with rosuvastatin 10 mg versus atorvastatin 20 mg (6.4% vs. 3.1%, p < 0.001). Lipid ratios and levels of apolipoprotein A-I also improved more with rosuvastatin 10 mg than with atorvastatin 20 mg. The use of rosuvastatin 10 mg was also cost-effective compared with atorvastatin 20 mg in both a US and a UK setting. Both treatments were well tolerated, with a similar incidence of adverse events (rosuvastatin 10 mg, 27.5%; atorvastatin 20 mg, 26.1%). No cases of rhabdomyolysis, liver, or renal insufficiency were recorded. CONCLUSION: In high-risk patients with hypercholesterolemia, rosuvastatin 10 mg was more efficacious than atorvastatin 20 mg at reducing LDL-C, enabling LDL-C goal achievement and improving other lipid parameters. Both treatments were well tolerated.

Journal Article↗

PubMed2006

Exposure of atorvastatin is unchanged but lactone and acid metabolites are increased several-fold in patients with atorvastatin-induced myopathy.

BACKGROUND: The most serious side effect from statin treatment is myopathy, which may proceed to rhabdomyolysis. This is the first study to investigate whether the pharmacokinetics of either atorvastatin or its metabolites, or both, is altered in patients with atorvastatin-related myopathy compared with healthy controls. METHODS: A 24-hour pharmacokinetic investigation was performed in 14 patients with atorvastatin-related myopathy. Relevant polymorphisms in SLCO1B1 (encoding organic anion transporting polypeptide 1B1), MDR1/ABCB1 (encoding P-glycoprotein), and CYP3A5 (encoding cytochrome P450 3A5) were determined. Data from 15 healthy volunteers were used as controls. RESULTS: No statistically significant difference in systemic exposure of atorvastatin was observed between the 2 groups. However, patients with atorvastatin-related myopathy had 2.4-fold and 3.1-fold higher systemic exposures of the metabolites atorvastatin lactone (P<.01) and p-hydroxyatorvastatin (P<.01), respectively, compared with controls. There were no differences in frequencies of SLCO1B1, MDR1, and CYP3A5 polymorphisms between the 2 groups. CONCLUSIONS: This study disclosed a distinct difference in the pharmacokinetics of atorvastatin metabolites between patients with atorvastatin-related myopathy and healthy control subjects. These results are of importance in the further search for the mechanism of statin-induced myopathy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Failure to protect the myocardium against ischemia/reperfusion injury after chronic atorvastatin treatment is recaptured by acute atorvastatin treatment: a potential role for phosphatase and tensin homolog deleted on chromosome ten?

OBJECTIVES: We sought to ascertain whether chronic oral therapy with atorvastatin protects against ischemia/reperfusion (I/R) injury. BACKGROUND: We have recently shown that acute atorvastatin treatment protects against reperfusion-induced injury by activating the PI3K/Akt/eNOS pathway. However, many patients are on chronic statin therapy, and it is necessary to investigate whether this, in itself, provides a therapeutic advantage. METHODS: Sprague-Dawley rats were orally treated for one day, three days, one week, or two weeks with 20 mg/kg of atorvastatin or vehicle, after which the hearts underwent 35 min of ischemia and 120 min reperfusion (IR). Two additional groups were treated for one or two weeks with atorvastatin and then received a supplementary dose of 40 mg/kg before IR. The risk zone was determined using Evans blue and infarct size (IR%) using triphenyltetrazolium chloride staining. RESULTS: Treatment with atorvastatin for one and three days significantly reduced infarct size versus controls (38.9 +/- 3.1% vs. 56.4 +/- 2.3%; 39.3 +/- 2.4% vs. 61.3 +/- 3.8%, respectively). However, after one or two weeks of treatment, no protection was observed (52.6 +/- 3.8% vs. 58.6 +/- 4.3%; 58.3 +/- 2.7% vs. 52.4 +/- 5.7%, respectively). Surprisingly, a supplementary dose of atorvastatin recaptured the protection in the groups treated chronically (36.2 +/- 2.8% vs. 58.6 +/- 4.3%; 26.8 +/- 1.5% vs. 51.2 +/- 6.7%, at one and two weeks, respectively). Interestingly, we observed an increased level of phosphatase and tensin homolog deleted on chromosome ten (PTEN), the phosphatidylinositol-3 kinase inhibitor, in the chronic treated hearts. CONCLUSIONS: In conclusion, atorvastatin appears to have an acute protective effect that wanes with time associated with an increase in PTEN levels. This waning protection can be recaptured by an acute high dose given immediately before IR. These results may have protential clinical relevance.

Animals↗

PubMed2006

Protection from procedural myocardial injury by atorvastatin is associated with lower levels of adhesion molecules after percutaneous coronary intervention: results from the ARMYDA-CAMs (Atorvastatin for Reduction of MYocardial Damage during Angioplasty-Cell Adhesion Molecules) substudy.

OBJECTIVES: The goal of this work was to investigate whether protection from myocardial injury during percutaneous coronary intervention (PCI) by atorvastatin is related to reduction of endothelial inflammatory response. BACKGROUND: In the randomized ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) trial, 7-day pre-treatment with atorvastatin before PCI significantly reduced procedural myocardial injury; mechanisms underlying this effect are not characterized. METHODS: In a planned subanalysis of the ARMYDA trial, a subgroup of 76 patients was blind-tested for measurement of plasma levels of vascular cell adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1 (ICAM-1), and E-selectin: 38 patients belonged to atorvastatin (40 mg/day) and 38 to the placebo arm. Adhesion molecules were evaluated 7 days before intervention, immediately before PCI, and after 8 and 24 h. RESULTS: Reduction of procedural myocardial injury after statin pre-treatment was also confirmed in this subgroup. Intercellular cell adhesion molecule-1, E-selectin, and VCAM-1 levels were not different at randomization and before intervention in either arm. At 8 h, increase of ICAM-1 levels was similar in the 2 arms, whereas 24-h levels were significantly lower in the atorvastatin versus placebo group (282 +/- 56 vs. 325 +/- 70 ng/ml; p = 0.007). Attenuation of E-selectin elevation occurred at 8 h in the atorvastatin group (50 +/- 8 vs. 59 +/- 13 ng/ml; p = 0.002) and became even more significant at 24 h (57 +/- 9 vs. 73 +/- 18 ng/ml; p = 0.0008). Vascular cell adhesion molecule-1 levels were not different at any time point in the 2 arms. CONCLUSIONS: In patients undergoing PCI, reduction of procedural myocardial injury after 7-day pre-treatment with atorvastatin is paralleled by concomitant attenuation of post-procedural increase of ICAM-1 and E-selectin levels; thus, reduction of endothelial inflammatory response may explain this protective effect of statins.

Angina Pectoris↗

PubMed1998

A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin Study Group.

BACKGROUND: To assess the lipid-lowering effects and safety of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. METHODS: We performed a randomized, open-label, parallel-design, active-controlled, study in eight centers in the United States. We enrolled 108 patients with total cholesterol (TC) of > or =200 mg/dL, serum triglycerides (TG) > or =200 and < or =800 mg/dL, and apolipoprotein B (apo B) > or =110 mg/dL. Patients were randomly assigned to receive atorvastatin 10 mg once daily (n=55) or immediate-release niacin 1 g three times daily for 12 weeks (n=53). Patients were stratified based on low-density lipoprotein cholesterol (LDL-C): Patients with LDL-C > or =135 mg/dL were considered to have combined hyperlipidemia and patients with LDL-C <135 mg/dL were considered to have isolated hypertriglyceridemia. The primary outcome measure was percent change from baseline in LDL-C. Other lipid levels were evaluated as secondary parameters. RESULTS: Atorvastatin reduced LDL-C 30% and TC 26% from baseline, and increased high-density lipoprotein cholesterol (HDL-C) 4%. Total TG were reduced 17%. Niacin reduced LDL-C 2%, TC 7%, increased HDL-C 25%, and reduced total TG 29% from baseline. There was a significant difference in LDL-C reduction, the primary efficacy parameter, between the two treatment groups (P <0.05, favoring atorvastatin), as well as a significant difference in the improvement in HDL-C (P <0.05, favoring niacin). The effect of atorvastatin was relatively consistent between patients with combined hyperlipidemia and isolated hypertriglyceridemia, whereas there was more variability between these strata in the niacin treatment group. Atorvastatin was better tolerated than niacin. CONCLUSION: Atorvastatin may allow patients with combined hyperlipidemia to be treated with monotherapy and offers an efficacious and well-tolerated alternative to niacin for the treatment of patients with isolated hypertriglyceridemia.

Adult↗

PubMed2001

Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial--FAT).

OBJECTIVE: It has been repeatedly proven that statins improve endothelial function in isolated hypercholesterolaemia but there is far less evidence in the case of combined hyperlipidaemia. Studies assessing the effects of fibrates on endothelium have been neglected. Therefore, we conducted a trial in which the effects of fenofibrate and atorvastatin monotherapy on both endothelium-dependent vascular reactivity and biochemical parameters were compared in patients with combined hyperlipidaemia. METHODS: 29 otherwise healthy males (aged 47.4+/-7.8 years) with combined hyperlipidaemia (total cholesterol 7.55+/-1.20 mmol/l, triglycerides 5.41+/-4.54 mmol/l) were included into the randomised, single-blind, cross-over study to receive either 200 mg of micronised fenofibrate or 10 mg of atorvastatin daily--each of the drugs for a period of 10 weeks. Analysed biochemical parameters were as follows: serum total-, LDL- and HDL-cholesterol, apolipoproteins A-I and B, triglycerides, fibrinogen, uric acid, C-reactive protein (CRP), insulin, and homocysteine. Endothelial function was investigated by duplex Doppler ultrasonography at the brachial artery. Two indices of endothelial-dependent postischaemic changes were used - the recently introduced index of peak blood flow (PBF) representing the level of reactive hyperaemia and traditional flow-mediated dilatation (FMD). RESULTS: We observed a small improvement in FMD after both fenofibrate and atorvastatin (from 2.26% to 2.98% and 2.87%, respectively; NS). PBF increased from 448 ml/min to 536 ml/min after fenofibrate (P=0.04) and to 570 ml/min after atorvastatin (P=0.03). The effects of both fenofibrate and atorvastatin on endothelial function did not differ significantly (P-values of 0.82 and 0.47 for FMD and PBF, respectively). Significant correlations (P<0.01) between the changes of vascular reactivity and biochemical indices were found between FMD and CRP (r=-0.60) and between both FMD and PBF, and insulinaemia (r=-0.48 and -0.56, respectively) only during treatment with fenofibrate. CONCLUSIONS: Both fenofibrate and atorvastatin significantly improved endothelium-dependent vascular reactivity without mutual difference. The PBF was superior to FMD for the detection of this improvement. The beneficial effect of both drugs did not correlate with the change of lipid profile during therapy. The improvement of vascular reactivity during treatment with fenofibrate (opposed to atorvastatin) was related to the reduction of indirect marker of chronic vessel wall inflammation and of insulin resistance. The PBF was more reproducible than FMD because of considerably lower intra-subject variability.

Adult↗

PubMed2006

Efficacy and safety of atorvastatin in the prevention of cardiovascular end points in subjects with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus (ASPEN).

OBJECTIVE: Cardiovascular disease (CVD) risk is increased in type 2 diabetes. The purpose of this study was to assess the effect of 10 mg of atorvastatin versus placebo on CVD prevention in subjects with type 2 diabetes and LDL cholesterol levels below contemporary guideline targets. RESEARCH DESIGN AND METHODS: Subjects were randomly assigned to receive 10 mg of atorvastatin or placebo in a 4-year, double-blind, parallel-group study. The composite primary end point comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization. RESULTS: A total of 2,410 subjects with type 2 diabetes were randomized. Mean LDL cholesterol reduction in the atorvastatin group over 4 years was 29% versus placebo (P < 0.0001). When we compared atorvastatin versus placebo, composite primary end point rates were 13.7 and 15.0%, respectively (hazard ratio 0.90 [95% CI 0.73-1.12]). In the subset of 1,905 subjects without prior myocardial infarction or interventional procedure, 10.4% of atorvastatin- and 10.8% of placebo-treated subjects experienced a primary end point (0.97 [0.74-1.28]). In the 505 subjects with prior myocardial infarction or interventional procedure, 26.2% of atorvastatin- and 30.8% of placebo-treated subjects experienced a primary end point (0.82 [0.59-1.15]). Relative risk reductions in fatal and nonfatal myocardial infarction were 27% overall (P = 0.10) and 19% (P = 0.41) and 36% (P = 0.11) for subjects without and with prior myocardial infarction or interventional procedure, respectively. CONCLUSIONS: Composite end point reductions were not statistically significant. This result may relate to the overall study design, the types of subjects recruited, the nature of the primary end point, and the protocol changes required because of changing treatment guidelines. For these reasons, the results of the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) did not confirm the benefit of therapy but do not detract from the imperative that the majority of diabetic patients are at risk of coronary heart disease and deserve LDL cholesterol lowering to the currently recommended targets.

Adult↗

PubMed2006

HPLC assay and pharmacokinetic study of atorvastatin in beagle dogs after oral administration of atorvastatin self-microemulsifying drug delivery system.

A specific and accurate reversed-phase HPLC with UV detection was developed for the assay of atorvastatin in beagle dog plasma. Indomethacin was used as the internal standard. Atorvastatin was extracted by protein precipitation, the extracts were injected into a Kromasil C8 column (150 mm x 4.6 mm, 5 microm) with UV wavelength set at 270 nm. The mobile phase consisted of acetonitrile:0.1 mol/L ammonium acetate buffer (pH 4.0) (65:35% v/v) at a flow rate of 1.0 ml/min. The column was at ambient temperature (25 degrees C). The injection volume was 25 microl. The blank plasma did not interfere with the determination of atorvastatin and indomethacin. A good linear relationship was obtained between the peak area ratio of atorvastatin to indomethacin and the concentration of atorvastatin over the range of 0.05 to 2.5 microg/mL. The limit of quantification was 25 ng/mL, the limit of detection was 8 ng/ml. The total chromatographic analysis time was within 9 min. The method is accurate, precise and fast for the assay of atorvastatin in plasma following oral administration of an atorvastatin SMEDDS to healthy beagle dogs.

Animals↗

PubMed2005

Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with hypercholesterolemia: the Vytorin Versus Atorvastatin (VYVA) study.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target in the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines. This study tested the hypothesis that ezetimibe/simvastatin, a lipid-lowering agent that inhibits both intestinal cholesterol absorption and cholesterol synthesis, provides greater LDL-C reductions than atorvastatin across dose ranges. METHODS: This multicenter, double-blind, 6-week parallel-group study randomized 1902 patients with LDL-C above ATP III goal to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40, or 10/80 mg). Patients were stratified by prerandomization LDL-C level. RESULTS: At each milligram-equivalent statin dose comparison, and averaged across doses, ezetimibe/simvastatin provided greater LDL-C reductions (47%-59%) than atorvastatin (36%-53%). Ezetimibe/simvastatin 10/40 and 10/80 mg also provided significantly greater high-density lipoprotein cholesterol (HDL-C) increases than atorvastatin 40 and 80 mg. Triglyceride reductions were similar for all comparisons. More ezetimibe/simvastatin than atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of <100 mg/dL and the optional LDL-C target of <70 mg/dL. C-reactive protein reductions were similar between treatment groups. Consecutive elevations in alanine aminotransferase and/or aspartate aminotransferase occurred in significantly more atorvastatin patients than ezetimibe/simvastatin patients. No myopathy or liver-related adverse events led to study discontinuation with either drug. CONCLUSIONS: Ezetimibe/simvastatin was more effective than atorvastatin in lowering LDL-C at each dose comparison and provided greater increases in HDL-C at the 40- and 80-mg statin dose. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment option for hypercholesterolemic patients.

Adult↗

PubMed1997

Comparison of one-year efficacy and safety of atorvastatin versus lovastatin in primary hypercholesterolemia. Atorvastatin Study Group I.

This double-blind study to evaluate long-term efficacy and safety of atorvastatin was performed in 31 community- and university-based research centers in the USA to directly compare a new 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (reductase inhibitor) to an accepted drug of this class in patients with moderate hypercholesterolemia. Participants remained on a cholesterol-lowering diet throughout the study. One thousand forty-nine patients were randomized to receive atorvastatin 10 mg, lovastatin 20 mg, or placebo. At 16 weeks the placebo group was randomized to either atorvastatin or lovastatin treatment. At 22 weeks, patients who had not met low-density lipoprotein (LDL) cholesterol target levels doubled the dose of reductase inhibitor. Efficacy evaluation was mean percent change from baseline in LDL cholesterol, triglycerides, total cholesterol, high-density-lipoprotein cholesterol, and apolipoprotein B (apoB). Safety profiles as determined by change from baseline in laboratory evaluations, ophthalmologic parameters, and reporting of adverse events were similar for the 2 reductase inhibitors. After 52 weeks, the atorvastatin group maintained a significantly greater reduction in LDL cholesterol (-37% vs -29%), triglyceride (-16% vs -8%), total cholesterol (-27% vs -21%), and apoB (-30% vs -22%) (p <0.05). More patients receiving atorvastatin achieved LDL cholesterol target levels than did lovastatin patients (78% vs 63%, respectively), particularly those with coronary heart disease (37% vs 11%, respectively). Atorvastatin is highly effective and well tolerated in patients with primary hypercholesterolemia with no increased risk of adverse events.

Analysis of Variance↗

PubMedDate not supplied

Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.

BACKGROUND: Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS: 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS: The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION: Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.

Adult↗

PubMed2001

Efficacy of atorvastatin in achieving National Cholesterol Education Program low-density lipoprotein targets in women with severe dyslipidemia and cardiovascular disease or risk factors for cardiovascular disease: The Women's Atorvastatin Trial on Cholesterol (WATCH).

BACKGROUND: Recent studies have demonstrated that women at high risk for cardiovascular disease (CVD) benefit from cholesterol lowering to an extent similar to that of men. The ability to achieve established treatment goals for low-density lipoprotein cholesterol (LDL-C) in women with clearly defined risk factors has not been examined in detail. METHODS AND RESULTS: We have determined the efficacy and frequency of achieving target levels for LDL-C with atorvastatin on the basis of National Cholesterol Education Program Adult Treatment Panel II recommendations in 318 women according to the presence of CVD (198 women) or risk factors for CVD (120 women) and the presence of mixed dyslipidemia with obesity with or without CVD (72 women). Mean baseline LDL-C concentrations for women with established CVD were in the upper 10% of the distribution for age-matched North American women and, for those without CVD, were also extremely elevated and were in the top 5% of the LDL-C distribution for age-matched women in this population. The majority of participants without CVD (63%) reached LDL-C targets (LDL-C or=2 CVD risk factors) with 10 mg atorvastatin and 79% reached targets with up to 20 mg of atorvastatin. For women with established CVD, 34% achieved an LDL-C <or=100 mg/dL (2.6 mmol/L) with 10 mg and 60% reached this target with up to 20 mg of atorvastatin. With maximal titration to the LDL-C target, up to and including 80 mg atorvastatin, 87% of women without CVD and 80% of women with established CVD achieved LDL-C targets. The presence of mixed dyslipidemia with obesity did not affect the frequency of achieving LDL-C targets. CONCLUSION: Atorvastatin is very effective in achieving National Cholesterol Education Program Adult Treatment Panel II target concentrations for LDL-C in the majority of women with established CVD or CVD risk factors.

Adult↗

PubMed2005

Effect of atorvastatin on in vitro expression of resistin in adipocytes and monocytes/macrophages and effect of atorvastatin treatment on serum resistin levels in patients with type 2 diabetes.

Resistin is a novel cysteine-rich protein that plays a role in the development of insulin resistance and atherosclerosis. HMG-CoA reductase inhibitors (statins) possess anti-inflammatory properties that are independent of their lipid-lowering action. The aims of this study were to investigate the effect of atorvastatin on expression of resistin in vitro and to determine the effect of 6 months of treatment with atorvastatin on serum levels of resistin in patients with type 2 diabetes. 3T3-L1 adipocytes and human monocytes/macrophages and preadipocytes were incubated with 1 and 10 micromol/l atorvastatin for 24 and 48 h, followed by measurement of resistin mRNA by the quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). Serum resistin concentration in the patients with type 2 diabetes was measured at baseline and after 6 months of atorvastatin treatment (10 mg/day). qRT-PCR analysis revealed that atorvastatin decreased resistin mRNA expression in a dose- and time-dependent manner. Serum resistin concentration tended to decrease after 6 months of atorvastatin treatment, although this decrease did not reach statistical significance. In conclusion, the findings of our in vitro study contribute to the growing volume of evidence on the anti-inflammatory and anti-atherosclerotic effects of statins, and led us to suggest that statins may control inflammatory responses by inhibiting expression of resistin mRNA. It is necessary to confirm the findings of our in vitro study by an appropriately designed large-scale clinical study.

3T3-L1 Cells↗

PubMed2004

Effect of atorvastatin on high density lipoprotein cholesterol and its relationship with coronary events: a subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study.

OBJECTIVE: To investigate the relationship between changes in high density lipoprotein cholesterol(HDL-C) levels after statin treatment and the risk for coronary heart disease (CHD)-related events in the secondary CHD prevention GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. These findings suggested that dose titration with atorvastatin (10-80 mg/day, mean 24 mg/day)achieves the National Cholesterol Educational Program treatment goals and significantly reduces morbidity and mortality, in comparison to usual care. METHODS: Analysis of variance was used to assess the effect of atorvastatin on HDL-C over time (up to 48 months) in 1600 CHD patients. The time-dependent multivariate Cox predictive model,involving backward stepwise logistic regression,was used to evaluate the relation between coronary events and HDL-C changes. RESULTS: The mean increase in HDL-C levels during the study was 7%. All doses of atorvastatin significantly increased HDL-C levels. Increases were greater in men (7.8 vs 6.1%; p = 0.02), in combined hyperlipidaemia (7.9 vs 6.4% for hypercholesterolaemia; p = 0.04), and in the lower baseline HDL-C quartile (9.2 vs 5.3%, 1st vs 4th quartile; p = 0.001). After adjustment for 24 predictors of coronary events, multivariate analysis revealed a Hazards Ratio of 0.85 (95% confidence interval 0.76-0.94; p = 0.002) for every 4 mg/dL(0.1 mmol/L) increase in HDL-C. CONCLUSIONS: There was a significant beneficial effect on HDL-C levels across the dose range of atorvastatin. Clinical outcomes in the structured care arm of GREACE were determined in part by the extent of atorvastatin-induced HDL-C increase. This effect was independent from benefit induced by low density lipoprotein cholesterol (LDL-C)reduction, suggesting that the CHD risk reduction associated with a rise in a low HDL-C at baseline remains significant under aggressive (-46%) LDL-C lowering conditions. However, the relationship between HDL-C and vascular risk may be weaker when LDL-C levels are aggressively lowered.

Adult↗

PubMed2005

Rapid emergence of effect of atorvastatin on cardiovascular outcomes in the Collaborative Atorvastatin Diabetes Study (CARDS).

AIMS/HYPOTHESIS: The aim of this study was to determine the pattern of the effect of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin on cardiovascular events in patients with type 2 diabetes and no prior history of cardiovascular disease (CVD). MATERIALS AND METHODS: A post hoc analysis of data from the Collaborative Atorvastatin Diabetes Study (CARDS), a randomised, placebo-controlled trial of 2,838 patients with type 2 diabetes, was performed. Patients received atorvastatin (10 mg daily) or placebo and were evaluated for cardiovascular and other outcomes over a median follow-up period of 3.9 years. Cox proportional hazards modelling was carried out, and the hazard ratios calculated for various times after randomisation to treatment were investigated. RESULTS: A reduction in the primary endpoint of major CVD events was apparent and statistically significant as soon as 18 months after treatment initiation. The effect of atorvastatin on CHD events was apparent by 6 months, and at 1 year was similar to the 37% relative risk reduction observed at trial closure. CONCLUSIONS/INTERPRETATION: Atorvastatin alters the pathogenesis of CVD rapidly, such that the effect on cardiovascular events is apparent within months of initiation of therapy.

Anticholesteremic Agents↗

PubMed2006

Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation in patients undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study.

BACKGROUND: Atrial fibrillation (AF) after cardiac surgery is associated with increased risk of complications, length of stay, and cost of care. Observational evidence suggests that patients who have undergone previous statin therapy have a lower incidence of postoperative AF. We tested this observation in a randomized, controlled trial. METHODS AND RESULTS: Two hundred patients undergoing elective cardiac surgery with cardiopulmonary bypass, without previous statin treatment or history of AF, were enrolled. Patients were randomized to atorvastatin (40 mg/d, n=101) or placebo (n=99) starting 7 days before operation. The primary end point was incidence of postoperative AF; secondary end points were length of stay, 30-day major adverse cardiac and cerebrovascular events, and postoperative C-reactive protein (CRP) variations. Atorvastatin significantly reduced the incidence of AF versus placebo (35% versus 57%, P=0.003). Accordingly, length of stay was longer in the placebo versus atorvastatin arm (6.9+/-1.4 versus 6.3+/-1.2 days, P=0.001). Peak CRP levels were lower in patients without AF (P=0.01), irrespective of randomization assignment. Multivariable analysis showed that atorvastatin treatment conferred a 61% reduction in risk of AF (odds ratio 0.39, 95% confidence interval 0.18 to 0.85, P=0.017), whereas high postoperative CRP levels were associated with increased risk (odds ratio 2.0, 95% confidence interval 1.2 to 7.0, P=0.01). The incidence of major adverse cardiac and cerebrovascular events at 30 days was similar in the 2 arms. CONCLUSIONS: Treatment with atorvastatin 40 mg/d, initiated 7 days before surgery, significantly reduces the incidence of postoperative AF after elective cardiac surgery with cardiopulmonary bypass and shortens hospital stay. These results may influence practice patterns with regard to adjuvant pharmacological therapy before cardiac surgery.

Aged↗