Evan A. Stein, MD, PhD†
Heart disease remains the leading cause of
death in the United States. Despite advances in surgical, interventional, and pharmacologic therapies
for heart disease, prevention remains paramount in
reducing morbidity and mortality. Almost 15 years
of clinical experience with statin-based lipid-lowering therapy, including data from multiple large, evidence-based clinical trials, has brought about
major changes in the approach to prevention of
coronary heart disease. However, even with the
gains of effective lipid-lowering therapy, a majority
of at-risk individuals continue to experience clinical
events, even with treatment.
Statin trials have provided a strong basis for
prevention of coronary disease and associated
events; however, it is time to take the next step
toward eradication of the disease. A number of
approaches are being evaluated, such as intensified reduction of low-density lipoprotein cholesterol
and increasing levels of high-density lipoprotein
cholesterol. Combination lipid-lowering therapy,
using existing agents or a combination of existing
and new drugs, represents one promising
approach to coronary risk reduction. Combination
therapy offers the opportunity to explore new and
emerging treatments in the reduction of coronary
risk, including inflammation.
(Adv Stud Med. 2003;3(4C):S306-S310)
*This article is based on a presentation given by Dr Stein
at a satellite symposium held during the 75th Annual
Scientific Sessions of the American Heart Association.
†Director, Metabolic and Atherosclerosis Research
Center, Cincinnati, Ohio.
Address correspondence to Evan Stein, MD, Director,
the Metabolic and Atherosclerosis Research Center,
3131 Harvey Ave, Suite 201, Cincinnati, OH 45229.
E-mail: [email protected]
oronary artery disease remains the leading cause of death among men and
women in the United States.
Approximately 14 million Americans
have a history of myocardial infarction
(MI) or angina. Each year, 1.1 million people have
MIs; one third of these patients die from the MI, and
one fourth of these patients will die within 1 hour of
experiencing the MI. Thus, almost half of all coronary heart disease (CHD) deaths occur outside of a
hospital, emphasizing that prevention of a first or
repeated CHD event represents the best option for
managing coronary disease risk. Among men, mortality from CHD decreased steadily from the mid1980s to the mid-1990s, but has since begun to
increase. There has also been a relative increase in
CHD in women, such that morbidity and mortality
from CHD is approaching that of males.1 The continuing morbidity and mortality trends clearly indicate a need for further improvement in strategies to
reduce CHD risk. However, results of large, randomized, placebo-controlled trials of lipid-lowering therapy on CHD have provided the evidence base and
should lead to the alteration of clinical practice that
will contribute to substantial reductions in CHD
mortality. The following discussion reviews the
progress to date, the challenges of the future, and the
potential strategies and options in lipid management
to prevent CHD events.
Beginning with the Scandinavian Simvastatin
Survival Study (4S) in 1994, results of 6 major clinical
trials of various statin-based lipid-lowering therapy
have now reported consistent and powerful evidence
in over 50 000 people that low-density lipoprotein
Vol. 3 (4C)
April 2003
cholesterol (LDL-C) therapy leads to a 25% to 35%
priori as an endpoint. The overall reduction in stroke risk
reduction in the relative risk (RR) for CHD morbidihas ranged between 11% and 40%, being primarily seen
ty and mortality. Moreover, the trials showed consisin secondary prevention trials.8
tent benefits regardless of the baseline LDL-C level.
With respect to RR reduction, virtually every populaClearly, the ideal objective would be to eliminate
tion studied has benefited from lowering of LDL.
all CHD events. In terms of lipid-lowering therapy,
Collectively, results of the trials have shown that
what magnitude would be required to achieve that
statins currently offer the most effective approach for
goal? Based on results from the major secondary prereducing CHD2-7 (Table 1).
The benefits of statin-based lipid-lowering therapy
vention trials, extrapolation shows an LDL-C of
have extended to every major subgroup of patients examapproximately 30 mg/dL might produce an event rate
ined. In the 4S trial, diabetic patients, who had a subof zero. Extrapolation from primary prevention trials,
stantially higher event rate compared with nondiabetic
which have involved a lower absolute risk, have indipatients, reduced their future risk of CHD after receiving
cated that an LDL-C level of approximately 50 mg/dL
simvastatin therapy to that of nondiabetic patients who
might result in total elimination of CHD events.
had not received the statin. The Air Force/Texas
Such extrapolation from clinical trial results raises
Coronary Atherosclerosis Prevention Study (AFCAPS/
2 obvious questions: will increasingly greater reducTexCAPS) demonstrated the benefits of treating low-risk
tions in LDL-C levels result in additional benefits, and
patients with a statin. Overall, the risk in AFCAPS/
is it feasible to attain those LDL-C levels? Data from
TexCAPS for a new coronary event, which averaged
the 4S trial suggest that greater reductions in LDL-C
approximately 1% per year, was significantly reduced
do translate into greater reductions in event rates. A
during 5 years of treatment with lovastatin. As in the
comparison of patients whose LDL-C levels declined
other statin trials, the benefits of treatment emerged early,
by <34% versus 34% to 44% showed a 5.6% absolute
after about 6 months of follow-up.5
reduction in event rate and those whose LDL-C levels
Until recently, even with 5 major trials completed,
declined by 44% to 70% with simvastatin therapy had
the data had a few gaps that left room for controversy
a further 2.3% reduction in absolute risk.9 While these
data suggest that greater reductions in LDL-C levels
about the benefits of statin therapy. In particular, relatively little data existed with respect to the
effects of statin therapy in women, in the
elderly, and in patients with low LDL-C levels. Of the approximate 20 000 patients
included in the Heart Protection Study (HPS)
Table 1. Effect of Statin Therapy on CHD
population, roughly one fourth of the participants were women and almost half of the
patients were between the ages of 65 and 80
Clinical Events Trials
years.7 Almost one third of the HPS populaBaseline On-Tx
tion had a baseline LDL-C level of less than
Event* Event
115 mg/dL. Overall, treatment with simvasTrial
(mg/dL) (% red.)
tatin resulted in a 24% reduction in the RR
for vascular events, and the benefits were con4S
122 (35)
28.0% 34% 8.6% 12
sistent in women, the elderly, and in patients
15.9% 24% 3.6% 28
112 (25)
who had low baseline LDL-C levels.
98 (32)
13.2% 24% 3.0% 34
The major clinical trials have also shown a
159 (26)
29% 2.2% 46
surprising beneficial effect of cholesterol reducAFCAPS
115 (25)
37% 2.0% 50
tion on stroke risk, which was not anticipated
when the trials were designed. Originally
*Nonfatal MI or CHD death in WOSCOPS, CARE, LIPID; nonfatal or fatal MI, unstable angina, or
sudden cardiac death in AFCAPS; nonfatal MI, coronary death, or resuscitated cardiac arrest in 4S.
observed in unplanned post-hoc analyses of the
†vs placebo
data from 4S, the stroke reduction has since
Reprinted with permission from Jacobson et al. Arch Intern Med. 1998;158:1977. Copyrighted
1998. American Medical Association.
been confirmed in trials that included stroke a
Advanced Studies in Medicine
do correlate with greater risk reduction, they do not
provide a definitive answer.
The Effects of Atorvastatin and Simvastatin on
Atherosclerosis Progression (ASAP) trial also provides
data on the relationship between LDL-C reduction
and cardiac risk.10 The trial compared aggressive lipidlowering and conventional lipid-lowering therapy in a
population of patients with familial hypercholesterolemia (average baseline LDL-C level nearly 300
mg/dL). The patients began therapy with atorvastatin
40 mg/day or simvastatin 20 mg/day, and the starting
doses were doubled after 4 weeks. The primary endpoint was change in carotid intimal-medial thickening
(IMT) after 2 years of treatment, as assessed by Bmode ultrasound. Participating patients randomized
to aggressive lipid-lowering therapy had an overall
reduction in carotid IMT, whereas patients treated
conventionally had an increase in IMT (P = .001).
The ASAP investigators noted that aggressive
cholesterol-lowering therapy induced regression of
carotid IMT despite a mean LDL-C level of 150
mg/dL on treatment (after a 51% reduction in baseline LDL-C levels). The investigators concluded that
future trials that have clinical, rather than anatomical, endpoints are necessary to demonstrate the benefits of aggressive cholesterol lowering on
cardiovascular morbidity and mortality.
Several ongoing trials might provide more definitive answers regarding the benefits of aggressive versus
conventional cholesterol-lowering therapy. The Study
of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine (SEARCH) trial
involves 12 000 CHD patients treated with simvastatin 20 mg/day or 80 mg/day with or without
folate/vitamin B12 supplementation. Patients are being
followed for 5 years, and the primary endpoints are
cardiovascular death and non-fatal MI. LDL-C targets
for the trial are 100 mg/dL in patients receiving 20 mg
of simvastatin and 70 mg/dL in patients receiving the
higher dose of the statin.
The Treat to New Targets (TNT) study involves 10
000 CHD patients randomized to atorvastatin 10
mg/day or 80 mg/day. The Incremental Decrease in
Endpoints through Aggressive Lipid Lowering
(IDEAL) trial includes 8888 patients randomized to
simvastatin 20-40 mg/day or to atorvastatin 80
mg/day. The follow-up and primary endpoints in both
trials are the same as in the SEARCH trial, and the
TNT trial has the same LDL-C goals as SEARCH.
How do we reach the goal of greater decreases in
vascular endpoints through lipid reductions? Strategies
focus first on lipid therapy, which has proven to be
efficacious in multiple clinical trials conducted over
the past 2 decades, and second on a broader approach
of antiatherosclerotic therapy.
With respect to lipid therapy, potential therapeutic
lipid targets include additional lowering of LDL-C,
lowering of LDL-C plus lowering of triglyceride and
raising of high-density lipoprotein cholesterol (HDLC), and lowering of triglyceride plus the raising of
HDL-C. Several strategies exist for achieving greater
reductions in LDL-C. Higher statin doses have already
been discussed. Other options include development of
more effective statins and the use of various combinations of statins and other drug classes such as bile acid
sequestrants, cholesterol absorption inhibitors, niacin,
or a peroxisome proliferator activated receptor (PPAR)
agonist. Other possibilities for combination with a
statin are in development, including bile acid transport inhibitors and microsomal triglyceride transport
protein inhibitors. (Table 2)
The new-generation statin, rosuvastatin, has been
shown to achieve LDL-C reductions of approximately
42% with a 10-mg dose, increasing to beyond 60%
with an 80-mg dose.11 The results represent a moderate improvement over the 52% reduction that can be
achieved with maximal doses of atorvastatin.
Studies of combination therapy with a statin and
bile acid sequestrant have shown that this achieves
Table 2. Lipid Therapy: Enhanced Efficacy
LDL cholesterol
More effective
Stating + BAS (bile acid sequestrants)
Statin + CAI (cholesterol absorption inhibitors)
Statin + IBAT (bile acid transport inhibitors)
Stating + MTPI (microsomal triglyceride transport inhibitors)
Statin + PPAR (peroxisome proliferator-activated receptor)
Statin + niacin
LDL + triglycerides + HDL Cholesterol
Triglycerides + HDL Cholesterol
LDL = low-density lipoprotein; HDL = high-density lipoprotein.
Vol. 3 (4C)
April 2003
greater lipid-lowering effects compared with a higher
statin dose alone.12 Such findings demonstrate that
drugs with different mechanisms of action work well
when added to a statin base.
A particularly promising new approach is to combine
a statin with a cholesterol absorption inhibitor. For
example, adding 10 mg of ezetimibe to 10 mg of simvastatin leads to an additional 15% decrease in LDL-C
compared with 10 mg of simvastatin alone.13
Furthermore, in 1 therapeutic step, the combination
achieves the same results as 3 dose escalations or an 8fold increase of simvastatin (from 10 mg to 20, 40, and
80 mg). Moreover, the combination of a low-dose statin
and ezetimibe is well tolerated and avoids potential concerns about high-dose statin monotherapy (Figure).
The combination of a statin and niacin has been
used for years in the United States. Niacin adds a relatively modest effect to a statin’s LDL-C lowering ability.
The primary impact of the combination is on triglycerides and HDL-C. One small placebo-controlled clinical trial demonstrated that the combination of niacin
and simvastatin reduced the RR of a clinical event by
90% in a few years, and the overall event rate fell to 3%
in patients who received the combination in a secondary prevention setting.14 The question remains
as to whether we can utilize this combination in a
large clinical trial and, by also lowering triglycerides
and raising HDL-C combined with significant
LDL-C reduction, achieve the same results.
If after appropriate use of a statin to reduce
LDL-C there is need to reduce triglycerides and
improve HDL-C, a logical therapeutic strategy
would be the combination of simvastatin with
niacin. However, given the patient and physician
acceptance of niacin, fibrates are more commonly
used in these patients. The combination with a
fibrate remains controversial, and there is no outcome evidence of the combination at all to guide
clinicians as to either the added effectiveness for
CHD prevention over either drug alone, or the
safety of the combination. The Veterans Affairs
HDL-C Intervention Trial (VA-HIT) demonstrated that a fibrate can significantly reduce the
risk of acute coronary events in high-risk patients
who have existing CHD.15
On the horizon are other potential combinations that await testing in clinical trials. These
include a fibrate and a cholesteryl ester transfer protein (CETP), a PPAR-alpha agonist and a CETP
Advanced Studies in Medicine
inhibitor, a PPAR-alpha agonist and a statin, and others.
We already know that we can improve lipoprotein profiles with these agents. However, if we “beautify” the
lipid profile, will this translate into a greater reduction in
clinical events?
Several options exist for antiatherosclerotic therapy.
Aspirin reduces the risk of clinical events, so the addition
of aspirin to a statin should lead to additional benefits.
Other agents with proven benefits for reducing clinical
events include angiotensin-converting enzyme
inhibitors, angiotensin receptor blockers, and betablockers. Adding 1 or more of these agents to a statin
makes sense, but the additional benefits have yet to be
proven, or even evaluated in some instances, in large,
well-designed clinical trials. On the horizon is the possibility of combining a statin with an acyl CoA:cholesterol
acyltransferase (ACAT) inhibitor, a drug that is designed
to reduce lipid uptake by the macrophage but has little if
any effect on plasma lipid levels.
Future improvements in reducing CHD risk will be
incremental. Perhaps giving patients higher doses of
Figure. New Role for Combination Therapy
LDL-C = low-density lipoprotein cholesterol.
statins to achieve greater reductions in LDL-C will reduce
the clinical event rate, as is being tested in the SEARCH,
TNT, and IDEAL trials. Once those trials are completed,
attention will turn to combination therapy in the hopes
of achieving even greater reductions in clinical events. A
statin might be studied in combination with niacin, a
cholesterol absorption inhibitor, or a newer class of drug.
Not to be overlooked is the emerging potential for
therapeutic agents that target inflammation, which is
the next step in atherosclerosis after apparent initiation
by LDL-C entering the vascular wall. Investigation
into the role of inflammation has uncovered numerous
potential therapeutic targets. Also not to be overlooked are the contributions of thrombosis and fibrinolysis to acute coronary events. Various clot-related
targets for reducing cardiovascular morbidity and mortality already are being explored.
Finally, the quest for better therapies should not
obscure the progress that has been made toward reducing
cardiovascular morbidity and mortality. With currently
available therapies, lowering LDL-C alone can prevent
30% to 35% of coronary events. Failure to implement
current knowledge into clinical practice represents one of
the biggest obstacles to reductions in coronary risk.
Perhaps no more than 20% of patients with CHD actually achieve the National Cholesterol Education Program
LDL-C target of less than 100 mg/dL.16
Heart disease remains the leading cause of death in
the United States. A high proportion of these deaths
occur suddenly and out of the hospital, emphasizing
that prevention offers the best option for reducing cardiovascular morbidity and mortality. Existing statins
have been shown to reduce the risk of coronary events
by 30% to 35%. More aggressive treatment can lead to
greater reductions in LDL-C, but the impact on cardiac
morbidity and mortality remains to be proven. Potential
strategies to achieve greater reductions in clinical event
rates include high-dose statin therapy, combination
therapy with a statin and other classes of lipid-lowering
agents, nonstatin combinations that primarily target
triglycerides and HDL-C, and antiatherosclerotic therapy that combines lipid and nonlipid therapies.
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