ATPIII2004修订版：近期数项临床研究的启示
Implications of Recent Clinical Trials for NCEP ATP III Guidelines Scott Grundy, MD, for the Writing Group
Implications of Recent Clinical Trials for NCEP ATP III Guidelines
Writing group: Grundy, Cleeman, Bairey Merz, Brewer, Clark, Hunninghake, Pasternak, Smith, Stone
NCEP Report
Endorsements
National Heart, Lung, and Blood Institute
American Heart Association
American College of Cardiology
Grundy SM et al. Circulation 2004;110:227–239.
ATP III: An Evidence-Based Report
Epidemiological evidence
Clinical trials
Prestatin trials (meta-analysis): ATP II
Small statin trials (meta-analysis)
Large statin trials
ATP III
LDL-C: Primary Target
of Lipid-Lowering Therapy
Post–ATP III Clinical Trials
HPS (simvastatin 40)
PROSPER (pravastatin 40)
ALLHAT-LLT (pravastatin 40)
ASCOT-LLA (atorvastatin 10)
PROVE IT (pravastatin 40 vs. atorvastatin 80)
ATP III Recommendations for High-Risk Patients
LDL-C ?130 mg/dL
Rx: Drug + TLC
LDL-C 100–129 mg/dL
Rx: options: LDL-lowering drug, fibrates, nicotinic acid, or TLC only
LDL-C <100 mg/dL
Rx: no treatment required
ATP III Treatment Algorithm for High-Risk Patients
LDL-C ?130
LDL-C
100–129
LDL-C
<100
LDL-Lowering Drug
Therapeutic Options
No LDL-Lowering Therapy
Diet Rx
Fibrates/ nicotinic acid
Statins
LDL-C goal
ATP III Risk Categories
High Risk
Moderately High Risk
Moderate Risk
Lower Risk
CHD, PAD, carotid disease, diabetes, 2+ RF (10-year risk >20%)
LDL-C goal <100 mg/dL
2+ RF (10-yr risk 10–20%)
LDL-C goal <130 mg/dL
2+ RF (10-yr risk <10%)
LDL-C goal <130 mg/dL
0–1 RF
LDL-C goal <160 mg/dL
Heart Protection Study: Design
20,536 UK adults (40–80 years)
High-risk patients: CHD, PVD, diabetes, high BP
Variable LDL-C at baseline
Rx: simvastatin 40 mg vs. placebo (also vitamin arm)
5-yr study
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.
Heart Protection Study: Results
13% reduction in all-cause mortality
24% reduction in major vascular events
27% reduction in major coronary events
25% reduction in stroke
24% reduction in revascularization
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.
Heart Protection Study: Major Findings
Risk reduction at all LDL-C levels
Risk reduction at LDL-C <100 mg/dL
Older patients benefited
Patients with diabetes benefited
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.
HPS: Reduction in Major Vascular Events According to Baseline LDL-C (mg/dL)
% Relative Risk Reduction
LDL-C <100
LDL-C 100–130
LDL-C >130
-22%
-30%
-22%
Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)
5804 subjects (70–82 yrs) at high risk
Rx: pravastatin 40 mg vs. placebo
19% reduction in major coronary events
24% reduction in CHD mortality
25% reduction in TIAs (no stroke reduction)
Conclusion: elderly patients benefit from LDL-C–lowering therapy
Shepherd J et al. Lancet 2002;360:1623–1630.
ALLHAT Lipid-Lowering Trial
10,355 persons ?55 years and higher risk
Rx: pravastatin 40 mg (nonblinded) vs. usual care
High crossover to active treatment (32% of usual-care subjects with CHD at baseline)
No reduction in major coronary events
African American subgroup benefited
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA 2002;288:2998–3007.
ASCOT Lipid-Lowering Arm
10,305 subjects with hypertension (40–79 yrs)
Primary prevention in higher-risk subjects
Mean LDL-C 132 mg/dL
Rx: atorvastatin 10 mg vs. placebo
Study stopped at 3.3 yr (positive outcome)
29% reduction in total coronary events
27% reduction in stroke
Sever PS et al. Lancet 2003;361:1149–1158.
PROVE IT
4162 patients post acute coronary syndrome
Rx: pravastatin 40 mg vs. atorvastatin 80 mg
On-Rx LDL-C levels: pravastatin 95 mg/dL, atorvastatin 62 mg/dL
2-yr mean follow-up
16% reduction in composite CVD endpoint on atorvastatin compared with pravastatin
Cannon CP et al. N Engl J Med 2004;350:1495-1504.
What is the Relationship between LDL-C and CHD Risk?
Possible Relationship between LDL-C Levels and CHD Risk (2001)
CHD Risk
100
LDL-C (mg/dL)
Threshold: Unnecessary to go very low
Linear: The lower, the better
Curvilinear: The lower, the better, with diminishing returns
0
1
Evidence for a Curvilinear (Log-Linear) Relationship between LDL-C and CHD Risk (2001)
CHD Risk Curvilinear or Log-Linear
100
LDL-C (mg/dL)
?
Clinical Trials
Epidemiology
Heart Protection Study (5-Year Trial)
Log CHD Risk
100
LDL-C (mg/dL)
Simvastatin 40 mg
60
26% Reduction in CVD
22% Reduction in CVD
Simvastatin 40 mg
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.
PROVE IT–TIMI 22 (2-Year Trial)
Log CHD Risk
100
LDL-C Level
60
Pravastatin 40 mg
16% Reduction in CVD
Atorvastatin 80 mg
Cannon CP et al. N Engl J Med 2004;350:1495-1504.
“The Lower, the Better”
Relative Risk for CHD (Log Scale)
3.7
2.9
2.2
1.7
1.3
1.0
LDL-C (mg/dL)
40
70
100
130
160
190
0
1
Grundy SM et al. Circulation 2004;110:227–239.
When to Start LDL-Lowering Drugs
Log CHD Risk
LDL-C (mg/dL)
130
100
Supported by HPS, PROVE IT
Supported by All Major Statin Trials
Not
Supported
by
Pravastatin
Trials;
Supported
by HPS
How Low to Lower LDL-C in High-Risk Patients?
LDL-C (mg/dL)
TNT? IDEAL? SEARCH?
Supported by All Major Statin Trials
Not
Supported
by
Pravastatin
Trials;
Supported
by HPS
Log CHD Risk
Rationale for ATP III’s 2001 Low LDL-C Goal <100 mg/dL
Epidemiology and clinical trial evidence congruent down to LDL-C at least as low as 100 mg/dL (2001)
No clinical trial evidence of benefit from achieving very low LDL-C
Practical goal with standard statin doses
Safety of high statin doses not documented in large clinical trials
Rationale for New Therapeutic Option: Very Low LDL-C Goal <70 mg/dL
HPS results
PROVE IT results
Not final word on very low LDL-C goals
TNT
IDEAL
SEARCH
Candidates for Very Low LDL-C Goal of <70 mg/dL
Very high risk patients
Established atherosclerotic CVD
+ multiple risk factors (esp. diabetes)
+ severe and poorly controlled risk factors (e.g., cigarette smoking)
+ metabolic syndrome (high TG, low HDL-C)
+ acute coronary syndromes (PROVE IT)
Considerations and Limitations for Achieving Very Low LDL-C Levels
Dangers from very low LDL-C (unlikely)
Side effects of high drug doses (still under study)
High baseline LDL-C levels (>150 mg/dL)
Maximum drug lowering: about 50%
Implications of Recent LDL-Lowering Trials
High-risk patients with various LDL-C levels
Patients with diabetes
Older patients
Acute coronary syndromes
Moderately high risk patients
Implications of Recent LDL-Lowering Trials
High-risk patients with various LDL-C levels
LDL-C ?130 mg/dL: drug + diet
LDL-C 100–129: LDL-lowering drug preferred (over other options)
LDL-C <100 mg/dL
Very high risk patients: LDL-C goal <70
Other high-risk patients: optional therapies including statins, fibrates, nicotinic acid
Implications of Recent LDL-Lowering Trials
Patients with diabetes
HPS supports ATP III’s high-risk status
Benefit of statin therapy (HPS, CARDS)
Older patients
Benefit of LDL lowering (HPS, PROSPER, ASCOT-LLA ± A