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(Circulation. 1995;92:646-656.)
© 1995 American Heart Association, Inc.
Articles |
Lipid Lowering, Regression, and Coronary Events
A Review of the Interdisciplinary Council on Lipids and Cardiovascular Risk Intervention, Seventh Council Meeting
From the Department of Medicine, Baylor College of Medicine, Internal Medicine Service, The Methodist Hospital, Houston, Tex.
Correspondence to Antonio M. Gotto, Jr, MD, Baylor College of Medicine, 6550 Fannin, MS SM-1423, Houston, TX 77030.
Key Words: atherosclerosis • coronary disease • clinicaltrials • lipids
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Introduction |
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 Top Introduction Development of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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Regression studies have provided the first clinical evidence that the natural history of atherosclerosis, which until recently was thought to be a relentlessly progressive disease, could be altered. In these studies, aggressive lipid lowering has been found to induce atherosclerotic lesion stabilization or even regression and to reduce clinical cardiovascular events, although the mechanisms responsible have not been determined. The clinical predictivity of the arterial changes measured by angiography or ultrasound suggests that this monitoring approach can help identify individuals most likely to benefit from early intervention.
The Interdisciplinary Council on Lipids and Cardiovascular Risk Intervention (see "Acknowledgments") met to review past studies and to evaluate recent studies that take advantage of the potent lipid-lowering capability of monotherapy with HMG-CoA reductase inhibitors. This group of experts discussed possible mechanisms involved in regression and suggested that future studies be directed toward determining whether other, nonlipid aspects of atherogenesis that may have been ameliorated contribute to the disproportionate decrease in cardiovascular events produced by relatively small changes measured in the artery.
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Development of Atherosclerosis |
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TopIntroductionDevelopment of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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Atherosclerotic plaque is believed to develop in response to endothelial dysfunction or injury,1 which can be caused by mechanical forces such as blood flow turbulence or by nonmechanical agents such as homocystine, carbon monoxide, immune complexes, and elevated LDL cholesterol. Oxidation of LDL may also contribute to endothelial damage; oxidized LDL is believed to be cytotoxic to endothelial cells as well as to smooth muscle cells.
Normally, the endothelium produces endothelium-derived relaxing factor (EDRF) and prostacyclin, which protect the arterial wall by consuming the products of the oxidation of free radicals, stimulating platelet disaggregation, and inhibiting smooth muscle cell proliferation, smooth muscle cell contraction, platelet aggregation, and platelet and monocyte adhesion. Release of EDRF is downregulated in the atherosclerotic artery and in the presence of hypercholesterolemia and oxidized LDL, which may reduce the activity of G proteins that interact with receptors in the endothelial cell to stimulate the production of EDRF.
In the normal coronary artery, acetylcholine stimulates the release of EDRF and so leads to dilation of the artery and an increase in coronary blood flow. However, in the damaged coronary artery, including human atherosclerotic arteries,2 infusion of acetylcholine results in constriction of the diameter of the artery and may produce a decrease in coronary blood flow. The resulting endothelial dysfunction with impaired diffusion of EDRF seriously compromises the ability of the blood vessel to react to stress.
After endothelial injury or dysfunction occurs, smooth muscle cells migrate from the media to the intima, where their proliferation is promoted by platelet-derived growth factor, endothelium-derived growth factor, macrophage-derived growth factor, insulin, and LDL. These smooth muscle cells, together with macrophages, fibrous tissue, and lipid, form the atherosclerotic plaque. Within the lesion, a core of necrotic and lipid-rich material develops, surrounded by a fibrous cap that prevents the highly thrombogenic contents from entering the circulation. When an accumulation of core lipid and lipid-filled macrophages is accompanied by a paucity of smooth muscle cells and by lysis of the collagen of the cap, the lesion can rupture, resulting in intraplaque hemorrhage and thrombosis.3
It is believed that most clinical coronary events are precipitated by plaque fissuring. The likelihood that atherosclerosis will progress from plaque instability to plaque fissuring or rupture and an acute clinical event is increased if there is a high lipid content in the core; a high concentration of foam cells, particularly along the shoulders of the atheroma; or a thin fibrous cap, which may reflect the cytotoxicity of oxidized LDL to smooth muscle cells. It is estimated that although the lesions most prone to fissuring make up only 10% to 20% of atherosclerotic lesions, they account for 80% to 90% of acute clinical events.3 Stabilization of these lesions, which generally cause less than 70% stenosis before rupture, is believed to decrease the risk of fissuring and the incidence of clinical events. Lipid-lowering therapy may promote plaque stabilization by reducing the lipid content of lesions and so decreasing both the shear stress at the edge of the fibrous cap and the production of proteases, normally secreted by the foam cells, which digest the extracellular matrix. Reducing the number of macrophages may decrease the release of tissue factor and of plasminogen activator inhibitor–1 (PAI-1).
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Regression Studies |
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TopIntroductionDevelopment of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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Historically, angiography has been the primary clinical method used to evaluate the natural history of atherosclerosis. Early regression studies consisted of angiograms of the same patient taken before and after a coronary event. In these studies, certain areas identified visually (qualitatively) were found to progress or regress spontaneously. Regression was uncommon and thus was not the focus of these studies. Only with more recent interventions has atherosclerosis been shown to be reversible.
To evaluate changes in atherosclerotic lesions, many subsequent studies
have used percent diameter stenosis (in which the lumen diameter at the
lesion site is compared with the lumen diameter of the normal vessel)
or minimum lumen diameter (which is the lumen diameter at the targeted
stenotic lesion). Worsened disease in a specific area defines
progression; improved disease defines regression. The two approaches
are equally effective in determining progression and regression as long
as the reference area used in the percent diameter stenosis method
remains unchanged. However, if the surrounding reference area of the
artery increases, whether by spontaneous vasodilation or regressive
changes in nonstenotic lesions, percent diameter stenosis shows
progression, or if there is narrowing in the reference area while the
lesion itself does not change, percent diameter stenosis reports
regression, whereas in both of these scenarios the minimum lumen
diameter technique correctly shows no change in stenosis
(Figure
). Although coronary atherosclerotic lesions are
usually focal, in some cases disease is fairly diffuse, without
well-defined, localized lesions. In these cases, the method used to
measure the stenotic lesion can affect the degree of progression or
regression reported. Some investigators offer the absolute measure of
minimum lumen diameter as a superior method, but there are problems
with this measure as well, because in the early stages of progression
of the disease, the minimum lumen diameter can remain stable or even
dilate slightly.4 In addition, minimum lumen diameter
measurements can be confounded by interindividual differences in artery
size and by distortion introduced by the imaging
equipment.5
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Retrospective Studies
In retrospective angiographic analyses,
follow-up angiography was
performed to evaluate worsening symptoms instead of any specific
intervention, and patients serve as their own controls. In these
studies, progression has been found in 50% to 75% of patients, and
regression is rare. Biases introduced by this methodology include
underestimation of progression, since only survivors are followed up,
and overestimation of progression, since the restudy is made only when
symptoms recur. These were some of the first studies to suggest that
atherosclerosis is a relentlessly progressive disease and regression a
relatively uncommon occurrence.
In one retrospective study of 256 patients with coronary heart disease (CHD), angiograms taken on two occasions ranging from less than 1 year to more than 5 years apart were compared by a three-member panel.6 Progression in at least one coronary artery segment was found in 56% of the patients, and regression was seen in 5%. Lesions causing 50% or more stenosis were the most likely to progress, although 40% of the patients with progression had progression only in segments with less than 50% stenosis.
Another retrospective study analyzed coronary angiograms, separated by an interval of at least 1 month and in some cases more than 10 years, of 317 patients with CHD, defined as 50% or more lumen diameter reduction in at least one coronary artery.7 Progression was found in 47%, no change in 48%, and regression in 5% of these patients.
Prospective Studies
In prospective analyses, atherosclerosis
is evaluated after a
specified period of time, often to test the effects of a particular
intervention. Results of angiographically monitored studies have been
reported for the coronary and femoral arteries, and results of studies
monitored by ultrasound have been reported for the carotid
arteries.
Coronary Atherosclerosis
Angiographically
monitored trials of lipid-lowering therapy to
reduce coronary atherosclerotic disease have used a variety of
interventions to reduce LDL cholesterol, including diet, single- and
combination-drug therapy, partial ileal bypass surgery, and LDL
apheresis (Table). The National Heart, Lung, and Blood
Institute (NHLBI) Type II Coronary Intervention Study was a randomized,
double-blind, placebo-controlled trial conducted in 143 men and women
with angiographic evidence of CHD and an LDL cholesterol level above
the 90th percentile (mean, 236 mg/dL [6.1 mmol/L]) after
diet.8 Both groups received moderate dietary therapy and
either cholestyramine or placebo for 5 years. In the drug-treated
group, total cholesterol level decreased 17% from baseline, and LDL
cholesterol level decreased 26%; respective changes in the placebo
group were 1% and 5%. On evaluation by three independent consensus
panels, progression was seen in 32% of the drug-treated group compared
with 49% of the placebo group, which was a statistically significant
difference; regression was seen in 7% of each group. In lesions
causing 50% or more stenosis at baseline, definite progression
occurred in significantly fewer subjects in the drug-treated group
(12%) than in the placebo group (33%). There was a trend that did not
reach significance for reduced mortality and nonfatal myocardial
infarction (MI) incidence in the drug-treated group. Of the 7 patients
who had nonfatal MI and repeat angiography, 6 were progressors.
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The Cholesterol Lowering Atherosclerosis Study (CLAS) was a randomized, selectively blinded, placebo-controlled trial completed in 162 nonsmoking men with previous coronary artery bypass graft surgery, angiographically demonstrated progressive atherosclerosis, and fasting total cholesterol level of 185 to 350 mg/dL (4.8 to 9.1 mmol/L).9 Although both groups were to follow low-fat, low-cholesterol diets, the diet of the drug-treated group was more restrictive. The drug-treated group also received a combination of colestipol and nicotinic acid. After 2 years, lipid changes in the drug-treated group included a 26% decrease in total cholesterol level and a 43% decrease in LDL cholesterol level; changes in the placebo group were 4% and 5%, respectively. Panel-assessed global change scores indicated progression in 39% of the drug-treated group compared with 61% of the placebo group, and 16% of the drug-treated group showed regression compared with less than 4% of the placebo group. On multivariate analysis, the significant predictor of progression in the drug-treated group was found to be the apolipoprotein C-III (apo C-III) content of HDL, which, as a marker of triglyceride-rich lipoprotein metabolism, indicates the importance of triglyceride-rich lipoproteins in atherosclerotic progression.10 Among placebo recipients, increased intake of total fat and polyunsaturated fat was associated with significantly increased risk for new atherosclerotic lesions.11 Of the 103 subjects completing 4-year follow-up angiography, 48% of the drug-treated group showed progression compared with 85% of the placebo group, and 18% of the drug-treated group showed regression compared with 6% of the placebo group; both of these differences were significant.12 Event rates did not differ significantly between groups.
The Familial Atherosclerosis Treatment Study (FATS) was conducted in 146 men with apo B levels of at least 125 mg/dL, family history of CHD, and angiographic evidence of atherosclerosis.13 All subjects received dietary counseling and were randomized to receive a combination of nicotinic acid and colestipol, a combination of lovastatin and colestipol, or placebo; placebo recipients whose baseline LDL cholesterol was higher than the 90th percentile for age also received colestipol (43% of placebo recipients). After 2.5 years of treatment, total cholesterol decreased 23% in the group receiving nicotinic acid plus colestipol, 34% in the group receiving lovastatin plus colestipol, and 3% in the placebo group; LDL cholesterol decreased 32%, 46%, and 7%, respectively. Average percent stenosis decreased in both drug-treated groups and increased in the placebo group; the difference was statistically significant. On quantitative assessment, progression as the only angiographic change was seen in 25% of the group receiving nicotinic acid plus colestipol, 21% of the group receiving lovastatin plus colestipol, and 46% of the placebo group; regression only was seen in 39%, 32%, and 11%, respectively. In univariate and multivariate analyses, lipoprotein[a] (Lp[a]) level and ratio of Lp[a] to HDL cholesterol were predictive of baseline percent stenosis.14 In subjects with minimal lipid-lowering response, defined as a decrease of less than 10% in the difference between LDL cholesterol level and Lp[a] cholesterol level, progression was associated with Lp[a] level and with ratio of Lp[a] to HDL cholesterol. However, in subjects with substantial lipid-lowering response, defined as a 10% or more decrease in the difference between LDL cholesterol level and Lp[a] cholesterol level, regression was the usual outcome, and change in percent stenosis was determined by the difference between LDL cholesterol level and Lp[a] cholesterol level and by the difference between total apo B and apo B in Lp[a]. Clinical events were significantly reduced in the drug-treated groups compared with the placebo group: events were reported in 2 subjects in the group receiving nicotinic acid plus colestipol, 3 subjects in the group receiving lovastatin plus colestipol, and 10 subjects (11 events) in the placebo group. In subjects with Lp[a] levels higher than the 90th percentile, 42% of those with minimal lipid-lowering response experienced clinical events compared with 4% of those with substantial lipid-lowering response.
The University of California, San Francisco, Arteriosclerosis Specialized Center of Research (UCSF-SCOR) Intervention Trial was conducted in 31 men and 41 women with heterozygous familial hypercholesterolemia randomized to receive diet only or diet plus drug therapy with various binary or ternary combinations of colestipol, nicotinic acid, and lovastatin for 26 months.15 The drug-treated group experienced a 31% decrease in total cholesterol level and a 39% decrease in LDL cholesterol level; corresponding changes in the diet-only group were 9% and 12%, respectively. Computer assessment of follow-up angiography showed a significant difference between groups in the primary end point of mean within-patient change in percent area stenosis. Secondary analysis of definite progression and definite regression, defined as a 10% or more change in diameter stenosis without an opposite change of at least 10% in any other lesions, found a strong but not statistically significant trend toward increased regression and decreased progression in the drug-treated group. When results for the women in the study were analyzed separately, the average change in mean percent area stenosis was significantly different between treatment groups, as in the overall study; the difference did not reach significance in separate analysis of the men. The only clinical event was one MI in a diet-only subject.
In the St Thomas' Atherosclerosis Regression Study (STARS), 90 men with CHD and hypercholesterolemia (mean total cholesterol, 280 mg/dL [7.2 mmol/L]) were randomized to receive lipid-lowering diet (no more than 27% of calories as fat and 8% to 10% of calories as saturated fat) plus cholestyramine, lipid-lowering diet only, or usual care for 39 months.16 Total cholesterol decreased 25% in the diet-plus-cholestyramine group, 14% in the diet-only group, and 2% in the usual-care group; LDL cholesterol level decreased 36%, 16%, and 3%, respectively. For the primary end point of mean absolute width of arterial segments as determined by computerized analysis of the angiograms, the diet-plus-cholestyramine group showed a definite increase, the diet-only group showed an increase of borderline significance, and the usual-care group showed narrowing in the width of the segments. There were significantly more clinical events in the usual-care group (10) than in the diet-plus-cholestyramine group (1) or the diet-only group (3).
Meta-analysis of these five coronary studies found that intensive, short-term lipid-lowering therapy reduced CHD risk by 58%.17 Therapy also reduced the incidence of clinical events in these studies: MI occurred in 3.8% of actively treated subjects compared with 7.7% of control subjects. It is estimated that, on average, intervention halves progression and triples regression.18
In the Program on Surgical Control of the Hyperlipidemias (POSCH), 838 men and women with hypercholesterolemia and one prior MI were randomized to receive dietary instruction or dietary instruction plus partial ileal bypass surgery.19 The primary end point was death of any cause. Follow-up angiograms were obtained at 3, 5, and 7 or 10 years and were evaluated visually. At 5 years, total cholesterol level was reduced 28% in the surgery group and 5% in the control group, and LDL cholesterol level was reduced 42% and 7%, respectively. At each follow-up, the surgery group had significantly less progression than the control group: 28% compared with 41% at 3 years, 37% compared with 65% at 5 years, 48% compared with 77% at 7 years, and 55% compared with 85% at 10 years. At 10 years, the surgery group had a 22% risk reduction in overall mortality and 28% risk reduction in CHD mortality, neither of which was significant. However, for the combined end point of CHD death and nonfatal MI, the surgical group had 82 events compared with 125 events in the control group, which was a highly significant difference. At a mean follow-up of 6.7 years, both overall mortality and CHD mortality were found to be associated with angiographic change at 3 years, occurring in 12% and 10%, respectively, of all subjects with progression compared with 7% and 4% of all subjects with regression or no change; CHD death or nonfatal MI occurred in 16% of the surgical group with progression compared with 8% of the surgical group with regression or no change and in 33% of control subjects with progression compared with 15% of control subjects with regression or no change.20 The POSCH results suggest that angiographic changes can serve as surrogate end points for clinical cardiovascular events.
Another lipid-lowering intervention evaluated by coronary angiography is LDL-specific apheresis. The LDL-Apheresis Regression Study (LARS) was conducted in 37 patients with hypercholesterolemia, including 32 patients with familial hypercholesterolemia (7 homozygous and 25 heterozygous).21 Most patients were treated with cholestyramine, pravastatin, or probucol alone or in various combinations; all received LDL apheresis every week, every 2 weeks, or every 4 weeks, depending on target LDL cholesterol level. Immediately after apheresis, total cholesterol level was decreased 74%, and LDL cholesterol level was decreased 78%. On repeat angiography more than 1 year later, as assessed both visually and by computer analysis, progression was found in 13% of these patients, and regression was found in 38%.
Femoral Atherosclerosis
A prospective
angiographic study of femoral atherosclerosis was
conducted in 13 patients with type II hyperlipidemia and 12 patients
with type IV hyperlipidemia, all without symptoms of peripheral
vascular disease and most already being treated with various regimens
of clofibrate, neomycin sulfate, and tibric acid.22
Dietary therapy was added to the existing drug therapy, and repeat
femoral angiography was performed after an average of 13 months.
Progression was seen in 13 patients, regression in 9 patients, and no
change in 3 patients. The average reduction in total cholesterol level
was 19% in subjects with progression and 65% in subjects with
regression.
Another prospective femoral study evaluated 24 patients with stable intermittent claudication.23 All received antismoking advice and a weight-reducing diet as appropriate. Those randomized to treatment also received instruction on a fat-modified diet and one or two lipid-lowering drugs appropriate for the type of hyperlipidemia: cholestyramine for type II (plus nicotinic acid in more than half of these subjects), clofibrate for type III, and nicotinic acid for type IV. Angiography was performed at entry into the study and after 15 to 24 months (mean, 19 months), and results were assessed both visually and by computerized image analysis. The effects of treatment on lipid profile included a 25% decrease in total cholesterol level and a 28% decrease in LDL cholesterol level; respective changes in the usual-care group were 3% and 1%. By visual assessment, 60% fewer segments with progression were found in the treatment group than in the usual-care group, and computer analysis revealed that change in edge irregularity was 2.5 times greater in the usual-care group. Although both groups demonstrated progression in most arterial segments, 15 of 46 segments in the treatment group and 7 of 46 segments in the usual-care group showed a decrease in edge irregularity, indicative of regression. This important trial was one of the first to suggest that lipid-regulating intervention can favorably influence the course of femoral atherosclerosis.
In the femoral component of CLAS, repeat femoral angiograms were obtained for 162 subjects.24 Computer estimates of atherosclerosis, which measured lumen abnormality, showed a tendency toward more regression and stabilization of progression in the patients treated aggressively.
Carotid Atherosclerosis
CLAS
also included ultrasound measurements of the intima-media
thickness of the far wall of the common carotid artery and the carotid
diameter in 24 drug-treated and 22 placebo recipients at baseline and 2
and 4 years.25 During the 4-year period, total cholesterol
level decreased 31% in the drug-treated group and 3% in the placebo
group; LDL cholesterol level decreased 42% and 7%, respectively.
Intima-media thickness showed the most dramatic change, revealing
significant regression in drug-treated patients and significant
progression in placebo recipients. Carotid diameter did not change
significantly between the groups. These measurements of carotid
atherosclerosis are believed to function as surrogate measurements for
changes taking place in the coronary circulation and for coronary
events.
Recent Studies
A number of recent regression studies have
evaluated the effect on
atherosclerosis of monotherapy with HMG-CoA reductase inhibitors, which
are the most potent of the approved lipid-lowering agents in reducing
LDL cholesterol. These drugs act by partially inhibiting HMG-CoA
reductase, the rate-limiting enzyme of cholesterol synthesis. The
resulting decrease in intrahepatic cholesterol causes an increase in
LDL receptor activity and enhanced clearance of LDL from the
circulation. The US Food and Drug Administration–approved reductase
inhibitors are fluvastatin, lovastatin, pravastatin, and
simvastatin.
Monitored Atherosclerosis Regression Study
The Monitored Atherosclerosis Regression Study (MARS) was a
randomized, double-blind, placebo-controlled, multicenter trial
conducted in 270 men and women with a total cholesterol level of 190 to
295 mg/dL (4.9 to 7.6 mmol/L) and angiographically demonstrated
CHD.26 The two treatment groups had the same dietary fat
and cholesterol goals. The experimental group received high-dose
lovastatin (80 mg/d). After 2 years, repeat angiograms were obtained
for 247 subjects.
In the drug-treated group, the total cholesterol level decreased 32%, and the LDL cholesterol level decreased 45%; respective changes in the placebo group were 2% and 3%. Clinical coronary events, defined as MI, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft surgery, coronary death, and hospitalization for unstable angina, occurred in 22 drug-treated subjects and 31 placebo recipients, a trend toward reduced events with treatment that did not reach significance.
For the primary end point of per-subject mean change in percent diameter stenosis of all lesions as evaluated by quantitative coronary angiography (QCA), there was a trend that did not reach significance for reduced progression with lovastatin therapy. Lesions causing 50% or more stenosis at baseline did show a significant difference, with regression occurring in the drug-treated group and slight progression in the placebo group. One reason the all-lesion analysis in MARS did not reach significance may be the wide range of coronary status at baseline, ranging from one-vessel disease to severe three-vessel disease, compared with, for example, CLAS, in which the study population was more homogeneous, being composed entirely of nonsmoking men who had undergone coronary artery bypass graft surgery.
Of the secondary end points in MARS, the QCA-derived minimum lumen diameter also showed no benefit in the all-lesion analysis and benefit for lesions causing 50% or more stenosis at baseline. However, global change score (estimated visually) demonstrated a significant benefit in all lesions with lovastatin therapy: fewer than half of the drug-treated subjects showed progression compared with two thirds of placebo recipients. This visual assessment also found severe progression likely to require revascularization to be twice as common in the placebo group. On the other hand, 23% of the drug-treated group showed regression by visual assessment compared with 11% of the placebo group. There is no doubt that the LDL reduction obtained in MARS conferred angiographic benefit. Although this benefit was identified by the panel (visually), it was not detected by QCA, raising the possibility that higher levels of evaluation, which panels can provide, are required to determine changes not only in individual lesions but also in the overall coronary status of the patient. Indeed, in addition to the potential intravessel confounders associated with percent stenosis and minimum lumen diameter measurement by QCA (presence of diffuse disease and vessel dilation as atherosclerosis progresses), there is the possibility of intervessel interaction. For example, changes defined as regression by QCA may be due to the development of collaterals to compensate for progression.27 When the frequency of these intervessel interactions was examined in MARS, mixed change was found in significantly more placebo recipients than drug-treated patients. Because of the limitations of measurement by any one method, human and quantitative analyses should be viewed as complementary.
Canadian Coronary Atherosclerosis Intervention Trial
The Canadian Coronary Atherosclerosis Intervention Trial (CCAIT)
was a randomized, double-blind, placebo-controlled study of 331 men and
women with angiographic evidence of diffuse CHD and total cholesterol
level of 220 to 300 mg/dL (5.7 to 7.8 mmol/L).28 All
subjects received initial intensive dietary counseling, and 299
completed repeat angiography after 2 years of placebo or lovastatin
dosed to achieve a target LDL cholesterol level of 130 mg/dL (3.4
mmol/L) or less (mean lovastatin dosage, 36 mg/d). The primary end
point was a coronary change score, defined as the per-subject mean of
the minimum lumen diameter changes of all lesions measured.
Over the course of the study, the drug-treated group demonstrated an average 21% decrease in total cholesterol level and 29% decrease in LDL cholesterol level; changes in these lipid levels in the placebo group were less than 2%. There was a trend toward fewer coronary events (cardiac death, MI, and unstable angina) in the lovastatin group, which had 15 events in 14 subjects compared with 20 events in 18 placebo recipients, but the difference was not statistically significant.
Both groups demonstrated progression, but the placebo group showed more severe progression than the lovastatin group. Progression without regression was significantly more likely in the placebo group (50%) than in the lovastatin group (33%). New lesions were significantly more likely to develop in the placebo group (32%) than in the lovastatin group (16%). Among subjects with baseline LDL cholesterol level above the median of 176 mg/dL (4.6 mmol/L), coronary change score was significantly better in the lovastatin group; the mean lovastatin dosage in these subjects was 43 mg/d compared with 28 mg/d for subjects with LDL cholesterol levels below the median. Regression or recanalization was uncommon in both treatment groups, although the investigators' clinical impression was that it was somewhat more frequent in the lovastatin group. There was no significant difference between groups in either regression or new occlusions.
Interestingly, in contrast to other studies in which the main benefit was in lesions causing more than 50% stenosis, in CCAIT the benefit was in lesions causing less than 50% stenosis. Because these milder lesions were more numerous, this study showed overall improvement. In MARS, there was no statistically significant improvement overall because the lesions that improved were the minority lesions. In CCAIT, however, lesions causing 50% or more stenosis at baseline, which accounted for less than 15% of all lesions, changed infrequently, and there was no significant difference between treatment groups.
Pravastatin Limitation of Atherosclerosis in the Coronary
Arteries
Pravastatin Limitation of Atherosclerosis in the Coronary
Arteries
(PLAC I) was a randomized, placebo-controlled, multicenter trial
conducted in 408 symptomatic men and women undergoing coronary
angiography for acute MI, PTCA, or angina who had at least one lesion
causing 50% or more stenosis, LDL cholesterol level of 130 to 190
mg/dL (3.4 to 4.9 mmol/L), and triglyceride level of 350 mg/dL (4.0
mmol/L) or less on a Step One Diet.29 Follow-up angiograms
were obtained after 3 years of pravastatin (40 mg/d) or placebo.
The primary end point was change in mean diameter of 10 coronary artery segments, instead of minimum stenosis or various focal lesions as in other studies, because of the diffuse nature of the atherosclerotic process. Secondary end points included mean minimum diameter; mean maximum diameter; mean percent stenosis; development of new lesions; incidence of progression, regression, mixed progression and regression, and no change; and lipoprotein and apolipoprotein measurements.
In the pravastatin group, total cholesterol level was reduced 18%, and LDL cholesterol level was reduced 26%.30 Although final results are not yet published, interim analyses have found a favorable effect of treatment on progression. Progression rates per year in the placebo group were found to be consistent with data published for other studies.
The incidence of MI was significantly lower in the pravastatin group than in the placebo group. Because early events may be due to factors other than therapy, a subanalysis was performed for events occurring after 90 days. In this subanalysis, MI incidence was still significantly lower with treatment, occurring in 5 pravastatin-treated patients compared with 17 placebo recipients, and other, combined events reached significance: nonfatal MI or death was reported in 8 pravastatin-treated patients compared with 19 placebo recipients, and nonfatal MI or death due to CHD was reported in 7 pravastatin-treated patients compared with 18 placebo recipients. As in CCAIT, lesions causing less than 50% stenosis showed the most improvement.
Pravastatin, Lipids, and Atherosclerosis in
the Carotid
Arteries
Pravastatin, Lipids, and Atherosclerosis in the Carotid
Arteries
(PLAC II) was a randomized, double-blind, placebo-controlled,
single-center study using B-mode ultrasound to evaluate the effects of
pravastatin monotherapy in 151 men and women with CHD, LDL cholesterol
level between the 60th and 90th percentile after diet (mean, 166 mg/dL
[4.3 mmol/L]), triglyceride level of no more than 350 mg/dL
(4.0 mmol/L), and at least one atherosclerotic plaque with an
intima-media thickness of 1.3 to 3.5 mm in an extracranial carotid
artery.31 All subjects received dietary counseling.
Pravastatin was dosed to achieve target LDL cholesterol level of 90 to
110 mg/dL (2.3 to 2.8 mmol/L); 23.5% of the pravastatin-treated
patients remained at the initial 20-mg/d dose, 4% decreased to 10
mg/d, and 72.5% increased to 40 mg/d.
The primary ultrasound end point was the progression rate of the mean maximum intima-media thickness for 12 specified carotid walls during the 3-year trial. Secondary ultrasound end points were the mean maxima for the four common carotid walls, the four carotid bifurcation walls, and the four internal carotid walls. Clinical end points were fatal coronary events combined with nonfatal MI, all-cause mortality, and nonfatal MI combined with all-cause mortality.
During the 3-year period, total cholesterol level decreased 22% and LDL cholesterol level decreased 28% in the pravastatin group compared with the placebo group. This change was in large part accomplished early in the trial and maintained for the remainder of the 3 years.
Comparison of mean maximum intima-media thickness for the 12 segments combined showed a 12% lower progression rate in the pravastatin group, but this difference was not significant. When this overall rate was broken down into secondary end points, progression rate in the common carotid artery was 35% lower in the pravastatin group than in the placebo group, which was a significant difference. Lesions in the common carotid appear to be more dependent on LDL cholesterol, whereas those in the bifurcation and internal carotid appear to be more dependent on hypertension. The differences in the carotid bifurcation and the internal carotid artery were not significant. Difficulties encountered in examining the internal carotid artery reduced the data available for these measurements.
Coronary event rates were almost 60% lower in the pravastatin group than in the placebo group, but this trend did not achieve statistical significance. All-cause mortality was not significantly different between the treatment groups. When coronary events were combined with all-cause death rate, there was a 61% reduction in the pravastatin group, which was statistically significant.
PLAC II demonstrates that progression can be measured noninvasively and directly. By the use of B-mode ultrasound to measure actual wall thickness rather than estimating the development of atherosclerosis based on percent stenosis or minimum lumen diameter, atherosclerosis may be detected at an earlier stage. Because compensatory arterial enlargement preserves lumen diameter in stenoses causing as much as 40% occlusion, angiography may underestimate the magnitude of these smaller lesions.4
Asymptomatic Carotid Artery
Progression Study
In the Asymptomatic Carotid Artery Progression Study
(ACAPS), a
randomized, double-blind, placebo-controlled, multicenter ultrasound
study with a 2x2 factorial design, 919 asymptomatic, high-risk
subjects (almost equally divided between men and women) with no history
of MI, stroke, or angina and with an LDL cholesterol level of 130 to
159 mg/dL (3.4 to 4.1 mmol/L) or, if no more than one risk factor was
present, as much as 189 mg/dL (4.9 mmol/L) and an intima-media
thickness of 1.5 to 3.5 mm in the common or internal carotid or 1.6 to
3.5 mm in the bifurcation in at least one segment were followed up for
3 years.32 Patients received either lovastatin plus
warfarin, lovastatin plus placebo, warfarin plus placebo, or placebo
only; all subjects were encouraged to take aspirin (81 mg/d).
Lovastatin dosage, titrated to achieve an LDL cholesterol level of 90
to 110 mg/dL (2.3 to 2.8 mmol/L), was 10 mg/d in 5% of subjects
receiving lovastatin, 20 mg/d in 44%, and 40 mg/d in 51%. Warfarin
dosage was 1 mg/d.
For the primary outcome measure of mean maximum intima-media thickness as determined by B-mode ultrasound, the lovastatin-plus-placebo group showed highly significant improvement compared with the placebo-only group. Mean maximum intima-media thickness for the lovastatin-plus-warfarin group was between the measurements for the single-drug groups.
Not all results are available yet, but preliminary findings suggest several predictors of progression. Dietary fat intake, as calculated by nutritional recall analysis, appears to have a positive association with progression, whereas hormone-replacement therapy and dietary antioxidant intake appear to be inversely related to progression.
Incidence of cardiovascular disease events (fatal or nonfatal MI, coronary death, fatal or nonfatal hemorrhagic or ischemic stroke) was significantly lower in the lovastatin-plus-warfarin group than in the placebo-only group. When the two groups taking lovastatin were combined, there were significantly fewer events than in the two groups not taking lovastatin. All-cause mortality was significantly lower for subjects taking lovastatin than for those not taking lovastatin.
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Mechanisms in Regression |
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TopIntroductionDevelopment of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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The slow, natural course of atherosclerosis allows for some vessel remodeling and compensation, which may appear to be regression or slowed progression. However, when an aggressive intervention such as dramatic cholesterol lowering is introduced, the compensatory change probably does not occur at the same rate as the action of the intervention. Therefore, the regression reported in these lipid-lowering studies likely represents actual improvement in disease. Changes in plaque size may be relatively small as measured angiographically but, when multiplied by the entire length of the coronary tree and then cubed to obtain volume, can represent a substantial reduction in the burden of atherosclerotic plaque.
The regression rate of atherosclerosis is defined both by rapid processes, such as plaque stabilization, and by slow processes, such as changes in plaque size, although the mechanisms underlying these processes have not been established. Possible mechanisms responsible include lysis of thrombus, depletion of lipid from the plaque, atrophy of smooth muscle cells, relaxation of smooth muscle cells within the vessel wall, lysis of collagen and other connective tissue, and stretching of connective tissue into the normal wall. Another mechanism under investigation is the inhibitory effect of the reductase inhibitors on smooth muscle cell growth in culture, although the relevance of their effect to plaque stabilization or to lesion development is completely unknown. Because many processes believed to be involved in atherogenesis are regulated by calcium, a recent study examined the effect of simvastatin on calcium response to vasopressin stimulation in rat smooth muscle cells; simvastatin depressed calcium response significantly but did not affect total cellular cholesterol.33
An unsolved question arising from regression trials is whether there is an absolute level of LDL cholesterol below which predictable changes occur or whether the magnitude of change in LDL cholesterol level is important. In the UCSF-SCOR study, benefit was associated not with an absolute LDL cholesterol level but rather with change in LDL cholesterol level.15 Aggressive LDL cholesterol lowering appears to induce regression in early lesions by lipid depletion from foam cells and in advanced lesions by depletion of the lipid-rich core, whereas intermediate lesions continue to progress, suggesting that lipid lowering does not inhibit smooth muscle cell proliferation.34 However, in FATS subjects, mild and moderate lesions (those causing less than 70% stenosis) progressed to a cardiac event significantly less in subjects receiving aggressive treatment than in the placebo group, but lipid lowering did not confer similar benefit on severe lesions.3 Occlusion of vessels by more severe lesions is probably flow related, whereas less severe lesions probably obstruct by plaque fissure.
Other trials designed to lower LDL cholesterol, including MARS, have reported increased benefit to more severe lesions, suggesting that early lesions may require additional therapy, such as calcium channel blockers, antioxidants, hormonal agents, or lipid-altering agents that target lipoproteins other than LDL.5 In the nicardipine study of the Montreal Heart Institute, neither LDL cholesterol nor apo B level was related to changes in stenosis, but IDL cholesterol level was directly related to lesion progression.35 Instead of an overemphasis on LDL cholesterol level alone, Lp[a] concentration, as reported in FATS, and triglyceride-rich lipoproteins and non-HDL cholesterol, as reported in CLAS, may be additional indicators of atherosclerotic progression. Also in CLAS, baseline triglyceride level that was higher than the median for the study (129 mg/dL [3.3 mmol/L]) was predictive of greater benefit of treatment as measured by 2-year global change score; benefit was associated with greater decrease in triglyceride level but not with greater decrease in LDL cholesterol level or increase in HDL cholesterol level.36 In MARS, progression was correlated with apo C-III level in lesions causing less than 15% stenosis at baseline, with total triglyceride level in lesions causing 15% to 50% stenosis at baseline, and with ratio of LDL cholesterol to HDL cholesterol in lesions causing 50% or more stenosis at baseline.37 Lp[a] was predictive of progression in both CLAS and MARS.5
Although a decrease in progression of disease is often associated with a lowering of LDL cholesterol level, regression is often correlated with HDL cholesterol level, although the antiatherosclerotic mechanism of HDL has not been defined. HDL provides a pool of apo C-II, which promotes catabolism of the triglyceride-rich lipoproteins through the action of lipoprotein lipase, and also contains apo A-I, which is a stabilizer of prostacyclin. HDL is a donor of arachidonic acid for prostacyclin synthesis and is believed to be involved in reverse cholesterol transport.
Another antiatherosclerotic agent being examined in angiographic trials is exogenous estrogen. In one study in 90 postmenopausal women, 20% of whom were taking estrogen, 22% of those taking estrogen had luminal diameter narrowing of 25% or more compared with 68% of the women not taking estrogen.38 This study also found the mean HDL cholesterol level to be 30% higher in the women taking estrogen, which was a significant increase.
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Lipid Lowering and Clinical Events |
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TopIntroductionDevelopment of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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Our present approach to the reduction of CHD risk through treatment of hypercholesterolemia is based on the results of studies such as the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), in which, compared with placebo, the cholestyramine-treated group had 8% lower total cholesterol level, 12% lower LDL cholesterol level, and 19% lower CHD incidence,39 and the Multiple Risk Factor Intervention Trial (MRFIT), which reported a direct relation between total cholesterol level of more than 180 mg/dL (4.7 mmol/L) and CHD mortality.40
Other early studies that evaluated the effects of lipid-lowering agents on coronary events include the Newcastle upon Tyne41 and Edinburgh42 studies, which used clofibrate; the Coronary Drug Project,43 which used clofibrate or nicotinic acid; the Stockholm Ischaemic Heart Disease Secondary Prevention Study,44 which used a combination of clofibrate and nicotinic acid; and the Oslo Study45 and two trials of the Medical Research Council,46 47 which used dietary interventions. Although not all of these secondary-prevention studies reported significant decreases in coronary events with treatment, meta-analysis showed that reduction of total cholesterol level by 10% reduced risk for MI by 15%, which was significant.48 This meta-analysis also found significantly fewer cardiovascular deaths with treatment and a trend that did not reach significance for lower all-cause mortality with treatment. In the same report, meta-analysis of primary-prevention studies—LRC-CPPT,39 Helsinki Heart Study,49 World Health Organization Cooperative Trial,50 and Wadsworth-Veterans Administration Diet Trial51 —revealed that reduction of total cholesterol level by 10% reduced risk for MI by 22%. In general, risk for CHD decreases 2% to 3% for each 1% decrease in cholesterol.52
A recent evaluation of CHD incidence and total cholesterol level in almost 500 000 men in 10 previously published prospective studies—British Regional Heart Study,53 British United Provident Association (BUPA) Study,54 Göteborg study,55 MRFIT,40 Renfrew and Paisley survey,56 Whitehall study,57 Honolulu Heart Program,58 Central Sweden study,59 Israeli Ischemic Heart Disease Study,60 and Pooling Project61 —reported that 10% lower total cholesterol at age 40 was associated with 54% lower incidence of CHD.62 A similar reduction in total cholesterol level at ages 50, 60, 70, and 80 was associated with decreases in CHD incidence of 39%, 27%, 20%, and 19%, respectively. Of these studies, only the Göteborg study included any intervention (dietary counseling and, if total cholesterol level remained more than 300 mg/dL [7.8 mmol/L], clofibrate and/or nicotinic acid), but this intervention produced no significant difference between treated and untreated subjects.
A meta-analysis combined clinical events from PLAC I, PLAC II, Regression Growth Evaluation Statin Study (REGRESS),63 and Kuopio Atherosclerosis Prevention Study (KAPS),64 all of which were regression trials using pravastatin monotherapy. A total of 1891 subjects were enrolled. The meta-analysis found a highly significant 62% reduction in risk for fatal or nonfatal MI in subjects treated with pravastatin.65
Although lipid lowering has been associated with decreased CHD events
in a number of trials, its effect on total mortality remained unclear
until the recent report of the Scandinavian Simvastatin Survival Study
(4S).66 This randomized, double-blind, placebo-controlled,
multicenter trial evaluated 4444 men and women with a history of angina
or MI and with a total cholesterol level of 212 to 309 mg/dL (5.5 to
8.0 mmol/L) and a triglyceride level of no more than 221 mg/dL (2.5
mmol/L) after diet. Simvastatin dosage was 10 mg/d in 2 subjects, 20
mg/d in 
63% of simvastatin subjects, and 40 mg/d in 37% of
simvastatin subjects. After a median of 5.4 years of treatment, the
primary end point of total mortality decreased 30% in the simvastatin
group, which was highly significant, and cardiovascular mortality
decreased 42%. Total cholesterol level decreased 25% and LDL
cholesterol level decreased 35% in the simvastatin group, compared
with 1% increases in both values in the placebo group. The
association between cholesterol lowering and total mortality was
definitively established in 4S.
Decreases in clinical events with lipid-lowering therapy may reflect underlying changes in lesion morphology, or they may reflect other mechanisms, including an association between high LDL level and platelet aggregability, the enhancement of factor VII complexes by triglyceride-rich lipoproteins, and thrombogenic properties of Lp[a], such as inhibiting the binding of plasminogen to fibrin and causing the release of PAI-1 from endothelial cells.
The relation between lipids and coagulation factors in CHD is not clear but is of great interest and importance. Components of the coagulation system associated with CHD in prospective epidemiological studies include fibrinogen, factor VII, PAI-1, platelet aggregability, and Lp[a]. The Framingham Heart Study67 and, subsequently, a number of other studies have shown the contribution of fibrinogen as an independent risk factor for CHD68 ; subjects with concomitant elevations of cholesterol and fibrinogen are at particularly high risk for CHD events. The Northwick Park Heart Study reported the association of both fibrinogen and factor VII with coronary events.69 Factor VII and PAI-1 strongly correlate with elevations in serum triglyceride, and platelet aggregability has been inconsistently associated with dietary fat consumption. Lp[a] has a high degree of homology with plasminogen and competitively inhibits the fibrinolytic system, although its exact role in coronary thrombosis remains to be determined.70
Elevated LDL cholesterol levels are believed to inhibit the release of EDRF, and low HDL cholesterol levels may interfere with endothelial production of prostacyclin and may promote degradation of prostacyclin. Even these short-term mechanisms could affect vasodilation and thrombotic events. It remains to be determined whether lipid lowering or lipid modification per se affects plaque stability and, if so, by what mechanism.
Lipid modification can produce changes in vascular reactivity that have been studied with coronary angiography, intracoronary ultrasound, peripheral infusion of acetylcholine, and cold pressor tests. A positive correlation has been reported between HDL cholesterol and normal vasoreactivity in both normal and diseased segments in the presence of acetylcholine.71 These findings suggest that HDL plays an important role in maintaining endothelial function. In a study in which 107 men and women with normal total cholesterol level and angiographically demonstrated CHD were followed up over a 13-year period, 75% of subjects with an HDL cholesterol level of less than 35 mg/dL (0.9 mmol/L) had cardiovascular events, compared with 45% of subjects with an HDL cholesterol level of 35 mg/dL (0.9 mmol/L) or more.72
Overall, clinical trials show that lowering cholesterol results in a substantial reduction of coronary events and that the beneficial effect of lipid-regulating therapy becomes evident after a relatively short period of intervention. These trial results can be translated into clinical practice and public health applications. Because atherosclerosis is now known to be a very diffuse disease with a natural course of relentless progression, treatment strategies should incorporate systemic intervention such as lipid lowering instead of using a more limited, lesion-specific approach.
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Future Research |
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TopIntroductionDevelopment of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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Future studies may use total apo B level as a superior entry criterion to LDL cholesterol level, since an elevated apo B level would include individuals with elevated IDL and VLDL levels as well as individuals with small, dense LDL, whose LDL cholesterol level may be relatively low. Additional studies are needed to determine the effect of reductase inhibitors on small, dense LDL and the relative benefit of reductase inhibitors and fibrates for concurrent elevations of LDL and triglyceride and for HDL subfractions. Areas of research should be expanded to include HDL and its mechanisms, instead of focusing too much on LDL. In the future, regression studies may concentrate more on the effects of lipid therapy in subjects with CHD, acceptable LDL cholesterol level, and low HDL cholesterol level.
Further investigation is needed to examine ways of inhibiting the production or action of various biologically active compounds that act on damaged endothelial cells, smooth muscle cells, or macrophages to induce or promote atherosclerosis. Techniques may be devised to interfere with their biological effect, which is mainly receptor mediation, or to alter the response they induce in the target cell.
Causal genetic mechanisms involved in atherosclerosis may be discovered with the rapidly advancing tools available in the field of molecular genetics. In-depth study of the molecular biology and pathophysiology of causal genes responsible for increased or decreased atherosclerotic risk may lead to improved methods of diagnosis and treatment. Increased understanding of causal genes, gene–gene interactions, and specific gene–environment interactions will permit better prevention and treatment. Gene therapy becomes the ultimate potential goal.
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Acknowledgments |
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The Interdisciplinary Council on Lipids and Cardiovascular Risk Intervention is supported by an unrestricted educational grant from Bristol-Myers Squibb. This article summarizes presentations made by Bruce D. Behounek, MD (guest speaker); Linda Cashin-Hemphill, MD (guest speaker); Antonio M. Gotto, Jr, MD, DPhil; Peter H. Jones, MD; G.B. John Mancini, MD (guest speaker); Thomas A. Pearson, MD, PhD; and Charles E. Rackley, MD; and additional discussion by Jerome D. Cohen, MD; Donald B. Hunninghake, MD; Moti L. Kashyap, MD; James M. McKenney, PharmD; Elliot M. Rapaport, MD; James A. Schoenberger, MD; and Roger R. Williams, MD.
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Footnotes |
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Circulation. 1995;92:646-656.
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Appendix 1 |
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TopIntroductionDevelopment of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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Interdisciplinary Council on Lipids and Cardiovascular Risk Intervention, Seventh Council Meeting Participants
Council Members
Antonio M. Gotto, Jr, MD, DPhil (chairman), Baylor College of Medicine, Houston, Tex; Jerome D. Cohen, MD, St Louis University Medical Center, St Louis, Mo; Donald B. Hunninghake, MD, University of Minnesota (Minneapolis); Peter H. Jones, MD, Baylor College of Medicine, Houston, Tex; Moti L. Kashyap, MD, University of California, Irvine, Long Beach, Calif; James M. McKenney, PharmD, Medical College of Virginia/Virginia Commonwealth University, Richmond, Va; Thomas A. Pearson, MD, PhD, Columbia University College of Physicians and Surgeons, Cooperstown, NY; Charles E. Rackley, MD, Georgetown University Medical Center, Washington, DC; Elliot Rapaport, MD, University of California, San Francisco; James A. Schoenberger, MD, Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill; and Roger R. Williams, MD, University of Utah Medical School (Salt Lake City).
Guest Speakers
Bruce D. Behounek, MD, Bristol-Myers
Squibb Pharmaceutical
Research Institute, Princeton, NJ; Linda Cashin-Hemphill, MD,
University of Southern California School of Medicine, Los Angeles,
Calif (Dr Cashin-Hemphill is now with the Boston Heart Foundation,
Cambridge, Mass); and G.B. John Mancini, MD, University of British
Columbia, Vancouver, BC, Canada.
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References |
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TopIntroductionDevelopment of Atherosclerosis Regression Studies Mechanisms in Regression Lipid Lowering and Clinical...Future Research Appendix 1References |
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