Coaated stents: a new eraHDL for atheroma regression
UT Southwestern Medical Center
Heartbeat – Dec 2003
AHA 2003
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
Heartbeat – Dec 2003
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
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."
TNT, SEARCH, IDEAL
REVERSAL
very promising."
AHA 2003
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
Average LDL reductions of 30% were right on target
"Those results were totally
How accurate is this technique?
Fuster
It's not so much the technique, but the biology of the disease
Incredibly dynamic
volume Nissen
+4.4
-0.9
0.02
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
detect
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
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
AHA 2003
REVERSAL: Pravastatin
"I was pretty surprised at how poorly the pravastatin group did."
Progression in patients in all 22 prespecified subgroups
More intensively treated
Fuster
"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
"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
will be an ATP IV
Grundy
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."
Heartbeat – Dec 2003
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
Heartbeat – Dec 2003
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
Heartbeat – Dec 2003
-1.06
+0.14
-14.1
-2.9
-0.042
-0.008
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
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
Grundy
ApoA-1 Milano: End points
Different calculations of the primary end point in the two trials
Agent
Pravastatin
+2.7
Atorvastatin
-0.4
ApoA-1 Milano: Drastic changes
"Effectively, we saw the elimination of a couple of years' worth of progression."
"We were just shocked when the statisticians delivered the data."
Large changes in big fatty plaques
Nissen
ApoA-1 Milano:
Elimination of macrophages
Many mechanisms for HDL
Reversal of cholesterol transport
Grundy
Why was the HDL low in the Italian village population?
How does ApoA-1 Milano work?
Cleared more rapidly from the circulation
Lower production rate
wild-type ApoA-1?
Nothing worked as well as the combination of ApoA-1 Milano
and phospholipid
REVERSAL
Effect on inflammatory processes with CRP
ApoA-1 Milano
Even with few patients, images show that you've accomplished something
Fuster
ApoA-1 Milano: Clinical trials
What could be a feasible strategy in a clinical study to raise HDL?
Early intervention in ACS patients might show immediate benefit in terms of reducing recurrent events
Takes a while for the statins to take hold
Grundy
What type of agent to use in clinical trials?
ApoA-1 derivative that could be produced in large amounts
Right now such an agent cannot be extracted from humans
Grundy
ApoA-1 Milano: The future
The manufacturing process of ApoA-1 Milano has come a long way
"We can make enough of this to do large-scale clinical trials."
5000-patient post-MI ACS study looking at morbidity and mortality under discussion
Phase 3 trial with the CETP
inhibitor torcetrapib launched
ApoA-1 Milano: Added to statin therapy
The agent would have to be given on top of a statin
Grundy
REVERSAL
We can do active-controlled trials with positive results
"If one statin can produce greater benefits than another statin, a statin plus agent x has a very good chance of beating a statin alone."
Nissen
REVERSAL
Lowering lipids as much as possible, even below normal, is important
Anti-inflammatory/antithrombotic aspects of statins
Fuster
Final word: Grundy
Statins can reduce CAD risk by one third, which leaves two thirds of people going to get into trouble
"These two studies are telling us that we may be able to shut down the plaques."
Reducing the frequency of syndromes, by further
lowering LDL and activating
Final word: Nissen
A future of intensive LDL reduction, along with activation of the HDL pathways
If we hit LDL and HDL hard, we can get beyond an event reduction of 30% to 35%
Next phase: using agents together will result in a 50% to 70% mortality reduction
"We will treat this disorder with a
cocktail of drugs, much like
they treat tuberculosis or HIV."
Nissen
0
1
2
3
4
5
6
7
Events
DeathMIStroke
PravastatinAtorvastatin
3.4
0.6
1.9
0.2
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
cholesterol
PravastatinAtorvastatin