Heartbeat – Dec 2003 AHA 2003 AHA 2003: Tackling LDL and HDL for atheroma regression Valentin...

Heartbeat – Dec 2003

AHA 2003

AHA 2003: Tackling LDL and HDL for atheroma regression

Valentin Fuster MDDirector, Cardiovascular InstituteMount Sinai Medical CenterNew York, NY

Steve Nissen MDProfessor of MedicineCleveland Clinic FoundationCleveland, OH

Scott Grundy MDDirector, Center for Human NutritionUT Southwestern Medical CenterDallas, TX


AHA 2003

REVERSALEffects of atorvastatin vs

pravastatin on atherosclerosis progression

ApoA-1 Milano Effect of an HDL mimic on

atherosclerosis progression

Topics


AHA 2003

REVERSing Atherosclerosis with Lipitor

REVERSAL


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


AHA 2003

Outcome Pravastatin (n=249)

Atorvastatin (n=253)

p

Final LDL level

110 79 <0.001

% change in atheroma volume

+2.7(progression)

-0.4(no change)

0.02

REVERSAL: Results

AHA 2003


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 ofatorvastatin?

Fuster


AHA 2003

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."


AHA 2003

REVERSAL: How low?

ATP III guidelines:Levels of LDL should be below 100

TNT, SEARCH, IDEALAddress the issue of how low to go

REVERSALFirst study to test this question

"The results, in my opinion, look very promising."

Grundy


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


AHA 2003

AHA 2003

25

46

18

34

0.05.0

10.015.020.025.030.035.040.045.050.0

Reducti

on (

%)

Reduction in LDL Reduction in totalcholesterol

Pravastatin Atorvastatin

REVERSAL: Cholesterol reduction

p<0.0001p<0.0001


AHA 2003

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

AHA 2003

REVERSAL: Adverse events

0

1

2

3

4

5

6

7

Even

ts

Death MI Stroke



AHA 2003

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


AHA 2003

End point Pravastatin Atorvastatin p

% change in atheroma volume

+2.7 -0.4 0.2

Change in total atheroma volume

+4.4 -0.9 0.02

Change in % obstructive volume

1.6 0.2 0.0002

REVERSAL: End points

AHA 2003


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


AHA 2003

REVERSAL: Plaque changes

Perhaps other changes in the plaqueoccurred, 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

AHA 2003

3.4

0.6

1.9

0.2

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Ch

an

ge in

%

ath

ero

ma v

olu

me

Patients withdiabetes

Patients withmetabolic syndrome


REVERSAL: Subgroups


AHA 2003

REVERSAL: Diabetics

Patients with diabetes 95Patients 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


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 patients had all the advantages

Nissen


AHA 2003

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


AHA 2003

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


AHA 2003

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


AHA 2003

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."


AHA 2003

Effect of recombinant ApoA-1 Milano

on atherosclerosis in ACS patients


AHA 2003

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


AHA 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


AHA 2003

Outcome Combined ETC-216 groups

Placebo

Mean change in atheroma volume (%)

-1.06 +0.14

Mean change in total atheroma volume (mm3)

-14.1 -2.9

Mean change in maximum atheroma thickness (mm)

-0.042 -0.008

ApoA-1 Milano: Results

AHA 2003


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


AHA 2003

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


AHA 2003

ApoA-1 Milano: End points

Different calculations of the primary end point in the two trials

Agent % change in total atheroma volume

Pravastatin +2.7

Atorvastatin -0.4

ApoA-1 Milano -4.2


AHA 2003

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


AHA 2003

ApoA-1 Milano: Mechanism

HDL may halt the progression of atherosclerotic disease

ApoA-1 Milano: •Elimination of excess of oxidized

LDL by macrophages• Elimination of macrophages

Fuster

Injection of human HDL into rabbits

Disappearance of the macrophage after four

weeks


AHA 2003

ApoA-1 Milano: Effects of HDL

Many mechanisms for HDL

•Reversal of cholesterol transport

•Anti-inflammatory agent

• Interference with atherogenic lipoproteins

Study does not differentiate between these mechanisms

Grundy


AHA 2003

ApoA-1 Milano: Effects of HDL

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

•Less ApoA-1 getting out

Grundy


AHA 2003

ApoA-1 Milano: Combination

Catabolism is certainly higher

Would we have seen the same with wild-type ApoA-1?

Animal experiments with ApoA-1 Milano

by PK Shah

• Nothing worked as well as the combination of ApoA-1 Milano and phospholipid

Nissen


AHA 2003

ApoA-1 Milano: Statins and raising HDL

REVERSAL•Basic mechanisms of

progression/regression with statin therapy

•Effect on inflammatory processes with CRP

ApoA-1 Milano•Therapeutically raising HDL•Even with few patients, images

show that you've accomplished something

Fuster


AHA 2003

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


AHA 2003

ApoA-1 Milano: Type of agent

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


AHA 2003

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

Nissen


AHA 2003

ApoA-1 Milano: Added to statin therapy

The agent would have to be given on top of a statin

Grundy

REVERSALWe 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


AHA 2003

Final word: Fuster

REVERSAL

• Lowering lipids as much as possible, even below normal, is important

•Anti-inflammatory/antithrombotic aspects of statins

ApoA1-Milano

•HDL as a defense mechanism

• Increasing the activity of LDL Fuster


AHA 2003

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 the HDL system

Grundy


AHA 2003

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

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