How Aggressive do How Aggressive do we get on Lipids? we get on Lipids?

Christopher Cannon, M.D.Christopher Cannon, M.D.Senior Investigator, TIMI Study GroupSenior Investigator, TIMI Study Group

Cardiovascular Division, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MABrigham and Women’s Hospital, Boston, MA

CHD Event Rates in Secondary Prevention and ACS Trials

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

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

LDL Cholesterol (mg/dl)

CH

D E

ven

ts (

%)

PROVE-IT-PR

PROVE-IT-AT CARE-S

LIPID-S

HPS-S4S-S

HPS-P

CARE-P

LIPID-P

4S-P

0

5

10

15

20

25

30

30 50 70 90 110 130 150 170 190 210

TNT 80TNT 10A2Z 80

A2Z 20

IDEAL S20/40IDEAL A80

Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials

50%

40%

30%

20%

10%

0%

-10%

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

0.5 1.0 1.5 2.0

Reduction in LDL Cholesterol (mmol/L)

Major Vascular EventsP

rop

ortio

nal R

educ

tion

in E

vent

Rat

e (S

E)

TNT

IDEAL

Recent Coronary IVUS Progression Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

MedianChange

In PercentAtheromaVolume

(%)

Mean Low-Density Lipoprotein Cholesterol (mg/dL)

REVERSALpravastatin

REVERSALatorvastatin

CAMELOTplacebo

A-Plusplacebo

ACTIVATEplacebo

Relationship between LDL-C and Progression Rate

ASTEROIDrosuvastatin

r2= 0.95p<0.001

Nissen S. JAMA 2006

High-dose statin better High-dose statin worse

Odds Reduction

Event Rates

No./Total (%)

High Dose Std Dose

-16%3972/13798

(28.8)4445/13750

(32.3)

-16%1097/13798

(8.0)1288/13750

(9.4)

-12%462/13798

(3.3)520/13750

(3.8)

+3%340/13798

(2.5)331/13750

(2.4)

-6%808/13798

(5.9)857/13750

(6.2)

-18%316/13798

(2.3)381/13750

(2.8)

Coronary Death or Any Cardiovascular Event

Coronary Death or MI

Cardiovascular Death

Non-Cardiovascular Death

Total Mortality

Stroke

0.5 1 2.5

OR 0.8295% CI, 0.71-0.96p=0.012

Odds Ratio (95% CI)

Meta-Analysis of Intensive Statin Therapy All Endpoints

Cannon CP, et al.

OR, 0.9495% CI, 0.85-1.04P=0.20

OR, 1.0395% CI, 0.88-1.20p=0.73

OR, 0.8895% CI, 0.78-1.00p=.054

OR, 0.8495% CI, 0.77-0.91p=0.00003

OR, 0.8495% CI, 0.80-0.89p<0.0001

Cannon CP, et al. JACC 2006; 48: 438 - 445.

Odds ratio

0.5 1 3.0

Study (n)

Treatment Achieved LDL (mg/dl)

Odds ratio (95% CI)

0.74 (0.58,0.94) TNT (10,001) Atorvastatin 8077

0.72 (0.52,0.98) A to Z (4497) Simvastatin 8063

0.54 (0.34,0.85) PROVE-IT (4162) Atorvastatin 8062

0.80 (0.61,1.05) IDEAL (8888) Atorvastatin 8081

0.73 (0.63,0.84), p<0.001 Overall (95% CI)

Intensive statintherapy better

Moderate statintherapy better

Atorvastatin 10101

Simvastatin 2077

Pravastatin 4095

Simvastatin 20104

Intensive Moderate

Scirica BM, et al. AHA 2005

Meta-Analysis of Intensive Statin Therapy CHF

Meta-Analysis of Intensive Statin Therapy in ACS

Any Cardiovascular EventHR (95% Cl)

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

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)

ACS Patients: Major Coronary ACS Patients: Major Coronary Events Events MI + CHD Death + Resuscitated Cardiac ArrestMI + CHD Death + Resuscitated Cardiac Arrest

Years Since Randomization

Cu

mu

lati

ve H

azar

d (

%)

0 1 2 3 4 50

4

8

12

16

20

HR = .66 (95% CI = 0.46, 0.95), P=.02

34% RRR

Simvastatin

Atorvastatin

Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

20

40

30

0

10

0 30 months 5 years

Summary: 5 Years Of Follow-Up In IDEAL Is The Summary: 5 Years Of Follow-Up In IDEAL Is The Longest Period Of Follow-Up Of ACS Patients On Longest Period Of Follow-Up Of ACS Patients On Statin TherapyStatin TherapyC

ard

iac

Eve

nt

(%)

50

60

Atorvastatin 80 mg

Pravastatin 40 mg

Simvastatin 20-40 mg

16% RRRP=0.005

PROVE IT

MI or UA

18% RRRP=0.04

IDEAL

All MI

Pedersen, Olsson, Cater et al. Presented at World Congress of Cardiology 2006

Month 4 LDL and Long-Term Risk of Death or Major CV Event

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

Wiviott SD, et al. JACC. 2005

0.80 (0.59, 1.07)

0.67 (0.50, 0.92)

0.61 (0.40, 0.91)

Hazard Ratio

Lower Better Higher Better

Referent

0 1 2

<40

> 40 - 60

>60 - 80

>80 - 100

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

Screening0

2

4

6

8

10

12

14

Major CV events CHD death Nonfatal MI Stroke

<64 65-77 78-90 91-106 >106 mg/dl

P < 0.0001*

P < 0.01*

P < 0.0001*

P < 0.05*

*P-value for trend across LDL-C

Major CV Events Across Quintiles of Achieved LDL

LaRosa JC. AHA. 2005

% p

atie

nts

The Statin Decade:The Statin Decade:For LDL: “Lower is Better”For LDL: “Lower is Better”

0

5

10

15

20

25

30R² = 0.9029R² = 0.9029p < 0.0001p < 0.0001

LDL Cholesterol (mg/dl)

CH

D E

ven

ts (

%)

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

30 50 70 90 110 130 150 170 190 210

4S

CARELIPID

HPS

PROVE IT –TIMI 22

IMPROVE ITIMPROVE IT66665252

TNT

ASA + Standard Medical TherapyASA + Standard Medical Therapy

Simvastatin 40 mg*Simvastatin 40 mg* Vytorin 10/40 mg*Vytorin 10/40 mg*

Duration: Minimum 2 1/2 year follow-up (>2955 events)Duration: Minimum 2 1/2 year follow-up (>2955 events)

Primary Endpoint: CV Death, MI, Hospital Admission for UA, Primary Endpoint: CV Death, MI, Hospital Admission for UA, revascularization (> 30 days after randomization), or Strokerevascularization (> 30 days after randomization), or Stroke Primary Endpoint: CV Death, MI, Hospital Admission for UA, Primary Endpoint: CV Death, MI, Hospital Admission for UA, revascularization (> 30 days after randomization), or Strokerevascularization (> 30 days after randomization), or Stroke

Study DesignStudy Design

Double-blindDouble-blind

Patients stabilized post Acute Coronary Syndrome < 10 daysPatients stabilized post Acute Coronary Syndrome < 10 daysLDL LDL << 125 mg/dL (or 125 mg/dL (or << 100 mg/dL if prior statin) 100 mg/dL if prior statin)

N=10,000N=10,000

Follow-Up Visit Day 30, Every 4 MonthsFollow-Up Visit Day 30, Every 4 Months

*uptitrated to 80mg if LDL>79

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

0.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.5

0.00

0.02

0.04

0.06

0.08

0.10

0.02

0.04

0.06

0.08

0.10

Rec

urr

ent

MI o

r C

oro

nar

y D

eath

(p

erce

nt)

Follow-Up (Years)

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

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

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

Clinical Relevance of Achieved LDL and Achieved CRP After Treatment with

Statin Therapy

Ridker PM. NEJM 2005;352:20-28

0

1

2

3

4

5

6

7

8

0 120 240 360 480 600

CRP < 2 and LDL< 70N = 659

CRP <2 and LDL ≥ 70N = 1140

CRP ≥ 2 and LDL ≥ 70N = 1244

CRP ≥ 2 and LDL < 70N = 500

Figure 4

Cumulative probability of death or MI (%)

Follow-up after Month 4 (days)

Achieved CRP and LDL vs. Outcomes

Death/MI/UA post-month 4, by Death/MI/UA post-month 4, by Month 4 Apo-B/Apo-A ratioMonth 4 Apo-B/Apo-A ratio

Month 4 Apo-B/Apo-A Ratio

End

poin

t P

roba

bilit

y

0.4 0.6 0.8 1.0

0.0

60

.08

0.1

00

.12

0.1

4

Combined

Month 4 Apo-B/Apo-A Ratio

En

dp

oin

t P

rob

abil

ity

0.4 0.6 0.8 1.0

0.0

60

.08

0.1

00

.12

0.1

4

CRP<2

CRP>=2

Ray AHA 05

The long term clinical risk of Apo The long term clinical risk of Apo B/AI can be further discriminated by B/AI can be further discriminated by

achieved CRP levels achieved CRP levels

Median Achieved hsCRP h

sCR

P m

g/d

l

0

1

2

3

1 mo 4 mo 8 mop = NS p < 0.001 p < 0.001

Placebo Simva 20

Simva 40 Simva 80

A to Z

p < 0.001

hsC

RP

mg

/dl

0

1

2

3

1 mo 4 mo 2 yrsp < 0.001 p < 0.001

Prava 40

Atorva 80PROVE IT

0 5 10 15 20 25 300

1

2

3

4

5Pravastatin 40 mg

Atorvastatin 80 mg

Hazard ratio = 0.72 (CI 0.52,0.99)

P=0.046

Days following randomization

% o

f p

atie

nts

wit

h d

eath

, MI o

r ,r

eho

spit

aliz

atio

n

for

AC

SDeath, MI or ACS Rehospitalization

(Early Phase)

KK Ray et al. JACC Oct. 2005 (in press)

What Factors are What Factors are Associated with Elevated Associated with Elevated CRP levels?CRP levels?Age (years) 1.01 <0.0001

Female on HRT vs Male 2.4 <0.0001

Female not on HRT vs Male 1.5 <0.0001

Current Smoker 1.5 <0.0001

BMI >25 kg/m2 1.4 <0.0001

HDLC <50mg/dl 1.2 0.0001

LDL 70 mg/dl 1.2 0.0003

Glucose >110 mg/dl 1.2 0.0009

Clinical Event Pre-month 4 1.4 0.0027

Trig >150 mg/dl 1.1 0.003

Atorvastatin 80mg 0.7 <0.0001

0

0.5

1

1.5

2

2.5

3

3.5

4

0 1 2 3 4 5 6-7

Number of Uncontrolled Risk Factors

CR

P m

g/L

Standard therapy (Prava 40)Intensive Therapy (Atorva 80)

Achieved CRP on Statin Therapy Achieved CRP on Statin Therapy vs. Number of Risk Factorsvs. Number of Risk Factors

Risk factors 1) BMI > 252) Current smoker3) HDL <504) TG > 1505) Glucose >1106) BP > 130/857) LDL >70

Ptrend <0.0001 for each

KK Ray et al.JACC 2005

Kaplan-Meier Estimates based on LDL-C Kaplan-Meier Estimates based on LDL-C < 70 mg/dL < 70 mg/dL oror TG < 150 mg/dL between TG < 150 mg/dL between 30 d and 2 yr follow-up30 d and 2 yr follow-up

0.0

00

.05

0.1

00

.15

0.2

0

0 200 400 600 800Days after Month 1 Visit

LDL > 70

LDL < 70

HR 1.32(1.12, 1.56)P=0.001

Eve

nt

Rat

e (%

)

0.0

00.

05

0.1

00.

15

0.2

0

0 200 400 600 800Days after Month 1 Visit

HR 1.34(1.13, 1.58)P=0.001

TG > 150

TG < 150

Eve

nt

Rat

e (%

)

Miller M AHA 2006

Triple Goal: Triple Goal: HHazard ofazard of death, MI and death, MI and

recurrent ACS with number of goals achieved based on recurrent ACS with number of goals achieved based on

LDL-C (< 70 mg/dL), CRP (< 2 mg/L) & TG (< 150 mg/dL)LDL-C (< 70 mg/dL), CRP (< 2 mg/L) & TG (< 150 mg/dL)

0

0 .2

0 .4

0 .6

0 .8

1

1 2 3

Ha

zar

d o

f d

eath

, M

I o

r

Re

cur

ren

t A

CS

aft

er

30

da

ys

0 .7 20 .6 3

0 .4 70 .5 7 -0 .9 2

0 .4 9 -0 .8 0

0 .3 5 -0 .6 3

P = 0 .0 0 8P < 0 .0 0 1

P < 0 .0 0 1

N u m b e r o f G o a ls A c h ie v e d

Miller M AHA 2006

Background 2004 National Cholesterol Education Program: Adult Treatment Panel III Update

100 mg/dL

Initiate TLC

100 mg/dL (<100 mg/dL: consider

drug options)

Consider Drug Therapy

non HDL-C

<130 mg/dL

LDL-C <100 mg/dL

(optional goal:

<70 mg/dL)

Target

GoalRisk Category

Secondary Consideration

(TG > 200 mg/dL)

High risk: CHD or CHD risk equivalents (10-y risk >20%)

Adapted from Grundy SM, et al. Circulation. 2004;110:227-239.

**Achieve at least 30%Achieve at least 30%--40% reduction in LDL40% reduction in LDL--C, regardless of baseline levelC, regardless of baseline level

Risk Category LDL-C Goal Initiate TLCConsider

Drug Therapy

Very High risk: ACS, or CHD w/ DM,mult CRF

<70 mg/dL 70 mg/dL > 70 mg/dL

High risk: CHD or CHD risk equivalents

(10-year risk >20%)

If LDL <100 mg/dl

<100 mg/dL (optional goal:

<70 mg/dL)

Goal <70 mg/dl

100 mg/dL > 100 mg/dL (<100 mg/dL:

consider drug Rx)

Moderately high risk: 2+ risk factors (10-year risk 10% to 20%)

<100 mg/dL 130 mg/dL > 130 mg/dL (100-129 mg/dL:

consider drug Rx)

Moderate risk: 2+ risk factors ( risk <10%)

<130 mg/dL 130 mg/dL > 160 mg/dL

Lower risk: 0-1 risk factor

<160 mg/dL 160 mg/dL >190 mg/dL

ATP III Update 2004: LDL-C Goals and Cutpoints for Therapy

in Different Risk Categories

Adapted from Grundy, S. et al., Circulation 2004;110:227-39.

-49%

-41%

-34%-33%

-60%-55%

-52%

-45%

–70%

–60%

–50%

–40%

–30%

–20%

–10%

0%

Vytorin (Ezetimibe + Simvastatin) Vytorin (Ezetimibe + Simvastatin) Greater LDL Reduction at Each DoseGreater LDL Reduction at Each Dose

Simva80 mg(n=67)

Ezetimibe +Simva80 mg(n=65)

Simva40 mg(n=65)

Ezetimibe +Simva40 mg(n=73)

Simva20 mg(n=61)

Ezetimibe +Simva20 mg(n=69)

Simva10 mg(n=70)

Ezetimibe +Simva10 mg(n=67)

Mean %Change in LDL-C

FromUntreatedBaseline

simvastatin Vytorin (ezetimibe +simvastatin)

P0.01 for Vytorin vs. simvastatin for each comparison Source: Vytorin package insert

-4

-8

-20

27

-36*

-44*

-32#

-26*

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

Med

ian

% C

han

ge

in C

RP

SimvastatinVytorin

Vytorin Reduces CRP More Vytorin Reduces CRP More than Simvastatin at Each than Simvastatin at Each DoseDose

10 mg 20 mg 40 mg 80 mg

Sager PT, Atherosclerosis 2005;179:361-7

* p < 0.01# p = 0.03

872 patients with LDL 145-250 enrolled in 2 RCTs

Conclusions: Early Benefit of Conclusions: Early Benefit of Intensive Statin Therapy PROVE IT-Intensive Statin Therapy PROVE IT-TIMI 22TIMI 22

Lower is betterLower is better– LDLLDL– CRP CRP – TriglyceridesTriglycerides

““Dual goal” and “triple goal” with statins Dual goal” and “triple goal” with statins Lower LDL Lower LDL andand CRP and Trig, and probably CRP and Trig, and probably HDL HDL

Dual and triple therapy is frequently needed Dual and triple therapy is frequently needed to achieve dual and triple goalsto achieve dual and triple goals

(and probably) higher is better for HDL