Download atorvastatin - Clinical Trial Results

Advances in
Lipid Management
The National Cholesterol Education Program (NCEP)
 Launched by National Heart, Lung, and
Blood Institute (NHLBI), a part of the NIH,
in November, 1985
 Impetus: Definitive evidence linking
coronary heart disease (CHD) to elevated
total cholesterol levels
 Goal: Educating, monitoring, and
developing guidelines for lowering blood
cholesterol levels
NCEP web site.
Coronary Heart Disease:
Despite Advances, Still the #1 Killer
Percentage Breakdown of Deaths From Cardiovascular Diseases
United States: 1995 Mortality, Final Data
22% Other
1% Rheumatic Fever/
Rheumatic Heart
Disease
1% Congenital
Heart Defects
50% Coronary Heart Disease
2% Atherosclerosis
4% Congestive
Heart Failure
4% High Blood Pressure
16% Stroke
American Heart Association. 1998 Heart and Stroke Facts: Statistical Update.
Major Risk Factors for CHD
The NCEP Adult Treatment Panel Identifies Positive Risk Factors (RF) for
CHD
Risk Factors
 Family history of early CHD
— parent
or sibling <55 years of age if male, <65 years of age if female
 Age
— male 45 years
— female




55 years, or premature menopause without estrogen replacement therapy (ERT)
Hypertensive (BP 140/90 mm/Hg or taking antihypertensive medication)
Current smoker
Diabetes mellitus
Low HDL-cholesterol (<35 mg/dL)
Negative Risk Factor
 If HDL-C is 60 mg/dL, subtract one risk factor
Risk Stratification for Adults Without CHD
Classification Based on LDL-C
LDL-C Level
Classification
<130 mg/dL
Desirable
130-159 mg/dL
Borderline-high risk
160 mg/dL
High risk
NCEP Primary CHD Risk Categories and Goals
for Lowering LDL-C
Risk Category
LDL-C Goal
No CHD <2 RF
<160 mg/dL
No CHD 2 RF
<130 mg/dL
CHD
100 mg/dL
The NCEP recommends lowering LDL-C even further than these goals, if possible.
High-Risk Adults Not Reaching LDL-C Goals
in NHANES-III
(National Health and Nutrition Examination Survey)
55%
55% of patients with
2 risk factors and no CHD
did not reach NCEP goal
83%
83% of CHD patients
did not reach NCEP goal
Unpublished data from the Third National Health and Nutrition Examination Survey (NHANES-III), CDC 1994; data from 1988–1991.
Lipid Treatment Assessment Project (L-TAP)
 Hypothesis
— majority of dyslipidemic
patients do not achieve
NCEP target LDL-C levels
 Primary Objective
— to determine percentage of primary care patients
on diet and/or drug therapy who are achieving
NCEP LDL-C goals
Pearson TA, Laurora IM. Scientific Sessions of the American Heart Association; 1997; Abstract 361.
L-TAP: % of Patients at LDL-C Goal
Risk group—
Lipid-lowering therapy
LDL-C goal
% Success
% Failure
Diet therapy
2RF (n=282)
2RF (n=361)
CHD
(n=108)
Total (n=751)
59
22
7
34
41
78
93
66
Drug therapy
2RF (n= 861)
2RF (n=1924)
CHD
(n=1352)
Total (n=4137)
70
40
18
39
30
60
82
61
 Does
not include patients who were nonevaluable.
Person’s chi-square=682.91; d=2; P=0.001.
Data on file. Parke-Davis; Morris Plains, NJ.
Pearson TA, Laurora IM. Scientific Sessions of the American Heart Association; 1997; Abstract 361.
P-Value
0.001
0.001
L-TAP: Identifying the Patient at Risk
Patient Profile With 2 Risk Factors
 92% Male 45 years
CHD Patients
30%
No CHD
<2 RF
No CHD
2 RF
47%
23%
Data on file. Parke-Davis; Morris Plains, NJ.
Female 55 years





70% Hypertensive (140/90 mm Hg)
41% Family history of early CHD
22% Low HDL-C level
21% Diabetes mellitus
19% Current smokers
L-TAP: Many High-Risk Adults Are Not
Reaching LDL-C Goals
63%
63% of patients with
2 risk factors and no CHD
did not reach NCEP goal
Data on file. Parke-Davis; Morris Plains, NJ.
82%
82% of CHD patients
did not reach NCEP goal
L-TAP: Distance From LDL-C Goal in
Patients With 2 Risk Factors
63%
Not at goal
No.
of patients
1000
900
800
700
600
500
400
300
200
100
0
At goal
n=849
n=816
n=494
n=126
<130
130-160
161-200
LDL-C (mg/dL)
Data on file. Parke-Davis; Morris Plains, NJ.
>200
L-TAP: Distance From LDL-C Goal in
Patients With CHD
82%
Not at goal
600
n=545
500
No.
of patients
n=416
400
At goal
300
n=256
n=243
200
100
0
100
101-130
131-160
LDL-C (mg/dL)
Data on file. Parke-Davis; Morris Plains, NJ.
>160
Relationship Between Cholesterol and CHD Risk:
Epidemiologic Trials
Multiple Risk Factor Intervention Trial
(MRFIT) (n=361,662)
Framingham Study (n=5209)
CHD indications per 1000
40
(Deaths/1000)
10-year CHD death rate
50
30
20
10
150
125
100
75
50
25
0
0
150
200
250
300
Serum cholesterol (mg/dL)
1% reduction in total cholesterol
resulted in a 2% decrease in CHD risk
Gotto AM Jr, et al. Circulation. 1990;81:1721-1733.
Castelli WP. Am J Med. 1984;76:4-12.
204
205-234
235-264
265-294
295
Serum cholesterol (mg/100 mL)
Each 1% increase in total cholesterol level is
associated with a 2% increase in CHD risk
Relationship Between Cholesterol and CHD Risk:
Epidemiologic Trials (cont’d)
Okinawa, Japan
400
40
Men
CHD mortality rates (%)
per 100,000 screened subjects in 2 years
Cumulative incidence of AMI
500
Seven Countries Study†
Women
300
200
100
20
10
0
0
Range
Mean
30
Northern Europe
Southern Europe, Mediterranean
United States
Serbia
Southern Europe, Inland
Japan
167
149.3
168-191
179.8
192-217
203.7
218
245.3
Serum cholesterol (mg/dL)
Cumulative incidence of acute myocardial infarction
(AMI) increased with the level of serum cholesterol
 Cumulative incidence of AMI
125
175
225
275
Serum cholesterol (mg/dL)
Using linear approximation, a 20-mg/dL
increase in total cholesterol corresponded
to a 17% increase in mortality risk
in each quartile of basal serum cholesterol, expressed per 100,000 screened subjects in 3 years.
Serum cholesterol was measured between April 1, 1983 and March 31, 1984.
† 25-year CHD mortality rates per baseline cholesterol quartile adjusted for age, cigarette smoking, and systolic blood pressure.
Wakugami K, Iscki R, Kimura Y, et al. Japanese Circulation Journal. 1998;62:7-14.
Verschuren WMM, Jacobs DR, Bloemberg BPM, et al. JAMA. 1995;274:131-136.
325
Atorvastatin Calcium (LIPITOR®):
Mechanism of Action
HMG-CoA reductase inhibition
Reduced cholesterol synthesis
Upregulation of LDL receptors
Decreased VLDL production
Increased removal and catabolism of LDL
Decreased TC, LDL-C, and TG
Conversion of VLDL to LDL
Atorvastatin Calcium (LIPITOR®) Indications
 An adjunct to diet to reduce elevated total-C, LDL-C, apoB,
and TG levels in patients with primary hypercholesterolemia
(heterozygous familial and nonfamilial) and mixed dyslipidemia
(Fredrickson Types IIa and IIb)
 As adjunctive therapy to diet for the treatment of patients with
elevated serum triglyceride levels (Fredrickson Type IV)
 For the treatment of patients with primary dysbetalipoproteinemia
(Fredrickson Type III) who do not respond adequately to diet
 To reduce total-C and LDL-C in patients with homozygous familial
hypercholesterolemia as an adjunct to other lipid-lowering treatments
(eg, LDL apheresis) or if such treatments are unavailable
 The effect of LIPITOR on cardiovascular morbidity and mortality has
not been determined
Mean % LDL-C reduction from baseline
Atorvastatin Calcium (LIPITOR®) Dose-Response
Relationship
0%
10 mg
20 mg
40 mg
80 mg
-10%
-20%
-30%
-40%
-41%

-50%
-60%
-70%
 P<0.05 vs placebo.
Nawrocki JW, et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.
-44%

-50%

-61%

In Head-to-Head Trials, Atorvastatin Calcium Showed
Superior LDL-C Reductions at Starting Doses
Mean % LDL-C change from baseline
0%
-5%
atorvastatin simvastatin
(n=132)
(n=45)
10 mg
10 mg
atorvastatin
(n=222)
pravastatin
(n=77)
atorvastatin
(n=707)
lovastatin
(n=191)
10 mg
20 mg
10 mg
20 mg
-10%
-15%
-20%
-23%
-27%
-25%
-30%
-30%
-35%
-37%
-40%
Dart et al.
-35%
P 0.05
Data on file. Parke-Davis; Morris Plains, NJ.
Dart A, et al. Am J Cardiol. 1997;80:39-44.
Bertolini S, et al. Atherosclerosis. 1997;130:191-197.
Davidson M, et al. Am J Cardiol. 1997;79:1475-1481.
Bertolini et al.
-36%
P 0.05
Davidson et al.
P 0.05
The impact on clinical outcomes of the differences in lipid-altering effects between
treatments shown in this slide is not known. This chart does not contain data comparing the
effects of atorvastatin with higher doses of simvastatin, pravastatin, and lovastatin.
Mean % triglyceride change from baseline
In Head-to-Head Trials, Atorvastatin Calcium Showed
Superior TG Reductions at Starting Doses
0%
atorvastatin
(n=132)
10 mg
simvastatin
(n=45)
10 mg
atorvastatin
(n=222)
pravastatin
(n=77)
atorvastatin
(n=707)
lovastatin
(n=191)
10 mg
20 mg
10 mg
20 mg
-6%
-5%
-9%
-10%
-15%
-15%
-20%
-25%
-17%
-17%
-23%
Dart et al.
P 0.05
Data on file. Parke-Davis; Morris Plains, NJ.
Dart A, et al. Am J Cardiol. 1997;80:39-44.
Bertolini S, et al. Atherosclerosis. 1997;130:191-197.
Davidson M, et al. Am J Cardiol. 1997;79:1475-1481.
Bertolini et al.
P 0.05
Davidson et al.
P 0.05
The impact on clinical outcomes of the differences in lipid-altering effects between
treatments shown in this slide is not known. This chart does not contain data comparing
the effects of atorvastatin with higher doses of simvastatin, pravastatin, and lovastatin.
CURVES Trial Design and Objective
 CURVES is a multicenter, open-label, randomized, parallelgroup, 8-week, comparative-dose efficacy and safety study
of once-daily atorvastatin compared with simvastatin,
pravastatin, lovastatin, and fluvastatin in patients with
elevated LDL-C
 Designed to assess comparative efficacy and safety of
atorvastatin relative to simvastatin, pravastatin, lovastatin,
and fluvastatin on lipids in patients with baseline
LDL-C 160 mg/dL and TG 400 mg/dL
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
CURVES Trial:
Mean Baseline LDL-C Levels
Treatment arm
(mg)
Mean baseline
LDL-C (mg/dL)
No. of
patients
atorvastatin
10
20
40
80
213
213
206
213
n=73
n=51
n=61
n=10
simvastatin
10
20
40
207
230
219
n=70
n=49
n=61
pravastatin
10
20
40
225
237
215
n=14
n=41
n=25
lovastatin
20
40
80
244
218
219
n=16
n=16
n=11
fluvastatin
20
40
236
192
n=12
n=12
Treatment arm sizes were powered to show statistical significance vs mg-equivalent dose of the other agents.
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
CURVES Trial:
Patient Inclusion Criteria and Demographics
Patient inclusion criteria
 At two consecutive visits
— LDL-C 160 mg/dL
— TG 400 mg/dL
 Men and women 18 and
80 years of age
 Body Mass Index (BMI) 32 kg/m2
Patient demographics
 Mean age: 55.2 years
 Modified intent-to-treat patients
59% male
— 41% female
—
 Family history of CHD: 37%
 Smokers: 13%
 Average BMI: 26.7 kg/m2
 Evenly
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
distributed across treatment groups.
CURVES Trial:
LDL-C Reductions vs Other Statins
-10

-20


Mean
% change
in LDL-C

-30



†
†
pravastatin
‡
†
-40
simvastatin
‡
lovastatin
‡
-50
(40 mg bid)
atorvastatin
(80 mg qd)
-60
10
20
40
Dose range (mg)
80

Significantly less than atorvastatin 10 mg (P<0.02).
Significantly less than atorvastatin 20 mg (P<0.01).
‡
Significantly greater than mg-equivalent doses of comparative agents (P0.01).
†
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown
in this chart is not known.
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
CURVES Trial:
Superior LDL-C Reductions at Usual Starting Doses
atorvastatin
simvastatin
pravastatin
lovastatin
fluvastatin
10 mg
20 mg
20 mg
20 mg
0
10 mg
Mean
% LDL-C
reduction
-10
-17%†
-20
-24%†
-28%†
-30
-40

†
-38%
-29%†
atorvastatin 10 mg efficacy
(38%)
Most commonly prescribed doses for each product. Source: IMS National Prescription Audit; February 1998.
Significantly less than atorvastatin 10 mg (P<0.01).
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown
in this chart is not known.
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
CURVES Trial:
Superior LDL-C Reductions at Usual First Titrations
atorvastatin
simvastatin
pravastatin
lovastatin
fluvastatin
0
20 mg
Mean
% LDL-C
reduction
20 mg
40 mg
40 mg
40 mg
-10
-20
-23%†
-30
-31%†
-35%†
-40
-50

†
-34%†
atorvastatin 10 mg efficacy
(38%)
-46%
Most commonly prescribed doses for each product. Source: IMS National Prescription Audit; February 1998.
Significantly less than atorvastatin 20 mg (P<0.01).
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown
in this chart is not known.
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
CURVES Trial:
LDL-C Reductions at Every Dose
Mean % LDL-C reduction from baseline
0
-15
-20
-35
-40
20 mg
10 mg
simvastatin
10 mg
20 mg
20 mg
lovastatin
fluvastatin
-30
10 mg
atorvastatin
pravastatin
-25
20 mg
20 mg
-45
-50
40 mg
40 mg
40 mg
40
mg
80 mg (40 mg bid)
40 mg
Mean LDL-C reductions at 80-mg doses: LIPITOR® 80 mg (qd)=54% vs lovastatin 80 mg (40 mg bid)=48%, P>0.05.
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown
in this chart is not known.
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
-55
80 mg
(qd)
CURVES Trial: Conclusions
 At usual starting doses and usual first
titrations, atorvastatin demonstrated
significantly greater LDL-C reductions
vs other statins
 All statins were well tolerated and no
serious adverse events were considered
related to any of the study medications
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
Treat-to-Target Trial: Design and Objectives
A 54-week, open-label, randomized study comparing the efficacy and safety of
 atorvastatin
 fluvastatin
 lovastatin
 simvastatin
in the reduction of LDL-C levels to NCEP goals
Data on file. Parke-Davis; Morris Plains, NJ.
Treat-to-Target Trial: Patient Entry Criteria
and Demographics
 Lipid entry criteria
— LDL-C: patients
with <2 risk factors (190 mg/dL),
patients with 2 risk factors (160 mg/dL)
— TG: all patients (400 mg/dL)
 LDL-C range: 129-448 mg/dL; LDL-C mean: 205 mg/dL
 Demographics
— mean
age: 56 years (53% women, 47% men)
— 24% had <2 CHD risk factors, 76% had 2 risk factors
— baseline LDL-C values were similar for all treatment groups
Data on file. Parke-Davis; Morris Plains, NJ.
Treat-to-Target Trial: Dosing Schedule
Statin
atorvastatin
Dosing schedule
20 mg
40 mg
fluvastatin
20 mg
40 mg
lovastatin
20 mg
40 mg
20 mg
40 mg
simvastatin
10 mg
10 mg
Data on file. Parke-Davis; Morris Plains, NJ.
With colestipol
80 mg
80 mg
5 g bid
5 g bid
10 g bid
5 g bid
10 g bid
5 g bid
10 g bid
Treat-to-Target Trial: Study Design
8-week dietary assessment (optional)
4-week lead-in
344 patients randomized (1:1:1:1)
atorvastatin vs fluvastatin vs lovastatin vs simvastatin for
54 weeks to reach <160 mg/dL for patients with <2 risk factors
(24%) or <130 mg/dL for patients with 2 risk factors (76%)
12 weeks
atorvastatin 10 mg
(n=85)
12 weeks
fluvastatin 20 mg
(n=82)
12 weeks
lovastatin 20 mg
(n=83)
If not at NCEP LDL-C goal, titrate at
12-week intervals for 54 weeks to maximum
dose and add colestipol if needed
Data on file. Parke-Davis; Morris Plains, NJ.
12 weeks
simvastatin 10 mg
(n=87)
Treat-to-Target Trial: 12-Week Results
80
70
71%
60
% Patients
reaching NCEP
LDL-C goal
by week 12
50
40
34%
30
16%
20
10
0
 Significantly
41%
10 mg
atorvastatin
(n=85)
20 mg
fluvastatin
(n=82)
20 mg
10 mg
lovastatin
(n=83)
simvastatin
(n=87)
less than atorvastatin 10 mg (P<0.001).
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown
in this chart is not known.
Data on file. Parke-Davis; Morris Plains, NJ.
Treat-to-Target Trial: 24-Week Results
100
90
80
70
% Patients
60
reaching NCEP
50
LDL-C goal
by week 24
40
30
20
10
0
 Significantly
84%
atorvastatin 10 mg efficacy at week 12
46%
53%
28%
atorvastatin
10-20 mg
(n=85)
fluvastatin
20-40 mg
(n=82)
lovastatin
20-40 mg
(n=83)
simvastatin
10-20 mg
(n=87)
less than atorvastatin (P<0.001).
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown
in this chart is not known.
Data on file. Parke-Davis; Morris Plains, NJ.
Treat-to-Target Trial: Summary of Results
 Compared with patients on fluvastatin, lovastatin, and
simvastatin, significantly more patients on atorvastatin
reached NCEP LDL-C goal

at usual starting doses

by every study interval

with fewer titrations

in fewer office visits
 95% of those on atorvastatin reached LDL-C goal by end
of study—all on monotherapy
Data on file. Parke-Davis; Morris Plains, NJ.
Effective for a Broad Range of Patient Populations
LDL-C and TG reductions with atorvastatin at the 10-mg starting dose
Elderly
(>70 years)
Women
(n=183)
Mean % change from baseline
0%
LDL-C
TG
(n=689)
LDL-C
TG
Hypertensives
(n=510)
LDL-C
TG
CHD
(n=196)
LDL-C
TG
NIDDM
(n=156)
LDL-C
TG
Mixed
dyslipidemics
(n=550)
LDL-C
TG
-5%
-10%
-15%
-18%
-18%
-21%
-20%
-21%
-21%
-24%
-25%
-30%
-35%
-39%
-38%
-37%
-37%
-36%
-40%
Pooled results from separate trials of atorvastatin 10 mg in more than 2000 patients for up to 52 weeks.
Data on file. Parke-Davis; Morris Plains, NJ.
-35%
Atorvastatin Calcium in Hard-to-Treat
Patient Populations
Atorvastatin 80 mg in severe hypercholesterolemia
(baseline total cholesterol 368 mg/dL; LDL-C 289 mg/dL)
Mean % change from baseline
10%
0%
+7%
Total-C
LDL-C
TG
ApoB
HDL-C
-10%
-20%
-33%
-30%
-40%
-50%
-60%
Data on file. Parke-Davis; Morris Plains, NJ.
-44%
-46%
-53%
Economic Considerations in the Management
of Hypercholesterolemia
Hypercholesterolemia
CHD events
Adverse events
Medications
Physician visits
Hospitalization
Dietary
counseling
Monitoring
Surgeries
Titration
Cost Considerations in LDL-C Reduction
CURVES Trial Results:
Monthly
cost
Percent LDL-C reduction
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
-50
-55
-60
atorvastatin
$54.72
$84.60
$101.88
simvastatin
$62.99
$109.88
$109.88
10 mg
20 mg
40 mg
-38%
-46%
-51%
10 mg
20 mg
40 mg
-28%
-35%
-41%
pravastatin
$60.33
$64.95
$106.77
10 mg
-19%
20 mg
40 mg
-24%
-34%
lovastatin
$69.85
$125.74
20 mg
40 mg
-29%
-31%
fluvastatin
$37.70
$37.70
20 mg
40 mg
-17%
-23%
Jones P, Kafonek S, Laurora I, Hunninghake D, for the CURVES Investigators. Am J Cardiol. 1998;81:582-587.
Red Book® Update. Montvale, NJ: Medical Economics Data Production Company. August 1998;46,47,51,59,71.
LIPITOR® 10 mg (n=73), 20 mg (n=51), 40 mg (n=61),
80 mg (n=10); simvastatin 10 mg (n=70), 20 mg (n=49),
40 mg (n=61); pravastatin 10 mg (n=14), 20 mg (n=41),
40 mg (n=25); lovastatin 20 mg (n=16), 40 mg (n=16),
80 mg (n=11); fluvastatin 20 mg (n=12), 40 mg (n=12).
Baseline LDL-C values were similar for all groups.
LDL-C reductions at 80-mg doses: LIPITOR 80 mg
(qd)=54% vs lovastatin 80 mg (40 mg bid)=48%,
P>0.05.
Average wholesale price (AWP) per tablet provided by
Red Book® Update, August 1998. Actual pharmacy or
out-of-pocket costs may differ. Cost comparisons do
not imply comparable efficacy or safety. Dosage price
for LIPITOR and lovastatin 80 mg is equal to double
their 40-mg tablet cost.
Atorvastatin Calcium:
Great Value at Every Dose
Dose
AWP
cost/day
AWP
cost/month
atorvastatin
10 mg
20 mg
40 mg
$1.82
$2.82
$3.40
$54.72
$84.60
$101.88
simvastatin
10 mg
20 mg
40 mg
80 mg
$2.10
$3.66
$3.66
$3.66
$62.99
$109.88
$109.88
$109.88
pravastatin
10 mg
20 mg
40 mg
$2.01
$2.17
$3.56
$60.33
$64.95
$106.77
lovastatin
20 mg
40 mg
$2.33
$4.19
$69.85
$125.74
fluvastatin
20 mg
40 mg
$1.26
$1.26
$37.70
$37.70
cerivastatin
0.2 mg
0.3 mg
$1.32
$1.32
$39.60
$39.60
Red Book ® Update. Montvale, NJ: Medical Economics Data Production Company. August 1998;23,46,47,51,59,71.
Atorvastatin Calcium Pharmacokinetics
 Absorption
— rapidly
absorbed
— maximum plasma concentrations in 1 to 2 h
— absorption increases in proportion to dose
 Bioavailability
— absolute:
~14%
— systemic: ~30%
 Distribution
— mean
Vd ~381 L
— 98% bound to plasma proteins
Atorvastatin Calcium Pharmacokinetics (cont’d)
 Metabolism
— metabolized
by hepatic cytochrome P450 3A4
— ~ 70% of inhibitory activity attributed to active metabolites
 Excretion
— eliminated
primarily in bile
— mean plasma elimination half-life ~14 h
 Half-life for inhibitory effects is 20 to 30 h (due to contribution
of active metabolites)
Well Tolerated in Clinical Trials
In head-to-head clinical trials, atorvastatin provided discontinuation rates
comparable with other statins
Discontinuation due to associated
adverse events
atorvastatin (n=1148)
2.7%
Combined statins (n=383)
3.4%
Pooled data from three comparative trials of patients taking either atorvastatin (10-20 mg),
simvastatin (10-20 mg, n=45), pravastatin (20-40 mg, n=78), or lovastatin (20-40 mg, n=260)
for 52 weeks.
Atorvastatin Calcium Safety Profile
 In clinical trials, the most common adverse events were
constipation, flatulence, dyspepsia, and abdominal pain
 It is recommended that liver function tests be performed prior to
and at 12 weeks following both the initiation of therapy and any
elevation of dose, and periodically thereafter
 LIPITOR is contraindicated in patients with hypersensitivity to any
component of this medication; in patients with active liver disease
or unexplained persistent elevations of serum transaminases; in
women during pregnancy and in nursing mothers
 With any statin, tell patients to promptly report muscle pain,
tenderness, or weakness. Discontinue drug if myopathy is
suspected, if creatine phosphokinase (CPK) levels rise markedly,
or if the patient has risk factors for rhabdomyolysis
Atorvastatin Calcium Safety Profile (cont’d)
 Contraindications
— hypersensitivity
to atorvastatin components
— active liver disease
— unexplained persistent elevations of serum transaminases
— pregnancy and lactation
 Potential drug interactions
— cyclosporine
— fibric acid derivatives
— niacin
— erythromycin
— azole antifungals
— digoxin
— oral contraceptives
Atorvastatin for a Broad Range of
Hypercholesterolemic Patients
 72% of patients reach NCEP LDL-C goal at the 10-mg starting dose
 Greater LDL-C reductions vs other statins at milligram-equivalent doses
across the 10- to 40-mg dose range




Reduces LDL-C 39% to 60% across the 10- to 80-mg dose range
Reduces TG 19% to 37% across the 10- to 80-mg dose range
Increases HDL-C 5% to 9%
10-mg starting dose lowers lipid measures (TC, TG, apoB) significantly more
than simvastatin, lovastatin, or pravastatin in comparative trials
 Indicated to reduce elevated LDL-C and TG in patients with
hypercholesterolemia

A multicenter, double-blind study of all hypercholesterolemic patients taking LIPITOR (10 mg, n=707) for 16 weeks. Baseline lipid
level:192 mg/dL. Target NCEP LDL-C goal based on CHD risk status, percentage of patients reaching goal, and total number of patients:
<2 CHD risk factors, <160 mg/dL, 95%, n=329; 2 CHD risk factors, <130 mg/dL, 67%, n=268; with CHD, 100 mg/dL, 18%, n=110.
Data on file. Parke-Davis; Morris Plains, NJ.
Nawrocki JW, et al. Arterioscler Thromb Vasc Biol. 1995;15:678-682.
Dart A, et al. Am J Cardiol. 1997;80:39-44.
Bertolini S, et al. Atherosclerosis. 1997;130:191-197.
Davidson M, et al. Am J Cardiol. 1997;79:1475-1481.