Statins: cardiovascular disease regression and plaque stabilization
Overview
The discovery of statins, an important milestone of the last decade, is a
major development in the pharmacotherapy of dyslipidemia and has led to
significant advances in the management of atherothrombotic vascular disease.
Statins exhibit variable dose-related efficacy in reducing LDL-C levels,
with some reduction in triglyceride levels as well as increase in HDL-C
levels. Individual studies and meta-analyses have proved that this
LDL-C–lowering effect significantly reduces coronary events, independent of
age or sex (LaRosa, 1999). Recent studies have indicated that additional
beneficial effects of statins include atherosclerotic plaque stabilization
and regression of atheromatous disease. This article reviews current
clinical benefits of statin therapy and emerging guidelines for lowering
LDL-C levels in patients with coronary artery disease (CAD).
Statins and plaque stabilization
Statins are known to reduce CAD-associated morbidity and mortality in
patients with hypercholesterolemia. However, several recent studies have
revealed that, even in the setting of normocholesterolemia, statins
reduce cardiovascular events and improve survival. This has led to the
theory that the salutary effects of statin therapy are caused not only
by an improved plasma lipid profile but also by beneficial effects on
the vascular wall. These “pleiotropic effects” include
anti-inflammatory, antithrombotic, antiproliferative, and antioxidative
effects that lead to improved endothelial function and, ultimately,
plaque stabilization.
The plaque-stabilizing effect of statins has been demonstrated in
various animal models and involves several mechanisms.
- Fukumoto et al (2001) established that statins reduce
smooth-muscle cell accumulation and collagen content in established
atheromatous lesions.
- Statins inhibit foam-cell formation by directly antioxidizing LDL,
inhibiting the uptake of oxidized LDL by receptors in the
atheromatous plaque, and inhibiting macrophage oxidative properties
(Aviram, 1998; Giroux, 1993).
- Statins reduce levels of several inflammatory markers, such as
C-reactive protein, interleukin-6, and tumor necrosis factor-a,
which have been shown to predict future risk of plaque rupture
(Albert, 2001; Blake, 2002; Jialal, 2001).
- Statins diminish the expression of adhesion molecules and
chemoattractants, which are responsible for the adhesion and
transmigration of leukocytes to the subendothelium as part of the
atherogenic process that leads to plaque instability (Romano, 2000;
Weitz-Schmidt, 2001).
- Statins stabilize the plaque by reducing macrophage production of
matrix metalloproteinases (MMPs), which have the potential to cause
collagen breakdown and to weaken fibrous cap (Bellosta, 1998).
Reducing LDL-C levels has been shown to shrink the lipid core,
leading to a more stable plaque (Llorente-Cortes, 1998).
Evidence for stabilization/regression of atheromatous disease
Results of studies involving carotid endarterectomy patients pretreated
with statins have shown significantly less lipid content, fewer macrophages,
and higher collagen content in the atheromatous plaque compared to results
from the placebo control group (Crisby, 2001). The Reversal of
Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study showed that,
in patients with coronary heart disease, intensive lipid-lowering treatment
with 80 mg of atorvastatin per day reduced progression of coronary
atherosclerosis compared to treatment with 40 mg of pravastatin per day
(Nissen, 2004). Results of randomized secondary prevention studies have
clinically validated these findings by showing reduction in
atherosclerosis-related events, including angina, death from cardiovascular
causes, nonfatal myocardial infarction, and the need for coronary
revascularization (LaRosa, 1999).
Emerging guidelines for lipid levels
Reducing LDL-C levels to approximately 100 mg/dL reduces cardiovascular
events by approximately 30%. However, a reduction in LDL-C levels beyond the
previously established targets has been found to confer even greater
benefits. The recent Treating to New Targets (TNT) study found that, in
patients with stable CAD, intensive lipid-lowering treatment with 80 mg of
atorvastatin per day (mean LDL-C level of 77 mg/dL) is associated with a 22%
risk reduction in major cardiovascular events compared to treatment with 10
mg of atorvastatin per day (mean LDL-C level of 100 mg/dL) (LaRosa, 2005).
Early and aggressive treatment with statins is now firmly established to
improve clinical outcome in the context of acute coronary syndromes (ACS).
The Pravastatin or Atorvastatin Evaluation and Infection
Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study
showed that, in patients with ACS, intensive statin therapy with 80 mg of
atorvastatin per day to achieve an LDL-C level of 62 mg/dL resulted in a
3.9% absolute risk reduction and a 16% relative risk reduction in major
cardiovascular events or death for up to 2 years compared to therapy with 40
mg of pravastatin per day (Cannon, 2004). The Myocardial Ischaemia Reduction
with Aggressive Cholesterol Lowering (MIRACL) study established that
initiation of 80 mg of atorvastatin in patients with non–ST-segment
elevation myocardial ischemia within 24-96 hours of admission reduced
cardiovascular events at 16 weeks compared with the placebo (Schwartz,
2001).
Current guidelines recommend an LDL-C level of less than 100 mg/dL for
patients with stable CAD and 70 mg/dL for patients at particularly high risk
(Grundy, 2004). Based on epidemiological studies, however, many clinicians
have suggested a goal of less than 70 mg/dL for patients with stable CAD
(Cannon, 2004). The TNT trial also supports this suggestion (LaRosa, 2005).
However, whether adopting the 70 mg/dL level for LDL-C in patients with
stable CAD is immediately necessary is debatable, as the overall mortality
rate was not reduced in this group. Also, 80 mg of atorvastatin per day
caused persistently elevated liver enzyme levels in 1.2% of the patients
compared to only 0.2% of the patients receiving 10 mg of atorvastatin, even
though no increase in myalgia or creatine kinase level was shown. For this
reason, weighing the risks and benefits before targeting the 70 mg/dL LDL-C
level in all patients with stable CAD may be prudent.
Future directions
Considering that 80 mg of atorvastatin did not reduce the overall
mortality rate, reducing LDL-C levels and achieving a similar risk reduction
in CAD by combination therapy may be preferable. For instance, adding
ezetimibe may allow the atorvastatin dose to be reduced while still
achieving a similar degree of lipid lowering with fewer adverse effects. The
ongoing Incremental Decrease in End Points Through Aggressive Lipid Lowering
(IDEAL) study and the Study of the Effectiveness of Additional Reduction in
Cholesterol and Homocysteine (SEARCH) with simvastatin and folic
acid/vitamin B-12 may confirm the effect of high-dose statins on overall
mortality. They may also help to more specifically identify the population
at risk for adverse cardiac events. Studies have suggested that the ratio of
apolipoprotein B to apolipoprotein A-1 may be a better indicator of
cardiovascular risk (Walldius, 2001). Further studies are needed to provide
further clarification.
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Summary of major clinical trials with statins
|
| Year |
Study |
Result |
| 1994 |
4S |
Absolute risk reduction in mortality of 4% with statin therapy
|
| 1995 |
WOSCOPS |
Relative risk reduction in CAD mortality of 31% and total mortality of
22% with statin therapy
|
| 1996 |
CARE |
Reduction of coronary deaths/recurrent MI by 24% with statin therapy
|
| 1998 |
AFCAPS |
Relative risk reduction in the first major coronary event
|
| 2002 |
HPS |
Risk reduction of CAD, peripheral vascular disease, and diabetes
mellitus for all lipid levels and patient populations
|
| 2003 |
ASCOT-LLA |
Benefits with atorvastatin for patients with hypertension and normal
lipid levels
|
| 2004 |
REVERSAL |
Reduction of coronary atherosclerosis with intensive lipid lowering
|
| |
PROVE IT-TIMI22 |
Benefits of early, aggressive statin therapy for patients with ACS |
| |
A to Z |
Benefits of statins beyond lipid lowering effect |
| 2005 |
TNT |
Reduction of cardiovascular events with aggressive lipid lowering
therapy in patients with stable CAD
|
| |
IDEAL |
Awaiting results |
| |
SEARCH |
Awaiting results |
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