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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.
Like other members of its class, atorvastatin inhibits hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase in vivo and in vitro, and impedes the formation of mevalonic acid, which is the rate-limiting step in the biosynthesis of cholesterol. The reduction in intracellular cholesterol increases the number of low-density lipoprotein (LDL) receptors, thus increasing the clearance of LDL-cholesterol from plasma.
Atorvastatin reduces plasma levels of total cholesterol, LDL-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, triglycerides and apolipoprotein B, as demonstrated in a number of studies in human volunteers and patients (see Therapeutic Efficacy section). The greater efficacy of atorvastatin than other currently available HMG-CoA reductase inhibitors in reducing total cholesterol and LDL-cholesterol levels is believed to result from a prolonged duration of HMG-CoA reductase inhibition rather than the degree of inhibition.
The marked reductions in triglyceride levels with atorvastatin result mainly from decreases in VLDL production, caused in part by inhibition of cholesterol synthesis. In addition, the increase in number of LDL receptors, combined with the decrease in LDL particles available to bind to these receptors, may enhance the binding of VLDL particles, thus reducing triglyceride levels.
Atorvastatin reduces LDL-cholesterol levels in patients with homozygous familial hypercholesterolaemia despite the absence of any functional LDL receptors in these patients. This effect appears to result from marked inhibition of cholesterol synthesis, which in turn decreases the rate of LDL production. The reductions in overall levels of triglycerides and cholesterol by atorvastatin are accompanied by an improvement in the LDL subfraction profile, with a shift towards the larger subfractions.
There is some evidence that atorvastatin, like other drugs of its class, may have beneficial pharmacodynamic effects in addition to lipid-lowering in patients with atherosclerosis and CHD. Atorvastatin improved endothelial function in patients with hypercholesterolaemia or diabetes mellitus. The improvement did not correlate with the reduction in cholesterol levels and is likely to be due to enhanced endothelial production of nitric oxide (NO) and/or decreased formation of oxygen-derived free radicals.
As well, atorvastatin possibly plays a role in the stabilisation of atherosclerotic plaques by reducing the accumulation of inflammatory cells within them. The drug reduced the activation in vitro of nuclear factor Kappa-B, an inducer of chemokines involved in the inflammation in the atheromatous plaque. In studies of other effects, atorvastatin abolished macrophage infiltration in the arterial neointimal lesions in addition to reducing atheromatous lesion size in a rabbit model of atherosclerosis, and inhibited smooth muscle cell migration and proliferation in both in vitro and in vivo studies.
Treatment with atorvastatin has been shown to reduce spontaneous and ADP-and epinephrine-induced platelet aggregation, probably because of its effect on intraplatelet NO metabolism through an increase in intraplatelet NO synthase activity. Atorvastatin also reduced the enhanced susceptibility of LDL to oxidation, decreased cholesterol accumulation in macrophages and improved red cell deformability.
Most data indicate the drug has positive or negligible effects on non-lipid risk factors for CHD. The drug generally had no appreciable effect on fibrinogen levels, and most data from randomised trials demonstrated a possibly dose-dependent reduction in C-reactive protein levels. The drug generally had no effect on lipoprotein (a) levels in dosages up to 40 mg/day, but the largest such clinical trial (the ASAP study) showed a significant reduction in this parameter after 2 years’ therapy with atorvastatin 80 mg/day.
About 30% of an oral dose of atorvastatin is absorbed and undergoes extensive first-pass metabolism. The drug has a bioavailability of about 14% and is >98% protein bound in the plasma. No significant changes in area under the plasma concentration-time curve or elimination half-life were observed with the administration of atorvastatin 30 minutes after food intake, although the rate of absorption was reduced.
The single-dose pharmacokinetic parameters of atorvastatin are linear. After single doses of atorvastatin 10, 20 or 40mg in healthy male volunteers, time to reach peak plasma concentration was 0.6 to 0.9 hours. The pharmacological response (lipid-lowering action) is more accurately predicted by the dose administered than the plasma drug concentrations.
Metabolism of atorvastatin by cytochrome P450 (CYP) 3A4 produces ortho-and para-hydroxylated derivatives and various β-oxidation products. 70% of the HMG-CoA reductase inhibitory activity associated with atorvastatin has been attributed to its active ortho- and para-hydroxylated metabolites, which are equipotent to the parent drug.
The peak plasma concentration of atorvastatin is significantly increased in patients with hepatic failure and dosage needs to be reduced in such patients. However, renal impairment has no significant effect on the pharmacokinetic parameters of atorvastatin.
Clinically significant interactions of atorvastatin are likely to occur with its concomitant use with other drugs metabolised by CYP 3A4 including erythromycin, itraconazole, ethinyl estradiol, fusidic acid and cyclosporin.
The lipid-lowering effects of atorvastatin have been investigated in patients with various types of dyslipidaemia. At present the only clinical outcomes data are from studies of aggressive atorvastatin therapy in patients with CHD, but many large trials of atorvastatin are under way to examine the effect of the drug on morbidity and mortality.
Primary hypercholesterolaemia. The lipid-lowering efficacy of atorvastatin in patients with primary hypercholesterolaemia is well established. The drug consistently reduces total and LDL-cholesterol levels in a nonlinear dose-dependent manner, with atorvastatin 10 to 80 mg/day producing reductions in serum LDL-cholesterol levels of about 35 to 60% in various placebo-controlled and non-comparative trials. Atorvastatin 10 to 80 mg/day reduced triglyceride levels by 17 to 45% and apolipoprotein B levels by 17 to 50%.
Target US National Cholesterol Education Program (NCEP) LDL-cholesterol levels (<4.1 mmol/L) were achieved in 91 and 100% of patients with low CHD risk receiving 10 and 20 mg/day of atorvastatin, respectively, in a placebo-controlled study. In the high CHD risk group, 27, 40, 64 and 82% of patients receiving atorvastatin 10, 20, 40 and 80mg, respectively, reached their target serum LDL-cholesterol levels (≤2.6 mmol/L).
Atorvastatin was more efficacious in lowering serum levels of LDL-cholesterol, total cholesterol and triglycerides than milligram equivalent doses of other currently available HMG-CoA reductase inhibitors in patients with hypercholesterolaemia. In large double-blind 1-year trials, reductions in total cholesterol, LDL-cholesterol, apolipoprotein B and triglyceride levels were significantly greater with atorvastatin 10 to 20 mg/day than with lovastatin 20 to 40 mg/day, pravastatin 20 to 40 mg/day or simvastatin 10 to 20 mg/day.
As well, a greater number of patients tended to reach US NCEP LDL-cholesterol goals or European Atherosclerosis Society goals with atorvastatin than with lovastatin, pravastatin, fluvastatin and simvastatin. Fewer patients receiving atorvastatin than these other agents require upward dose titration. Atorvastatin increased high-density lipoprotein (HDL)-cholesterol levels by about 5 to 9% in most studies comparing the drug with others of its class.
Mixed hyperlipidaemia. In patients with mixed hyperlipidaemia, atorvastatin 10 to 20 mg/day produced greater reductions in serum LDL-cholesterol and total cholesterol but lesser reductions in serum triglyceride levels than fenofibrate 200 or 300 mg/day, bezafibrate 400 mg/day and nicotinic acid 3 g/day. The increase in HDL-cholesterol was less than that with fenofibrate and nicotinic acid and similar to that with bezafibrate.
Atorvastatin 10 mg/day was more efficacious in reducing serum LDL-cholesterol and triglyceride levels than simvastatin 10 mg/day in a well-designed, 6-week study involving 1378 evaluable patients with mixed dyslipidaemia (the ASSET trial), and than other comparator HMG-CoA reductase inhibitors in a smaller trial.
Type 2 diabetes mellitus. The efficacy of atorvastatin in lowering serum LDL-cholesterol levels is similar in patients with type 2 diabetes mellitus and those without the condition. Atorvastatin 10 mg/day produced a greater reduction in serum LDL-cholesterol levels than simvastatin 10 mg/day, pravastatin 20 mg/day or lovastatin 20 mg/day in patients with type 2 diabetes mellitus after 6 months, and the drug was superior to simvastatin after 54 weeks in the ASSET trial. More patients given atorvastatin 80 mg/day than 10 mg/day achieved target NCEP LDL-cholesterol goals in the DALI study.
Familial hypercholesterolaemia. Atorvastatin reduced serum LDL-cholesterol levels further in patients with familial hypercholesterolaemia who had previously received simvastatin alone, or in combination with cholestyramine. Reductions were similar to those in patients previously treated with combinations of simvastatin and fenofibrate or nicotinic acid. In the ASAP trial, atorvastatin 80 mg/day significantly reduced, and simvastatin 40 mg/day increased, carotid intimai media thickness in patients with familial hypercholesterolaemia after 2 years.
Atorvastatin 80 mg/day significantly reduced total cholesterol and LDL-cholesterol levels in small numbers of patients with homozygous familial hypercholesterolaemia treated for 2 months.
Aggressive therapy in patients with coronary heart disease.
Atorvastatin is generally more efficacious than the other HMG-CoA reductase inhibitors in achieving the stricter serum LDL-cholesterol target levels in patients with established CHD, in terms of the percentage of patients achieving the targets on monotherapy with these drugs as well as the proportion of patients requiring upward dose titration or a combination with other lipid-lowering agents. This has led to investigation of whether more aggressive therapy can provide clinical benefits.
Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L, well below the recommended target, with atorvastatin 80 mg/day for 16 weeks in patients with unstable angina or non-Q-wave myocardial infarction significantly reduced the incidence of the combined primary end-point (p = 0.048 vs placebo) and the secondary end-point of recurrent ischaemic events requiring rehospitalisation (p = 0.02) in the large (n = 3086) randomised, double-blind, placebo-controlled MIRACL trial. There were no significant differences in other secondary end-points (death, myocardial infarction and cardiac arrest).
As well, the results of the AVERT trial showed that 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.
Other special patient groups. Use of atorvastatin in place of the previous unsuccessful lipid-lowering therapy in patients with severe resistant hypercholesterolaemia resulted in a significant further reduction in serum LDL-cholesterol and triglyceride levels and achievement of target serum LDL-cholesterol in a significant proportion of these patients.
Although there are no large controlled studies comparing atorvastatin with other HMG-CoA reductase inhibitors in patients with organ transplants, small studies, some of them retrospective, have found atorvastatin to further reduce serum LDL-cholesterol and triglyceride levels in patients with renal or cardiac transplants switched to this drug after previous unsuccessful therapy with simvastatin, pravastatin and fluvastatin. Atorvastatin was superior to pravastatin in a small 4-month trial in patients with cardiac transplants.
Similarly, preliminary results from generally small studies suggest that atorvastatin is effective in patients with end-stage renal disease undergoing dialysis.
Atorvastatin has been well tolerated in long-term clinical trials. In placebo-controlled studies, the incidence of adverse events (18%) in 1122 patients receiving atorvastatin up to 80 mg/day was similar to that in patients receiving placebo (18%; n = 270). No dose-related increase in adverse events was observed in these studies. Overall, the most frequently reported adverse events were constipation, flatulence, dyspepsia, abdominal pain, headache and myalgia. Adverse events reported with atorvastatin have been mild and transient.
Fewer than 2% of the 2502 patients who received atorvastatin withdrew from the trials because of adverse effects related to treatment. The incidence of withdrawal was not dose dependent. In general, the adverse event profile for ator- vastatin was similar to that observed with other HMG-CoA reductase inhibitors.
Mild hepatic involvement in the form of asymptomatic elevations in serum transaminase levels has been reported during treatment with atorvastatin in 0.7% of patients and was responsible for discontinuation of atorvastatin in 0.3%. The incidence of persistent elevation of transaminase levels was higher in patients receiving atorvastatin in doses of 80 mg/day (2.3%) than those receiving lower doses (up to 0.6%).
The incidence of myalgia with the use of atorvastatin (1%) has been found similar to that with placebo (1%) and other HMG-Coa reductase inhibitors (2%). Although isolated asymptomatic elevation of creatine phosphokinase (CPK) has been observed in patients receiving atorvastatin, persistent elevation of CPK (>10 times elevation on 2 consecutive occasions) along with muscle pain, tenderness or weakness has not so far been reported. Case reports of rhabdomyolysis are rare with atorvastatin use, most occurring with concomitant use with other drugs such as cyclosporin, fusidic acid and gemfibrozil.
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. Atorvastatin has been found to be more cost effective than most other HMG-CoA reductase inhibitors, in terms of cost per year of life saved and cost of achieving target LDL-cholesterol levels. Atorvastatin 10 mg/day had the lowest acquisition cost per percent reduction in LDL-cholesterol levels among various dosages of the HMG-CoA reductase inhibitors investigated.
Dosage and Administration
Atorvastatin 10 to 80 mg/day may be used to reduce the raised lipid levels in patients with primary hypercholesterolaemia (heterozygous familial, homozygous familial or nonfamilial) or combined dyslipidaemia and diabetic dyslipidaemia.
The dosage of atorvastatin should be adjusted according to response. Atorvastatin may be taken at any time of day with or without food. Dosage reduction may be required in patients with hepatic insufficiency. The drug is contraindicated in patients with active hepatic disease or unexplained persistent elevations in serum transaminase levels.
Concomitant use of atorvastatin with cyclosporin, nicotinic acid, fibrates, erythromycin or azole antifungals is likely to increase the risk of adverse events such as myopathy and rhabdomyolysis.
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