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Ask The Experts
March 24-27, 2007
New Orleans, LA
LDL or HDL:
Which is More Important?
Christopher P. Cannon, MD
Senior Investigator, TIMI Study Group
Cardiovascular Division
Brigham and Women's Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, MA
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
The Case for LDL
CHD Event Rates in Secondary
Prevention and ACS Trials
30
y = 0.1629x · 4.6776
R² = 0.9029
p < 0.0001
CHD Events (%)
25
4S-P
20
HPS-P
4S-S
15
LIPID-P
HPS-S
A2Z 20
CARE-P
A2Z 80
TNT 10 LIPID-S
IDEAL S20/40
PROVE-IT-AT TNT 80
CARE-S
IDEAL
A80
PROVE-IT-PR
10
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
Major Vascular Events
Proportional Reduction in Event Rate (SE)
50%
40%
30%
TNT
20%
IDEAL
10%
0%
0.5
-10%
1.0
1.5
Reduction in LDL Cholesterol (mmol/L)
Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78
2.0
Meta-Analysis of Intensive Statin Therapy
Coronary Death or MI
Odds
Reduction
Odds Ratio (95% CI)
Event Rates
No./Total (%)
High Dose
Std Dose
PROVE IT-TIMI 22
-17%
147/2099
(7.0)
172/2063
(8.3)
A-to-Z
-15%
205/2265
(9.1)
235/2232
(10.5)
TNT
-21%
334/4995
(6.7)
418/5006
(8.3)
IDEAL
-12%
411/4439
(9.3)
463/4449
(10.4)
-16%
1097/13798
(8.0)
1288/13750
(9.4)
OR, 0.84
95% CI, 0.77-0.91
p=0.00003
Total
0.658451
High-dose better
Cannon CP, et al.
Cannon CP, et al.
1
1.51872
High-dose worse
Meta-Analysis of Intensive Statin Therapy
Odds Ratio (95% CI)
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)
OR, 1.03
p=0.73
+3%
340/13798
(2.5)
331/13750
(2.4)
Total Mortality
OR, 0.94
P=0.20
-6%
808/13798
(5.9)
857/13750
(6.2)
Stroke
OR 0.82
p=0.012
-18%
316/13798
(2.3)
381/13750
(2.8)
Coronary Death or
Any Cardiovascular
Event
Coronary Death or
MI
Cardiovascular
Death
Non-Cardiovascular
Death
0.5
1
High-dose statin better
Cannon CP, et al.
OR, 0.84
p<0.000001
OR, 0.84
p=0.00003
OR, 0.88
p=.054
2.5
High-dose statin worse
Cannon CP, et al. JACC 2006; 48: 438 - 445. slides available www.timi.org - TIMI Library
Meta-Analysis of Intensive Statin Therapy
CHF
Study (n)
Odds ratio
(95% CI)
Treatment
Achieved LDL (mg/dl)
Intensive
Moderate
TNT (10,001)
0.74 (0.58,0.94)
Atorvastatin 80 Atorvastatin 10
77
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 Simvastatin 20
81
104
Overall (95% CI)
0.5
Intensive statin
therapy better
0.73 (0.63,0.84), p<0.001
3.0
1
Moderate statin
therapy better
Scirica BM, et al. AHA 2005 Odds ratio
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
Hazard Ratio
>80 - 100
Referent
>60 - 80
0.80 (0.59, 1.07)
> 40 - 60
0.67 (0.50, 0.92)
<40
0.61 (0.40, 0.91)
0
1
Lower Better
Wiviott
SD, SD
et al.et
JACC.
Wiviott
al. J2005
Am
2
Higher Better
Coll Cardiol. 2005;46:1411-1416.
*Adjusted for age, gender,
DM, prior MI, baseline LDL
Major CV Events Across Quintiles
of Achieved LDL
14
12
<64
65-77
78-90
91-106
>106 mg/dl
P < 0.0001*
% patients
10
8
P < 0.0001*
6
P < 0.05*
4
2
0 Screening
Major CV events
P < 0.01*
CHD death
Nonfatal MI
Stroke
*P-value for trend across LDL-C
LaRosa JC. AHA. 2005
Nissen et al JAMA 2004
Recent Coronary IVUS Progression Trials
Relationship between LDL-C and Progression Rate
1.8
CAMELOT
placebo
1.2
Median
Change 0.6
In Percent
Atheroma
0
Volume
(%)
REVERSAL
pravastatin
ACTIVATE
placebo
REVERSAL
atorvastatin
A-Plus
placebo
-0.6
r2= 0.95
p<0.001
ASTEROID
rosuvastatin
-1.2
50
60
70
80
90
100
110
Mean Low-Density Lipoprotein Cholesterol (mg/dL)
Nissen S. JAMA 2006
120
The Statin Decade:
For LDL: “Lower is Better”
30
R² = 0.9029
p < 0.0001
CHD Events (%)
25
4S
20
LIPID
CARE
HPS
15
TNT
PROVE IT –TIMI 22
10
5
52
0
30
50
66 IMPROVE IT
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.
Lipid Management Goal
I IIa IIb III
LDL-C should be less than 100 mg/dL
I IIa IIb III
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
Subgroups: Reduction in All-Cause
Mortality or Major CV Events
2 Year Events
% of Pts
78 22
Atorva 80
Prava40
23.0%
20.3%
26.2%
27.0%
18 82
30
70
28.8%
21.0%
34.6%
24.6%
Age > 65
Age < 65
25
75
28.1%
20.1%
29.5%
25.0%
Prior Statin
No Prior Statin
44
56
27.5%
20.6%
28.9%
25.5%
HDL-C > 40
HDL-C < 40
27
73
21.7%
23.1%
26.7%
26.0%
20.1%
23.5%
28.2%
25.6%
Male
Female
Diabetes
No Diabetes
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
The Case for HDL
Frequency of Low HDL-C in Men
With Premature CHD
Risk factor
Controls
(n = 601)
Cigarette smoking
29%
HDL-C < 35 mg/dL
19%
Hypertension
21%
LDL-C  160 mg/dL
26%
Diabetes mellitus
1%
*Significantly different from controls (P < 0.001)
Genest JJ et al. Am J Cardiol 1991;67:1185–1189
Cases
(n = 321)
67%*
57%*
41%*
34%*
12%*
Low HDL-C is a Risk Factor for CHD Even
When LDL-C Levels are Well Controlled
3.0
2.0
Risk of CHD
After 4 Yrs
1.0
25
45
0.0
65
100
160
LDL (mg/dL)
Am J Med 1977;62:707-714
220
85
HDL (mg/dL)
Low HDL-C is a Predictor of Coronary
Events in Statin Treated Patients
Coronary Events (%)
Statin
35
30
25
20
15
10
5
0
4S
LIPID
Placebo
CARE
HPS
HDL-C (mg/dl)
mmol/L  1.35  0.99
mg/dl
52
38
 1.0 < 1.0
39
39
 1.26 < 0.75
44
33
 1.1 < 0.9
42 35
Adapted from Ballantyne CM et al. Circulation 1999;99:736-743.
“On-treatment” HDL-C Predicts
Cardiovascular Events: TNT
Major Cardiovascular Events
14
12
On treatment
HDL-C (mg/dL)
10
%
<40
8
>40-50
6
>50-60
4
>60
2
0
Atorva 10
Mean LDL-C
99 mg/dL
Barter et al. ACC 2006. Abstract 914-203.
Atorva 80
Mean LDL-C
73 mg/dL
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
Survival (%)
Long-Term Mortality Benefit of Niacin in Post-MI
Patients
100
90
80
70
60
50
40
30
20
10
Niacin
Placebo
P = 0.0012
0
2
4 6 8 10 12 14 16
Years of follow-up
Canner PL et al. J Am Coll Cardiol 1986;8:1245–1255
AIM-HIGH
Study Overview
Vascular Dz.
Age >45 years
Atherogenic
Dyslipidemia
(HDL<40 or
50; TGL>149;
LDL<160)
Simvastatin
3-5 yr
Simvastatin +
niaspan
2 year enrollment
3300 patients from 60
sites (U.S. and Canada
LDL-C target <80
mg/dl both groups
(may add ezetimibe
if needed)
CV Death
NFMI
Stroke
ACS
Hypothesis
-30% event rate
with Simva
-23% event rate
with simva-nia
- 50% relative
reduction based
on ~46%
placebo rate
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.
REVERSAL
CAMELOT
ACTIVATE
ASTEROID
n=502
n=240
n=364
n=349
18 or 24 mos. follow-up
Primary Endpoint: Relationship between changes in LDL-C and
HDL-C levels and atheroma burden.

Clinical Trial Results . org
Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.
Statins, High-Density Lipoprotein Cholesterol, and
Regression of Coronary Atherosclerosis: Study Design
Nicholls SJ, et al. JAMA. 2007 Feb; 297(5): 499-508.
Clinical Trial Results . org
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
Kaplan-Meier Estimates by TG Quintiles between
30 d and 2 yr follow-up
Kaplan-Meier Event Rate (%)
20
P< 0.0006; Quintiles 4-5 versus 1-3
15
18.9
P for overall trend < 0.0001
13.1
13.5
15.4
12.9
10
5
0
1
2
3
4
5
771
163.1 (15.5)
140-193
767
294.7 (118.5)
194-1122
Triglyceride Quintiles
N
Mean
Range
785
67.1 (11.6)
26-83
782
96.3 (7.3)
84-108
769
122.9 (8.6)
109-139
TG Quintiles
Miller M AHA 2006
Triple Goal:
Hazard of death, MI and recurrent
Hazard of death, MI or
Recurrent ACS after 30 days
ACS with number of goals achieved based on
LDL-C (< 70 mg/dL), CRP (< 2 mg/L) & TG (< 150 mg/dL)
P=0.008
1
P< 0.001
0.72
0.8
0.6
0.63
0.57-0.92
0.47
0.49-0.80
0.35-0.63
0.4
0.2
0
1
2
Number of Goals Achieved
Miller M AHA 2006
P< 0.001
3
0.10
Clinical Relevance of Achieved LDL
and CRP Post Statin Therapy
Treatment
0.08
LDL > 70 mg/dL, CRP >2 mg/L
0.06
LDL >70 mg/dL, CRP <2 mg/L
LDL <70 mg/dL, CRP >2 mg/L
0.04
LDL <70 mg/dL, CRP <2 mg/L
0.00
0.02
LDL <70 mg/dL, CRP <1 mg/L
0.0
0.5
1.0
1.5
2.0
Follow-Up (Years)
2.5
Ridker PM, et al. N Engl J Med. 2005;352:20-28.
Figure 4
Achieved CRP and LDL vs. Outcomes
Cumulative probability
of death or MI (%)
8
CRP ≥ 2 and LDL ≥ 70
N = 1244
7
CRP ≥ 2 and LDL < 70
N = 500
6
CRP <2 and LDL ≥ 70
N = 1140
5
CRP < 2 and LDL< 70
N = 659
4
3
2
1
0
0
120
240
360
Follow-up after Month 4 (days)
480
600
Morrow JACC 2006
Cardiomonitor: Trends in LDL
Levels in Acute Coronary
Syndrome Patients
100%
90%
23%
17%
14%
12%
11%
10%
14%
80%
% US CVD Patients
70%
60%
50%
41%
52%
60%
58%
56%
54%
LDL Not Recorded
39%
>=100 mg/dL
70 to <100 mg/dL
40%
<70 mg/dL
30%
20%
20%
24%
30%
28%
38%
33%
10%
15%
5%
6%
6%
10%
0%
5%
13%
3%
1998
1999
2000
2001
2003
2004
2005
Statin Treatment
Cardiomonitor
• 4,676 U.S. outpatients with CVD from
250 primary care physicians and 50
100 cardiologists
90
80
70
60
50
40
30
20
10
0
On Any Statin (%)
0-1 Risk Factors
CHD
Cerebrovascular Disease
CHD/Equivalent
On High-dose Statin (%)*
2+ Risk Factors
PAD
DM
Conclusion
In 2007: LDL > HDL
But
Both are important
(as well as Trig, and BP, gluc…)
We need to do better on implementation
Question
&
Answer
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