Which factors are assessed when antilipemics drugs are prescribed

Studies have shown the efficacy of statin drugs in reducing coronary heart disease (CHD) events, CHD death, and total mortality rates. Efficacy for LDL-C lowering at approved doses of statins is listed in Medical Care. Primary prevention implies the use of statins in an asymptomatic population, which may include some people with clinically occult disease. Secondary prevention implies the use of statins in patients with clinically apparent disease.

The Scandinavian Simvastatin Survival Study (4S) was the first study to show significant reduction (compared with placebo) in the all-cause mortality rate (30%), in CHD events (34%), and in the CHD mortality rate (42%). In addition, subjects with CHD (secondary prevention) who were treated for moderate hypercholesterolemia (eg, treatment with simvastatin, mean dose 27 mg/d) maintained total cholesterol levels of less than or equal to 201 mg/dL for 5.4 years, which was the median follow-up period.

The West of Scotland Coronary Prevention Study (WOSCOPS) studied high-risk male subjects who had no history of CHD events (primary prevention). Pravastatin was administered at a dose of 40 mg/d for 4.9 years. Cardiovascular events were reduced by 31%, and the treatment caused a borderline statistically significant reduction of 31% in the total mortality rate compared with placebo.

The Cholesterol and Recurrent Events (CARE) study of subjects with CHD and cholesterol concentrations within the reference range (mean LDL-C level of 138 mg/dL) examined the effects of pravastatin at a dose of 40 mg/d. Compared with placebo, the CHD events were reduced by 24% at 5 years, with no significant change in total mortality.

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) enrolled more than 6000 subjects with average LDL-C concentrations and below-average high-density lipoprotein cholesterol (HDL-C) values. Lovastatin was administered at a dose of 20-40 mg/d for approximately 5 years, resulting in a 37% reduction in first major acute coronary events compared with placebo therapy.

The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study used pravastatin at a dose of 40 mg/d for an average of 6.2 years in subjects with CHD; the CHD mortality rate decreased by 24%, and the total mortality rate decreased by 22% compared with placebo treatment.

The Atorvastatin versus Revascularization Treatment (AVERT) Study compared 80 mg atorvastatin daily with standard therapy and angioplasty in subjects with CHD. Although event rates at 18 months were the same between both groups, the time until the first CHD event was longer, with aggressive LDL-C lowering. Angioplasty alone has not been proven to prevent events, so this is not necessarily tantamount to a no-therapy comparison trial.

The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial showed borderline significant reduction in coronary events in subjects treated with atorvastatin (80 mg/d) who presented with an acute coronary syndrome, although significant abnormalities revealed via liver function test were common. The major positive finding from this study was a 61% reduction in stroke in the atorvastatin-treated group.

In the Pravastatin in Elderly Individuals at Risk of Vascular Disease (PROSPER) study that compared pravastatin 40 mg/d versus placebo in subjects aged 70-82 years with a history of CHD or risk factors for CHD, active therapy reduced cardiovascular events by 15%.

The Medical Research Council/British Heart Foundation Heart Protection Study (HPS) assessed the effects of simvastatin (40 mg/d) versus placebo in approximately 20,000 subjects with vascular disease or at high risk for CHD with total cholesterol levels greater than 135 mg/dL, including approximately 6000 subjects with diabetes mellitus. CHD endpoints were reduced by approximately 24% and were effective in multiple subgroups, including subjects with diabetes. The mortality rate was reduced by approximately 15%.

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) used 10 mg of atorvastatin versus placebo in approximately 10,000 subjects with hypertension. CHD event rates were reduced approximately 36%. However, most subgroups, including subjects with diabetes mellitus or metabolic syndrome, did not return positive results, perhaps because of the short duration (3.3 y) of the study.

The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared treatment with atorvastatin (80 mg) with treatment with pravastatin (40 mg) in subjects with CHD. After 18 months, the atorvastatin treatment group had a slight decrease in atheroma volume based on intravascular ultrasonography evaluations, and the pravastatin group had a slightly increased atheroma volume.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) study also compared atorvastatin therapy (80 mg/d) with pravastatin therapy (40 mg/d) in subjects who had been hospitalized for acute coronary syndromes. The baseline LDL-C level was approximately 106 mg/dL. After a mean follow-up of 2 years, the intensively treated group had LDL-C levels of approximately 62 mg/dL, compared with approximately 95 mg/dL in the pravastatin group. Cardiovascular events were reduced by 16%.

Unfortunately, the study had a dropout rate of approximately one third. The number of patients needed to treat was 26, but the number needed to cause transaminase values to exceed 3 times the upper limit of normal was only 46 patients. In this scenario, 26 patients would have to be treated to prevent one clinical event, and 46 patients would have to be treated to see one case of transaminases >3 X ULN (and possibly end up stopping therapy). Interestingly, subjects pretreated with statins or those with baseline LDL-C levels of less than 125 mg/dL did not show a benefit from high-dose atorvastatin therapy compared with pravastatin therapy (40 mg).

A pooled analysis of 5 statin trials revealed that intensive-dose therapy was associated with a greater risk of diabetes when compared with moderate dosing.

The Treating to New Targets (TNT) study assessed the effect of therapy with atorvastatin 80 mg/d versus atorvastatin 10 mg/d in patients with stable CHD for a period of 4.9 years. The mean on-treatment LDL-C level was 77 mg/dL in the former group and 101 mg/dL in the latter group. The relative risk of cardiovascular events was reduced by 22%. Mortality was higher but not significantly statistically different in the high-dose atorvastatin group, although persistent transaminase elevations were 6 times higher in this group.

The statins lower LDL-C by inhibiting HMG-CoA reductase, the enzyme that regulates the rate-limiting step in cholesterol synthesis. The amount of the intermediate (i.e., mevalonate) is lowered, and, subsequently, cholesterol levels are reduced in hepatic cells. This, in turn, results in up-regulation of LDL receptors and increased hepatic uptake of LDL from the circulation.

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Atorvastatin is highly efficacious at high doses, resulting in as much as a 60% reduction in LDL-C. It inhibits HMG-CoA reductase, which, in turn, inhibits cholesterol synthesis and increases cholesterol metabolism. The half-lives of atorvastatin and its active metabolites are longer than those of all other statins (ie, approximately 17 h for native drug, approximately 48 h for active metabolites, compared with 3-4 h for other drugs).

Atorvastatin was used for primary prevention (10-mg dose) in the ASCOT trial of subjects with hypertension and at the 80-mg dose in the AVERT, MIRACL, REVERSAL, PROVE-IT, and TNT trials.

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Fluvastatin is the least potent of statin drugs. The Lescol Intervention Prevention Study showed that in subjects with CHD monitored after a first percutaneous intervention, fluvastatin at 80 mg/d reduced CHD events compared with placebo. It is a synthetically prepared HMG-CoA reductase inhibitor with some similarities to lovastatin, simvastatin, and pravastatin. However, it is structurally distinct and has a different biopharmaceutical profile (eg, no active metabolites, extensive protein binding, minimal CSF penetration). Fluvastatin has been shown to reduce CHD events after revascularization.

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Lovastatin was the first statin approved by the FDA. It has been shown to retard atherosclerosis in angiographic and carotid ultrasound trials and to reduce clinical events in primary prevention (AFCAPS/TexCAPS). It is a prodrug hydrolyzed in vivo to mevinolinic acid, one of several active metabolites. Once hydrolyzed, it competes with HMG-CoA for HMG-CoA reductase, a hepatic microsomal enzyme, thus reducing the quantity of mevalonic acid, a precursor of cholesterol. Cholesterol can also be taken up by the liver from LDL by endocytosis. The diminishing de novo synthesis of cholesterol leads to increased clearance of circulating LDL. In the AFCAPS/TexCAPS study, 20-40 mg lovastatin daily reduced the incidence of CHD events in a relatively low-risk primary prevention population. Lovastatin is available as IR (Mevacor and generic) and SR (Altocor) dosage forms.

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Pravastatin reduces CHD events when used in primary prevention in patients with marked LDL-C elevations (WOSCOPS). It also reduces CHD events and mortality rates in patients with CHD and moderate increases in LDL-C (LIPID study). Pravastatin reduces CHD events in patients with cholesterol levels within reference range and known CHD (CARE study), and it reduces cardiovascular events in elderly persons (PROSPER).

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Simvastatin was the first drug shown to reduce total mortality rate by reducing LDL-C concentrations in patients with CHD with marked LDL-C elevations at baseline (4S). It markedly affects mortality rates and CHD events in patients with CHD and marked hypercholesterolemia (4S). It also reduces CHD events by more than 40% in similar patients with type 2 diabetes mellitus. Simvastatin has also been shown to reduce CHD events in patients with a wide variety of cholesterol concentrations (>135 mg/dL) at baseline, ie, in the HPS. Adverse effects, including LFT abnormalities and myalgia, were minimal at this dose.

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Rosuvastatin is an HMG-CoA reductase inhibitor that decreases cholesterol synthesis and increases cholesterol metabolism. It reduces total cholesterol, LDL-C, and triglyceride levels and increases the HDL-C level. Rosuvastatin is used adjunctively with diet and exercise to treat hypercholesterolemia. It is the most efficacious of the statins. It may raise HDL-C at higher doses than equally effective doses of atorvastatin. It is not metabolized by the cytochrome P450 system. A dose of 40 mg is associated with hematuria and proteinuria, which is of unknown clinical significance. No clinical outcome studies have been completed as yet.

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Pitavastatin is an HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.