Dr ranjith mp.statins for primary prevention of coronary heart disease

Dr Ranjith MP

Senior Resident

Department of Cardiology

Government Medical college

Kozhikode

INTRODUCTION

Primary prevention is treating hypercholesterolemia inpatients 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

STATINS

Inhibit HMG-CoA reductase

Statin Pleiotropy

Earlier Clinical Trials

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

West of Scotland Coronary Prevention Study (WOSCOPS)

Designed to determine whether the administration ofpravastatin to men with hypercholesterolemia and nohistory of myocardial infarction reduced the combinedincidence of nonfatal myocardial infarction and deathfrom coronary heart disease

James Shepherd, et al, N Engl J Med 1995;333:1301-7

West of Scotland Coronary Prevention Study Group (WOS)

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


Baseline Characteristics (WOS)

WOSCOPS Endpoints

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

WOSCOPS Reduction in Lipids

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

LD

L c

ho

leste

rol

mg

/dL

placebo (intention -to-treat)

placebo (actual treatment)

pravastatin (intention-to-treat)

pravastatin (actual treatment)


Nonfatal MI or CHD Death(Primary Endpoint)

0

2

4

6

8

10

12

0 1 2 3 4 5 6

Years in Study

Percent

with

Events

Pravastatin

Placebo31%

Risk

Reduction

P=0.0001


Non-Fatal MI(Secondary Endpoint)

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=0.000

5


CHD Death(Secondary Endpoint)

0

0.5

1

1.5

2

2.5

0 1 2 3 4 5 6

Years in Study

Percent

with

Events

Pravastain Placebo28%

Risk

Reduction

P=0.13


Cardiovascular Death

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 Placebo32%

Risk

Reduction

P=0.03

3


Total Mortality

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


Coronary Interventions

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


WOSCOPS Results/Clinical Events

Event % Reduction p value

Nonfatal MI + CHD death 31% < 0.001

Definite nonfatal MI 31% < 0.001

Definite CHD death 28% 0.13 (NS)

Definite and suspected CHD death 33% 0.042

All cardiovascular deaths 32% 0.033

Total mortality 22% 0.051 (NS)

CABG/PTCA 37% 0.029


WOSCOPS Conclusions

Treatment with pravastatin significantly reduced theincidence of myocardial infarction and death fromcardiovascular causes without adversely affecting therisk of death from noncardiovascular causes in menwith moderate hypercholesterolemia and no history ofmyocardial infarction

Pravastatin had no effect on noncardiovascular-relatedhospital admissions

Pravastatin therapy also resulted in a 30 percentreduction in the risk of developing diabetes


WOS Projected Benefits

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


Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese

(MEGA) Trial

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 + Pravastatin10-20 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/dLMean 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.

Eishu Nango et al, lancet 2006;368:11555-63

MEGA Trial: Cholesterol and Triglyceride Levels

-11.5

-18.0

5.8

-3.1-2.1-3.2

3.21.3

-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

CholesterolLDL HDL Triglycerides

mg/d

L


MEGA Trial: Primary Composite Endpoint

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

# p

er

1000 p

ati

en

t years


MEGA Trial: Secondary Endpoints

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+TIAPravastatin+diet Diet

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

er

1000 p

ati

en

t years

p=0.23


MEGA Trial: Safety Data

5.5 5.7

0

1

2

3

4

5

6


# p

er

10

00

pa

tie

nt

ye

ars

• 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%

Pravastatin+diet Diet%

Frequency of cancer

(per 1000 patient years)

Frequency of elevated liver function

abnormalities (%)


MEGA Trial: Summary

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

ALLHAT-LLT: Effects of statin or usual care on outcomes

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)

ALLHAT: Clinical implications

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 usedALLHAT-LLT results are consistent with other statin trials

Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)

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

Shepherd J et al. Lancet 2002;360:1623–1630

Major Endpoints: PROSPER

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


Mortality by Cause: PROSPER

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

Shepherd J et al. Lancet 2002;360:1623–1630Shepherd J et al. Lancet 2002;360:1623–1630

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


PROSPER Conclusion

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)

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

Downs JR, et al, JAMA 1998;279:1615-1622

AFCAPS/TexCAPS Endpoints

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 EffectsDowns JR, et al, JAMA 1998;279:1615-1622

Baseline Characteristics(AFCAPS)


Baseline Lipid LevelsCompared with U.S. Reference Population Based Upon NHANES III

Lipid Level(mg/dL)

Wilford HallAvg + SD(mg/dL)N=6605

NHANESPercentile1

U.S. NHANES Ref.Population2

Mean + SD(mg/dL)

Mean TCMean LDLMean HDL Men WomenMedian TG

221 + 21150 + 17

36 + 540 + 5

158 + 76

5160

251663

225 + 45142 + 3750 + 16

140 + 120

1 Percentile ranks from US NHANES III reference population for study population averages2 Men aged 45-73, and women aged 55-73, without cardiovascular disease


AFCAPS Reduction in Lipids-year

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


Percent Change in Lipid Parameters Baseline to Year 1

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

Pe

rce

nt

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


Primary Endpoint ~ First Acute Major Coronary Event*

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-up0 1 2 3 4 5 5+ Years

Cu

mu

lati

ve

Inci

den

ce

37% Risk Reduction(p < 0.001)

*Includes unstable angina, fatal and non-fatal MI &sudden cardiac death


Primary Endpoint ~ First Acute Major Coronary Event*

40

66

100

135

183

23

46

7091

116

0

50

100

150

200

250

1 2 3 4 5+ years

Years Since Randomization

Cum

ula

tive N

um

ber

of

Part

icip

ants

wit

h E

vents

Placebo (n=3301)

Lovastatin (n=3304)

Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac

Death

reduced by 37% (p < 0.0008)


Lovastatin Reduced the Risk of First Acute Major Coronary Events

-37

-46

-31

-58

-38-42

-70

-60

-50

-40

-30

-20

-10

0

Pe

rce

nt

Ris

k R

ed

ucti

on

Men

N=5608

Women

N=997

> Median

by Age

N=3180

Smokers

N=818

Hypertension

N=1448

Diabetes

N=156


Lovastatin Reduced the Risk of First Acute Major Coronary Events in All Baseline LDL Tertiles

-34 -36-41

-60

-50

-40

-30

-20

-10

0

90.4-141.9 142.0-156.8 156.9-235.4

Pe

rce

nt

Ch

an

ge

Relative Risk Reduction

Baseline LDL Tertiles


AFCAPS/TexCAPSRole of Baseline LDL on Outcomes

54 52

77

3733

46

0

10

20

30

40

50

60

70

80

90

< 142, n=2210 143-156, n=2195 > 157, n=2199

Nu

mb

er o

f E

ven

ts

Placebo

Lovastatin

Baseline LDL Level (mg/dL)


AFCAPS/TexCAPSRole of Baseline HDL on Outcomes

7168

4440 41

35

0

10

20

30

40

50

60

70

80

< 34 35-39 > 40

Nu

mb

er o

f E

ven

ts

Placebo

Lovastatin

Baseline HDL Level (mg/dL)


Secondary Endpoint AnalysesFatal and Non-Fatal MI

N=3304 N=3281 N=3249 N=3214 N=3174 N=1717N=3301 N=3270 N=3237 N=3200 N=3148 N=1692

# At RiskLovastatinPlacebo

0.00

0.01

0.02

0.03

Years of Follow-up

0 1 2 3 4 5 5+ years

Lovastatin

Placebo

Cum

ula

tive Incid

ence 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

Cum

ula

tive Incid

ence

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

Cum

ula

tive Incid

ence

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*

Cum

ula

tive Incid

ence

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)


AFCAPS/TexCAPSCoronary Revascularizations

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-up0 1 2 3 4 5 5+ Years

33% Risk Reduction(p = 0.001)

Cum

ula

tive

Incid

ence


AFCAPS/TexCAPSMortality

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


Tertiary AnalysisFatal and Non-Fatal Cancer*

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 RiskLovastatinPlacebo

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

Cum

ula

tive I

ncid

ence

P = NS

*Excludes non-melanoma skin cancer


AFCAPS/TexCAPS Summary of Results

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


AFCAPS/TexCAPS Conclusions

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


The Anglo-Scandinavian Cardiac outcomes Trial(ASCOT )

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 Anglo-Scandinavian Cardiac outcomes Trial

Sever PS et al, Lancet 2003; 361:1149.

ASCOT-LLA trial

Sever PS et al, Lancet 2003; 361:1149.

ASCOT-LLA trial

Sever PS et al, Eur Heart J 2008;29:499–508

ASCOT-LLA trial Extension

Sever PS et al, Eur Heart J 2008;29:499–508

The Anglo-Scandinavian Cardiac OutcomesTrial: 11-year mortality follow-up of the

lipid-lowering arm in the UK

• 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

Sever PS et al, Eur Heart J August 28, 2011

ASCOT-LLA 11 year mortality study profile


ASCOT-LLA trial Extension


Collaborative Atorvastatin Diabetes Study (CARDS)

Colhoun HM et al. Lancet 2004;364:685-696.

• 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)

CARDS: Patient Baseline Characteristics

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%)



CARDS: Patient Baseline Lipids

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)

CARDS: Lipid Levels by Treatment


0

80

160

240

Total Cholesterol (mg/dL)

Average difference 26%,

54 mg/dL; P<0.0001

Media

n T

C (

mg/d

L)*

Years of Study

0 1 2 3 4 4.50

40

80

120

160

Med

ian

LD

L-C

(m

g/d

L)*

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

PlaceboPlacebo

CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke


0

5

10

15

Cum

ula

tive H

azard

, (%

)

Years0 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

Placebo127 events

Atorvastatin83 events

CARDS: Adverse and Serious Adverse Events


Type of Event

Patients (%) with Event

Placebo(n = 1410)

Atorvastatin 10 mg(n = 1428)

Serious adverse eventpossibly 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

CARDS Implications and Clinical Relevance


Primary Prevention Trials of Lipid-Altering Therapy Including Patients with Diabetes

TrialDiabetic,*

n

Total N in

StudyLipid-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

Measuring Effects of Intima-Media Thickness: An Evaluation of Rosuvastatin

METEOR Trial

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

Crouse JR 3rd, et al, JAMA 2007; 297:1344.

METEOR Trial: Study Design

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 CVDaccording 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

METEOR Trial: Primary Endpoint

-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).

Change in C

IMT

for

12 C

aro

tid A

rtery

sites

(mm

/ye

ar)

n = 702

n = 282

p < 0.001

Change in maximum CIMT with rosuvastatin vs. placebo

Rosuvastatin

Placebo

METEOR Trial: Secondary Endpoint

-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


(p<0.001).

Change in C

IMT

for

com

mon c

aro

tid s

ites (

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


(p<0.001).

Change in C

IMT

for

caro

tid b

ulb

sites (

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)

Change in C

IMT

for

inte

rnal caro

tid a

rtery

sites

(mm

/ye

ar)

n = 702 n = 282

p = 0.02


Rosuvastatin Placebo

METEOR Trial: Limitations & Summary

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

Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating

Rosuvastatin (JUPITER)

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

Ridker et al, NEJM 2008359:2195-07

JUPITER


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

0.0

00

.02

0.0

40

.06

0.0

8

Cu

mu

lati

ve

In

cid

en

ce

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

JUPITERGrouped Components of the Primary Endpoint


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

0.0

00.0

10.0

20.0

30.0

40.0

50.0

6

Cu

mu

lati

ve I

ncid

en

ce

Follow-up (years)

0 1 2 3 4

0.0

00.0

10.0

20.0

30.0

40.0

5

Cu

mu

lati

ve I

ncid

en

ce

Follow-up (years)

Placebo

Rosuvastatin

- 47 %- 47 %

JUPITERIndividual components of the Primary Endpoint

*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 <0.00001Any MI 31 68 0.46 0.30-0.70 <0.0002

Non-fatal Stroke 30 58 0.52 0.33-0.80 0.003Any Stroke 33 64 0.52 0.34-0.79 0.002

Revascularizationor 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


JUPITER

Primary Endpoint – Subgroup Analysis


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


JUPITER

Primary Endpoint – Subgroup Analysis

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/m2

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

JUPITER

Adverse Events and Measured Safety Parameters


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

JUPITER

Statins and the Development of Diabetes


0.25 0.5 1.0 2 4

WOSCOPS Pravastatin

HPS Simvastatin

ASCOT-LLA Atorvastatin

JUPITER Rosuvastatin

PROVE-IT AtorvastatinVS

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)

JUPITER

Secondary Endpoint – All Cause Mortality


Placebo 247 /

8901

Rosuvastatin 198 / 8901

HR 0.80, 95%CI 0.67-0.97

P= 0.02

- 20 %

0 1 2 3 4

0.0

00

.01

0.0

20

.03

0.0

40

.05

0.0

6

Cu

mu

lati

ve

In

cid

en

ce

Number at RiskFollow-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

JUPITERConclusions

In this trial of low LDL/high hsCRP individuals who do not currently qualify for statin therapy, rosuvastatinsignificantly reduced

All-cause mortality by 20 percent

Incident myocardial infarction, stroke, and cardiovascular death by 47 percent


CONCLUDE

Statin trials in primary prevention, starting with thelandmark WOSCOPS trial, have found substantialrelative reductions in cardiovascular events withoutan increase in noncardiovascular mortality

In view of the evidence, statins should be seriouslyconsidered in people with diabetes at least by age 50in men and 60 in women

Also, men aged 55 years or above with multiple riskfactors, and women aged 65 years or above, should beseriously considered for generic statin use.

THANK YOU

Dr ranjith mp.statins for primary prevention of coronary heart disease

Education

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