该幻灯内容为AHA2003年会上Valentin Fuster、Steve Nissen和Scott Grundy教授对REVERSAL 研究和ApoA-1 Milano研究的讨论，总结了这2个研究对动脉粥样硬化治疗的重要临床意义，内容精彩，推荐下载！
AHA 2003: Tackling LDL and HDL for atheroma regression
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, NY
Steve Nissen MD
Professor of Medicine
Cleveland Clinic Foundation
Cleveland, OH
Scott Grundy MD
Director, Center for Human Nutrition
UT Southwestern Medical Center
Dallas, TX
REVERSAL Effects of atorvastatin vs pravastatin on atherosclerosis progression
ApoA-1 Milano Effect of an HDL mimic on atherosclerosis progression
Topics
REVERSing Atherosclerosis with Lipitor
REVERSAL
REVERSAL: Design
654 patients randomized at 24 US centers, with indication for atherosclerotic disease, stenosis of >20%, and LDL levels between 125 and 210 mg/dL
Intensive atorvastatin (80 mg daily) vs moderate pravastatin (40 mg daily) therapy
Primary end point: percent change in coronary plaque volume, as measured by IVUS between baseline and 18 months
REVERSAL: Results
AHA 2003
REVERSAL: Type of statin
Pravastatin:
40 mg/day is the highest dose approved by the FDA
This was not the ideal dose to use to compare effects on the lipid profile
Why did you not compare two
different dosages of atorvastatin?
Fuster
REVERSAL: Lowering LDL
Nissen
Question: Does lowering LDL below target levels have a measurable effect on atherosclerosis progression rate?
Objective in REVERSAL: Group 1 with LDL around 100, group 2 with much lower LDL levels
"It was really designed as an
'is-lower-better?' trial."
REVERSAL: How low?
ATP III guidelines: Levels of LDL should be below 100
TNT, SEARCH, IDEAL Address the issue of how low to go
REVERSAL First study to test this question
"The results, in my opinion, look very promising."
Grundy
REVERSAL: Surprised
In the pravastatin group, 176 patients had LDL <100, with a mean LDL of 88
They still showed highly significant progression
Different progression rates for every LDL level between groups
"We were very surprised by this outcome."
Nissen
AHA 2003
REVERSAL: Cholesterol reduction
p<0.0001
p<0.0001
Baseline LDL: 150
Slightly higher than normal (135-140)
Average LDL reductions of 30% were right on target
"Those results were totally
predictable."
Grundy
AHA 2003
REVERSAL: Adverse events
REVERSAL: IVUS
Plaque volume measured by IVUS showed high person-to-person variability.
How accurate is this technique? Fuster
It's not so much the technique, but the biology of the disease
Incredibly dynamic
Patients with large increases, others with decreases in atheroma volume Nissen
REVERSAL: End points
AHA 2003
REVERSAL: Impact
Despite the significant results, the impact was very small, with only 18 months of follow-up Fuster
Angiographic trials: Small plaque changes did correlate with changes in clinical end points
IVUS: It is not known whether small changes can predict clinical events Grundy
REVERSAL: Plaque changes
Perhaps other changes in the plaque
occurred, which IVUS was unable to
detect
Changes in plaque composition Fuster
Plaque composition cannot easily be measured by IVUS
The study showed a huge range of changes, with a 40% to 50% decrease in some patients
Nissen
AHA 2003
REVERSAL: Subgroups
REVERSAL: Diabetics
Patients with diabetes 95
Patients with metabolic 204 syndrome
Most important change in percentage of atheroma in diabetic patients
Multivariate analysis to understand the drivers of progression vs regression
Diabetics have more inherent underlying progression and need more aggressive treatment
Nissen
REVERSAL: Pravastatin
"I was pretty surprised at how poorly the pravastatin group did."
Progression in patients in all 22 prespecified subgroups
More intensively treated patients had all the advantages
Nissen
REVERSAL: Waiting for definite answers
Dose of pravastatin never increased Fuster
Only about 3% additional LDL lowering with 80-mg pravastatin
"This was not an events trial."
We will know more when TNT, SEARCH, and IDEAL will come out
"REVERSAL tells us what we're likely to see." Nissen
REVERSAL summary: Fuster
"Very good news."
We have a strategy that prevents progression, at least for 18 months
Minimal changes, but over a short time period
"I wonder if over a period of a few years this will be very significant."
Fuster
REVERSAL summary: Grundy
Aggressive LDL lowering, well below 100
"My guess: the lower the better for LDL."
Some questions remain unanswered, but an important first step
NCEP will evaluate existing trials and issue an updated ATP III in the next six months
At completion of all new trials there will be an ATP IV
Grundy
REVERSAL summary: Nissen
Nissen
Progression rate
3% difference between pravastatin and atorvastatin arms
"These are not small differences, they are actually large differences that over a period of years will translate into important differences in morbidity and mortality."
Effect of recombinant ApoA-1 Milano on atherosclerosis in ACS patients
ApoA-1 Milano: Background
Pilot trial of recombinant apolipoprotein A-1 Milano on atherosclerosis in patients with acute coronary syndromes
Little has been done to prove that raising HDL reduces CAD risk
People in a small Italian village, with low HDL and low CAD rates, carry ApoA-1 variant: ApoA-1 Milano
Esperion Therapeutics developed agent ETC-216
ApoA-1 Milano: Design
57 patients with ACS randomized to two doses of ETC-216 (15 mg/kg or 45 mg/kg) or placebo
IVUS to assess changes in atheroma within two weeks of ACS diagnosis and after five weeks of ApoA-1 Milano treatment
ApoA-1 Milano: Results
AHA 2003
ApoA-1 Milano: Conclusions
Some regression of atherosclerosis after five weeks of ETC-216 infusion
"Very fascinating"
HDL may halt the progression of atherosclerotic disease by helping the artery to get rid of the excess oxidized LDL
Fuster
ApoA-1 Milano: The HDL question
REVERSAL "Putting icing on a cake that we already have."
"This work is pioneering, because it will get into the HDL question."
HDL known to be associated with CAD
Prevention of atherosclerosis by affecting HDL has been questioned
Grundy
ApoA-1 Milano: End points
Different calculations of the primary end point in the two trials