Risk in the wake of ATP III

1
Risk in the wake of ATP III
Valentin Fuster MD (Chair) Director,
Cardiovascular Institute Mount Sinai Medical
Center New York, NY Christopher Cannon
MD Cardiologist Brigham and Womens
Hospital Boston, MA Michael Weber MD Professor
of Medicine SUNY Downstate College of
Medicine Brooklyn, NY

• James Cleeman MD
• Coordinator
• National Cholesterol Education Program NHLBI
• Bethesda, MD
• Richard Pasternak MD
• Director of Preventive Cardiology
• Massachusetts General Hospital
• Boston, MA

2
Prevention at different levels of risk
Risk in the wake of ATP III
3
Acute Coronary Syndrome
Risk in the wake of ATP III
4
Educating the public
Risk in the wake of ATP III

• "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

ACS
5
Educating the public
Risk in the wake of ATP III

• "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

ACS
6
MIRACL
Risk in the wake of ATP III

• 14.8 of patients on atorvastatin demonstrated a
  primary endpoint vs 17.4 on placebo (16
  reduction, p0.048).
• This 16 reduction was primarily due to a
  favorable effect of atorvastatin on recurrent
  symptomatic myocardial ischemia (26 reduction,
  p0.02).

Levels of LDL fell by 40 in those patients
treated with atorvastatin.
ACS
7
Straight to the statins
Risk in the wake of ATP III

• "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

ACS
8
Straight to the statins
Risk in the wake of ATP III

• "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
9
Straight to the statins
Risk in the wake of ATP III

• "So far, we still dont 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
10
CURE
Risk in the wake of ATP III
Benefit of clopidogrel ( ASA) for the chronic
treatment of ACS
p value
Relative risk
Aspirin clopidogrel (n6259)
Aspirin (n6303)
Endpoint
CV death, MI, stroke (primary endpoint)
11.47
9.28
0.80
0.00005
5.06
N/A
CV death
5.4
0.92
6.68
5.19
0.77
MI
Stroke
1.2
1.4
0.85
N/A
0.67
N/A
Non-CV death
0.70
0.96
ACS
11
Clopidogrel with IIb/IIIa
Risk in the wake of ATP III

• 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

ACS
12
Clopidogrel post MI
Risk in the wake of ATP III

• 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

ACS
13
Surgical risk
Risk in the wake of ATP III

• "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

ACS
14
Length of clopidogrel treatment
Risk in the wake of ATP III

• 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

ACS
15
Chronic coronary atherosclerosis
Risk in the wake of ATP III
16
Clopidogrel for angina?
Risk in the wake of ATP III

• 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

Coronary disease
17
Risk in the wake of ATP III
EuroASPIRE
Prophylactic drug use among patients enrolled in
EUROASPIRE 1 and 2
EuroASPIRE 1
Drug use
EuroASPIRE 2
84
Aspirin / antiplatelet
81
Beta blocker
66
54
ACE inhibitors
43
30
Lipid lowering drugs
63
32
Anticoagulants
8
7
Coronary disease
18
Risk in the wake of ATP III
Achieving compliance
Coronary disease
adapted from the NCEP Adult Treatment Panel III
Guidlines
19
One pill only?
Risk in the wake of ATP III

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

Coronary disease
20
Difficulty with compliance
Risk in the wake of ATP III

• 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

Coronary disease
21
Out with the old, in with the new
Risk in the wake of ATP III

• 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 Im 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

Coronary disease
22
Risk in the wake of ATP III
LDL goals in ATP I, II, and III

• 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
• ATP II
• Intensive management of LDL in people with CHD
• (LDL goal
• 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
23
Risk in the wake of ATP III
LDL lowering methods

• LDL goal
• LDL ? 100 mg/dL
• Initiate lifestyle changes, drug treatment
  optional
• LDL ? 130 mg/dL
• Consider full intensive therapy drugs plus
  lifestyle changes

adapted from the NCEP Adult Treatment Panel III
Guidlines
Coronary disease
24
Vascular disease
Risk in the wake of ATP III
25
Mortality in peripheral disease
Risk in the wake of ATP III

• 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

Vascular disease
26
Risk in the wake of ATP III
Statins against stroke
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 2001103387-92
Vascular disease
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Other statin effects
Risk in the wake of ATP III

• "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

Vascular disease
28
Subclinical disease
Risk in the wake of ATP III
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Risk in the wake of ATP III
EBCT
Score
No identifiable atherosclerotic plaque
0
Minimal identifiable plaque Significant CAD
unlikely
1-10
Definite but mild plaque. Risk factor
modification recommended
11-100
Definite, moderate plaque. Aggressive risk factor
modification, noninvasive stress testing
101-400
Major plaque. Likelihood of "significant"
stenosis. Aggressive risk factor modification
recommended, noninvasive stress testing
angiography
400
Subclinical disease
30
EBCT as supplemental information
Risk in the wake of ATP III

• "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

Subclinical disease
31
Risk in the wake of ATP III
Ankle-Brachial Index
ABI score
Severity
0.97-1.0
Normal
0.8-0.96
Mild ischemia
Moderate-severe ischemia
0.4-0.79

Severe ischemia
Subclinical disease
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Patients with multiple risk factors
Risk in the wake of ATP III
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New Features of ATP III
Risk in the wake of ATP III

• Focus on Multiple Risk Factors
• Diabetes CHD risk equivalent
• Framingham projections of 10-year CHD risk
• Identify certain patients with multiple risk
  factors for more intensive treatment
• Multiple metabolic risk factors (metabolic
  syndrome)
• Intensified therapeutic lifestyle changes

adapted from the NCEP Adult Treatment Panel III
Guidlines
High risk
34

Risk in the wake of ATP III
Metabolic syndrome

• "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
35

Risk in the wake of ATP III
Coronary risk equivalents

• 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
36

Risk in the wake of ATP III
Primary vs secondary prevention

• "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
37

Risk in the wake of ATP III
HDL in ATP III

• HDL is an enormously important predictor of
  coronary disease.
• Low HDL has been raised to
• "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
38
Risk in the wake of ATP III
Raising HDL
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
High risk
39

Risk in the wake of ATP III
Evidence based medicine

• 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
40

Risk in the wake of ATP III
HDL dilemma

• Patient with HDL 27 mg/dL, LDL 104 mg/dL
• No 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
41

Risk in the wake of ATP III
HDL and triglyceride as targets

• 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
42

Risk in the wake of ATP III
Problems with ratios

• 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
43

Risk in the wake of ATP III
Global risk score

• "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
44

Risk in the wake of ATP III
Motivational tool

• 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
45

Risk in the wake of ATP III
Compliance

• "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
46

Risk in the wake of ATP III
Understanding the patient

• "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
47

Risk in the wake of ATP III
A wake-up call

• "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
48
Overall population
Risk in the wake of ATP III
49
Risk in the wake of ATP III
CHD prevention Finland
Mean level of coronary risk factors and ischemic
heart disease mortality in Finnish men
1972
Risk factors and mortality
1992
Mean cholesterol (mmol/L)
6.78
5.90
Diastolic BP (mm Hg)
84.2
92.8
Percent smokers
53
37
Mean mortality from ischemic HD (per 100 000)
647
289
Vartiainen et al. BMJ 1994 309 23-7
Overall population
50

Risk in the wake of ATP III
Advocacy

• "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
51

Risk in the wake of ATP III
Spillover effect

• "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
52
Prevention at different levels of risk
Risk in the wake of ATP III