Efficacy and safety of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia: a randomized controlled trial.

INTRODUCTION: The long half-life of atorvastatin and fenofibrate makes them suitable for alternate day therapy. Hence, we aimed to study the efficacy, safety, and cost-effectiveness of alternate day therapy with atorvastatin and fenofibrate combination in mixed dyslipidemia. METHODS: Eligible patients with mixed dyslipidemia were randomly allotted into 2 equal parallel groups-alternate day therapy group (group 1) and daily therapy group (group 2). Patients in groups 1 and 2 received fixed dose combination of atorvastatin 10 mg and fenofibrate 160 mg on alternate days and daily, respectively, for 12 weeks. Mean percentage change from baseline in triglycerides (TGLs), non-high-density lipoprotein cholesterol (non-HDL-C), HDL-C, low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and TC-HDL ratio, incidence of adverse effects, and cost-effectiveness were compared in both the groups. RESULTS: Among 110 patients randomized, 99 completed the study till 12 weeks treatment duration. The TGLs, non-HDL-C, TC, and LDL-C decreased by 56.4%, 49.7%, 36.5%, and 39.2%, respectively, in alternate day therapy group and by 57.5%, 51.2%, 37.5%, and 39.4%, respectively, in daily therapy group. The HDL-C levels increased by 20.1% in alternate day therapy group compared to 21.8% in daily therapy group. No statistically significant difference was seen between both the groups in mean percentage change in lipid parameters from baseline to end of 12 weeks. Incidence of adverse events was reasonably less in alternate day therapy group. CONCLUSION: Alternate day therapy with atorvastatin-fenofibrate combination is an effective and safe alternative to daily therapy in mixed dyslipidemia. Apart from significant cost savings, reasonable reduction in the incidence of adverse events is seen with alternate day regimen. However, larger studies are needed to more reliably confirm our interesting but preliminary results.

Effects of adding statins before surgery on mortality and major morbidity: a meta-analysis.

OBJECTIVE: To re-evaluate the effects of adding a statin before surgery on mortality at 30 days and at 1 year and on major morbidity at 0-30 days. DESIGN: A meta-analysis of parallel, randomized, controlled trials published in English. SETTING: A university-based electronic search. PARTICIPANTS: Adult patients undergoing any type of procedure. INTERVENTION: Adding a statin before a procedure compared to a placebo or no intervention. MEASUREMENTS AND MAIN RESULTS: A search for all randomized controlled trials (RCT) was done in PubMed, Embase, Ovid MEDLINE and the Cochrane Central Register of Controlled Trials in November 2012. The quality of each study was assessed with the Cochrane Collaboration Tools. An I-square ≥ 25% was chosen as the cut-off point for heterogeneity exploration. The search produced 29 trials. Statins reduced the 0-30 days' risk of myocardial infarction: risk ratio (RR) 0.48 (95%CI 0.38, 0.61); I-square 13.2%; p<0.001; number needed-to-treat 17 (14, 24). There were no statistical differences at 0-30 days for stroke RR 0.70 (0.25, 1.95), acute renal insufficiency RR 0.54 (0.26, 1.12) or reoperation RR 1.10 (0.51, 2.38). There was a trend for a reduced mortality at 1 year RR 0.26 (0.06, 1.02); I-square 0%; p = 0.053. The hospital length of stay was slightly decreased with atorvastatin: standardized mean difference (SMD) -0.27 (-0.39, -0.14), p<0.001; fluvastatin SMD -0.95 (-1.56, -0.34), p = 0.002; and rosuvastatin SMD -0.69 (-0.98, -0.40), p<0.001 but not with simvastatin SMD -0.04 (-0.41, 0.48). CONCLUSIONS: Adding a statin before a high risk cardiac procedure reduces the 0-30 days' risk of myocardial infarction.

Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy.

BACKGROUND: Many high-risk coronary heart disease (CHD) patients on statin monotherapy do not achieve guideline-recommended low-density lipoprotein cholesterol (LDL-C) goals, and combination lipid-lowering therapy may be considered for these individuals. The effect of adding ezetimibe to simvastatin, atorvastatin, or rosuvastatin therapy versus titrating these statins on LDL-C changes and goal attainment in CHD or CHD risk-equivalent patients was assessed in a large, managed-care database in the US. METHODS: Eligible patients (n=17,830), initially on statin monotherapy who were ≥18 years with baseline and follow-up LDL-C values, no concomitant use of other lipid-lowering therapy, and on lipid-lowering therapy for ≥42 days, were identified between November 1, 2002 and September 30, 2009. The percent change from baseline in LDL-C levels and the odds ratios for attainment of LDL-C<1.8 and <2.6 mmol/L (70 and 100 mg/dL) were estimated using an analysis of covariance and logistic regression, respectively, adjusted for various baseline factors. RESULTS: LDL-C reductions from baseline and goal attainment improved substantially in patients treated with ezetimibe added onto simvastatin, atorvastatin, or rosuvastatin therapy (n=2,312) versus those (n=13,053) who titrated these statins. In multivariable models, percent change from baseline in LDL-C was -13.1% to -14.8% greater for those who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus those who titrated. The odds of attaining LDL-C<1.8 and <2.6 mmol/L (70 and 100 mg/dL) increased by 2.6-3.2-fold and 2.5-3.1-fold, respectively, in patients who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin versus titrating statins. CONCLUSION: CHD/CHD risk-equivalent patients in a large US managed-care database, who added ezetimibe onto simvastatin, atorvastatin, or rosuvastatin, had greater LDL-C reductions and goal attainment than those who uptitrated these statin therapies. Our study suggests that high-risk CHD patients in need of more intensive LDL-C lowering therapy may benefit by adding ezetimibe onto statin therapy.

Assessment of the efficacy and tolerability of 2 formulations of atorvastatin in Korean adults with hypercholesterolemia: a multicenter, prospective, open-label, randomized trial.

BACKGROUND: A manufacturer of atorvastatin is seeking marketing approval in Korea of a generic product for adult patients with primary hypercholesterolemia. OBJECTIVE: The objective of this study was to compare the efficacy and tolerability of a new generic formulation of atorvastatin (test) with those of an original formulation of atorvastatin (reference) to satisfy regulatory requirements for marketing of the generic product in Korea. METHODS: Patients enrolled were aged 20 to 79 years with documented primary hypercholesterolemia who did not respond adequately to therapeutic lifestyle changes and with a LDL-C level >100 mg/dL from a high-risk group of coronary artery disease patients. Eligible patients were randomized to receive 1 of the 2 formulations of atorvastatin 20 mg per day for 8 weeks. The primary end point was the percent change in LDL-C level from baseline to week 8. Secondary end points included the percent change in total cholesterol, triglycerides, HDL-C level, apolipoprotein B:apolipoprotein A-I ratio, LDL:HDL ratio, LDL-C particle size, high-sensitivity C-reactive protein from baseline to week 8, and achievement rate of the LDL-C goal. RESULTS: A total of 298 patients (141 men and 157 women; 149 patients in each group; mean [SD] age, 62.4 [9.2] in the test group vs 60.3 [8.9] years in the reference group) were included. LDL-C levels were significantly decreased from baseline to week 8 in both groups, and there was no significant difference in the percent change in LDL-C level between groups (-44.0% [17.2%] in the test group, -45.4% [16.9%] in the reference group; P = 0.49). The between-group differences in the percent changes in total cholesterol and triglyceride levels were not statistically significant. In addition, there was no significant difference between the 2 groups in percent changes in HDL-C, apolipoprotein B:apolipoprotein A-I ratio, LDL-C:HDL-C ratio, LDL-C particle size, high-sensitivity C-reactive protein, and the achievement rate of the LDL-C goal. Two (1.3%) patients in the reference group (N = 150) experienced treatment-related serious adverse events (AEs): toxic hepatitis and aggravation of chest pain. Common AEs were cough (4.1%), myalgia (2.1%), and indigestion (1.4%) in the test formulation group and cough (5.3%), creatine kinase elevation (2.7%), and edema (0.7%) in the reference formulation group; however, the differences in overall prevalence of AEs between the 2 treatment groups was not significant (P = 0.88). CONCLUSIONS: There were no significant differences observed in the efficacy and tolerability between the test and reference formulations of atorvastatin in these Korean adult patients with primary hypercholesterolemia.

Proactive cardiovascular risk management versus usual care in patients with and without diabetes mellitus: CRUCIAL trial subanalysis.

UNLABELLED: Patients with diabetes mellitus (DM) and additional cardiovascular (CV) risk factors are at very high risk for future CV events. This study investigated the efficacy and safety of a proactive, multifactorial CV risk factor-management strategy based on single-pill amlodipine/atorvastatin (SPAA) versus continuing physicians' usual care (UC) over 52 weeks in patients with and without DM. Patients with hypertension and ≥ 3 additional CV risk factors from the Cluster Randomized Usual Care vs Caduet Investigation Assessing Long-Term-Risk (CRUCIAL) trial--an open-label, cluster-randomized trial conducted in 19 countries--were enrolled and randomized to receive proactive intervention (based on SPAA 5/10 to 10/20 mg) or UC (based on investigators' best clinical judgment). Patients were analyzed according to baseline DM status. Six hundred patients had DM. Patients with DM in the SPAA and UC arms had mean ages of 61.8 and 61.5 years, respectively, and an absolute coronary heart disease (CHD) risk of 25.2% and 21.5%, respectively. Among non-DM patients, mean ages were 58.6 and 59.5 years, respectively, and CHD risk was 16.0% vs 15.7%, respectively. Least-squares mean treatment differences in percentage change from baseline in calculated 10-year Framingham CHD risk were -26.3% vs -27.3% among DM and non-DM patients (adjusted for respective baseline values) (both P < 0.0001). Among DM and non-DM patients, adverse events were reported in 52.8% versus 45.6% in the SPAA and 49.6% versus 41.6% in the UC arms, respectively. This global risk-management approach, simultaneously targeting blood pressure and lipids, was more effective for reducing calculated 10-year Framingham CHD risk than UC in patients with DM. While blood pressure changes were of smaller magnitude among patients with DM, this strategy reduced overall risk to an extent comparable with that observed in non-DM patients. Further studies are thus warranted to study this proactive risk factor intervention on CV or mortality endpoints in patients with and without DM. TRIAL REGISTRATION: www.ClinicalTrials.gov identifier NCT00407537.

[Individual pharmacotherapy safety in the assessment of cytochrome P-450 3A4 (CYP3A4) isoenzyme activity].

Modern methods for the evaluation of drug interaction at the level of biotransformation system are discussed with special reference to the lidocaine test (MEGX) and measurement of cytochrome P-450 activity in patients with drug-induced oxidative processes in the liver. Interaction of atorvastatin with clopidogrel are shown to slightly reduce the desaggregative effect of the latter. It is concluded that MEGX test widens opportunities for personalization and safe pharmacotherapy.

Pharmacokinetics and bioequivalence evaluation of two different atorvastatin calcium 10-mg tablets: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy fasted Chinese adult males.

BACKGROUND: Atorvastatin calcium is a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor indicated for the prevention of cardiovascular disease and for the treatment of dyslipidemia. Information on the pharmacokinetics of atorvastatin in a Chinese population is lacking, and regulatory requirements necessitate a bioequivalence study for the marketing of a generic product in China. OBJECTIVE: The aim of the present study was to assess the pharmacokinetics and bioequivalence of a test and branded reference formulation of atorvastatin calcium 10-mg tablets in healthy fasted Chinese male volunteers. METHODS: This was a single-dose, randomized-sequence, open-label, 2-period crossover study with a 2-week washout period between doses. Healthy Chinese males were randomly assigned to receive 20 mg of either the test or reference formulation, and 13 blood samples were obtained over a 48-hour interval. Plasma concentrations of parent atorvastatin and ortho-hydroxy-atorvastatin (primary active metabolite) were simultaneously determined using a validated liquid chromatography-isotopic dilution mass spectrometry method. Pharmacokinetic parameters, including C(max), T(max), t((1/2)), AUC(0-t), and AUC(0-infinity)), were calculated. The 2 formulations were to be considered bioequivalent if 90% CIs for the log transformed ratios of AUC and C(max) of atorvastatin were within the predetermined bioequivalence range (0.80-1.25 for AUC and 0.70-1.43 for C(max)) as established by the State Food and Drug Administration of China. Tolerability was evaluated throughout the study by vital signs monitoring, physical examinations, 12-lead ECGs, and subject interviews on adverse events (AEs). RESULTS: A total of 66 subjects were assessed for inclusion; 20 were excluded prior to study initiation. Of the 46 healthy subjects (mean [SD] age, 24.1 [2.5] years; height, 170.8 [5.1] cm; weight, 64.6 [6.4] kg; body mass index (BMI), 22.1 [1.7] kg/m(2)) who completed the study, 45 subjects (mean [SD] age, 24.1 [2.5] years; height, 171.1 [4.9] cm; weight, 64.8 [6.3] kg; BMI, 22.1 [1.7] kg/m(2)) were included in the pharmacokinetic and bioequivalence analyses; 1 subject was excluded from these analyses because he mistakenly received the same formulation in both periods. No period or sequence effect was observed. The mean values of C(max), AUC(0-t), and AUC(0-infinity)) for the test and reference formulations of atorvastatin (8.78 and 10.76 ng/mL, 38.22 and 40.02 ng/mL/h, 42.73 and 44.51 ng/mL/h, respectively) and ortho-hydroxy-atorvastatin (5.78 and 5.77 ng/mL, 47.32 and 48.47 ng/mL/h, 52.36 and 53.14 ng/mL/h) were not significantly different. The 90% CIs for natural log-transformed ratios of C(max), AUC(0-t), and AUC(0-infinity)) of both atorvastatin (0.73-0.91, 0.92-1.02, and 0.91-1.01, respectively) and ortho-hydroxy-atorvastatin (0.83-1.05, 0.92-1.02, and 0.93-1.02) were within the bioequivalence acceptance limits. Three subjects (6.5%) reported a total of 4 mild AEs (1 abdominal discomfort and 3 venipuncture syncope), which were not considered to be associated with administration of the study drug. CONCLUSIONS: This single-dose (20 mg) study found that the test and reference formulations of atorvastatin calcium 10-mg tablet met the regulatory definition for assuming bioequivalence in these healthy fasted Chinese male volunteers. Both formulations were generally well tolerated in the population studied. Chinese National Registry Code: 2007L02512.

Comparative efficacy and safety of low-dose pitavastatin versus atorvastatin in patients with hypercholesterolemia.

BACKGROUND: Previous studies have shown conflicting results on low-density lipoprotein cholesterol (LDL-C) reduction for comparable doses of pitavastatin and atorvastatin. OBJECTIVE: To compare the efficacy of pitavastatin 1 mg once daily with that of atorvastatin 10 mg once daily on lipoprotein change, safety, and cost per percent LDL-C reduction. METHODS: An 8-week, randomized, open-label, parallel trial was conducted in patients with hypercholesterolemia. One hundred patients were equally randomized to receive pitavastatin 1 mg once daily or atorvastatin 10 mg once daily; 98 completed the study. Outcomes were assessed at baseline and at the end of the study. RESULTS: Pitavastatin lowered LDL-C levels from baseline by 37% compared with 46% in the atorvastatin group (p < 0.001). The reduction of total cholesterol (TC) levels from baseline was significantly different between the pitavastatin (28%) and atorvastatin (32%) groups (p = 0.005). There was no significant difference in the percentage of changes in triglyceride and high-density lipoprotein cholesterol levels between groups. The percentage of patients who achieved LDL-C goals according to National Cholesterol Education Program-Adult Treatment Panel III guidelines was not significantly different between the pitavastatin (74%) and atorvastatin (84%) groups (p = 0.220). In addition, both regimens were well tolerated, with no patient developing an elevation of more than 3 times the upper normal limit of alanine aminotransferase or 10 times that of creatine kinase. The monthly cost per percent LDL-C reduction in the pitavastatin group ($0.77) was about 50% lower than the cost in the atorvastatin ($1.56) group. CONCLUSIONS: Although pitavastatin 1 mg daily was not as effective at lowering LDL-C and TC levels as atorvastatin 10 mg daily, the number of patients achieving their LDL-C goals with pitavastatin was comparable with the number using atorvastatin. Pitavastatin 1 mg once daily may be an alternative regimen with cost-saving benefits but without a significant decrease in therapeutic benefit or increase in adverse events in patients with hypercholesterolemia.

Fixed combination of amlodipine and atorvastatin in cardiovascular risk management: patient perspectives.

Hypertension and dyslipidemia are two of the most commonly co-occurring cardiovascular risk factors which together cause an increase in coronary heart disease-related events that is more than simply additive for anticipated event rates with each condition. Data have shown that even relatively small reductions in both blood pressure and cholesterol levels can lead to large reductions in the risk for cardiovascular events. However, though there are robust data on the beneficial effect of concomitant reduction in these risk factors, the reality is that this is achieved in <10% of patients. There is nonadherence with prescribed therapies with up to 50% of patients stopping their medications of their own volition for a variety of reasons. There is a reasonable evidence base to suggest that simplifying drug regimens and reducing pill burden will enhance patient adherence. The fixed-dose combination containing the antihypertensive agent amlodipine besylate and the statin atorvastatin is the first combination of its kind, which is both efficacious and safe and could potentially improve medication compliance, thereby improving the outcomes in these patients.

Coadministration of dabigatran etexilate and atorvastatin: assessment of potential impact on pharmacokinetics and pharmacodynamics.

BACKGROUND: Dabigatran etexilate, a novel oral direct thrombin inhibitor, has been approved for prophylaxis of thromboembolism in patients undergoing total knee or total hip replacement, and is under clinical investigation for treatment of venous thromboembolism, prevention of stroke in patients with atrial fibrillation, and the treatment of thromboembolic complications following acute coronary syndromes. OBJECTIVE: To evaluate the potential impact of atorvastatin coadministration on the pharmacokinetics, pharmacodynamics, and safety of dabigatran etexilate. METHODS: Healthy male and female volunteers (n = 22) were recruited to this open, randomized, multiple-dose, three-way crossover study. They received dabigatran etexilate 150 mg twice daily on days 1-3 and once daily on day 4, atorvastatin 80 mg once daily on days 1-4, or both treatments together on days 1-4. RESULTS: Exposure to dabigatran at steady state (area under the drug plasma concentration-time curve at steady state) was reduced by 18% with concomitant atorvastatin administration. An 18% increase in plasma atorvastatin concentration occurred with coadministration of dabigatran etexilate. Exposure to its metabolite 2'-hydroxy-atorvastatin remained essentially unchanged and exposure to 4'-hydroxy-atorvastatin was increased by 15%. The small changes observed are deemed of little clinical relevance given the overall inter-individual variability in the metabolism of atorvastatin. Furthermore, there were no changes in the concentrations of active HMG-CoA reductase inhibitors in plasma following dabigatran etexilate coadministration. Six subjects in the atorvastatin treatment group, six subjects during combination treatment, and eight subjects in the dabigatran treatment group reported adverse events. Most of the adverse events reported were nervous system disorders such as dizziness and headache, and general disorders such as fatigue. All adverse events were resolved at the end of the study. CONCLUSION: Results of this randomized, open-label, three-way crossover design study in healthy male and female volunteers showed that atorvastatin had no influence on the pharmacokinetic/pharmacodynamic profile of dabigatran, and vice versa, dabigatran etexilate had no impact on the pharmacokinetic/pharmacodynamic profile of atorvastatin. Both drugs were well tolerated when given alone or in combination.

Assessment of the efficacy and tolerability of a fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg in diabetic dyslipidaemia in adult Indian patients.

Type 2 diabetes mellitus is associated with a marked increase in the risk of coronary heart disease (CHD) or stroke (by a factor of two to three compared with non-diabetic patients), and cardiovascular disease (CVD) accounts for the majority of deaths among patients with diabetes. A new fixed dose combination containing atorvastatin 10 mg + metformin SR 500 mg is being introduced in the Indian market for the treatment of dyslipidaemia in diabetic patients. The present study was therefore undertaken to assess efficacy, safety and tolerability of a fixed dose combination of atorvastatin 10mg + metformin SR 500mg in adult Indian patients with diabetic dyslipidaemia. The final protocol was approved by relevant ethics committee before the initiation of study. Informed consent was obtained from all the patients prior to enrollment in study. The total duration of study was 14 weeks including two weeks dietary run in period. Patients fulfilling the selection criteria received a single oral tablet of fixed dose combination of atorvastatin 10mg + metformin SR 500mg once daily for 12 weeks. The primary efficacy parameters were assessed by evaluating reduction in fasting and postprandial plasma glucose concentration levels at baseline and thereafter at each follow up visit at 2, 4, 8 and 12 weeks and plasma lipid profile and glycosylated Hb levels at baseline and end of study. The secondary efficacy parameters were assessed by evaluating percentage change from baseline at the end of the study (week 12) in the plasma concentration of the various lipid parameters such as total, HDL-, LDL- and very low density (VLDL)-cholesterol, triglycerides, Apo B, Apo A1, TC/LDL ratio, LDL/ HDL ratio, and percentage of patients achieving LDL-cholesterol goals as per NCEP ATP III guidelines. A total of 213 patients were enrolled in the study. Of these seven patients were lost to follow-up and considered as drop-outs. Therapy with the fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg resulted in a significant reduction in the mean plasma fasting and postprandial glucose levels (35 and 38.8% respectively). There was a steep fall in the HbA1c levels from baseline levels of 8.76% to 6.74% (23.1%). There was also a significant (p < 0.05) reduction in mean total cholesterol (31.2%), LDL cholesterol (35.4%), VLDL-cholesterol (19.6%) and a significant increase HDL-cholesterol (9.5%). Thus there appeared to be trend towards reducing atherosclerosis following therapy with the fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg. Mean body mass index was significantly reduced in the patients in the present study following therapy with the study drugs. The fixed dose combination of atorvastatin with metformin was well tolerated with mostly gastro-intestinal adverse events being reported in the current study. Moreover, most of the adverse events were mild to moderate in intensity and disappeared with continued treatment. In conclusion, the results of the present study suggest that, the fixed dose combination of atorvastatin 10 mg + metformin SR 500 mg is efficacious and well tolerated therapeutic modality in patients with diabetic dyslipidaemia. Furthermore this combination offers dosage convenience to the patient and by virtue of its dual mode of action is a useful addition to the therapeutic armamentarium for patients with diabetic dyslipidaemia.

Differences in cardiovascular event rates between atorvastatin and simvastatin among new users: managed-care experience.

OBJECTIVE: Recent clinical trials and observational studies have suggested that reduction in low-density lipoprotein cholesterol (LDL-C) does not account for all differences among statins' effects on cardiovascular (CV) events, but that these effects may vary with time. Using a large US managed-care claims data set for 2002-2005, we assessed whether a difference in the rate of inpatient CV event rates could be observed between new atorvastatin and simvastatin users taking doses with comparable LDL-C-lowering potency, when prior risk factors are controlled and varying observation periods are employed. RESEARCH DESIGN AND METHODS: Eligible patients had a 6-month period of no statin use prior to the initial statin prescription, an initial statin dosage of either 20 or 40 mg of simvastatin or 10 or 20 mg of atorvastatin (the most commonly used doses of both drugs), a 0 to 3-month 'qualifying period' after the first prescription to allow for varying minimum lengths of statin use, and no statin switches. In the primary analysis, patients were observed until an event or significant non-adherence occurred, up to 3.5 years; in secondary analyses, maximum 3-month, 6-month and 1-year observation periods were used. The primary endpoint was the first inpatient admission due to a CV event after the end of the qualifying period; multivariate Cox regression analysis controlled for a variety of demographic and CV risk characteristics and statin type. RESULTS: At baseline, simvastatin users had significantly higher observed risk factors and higher subsequent, unadjusted CV event rates. In the primary Cox regression analyses, the CV event hazard rates for atorvastatin ranged from 0.899 (1-month qualifying period, p = 0.027) to 0.936 (3-month qualifying period, p = 0.33) versus simvastatin. Cox-based hazard rates for atorvastatin during 3-month to 1-year observation periods ranged from 0.908 to 0.915 for the 0-day qualifying period and from 0.851 to 0.884 for the 1-month qualifying period cohort (all p < 0.05); rates for the 3-month qualifying period cohort remained non-significant. LIMITATIONS: Since this was not a prospective randomized study, there is the potential for unobserved risk factors to be responsible for some or all of the differences observed. CONCLUSIONS: These results indicate an association between atorvastatin use and lower CV event rates, particularly in the first year of use, when observable risk factor differences are controlled. The implied absolute risk reduction of 2-3 events per 1000 patients per year may be considered clinically significant when viewed relative to major clinical trial results.

A large observational study of cardiovascular outcomes associated with atorvastatin or simvastatin therapy in diabetic patients without prior cardiovascular disease.

Analysis of claims data from 46,076 diabetic patients without cardiovascular disease initiating atorvastatin or simvastatin therapy suggested that, after adjusting for demographic and clinical confounders, use of atorvastatin was associated with fewer cardiovascular events versus simvastatin at doses of similar potency (HR 0.88, 95% CI 0.80-0.97, P=0.01).

Risk management of simvastatin or atorvastatin interactions with CYP3A4 inhibitors.

BACKGROUND: Co-administration of cytochrome P450 (CYP) 3A4 inhibitors with simvastatin or atorvastatin is associated with increased risk of developing myopathy or rhabdomyolysis. OBJECTIVE: To detect co-prescriptions of CYP3A4 inhibitors with simvastatin or atorvastatin in community pharmacies and assess the risk-preventive actions taken by the prescribing physicians who were alerted about the co-prescription by the pharmacist. METHODS: This naturalistic study was performed during four separate 6-week periods in 2004 and 2005, and involved 110 Norwegian community pharmacists (25-30 in each period). Co-prescription of the selected CYP3A4 inhibitors diltiazem, verapamil, clarithromycin, erythromycin, fluconazole, itraconazole and ketoconazole with either simvastatin or atorvastatin was detected with the aid of a simple computer programme. In instances where the pharmacist alerted the prescribing physician about the co-prescription, information on possible strategies to minimize the risk associated with the interaction was also provided. Odds ratios (ORs) were estimated to describe the associations between prescription variables and frequencies of physician information and prescription change, respectively. RESULTS: In total, 245 co-prescriptions of CYP3A4 inhibitors with simvastatin (134 events) or atorvastatin (111) were detected. Diltiazem (86 events), verapamil (72), erythromycin (48) and clarithromycin (29) were the most commonly co-prescribed CYP3A4 inhibitors. Physicians were informed in 168 out of 245 cases (68.6%). The prescription was subsequently changed in 100 out of 168 cases (59.5%). Another 50 physicians (29.8%) responded that they would consult the patient and monitor potential adverse effects, while only 18 physicians (10.7%) replied that they had already managed the interactions or considered the issue as irrelevant. The adjusted OR for the informing of the physician was 1.89 (95% CI 0.98, 3.63) in patients receiving a daily HMG-CoA reductase inhibitor ('statin') dose of >or=40 mg compared with patients receiving a statin dose of <40 mg/day. The adjusted OR for prescription change was 4.98 (95% CI 2.36, 10.52) if co-prescription was detected prior to the initiation of concurrent use compared with if it was detected during concurrent use. CONCLUSION: Nine out of ten physicians changed prescriptions or monitored potential adverse effects when informed by community pharmacists about the risk associated with co-prescription of CYP3A4 inhibitors with simvastatin or atorvastatin. This suggests that an important risk factor for myotoxicity due to these statins could be minimized through interdisciplinary co-operation.

Amlodipine/atorvastatin fixed-dose combination: a review of its use in the prevention of cardiovascular disease and in the treatment of hypertension and dyslipidemia.

Amlodipine/atorvastatin (Caduet) is a once-daily fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. In Europe, the combination is indicated for the prevention of cardiovascular events in hypertensive patients with three concomitant cardiovascular risk factors and, in the US, it is indicated for the management of hypertension and dyslipidemia in patients for whom treatment with both agents is appropriate. In clinical trials, the fixed-dose combination of amlodipine/atorvastatin effectively managed two important risk factors simultaneously in hypertensive patients at risk of cardiovascular disease or in those with concomitant hypertension and dyslipidemia. The combination is bioequivalent to amlodipine and atorvastatin given alone and does not modify the efficacy of either single agent. Amlodipine/atorvastatin is generally well tolerated, with a tolerability profile consistent with that of each single agent. Compared with the coadministration of each single agent, the convenience of single-pill amlodipine/atorvastatin has the potential to improve patient adherence and the management of cardiovascular risk in selected patients, thereby improving clinical outcomes.

Effect of atorvastatin on energy expenditure and skeletal muscle oxidative metabolism at rest and during exercise.

Statins are associated with adverse effects in skeletal muscle. This study tested the hypothesis that atorvastatin would increase the respiratory exchange ratio (RER) at rest and during exercise. Twenty-eight healthy subjects (mean age 52 years) were enrolled in a double-blind, placebo-controlled, randomized study of the effects of atorvastatin (40 mg/day) on whole body energetics over 8 weeks. Ventilatory gas exchange measurements, at rest and during bicycle ergometry, were used to assess muscle oxidative metabolism. Thirteen subjects from each treatment arm completed the study. Eight weeks of atorvastatin lowered plasma low-density lipoprotein cholesterol concentration but had no effect on resting or submaximal energy expenditure, RER, or calculated fatty acid oxidation rates. Atorvastatin did not affect maximal exercise oxygen consumption or the anaerobic threshold. Eight weeks of atorvastatin therapy was not associated with alterations in substrate oxidation, or muscle oxidative function at rest, or during exercise in healthy adults.

Atorvastatin: a pharmacoeconomic review of its use in the primary and secondary prevention of cardiovascular events.

Atorvastatin is a lipid-lowering agent that has been evaluated in a number of primary and secondary intervention studies. In the primary prevention trials ASCOT-LLA and CARDS, atorvastatin 10 mg/day significantly reduced cardiovascular events compared with placebo. A prospectively conducted economic analysis of the 3.3-year ASCOT-LLA trial showed that atorvastatin was associated with incremental cost-effectiveness ratios (ICERs) of euro11,693 (UK) and euro12,673 (Sweden) per event avoided (2002 values). Longer-term modelled analyses using data from CARDS showed ICERs of euro8046 (Spain) and 6471pound (UK) per QALY gained (2003/2004 values), and a US analysis showed atorvastatin was dominant versus no statin when modelled over the lifetime of a representative US diabetic primary prevention population. In a modelled analysis based on results of the IDEAL trial, which showed significant reductions in cardiovascular endpoints with high-dose atorvastatin (80 mg/day) compared with conventional-dose simvastatin in patients with stable coronary heart disease, ICER values were below the commonly used cost-effectiveness threshold of euro50,000 per QALY gained in Norway, Sweden and Denmark, but were above this threshold in Finland (2005 values). A modelled US analysis that also included data from IDEAL and other sources showed an ICER of $US33,400 per QALY gained, assuming the incremental difference in acquisition cost between high-dose atorvastatin and conventional-dose simvastatin was $US1.40/day (2005 value). Most cost-effectiveness analyses with atorvastatin in patients with acute coronary syndrome used data from the 16-week MIRACL study, which showed a significant reduction in cardiovascular events with high-dose atorvastatin compared with placebo. Analyses were conducted in North America and Europe and showed that 31-86% of the acquisition cost of high-dose atorvastatin was offset by reductions in costs associated with cardiovascular events. Across five countries, ICER values ranged from approximate $US850 to $US4100 per event avoided (2000/2001 values). Another analysis conducted in the US used longer-term data and showed that high-dose atorvastatin versus conventional-dose statin was associated with an ICER of $US12,900 per QALY gained, assuming the daily difference in acquisition cost was $US1.40 (2005 value). In conclusion, atorvastatin has demonstrated beneficial effects on various cardiovascular endpoints in large, well designed primary and secondary intervention trials. These benefits in moderate- to high-risk patients were achieved at a relatively low incremental cost and, across the economic analyses, a substantial proportion of atorvastatin acquisition costs was offset by reductions in healthcare resource use associated with cardiovascular events. Cost-effectiveness analyses based on major clinical trials comparing atorvastatin with placebo, usual medical care, simvastatin or pravastatin have generally shown that atorvastatin is associated with favourable ICER values, often well below commonly used cost-effectiveness thresholds. These modelled analyses have the inherent limitation that projecting long-term outcomes beyond the time period of a clinical trial imparts a degree of uncertainty to the results. Nevertheless, while some findings were sensitive to changes in model assumptions, such as the long-term benefits of statin therapy, most sensitivity analyses showed that results of the base-case analyses were robust to plausible changes in key parameters. Although a clear pattern is not evident from available data, intuitively, the value of atorvastatin would be expected to increase with the patient's risk for serious cardiovascular events.

A dose-specific meta-analysis of lipid changes in randomized controlled trials of atorvastatin and simvastatin.

BACKGROUND: The available statins exhibit differences in the potency with which they alter serum lipid levels. OBJECTIVE: Meta-analyses were conducted to assess the relative potency of atorvastatin and simvastatin (the 2 most commonly prescribed statins) across all possible dose combinations in terms of changes in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C). METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, National Health Service (NHS) Centre for Reviews and Dissemination database, NHS Economic Evaluation Database, and Database of Abstracts of Reviews of Effects were searched for randomized, head-to-head trials of atorvastatin and simvastatin in patients aged >or=18 years with elevated levels of serum TC and LDL-C. Reference lists of the identified articles, letters, and editorials also were reviewed. The manufacturers of atorvastatin and simvastatin products were contacted for relevant unpublished data. All studies were reviewed and rated for quality by 2 independent reviewers. The maximum quality score was 4 points; trials with a score of <2 points were considered to be of poor quality and were excluded from analysis. Dose comparisons were abstracted in pairs from each trial. Meta-analyses were conducted on the fixed-dose pairs for each lipid parameter. Weighted mean differences in the change in TC, LDL-C, TG, and HDL-C were estimated using the Der Simonian and Laird random-effects model. RESULTS: Seventeen published trials and 1 unpublished study were included in the meta-analyses. Atorvastatin treatment was associated with significantly greater reductions in TC, LDL-C, and TG in the majority of dose comparisons with simvastatin. The potency of atorvastatin and simvastatin was comparable at dose ratios between 1:2 and 1:4. Higher doses of simvastatin were more effective in increasing HDL-C levels than atorvastatin, with no apparent dose-equivalence point. The HDL-C advantage of simvastatin was greatest when simvastatin 80 mg was compared with atorvastatin 80 mg (weighted mean difference, -4.35%; 95% CI, -5.64 to -3.08, P < 0.001). CONCLUSIONS: In these meta-analyses, atorvastatin was 2 to 4 times as potent as simvastatin in reducing TC, LDL-C, and TG, indicating that the dose equivalence of atorvastatin and simvastatin lay between 1:2 and 1:4. In contrast, simvastatin was more effective than atorvastatin in increasing HDL-C, but without any indication of a point of dose equivalence.