Download beyond ncep atp iii: lessons learned and future directions

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BEYOND NCEP ATP III:
LESSONS LEARNED AND FUTURE DIRECTIONS*
—
Benjamin J. Ansell, MD, FACP†
ABSTRACT
The National Cholesterol Education
Program (NCEP) Third Adult Treatment Panel
(ATP III) guidelines provide an important first
step in identifying individuals who would most
benefit from statin therapy. With heart disease
as the number-one killer in the United States,
prevention is crucial. The NCEP ATP III guidelines formally outline treatment goals of reducing low-density lipoprotein (LDL) cholesterol
levels based on a calculated risk of coronary
heart disease (CHD). Determining CHD risk is
necessary to define optimal dyslipidemia treatment strategies. CHD risk is determined by a
number of major risk factors: LDL cholesterol,
high-density lipoprotein cholesterol, hypertension, age, sex, diabetes status, and smoking
status. Those with multiple risk factors and CHD
risk equivalents should be aggressively targeted
for lowering LDL cholesterol with drug therapy;
however, since the publication of the guidelines, important new data have been published.
These data suggest additional benefit with even
more aggressive LDL lowering to below 100
mg/dL in those at risk for CHD and in those with
acute coronary syndromes. The metabolic syndrome is a secondary target of therapy that
*Based on a presentation given by Dr Ansell at a symposium held in conjunction with the Pri-Med Midwest 2003
Conference and Exhibition.
†Director, UCLA Comprehensive Health Program,
University of California, Los Angeles.
Address correspondence to: Benjamin J. Ansell, MD,
Department of Medicine, UCLA School of Medicine, 200
UCLA Medical Plaza, Suite 370, Los Angeles, CA
90095. E-mail: [email protected].
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should be addressed early. Current studies will
help to better define the “optimal” treatment
target.
(Adv Stud Med. 2004;4(1B):S38-S43)
he updated guidelines from the National
Cholesterol Education Program (NCEP)
Third Adult Treatment Panel (ATP III)
mark an important change in the management of dyslipidemia and coronary
heart disease (CHD). Heart disease is the number-one
killer in the United States. The medical community
has made marked efforts to increase awareness and,
therefore, prevention of the perils of CHD, yet
myocardial infarction (MI) remains the first sign of
heart disease in most victims. Too often, this sentinel
event is fatal.
The NCEP ATP III guidelines formally outline treatment goals of reducing low-density lipoprotein (LDL)
cholesterol based on a calculated risk of CHD. Whereas
the treatment goal is defined by LDL cholesterol, the
ultimate therapeutic goal is the reduction in vascular disease. The intensity of any LDL-lowering therapy is
matched to absolute CHD risk, which is defined based
on lipid (LDL cholesterol, high-density lipoprotein
[HDL] cholesterol) and nonlipid (hypertension, age, sex,
diabetes, and smoking) factors. For cost-effective and
clinical reasons, efforts toward preventing CHD have
been focused on patients at highest risk. LDL cholesterol
has been chosen as the treatment target because it is a
universal pathway by which the associated risk for CHD
T
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can be reduced, even in patients with normal baseline
LDL cholesterol levels.
The NCEP ATP III guidelines assess CHD risk
based on the totality of risk factors (a global risk assessment) for a particular individual without known atherosclerosis. These risk factors are weighted based on their
epidemiologic prediction of an actual risk of a CHD
event in the next 10 years. A critical change in the NCEP
ATP III guidelines (from the ATP II guidelines) is the
inclusion of some risk factors as CHD risk equivalents
(ie, they pose the same risk as having had a CHD
event—most notably, diabetes) and the inclusion of
other forms of vascular disease (eg, significant carotid
artery disease, peripheral vascular disease, abdominal
aortic aneurysm, stroke).1
CHD risk is determined via a complete history to
identify risk factors and a complete fasting lipid profile.
The components of a lipid profile include LDL cholesterol, HDL cholesterol, non-HDL cholesterol (total
cholesterol minus HDL cholesterol), and triglycerides.
Table 1 outlines the treatment goals according to CHD
risk categories for both LDL cholesterol and non-HDL
cholesterol. In general, non-HDL cholesterol targets are
30 points above LDL cholesterol targets and are driven
predominantly by elevated triglycerides. Non-HDL cholesterol is a secondary treatment target in those with
triglyceride levels of 200 mg/dL or above.1 An LDL cholesterol level of 160 mg/dL is the highest “tolerable”
blood level in a healthy individual; however, based on the
large, randomized, controlled trials available at the time
of NCEP ATP III, LDL cholesterol levels below 100
mg/dL are considered optimal. With the NCEP ATP III
guidelines, the number of Americans who are eligible for
lipid-lowering drug therapy has tripled to approximately
36 million persons, largely due to the inclusion of those
who have CHD risk equivalents.2
Since the publication of these guidelines nearly 3
years ago, important new data have been published.
These data suggest additional benefit with even more
aggressive LDL lowering to below 100 mg/dL in those
at risk for CHD and in those with acute coronary syndromes.3 Therapy may even benefit at-risk patients
whose LDL is currently below 100 mg/dL.
STATINS IN ACUTE CORONARY SYNDROMES
CHD risk is highest in those with unstable angina or a non–Q-wave MI, as evidenced by the 1-year
mortality in the Fragmin and Fast Revascularization
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During Instability in Coronary Artery Disease II
(FRISC II) study compared with 1-year mortality
in patients with stable chronic angina in the
Swedish Angina Pectoris Aspirin Trial (SAPAT;
Figure 1).3 In those who survive the event and
return home from the hospital, there is a 10% risk of
Table 1. LDL and Non-HDL Treatment Goals: NCEP
ATP III
LDL Cholesterol
Goal (mg/dL)
Non-HDL Cholesterol
Goal (mg/dL)
<100
<130
2+ risk factors
(10-year risk, 10% to 20%)
<130
<160
2+ risk factors
(10-year risk <10%)
<160
<190
0 to 1 risk factor
<160
<190
Risk Category
CHD or CHD risk
equivalent
LDL = low-density lipoprotein; HDL = high-density lipoprotein; NCEP = National
Cholesterol Education Program; ATP III = Third Adult Treatment Panel; CHD =
coronary heart disease.
Adapted with permission from the Journal of the American Medical Association.
2001;285(19):2486-2497.1
Figure 1. One-Year Mortality Following Acute Coronary
Syndrome Exceeds That in Stable Angina
Short-term outcome for patients with unstable angina or non–Q-wave MI is much
worse than the outcome for patients with stable angina.
MI = myocardial infarction; FRISC II = Fragmin and Fast Revascularization During
Instability in Coronary Artery Disease; SAPAT = Swedish Angina Pectoris Aspirin Trial.
Reproduced with permission from Elsevier. Waters et al. Am J Cardiol.
2000;86(suppl B):35J-43J.3
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death or another MI within 2 months after the event—
a very high level of risk, considering that NCEP ATP III
defined high risk as a 20% 10-year risk of an event.4-6
Patients with unstable angina/non–Q-wave MI are most
receptive to aggressive lipid-lowering therapy because
they have experienced firsthand that the risk can translate into an event and because they understand that
lipid-lowering drugs are ultimately heart medications.
In the original studies on which the NCEP ATP III
guidelines were based, patients with unstable angina
were excluded. Current guidelines recommend that
patients with LDL cholesterol levels below 130
mg/dL, even with unstable angina, should try therapeutic lifestyle changes for 3 months before initiating
drug therapy. New evidence from the Myocardial
Ischemia Reduction with Aggressive Cholesterol
Lowering (MIRACL) study suggests that patients can
benefit clinically from statin therapy immediately following a cardiovascular event, above and beyond the
long-term compliance benefit. More than 3000
patients were randomized within 24 to 96 hours from
hospital admission for non–Q-wave MI or unstable
angina and received either atorvastatin 80 mg or placebo in addition to other usual care for 4 months. The
results show the expected decreases in total cholesterol
and LDL cholesterol levels in the atorvastatin group,
even with baseline LDL cholesterol levels below 130
mg/dL (Table 2). By 4 months, these effects translated
into a significant reduction in risk (17.4% vs 14.8%;
relative risk, 0.84; P = .048) of the first cardiovascular
event (ie, death due to any cause, nonfatal MI, resuscitated cardiac arrest, or worsening angina with new
objective evidence requiring urgent rehospitalization)
since randomization in patients taking atorvastatin.
The risk of stroke was also cut in half (1.6% vs 0.8%;
P < .045) by 4 months. The composite endpoint of the
first cardiovascular event is broadly defined but is an
expensive endpoint (in human and monetary cost). A
harder endpoint, such as stroke, confirms the benefit
from statin therapy and provides more direct evidence
of clinical and cost effectiveness.7
mary or secondary prevention of a CHD event, irrespective of baseline LDL cholesterol levels. The optimal LDL
cholesterol appeared to be below 100 mg/dL in both primary and secondary prevention.8 Comparing separate
trials is not, however, the most scientifically sound
method to determine a treatment goal. The optimal trial
would select 1 group of high-risk patients and treat to at
least 2 increasingly aggressive treatment goals. Only 1
study with clinical endpoints to date has been designed
with 2 different treatment goals—the Post-Coronary
Table 2. Plasma Lipid Level Changes:The MIRACL
Study
Baseline
End of Study
Both Groups,
mean (mg/dL)
Placebo,
mg/dL
(% change)
Atorvastatin,
mg/dL
(% change)
Total cholesterol
206
217 (+7)
147 (-27)
LDL
124
135 (+12)
72 (-40)
HDL
46
46 (+4)
48 (+5)
Triglycerides
184
187 (+9)
139 (-16)
LDL = low-density lipoprotein; HDL = high-density lipoprotein.
Data from Schwartz et al.7
Figure 2. LDL Lowering with Statins: Reduced
CHD Events
BASELINE LDL CHOLESTEROL
LOWERING LDL CHOLESTEROL
VERSUS
The updated recommendations in the NCEP ATP
III guidelines were supported by 5 major statin trials. As
shown in Figure 2, the lesson from these trials was that
LDL lowering with a statin is beneficial for either pri-
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LDL = low-density lipoprotein; CHD = coronary heart disease.
Reproduced with permission from Illingworth. Med Clin North Am.
2000;84(1):23-42.8
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Artery Bypass Graft (Post-CABG) study, which compared different outcomes in patients treated with lovastatin, warfarin, or placebo to target LDL cholesterol
levels of approximately 130 mg/dL versus below 100
mg/dL. The study cohort consisted of approximately
1300 patients with a history of bypass surgery (ie, highrisk patients). Significant decreases in angiographic progression (in both the saphenous vein and the left main
coronary artery), revascularization rate, and coronary
events were observed in those with an LDL cholesterol
target of below 100 mg/dL compared with those whose
LDL cholesterol was moderately lowered (Figure 3).9-11
Three trials are also under way to assess conventional versus maximal doses of simvastatin and/or atorvastatin in reducing CHD events in large populations. The
Treat to New Targets (TNT) study is a 5-year study of
10 000 patients comparing the rates of CHD events
with LDL cholesterol lowering to near 100 mg/dL versus approximately 75 mg/dL. The Incremental Decrease
in Endpoints through Aggressive Lipid Lowering
(IDEAL) study compares atorvastatin 80 mg versus simvastatin 20 mg or 40 mg in 8600 patients. In the Study
of Effectiveness of Additional Reductions of Cholesterol
and Homocysteine (SEARCH), 2 doses of simvastatin
(20 mg vs 80 mg) will be compared in 10 000 patients.12
Another study is also under way to assess the benefits of
LDL cholesterol lowering in patients with previous
stroke or transient ischemic attack but no history of
coronary problems—the Stroke Prevention by
Aggressive Reduction in Cholesterol Levels (SPARCL).13
The data for these studies will be available in the next
couple of years.
An important early finding on this issue is found in
the Heart Protection Study, which examined the rate
of vascular events in 20 536 adults at high risk for
CHD, although not necessarily dyslipidemic. In this
study population, participants had increased CHD
risk due to previous MI, history of CHD, history of
peripheral vascular disease, type 2 diabetes, or treated
hypertension as well as a nonfasting total cholesterol
level of at least 135 mg/dL (a common criteria, especially in those with a history of vascular disease).
Participants received simvastatin 40 mg; a combination of vitamin E, beta-carotene, and vitamin C; both
treatments; or placebo. The results after a mean of 5.5
years of follow-up showed a significant decrease in first
vascular event in patients taking a statin versus placebo (19.8% vs 25.2%, P < .001), a 24% reduction in
event rate. More importantly, the reduction in risk
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(relative and absolute) was observed irrespective of history of CHD (Figure 4) or baseline LDL cholesterol
level—including baseline LDL levels below 100
mg/dL (Figure 5).14,15 The data suggest that every highrisk patient would benefit from lipid-lowering therapy.
Figure 3. Post-CABG Trial: Results with Moderate
vs Aggressive Treatment Goals
CABG = coronary artery bypass graft; LDL = low-density lipoprotein.
Data from Knatterud et al9; Post-CABG Trial Investigators10; White et al.11
Figure 4. Results from HPS: Risk of Major Vascular Event
Based on Baseline CHD
HPS = Heart Protection Study; CHD = coronary heart disease; MI = myocardial
infarction; CVD = cardiovascular disease; PVD = peripheral vascular disease.
Adapted with permission from Elsevier. Lancet. 2002;360(9326):7-22.14
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Unanswered clinical questions now focus on whether
statin treatment is sufficient to reduce the risk of CHD.
Should combination therapy with a fibrate be used to
address low HDL cholesterol or high triglyceride levels?
Should statin treatment be based on LDL cholesterol
level or strictly on global risk assessment? The NCEP
ATP III provides an important first step in identifying
individuals in the general population who would most
benefit from statin therapy.
risk factors are weighted based on epidemiology,
including HDL cholesterol level and age. CHD risk
is determined by the sum total of the risk factors.
Those with multiple risk factors and CHD risk
equivalents should be aggressively targeted for LDLlowering drug therapy. NCEP ATP III guidelines
have brought important criteria for identifying those
at greatest risk of CHD. Our next steps will be to further define the optimal treatment goals.
THE METABOLIC SYNDROME
Another group of individuals is also being closely
examined for risk of CHD based on the types of markers used to calculate CHD risk. The metabolic syndrome has been known by other monikers (eg,
syndrome X). The NCEP ATP III guidelines characterize the metabolic syndrome as a composite of
potentially subtle abnormalities: abdominal obesity
(waist circumference >40 in [men] or >35 in
[women]), high triglyceride levels (≥150 mg/dL), low
HDL cholesterol (<40 mg/dL [men], <50 mg/dL
[women]), hypertension (≥130/≥85 mm Hg), and
fasting blood glucose of 110 mg/dL or greater. The
metabolic syndrome is defined by NCEP ATP III as a
presence of 3 or more of these risk determinants.
Patients with the metabolic syndrome often develop
atherosclerosis if these risk determinants remain
untreated. The prevalence of the metabolic syndrome
is increasing rapidly with our concurrent epidemics of
obesity and type 2 diabetes. General prevalence rates
for adults older than 20 years are about 24%, with the
vast majority in those older than 50 years (Figure 6).16
The treatment approach to the metabolic syndrome is multifaceted, targeting both lipid and nonlipid risk factors primarily with weight reduction,
diet, and exercise, as well as aspirin to address the
prothrombotic state. Triglyceridemia is most common in people with the metabolic syndrome and
can be treated with therapeutic lifestyle changes for
borderline high levels (150–199 mg/dL). For those
with very high levels (200–499 mg/dL), several drug
strategies are available, including intensification of
statin therapy or addition of niacin or fibrate.1
Figure 5. Results from HPS: Risk of Vascular Events
based on Baseline LDL-C
HPS = Heart Protection Study; LDL = low-density lipoprotein.
Reproduced with permission from the MRC/BHF Heart Protection Study Web site.
Available at: www.hpsinfo.org.15
Figure 6. Prevalence of the Metabolic Syndrome Among
US Adults
CONCLUSION
Determining CHD risk is necessary to define
optimal dyslipidemia treatment strategies. The CHD
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Reproduced with permission from the Journal of the American Medical
Association. 2002;287(3):356-359.16
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REFERENCES
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