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slide1
Welcome

Ask The Experts

March 24-27, 2007

New Orleans, LA

slide2

Christopher P. Cannon, MDSenior Investigator, TIMI Study GroupCardiovascular DivisionBrigham and Women\'s HospitalAssociate Professor of MedicineHarvard Medical SchoolBoston, MA

LDL or HDL:

Which is More Important?

ldl or hdl which is more important

LDL or HDL: Which is More Important?

Christopher Cannon, M.D.

Senior Investigator, TIMI Study Group

Cardiovascular Division,

Brigham and Women’s Hospital, Boston, MA

slide5

A2Z 20

A2Z 80

TNT 10

IDEAL S20/40

TNT 80

IDEAL A80

CHD Event Rates in Secondary Prevention and ACS Trials

30

y = 0.1629x · 4.6776R² = 0.9029p < 0.0001

4S-P

25

20

HPS-P

LIPID-P

CHD Events (%)

4S-S

15

HPS-S

CARE-P

LIPID-S

10

PROVE-IT-AT

CARE-S

PROVE-IT-PR

5

0

30

50

70

90

110

130

150

170

190

210

LDL Cholesterol (mg/dl)

Updated from - O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

cholesterol trialist collaboration meta analysis of dyslipidemia trials

TNT

IDEAL

Cholesterol Trialist CollaborationMeta-Analysis of Dyslipidemia Trials

Major Vascular Events

50%

40%

30%

Proportional Reduction in Event Rate (SE)

20%

10%

0%

0.5 1.0 1.5 2.0

-10%

Reduction in LDL Cholesterol (mmol/L)

Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78

meta analysis of intensive statin therapy coronary death or mi
Meta-Analysis of Intensive Statin Therapy Coronary Death or MI

Odds Ratio (95% CI)

PROVE IT-TIMI 22

A-to-Z

TNT

IDEAL

OR, 0.84

95% CI, 0.77-0.91

p=0.00003

Total

0.658451

1

1.51872

High-dose better

High-dose worse

Cannon CP, et al.

Cannon CP, et al.

meta analysis of intensive statin therapy
Meta-Analysis of Intensive Statin Therapy

Odds Ratio (95% CI)

OR, 0.84

p<0.000001

OR, 0.84

p=0.00003

OR, 0.88

p=.054

OR, 1.03

p=0.73

OR, 0.94

P=0.20

OR 0.82

p=0.012

0.5

1

2.5

High-dose statin better

High-dose statin worse

Cannon CP, et al.

Cannon CP, et al. JACC 2006; 48: 438 - 445. slides available www.timi.org - TIMI Library

slide9

Meta-Analysis of Intensive Statin Therapy CHF

Study (n)

Odds ratio

(95% CI)

Treatment

Achieved LDL (mg/dl)

Moderate

Intensive

TNT (10,001)

0.74 (0.58,0.94)

Atorvastatin 80

77

Atorvastatin 10

101

A to Z (4497)

0.72 (0.52,0.98)

Simvastatin 80

63

Simvastatin 20

77

PROVE-IT (4162)

0.54 (0.34,0.85)

Atorvastatin 80

62

Pravastatin 40

95

IDEAL (8888)

0.80 (0.61,1.05)

Atorvastatin 80

81

Simvastatin 20

104

Overall (95% CI)

0.73 (0.63,0.84), p<0.001

0.5

3.0

1

Moderate statin

therapy better

Intensive statin

therapy better

Odds ratio

Scirica BM, et al. AHA 2005

meta analysis of intensive statin therapy in acs
Meta-Analysis of Intensive Statin Therapy in ACS

Any Cardiovascular Event

HR (95% Cl)

1.02 (0.95-1.09)

0.84 (0.72-1.02)

0.76 (0.70-0.84)

0.80 (0.76-0.84)

0.81 (0.77-0.87)

0.84 (0.76-0.94)

Hulten E, et al. Arch Intern Med. 2006;166:1814-1821

month 4 ldl and long term risk of death or major cv event
Month 4 LDL and Long-Term Risk of Death or Major CV Event

Hazard Ratio

Referent

>80 - 100

0.80 (0.59, 1.07)

>60 - 80

0.67 (0.50, 0.92)

> 40 - 60

0.61 (0.40, 0.91)

<40

0

1

2

*Adjusted for age, gender, DM, prior MI, baseline LDL

Lower Better

Higher Better

Wiviott SD et al. J Am Coll Cardiol. 2005;46:1411-1416.

Wiviott SD, et al. JACC. 2005

slide12

Major CV Events Across Quintiles of Achieved LDL

P < 0.0001*

P < 0.0001*

% patients

P < 0.05*

P < 0.01*

*P-value for trend across LDL-C

LaRosa JC. AHA. 2005

recent coronary ivus progression trials
Recent Coronary IVUS Progression Trials

Relationship between LDL-C and Progression Rate

1.8

CAMELOT

placebo

REVERSAL

pravastatin

1.2

Median

Change

In Percent

AtheromaVolume

(%)

ACTIVATE

placebo

0.6

REVERSAL

atorvastatin

A-Plus

placebo

0

r2= 0.95

p<0.001

-0.6

ASTEROID

rosuvastatin

-1.2

50

60

70

80

90

100

110

120

Mean Low-Density Lipoprotein Cholesterol (mg/dL)

Nissen S. JAMA 2006

slide15

IMPROVE IT

66

52

The Statin Decade:

For LDL: “Lower is Better”

R² = 0.9029p < 0.0001

4S

LIPID

CHD Events (%)

CARE

HPS

TNT

PROVE IT –TIMI 22

30 50 70 90 110 130 150 170 190 210

LDL Cholesterol (mg/dl)

Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.

slide16

I

I

I

IIa

IIa

IIa

IIa

IIb

IIb

IIb

IIb

III

III

III

III

I

I

I

IIa

IIa

IIa

IIa

IIb

IIb

IIb

IIb

III

III

III

III

I

I

I

IIa

IIa

IIa

IIa

IIb

IIb

IIb

IIb

III

III

III

III

Lipid Management Goal

LDL-C should be less than 100 mg/dL

Further reduction to LDL-C to < 70 mg/dL is reasonable

If TG >200 mg/dL, non-HDL-C should be < 130 mg/dL*

*Non-HDL-C = total cholesterol minus HDL-C

slide17

Subgroups: Reduction in All-Cause Mortality or Major CV Events

2 Year Events

Atorva 80 Prava40

23.0% 26.2% 20.3% 27.0%

28.8% 34.6%

21.0% 24.6%

28.1% 29.5% 20.1% 25.0%

27.5% 28.9% 20.6% 25.5%

21.7% 26.7% 23.1% 26.0%

20.1% 28.2% 23.5% 25.6%

% of Pts

78 22

18 82

30

70

25

75

44 56

27 73

Male

Female

Diabetes

No Diabetes

Age > 65

Age < 65

Prior Statin

No Prior Statin

HDL-C > 40

HDL-C < 40

LDL-C > 125

LDL-C < 125

All pinteraction = NS except as noted

0.5

0.75

1.0

1.25

1.5

Atorvastatin 80 mg Better

Pravastatin 40 mg Better

frequency of low hdl c in men with premature chd
Frequency of Low HDL-C in Men With Premature CHD

Risk factor Controls Cases

(n = 601) (n = 321)

Cigarette smoking 29% 67%*

HDL-C < 35 mg/dL 19% 57%*

Hypertension 21% 41%*

LDL-C ³ 160 mg/dL 26% 34%*

Diabetes mellitus 1% 12%*

*Significantly different from controls (P < 0.001)

Genest JJ et al. Am J Cardiol 1991;67:1185–1189

low hdl c is a risk factor for chd even when ldl c levels are well controlled
Low HDL-C is a Risk Factor for CHD Even When LDL-C Levels are Well Controlled

Risk of CHD

After 4 Yrs

HDL (mg/dL)

LDL (mg/dL)

Am J Med 1977;62:707-714

slide22

Low HDL-C is a Predictor of Coronary Events in Statin Treated Patients

Statin

Placebo

4S

LIPID

CARE

HPS

35

30

25

20

Coronary Events (%)

15

10

5

0

HDL-C (mg/dl)

mmol/L

mg/dl

 1.35

52

 0.99

38

 1.0

39

 1.0

39

 1.26

44

 0.75

33

 1.1

42

< 0.9

35

Adapted from Ballantyne CM et al. Circulation 1999;99:736-743.

on treatment hdl c predicts cardiovascular events tnt
“On-treatment” HDL-C Predicts Cardiovascular Events: TNT

Major Cardiovascular Events

On treatmentHDL-C (mg/dL)

%

Mean LDL-C99 mg/dL

Mean LDL-C73 mg/dL

Barter et al. ACC 2006. Abstract 914-203.

coronary drug project
Coronary Drug Project
  • Long-term efficacy and safety of five lipid-influencing drugs
    • Niacin, clofibrate, dextrothyroxine, and two estrogen regimens
  • 8,341 men (aged 30–64 y) with previous MI
  • Initial study conducted between 1966 and 1975 (mean follow-up: 6.2 y)
  • At end of study, 6,008 survivors followed for additional mean 8.8 y

Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

coronary drug project long term mortality benefit of niacin in post mi patients
Coronary Drug Project Long-Term Mortality Benefit of Niacin in Post-MI Patients

100

90

80

70

Niacin

60

Survival (%)

50

Placebo

40

30

P = 0.0012

20

10

16

14

12

10

6

8

4

0

2

Years of follow-up

Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255

aim high study overview
AIM-HIGHStudy Overview

Simvastatin

Atherogenic Dyslipidemia

(HDL<40 or 50; TGL>149; LDL<160)

CV Death

NFMI

Stroke

ACS

3-5 yr

Vascular Dz.

Age >45 years

Simvastatin + niaspan

2 year enrollment

Hypothesis

-30% event rate

with Simva

-23% event rate with simva-nia

- 50% relative reduction based on ~46% placebo rate

3300 patients from 60

sites (U.S. and Canada

LDL-C target <80 mg/dl both groups (may add ezetimibe if needed)

slide27
Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis: Study Design

1455 patients from 4 trials (REVERSAL, CAMELOT, ACTIVATE, ASTEROID) with CAD undergoing serial intravascular ultrasonography while receiving statin treatment.

Post-hoc analysis of raw data from the four prospective, randomized trials. Follow-up at 18 or 24 months.

Exclusion criteria: Target segment selected was required to have no greater than 50% lumen narrowing for a length of at least 30 mm and target vessel required to have not previously undergone percutaneous coronary intervention.

ASTEROID

n=349

ACTIVATE

n=364

CAMELOT

n=240

REVERSAL

n=502

18 or 24 mos. follow-up

  • Primary Endpoint: Relationship between changes in LDL-C and

HDL-C levels and atheroma burden.

Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

slide28
Statins, High-Density Lipoprotein Cholesterol, and Regression of Coronary Atherosclerosis: Study Design

Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.

slide29

The Case for HDL

  • Many patients have low HDL
  • Low HDL-C is a major predictor of CV events (even with low LDL-C)
  • Niacin worked in large outcomes trial
slide31

Triple Goal: Hazard ofdeath, MI and recurrent ACS with number of goals achieved based on LDL-C (< 70 mg/dL), CRP (< 2 mg/L) & TG (< 150 mg/dL)

Miller M AHA 2006

slide32

0.10

0.10

0.08

0.08

LDL >70 mg/dL, CRP <2 mg/L

LDL <70 mg/dL, CRP >2 mg/L

0.06

0.06

Recurrent MI or Coronary Death

(Percent)

0.04

0.04

LDL <70 mg/dL, CRP <2 mg/L

LDL <70 mg/dL, CRP <1 mg/L

0.02

0.02

0.00

0.0

0.0

0.0

0.0

0.5

0.5

0.5

0.5

1.0

1.0

1.0

1.0

1.5

1.5

1.5

1.5

2.0

2.0

2.0

2.0

2.5

2.5

2.5

2.5

Follow-Up (Years)

Clinical Relevance of Achieved LDL and CRP Post Statin TherapyTreatment

LDL > 70 mg/dL, CRP >2 mg/L

Ridker PM, et al. N Engl J Med. 2005;352:20-28.

slide33

Achieved CRP and LDL vs. Outcomes

Figure 4

Cumulative probability of death or MI (%)

CRP ≥ 2 and LDL ≥ 70N = 1244

CRP ≥ 2 and LDL < 70N = 500

CRP <2 and LDL ≥ 70N = 1140

CRP < 2 and LDL< 70N = 659

Follow-up after Month 4 (days)

Morrow JACC 2006

cardiomonitor
Cardiomonitor
  • 4,676 U.S. outpatients with CVD from 250 primary care physicians and 50 cardiologists
conclusion
Conclusion
  • In 2007: LDL > HDL
  • But
  • Both are important
  • (as well as Trig, and BP, gluc…)
  • We need to do better on implementation
slide37
Question

&

Answer

slide38
Thank You!

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