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Measuring Effects of Intima-Media Thickness

Dr Mubashar A Choudry Md


INTRODUCTION 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


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) ď śDesigned 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


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 LDL cholesterol mg/dL

200

placebo (intention -to-treat)

180

placebo (actual treatment)

160

pravastatin (intention-to-treat)

140

pravastatin (actual treatment)

120 100 6

12

18

24

30 36 Months

42

48

20% reduction in TC 26% reduction in LDL 12% reduction in Trigs 5% increase in HDL

54

60


Nonfatal MI or CHD Death (Primary Endpoint) 12 Pravastatin

10

31% Risk Reduction

Placebo

8 Percent with 6 Events 4

P=0.0001

2 0 0

1

2

3 Years in Study

4

5

6


Non-Fatal MI (Secondary Endpoint) 10 Pravastain

8

Placebo

31% Risk Reduction

Percent 6 with Events 4

P=0.0005

2 0 0

1

2

3

Years in Study

4

5

6


CHD Death (Secondary Endpoint) 2.5 Pravastain

2

Placebo

28% Risk Reduction

Percent 1.5 with Events 1

P=0.13

0.5 0 0

1

2

3 Years in Study

4

5

6


Cardiovascular Death 3.5 Pravastain

3

Placebo

32% Risk Reduction

2.5 Percent 2 with Events 1.5 1

P=0.033

0.5 0 0

1

2

3 Years in Study

4

5

6


Total Mortality 6 Pravastain

5

Placebo

22% Risk Reduction

4

Percent with 3 Events 2

P=0.051

1 0 0

1

2

3 Years in Study

4

5

6


Coronary Interventions Intervention

Coronary Angiography PTCA / CABG

Placebo (n= 3293)

Pravastatin (n=3302)

Risk Reductions

128

90

31%

0.007

80

51

37%

0.009

p-value


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 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 noncardiovascularrelated hospital admissions Pravastatin therapy also resulted in a 30 percent reduction 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 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.

Diet Modification

Diet Modification + Pravastatin

n=3,966

n=3,866

10-20 mg/day

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.


MEGA Trial: Cholesterol and Triglyceride Levels Total Cholesterol

LDL

HDL

5.8

mg/dL

4

Triglycerides

3.2

1.3

0 -4

-2.1

-3.2

-3.1

-8 -12 -16 -20

â&#x20AC;˘HDL increase was greater in the pravastatin group

-11.5 -18.0

Pravastatin+diet

â&#x20AC;˘ Total cholesterol, LDL, Triglyceride reduction was larger in the pravastatin group

Diet


MEGA Trial: Primary Composite Endpoint Primary composite endpoint of coronary heart disease events p = 0.01 5.0

# per 1000 patient years

5 4

3.3

3 2 1 0 Pravastatin+diet

Diet

3.3 vs 5.0 per 1000 patient years, hazard ratio 0.67, p=0.01


MEGA Trial: Secondary Endpoints •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) 3.8

4

p=0.055

2

1

0

# per 1000 patient years

3

3.0

p=0.33

2.7

2.5

p=0.232.6 2.0

p=0.03

1.6

0.9

Total mortality

MI Pravastatin+diet

Stroke Diet

Cerebral infarction+TIA


MEGA Trial: Safety Data Frequency of cancer (per 1000 patient years)

5.5

5.7

3.0%

5

2.5%

4

2.0%

3

1.5%

2

1.0%

1

0.5%

0

0.0%

2.8%

2.8%

Pravastatin+diet

Diet

%

# per 1000 patient years

6

Frequency of elevated liver function abnormalities (%)

Pravastatin+diet

Diet

â&#x20AC;˘ There was no difference in the frequency of cancer or elevated liver function abnormalities and no cases of rhabdomyolysis.


MEGA Trial: Summary ď ś Among Japanese patients with hypercholesterolemia,

treatment with pravastatin was associated with a reduction in the primary composite endpoint of coronary heart disease ď ś 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. ď ś 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) 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

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 ALLHAT-LLT:

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) *Arm discontinued

Usual care (n = 5185) ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997, 2998-3007.


ALLHAT-LLT: Effects of statin or usual care on outcomes 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) All-cause mortality

CHD death + nonfatal MI

18

18

15

Cumulative rate (%)

12

12

9

9

6

6

3

3

0

0 0

1

2

3

4

RR = 0.91 (95% CI, 0.79–1.04)

15

RR = 0.99 (95% CI, 0.89–1.11)

5

Time to death (years)

Pravastatin

6

0

1

2

3

4

Time to event (years)

Usual care

5

6


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 used ALLHAT-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


Major Endpoints: PROSPER Endpoint

Pravastatin (%)

Placebo (%)

Hazard ratio

p

Primary endpoint: CHD death/MI/stroke

14.1

16.2

0.85

0.014

10.1

12.2

0.81

0.006

4.7

4.5

1.03

0.81

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

15.7

18.0

0.85

0.012

Secondary endpoints: CHD death/MI Fatal or nonfatal stroke Other outcomes:

All CV events


Mortality by Cause: PROSPER Cause of death

Pravastatin (%)

Placebo (%)

Hazard ratio 0.76

p

CHD

3.3

4.2

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

10.3

10.5

All causes

0.97

0.74


PROSPER Conclusion ď śPravastatin given for 3 years reduced the risk of coronary

disease in elderly individuals ď ś PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people


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


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 Effects


Baseline Characteristics(AFCAPS)


Baseline Characteristics(AFCAPS)


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

Lipid Level (mg/ dL) M ean TC M ean LDL M ean H DL M en Women M edian TG 1 2

Wilford H all A vg + SD (mg/ dL) N =6605

N H A N ES Percentile1

221 + 21 150 + 17

51 60

36 + 5 40 + 5 158 + 76

25 16 63

U.S. N H A NES Ref. Population 2 M ean + SD (mg/ dL) 225 + 45 142 + 37 50 + 16

140 + 120

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


AFCAPS Reduction in Lipids-year Placebo

Lovastatin

Mean TC

228.1 + 27.7

183.7 + 23.8

Mean LDL-C

156.4 + 24.5

114.6 + 20.1

Mean HDL-C

37.5 + 7.9

39.3 + 8.0

162.8 + 82.1

142.8 + 72.8

Mean LDL-C/HDL-C

4.3 1.1

3.0 + 0.8

Mean TC/HDL-C

6.3 + 2.5

4.8 + 1.0

Median TG Ratios

+


Percent Change in Lipid Parameters Baseline to Year 1 30 20

Percent

10

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%)

0.9

1.5

1.2

6

1.7

1.6

0 -2.3

-10 -20

-18.4 -25

-30 -40

-15

TC

LDL

Placebo Lovastatin, avg dose 30 mg HDL

TG

-21.8 -28 TC/HDL

LDL/HDL


Primary Endpoint ~ First Acute Major Coronary Event*

Cumulative Incidence

0.06

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

0.05

37% Risk Reduction (p < 0.001)

0.04 0.03

Lovastatin

0.02 0.01 0.00

# At Risk Lovastatin Placebo

0

1

2

N=3304 N=3301

N=3270 N=3251

N=3228 N=3211

3

4

N=3184 N=3159

N=3134 N=3092

Years of Follow-up

5 5+ Years

N=1688 N=1644


Cumulative Number of Participants with Events

Primary Endpoint ~ First Acute Major Coronary Event* Fatal & Non-fatal MI, Unstable Angina, Sudden Cardiac Death reduced by 37% (p < 0.0008) 250 Placebo (n=3301) Lovastatin (n=3304) 183 200 135

150 100

100 50

91 70

66 40

116

46 23

0 1

2 3 4 Years Since Randomization

5+ years


Lovastatin Reduced the Risk of First Acute Major Coronary Events

0

Men N=5608

Women N=997

> Median by Age N=3180

Smokers Hypertension Diabetes N=818 N=1448 N=156

Percent Risk Reduction

-10 -20 -30 -40 -50 -60 -70

-31 -37

-38 -46 -58

-42


Lovastatin Reduced the Risk of First Acute Major Coronary Events in All Baseline LDL Tertiles 0

Percent Change

-10 -20 -30 -40 -50

-34

-36

Relative Risk Reduction

-41

-60 90.4-141.9

142.0-156.8 Baseline LDL Tertiles

156.9-235.4


AFCAPS/TexCAPS Role of Baseline LDL on Outcomes 90 80 Number of Events

70 60 50 40

77

Placebo Lovastatin 54

52 37

46 33

30 20 10 0 < 142, n=2210

143-156, n=2195

> 157, n=2199

Baseline LDL Level (mg/dL)


AFCAPS/TexCAPS Role of Baseline HDL on Outcomes 80

71

68

Number of Events

70

Placebo Lovastatin

60 50

40

40

41

44 35

30 20 10 0 < 34

35-39

Baseline HDL Level (mg/dL)

> 40


Secondary Endpoint Analyses Cardiovascular Events*

Fatal and Non-Fatal MI

0.08

0.03

0.02

Lovastatin

0.01

Cumulative Incidence

Cumulative Incidence

40% Risk Reduction (p = 0.002)

Placebo

25% Risk Reduction (p = 0.003)

Placebo

0.07

0.06

0.05

0.04

Lovastatin

0.03

0.02

0.01

0.00

0.00

0

1

2

3

4

5

# At Risk Lovastatin Placebo

N=3304 N=3301

N=3281 N=3270

N=3249 N=3237

N=3214 N=3200

N=3174 N=3148

0

5+ years

Years of Follow-up

1

3

4

5

5+ years

Years of Follow-up

N=1717 N=1692

Unstable Angina

Coronary Events*

0.03

0.07

Placebo

32% Risk Reduction (p = 0.02)

0.02

0.01

Lovastatin

0.06

Cumulative Incidence

Cumulative Incidence

2

# At Risk Lovastatin N=3304 N=3260 N=3206 N=3147 N=3088 N=1651 Placebo N=3301 N=3242 N=3187 N=3124 N=3045 N=1615

25% Risk Reduction (p = 0.006)

Placebo

0.05

0.04

0.03

Lovastatin

0.02

0.01

0.00

0.00

0

1

2

3

4

Years of Follow-up

5

# At Risk Lovastatin N=3304 N=3281 N=3250 N=3217 N=3174 N=1707 Placebo N=3301 N=3267 N=3240 N=3205 N=3150 N=1678

5+ years

0

1

2

3

4

Years of Follow-up

5

# At Risk Lovastatin N=3304 N=3264 N=3215 N=3160 N=3106 N=1666 Placebo N=3301 N=3246 N=3201 N=3141 N=3069 N=1634

5+ years


AFCAPS/TexCAPS Coronary Revascularizations

Cumulative Incidence

0.05

0.04

33% Risk Reduction

Placebo

(p = 0.001)

0.03

0.02

Lovastatin 0.01

0.00

0

# At Risk Lovastatin Placebo

1

2

3

4

5

Years of Follow-up N=3304 N=3301

N=3277 N=3258

N=3237 N=3221

N=3192 N=3174

N=3148 N=3108

N=1691 N=1659

5+ Years


AFCAPS/TexCAPS Mortality Event

Placebo Lovastatin n=3301 n=3304

P-value

Total Mortality

77

80

N.S.

Cardiovascular

25

17

too few*

Non-cardiovascular

*Too few for survival analyses

52

63

N.S.


Tertiary Analysis Fatal and Non-Fatal Cancer* 0.08

*Excludes non-melanoma skin cancer

Cumulative Incidence

0.07

P = NS Placebo

0.06 0.05

Lovastatin 0.04 0.03 0.02 0.01 0.00 0

# At Risk Lovastatin Placebo

1

2

3

4

5

Years of Follow-up N=3304 N=3301

N=3249 N=3234

N=3188 N=3171

N=3117 N=3105

N=3059 N=3043

N=1626 N=1603

5+ years


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


ASCOT-LLA trial


ASCOT-LLA trial


ASCOT-LLA trial


ASCOT-LLA trial


ASCOT-LLA trial Extension


The Anglo-Scandinavian Cardiac Outcomes Trial: 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


ASCOT-LLA 11 year mortality study profile


ASCOT-LLA trial Extension


ASCOT-LLA trial Extension


ASCOT-LLA trial Extension


ASCOT-LLA trial Extension


Collaborative Atorvastatin Diabetes Study (CARDS) Atorvastatin 10 mg (n=1428)

Patient Population • Type 2 diabetes mellitus • Men and women 40–75 years of age • LDL-C 160 mg/dL (4.14 mmol/L)

2838 patients

4-year follow-up Double-blind placebo (n=1410)

• TG 600 mg/dL (6.78 mmol/L) • 1 additional RF –

HTN (or on HTN treatment)

Retinopathy

Albuminuria

Current smoking

 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


CARDS: Patient Baseline Characteristics Placebo (n = 1410)

Atorvastatin (n = 1428)

Mean (SD) years

61.8 (8.0)

61.5 (8.3)

<60

529 (38%)

558 (39%)

60â&#x20AC;&#x201C;70

708 (50%)

703 (49%)

>70

173 (12%)

167 (12%)

Women

453 (32%)

456 (32%)

1326 (94%)

1350 (95%)

Mean (SD), kg/m2

28.8 (3.5)

28.7 (3.6)

Obese (BMI >30 kg/m2)

538 (38%)

515 (36%)

Age

White ethnicity BMI


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)

148 (104–212) 1.67 (1.17–2.40)

150 (106–212) 1.70 (1.20–2.40)

Triglycerides* (mg/dL) (mmol/L)

*Median (interquartile range)


Total Cholesterol (mg/dL)

LDL Cholesterol (mg/dL)

Average difference 26%,

Average difference 40%,

54 mg/dL; P<0.0001

46 mg/dL; P<0.0001

240

Median LDL-C (mg/dL)*

Median TC (mg/dL)*

CARDS: Lipid Levels by Treatment

Placebo

160

Atorvastatin 80 0

0

1

2

3

Years of Study

4 4.5

160

Placebo

120 80

Atorvastatin

40 0 0

1

2

3

Years of Study

4 4.5


Cumulative Hazard, (%)

CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke 15

Relative Risk Reduction 37% (95% CI, 17â&#x20AC;&#x201C;52) P = 0.001

Placebo 127 events

10 5 0 0

Placebo 1410 Atorvastatin 1428

Atorvastatin 83 events

1

2

1351 1392

1306 1361

3

4

4.75

1022 1074

651 694

305 328

Years


CARDS: Adverse and Serious Adverse Events 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%)

0

0

1 (0.1%)

1 (0.1%)

10 (0.7%)

2 (0.1%)

ALT 3  ULN

14 (1%)

17 (1%)

AST 3  ULN

4 (0.3%)

6 (0.4%)

Type of Event

Rhabdomyolysis Myopathy AE report CPK 10  ULN


CARDS Implications and Clinical Relevance 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

CARDS †

Total N Diabetic,* in n Study

Lipid-Altering Drug, mg/d

CHD* Risk vs Placebo in Diabetic Patients, %

2,838

2,838

Atorvastatin 10

–37 (p=.001)

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)

AFCAPS

* † ‡ §

By history Prospective trial in diabetic subjects; others are subgroup analyses Mean 30 mg/d Type 1 or 2 diabetes

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;361:11491158. | Shepherd J et al. Lancet 2002;360:1623-1630. | Koskinen P et al. Diabetes Care 1992;15:820-825.


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


METEOR Trial: Study Design 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 Rosuvastatin (40mg)

n=702

Placebo

n=282 6, 12, 18 and 24 mos. follow-up

   

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.


METEOR Trial: Primary Endpoint Change in maximum CIMT with rosuvastatin vs. placebo

Change in CIMT for 12 Carotid Artery sites (mm/year)

0.015

0.0131

0.010

p < 0.001

0.005

0.000

Rosuvastatin

n = 282

n = 702

Placebo

-0.0014

-0.005

â&#x20AC;˘ 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).


METEOR Trial: Secondary Endpoint Change in CIMT for common carotid sites (mm/year)

Change in maximum CIMT with rosuvastatin vs. placebo

0.010

0.0084

0.005

0.000

-0.005

p < 0.001

Rosuvastatin

n = 282

n = 702

Placebo

-0.0039

â&#x20AC;˘ After two years, treatment with rosuvastatin was associated with a statistically significant reduction in the rate of progression of CIMT thickening in common carotid sites, while the placebo group displayed progression (p<0.001).


METEOR Trial: Secondary Endpoint

Change in CIMT for carotid bulb sites (mm/year)

Change in maximum CIMT with rosuvastatin vs. placebo

0.020

0.0172

0.015 p < 0.001

0.010 0.005 Rosuvastatin

n = 282

0.000

n = 702

Placebo

-0.005

-0.0040

â&#x20AC;˘ After two years, treatment with rosuvastatin was associated with a statistically significant reduction in the rate of progression of CIMT thickening in carotid bulb sites, while the placebo group displayed progression (p<0.001).


METEOR Trial: Secondary Endpoint

Change in CIMT for internal carotid artery sites (mm/ year)

Change in maximum CIMT with rosuvastatin vs. placebo

0.0145

0.015

0.010

0.005

0.000

â&#x20AC;˘ After two years, treatment with rosuvastatin was associated with a statistically significant lower progression in CIMT thickening in internal carotid sites as compared with the placebo group (p=0.02)

p = 0.02

0.0039

n = 702

n = 282

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 LDLC levels


JUPITER No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dL 4-week hsCRP >2 mg/L run-in

Rosuvastatin 20 mg (N=8901) Placebo (N=8901)

Baseline LDLC Baseline HDLC Baseline hsCRP Women Non-Caucasian

104 mg/dL 49 mg/dL 4.2 mg/L 6,800 5,000

MI Stroke Unstable Angina CVD Death CABG/PTCA


JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death 0.08

HR 0.56, 95% CI 0.46-0.69 P < 0.00001

Placebo 251 / 8901

0.04

- 44 %

Rosuvastatin 142 / 8901

0.00

0.02

Cumulative Incidence

0.06

Number Needed to Treat (NNT5) = 25

0

1

2

4

Follow-up (years)

Number at Risk Rosuvastatin Placebo

3

8,901 8,901

8,631 8,621

8,412 8,353

6,540 6,508

3,893 3,872

1,958 1,963

1,353 1,333

983 955

544 534

157 174


JUPITER Grouped Components of the Primary Endpoint Arterial Revascularization or Hospitalization for Unstable Angina

HR 0.53, CI 0.40-0.69 P < 0.00001

HR 0.53, CI 0.40-0.70 P < 0.00001 0.06

0.05

Myocardial Infarction, Stroke, or Cardiovascular Death

0.04 0.03 0.02

- 47 % Rosuvastatin

0.00

0.01

0.01

Rosuvastatin

Cumulative Incidence

0.04 0.03 0.02

- 47 %

0.00

Cumulative Incidence

Placebo

0.05

Placebo

0

1

2

Follow-up (years)

3

4

0

1

2

3

Follow-up (years)

4


JUPITER Individual components of the Primary Endpoint Endpoint

RosuvastatinPlacebo HR

Primary Endpoint*

142

251

Non-fatal MI Any MI

22

62

31

Non-fatal Stroke Any Stroke

68 30 33

95%CI

P

0.56 0.46-0.69

<0.00001

0.35 0.22-0.58 <0.00001 0.46 0.30-0.70 <0.0002

58 64

0.52 0.33-0.80 0.52 0.34-0.79

0.003 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

*Nonfatal MI, nonfatal stroke, revascularization, unstable angina, CV death


JUPITER Primary Endpoint â&#x20AC;&#x201C; Subgroup Analysis N Men Women

P for Interaction

11,001 6,801

0.80

Age < 65 Age > 65

8,541 9,261

0.32

Smoker Non-Smoker

2,820 14,975

0.63

Caucasian Non-Caucasian

12,683 5,117

0.57

USA/Canada Rest of World

6,041 11,761

0.51

Hypertension No Hypertension

10,208 7,586

0.53

All Participants

17,802

0.25

0.5 Rosuvastatin Superior

1.0

2.0 Rosuvastatin Inferior

4.0


N

P for Interaction

Family HX of CHD No Family HX of CHD

2,045 15,684

0.07

BMI < 25 kg/m2 BMI 25-29.9 kg/m 2 BMI> 30 kg/m 2

4,073 7,009 6,675

0.70

Metabolic Syndrome No Metabolic Syndrome

7,375 10,296

0.14

Framingham Risk < 10% Framingham Risk > 10%

8,882 8,895

0.99

hsCRP > 2 mg/L Only hsCRP > 2 mg/L Only

6,375 6,375

JUPITER Primary Endpoint â&#x20AC;&#x201C; Subgroup Analysis

All Participants

17,802 0.25

0.5 Rosuvastatin Superior

1.0

2.0 Rosuvastatin Inferior

4.0


JUPITER Adverse Events and Measured Safety Parameters Event

Rosuvastatin Placebo

Muscle weakness Myopathy Rhabdomyolysis Incident Cancer Cancer Deaths Hemorrhagic stroke

1,421 10 1 298 35 6

GFR (ml/min/1.73m at 12 mth) ALT > 3xULN 2

(16.0) (0.1) (0.01)* (3.4) (0.4) (0.1)

P

1,375 (15.4) 9 (0.1) 0.82 0 (0.0) -314 (3.5) 0.51 58 (0.7) 0.02 9 (0.1) 0.44

66.8 (59.1-76.5) 66.6 (58.8-76.2) 23 (0.3) 17 (0.2) 0.34

Fasting glucose (24 mth) 98 HbA1c (% at 24 mth) 5.9 Glucosuria (12 mth) 36 Incident Diabetes** 270

(91-107) (5.7-6.1) (0.5) (3.0)

*Occurred after trial completion, trauma induced. **Physician reported

98 5.8 32 216

(90-106) (5.6-6.1) (0.4) (2.4)

0.34

0.02

0.12 0.01 0.64 0.01

All values are median (interquartile range) or N (%)


JUPITER Statins and the Development of Diabetes HR

(95% CI)

WOSCOPS

Pravastatin

0.70 (0.50–0.98)

PROSPER

Pravastatin

1.34 (1.06–1.68)

HPS

Simvastatin

1.20 (0.98–1.35)

ASCOT-LLA

Atorvastatin

1.20 (0.91–1.44)

PROVE-IT

Atorvastatin

1.11 (0.67–1.83)

VS

Pravastatin JUPITER

Rosuvastatin

1.25 (1.05–1.54) 0.25

0.5

Statin Better

1.0

2

Statin Worse

4


0.05

0.06

HR 0.80, 95%CI 0.67-0.97 P= 0.02

Placebo 247 / 8901

- 20 %

JUPITER

0.04

0.03 0.02

Rosuvastatin 198 / 8901

0.00

0.01

Cumulative Incidence

Secondary Endpoint â&#x20AC;&#x201C; All Cause Mortality

0 Number at Risk Rosuvastatin 8,901 Placebo 8,901

1

2

3

4

Follow-up (years) 8,847 8,852

8,787 8,775

6,999 6,987

4,312 4,319

2,268 2,295

1,602 1,614

1,192 1,196

683 684

227 246


JUPITER Conclusions

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


CONCLUDE 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.


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Mubashar A Choudry MD | Measuring Effects of Intima-Media Thickness  

Dr. Mubashar A Choudry MD explained here about measuring the effects of intima-media thickness. Dr. Mubashar Choudry is a great cardiologist...

Mubashar A Choudry MD | Measuring Effects of Intima-Media Thickness  

Dr. Mubashar A Choudry MD explained here about measuring the effects of intima-media thickness. Dr. Mubashar Choudry is a great cardiologist...

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