risk in the wake of atp iii valentin fuster md (chair) director, cardiovascular institute mount...

Risk in the wake of ATP III

Valentin Fuster MD (Chair)Director, Cardiovascular Institute

Mount Sinai Medical CenterNew York, NY

Christopher Cannon MDCardiologistBrigham and Women’s HospitalBoston, MA

Michael Weber MDProfessor of MedicineSUNY Downstate College of MedicineBrooklyn, NY

James Cleeman MDCoordinatorNational Cholesterol Education Program NHLBIBethesda, MD

Richard Pasternak MDDirector of Preventive CardiologyMassachusetts General HospitalBoston, MA


Prevention at different levels of risk

Acute Coronary Syndrome

Coronary Atherosclerosis

Vascular disease

Subclinical disease

Patients with multiple risk factors

Overall population





Vascular disease

Subclinical disease


Overall population

"Once they get to the hospital, we have lots of things to do and making sure people get there is the key thing."

National Heart Attack Alert Program is aimed at increasing public awareness

More and more AEDs are available in public places

C Cannon


Educating the public

ACS

"Thinking through and improving the whole chain of events that occurs from the onset of a symptom to dealing with a symptom […] is a major effort of the acute disease programs within the American Heart Association." Also need to think of prevention of sudden cardiac death separately from ACS, and be aware of the different electrophysiologic underpinnings involved.

R Pasternak


Educating the public

ACS

14.8% of patients on atorvastatin demonstrated a primary endpoint vs 17.4% on placebo (16% reduction, p=0.048).

This 16% reduction was primarily due to a favorable effect of atorvastatin on recurrent symptomatic myocardial ischemia (26% reduction, p=0.02).

Levels of LDL fell by 40% in those patients treated with atorvastatin.


MIRACL

ACS

"The view of the guidelines [NCEP] is that this [MIRACL] does support an early benefit from statin treatment in hospital, which is a good idea in any case since it means these people will not be lost to follow-up and will be discharged on a statin."

Anyone admitted to hospital should have an LDL drawn and LDL > 100 mg/dL should be treated with a statin in hospital

J Cleeman


Straight to the statins

ACS

"I can't see any downside to starting a statin as early as possible. And I like the idea of getting these patients, of whom I would suspect 70 or 80% in any case are going to have LDLs above 100, on treatment as rapidly as possible."

M Weber



ACS

"So far, we still don’t have data to support the necessity of treating people with an LDL under 100 and this trial doesn't confirm that that is absolutely the case. I think there are a couple of other large trials that will help us with that issue. So I'm in favor of measuring it in everybody and treating those who are over 100 before they leave the hospital."

R Pasternak



ACS

CURE

p valueRelative risk

Aspirin (n=6303)

Endpoint

N/A

6.68%

5.06%

CV death, MI, stroke (primary endpoint)

Stroke

Aspirin + clopidogrel(n=6259)

1.2%

0.67%

<0.001

N/A

CV death

Non-CV death

0.70%

1.4%

5.4%

11.47% 9.28%

5.19%

0.80

0.92

0.77

0.85

0.96

0.00005

N/A

Benefit of clopidogrel (+ ASA) for the chronic treatment of ACS

MI


ACS

The trial data support using clopidogrel right away on a patient coming to the emergency room with unstable angina.

There aren't data on upstream Gp IIb/IIIa inhibition and clopidogrel but one would expect they would be additive.

C Cannon


Clopidogrel with IIb/IIIa

ACS

Don't use clopidogrel in an MI patient who is receiving thrombolysis.

"Definitely not. There, with thrombolysis, there is a large 40 000 patient trial ongoing and one really needs the safety data."

We have data on clopidogrel benefit in: unstable angina and non-ST elevation MI, stenting, long-term secondary prevention

C Cannon


Clopidogrel post MI

ACS

"The same type anecdotes used to be present for aspirin, that the surgeons wouldn't operate on anyone who had taken aspirin in the last week. I think we really need to wait and see what the data look like."

C Cannon


Surgical risk

ACS

Patients should get clopidogrel for at least 1 year, possibly for life.

If the data shows benefit from 1 month to 1 year, why wouldn't the benefit continue beyond that?

We also have data from CAPRIE for stable patients showing benefit out to several years.

C Cannon


Length of clopidogrel treatment

ACS


Chronic coronary atherosclerosis



Vascular disease

Subclinical disease


Overall population

CAPRIE showed a benefit for clopidogrel over aspirin for people with recent MI.

I would target the higher risk patient.

I would tend to the combination of clopidogrel and aspirin, since that's what we have the data on.

C Cannon


Clopidogrel for angina?

Coronary disease

EuroASPIRE 1Drug use EuroASPIRE 2

Prophylactic drug use among patients enrolled in EUROASPIRE 1 and 2

81%

54%

7%

32%

30%

EuroASPIRE

Aspirin / antiplatelet

Beta blocker

ACE inhibitors

Lipid lowering drugs

Anticoagulants

84%

66%

8%

63%

43%


Coronary disease

•Teach and remind peers about lipid guidelines•Follow-up on missed appointments•Develop a standardized treatment plan•Use patient feedback to improve care

For

Docto

rs

•Simplify drug regimens•Involve patients, family, friends•Use systems to reinforce and reward adherence •Maintain contact with patient and increase convenience

For

Pati

en

ts

•Use lipid clinics & case management by nurses•Deploy telemedicine•Collaborate with pharmacists•Use/create critical care pathways in hospitals

For

Healt

h

Delivery

S

yste

ms

Achieving compliance

adapted from the NCEP Adult Treatment Panel III GuidlinesCoronary disease


A single pill with aspirin, a statin, ACE inhibitor or some other effective combination will be part of the future.

M Weber


One pill only?

Coronary disease

One of the reasons the guidelines weren't updated earlier was because of problems with compliance. "Although obviously physicians intend to do the right thing, it's extraordinarily complicated and I think, given the pressures of managed care and other pressures of managed care, it's extremely difficult."

R Pasternak


Difficulty with compliance

Coronary disease

Trials show benefit for new interventions, but we only have some subgroup analyses that suggest a combination pill would be effective.

"For example with clopidogrel, that's one area where I’m concerned. As we push that on the front of the truck, I'm afraid that other important things with even more convincing data fall off the back of the truck."

R Pasternak


Out with the old, in with the new

Coronary disease

ATP I

•Primary CHD prevention in people with:

LDL > 160 mg/dL or LDL 130-159 mg/dL and multiple (2+) risk factors (LDL goal <130 mg/dL)

ATP II

•Intensive management of LDL in people with CHD

(LDL goal < 100mg/dL)

ATP III

•Primary CHD prevention in people with multiple risk factors

•People with diabetes patients categorized as CHD "risk equivalents"

LDL goals in CHD patients and risk equivalents: < 100mg/dL

Coronary disease


LDL goals in ATP I, II, and III

LDL goal < 100 mg/dL

LDL 100 mg/dL

•Initiate lifestyle changes, drug treatment optional

LDL 130 mg/dL

•Consider full intensive therapy – drugs plus lifestyle changes

Coronary disease


LDL lowering methods

adapted from the NCEP Adult Treatment Panel III Guidlines


Vascular disease



Vascular disease

Subclinical disease


Overall population

The principal cause of mortality in patients with peripheral vascular disease is coronary artery disease. It is appropriate to be aggressive in treating these patients to prevent coronary disease.

R Pasternak


Mortality in peripheral disease

Vascular disease

CARE and LIPID (secondary prevention) trials: 22% reduction in total strokes 25% reduction in nonfatal strokes

WOSCOPS, (primary prevention) trial: 23% reduction in total nonhemorrhagic stroke No significant reduction in hemorrhagic stroke

Byington RP et al. Circulation 2001;103:387-92


Statins against stroke

Vascular disease

"It is increasingly clear that statins have many favorable effects. I'd still argue that most of them are mediated through LDL lowering, but I'm sure it's not true of all of them."

R Pasternak


Other statin effects

Vascular disease


Subclinical disease



Vascular disease

Subclinical disease


Overall population

Minimal identifiable plaque Significant CAD unlikely

Definite but mild plaque. Risk factor modification recommended

No identifiable atherosclerotic plaque

Definite, moderate plaque. Aggressive risk factor modification, noninvasive stress testing

Major plaque. Likelihood of "significant" stenosis. Aggressive risk factor modification recommended, noninvasive stress testing + angiography

Score

0

1-10

11-100

101-400

>400


EBCT

Subclinical disease

"The view of the guidelines is that EBCT is an emerging risk factor. It can tip you over the edge in a particular patient and convince you that this person deserves more aggressive attention, but it does not displace the standard risk factors."

J Cleeman


EBCT as supplemental information

Subclinical disease

ABI score

0.97-1.0

0.8-0.96

Moderate-severe ischemia

Normal

0.4-0.79

<0.4

Mild ischemia

Severe ischemia

Severity


Ankle-Brachial Index

Subclinical disease





Vascular disease

Subclinical disease


Overall population

New Features of ATP III

Focus on Multiple Risk Factors

Diabetes: CHD risk equivalent

Framingham projections of 10-year CHD riskIdentify certain patients with multiple risk

factors for more intensive treatment

Multiple metabolic risk factors (metabolic syndrome)Intensified therapeutic lifestyle changes


High riskadapted from the NCEP Adult Treatment Panel III Guidlines

"I think as we look forward to trying to prevent where this country is going with risk factors it's an extraordinarily important area to look at because we're getting heavier, less glucose-tolerant, and having higher blood pressures and higher lipids as a result."

R Pasternak


High risk

Metabolic syndrome

Patients with coronary disease have a MI risk >20% in the next ten years.

Patients with diabetes or with a Framingham risk of >20% in the next ten years have an equivalent risk

"They need to have their LDL lowered to less than a 100 and they qualify for intensive therapy at just the same levels as the people who have overt, established coronary disease."

J Cleeman


High risk

Coronary risk equivalents

"I think the line between those [primary and secondary prevention] deserves to be very blurry. The patient the moment before the infarction may not be altogether different than the moment after the infarction in terms of the basic biology."

J Cleeman


High risk

Primary vs secondary prevention

HDL is an enormously important predictor of coronary disease.

Low HDL has been raised to < 40 mg/dL

"We just don't have enough clinical trial evidence to set an actual goal of therapy, how high should you shoot for. Moreover we don't have agents that would let you get to a goal if you actually set one."

J Cleeman


High risk

HDL in ATP III

Veterans Affairs HDL Intervention Trial (VA-HIT)

Treatment with 1200 mg/day of gemfibrozil resulted in a significant 22% reduction in the combined incidence of nonfatal MI and CHD death over 5 years of follow-up.1

Bezafibrate Infarction Prevention (BIP) study

Treatment with 400 mg bezafibrate resulted in an 18% increase in HDL, but no significant reduction in MI or sudden death.2

1. Haffner S. Circulation 2000; 102: 2-4

2. BIP Study Group. Circulation 2000; 102: 21-2


Raising HDL

High risk

There has been a move from expert consensus reports to evidence based reports.

ATP III is directly related to specific evidence.

We don't yet have clinical trial evidence that supports a specific HDL target.

R Pasternak


High risk

Evidence based medicine

Patient with HDL 27 mg/dL, LDL 104 mg/dLNo other risk factors.

My approach is to lower LDL even further, because if you cannot attack one parameter, you can attack the others to get a good result.

The ratio can be used as an important goal.

V Fuster


High risk

HDL dilemma

Attacking triglyceride/cholesterol ratio type can have benefit

Many trials have suggested that if you modify the ratio you have a significant benefit

"I would try to give the physician a little bit of hope."

V Fuster


High risk

HDL and triglyceride as targets

We've been nervous about making the ratio as a target of therapy because it submerges the individual components of the ratio.

You lose track of which components you are addressing with your intervention.

J Cleeman


High risk

Problems with ratios

"We should begin to think of the global risk score as a kind of a vital sign that should be in everyone's chart, that should be communicated to patients. And I hope we will see a sea change of thinking because of this."

R Pasternak


High risk

Global risk score

A powerful patient education and motivation tool

Not only on the Palm for the doctors, it is also in the patient literature and available on the web for patients to use.

J Cleeman


High risk

Motivational tool

"One thing I've come to learn is that even knowing that you are at high risk doesn't necessarily make people do the right thing. […] There's a lot we still have to learn about what motivates people to follow treatment even when the benefit of treatment is very, very well established."

M Weber


High risk

Compliance

"Maybe we have to understand better the psychology of the patient; why the patient is obese, or why the patient smokes, and then maybe attack the problem at a different level.

"However, I don't think the health system is prepared to do such a thing when in fact we have trouble even giving a pill."

V Fuster


High risk

Understanding the patient

"This is the kind of red flag that wakes people up and gets the ball rolling […] And once these things are prescribed, then that's the first step in getting compliance."

C Cannon


High risk

A wake-up call


Overall population



Vascular disease

Subclinical disease


Overall population

1972Risk factors and mortality

Mean cholesterol (mmol/L)

1992

Diastolic BP (mm Hg)

Percent smokers

Mean mortality from ischemic HD (per 100 000)

6.78

647

53

289

5.90

84.2

37

92.8

Vartiainen et al. BMJ 1994; 309: 23-7

Mean level of coronary risk factors and ischemic heart disease mortality in Finnish men


CHD prevention: Finland

Overall population

"We have to be much more aggressive advocating in the public health forum […] With legislators, with policy makers, with insurance companies, and with organizations that have the power to change things for a whole population."

R Pasternak


Overall population

Advocacy

"If we can already get the message to all these 4 levels of risk, that will spill over to family members and other people around"

C Cannon


Overall population

Spillover effect


Prevention at different levels of risk



Vascular disease

Subclinical disease


Overall population

risk in the wake of atp iii valentin fuster md (chair) director, cardiovascular institute mount...

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