Mubashar A Choudry MD | Effects of statin or usual care on outcomes

Primary prevention is treating
hypercholesterolemia in patients who do not have
clinical evidence of CAD
What is the rationale for this approach ?
Grundy et al. Recent Clinical
Trials and NCEP ATP III ,
JACC Vol. 44, No. 3, 2004
August 4, 2004:720–32

Inhibit HMG-CoA reductase
Statin Pleiotropy

WHO Cooperative Trial (clofibrate ) - 10,577
patients
Lipid Research Clinics Coronary Primary Prevention
Trial (cholestyramine) - 3806 patients
Helsinki Heart Study (gemfibrozil ) - 4081 patients
These trials demonstrated
 Significant reductions in coronary events (25, 19 & 34
% respectively)
 No reduction in coronary mortality
 Increase in mortality from noncardiovascular causes

Designed to determine whether the administration
of pravastatin to men with hypercholesterolemia
and no history of myocardial infarction reduced
the combined incidence of nonfatal myocardial
infarction and death from coronary heart disease

Randomized, double-blind, placebo controlled
6595 men, 45 to 64 years of age
Average follow-up of 4.9 years (seen at 3 month
intervals)
Pravastatin (40 mg each evening) vs. placebo

Primary
 Non-fatal MI or coronary heart disease death as a first event
Secondary
 Non-fatal MI
 Coronary heart disease death
Other Endpoints
 Cardiovascular mortality
 Total mortality
 Coronary revascularization procedures

20% reduction in TC 26% reduction in LDL
12% reduction in Trigs 5% increase in HDL
100
120
140
160
180
200
6 12 18 24 30 36 42 48 54 60
Months
LDLcholesterolmg/dL
placebo (intention -to-treat)
placebo (actual treatment)
pravastatin (intention-to-treat)
pravastatin (actual treatment)

0
2
4
6
8
10
12
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastatin
Placebo
31%
Risk
Reduction
P=0.0001

0
2
4
6
8
10
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo
31%
Risk
Reduction
P=0.0005

0
0.5
1
1.5
2
2.5
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo
28%
Risk
Reduction
P=0.13

0
0.5
1
1.5
2
2.5
3
3.5
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo
32%
Risk
Reduction
P=0.033

0
1
2
3
4
5
6
0 1 2 3 4 5 6
Years in Study
Percent
with
Events
Pravastain Placebo
P=0.051
22%
Risk
Reduction

Intervention Placebo Pravastatin Risk
(n= 3293)(n=3302) Reductions p-value
Coronary
Angiography 128 90 31% 0.007
PTCA / CABG 80 51 37% 0.009

E v e n t % R e d u c tio n p v a lu e
N o n fa ta l M I + C H D d e a th 3 1 %  < 0 .0 0 1
D e fin ite n o n fa ta l M I 3 1 %  < 0 .0 0 1
D e fin ite C H D d e a th 2 8 %  0 .1 3 (N S )
D e fin ite a n d s u s p e c te d C H D d e a th 3 3 %  0 .0 4 2
A ll c a rd io v a s c u la r d e a th s 3 2 %  0 .0 3 3
T o ta l m o rta lity 2 2 %  0 .0 5 1 (N S )
C A B G /P T C A 3 7 %  0 .0 2 9

Treatment with pravastatin significantly reduced
the incidence of myocardial infarction and death
from cardiovascular causes without adversely
affecting the risk of death from noncardiovascular
causes in men with moderate
hypercholesterolemia and no history of myocardial
infarction
Pravastatin had no effect on noncardiovascular-
related hospital admissions
Pravastatin therapy also resulted in a 30 percent
reduction in the risk of developing diabetes

Treatment of 1000 hypercholesterolemic middle
aged men with pravastatin for five years will avoid:
 14 coronary angiograms
 8 revascularization procedures
 20 nonfatal MIs
 7 CHD deaths
 2 additional deaths

Diet Modification
n=3,966
Primary Endpoints: Composite of coronary heart disease events, defined as cardiac
and sudden death, fatal and nonfatal myocardial infarction (MI), angina and cardiac or
vascular intervention.
Secondary Endpoints: Stroke, CHD composite or cerebral infarction, any
cardiovascular event, total mortality.
Diet Modification + Pravastatin
10-20 mg/day
n=3,866
7,832 ,men age 40-70 years and postmenopausal women up to age 70 with
total cholesterol 220-270 mg/dL
Mean BMI 23.8 kg/m2, 21% Diabetics, 20% Current Smokers,
baseline total cholesterol 242.6 mg/dL, LDL 157 mg/dL, HDL 57.5 mg/dL, triglycerides 127 mg/dL
32% Female, Mean Age 58 years, Mean Follow-Up 5.3 years
Prospective. Randomized. Open-label.

-11.5
-18.0
5.8
-3.1-2.1 -3.2
3.2
1.3
-20
-16
-12
-8
-4
0
4
Pravastatin+diet Diet
• Total cholesterol,
LDL, Triglyceride
reduction was larger
in the pravastatin
group
•HDL increase was
greater in the
pravastatin group
Total
Cholesterol
LDL HDL Triglycerides
mg/dL

3.3
5.0
0
1
2
3
4
5
3.3 vs 5.0 per 1000 patient
years, hazard ratio 0.67,
p=0.01
Primary composite endpoint of coronary
heart disease events
p = 0.01
#per1000patientyears

2.7
0.9
2.5
2.0
3.8
1.6
3.0
2.6
0
1
2
3
4
Total mortality MI Stroke Cerebral
infarction+TIA
p=0.055
p=0.03
p=0.33
•Total mortality was non-significantly lower in the pravastatin group (2.7 vs 3.8, HR 0.71,
p=0.055)
•MI occurred less often in the pravastatin group (0.9 vs 1.6, p=0.03)
•No significant difference was observed in stroke (2.5 vs 3.0, p=0.33) or cerebral infarction
plus TIA (2.0 vs 2.6, p=0.23)
p=0.23

5.5 5.7
0
1
2
3
4
5
6
• There was no difference in the frequency of cancer or elevated liver function
abnormalities and no cases of rhabdomyolysis.
2.8% 2.8%
0.0%
0.5%
1.0%
1.5%
2.0%
2.5%
3.0%
%
Frequency of cancer
(per 1000 patient years)
Frequency of elevated liver function
abnormalities (%)

 Among Japanese patients with hypercholesterolemia,
treatment with pravastatin was associated with a
reduction in the primary composite endpoint of
coronary heart disease
 The cardiac morbidity and mortality in Japan is much
lower than in the U.S. and other western countries
where statin therapy has been predominantly studied.
 The present study demonstrated that even in this
lower risk population, primary prevention with low-dose
statin therapy can be effective in reducing cardiac
events, with a modest reduction in lipid parameters.

Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial and ALLHAT–Lipid-Lowering Trial (ALLHAT)
N = 42,418: stage 1/2 hypertension + >1 CV risk factor
Chlorthalidone
12.5–25 mg/d
n = 15,255
Amlodipine
2.5–10 mg/d
n = 9048
Lisinopril
10–40 mg/d
n = 9054
Doxazosin*
2–8 mg/d
n = 9061
ALLHAT:
Step 1: titration
Step 2: open-label atenolol 25–100 mg/d, clonidine 0.1–0.3 mg bid, reserpine 0.05–0.2 mg/d
Step 3: open-label hydralazine 25–100 mg bid
N = 10,355; CHD, LDL-C 100 to 129 mg/dL or no CHD, LDL-C 120 to 189 mg/dL
Pravastatin 40 mg/d (n = 5170) Usual care (n = 5185)
ALLHAT-LLT:
ALLHAT Collaborative Research Group.
JAMA. 2002;288:2981-2997, 2998-3007.*Arm discontinued

Cumulative
rate
(%)
6543210
0
3
6
9
12
15
18
Time to death (years) Time to event (years)
6543210
0
3
6
9
12
15
18
All-cause mortality CHD death + nonfatal MI
RR = 0.99
(95% CI, 0.89–1.11)
RR = 0.91
(95% CI, 0.79–1.04)
Pravastatin Usual care
N = 10,355 with treated hypertension, baseline LDL-C 120–189 mg/dL
(no CHD) or LDL-C 100–129 mg/dL (CHD)
At 4 yrs, LDL-C  by 28% (statin) and 11% (usual care)

BP-lowering trial
Diuretic, ACEI, CCB equivalent in  CHD death and MI
Lipid-lowering trial (ALLHAT-LLT)
Statin, usual care equivalent in  all-cause mortality
 Modest differential in on-treatment cholesterol levels
may have contributed to result
ALLHAT BP results support importance of BP lowering,
regardless of drug class used
ALLHAT-LLT results are consistent with other statin trials

5804 patients aged 70–82 years with a history of vascular
disease or with cardiovascular risk factors
Randomized to pravastatin 40 mg/d or placebo
Baseline TC 155–348 mg/dL
Follow-up 3.2 years (mean)
Primary endpoint (composite): coronary death, nonfatal
MI, fatal or nonfatal stroke

Endpoint
Pravastatin
(%)
Placebo
(%)
Hazard
ratio p
Primary endpoint:
CHD death/MI/stroke 14.1 16.2 0.85 0.014
Secondary endpoints:
CHD death/MI 10.1 12.2 0.81 0.006
Fatal or nonfatal stroke 4.7 4.5 1.03 0.81
Other outcomes:
Nonfatal MI 7.7 8.7 0.86 0.10
Nonfatal stroke 4.0 4.1 0.98 0.85
Transient ischemic attack 2.7 3.5 0.75 0.051
All CV events 15.7 18.0 0.85 0.012

Cause of death
Pravastatin
(%)
Placebo
(%)
Hazard
ratio p
CHD 3.3 4.2 0.76 0.043
Stroke 0.8 0.5 1.57 0.19
Vascular 4.7 5.4 0.85 0.16
Nonvascular 5.6 5.1 1.11 0.38
Cancer 4.0 3.1 1.28 0.082
Trauma/suicide 0.1 0.2 NA NA
All causes 10.3 10.5 0.97 0.74

Pravastatin given for 3 years reduced the risk of coronary
disease in elderly individuals
 PROSPER therefore extends to elderly individuals the
treatment strategy currently used in middle aged people

Randomized, double-blind, placebo-controlled trial
To compare lovastatin with placebo for prevention of the
first acute major coronary event (UA, fatal and non-fatal
MI and sudden cardiac death)
6605 pts without CHD , 5608 men and 997 women
Average follow-up was 5.2 years
Lovastatin (20-40 mg daily) or placebo

Primary
 First Acute Major Coronary Event (UA, Fatal or Non-fatal MI
,Sudden Cardiac Death)
 Secondary
 Fatal or Non-Fatal MI
 Unstable Angina
 Fatal or Non-Fatal Cardiovascular Events
 Fatal or Non-Fatal Coronary Events
 Tertiary Endpoints
 Total Mortality, Non-Cardiovascular Mortality
 Fatal and Non-Fatal Cancer
 Discontinuation of Medication because of Adverse Effects

Lipid Level
(mg/dL)
Wilford Hall
Avg + SD
(mg/dL)
N=6605
NHANES
Percentile1
U.S. NHANES Ref.
Population2
Mean + SD
(mg/dL)
Mean TC
Mean LDL
Mean HDL
Men
Women
Median TG
221 + 21
150 + 17
36 + 5
40 + 5
158 + 76
51
60
25
16
63
225 + 45
142 + 37
50 + 16
140 + 120
1 Percentile ranks from US NHANES III reference population for study population averages
2 Men aged 45-73, and women aged 55-73, without cardiovascular disease

Mean TC
Mean LDL-C
Mean HDL-C
Median TG
Ratios
Mean LDL-C/HDL-C
Mean TC/HDL-C
Placebo
228.1 + 27.7
156.4 + 24.5
37.5 + 7.9
162.8 + 82.1
4.3 + 1.1
6.3 + 2.5
Lovastatin
183.7 + 23.8
114.6 + 20.1
39.3 + 8.0
142.8 + 72.8
3.0 + 0.8
4.8 + 1.0

0.9 1.5 1.2
-2.3
1.7 1.6
-18.4
-25
6
-15
-21.8
-28
-40
-30
-20
-10
0
10
20
30
Percent
Placebo
Lovastatin, avg dose 30 mg
p-value < 0.001 for all lovastatin treatment groups
42% of lovastatin patients achieved LDL-C goal of < 110 mg/dL (placebo 3%)
81% of lovastatin patients achieved LDL-C goal of < 130 mg/dL (placebo 12%)
TC LDL HDL TG TC/HDL LDL/HDL

N=3304 N=3270 N=3228 N=3184 N=3134 N=1688
Lovastatin
N=3301 N=3251 N=3211 N=3159 N=3092 N=1644
Placebo
# At Risk
Lovastatin
Placebo
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Years of Follow-up
0 1 2 3 4 5 5+ Years
CumulativeIncidence
37% Risk Reduction
(p < 0.001)
*Includes unstable angina,
fatal and non-fatal MI &
sudden cardiac death

40
66
100
135
183
23
46
70
91
116
0
50
100
150
200
250
1 2 3 4 5+ years
Years Since Randomization
CumulativeNumberofParticipants
withEvents
Placebo (n=3301)
Lovastatin (n=3304)
Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac
Death
reduced by 37% (p < 0.0008)

-37
-46
-31
-58
-38
-42
-70
-60
-50
-40
-30
-20
-10
0
PercentRiskReduction
Men
N=5608
Women
N=997
> Median
by Age
N=3180
Smokers
N=818
Hypertension
N=1448
Diabetes
N=156

-34 -36
-41
-60
-50
-40
-30
-20
-10
0
90.4-141.9 142.0-156.8 156.9-235.4
PercentChange
Relative Risk Reduction
Baseline LDL Tertiles

54 52
77
37
33
46
0
10
20
30
40
50
60
70
80
90
< 142, n=2210 143-156, n=2195 > 157, n=2199
NumberofEvents
Placebo
Lovastatin
Baseline LDL Level (mg/dL)

AFCAPS/TexCAPS
Role of Baseline HDL on Outcomes
71
68
44
40 41
35
0
10
20
30
40
50
60
70
80
< 34 35-39 > 40
NumberofEvents
Placebo
Lovastatin
Baseline HDL Level (mg/dL)

Fatal and Non-Fatal MI
N=3304 N=3281 N=3249 N=3214 N=3174 N=1717
N=3301 N=3270 N=3237 N=3200 N=3148 N=1692
# At Risk
Lovastatin
Placebo
0.00
0.01
0.02
0.03
Years of Follow-up
0 1 2 3 4 5 5+ years
Lovastatin
Placebo
CumulativeIncidence
40% Risk Reduction
(p = 0.002)
25% Risk Reduction
(p = 0.003)
Cardiovascular Events*
N=3304 N=3260 N=3206 N=3147 N=3088 N=1651
N=3301 N=3242 N=3187 N=3124 N=3045 N=1615
# At Risk
Lovastatin
Placebo
CumulativeIncidence
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Years of Follow-up
0 1 2 3 4 5 5+ years
Lovastatin
Placebo
N=3304 N=3281 N=3250 N=3217 N=3174 N=1707
N=3301 N=3267 N=3240 N=3205 N=3150 N=1678
# At Risk
Lovastatin
Placebo
Years of Follow-up
Unstable Angina
CumulativeIncidence
0.00
0.01
0.02
0.03
0 1 2 3 4 5 5+ years
Lovastatin
Placebo 32% Risk Reduction
(p = 0.02)
N=3304 N=3264 N=3215 N=3160 N=3106 N=1666
N=3301 N=3246 N=3201 N=3141 N=3069 N=1634
# At Risk
Lovastatin
Placebo
Coronary Events*
CumulativeIncidence
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
Years of Follow-up
0 1 2 3 4 5 5+ years
Lovastatin
Placebo 25% Risk Reduction
(p = 0.006)

N=3304 N=3277 N=3237 N=3192 N=3148 N=1691
N=3301 N=3258 N=3221 N=3174 N=3108 N=1659
# At Risk
Lovastatin
Placebo
Lovastatin
Placebo
0.00
0.01
0.02
0.03
0.04
0.05
Years of Follow-up
0 1 2 3 4 5 5+ Years
33% Risk Reduction
(p = 0.001)
CumulativeIncidence

Placebo Lovastatin
Event n=3301 n=3304 P-value
Total Mortality 77 80 N.S.
Cardiovascular 25 17 too few*
Non-cardiovascular 52 63 N.S.
*Too few for survival analyses

N=3304 N=3249 N=3188 N=3117 N=3059 N=1626
Lovastatin
N=3301 N=3234 N=3171 N=3105 N=3043 N=1603
Placebo
# At Risk
Lovastatin
Placebo
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Years of Follow-up
0 1 2 3 4 5 5+ years
CumulativeIncidence
P = NS
*Excludes non-melanoma skin cancer

Clinical benefit
appeared within the first year of treatment and
continued
was apparent for all LDL-C tertiles
 Range 90-235 mg/dl
was consistent for subgroups
 Women
 Risk Factors - Age, DM, HTN, Smokers

In conjunction with a prudent diet, regular exercise and
risk factor modification Lovastatin 20-40 mg/day could be
used to lower the risk of the first acute major coronary
event for primary prevention candidates -
 Men > 45 years, Women > 55 years
 HDL < 50 mg/dl
 LDL > 130 mg/dl

Multicenter trial with 2 treatment comparison
 A prospective, randomized, open, blinded end point
design comparing 2 antihypertensive regimen
 A double blind placebo controlled trial of atorvastatin
10mg/day in the substrate of patients with total
cholesterol ≤250mg/dl
Primary end point: nonfatal MI or CHD death
Planned follow up average of 5yr

 The aim of this study was to determine the outcome
benefits in those originally assigned atorvastatin in ASCOT
Trial—8 years after closure of the lipid-lowering arm of
the trial among the UK population
 Post trial mortality data were collected every 2-3months

• Type 2 diabetes mellitus
• Men and women 40–75
years of age
• LDL-C 160 mg/dL (4.14
mmol/L)
• TG 600 mg/dL
(6.78 mmol/L)
• 1 additional RF
– HTN (or on HTN
treatment)
– Retinopathy
– Albuminuria
– Current smoking
Patient Population
 Primary endpoint: time to first major CV event
(CHD death, nonfatal MI, unstable angina,
resuscitated cardiac arrest, coronary
revascularization, stroke
 Secondary endpoints: total mortality, any CV
endpoint, lipids, and lipoproteins
2838 patients 4-year follow-up
Atorvastatin 10 mg
(n=1428)
Double-blind placebo
(n=1410)

Placebo
(n = 1410)
Atorvastatin
(n = 1428)
Age
Mean (SD) years 61.8 (8.0) 61.5 (8.3)
<60 529 (38%) 558 (39%)
60–70 708 (50%) 703 (49%)
>70 173 (12%) 167 (12%)
Women 453 (32%) 456 (32%)
White ethnicity 1326 (94%) 1350 (95%)
BMI
Mean (SD), kg/m2 28.8 (3.5) 28.7 (3.6)
Obese (BMI >30 kg/m2) 538 (38%) 515 (36%)

Placebo
(n = 1410)
Mean (SD)
Atorvastatin
(n = 1428)
Mean (SD)
Total cholesterol (mg/dL)
(mmol/L)
207 (32)
5.35 (0.82)
207 (32)
5.36 (0.83)
LDL cholesterol (mg/dL)
(mmol/L)
117 (27)
3.02 (0.70)
118 (28)
3.04 (0.72)
HDL cholesterol (mg/dL)
(mmol/L)
55 (13)
1.42 (0.34)
54 (12)
1.39 (0.32)
Triglycerides* (mg/dL)
(mmol/L)
148 (104–212)
1.67 (1.17–2.40)
150 (106–212)
1.70 (1.20–2.40)
*Median (interquartile range)

0
80
160
240
Total Cholesterol (mg/dL)
Average difference 26%,
54 mg/dL; P<0.0001
MedianTC(mg/dL)*
Years of Study
0 1 2 3 4 4.5
0
40
80
120
160
MedianLDL-C(mg/dL)*
Years of Study
0 1 2 3 4 4.5
LDL Cholesterol (mg/dL)
Average difference 40%,
46 mg/dL; P<0.0001
Atorvastatin
Atorvastatin
Placebo
Placebo

0
5
10
15
CumulativeHazard,(%)
Years
0 1 2 3 4
Relative Risk Reduction 37% (95% CI, 17–52)
P = 0.001
1410
1428
1351
1392
Placebo
Atorvastatin
4.75
1306
1361
1022
1074
651
694
305
328
Placebo
127 events
Atorvastatin
83 events

Type of Event
Patients (%) with Event
Placebo
(n = 1410)
Atorvastatin 10 mg
(n = 1428)
Serious adverse event
possibly associated
with study drug
20 (1.1%) 19 (1.1%)
Discontinued for AE 145 (10%) 122 (9%)
Rhabdomyolysis 0 0
Myopathy AE report 1 (0.1%) 1 (0.1%)
CPK 10  ULN 10 (0.7%) 2 (0.1%)
ALT 3  ULN 14 (1%) 17 (1%)
AST 3  ULN 4 (0.3%) 6 (0.4%)

In patients with Type 2 DM with lower LDL-C levels,
atorvastatin 10 mg daily was safe, well tolerated &
significantly efficacious in reducing the risk of first CHD
events
 CARDS supports recommendations that made by the ADA
that patients with Type 2 DM should be considered as
candidates for statin treatment—even at lower LDL-C levels

Primary Prevention Trials of Lipid-Altering
Therapy Including Patients with Diabetes
Trial
Diabetic,*
n
Total N
in
Study
Lipid-Altering
Drug, mg/d
CHD* Risk vs
Placebo in Diabetic
Patients, %
CARDS † 2,838 2,838 Atorvastatin 10 –37 (p=.001)
AFCAPS 155 6,605 Lovastatin 20–40 ‡ –44 (NS)
HPS § 2,912 7,150 Simvastatin 40 –33 (p=.0003)
ASCOT 2,532 10,305 Atorvastatin 10 –16 (NS)
PROSPER 623 5,804 Pravastatin 40 +27 (NS)
HHS 135 4,081 Gemfibrozil 1200 –68 (NS)
Bays H et al. Future Cardiology 2005;1:39-59. | Colhoun HM et al. Lancet 2004;364:685-696. | Downs JR et al. JAMA
1998;279:1615-1622. | HPS Collaborative Group. Lancet 2003;361:2005-2016. | Sever PS et al. Lancet 2003;361:1149-
1158. | Shepherd J et al. Lancet 2002;360:1623-1630. | Koskinen P et al. Diabetes Care 1992;15:820-825.
* By history
† Prospective trial in diabetic subjects; others are subgroup analyses
‡ Mean 30 mg/d
§ Type 1 or 2 diabetes

Evaluated the effect of rosuvastatin compared with
placebo on carotid intima-media thickness (CIMT)
among asymptomatic patients at low risk for
cardiovascular disease
Study period was two-year
Randomized controlled trial
Rosuvastatin 40 mg daily vs placebo

 Primary Endpoint: Annualized rate of change in maximum CIMT
 Secondary Endpoint: Annualized rate of change in maximum CIMT derived
from the near and far walls of the right and left common carotid artery; the
right and left carotid bulb; the right and left internal carotid artery; and
annualized rate of change in mean CIMT for the near and far walls of the
right and left common carotid artery.
Rosuvastatin (40mg)
n=702
Placebo
n=282
984 asymptomatic patients with moderately elevated cholesterol and low risk of CVD
according to the National Cholesterol Education Program Adult Treatment Panel III guidelines criteria (0-1 risk factor
and LDL 120-190mg/dL or > 2 risk factors and LDL 120 to <160mg/dL with a 10-year coronary heart disease risk < 10%);
HDL-C <60mg/dL; triglycerides <500mg/dL; evidence of thickening of the walls of the extracranial carotid arteries as
measured by B-mode ultrasound (max CIMT between 1.2 and <3.5mm)
5:2 Randomized. Double-blinded. Placebo-controlled.
Mean age = 57 years. 40% Female.
R
6, 12, 18 and 24 mos. follow-up

-0.0014
0.0131
-0.005
0.000
0.005
0.010
0.015 • After two years,
treatment with
rosuvastatin was
associated with a
statistically significant
reduction in the rate of
progression of CIMT
thickening in overall
carotid segments, while
the placebo group
displayed progression
(p<0.001).
ChangeinCIMTfor12CarotidArterysites
(mm/year)
n = 702
n = 282
p < 0.001
Change in maximum CIMT with rosuvastatin vs. placebo
Rosuvastatin
Placebo

-0.0039
0.0084
-0.005
0.000
0.005
0.010 • After two years,
treatment with
rosuvastatin was
associated with a
progression of CIMT
thickening in common
carotid sites, while the
placebo group displayed
progression (p<0.001).
ChangeinCIMTforcommoncarotidsites(mm/year)
n = 702
n = 282
p < 0.001
Rosuvastatin
Placebo

-0.0040
0.0172
-0.005
0.000
0.005
0.010
0.015
0.020
• After two years,
treatment with
rosuvastatin was
associated with a
progression of CIMT
thickening in carotid
bulb sites, while the
placebo group displayed
progression (p<0.001).
ChangeinCIMTforcarotidbulbsites(mm/year)
n = 702
n = 282
p < 0.001
Rosuvastatin
Placebo

0.0039
0.0145
0.000
0.005
0.010
0.015
• After two years, treatment
with rosuvastatin was
associated with a
lower progression in
CIMT thickening in
internal carotid sites as
compared with the
placebo group (p=0.02)
ChangeinCIMTforinternalcarotidarterysites
(mm/year)
n = 702 n = 282
p = 0.02
Rosuvastatin Placebo

 Compared with placebo, subjects treated with
rosuvastatin had a marked reduction in LDL-cholesterol
(-49 versus -0.3 percent)
 The study was not designed to evaluate clinical events,
 It is uncertain how well changes in CIMT predict clinical
events, particularly in this low risk population.
 This study does not convincingly support the use of
high dose statins (such as rosuvastatin 40 mg daily) for
primary prevention in patients at low risk for CHD
events

JUPITER is the first large-scale, prospective study to
examine the role of statin therapy in individuals with low
to normal LDL-C levels, but with increased cardiovascular
risk identified by elevated CRP
Nearly half of all cardiovascular events occur in patients
who are apparently healthy and who have low or normal
levels of LDL-C
hsCRP predicts cardiovascular disease independent of LDL-
C levels

Rosuvastatin 20 mg (N=8901) MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
4-week
run-in
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
Placebo (N=8901)
Baseline LDLC 104 mg/dL
Baseline HDLC 49 mg/dL
Baseline hsCRP 4.2 mg/L
Women 6,800
Non-Caucasian 5,000

Placebo 251 /
8901
Rosuvastatin 142 /
8901
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Number Needed to Treat (NNT5) = 25
- 44 %
0 1 2 3 4
0.000.020.040.060.08
CumulativeIncidence
Number at Risk Follow-up (years)
Rosuvastatin
Placebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157
8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
JUPITER
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death

HR 0.53, CI 0.40-0.70
P < 0.00001
Rosuvastatin
Placebo
Myocardial Infarction, Stroke, or
Cardiovascular Death
Arterial Revascularization or
Hospitalization for Unstable Angina
HR 0.53, CI 0.40-0.69
P < 0.00001
0 1 2 3 4
0.000.010.020.030.040.050.06
CumulativeIncidence
Follow-up (years)
0 1 2 3 4
0.000.010.020.030.040.05
CumulativeIncidence
Follow-up (years)
Placebo
Rosuvastatin
- 47 %
- 47 %

*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death
Endpoint Rosuvastatin Placebo HR 95%CI P
Primary Endpoint* 142 251 0.56 0.46-0.69 <0.00001
Non-fatal MI 22 62 0.35 0.22-0.58 <0.00001
Any MI 31 68 0.46 0.30-0.70 <0.0002
Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003
Any Stroke 33 64 0.52 0.34-0.79 0.002
Revascularization
or Unstable Angina 76 143 0.53 0.40-0.70 <0.00001
MI, Stroke, CV Death 83 157 0.53 0.40-0.69 <0.00001

0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Men
Women
Age < 65
Age > 65
Smoker
Non-Smoker
Caucasian
Non-Caucasian
USA/Canada
Rest of World
Hypertension
No Hypertension
All Participants
N P for Interaction
11,001 0.80
6,801
8,541 0.32
9,261
2,820 0.63
14,975
12,683 0.57
5,117
6,041 0.51
11,761
10,208 0.53
7,586
17,802

0.25 0.5 1.0 2.0 4.0
Rosuvastatin Superior Rosuvastatin Inferior
Family HX of CHD
No Family HX of CHD
BMI < 25 kg/m
2
BMI 25-29.9 kg/m
BMI>30 kg/m
Metabolic Syndrome
No Metabolic Syndrome
Framingham Risk< 10%
Framingham Risk > 10%
hsCRP > 2 mg/L Only
All Participants
N P for Interaction
2,045 0.07
15,684
4,073 0.70
7,009
6,675
7,375 0.14
10,296
8,882 0.99
8,895
6,375
17,802
2
2
hsCRP > 2 mg/L Only 6,375

Event Rosuvastatin Placebo P
Muscle weakness 1,421 (16.0) 1,375 (15.4) 0.34
Myopathy 10 (0.1) 9 (0.1) 0.82
Rhabdomyolysis 1 (0.01)* 0 (0.0) --
Incident Cancer 298 (3.4) 314 (3.5) 0.51
Cancer Deaths 35 (0.4) 58 (0.7) 0.02
Hemorrhagic stroke 6 (0.1) 9 (0.1) 0.44
GFR (ml/min/1.73m2 at 12 mth) 66.8 (59.1-76.5) 66.6 (58.8-76.2) 0.02
ALT > 3xULN 23 (0.3) 17 (0.2) 0.34
Fasting glucose (24 mth) 98 (91-107) 98 (90-106) 0.12
HbA1c (% at 24 mth) 5.9 (5.7-6.1) 5.8 (5.6-6.1) 0.01
Glucosuria (12 mth) 36 (0.5) 32 (0.4) 0.64
Incident Diabetes** 270 (3.0) 216 (2.4) 0.01
*Occurred after trial completion, trauma induced. All values are median (interquartile range) or N (%)
**Physician reported

0.25 0.5 1.0 2 4
WOSCOPS Pravastatin
HPS Simvastatin
ASCOT-LLA Atorvastatin
JUPITER Rosuvastatin
PROVE-IT Atorvastatin
VS
Pravastatin
0.70 (0.50–0.98)
1.20 (0.98–1.35)
1.20 (0.91–1.44)
1.11 (0.67–1.83)
1.25 (1.05–1.54)
Statin Better Statin Worse
HR (95% CI)
PROSPER Pravastatin 1.34 (1.06–1.68)

Placebo 247 / 8901
Rosuvastatin 198 / 8901
HR 0.80, 95%CI 0.67-0.97
P= 0.02
- 20 %
0 1 2 3 4
0.000.010.020.030.040.050.06
CumulativeIncidence
Number at Risk
Follow-up (years)
Rosuvastatin
Placebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 227
8,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246

In this trial of low LDL/high hsCRP individuals who do not
currently qualify for statin therapy, rosuvastatin
significantly reduced
 All-cause mortality by 20 percent
 Incident myocardial infarction, stroke, and cardiovascular death by
47 percent

 Statin trials in primary prevention, starting with the
landmark WOSCOPS trial, have found substantial
relative reductions in cardiovascular events without an
increase in noncardiovascular mortality
 In view of the evidence, statins should be seriously
considered in people with diabetes at least by age 50 in
men and 60 in women
 Also, men aged 55 years or above with multiple risk
factors, and women aged 65 years or above, should be
seriously considered for generic statin use.

Mubashar A Choudry MD | Effects of statin or usual care on outcomes

Mubashar A Choudry MD | Effects of statin or usual care on outcomes

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