Creative Consultants
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Creative Consultants |
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CLINICAL TRIAL REPORTS CHD
remains the leading cause of death and is a major cause of morbidity
among men and women. The role of elevated levels of cholesterol and LDL-cholesterol
in the pathogenesis of atherosclerosis has been well established. Reduction of
plasma cholesterol levels by pharmacological means in patients with
hypercholesterolaemia has been shown to prevent atherosclerotic plaque
progression and reduce both fatal and nonfatal coronary events in patients with
or without coronary artery disease.
The considerable evidence showing reduction of CHD risk with the reduction of elevated cholesterol levels is reflected in the inclusion of cholesterol lowering as an essential part of the recommendations on CHD prevention. The treatment guidelines for primary and secondary prevention, both from the US and Europe, emphasise the need for assessment of overall CHD risk in an individual in order to determine when to start lipid-lowering treatment. It
is generally recommended that initial cholesterol lowering should begin with
lifestyle changes. These include increased physical activity, weight reduction
and change in dietary habits. The reductions in cholesterol levels achieved by
these measures are modest and most patients require drug therapy to achieve
cholesterol reduction goals. HMG-CoA
reduclase inhibitors (statins) are more effective than other classes of
lipid-lowering drugs in reducing LDL-cholesterol to target levels and reducing
CHD risk. As a result, HMG-CoA reductase inhibitors are recommended as
first-line lipid-lowering drug therapy in patients who are risk of CHD or who
have established CHD. The HMG-CoA reductase inhibitors currently available are atorvastatin, lovastatin, pravastatin, fluvastatin and simvastatin. Comparative efficacy studies have established that atorvastatin produces the greatest reductions in LDL-cholesterol levels at milligram equivalent doses as well as at maximum recommended doses. Atorvastatin therapy is also more likely to achieve target LDL-cholesterol levels than other HMG-CoA reductase inhibitors. A variety of
clinical studies have demonstrated that elevated levels of total-C, LDL-C, and
apo B (a membrane complex for LDL-C) promote human atherosclerosis. Similarly,
decreased levels of HDL-C (and its transport complex, apo A) are associated with
the development of atherosclerosis. Epidemiologic investigations have
established that cardiovascular morbidity and mortality vary directly with the
level of total-C and LDL-C, and inversely with the level of HDL-C.(34)
Atorvastatin reduces total-C,
LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial
forms of hypercholesterolemia, and mixed dyslipidemia. Atorvastatin also reduces
VLDL-C and TG and produces variable increases in HDL-C and apolipoprotein A-1.
Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and
increases HDL-C in patients with isolated hypertriglyceridermia. Atorvastatin
reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with
dysbetalipoproteinemia..(34) Atorvastatin
influences the lipid-related risk for CHD in two ways: first, it significantly
decreases LDL-C and TG levels while increasing HDL-C, and second, it
significantly shifts the HDL subpopulation profile of CHD patients toward that
observed in subjects without CHD.(35). Lowering of serum cholesterol levels by pharmacologic intervention with statins reduces the incidence of cardiovascular events in subjects with and without atherosclerotic manifestations. Atorvastatin, 10 mg/day produced significant reductions in LDL-C, total cholesterol and triglycerides and an elevation of HDL-C levels when used as an adjunct to diet in hyperlipidemic patients. The majority of the clinical effects could be attained by week 4. LDL-C, was reduced by 40% and 42% after 4 and 8 weeks of treatment in the atorvastatin treated patients. The reductions in total cholesterol and triglycerides were up to 31% and 23%, respectively. The HDL-C levels increased up to 11%. The overall safety profile of atorvastatin was similar to that of placebo.(36) A randomized,
placebo-controlled, double-masked, parallel-group trial assessed the serum
cholesterol-lowering effects of atorvastatin, over 26 weeks in patients with
primary hypercholesterolemia. Patients were randomized to one of two treatment
groups and received either atorvastatin 10 mg or placebo once daily.
Atorvastatin rapidly and significantly reduced serum total cholesterol,
low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B levels. LDL-C
was reduced 35% with atorvastatin 10 mg. Atorvastatin significantly reduced
triglyceride levels, with improvements occurring over time. At 26 weeks,
triglyceride levels were reduced by 21% with atorvastatin treatment compared
with a 14% increase with placebo. The drug was well tolerated and no clinically
significant laboratory abnormalities were detected.(37) A randomized
double-blind, placebo-controlled, multicenter trial was conducted to assess the
lipid-lowering effect of atorvastatin on levels of serum triglycerides and other
lipoprotein fractions in patients with primary hypertriglyceridemia and to
determine if atorvastatin caused a redistribution of triglycerides in various
lipoprotein fractions. In atorvastatin treatment groups, total serum
triglyceride levels decreased in a dose-dependent manner, reductions in the
20-mg and 80-mg groups were statistically significant (P < .05) compared with
placebo. Atorvastatin did not cause a redistribution of triglycerides but
consistently lowered triglycerides in all lipoprotein fractions.(38) In CHD patients with diabetes mellitus (GREACE Study), structured care of dyslipidemia with atorvastatin to achieve the National Cholesterol Education Program LDL-C treatment goal, reduces all cause and coronary mortality, coronary morbidity, and stroke by more than one half within a 3-year period, in comparison to usual care. Clinical benefit is manifested as early as the sixth month of treatment.(39) Cholesterol modification reduces cardiovascular events in patients with atherosclerosis, including those with peripheral arterial disease. In a randomized, double-blind, parallel-design study included 354 persons with claudication attributable to peripheral arterial disease were treated with placebo, atorvastatin (10 mg per day), or atorvastatin (80 mg per day) for 12 months. Atorvastatin improved pain-free walking distance and community-based physical activity in patients with intermittent claudication. When treated with atorvastatin, patients with peripheral arterial disease may experience improvement in symptoms to complement the anticipated reduction in cardiovascular events reported in other studies of statins.(40) Treatment with atorvastatin for 12 months was effective and safe for pediatric subjects with known familial hypercholesterolemia or severe hypercholesterolemia. Atorvastatin (10 to 20 mg) caused a highly significant reduction in LDL-C compared with placebo (-40% vs -0.4%). Percent changes also significantly favored atorvastatin for total cholesterol (-32% vs -1.5%), triglycerides (-12% vs +1.0%) and apolipoprotein B (-34% vs +0.7%), with a significantly greater increase in HDL cholesterol with atorvastatin compared with placebo (+2.8% vs -1.8%). Atorvastatin was as well-tolerated as placebo.(41) The lowering
of cholesterol concentrations in individuals at high risk of cardiovascular
disease improves outcome. In an effort to assess the benefits of cholesterol
lowering in the primary prevention of coronary heart disease (CHD) in
hypertensive patients, 10305
hypertensive patients (with at least three
other cardiovascular risk factors)
with non-fasting
total cholesterol 6.5
mmol/L or less were randomly assigned atorvastatin
10 mg or placebo in
addition to antihypertensive regimen.
These patients
formed the
lipid- The MIRACL
study has shown that for patients with acute coronary syndrome, lipid-lowering
therapy with atorvastatin, 80 mg/day, reduces recurrent ischemic events in the
first 16 weeks, mostly recurrent symptomatic ischemia requiring
rehospitalization.(44) A 4 week
study of atorvastatin therapy (10
mg/day) on postprandial lipoprotein metabolism in 10 hypertriglyceridemic
patients showed that atorvastatin significantly decreased fasting cholesterol (-27%), triglycerides (-43%),
LDL-cholesterol (-28%), and apoB-100 (-31%), and increased HDL-cholesterol
(+19%). These findings show that atorvastatin improves postprandial lipoprotein
metabolism in addition to decreasing fasting lipid levels in
hypertriglyceridemia. Such changes would be expected to improve the atherogenic
profile.(45) In patients with type 2 diabetes, intensive glucose regulation, although effective for microangiopathy, has not been shown to have unambiguous preventive effects on the occurrence of cardiovascular disease. Patients with diabetes show a characteristic dyslipidemia (high triglyceride level, low HDL cholesterol level). Aggressive reduction of triglycerides might be an effective method to reduce the cardiovascular risk in these patients. Administration of 10- and 80-mg doses of atorvastatin provides similar, significant reductions from baseline in triglyceride levels in patients with type 2 diabetes. A higher dose of atorvastatin improves cholesterol-related parameters. Both doses were well tolerated in this patient population.(46) The
Atorvastatin versus Revascularization Treatment (AVERT) trial was the first
study designed to compare the efficacy of aggressive cholesterol-lowering
therapy versus percutaneous transluminal coronary angioplasty in low risk,
stable patients with coronary artery disease. Results favour the use of
aggressive lipid lowering over percutaneous transluminal coronary angioplasty in
patients with mild to moderate coronary disease. Treatment with atorvastatin
significantly reduced low density lipoprotein cholesterol levels, and was
associated with a 36% reduction in ischemic events and a significant delay in
time to first ischemic event.(47) Apheresis only partially controls raised low density lipoprotein cholesterol levels in patients with homozygous familial hypercholesterolemia, who usually respond poorly to lipid-lowering drugs. The efficacy of atorvastatin was investigated in seven homozygotes undergoing apheresis. One receptor-negative and six receptor-defective homozygotes undergoing plasma exchange or LDL apheresis every 2 weeks were studied during 2 months each on placebo and on atorvastatin 80 mg daily. All subjects had significant improvements on atorvastatin. Mean decreases in low density lipoprotein cholesterol were 31% greater both pre- and post-apheresis on atorvastatin compared with placebo. The mean production rates of low density lipoprotein cholesterol and apolipoprotein B were 21% and 25% lower, respectively, on atorvastatin than on placebo but changes in mean fractional clearance rates were not statistically significant. Atorvastatin enhances the efficacy of plasma exchange and low density lipoprotein apheresis in patients who lack low density lipoprotein receptors. This effect appears to be due to marked inhibition of cholesterol synthesis which results in a decreased rate of production of low density lipoprotein.(48) Atorvastatin
was the most effective statin tested in lowering cholesterol in low-density
lipoprotein (LDL), non--high-density lipoprotein (non-HDL) and remnant
lipoprotein (RLP) in the fasting and fed states, and getting patients with CHD
to established goals, with fluvastatin, pravastatin, lovastatin, and simvastatin
having about 33%, 50%, 60%, and 85% of the efficacy of atorvastatin,
respectively, at the same dose in the same patients.(49) Atorvastatin
20 or 40 mg/day for up to 1 year of treatment was significantly more effective
than simvastatin 20 or 40 mg/day in reducing LDL-C and TG levels and at
achieving recommended lipid targets in patient population with cardiovascular
disease and dyslipidemia. Compared with simvastatin, atorvastatin produced
significantly greater reductions in LDL-C (8 weeks: -46% vs -40%; 52 weeks: -49%
vs -44%) and in TG (8 weeks: -23% vs -14%; 52 weeks: -24% vs -16%). Compared
with simvastatin-treated patients, a significantly greater number of
atorvastatin-treated patients reached the LDL-C target after 8 weeks (45% vs
24%). Both statins were well tolerated.(50). Similar results
were obtained in people of Asian origin with primary hypercholesterolemia
in whom treatment with atorvastatin had lower LDL-C, VLDL-C, TG, and TC after 8
weeks and 16 weeks of treatment than those treated with simvastatin.(51)
Simvastatin 40 to 80 mg/day has been found to increase high-density lipoprotein
cholesterol (HDL-C) levels significantly more than atorvastatin at equipotent
doses (ie, 20-80 mg/d).(52) Atorvastatin (80 mg/day) was substantially more potent for LDL-C reduction after 12 months as compared to pravastatin (40 mg/day). In the atorvastatin group, LDL cholesterol was 76 ± 23 mg/dL after 12 months (-48.5%); LDL cholesterol was 110 ± 30 mg/dL in the pravastatin group (-27.2%). Atorvastatin induced progressive carotid intima-media thickness (CIMT) regression over 12 months whereas CIMT was stable in the pravastatin group.(53) In a study to
compare the efficacy and safety of atorvastatin and lovastatin, 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. 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%). 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).(54) To compare the effects of atorvastatin, gemfibrozil, and their combination on the components of diabetic dyslipidemia, 12 week treatments with atorvastatin (10-20 mg/d) and gemfibrozil (900-1200 mg/d) were given in random order in an open, cross-over study and then combined (10 mg atorvastatin and 900 mg gemfibrozil) for 12 additional week. Atorvastatin was more effective in lowering LDL-C, non-HDL-C and apoB and in achieving treatment goals, whereas gemfibrozil lowered triglyceride levels more effectively and increased LDL size. Combined treatment with both drugs reduced LDL-C, triglyceride, non-HDL-C and apoB by 26.5%, 24.1%, 30.4% and 21.8%, respectively; increased HDL-C by 4.8% and LDL size by 0.1 nm; and was the most effective treatment in reaching the therapeutic targets, especially in patients with triglyceride levels higher than 150 mg/dl. Thus, statins are first choice drugs in diabetic patients with low to moderate risk LDL-C, although their combination with fibrates might be the most appropriate treatment, especially when triglyceride levels are above the therapeutic goal.(55) This analysis
assessed the safety of atorvastatin in the 10- to 80-mg dose range using pooled
data from 44 completed trials comprising 16,495 dyslipidemic patients treated
with atorvastatin (n = 9,416), placebo (n = 1,789), and other statins (n =
5,290). A retrospective analysis was conducted and included treatment-associated
adverse events, serious adverse events, and musculoskeletal and hepatic adverse
events. Only 3% (n = 241) of atorvastatin-treated patients withdrew from studies
due to treatment-associated adverse events, compared with 1% of those (n = 16)
on placebo and 4% of those (n = 188) receiving other statins; the most
frequently reported treatment-associated adverse events were related to the
digestive system. Serious adverse events were rare and seldom led to withdrawal.
Persistent elevations in hepatic transaminases to >3 times the upper limit of
normal (ULN) were experienced by 0.5% (n = 47) of atorvastatin-treated patients.
A persistent elevation in creatine phosphokinase (CPK) (>10 x ULN) was
observed in only 1 atorvastatin-treated patient and was not associated with
myopathy. The incidence of treatment-associated myalgia was low in the
atorvastatin (1.9% [n = 181]), placebo (0.8% [n = 14]), and other statin (2.0%
[n = 105]) groups, and was not related to the atorvastatin dose. No cases of
rhabdomyolysis or myopathy were reported. Thus, the overall incidence of
treatment-associated adverse events observed with atorvastatin did not increase
in the 10- to 80-mg dose range, and was similar to that observed with placebo
and in patients treated with other statins. Specific analysis of musculoskeletal
and hepatic adverse events showed that these occurred infrequently and rarely
resulted in treatment discontinuation.(56) Statins effectively lower LDL-cholesterol and some members of this class have been shown to reduce the risk of major cardiovascular events and total mortality in patients with or at risk for coronary heart disease. Statins are in general well tolerated. Withdrawal rates related to adverse events are low (£ 3%). The most common adverse events are mild gastrointestinal symptoms. Elevated serum transaminase
levels occur infrequently (£
1.5%). These are generally asymptomatic, reversible and rarely require drug
withdrawal. Statins do not cause adverse endocrine effects, do not alter
glycemic control in diabetic patients, and do not increase cancer risk.
Dose-related myopathy and/or rhabdomyolysis also occurs very rarely, although
the risk is increased by concomitant administration of cyclosporine, niacin,
fibrates, or by CYP3A4 isoenzyme inhibitors (e.g. erythromycin, systemic azole
antifungal agents etc.) with statins metabolized by this isoenzyme. The
pharmacokinetics of the individual statin should be considered in patients
receiving polypharmacological treatments, to minimize the risk of unfavorable
drug interactions. Atorvastatin is well tolerated in long-term treatment of
dyslipidemia and is characterized by a safety profile similar to the other
available statins.(57)
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