Clinical Studies with Amlodipine
Amlodipine Effects in 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 doses, 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 5 mg amlodipine at the end of
8 weeks had lower 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. Adverse
events were similar to those seen in adults.
Amlodipine Effects in 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 Effects in 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
due to lack of clinical improvement.
Amlodipine Effects in Documented Coronary Artery Disease:
In PREVENT, 825 patients with angiographically documented coronary artery
disease 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 US
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%), anti-coagulants (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
4). Effects in various subgroups are shown in Figure 2.
In a 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 subgroups
Table 4 below summarizes the significant 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 4. Incidence of Significant Clinical Outcomes for CAMELOT
Amlodipine Effects in Patients with Congestive 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 LVEF. 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 inhibitor
(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.
Clinical Studies with Atorvastatin
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 mm Hg 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 which 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 nonfatal 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.
Due to the small number of events, results for women were inconclusive.
Figure 3: Effect of Atorvastatin 10 mg/day on Cumulative Incidence
of Nonfatal 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 due to 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 (CVD) 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 (1429) or placebo (1411) 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.
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.
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).
In the Treating to New Targets Study (TNT), the effect of LIPITOR
80 mg/day vs. LIPITOR 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 LIPITOR 10 mg/day. Subjects were randomly assigned to either
10 mg/day or 80 mg/day of LIPITOR 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 due
to 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 LIPITOR and 99, 177, 152, 129, and 48
mg/dL during treatment with 10 mg of LIPITOR.
Treatment with LIPITOR 80 mg/day significantly reduced the rate of
MCVE (434 events in the 80mg/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 Figure5 and Table 5). The overall risk reduction was consistent
regardless of age (<65, ≥65) or gender.
Figure 5. Effect of LIPITOR 80 mg/day vs.10 mg/day on Time to
Occurrence of Major Cardiovascular Events (TNT)
TABLE 5. Overview of Efficacy Results in TNT
Of the events that comprised the primary efficacy endpoint, treatment
with LIPITOR 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 5). Of the predefined secondary endpoints, treatment
with LIPITOR 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 5). The proportions of subjects who experienced
cardiovascular death, including the components of CHD death and fatal
stroke, were numerically smaller in the LIPITOR 80 mg group than in the
LIPITOR 10 mg treatment group. The proportions of subjects who experienced noncardiovascular death were numerically larger in the LIPITOR 80 mg
group than in the LIPITOR 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid
Lowering Study (IDEAL), treatment with LIPITOR 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 LIPITOR 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, nonfatal MI and resuscitated cardiac arrest): 411 (9.3%) in the
LIPITOR 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 LIPITOR 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 LIPITOR
80 mg group and the simvastatin 20–40 mg group.
Atorvastatin Studies in 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 6).
Table 6. Dose-Response in Patients With Primary Hyperlipidemia
(Adjusted Mean Percent Change From Baseline)a
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 7).
Table 7. Mean Percent Change From Baseline at Endpoint
(Double-Blind, Randomized, Active-Controlled Trials)
The impact on clinical outcomes of the differences in lipid-altering
effects between treatments shown in Table 7 is not known. Table 7 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 Effects in 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 8). For the atorvastatin-treated patients, median (min,
max) baseline TG level was 565 (267–1502).
Table 8. Combined Patients With Isolated Elevated TG:
Median (min, max) Percent Changes From Baseline
Atorvastatin Effects in Dysbetalipoproteinemia (Fredrickson
Type III): The results of an open-label crossover study of atorvastatin
in 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia
(Fredrickson Type III) are shown in the table below (Table 9).
Table 9. Open-Label Crossover Study of 16 Patients
With Dysbetalipoproteinemia (Fredrickson Type III)
Atorvastatin Effects in 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 Effects in Heterozygous Familial Hypercholesterolemic
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 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 placebo group. The dosage of atorvastatin (once daily) was 10 mg
for the first 4 weeks and up-titrated to 20 mg if the LDL-C level was
> 130 mg/dL. The number of atorvastatin-treated patients who required
up-titration to 20 mg after Week 4 during the double-blind phase was
80 (57.1%).
Atorvastatin significantly decreased plasma levels of total-C, LDL-C,
triglycerides, and apolipoprotein B during the 26 week double-blind
phase (see Table 10).
Table 10. Lipid-altering Effects of Atorvastatin in Adolescent
Boys and Girls with Heterozygous Familial Hypercholesterolemia or Severe
Hypercholesterolemia (Mean Percent Change From Baseline at Endpoint
in Intention-to-Treat Population)
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 atorvastatin 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.
Clinical Study of Combined Amlodipine and Atorvastatin in Patients
with 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 11).
Table 11. Efficacy in Terms of Reduction in Blood Pressure and
LDL-C
