CLINICAL PHARMACOLOGY
Mechanism Of Action
CADUET is a combination of two drugs, a dihydropyridine
calcium channel blocker (amlodipine) and an HMG-CoA reductase inhibitor
(atorvastatin). The amlodipine component of CADUET inhibits the transmembrane
influx of calcium ions into vascular smooth muscle and cardiac muscle. The
atorvastatin component of CADUET is a selective, competitive inhibitor of
HMG-CoA reductase, the rate-limiting enzyme that converts
3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols,
including cholesterol.
Amlodipine
Amlodipine binds to both dihydropyridine and
nondihydropyridine binding sites. The contractile processes of cardiac muscle
and vascular smooth muscle are dependent upon the movement of extracellular
calcium ions into these cells through specific ion channels. Amlodipine
inhibits calcium ion influx across cell membranes selectively, with a greater
effect on vascular smooth muscle cells than on cardiac muscle cells. Negative
inotropic effects can be detected in vitro but such effects have not been seen
in intact animals at therapeutic doses. Serum calcium concentration is not
affected by amlodipine.
Amlodipine is a peripheral arterial vasodilator that acts
directly on vascular smooth muscle to cause a reduction in peripheral vascular
resistance and reduction in blood pressure.
The precise mechanisms by which amlodipine relieves
angina have not been fully delineated, but are thought to include the following:
Exertional Angina
In patients with exertional angina, amlodipine reduces
the total peripheral resistance (afterload) against which the heart works and
reduces the rate pressure product, and thus myocardial oxygen demand, at any
given level of exercise.
Vasospastic Angina
Amlodipine has been demonstrated to block constriction
and restore blood flow in coronary arteries and arterioles in response to
calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in
experimental animal models and in human coronary vessels in vitro. This
inhibition of coronary spasm is responsible for the effectiveness of amlodipine
in vasospastic (Prinzmetal’s or variant) angina.
Atorvastatin
Cholesterol and triglycerides circulate in the
bloodstream as part of lipoprotein complexes. With ultracentrifugation, these
complexes separate into HDL (high-density lipoprotein), IDL
(intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL
(very-low-density lipoprotein) fractions. Triglycerides (TG) and cholesterol in
the liver are incorporated into VLDL and released into the plasma for delivery
to peripheral tissues. LDL is formed from VLDL and is catabolized primarily
through the high-affinity LDL receptor.
Clinical and pathologic studies show that elevated plasma
levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and
apolipoprotein B (apo B) promote human atherosclerosis and are risk factors for
developing cardiovascular disease, while increased levels of HDL-C are
associated with a decreased cardiovascular risk.
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.
In animal models, atorvastatin lowers plasma cholesterol
and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol
synthesis in the liver and by increasing the number of hepatic LDL receptors on
the cell surface to enhance uptake and catabolism of LDL; atorvastatin also
reduces LDL production and the number of LDL particles.
Atorvastatin reduces total-C, LDL-C, and apo B in
patients with homozygous and heterozygous familial hypercholesterolemia (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 hypertriglyceridemia.
Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in
patients with dysbetalipoproteinemia.
Like LDL, cholesterol-enriched triglyceride-rich
lipoproteins, including VLDL, (IDL), and remnants, can also promote atherosclerosis.
Elevated plasma triglycerides are frequently found in a triad with low HDL-C
levels and small LDL particles, as well as in association with non-lipid
metabolic risk factors for coronary heart disease. As such, total plasma TG has
not consistently been shown to be an independent risk factor for CHD.
Furthermore, the independent effect of raising HDL or lowering TG on the risk
of coronary and cardiovascular morbidity and mortality has not been determined.
Pharmacodynamics
Amlodipine
Following administration of therapeutic doses to patients
with hypertension, amlodipine produces vasodilation resulting in a reduction of
supine and standing blood pressures. These decreases in blood pressure are not
accompanied by a significant change in heart rate or plasma catecholamine
levels with chronic dosing. Although the acute intravenous administration of
amlodipine decreases arterial blood pressure and increases heart rate in
hemodynamic studies of patients with chronic stable angina, chronic oral
administration of amlodipine in clinical trials did not lead to clinically
significant changes in heart rate or blood pressures in normotensive patients
with angina.
With chronic once daily oral administration,
antihypertensive effectiveness is maintained for at least 24 hours. Plasma
concentrations correlate with effect in both young and elderly patients. The
magnitude of reduction in blood pressure with amlodipine is also correlated
with the height of pretreatment elevation; thus, individuals with moderate
hypertension (diastolic pressure 105–114 mmHg) had about a 50% greater response
than patients with mild hypertension (diastolic pressure 90– 104 mmHg).
Normotensive subjects experienced no clinically significant change in blood
pressures (+1/–2 mmHg).
In hypertensive patients with normal renal function,
therapeutic doses of amlodipine resulted in a decrease in renal vascular
resistance and an increase in glomerular filtration rate and effective renal
plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic
measurements of cardiac function at rest and during exercise (or pacing) in
patients with normal ventricular function treated with amlodipine have
generally demonstrated a small increase in cardiac index without significant
influence on dP/dt or on left ventricular end diastolic pressure or volume. In
hemodynamic studies, amlodipine has not been associated with a negative
inotropic effect when administered in the therapeutic dose range to intact
animals and man, even when co-administered with beta-blockers to man. Similar
findings, however, have been observed in normal or well-compensated patients
with heart failure with agents possessing significant negative inotropic
effects.
Amlodipine does not change sinoatrial nodal function or
atrioventricular conduction in intact animals or man. In patients with chronic
stable angina, intravenous administration of 10 mg did not significantly alter
A-H and H-V conduction and sinus node recovery time after pacing. Similar
results were obtained in patients receiving amlodipine and concomitant
beta-blockers. In clinical studies in which amlodipine was administered in
combination with beta-blockers to patients with either hypertension or angina,
no adverse effects on electrocardiographic parameters were observed. In
clinical trials with angina patients alone, amlodipine therapy did not alter
electrocardiographic intervals or produce higher degrees of AV blocks.
Atorvastatin
Atorvastatin, as well as some of its metabolites, are
pharmacologically active in humans. The liver is the primary site of action and
the principal site of cholesterol synthesis and LDL clearance. Drug dosage,
rather than systemic drug concentration, correlates better with LDL-C
reduction. Individualization of drug dosage should be based on therapeutic
response [see DOSAGE AND ADMINISTRATION].
Drug Interactions
Sildenafil
When amlodipine and sildenafil were used in combination,
each agent independently exerted its own blood pressure lowering effect [see DRUG
INTERACTIONS].
Pharmacokinetics
Absorption
Amlodipine
After oral administration of therapeutic doses of
amlodipine alone, absorption produces peak plasma concentrations between 6 and
12 hours. Absolute bioavailability has been estimated to be between 64% and
90%.
Atorvastatin
After oral administration alone, atorvastatin is rapidly
absorbed; maximum plasma concentrations occur within 1 to 2 hours. Extent of
absorption increases in proportion to atorvastatin dose. The absolute
bioavailability of atorvastatin (parent drug) is approximately 14% and the
systemic availability of HMG-CoA reductase inhibitory activity is approximately
30%. The low systemic availability is attributed to presystemic clearance in
gastrointestinal mucosa and/or hepatic first-pass metabolism. Plasma
atorvastatin concentrations are lower (approximately 30% for Cmax and AUC)
following evening drug administration compared with morning. However, LDL-C
reduction is the same regardless of the time of day of drug administration [see
DOSAGE AND ADMINISTRATION].
CADUET
Following oral administration of CADUET, peak plasma
concentrations of amlodipine and atorvastatin are seen at 6 to 12 hours and 1
to 2 hours post dosing, respectively. The rate and extent of absorption
(bioavailability) of amlodipine and atorvastatin from CADUET are not
significantly different from the bioavailability of amlodipine and atorvastatin
administered separately (see above).
The bioavailability of amlodipine from CADUET was not
affected by food. Food decreases the rate and extent of absorption of
atorvastatin from CADUET by approximately 32% and 11%, respectively, as it does
with atorvastatin when given alone. LDL-C reduction is similar whether
atorvastatin is given with or without food.
Distribution
Amlodipine
Ex vivo studies have shown that approximately 93% of the
circulating amlodipine drug is bound to plasma proteins in hypertensive
patients. Steady-state plasma levels of amlodipine are reached after 7 to 8
days of consecutive daily dosing.
Atorvastatin
Mean volume of distribution of atorvastatin is
approximately 381 liters. Atorvastatin is ≥98% bound to plasma proteins.
A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into
red blood cells. Based on observations in rats, atorvastatin calcium is likely
to be secreted in human milk [see CONTRAINDICATIONS and Use In Specific
Populations].
Metabolism
Amlodipine
Amlodipine is extensively (about 90%) converted to
inactive metabolites via hepatic metabolism.
Atorvastatin
Atorvastatin is extensively metabolized to ortho-and
parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition
of HMG-CoA reductase by ortho-and parahydroxylated metabolites is equivalent to
that of atorvastatin. Approximately 70% of circulating inhibitory activity for
HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest
the importance of atorvastatin metabolism by cytochrome P4503A4, consistent
with increased plasma concentrations of atorvastatin in humans following
co-administration with erythromycin, a known inhibitor of this isozyme [see DRUG
INTERACTIONS]. In animals, the ortho-hydroxy metabolite undergoes further
glucuronidation.
Excretion
Amlodipine
Elimination from the plasma is biphasic with a terminal
elimination half-life of about 30-50 hours. Ten percent of the parent
amlodipine compound and 60% of the metabolites of amlodipine are excreted in
the urine.
Atorvastatin
Atorvastatin and its metabolites are eliminated primarily
in bile following hepatic and/or extra-hepatic metabolism; however, the drug
does not appear to undergo enterohepatic recirculation. Mean plasma elimination
half-life of atorvastatin in humans is approximately 14 hours, but the
half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours
because of the contribution of active metabolites. Less than 2% of a dose of
atorvastatin is recovered in urine following oral administration.
Specific Populations
Geriatric
Amlodipine
Elderly patients have decreased clearance of amlodipine
with a resulting increase in AUC of approximately 40-60%, and a lower initial
dose of amlodipine may be required.
Atorvastatin
Plasma concentrations of atorvastatin are higher
(approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age
≥65 years) than in young adults. Clinical data suggest a greater degree
of LDL-lowering at any dose of atorvastatin in the elderly population compared
to younger adults [see Use In Specific Populations].
Pediatric
Amlodipine
Sixty-two hypertensive patients aged 6 to 17 years
received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted
clearance and volume of distribution were similar to values in adults.
Atorvastatin
Pharmacokinetic data in the pediatric population are not
available.
Gender
Atorvastatin
Plasma concentrations of atorvastatin in women differ
from those in men (approximately 20% higher for Cmax and 10% lower for AUC);
however, there is no clinically significant difference in LDL-C reduction with
atorvastatin between men and women.
Renal Impairment
Amlodipine
The pharmacokinetics of amlodipine are not significantly
influenced by renal impairment. Patients with renal failure may therefore
receive the usual initial amlodipine dose.
Atorvastatin
Renal disease has no influence on the plasma
concentrations or LDL-C reduction of atorvastatin; thus, dose adjustment of
atorvastatin in patients with renal dysfunction is not necessary [see DOSAGE
AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].
Hemodialysis
While studies have not been conducted in patients with
end-stage renal disease, hemodialysis is not expected to clear atorvastatin or
amlodipine since both drugs are extensively bound to plasma proteins.
Hepatic Impairment
Amlodipine
Elderly patients and patients with hepatic insufficiency
have decreased clearance of amlodipine with a resulting increase in AUC of
approximately 40-60%.
Atorvastatin
In patients with chronic alcoholic liver disease, plasma
concentrations of atorvastatin are markedly increased. Cmax and AUC are each
4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC of
atorvastatin are approximately 16-fold and 11-fold increased, respectively, in
patients with Childs-Pugh B disease [see CONTRAINDICATIONS].
Atorvastatin is contraindicated in patients with active
liver disease.
Heart Failure
Amlodipine
In patients with moderate to severe heart failure, the
increase in AUC for amlodipine was similar to that seen in the elderly and in
patients with hepatic insufficiency.
Effects Of Other Drugs On CADUET
Amlodipine
Co-administered cimetidine, magnesium-and aluminum
hydroxide antacids, sildenafil, and grapefruit juice have no impact on the
exposure to amlodipine.
CYP3A Inhibitors
Co-administration of a 180 mg daily dose of diltiazem
with 5 mg amlodipine in elderly hypertensive patients resulted in a 60%
increase in amlodipine systemic exposure. Erythromycin co-administration in
healthy volunteers did not significantly change amlodipine systemic exposure.
However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may
increase the plasma concentrations of amlodipine to a greater extent [see DRUG
INTERACTIONS].
Atorvastatin
Table 4 shows effects of other drugs on the
pharmacokinetics of atorvastatin.
Table 4: Effect of Co-administered Drugs on the
Pharmacokinetics of Atorvastatin
Co-administered drug and dosing regimen |
Atorvastatin |
Dose (mg) |
Change in AUC |
Change in Cmax |
#Cyclosporine 5.2 mg/kg/day, stable dose |
10 mg QD for 28 days |
↑ 870% |
↑1070% |
#Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days |
10 mg, SD |
↑ 940% |
↑ 860% |
#Telaprevir 750 mg q8h, 10 days |
20 mg, SD |
↑ 790% |
↑ 1060% |
#, ‡Saquinavir 400 mg BID/ritonavir 400mg BID, 15 days |
40 mg QD for 4 days |
↑ 390% |
↑430% |
#Clarithromycin 500 mg BID, 9 days |
80 mg QD for 8 days |
↑440% |
↑540% |
#Darunavir 300 mg BID/ritonavir 100 mg BID, 9 days |
10 mg QD for 4 days |
↑ 340% |
↑230% |
#Itraconazole 200 mg QD, 4 days |
40 mg SD |
↑ 330% |
↑20% |
#Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days |
10 mg QD for 4 days |
↑ 250% |
↑280% |
#Fosamprenavir 1400 mg BID, 14 days |
10 mg QD for 4 days |
↑230% |
↑400% |
#Nelfinavir 1250 mg BID, 14 days |
10 mg QD for 28 days |
↑74% |
↑220% |
#Grapefruit Juice, 240 mL QD* |
40 mg, SD |
↑37% |
↑16% |
Diltiazem 240 mg QD, 28 days |
40 mg, SD |
↑ 51% |
No change |
Erythromycin 500 mg QID, 7 days |
10 mg, SD |
↑ 33% |
↑38% |
Amlodipine 10 mg, single dose |
80 mg, SD |
↑ 15% |
↓12 % |
Cimetidine 300 mg QID, 2 weeks |
10 mg QD for 2 weeks |
↓ Less than 1% |
↓11% |
Colestipol 10 mg BID, 28 weeks |
40 mg QD for 28 weeks |
Not determined |
↓26%** |
Maalox TC® 30 mL QD, 17 days |
10 mg QD for 15 days |
↓33% |
↓34% |
Efavirenz 600 mg QD, 14 days |
10 mg for 3 days |
↓ 41% |
↓1% |
#Rifampin 600 mg QD, 7 days (coadministered) † |
40 mg SD |
↑30% |
↑ 2.7-fold |
#Rifampin 600 mg QD, 5 days (doses separated) † |
40 mg SD |
↓ 80% |
↓40% |
#Gemfbrozil 600 mg BID, 7 days |
40mg SD |
↑ 35% |
↓ Less than 1% |
#Fenofibrate 160 mg QD, 7 days |
40mg SD |
↑ 3% |
↑2% |
Boceprevir 800 mg TID, 7 days |
40 mg SD |
↑2.30 fold |
↑2.66 fold |
# See WARNINGS AND PRECAUTIONS and DRUG
INTERACTIONS for clinical significance.
* Greater increases in AUC (up to 2.5-fold) and/or Cmax (up to 71%) have been
reported with excessive grapefruit consumption (≥ 750 mL – 1.2 liters per
day).
** Single sample taken 8-16 h post dose.
† Because of the dual interaction mechanism of rifampin, simultaneous
co-administration of atorvastatin with rifampin is recommended, as delayed
administration of atorvastatin after administration of rifampin has been
associated with a significant reduction in atorvastatin plasma concentrations.
‡ The dose of saquinavir plus ritonavir in this study is not the clinically
used dose. The increase in atorvastatin exposure when used clinically is likely
to be higher than what was observed in this study. Therefore, use the lowest
dose necessary. |
Effects Of CADUET On Other Drugs
Amlodipine
Amlodipine is a weak inhibitor of CYP3A and may increase
exposure to CYP3A substrates.
In vitro data indicate that amlodipine has no effect on
the human plasma protein binding of digoxin, phenytoin, warfarin, and
indomethacin.
Co-administered amlodipine does not affect the exposure
to atorvastatin, digoxin, ethanol and the warfarin prothrombin response time.
Cyclosporine
A prospective study in renal transplant patients (N=11)
showed on an average of 40% increase in trough cyclosporine levels when
concomitantly treated with amlodipine [see DRUG INTERACTIONS].
Tacrolimus
A prospective study in healthy Chinese volunteers (N=9)
with CYP3A5 expressers showed a 2.5-to 4-fold increase in tacrolimus exposure
when concomitantly administered with amlodipine compared to tacrolimus alone.
This finding was not observed in CYP3A5 non-expressers (N= 6). However, a
3-fold increase in plasma exposure to tacrolimus in a renal transplant patient
(CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of
post-transplant hypertension resulting in reduction of tacrolimus dose has been
reported. Irrespective of the CYP3A5 genotype status, the possibility of an
interaction cannot be excluded with these drugs [see DRUG INTERACTIONS].
Atorvastatin
Table 5 shows the effects of atorvastatin on the
pharmacokinetics of other drugs.
Table 5: Effect of Atorvastatin on the
Pharmacokinetics of Co-administered Drugs
Atorvastatin |
Co-administered drug and dosing regimen |
Drug/Dose (mg) |
Change in AUC |
Change in Cmax |
80 mg QD for 15 days |
Antipyrine, 600 mg SD |
↑3% |
↓ 11% |
80 mg QD for 14 days |
Digoxin 0.25 mg QD, 20 days |
↑ 15% |
↑20 % |
40 mg QD for 22 days |
Oral contraceptive QD, 2 months |
- norethindrone 1mg |
↑28% |
↑ 23% |
- ethinyl estradiol 35 μg |
↑ 19% |
↑30% |
10 mg, SD |
Tipranavir 500 mg BID/ritonavir 200 mg BID, 7 days |
No change |
No change |
10 mg QD for 4 days |
Fosamprenavir 1400 mg BID, 14 days |
↓ 27% |
↓18% |
10 mg QD for 4 days |
Fosamprenavir 700 mg BID/ritonavir 100 mg BID, 14 days |
No change |
No change |
Clinical Studies
Amlodipine For Hypertension
Adult Patients
The antihypertensive efficacy of amlodipine has been
demonstrated in a total of 15 double-blind, placebo-controlled, randomized
studies involving 800 patients on amlodipine and 538 on placebo. Once daily
administration produced statistically significant placebo-corrected reductions
in supine and standing blood pressures at 24 hours postdose, averaging about
12/6 mmHg in the standing position and 13/7 mmHg in the supine position in
patients with mild to moderate hypertension. Maintenance of the blood pressure
effect over the 24-hour dosing interval was observed, with little difference in
peak and trough effect. Tolerance was not demonstrated in patients studied for
up to 1 year. The 3 parallel, fixed dose, dose response studies showed that the
reduction in supine and standing blood pressures was dose related within the
recommended dosing range. Effects on diastolic pressure were similar in young
and older patients. The effect on systolic pressure was greater in older
patients, perhaps because of greater baseline systolic pressure. Effects were
similar in black patients and in white patients.
Pediatric Patients
Two hundred sixty-eight hypertensive patients aged 6 to
17 years were randomized first to amlodipine 2.5 or 5 mg once daily for 4 weeks
and then randomized again to the same dose or to placebo for another 4 weeks.
Patients receiving 2.5 mg or 5 mg at the end of 8 weeks had significantly lower
systolic blood pressure than those secondarily randomized to placebo. The
magnitude of the treatment effect is difficult to interpret, but it is probably
less than 5 mmHg systolic on the 5 mg dose and 3.3 mmHg systolic on the 2.5 mg
dose. Adverse events were similar to those seen in adults.
Amlodipine For Chronic Stable Angina
The effectiveness of 5–10 mg/day of amlodipine in
exercise-induced angina has been evaluated in 8 placebo-controlled,
double-blind clinical trials of up to 6 weeks duration involving 1038 patients
(684 amlodipine, 354 placebo) with chronic stable angina. In 5 of the 8
studies, significant increases in exercise time (bicycle or treadmill) were
seen with the 10 mg dose. Increases in symptom-limited exercise time averaged
12.8% (63 sec) for amlodipine 10 mg, and averaged 7.9% (38 sec) for amlodipine
5 mg. Amlodipine 10 mg also increased time to 1 mm ST segment deviation in
several studies and decreased angina attack rate. The sustained efficacy of
amlodipine in angina patients has been demonstrated over long-term dosing. In
patients with angina, there were no clinically significant reductions in blood
pressures (4/1 mmHg) or changes in heart rate (+0.3 bpm).
Amlodipine For Vasospastic Angina
In a double-blind, placebo-controlled clinical trial of 4
weeks duration in 50 patients, amlodipine therapy decreased attacks by
approximately 4/week compared with a placebo decrease of approximately 1/week
(p<0.01). Two of 23 amlodipine and 7 of 27 placebo patients discontinued
from the study for lack of clinical improvement.
Amlodipine For Coronary Artery Disease
In PREVENT, 825 patients with angiographically documented
CAD were randomized to amlodipine (5–10 mg once daily) or placebo and followed
for 3 years. Although the study did not show significance on the primary
objective of change in coronary luminal diameter as assessed by quantitative
coronary angiography, the data suggested a favorable outcome with respect to
fewer hospitalizations for angina and revascularization procedures in patients
with CAD.
CAMELOT enrolled 1318 patients with CAD recently
documented by angiography, without left main coronary disease and without heart
failure or an ejection fraction <40%. Patients (76% males, 89% Caucasian,
93% enrolled at U.S. sites, 89% with a history of angina, 52% without PCI, 4%
with PCI and no stent, and 44% with a stent) were randomized to double-blind
treatment with either amlodipine (5–10 mg once daily) or placebo in addition to
standard care that included aspirin (89%), statins (83%), beta-blockers (74%),
nitroglycerin (50%), anticoagulants (40%), and diuretics (32%), but excluded
other calcium channel blockers. The mean duration of follow-up was 19 months.
The primary endpoint was the time to first occurrence of one of the following
events: hospitalization for angina pectoris, coronary revascularization,
myocardial infarction, cardiovascular death, resuscitated cardiac arrest,
hospitalization for heart failure, stroke/TIA, or peripheral vascular disease.
A total of 110 (16.6%) and 151 (23.1%) first events occurred in the amlodipine
and placebo groups, respectively, for a hazard ratio of 0.691 (95% CI:
0.540–0.884, p = 0.003). The primary endpoint is summarized in Figure 1 below.
The outcome of this study was largely derived from the prevention of
hospitalizations for angina and the prevention of revascularization procedures
(see Table 6). Effects in various subgroups are shown in Figure 2.
In an angiographic substudy (n=274) conducted within
CAMELOT, there was no significant difference between amlodipine and placebo on
the change of atheroma volume in the coronary artery as assessed by
intravascular ultrasound.
Figure 1: Kaplan-Meier Analysis of Composite Clinical
Outcomes for Amlodipine versus Placebo
Figure 2: Effects on Primary Endpoint of Amlodipine
versus Placebo across Sub-Groups
Table 6 below summarizes the significant composite
endpoint and clinical outcomes from the composites of the primary endpoint. The
other components of the primary endpoint including cardiovascular death,
resuscitated cardiac arrest, myocardial infarction, hospitalization for heart
failure, stroke/TIA, or peripheral vascular disease did not demonstrate a
significant difference between amlodipine and placebo.
Table 6: Incidence of Significant Clinical Outcomes
for CAMELOT
Clinical Outcomes N (%) |
Amlodipine
(N=663) |
Placebo
(N=655) |
Risk Reduction (p-value) |
Composite CV Endpoint |
110 (16.6) |
151 (23.1) |
31% (0.003) |
Hospitalization for Angina* |
51 (7.7) |
84 (12.8) |
42% (0.002) |
Coronary Revascularization* |
78 (11.8) |
103 (15.7) |
27% (0.033) |
* Total patients with these events. |
Amlodipine For Heart Failure
Amlodipine has been compared to placebo in four 8–12 week
studies of patients with NYHA Class II/III heart failure, involving a total of
697 patients. In these studies, there was no evidence of worsened heart failure
based on measures of exercise tolerance, NYHA classification, symptoms, or left
ventricular ejection fraction. In a long-term (follow-up at least 6 months,
mean 13.8 months) placebo-controlled mortality/morbidity study of amlodipine
5–10 mg in 1153 patients with NYHA Classes III (n=931) or IV (n=222) heart
failure on stable doses of diuretics, digoxin, and ACE inhibitors, amlodipine
had no effect on the primary endpoint of the study which was the combined
endpoint of all-cause mortality and cardiac morbidity (as defined by
life-threatening arrhythmia, acute myocardial infarction, or hospitalization
for worsened heart failure), or on NYHA classification, or symptoms of heart
failure. Total combined all-cause mortality and cardiac morbidity events were
222/571 (39%) for patients on amlodipine and 246/583 (42%) for patients on placebo;
the cardiac morbid events represented about 25% of the endpoints in the study.
Another study (PRAISE-2) randomized patients with NYHA
Class III (80%) or IV (20%) heart failure without clinical symptoms or
objective evidence of underlying ischemic disease, on stable doses of ACE
inhibitors (99%), digitalis (99%), and diuretics (99%), to placebo (n=827) or
amlodipine (n=827) and followed them for a mean of 33 months. There was no
statistically significant difference between amlodipine and placebo in the
primary endpoint of all-cause mortality (95% confidence limits from 8%
reduction to 29% increase on amlodipine). With amlodipine there were more
reports of pulmonary edema.
Atorvastatin For Prevention Of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT),
the effect of atorvastatin on fatal and non-fatal coronary heart disease was
assessed in 10,305 hypertensive patients 40–80 years of age (mean of 63 years),
without a previous myocardial infarction and with TC levels ≤ 251 mg/dL
(6.5 mmol/L). Additionally, all patients had at least 3 of the following
cardiovascular risk factors: male gender (81.1%), age > 55 years (84.5%),
smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative
(26%), TC:HDL > 6 (14.3%), peripheral vascular disease (5.1%), left
ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific
ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind,
placebo-controlled study, patients were treated with anti-hypertensive therapy
(Goal BP < 140/90 mmHg for non-diabetic patients; < 130/80 mm Hg for
diabetic patients) and allocated to either atorvastatin 10 mg daily (n=5168) or
placebo (n=5137), using a covariate adaptive method that took into account the
distribution of nine baseline characteristics of patients already enrolled and
minimized the imbalance of those characteristics across the groups. Patients
were followed for a median duration of 3.3 years.
The effect of 10 mg/day of atorvastatin on lipid levels
was similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of coronary
events [either fatal coronary heart disease (46 events in the placebo group vs.
40 events in the atorvastatin group) or non-fatal MI (108 events in the placebo
group vs. 60 events in the atorvastatin group)] with a relative risk reduction
of 36% [(based on incidences of 1.9% for atorvastatin vs. 3.0% for placebo),
p=0.0005 (see Figure 3)]. The risk reduction was consistent regardless of age,
smoking status, obesity, or presence of renal dysfunction. The effect of
atorvastatin was seen regardless of baseline LDL levels. Because of the small
number of events, results for women were inconclusive.
Figure 3: Effect of Atorvastatin 10 mg/day on
Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart
Disease Death (in ASCOT-LLA)
Atorvastatin also significantly decreased the relative
risk for revascularization procedures by 42%. Although the reduction of fatal
and non-fatal strokes did not reach a pre-defined significance level (p=0.01),
a favorable trend was observed with a 26% relative risk reduction (incidences
of 1.7% for atorvastatin and 2.3% for placebo). There was no significant
difference between the treatment groups for death from cardiovascular causes
(p=0.51) or noncardiovascular causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS),
the effect of atorvastatin on cardiovascular disease endpoints was assessed in
2838 subjects (94% white, 68% male), ages 40–75 with type 2 diabetes based on
WHO criteria, without prior history of cardiovascular disease, and with LDL
≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects
had 1 or more of the following risk factors: current smoking (23%),
hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria
(3%). No subjects on hemodialysis were enrolled in the study. In this
multicenter, placebo-controlled, double-blind clinical trial, subjects were
randomly allocated to either atorvastatin 10 mg daily (1,429) or placebo
(1,411) in a 1:1 ratio and were followed for a median duration of 3.9 years.
The primary endpoint was the occurrence of any of the major cardiovascular
events: myocardial infarction, acute CHD death, unstable angina, coronary
revascularization, or stroke. The primary analysis was the time to first
occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62
years; mean HbA1c 7.7%; median LDL-C 120 mg/dL; median TC 207 mg/dL; median TG
151 mg/dL; median HDL-C 52 mg/dL.
The effect of atorvastatin 10 mg/day on lipid levels was
similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of major
cardiovascular events (primary endpoint events) (83 events in the atorvastatin
group vs. 127 events in the placebo group) with a relative risk reduction of
37%, HR 0.63, 95% CI (0.48, 0.83) (p=0.001) (see Figure 4). An effect of
atorvastatin was seen regardless of age, sex, or baseline lipid levels.
Atorvastatin significantly reduced the risk of stroke by
48% (21 events in the atorvastatin group vs. 39 events in the placebo group),
HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of MI by 42% (38
events in the atorvastatin group vs. 64 events in the placebo group), HR 0.58,
95.1% CI (0.39, 0.86) (p=0.007). There was no significant difference between
the treatment groups for angina, revascularization procedures, and acute CHD
death.
There were 61 deaths in the atorvastatin group vs. 82
deaths in the placebo group (HR 0.73, p=0.059).
Figure 4: Effect of Atorvastatin 10 mg/day on Time to
Occurrence of Major Cardiovascular Events (myocardial infarction, acute CHD
death, unstable angina, coronary revascularization, or stroke) in CARDS
 |
In the Treating to New Targets Study (TNT), the effect of
atorvastatin 80 mg/day vs. atorvastatin 10 mg/day on the reduction in
cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38%
≥ 65 years) with clinically evident coronary heart disease who had
achieved a target LDL-C level < 130 mg/dL after completing an 8-week,
open-label, run-in period with atorvastatin 10 mg/day. Subjects were randomly
assigned to either 10 mg/day or 80 mg/day of atorvastatin and followed for a
median duration of 4.9 years. The primary endpoint was the time to first
occurrence of any of the following major cardiovascular events (MCVE): death
from CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and
fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL
cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during
treatment with 80 mg of atorvastatin and 99, 177, 152, 129, and 48 mg/dL during
treatment with 10 mg of atorvastatin.
Treatment with atorvastatin 80 mg/day significantly
reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in
the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI
(0.69, 0.89), p=0.0002 (see Figure 5 and Table 7). The overall risk reduction
was consistent regardless of age (< 65, ≥ 65) or gender.
Figure 5: Effect of Atorvastatin 80 mg/day vs. 10
mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
Table 7: Overview of Efficacy Results in TNT
Endpoint |
Atorvastatin 10 mg
(N=5006) |
Atorvastatin 80 mg
(N=4995) |
HRa (95% CI) |
PRIMARY ENDPOINT |
n(%) |
n(%) |
|
First major cardiovascular endpoint |
548 (10.9) |
434 (8.7) |
0.78 (0.69, 0.89) |
Components of the Primary Endpoint |
CHD death |
127 (2.5) |
101 (2.0) |
0.80 (0.61, 1.03) |
Non-fatal, non-procedure related MI |
308 6.2) |
243 (4.9) |
0.78 (0.66, 0.93) |
Resuscitated cardiac arrest |
26 (0.5) |
25 (0.5) |
0.96 (0.56, 1.67) |
Stroke (fatal and non-fatal) |
155 (3.1) |
117 (2.3) |
0.75 (0.59, 0.96) |
SECONDARY ENDPOINTS* |
First CHF with hospitalization |
164 (3.3) |
122 (2.4) |
0.74 (0.59, 0.94) |
First PVD endpoint |
282 (5.6) |
275 (5.5) |
0.97 (0.83, 1.15) |
First CABG or other coronary revascularization procedureb |
904 (18.1) |
667 (13.4) |
0.72 (0.65, 0.80) |
First documented angina endpointb |
615 (12.3) |
545 (10.9) |
0.88 (0.79, 0.99) |
All-cause mortality |
282 (5.6) |
284 (5.7) |
1.01 (0.85, 1.19) |
Components of All-Cause Mortality |
Cardiovascular death |
155 (3.1) |
126 (2.5) |
0.81 (0.64, 1.03) |
Noncardiovascular death |
127 (2.5) |
158 (3.2) |
1.25 (0.99, 1.57) |
Cancer death |
75 (1.5) |
85 (1.7) |
1.13 (0.83, 1.55) |
Other non-CV death |
43 (0.9) |
58 (1.2) |
1.35 (0.91, 2.00) |
Suicide, homicide, and other traumatic non-CV death |
9 (0.2) |
15 (0.3) |
1.67 (0.73, 3.82) |
mg: atorvastatin 10 mg
b Component of other secondary endpoints
* Secondary endpoints not included in primary endpoint HR=hazard ratio;
CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction;
CHF=congestive heart failure; CV=cardiovascular; PVD=peripheral vascular
disease; CABG=coronary artery bypass graft Confidence intervals for the
Secondary Endpoints were not adjusted for multiple comparisons. |
Of the events that comprised the primary efficacy
endpoint, treatment with atorvastatin 80 mg/day significantly reduced the rate
of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not
CHD death or resuscitated cardiac arrest (Table 7). Of the predefined secondary
endpoints, treatment with atorvastatin 80 mg/day significantly reduced the rate
of coronary revascularization, angina, and hospitalization for heart failure,
but not peripheral vascular disease. The reduction in the rate of CHF with
hospitalization was only observed in the 8% of patients with a prior history of
CHF.
There was no significant difference between the treatment
groups for all-cause mortality (Table 7). The proportions of subjects who
experienced cardiovascular death, including the components of CHD death and
fatal stroke, were numerically smaller in the atorvastatin 80 mg group than in
the atorvastatin 10 mg treatment group. The proportions of subjects who
experienced noncardiovascular death were numerically larger in the atorvastatin
80 mg group than in the atorvastatin 10 mg treatment group.
In the Incremental Decrease in Endpoints Through
Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin 80 mg/day
was compared to treatment with simvastatin 20–40 mg/day in 8,888 subjects up to
80 years of age with a history of CHD to assess whether reduction in CV risk
could be achieved. Patients were mainly male (81%), white (99%) with an average
age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76%
were on statin therapy. In this prospective, randomized, open-label, blinded
endpoint (PROBE) trial with no run-in period, subjects were followed for a
median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL
cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during
treatment with 80 mg of atorvastatin and 105, 179, 142, 47, and 132 mg/dL
during treatment with 20–40 mg of simvastatin.
There was no significant difference between the treatment
groups for the primary endpoint, the rate of first major coronary event (fatal
CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the
atorvastatin 80 mg/day group vs. 463 (10.4%) in the simvastatin 20–40 mg/day
group, HR 0.89, 95% CI ( 0.78, 1.01), p=0.07.
There were no significant differences between the
treatment groups for all-cause mortality: 366 (8.2%) in the atorvastatin 80
mg/day group vs. 374 (8.4%) in the simvastatin 20–40 mg/day group. The
proportions of subjects who experienced CV or non-CV death were similar for the
atorvastatin 80 mg group and the simvastatin 20–40 mg group.
Atorvastatin For Hyperlipidemia (Heterozygous Familial And
Nonfamilial) And Mixed Dyslipidemia (Fredrickson Types IIa And IIb)
Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, and
TG, and increases HDL-C in patients with hyperlipidemia and mixed dyslipidemia.
Therapeutic response is seen within 2 weeks, and maximum response is usually
achieved within 4 weeks and maintained during chronic therapy.
Atorvastatin is effective in a wide variety of patient
populations with hyperlipidemia, with and without hypertriglyceridemia, in men
and women, and in the elderly.
In two multicenter, placebo-controlled, dose-response
studies in patients with hyperlipidemia, atorvastatin given as a single dose
over 6 weeks significantly reduced total-C, LDL-C, apo B, and TG. (Pooled
results are provided in Table 8.)
Table 8: Dose Response in Patients with Primary
Hyperlipidemia (Adjusted Mean % Change From Baseline)a
Dose |
N |
TC |
LDL- C |
Apo B |
TG |
HDL- C |
Non-HDL- C/HDL-C |
Placebo |
21 |
4 |
4 |
3 |
10 |
-3 |
7 |
10 |
22 |
-29 |
-39 |
-32 |
-19 |
6 |
-34 |
20 |
20 |
-33 |
-43 |
-35 |
-26 |
9 |
-41 |
40 |
21 |
-37 |
-50 |
-42 |
-29 |
6 |
-45 |
80 |
23 |
-45 |
-60 |
-50 |
-37 |
5 |
-53 |
a Results are pooled from 2 dose-response
studies. |
In patients with Fredrickson Types IIa and IIb
hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and
75th percentile) percent changes from baseline in HDL-C for
atorvastatin 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0,
16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled
data demonstrated consistent and significant decreases in total-C, LDL-C, TG,
total-C/HDL-C, and LDL-C/HDL-C.
In three multicenter, double-blind studies in patients
with hyperlipidemia, atorvastatin was compared to other statins. After
randomization, patients were treated for 16 weeks with either atorvastatin 10
mg per day or a fixed dose of the comparative agent (Table 9).
Table 9: Mean Percentage Change from Baseline at
Endpoint (Double-Blind, Randomized, Active-Controlled Trials)
Treatment (Daily Dose) |
N |
Total-C |
LDL-C |
Apo B |
TG |
HDL-C |
Non-HDL-C/ HDL-C |
Study 1 |
Atorvastatin 10 mg |
707 |
-27a |
-36a |
-28a |
-17a |
+7 |
-37a |
Lovastatin 20 mg |
191 |
-19 |
-27 |
-20 |
-6 |
+7 |
-28 |
95% CI for Diff1 |
|
.5 6. - 9. - |
-10.7, -7.1 |
-10.0, -6.5 |
-15.2, -7.1 |
-1.7, 2.0 |
-11.1, -7.1 |
Study 2 |
Atorvastatin 10 mg |
222 |
-25b |
-35b |
-27b |
-17b |
+6 |
-36b |
Pravastatin 20 mg |
77 |
-17 |
-23 |
-17 |
-9 |
+8 |
-28 |
95% CI for Diff1 |
|
-10.8, -6.1 |
-14.5, -8.2 |
-13.4, -7.4 |
-14.1, -0.7 |
-4.9, 1.6 |
-11.5, -4.1 |
Study 3 |
Atorvastatin 10 mg |
132 |
-29c |
-37c |
-34c |
-23c |
+7 |
-39c |
Simvastatin 10 mg |
45 |
-24 |
-30 |
-30 |
-15 |
+7 |
-33 |
95% CI for Diff1 |
|
-8.7, -2.7 |
-10.1, -2.6 |
-8.0, -1.1 |
-15.1, -0.7 |
-4.3, 3.9 |
-9.6, -1.9 |
1 A negative value for the 95% CI for the
difference between treatments favors atorvastatin for all except HDL-C, for
which a positive value favors atorvastatin. If the range does not include 0,
this indicates a statistically significant difference.
a Significantly different from lovastatin, ANCOVA, p ≤ 0.05
b Significantly different from pravastatin, ANCOVA, p ≤ 0.05
c Significantly different from simvastatin, ANCOVA, p ≤ 0.05 |
The impact on clinical outcomes of the differences in
lipid-altering effects between treatments shown in Table 9 is not known. Table
9 does not contain data comparing the effects of atorvastatin 10 mg and higher
doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the
studies summarized in the table are not necessarily interchangeable.
Atorvastatin For Hypertriglyceridemia (Fredrickson Type
IV)
The response to atorvastatin in 64 patients with isolated
hypertriglyceridemia treated across several clinical trials is shown in the
table below (Table 10). For the atorvastatin-treated patients, median (min,
max) baseline TG level was 565 (267–1502).
Table 10: Combined Patients with Isolated Elevated TG:
Median (min, max) Percentage Change From Baseline
|
Placebo
(N=12) |
Atorvastatin 10 mg
(N=37) |
Atorvastatin 20 mg
(N=13) |
Atorvastatin 80 mg
(N=14) |
Triglycerides |
-12.4 (-36.6, 82.7) |
-41.0 (-76.2, 49.4) |
-38.7 (-62.7, 29.5) |
-51.8 (-82.8, 41.3) |
Total-C |
-2.3 (-15.5, 24.4) |
-28.2 (-44.9, -6.8) |
-34.9 (-49.6, -15.2) |
-44.4 (-63.5, -3.8) |
LDL-C |
3.6 (-31.3, 31.6) |
-26.5 (-57.7, 9.8) |
-30.4 (-53.9, 0.3) |
-40.5 (-60.6, -13.8) |
HDL-C |
3.8 (-18.6, 13.4) |
13.8 (-9.7, 61.5) |
11.0 (-3.2, 25.2) |
7.5 (-10.8, 37.2) |
VLDL-C |
-1.0 (-31.9, 53.2) |
-48.8 (-85.8, 57.3) |
-44.6 (-62.2, -10.8) |
-62.0 (-88.2, 37.6) |
non-HDL-C |
-2.8 (-17.6, 30.0) |
-33.0 (-52.1, -13.3) |
-42.7 (-53.7, -17.4) |
-51.5 (-72.9, -4.3) |
Atorvastatin For Dysbetalipoproteinemia (Fredrickson Type III)
The results of an open-label crossover study of 16
patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia (Fredrickson
Type III) are shown in the table below (Table 11).
Table 11: Open-Label Crossover Study of 16 Patients
with Dysbetalipoproteinemia (Fredrickson Type III)
|
Median (min, max) at Baseline (mg/dL) |
Median % Change (min, max) |
Atorvastatin 10 mg |
Atorvastatin 80 mg |
Total-C |
442 (225, 1320) |
-37 (-85, 17) |
-58 (-90, -31) |
Triglycerides |
678 (273, 5990) |
-39 (-92, -8) |
-53 (-95, -30) |
IDL-C + VLDL-C |
215 (111, 613) |
-32 (-76, 9) |
-63 (-90, -8) |
non-HDL-C |
411 (218, 1272) |
-43 (-87, -19) |
-64 (-92, -36) |
Atorvastatin For Homozygous Familial Hypercholesterolemia
In a study without a concurrent control group, 29
patients ages 6 to 37 years with homozygous FH received maximum daily doses of
20 to 80 mg of atorvastatin. The mean LDL-C reduction in this study was 18%.
Twenty-five patients with a reduction in LDL-C had a mean response of 20%
(range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases
in LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2
patients also had a portacaval shunt and had no significant reduction in LDL-C.
The remaining 3 receptor-negative patients had a mean LDL-C reduction of 22%.
Atorvastatin For Heterozygous Familial
Hypercholesterolemia In Pediatric Patients
In a double-blind, placebo-controlled study followed by
an open-label phase, 187 boys and postmenarchal girls 10-17 years of age (mean
age 14.1 years) with heterozygous familial hypercholesterolemia (FH) or severe
hypercholesterolemia, were randomized to atorvastatin (n=140) or placebo (n=47)
for 26 weeks and then all received atorvastatin for 26 weeks. Inclusion in the
study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline
LDL-C level ≥ 160 mg/dL and positive family history of FH or documented
premature cardiovascular disease in a first or second-degree relative. The mean
baseline LDL-C value was 218.6 mg/dL (range: 138.5–385.0 mg/dL) in the
atorvastatin group compared to 230.0 mg/dL (range: 160.0–324.5 mg/dL) in the
placebo group. The dosage of atorvastatin (once daily) was 10 mg for the first
4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The
number of atorvastatin-treated patients who required uptitration to 20 mg after
Week 4 during the double-blind phase was 78 (55.7 %).
Atorvastatin significantly decreased plasma levels of
total-C, LDL-C, triglycerides, and apolipoprotein B during the 26-week
double-blind phase (see Table 12).
Table 12: Lipid-Altering Effects of Atorvastatin in
Adolescent Boys and Girls with Heterozygous Familial Hypercholesterolemia or
Severe Hypercholesterolemia (Mean Percentage Change from Baseline at Endpoint
in Intention-to-Treat Population)
DOSAGE |
N |
Total-C |
LDL-C |
HDL-C |
TG |
Apo B |
Placebo |
47 |
-1.5 |
-0.4 |
-1.9 |
1.0 |
0.7 |
Atorvastatin |
140 |
-31.4 |
-39.6 |
2.8 |
-12.0 |
-34.0 |
The mean achieved LDL-C value was 130.7 mg/dL (range:
70.0–242.0 mg/dL) in the atorvastatin group compared to 228.5 mg/dL (range:
152.0–385.0 mg/dL) in the placebo group during the 26-week double-blind phase.
The safety and efficacy of doses above 20 mg have not
been studied in controlled trials in children. The long-term efficacy of
atorvastatin therapy in childhood to reduce morbidity and mortality in
adulthood has not been established.
CADUET For Hypertension And Dyslipidemia
In a double-blind, placebo-controlled study, a total of
1660 patients with co-morbid hypertension and dyslipidemia received once daily
treatment with eight dose combinations of amlodipine and atorvastatin (5/10,
10/10, 5/20, 10/20, 5/40, 10/40, 5/80, or 10/80 mg), amlodipine alone (5 mg or
10 mg), atorvastatin alone (10 mg, 20 mg, 40 mg, or 80 mg), or placebo. In
addition to concomitant hypertension and dyslipidemia, 15% of the patients had
diabetes mellitus, 22% were smokers, and 14% had a positive family history of
cardiovascular disease. At eight weeks, all eight combination-treatment groups
of amlodipine and atorvastatin demonstrated statistically significant
dose-related reductions in systolic blood pressure (SBP), diastolic blood
pressure (DBP), and LDL-C compared to placebo, with no overall modification of
effect of either component on SBP, DBP, and LDL-C (Table 13).
Table 13. Effects of Amlodipine and Atorvastatin on
Blood Pressure and LDL-C
BP (mmHg) |
Atorvastatin |
Amlodipine |
0 mg |
10 mg |
20 mg |
40 mg |
80 mg |
0 mg |
|
-1.5/-0.8 |
-3.2/-0.6 |
-3.2/-1.8 |
-3.4/-0.8 |
5 mg |
-9.8/-4.3 |
-10.7/-4.9 |
-12.3/-6.1 |
-9.7/-4.0 |
-9.2/-5.1 |
10 mg |
-13.2/-7.1 |
-12.9/-5.8 |
-13.1/-7.3 |
-13.3/-6.5 |
-14.6/-7.8 |
LDL-C (% change) |
Atorvastatin |
Amlodipine |
0 mg |
10 mg |
20 mg |
40 mg |
80 mg |
0 mg |
— |
-32.3 |
-38.4 |
-42.0 |
-46.1 |
5 mg |
1.0 |
-37.6 |
-41.2 |
-43.8 |
-47.3 |
10 mg |
-1.4 |
-35.5 |
-37.5 |
-42.1 |
-48.0 |
REFERENCE
4 Based on patient weight of 50 kg.