Context Statin drugs reduce both atherogenic lipoproteins and cardiovascular
morbidity and mortality. However, the optimal strategy and target level for
lipid reduction remain uncertain.
Objective To compare the effect of regimens designed to produce intensive lipid
lowering or moderate lipid lowering on coronary artery atheroma burden and
progression.
Design, Setting, and Patients Double-blind, randomized active control multicenter trial (Reversal
of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL]) performed at
34 community and tertiary care centers in the United States comparing the
effects of 2 different statins administered for 18 months. Intravascular ultrasound
was used to measure progression of atherosclerosis. Between June 1999 and
September 2001, 654 patients were randomized and received study drug; 502
had evaluable intravascular ultrasound examinations at baseline and after
18 months of treatment.
Interventions Patients were randomly assigned to receive a moderate lipid-lowering
regimen consisting of 40 mg of pravastatin or an intensive lipid-lowering
regimen consisting of 80 mg of atorvastatin.
Main Outcome Measures The primary efficacy parameter was the percentage change in atheroma
volume (follow-up minus baseline).
Results Baseline low-density lipoprotein cholesterol level (mean, 150.2 mg/dL
[3.89 mmol/L] in both treatment groups) was reduced to 110 mg/dL (2.85 mmol/L)
in the pravastatin group and to 79 mg/dL (2.05 mmol/L) in the atorvastatin
group (P<.001). C-reactive protein decreased 5.2%
with pravastatin and 36.4% with atorvastatin (P<.001).
The primary end point (percentage change in atheroma volume) showed a significantly
lower progression rate in the atorvastatin (intensive) group (P = .02). Similar differences between groups were observed for secondary
efficacy parameters, including change in total atheroma volume (P = .02), change in percentage atheroma volume (P<.001), and change in atheroma volume in the most severely diseased
10-mm vessel subsegment (P<.01). For the primary
end point, progression of coronary atherosclerosis occurred in the pravastatin
group (2.7%; 95% confidence interval [CI], 0.2% to 4.7%; P = .001) compared with baseline. Progression did not occur in the
atorvastatin group (−0.4%; CI −2.4% to 1.5%; P = .98) compared with baseline.
Conclusions For patients with coronary heart disease, intensive lipid-lowering treatment
with atorvastatin reduced progression of coronary atherosclerosis compared
with pravastatin. Compared with baseline values, patients treated with atorvastatin
had no change in atheroma burden, whereas patients treated with pravastatin
showed progression of coronary atherosclerosis. These differences may be related
to the greater reduction in atherogenic lipoproteins and C- reactive protein
in patients treated with atorvastatin.
In a series of pivotal clinical trials, statin drugs have been shown
to reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality.1-5 However,
the optimal approach to lipid reduction with statins in patients with established
coronary artery disease (CAD) remains uncertain. Although the efficacy of
the various statins in reducing atherogenic lipoproteins and vascular inflammation
varies significantly,6 the impact of these
differences on clinical outcome is unknown. Because the large trials assessing
morbidity and mortality were placebo controlled, they provide limited insight
into differences between alternative strategies and target levels for lipid
reduction. Accordingly, there is little scientific basis for recommending
treatment to reduce low-density lipoprotein cholesterol (LDL-C) levels below
the current recommended guidelines.7,8
We compared the effects of 2 statin regimens by using intravascular
ultrasound. One of the regimens was designed to produce a moderate reduction
in LDL-C level and the other was designed to produce an intensive (maximal)
reduction in LDL-C level. Intravascular ultrasound provides detailed images
of the vessel wall with a high-frequency (30 MHz), miniaturized, ultrasound
transducer. Using a motorized pullback device, cross-sectional images are
generated throughout the vessel length, enabling precise quantification of
atherosclerotic disease burden. This study, the Reversal of Atherosclerosis
with Aggressive Lipid Lowering (REVERSAL) trial, measured the rate of disease
progression in patients treated with 2 different statins over an 18-month
treatment period.
The institutional review boards of all participating centers approved
the REVERSAL protocol and all patients provided written informed consent.
The protocol specified enrollment of patients aged 30 to 75 years who required
coronary angiography for a clinical indication and demonstrated at least 1
obstruction with angiographic luminal diameter narrowing of 20% or more. The
"target vessel" for intravascular ultrasound interrogation must not have undergone
angioplasty or have a luminal narrowing of more than 50% throughout a "target
segment" with a minimum length of 30 mm. Lipid criteria required an LDL-C
level between 125 mg/dL (3.24 mmol/L) and 210 mg/dL (5.44 mmol/L) after a
4- to 10-week washout period.
The study design sought to compare the effects on coronary disease progression
of treatment regimens designed to produce an intensive lipid-lowering effect
or a moderate lipid-lowering effect. For the moderate regimen, a 40-mg dose
of pravastatin was selected because it was the highest approved dose at the
time of study initiation and was one of the best-studied regimens in secondary
prevention of coronary events.2,4 In
addition, pravastatin carried a label approved by the Food and Drug Administration
for reduction in atherosclerotic progression based on prior angiographic trials.9,10 Because a baseline LDL-C level of
approximately 150 mg/dL (3.89 mmol/L) was anticipated, the regimen of 40 mg
of pravastatin was expected to lower LDL-C to approximately 100 mg/dL (2.59
mmol/L). A dose of 80 mg of atorvastatin was selected as the more intensive
agent because this dose was capable of producing the largest reduction in
atherogenic lipoproteins of any available therapy.
Randomization and Allocation Concealment
Lipid-lowering medications were discontinued for at least 4 weeks. After
a 2-week placebo run-in period, patients were randomized to receive either
80 mg of atorvastatin (2 × 40 mg) daily and a pravastatin placebo or
40 mg of pravastatin (1 × 40 mg) daily and 2 atorvastatin placebos (Figure 1). The patients and all study personnel
were blinded to treatment assignment and lipid measurements. The intravascular
ultrasound reading was performed by personnel who were blinded to treatment
assignment. The randomization code was generated using a permuted block size
of 4 (stratified by site) by a consulting statistician not otherwise involved
in the trial. No other restrictions were used in the randomization procedure.
Catheterization and Intravascular Ultrasound
Following diagnostic angiography, intravascular ultrasound examination
was performed in both the longest and least angulated target vessel meeting
inclusion criteria. After administration of between 100 and 300 µg of
intracoronary nitroglycerin, a 30 MHz, 2.6 F (0.87 mm) intravascular ultrasound
catheter (Ultracross, Boston Scientific Scimed Inc, Maple Grove, Minn) was
advanced into the target vessel and the transducer was positioned distal to
a side branch (distal fiduciary site). A motor drive progressively withdrew
the transducer at a speed of 0.5 mm/s. During pullback, images were obtained
at 30 frames/s and recorded on videotape. The intravascular ultrasound examination
was screened for image quality in a core laboratory at the Cleveland Clinic
Foundation. Only patients meeting prespecified image quality requirements
were eligible for randomization.
The patients were examined during scheduled clinic visits every 3 months.
A central laboratory performed all biochemical determinations (Medical Research
Laboratory, Highland Heights, Ky).
After an 18-month treatment period, actively participating patients
underwent repeat cardiac catheterization and intravascular ultrasound examination.
The operator placed the intravascular ultrasound catheter in the vessel originally
interrogated and positioned it distal to the original fiduciary site. A motorized
pullback was repeated under conditions identical to the baseline study. (See Video.)
Intravascular Ultrasound Core Laboratory Analysis
Videotapes containing the intravascular ultrasound pullbacks were analyzed
in a blinded fashion by the core laboratory as previously reported.11 The operator selected a distal fiduciary site, usually
a branch site, as the beginning point for analysis. Subsequently, every 60th
image was analyzed, generating a series of cross-sections spaced exactly 1.0-mm
apart. The final cross-section analyzed was obtained at a proximal fiduciary
site.
Intravascular Ultrasound Measurements
Intravascular ultrasound measurements were performed in accordance with
the standards of the American College of Cardiology and the European Society
of Cardiology.12 Using the National Institutes
of Health Image (version 1.62, National Institutes of Health public domain
software, Bethesda, Md), the operator performed a calibration by measuring
1-mm grid marks encoded in the image. Manual planimetry was used to trace
the leading edges of the luminal and external elastic membrane (EEM) borders.
The accuracy and reproducibility of this method has been previously reported.13 In addition, intraobserver and interobserver variability
were determined for a subset of patients in this trial. A total of 48 individually
paired (baseline and follow-up) patient data sets were randomly chosen for
evaluation by 6 intravascular ultrasound reviewers. Each reviewer reanalyzed
3 of his/her original intravascular ultrasound tapes—a total of 18 paired
reviews for the analysis of intrareviewer variability. Each of the 6 reviewers
also reanalyzed one of the other 5 reviewer's original intravascular ultrasound
tapes—a total of 30 paired reviews for the analysis of interreviewer
variability.
The primary end point (percentage change in total atheroma volume) was
computed as:
Graphic Jump Location
where TAV is total atheroma volume. Total atheroma volume was calculated
as the sum of the differences between EEM and lumen areas across all evaluable
slices: total atheroma volume = Σ(EEMCSA −
LUMENCSA), where EEMCSA = external elastic membrane
cross-sectional area and LUMENCSA = luminal cross-sectional area.
A secondary efficacy parameter, change in percentage atheroma volume (PAV)
was calculated as PAV = PAV (month 18) − PAV (baseline). PAV was calculated
using the following formula:
Graphic Jump Location
Other prespecified secondary efficacy measures included the nominal
change in atheroma volume for the 10 contiguous cross-sections with the greatest
and least atheroma volume.
In the protocol, the assumptions used for power calculations required
a sample size of 200 patients per treatment group to provide 90% power (assuming
a SD of 23%) to detect a 7.4% difference in the primary end point with a 5%
type I error rate for a 2-sided test. With an anticipated dropout rate of
approximately 35%, enrollment of 300 patients per treatment group (total 600
randomized patients) was specified to provide an adequate number of evaluable
patients.
Demographic and laboratory characteristics are summarized for all randomized
patients completing the trial. The analysis of safety was performed in all
patients who received at least 1 dose of drug. Categorical variables are described
using frequencies, while continuous variables are reported as mean, median
(with 95% confidence intervals [CIs]), and SDs. For the efficacy analyses
comparing treatment arms, an analysis of covariance model applied to rank-transformed
data was used. For comparisons within treatment groups from baseline to follow-up,
a Wilcoxon signed rank test was performed. Analysis of variance was used to
analyze lipid parameters and log-transformed C-reactive protein (CRP) data.
The relationship between reduction in LDL-C level and change in atheroma volume
was assessed using linear regression analysis. Analyses were performed using
SAS statistical software (version 8.12, SAS Institute Inc, Cary, NC).
Between June 1999 and September 2001, 2163 patients were screened, 657
were randomized, and 654 received study drug at 34 centers. A total of 502
patients had evaluable intravascular ultrasound examinations at both baseline
and 18-month follow-up (249 in the pravastatin group and 253 in the atorvastatin
group). Of the 155 patients who were not included in the intravascular ultrasound
analysis: 3 never received either study drug; 85 withdrew before a final intravascular
ultrasound could be obtained; 15 were withdrawn for an adverse event; 27 did
not have a final intravascular ultrasound; and 25 had an intravascular ultrasound
examination that was not analyzable due to artifacts or pullbacks shorter
than the prespecified minimum length of 30 mm. The distribution of these patients
in the 2 study groups is summarized in Figure
1. Baseline demographic and laboratory characteristics are summarized
in Table 1.
Table 2 summarizes laboratory
values at trial completion for the 2 treatment cohorts. The mean (SD) LDL-C
level was 79 (30) mg/dL (2.05 [0.78] mmol/L) in the intensive (atorvastatin)
group and 110 mg/dL (26) (2.85 [0.67] mmol/L) in the moderate (pravastatin)
group (P<.001). Significant differences in the
reduction in CRP were also observed: 36.4% in the atorvastatin group vs 5.2%
in the pravastatin group (P<.001).
Primary Efficacy.Table 3 illustrates the results for the percentage change in atheroma
volume, which is the primary efficacy parameter. Comparing the 2 regimens,
the progression rate was significantly lower in the atorvastatin group (P = .02). The change in atheroma volume was positive in
the pravastatin group (2.7%; 95% CI, 0.24-4.67), indicating net progression
(P = .001 compared with baseline). In the atorvastatin
group, the change was negative (−0.4%; 95% CI, −2.35 to 1.49),
showing no disease progression (P = .98 compared
with baseline).
Secondary Efficacy.Table 3 also illustrates the results for prespecified secondary
efficacy analyses. Significant differences favoring intensive lipid lowering
were observed for the nominal change in total atheroma volume (P = .02). Larger differences were observed for change in PAV (P<.001). Progression was observed in the pravastatin-treated
group (P<.001 for both end points compared with
baseline) and no progression occurred in the atorvastatin group (Table 3).
For the 10-mm subsegment with the greatest disease burden on intravascular
ultrasound, differences between treatments were also significant (P<.01). There was net regression in both groups (P<.001 compared with baseline in the atorvastatin group and P = .05 compared with baseline in the pravastatin group).
No differences between treatment groups were observed for the 10-mm subsegment
with the least disease burden (P = .20).
Prespecified Subgroups.Table 4 illustrates the results for the primary end point (percentage
change in atheroma volume) for 22 prespecified subgroups and 1 subgroup defined
post-hoc. The results were similar for patients with baseline LDL-C levels
above or below the mean. Compared with baseline, absence of progression was
evident in the intensive lipid-lowering group (atorvastatin) for all 22 subgroups,
whereas 15 of these subgroups showed statistically significant progression
in the moderate lipid-lowering group (pravastatin).
Observer Variability. For the 18 patients included
in the analysis for intraobserver variability, there were a total of 1177
images analyzed. The mean (SD) differences were negligible for both EEM (−0.16
mm2 [0.68 mm2]) and lumen areas (−0.02 mm2 [0.75 mm2]). Linear regression analysis showed close correlations
between the original analysis and reanalysis (r =
0.99 for EEM; r = 0.98 for lumen areas). Of the 30
patients included in the analysis for interobserver variability, there were
a total of 2151 images. The mean (SD) differences were negligible for both
EEM (−0.07 [0.93] mm2) and lumen areas (−0.07 [0.93]
mm2). Regression analysis showed close correlations between the
original analysis and subsequent analyses (r = 0.99
for EEM; r = 0.98 for lumen areas).
Exploratory Analyses. We also compared the
progression rates in the 2 treatment groups for patients attaining the guideline
LDL-C level of less than 100 mg/dL (2.59 mmol/L) in post-hoc analysis. In
the pravastatin group, 161 (65%) of 249 patients reached the guideline LDL-C
level of less than 100 mg/dL (2.59 mmol/L) (mean [SD] level, 87.5 [9.8] mg/dL
[2.27 {0.25} mmol/L]). In the atorvastatin group, 246 (97%) of 253 patients
achieved the guideline LDL-C level of less than 100 mg/dL (2.59 mmol/L) (mean
[SD] level, 67.7 [16.1] mg/dL [1.75 {0.42} mmol/L]). When the 2 treatment
regimens were compared, there was a strong trend toward a lower progression
rate in the atorvastatin group (P = .07). In the
subgroup attaining low LDL-C levels, there was progression in the pravastatin
group (P<.01) and no progression in the atorvastatin
group (P = .93) compared with baseline (Table 4).
Sensitivity Analysis. Because invasive regression-progression
trials require patients to consent to a repeat catheterization for research
purposes, all such trials have experienced a significant dropout rate during
the course of the study. In REVERSAL, 78 pravastatin-treated patients and
74 atorvastatin patients did not complete the trial (and 3 patients never
received either study drug). To examine the possibility that these patients
might have altered the outcome, we performed 2 sensitivity analyses in which
all 155 patients who did not complete the trial were imputed as showing no
benefit from the more intensive regimen. In one of these analyses, all noncompleters
in both treatment groups were assigned the median change observed for all
patients. A second approach imputed all 155 noncompleters as showing no change
from baseline in atheroma volume. For the imputed data, the mean and median
values, SDs, and interquartile ranges are shown in Table 5. Because the imputed values are close to the central tendency
for both treatment groups, the median values in Table 5 are identical for the 2 treatment groups and the P values for comparison with baseline cannot be readily interpreted.
However, using both imputation methods, the primary efficacy analysis and
both major secondary efficacy analyses (between-group comparisons) retained
statistical significance.
Table 6 shows the adverse
events and clinical end points encountered in the trial. Both regimens were
well tolerated. The number of clinical events in this 18-month trial was too
small for any meaningful analysis of morbidity and mortality.
Although statin drugs are among the best-studied contemporary cardiovascular
therapies, the optimal approach to cholesterol reduction in patients with
established CAD remains controversial. Current US and European guidelines
emphasize reducing LDL-C level to less than 100 mg/dL (2.59 mmol/L).7,8 The guidelines assume that different
strategies for lipid lowering will provide similar benefits as long as patients
attain the recommended LDL-C target level. Because major statin trials typically
have used a uniform dose of a single statin in all patients, no comparative
data exist to suggest a greater clinical benefit for more aggressive targets
or alternative agents. We approached this knowledge gap by performing the
first active-control statin trial of CAD progression.
In the current trial, patients with moderate cholesterol elevations
received 18 months of intensive therapy with 80 mg of atorvastatin and showed
significantly reduced progression of coronary atherosclerosis in comparison
with patients who received a more moderate regimen consisting of 40 mg of
pravastatin. For the primary and secondary efficacy measures, lower progression
rates were observed in the intensively treated patients (P = .02 to P<.001). Numerically similar
results were observed in prespecified subgroups (Table 4). Overall, these findings provide strong evidence that intensive
treatment using the maximum approved dose of atorvastatin reduces progression
of atherosclerosis compared with a more moderate regimen consisting of 40
mg of pravastatin.
These findings have potential implications for treatment guidelines
for patients with dyslipidemia and established CAD. Current recommendations
are based on the principle of a recommended threshold for optimal benefit
(established as a level of LDL-C of <100 mg/dL [<2.59 mmol/L]) for secondary
prevention. The current study suggests that optimal benefits are achieved
using a more intensive regimen (atorvastatin) designed to achieve LDL-C levels
well below current guidelines. Differences between the 2 treatment regimens
were evident for patients with baseline LDL-C and high-density lipoprotein
cholesterol levels above and below the mean (Table 4). Thus, patients with entry LDL-C levels below the mean
actually showed similar benefit when they received the more intensive (atorvastatin)
regimen (P = .02; Table 4). This finding is consistent with other recent clinical
trials, such as the Heart Protection Study, which demonstrated a further risk
reduction when simvastatin was administered to patients with baseline LDL-C
levels above and below 100 mg/dL (2.59 mmol/L).5 Although
the current study does not provide sufficient evidence to modify guidelines,
several ongoing trials are examining clinical outcomes following more intensive
compared with less intensive treatment.
The REVERSAL trial suggests several potential mechanisms for the greater
benefit observed with an intensive treatment regimen. Most atherogenic lipoproteins
were reduced to a greater extent in the intensive treatment group (atorvastatin),
including levels of LDL-C, total cholesterol, and triglycerides. However,
factors other than greater LDL-C–reducing efficacy may also have influenced
the results, including the differential effect of the 2 treatment regimens
on inflammation. The 36.4% reduction in CRP in the atorvastatin group compared
with the 5.2% reduction in the pravastatin group was larger than expected
and significant (P<.001). Further analysis will
be required to elucidate the relationship between the extent of reduction
in CRP or other inflammatory markers and the effect on the progression of
coronary atherosclerosis.
In addition to unpaired comparisons between the 2 treatment groups,
the study prespecified paired analysis within groups to determine whether
progression or regression had occurred from baseline to follow-up. Absence
of measurable progression in the intensively treated cohort was evident for
the primary end point, 3 prespecified secondary end points, and 22 prospectively
defined subgroups (Table 3 and Table 4). These subgroups included men
and women, individuals with or without diabetes, and individuals with or without
hypertension. In contrast, patients treated with a more moderate regimen of
40 mg of pravastatin showed significant progression (P =
.01 to P<.001 compared with baseline) for all
4 prespecified efficacy parameters (Table
3) and 15 of 22 subgroups (Table
4).
An inverse relationship between percentage reduction in LDL-C level
and atherosclerosis progression (change in atheroma volume) for both drugs
was apparent from linear regression analysis (Figure 2). Expressed as percentage change, each 10% reduction in
LDL-C level (15 mg/dL [0.39 mmol/L]) yielded approximately a 1% reduction
in the change in atheroma volume after 18 months. However, LDL-C level reductions
alone did not explain all of the differences in efficacy. Although the 2 regression
lines are parallel, the progression rate at any level of LDL-C reduction was
lower with atorvastatin compared with pravastatin. The lower progression rate
in the atorvastatin group was equivalent to an additional 20% (30 mg/dL [0.78
mmol/L]) reduction in LDL-C level. These data strongly suggest that other
factors played an important role in the improved outcome in the group treated
with atorvastatin. The most likely explanation is the larger reduction in
CRP and other atherogenic lipoproteins, such as triglycerides, in the atorvastatin
group. Supporting this observation, progression occurred even in the patients
in whom pravastatin lowered LDL-C level below the recommended goal of 100
mg/dL (2.59 mmol/L) (mean [SD], 88 [9.8] mg/dL [2.27 {0.25} mmol/L]; Table 4). Importantly, the lower progression
rate in the more intensive atorvastatin treatment group was achieved with
a safety and tolerability profile similar to the more moderate pravastatin
regimen (Table 6).
This is the first large randomized trial to directly compare the rate
of CAD progression for patients treated with 2 different statins. All prior
coronary regression-progression trials were placebo controlled and had a longer
duration (2-3 years). Although a recent single center study using a combination
of simvastatin and niacin showed reduction in angiographic stenosis severity,
most prior trials have shown only slowing of the progression of the disease
but neither regression nor an absence of progression.9,10,14-16 However,
these studies used typical starting doses of statins and therefore did not
explore the potential of more intensive therapy to delay or prevent progression.
The current study had several important advantages over earlier studies. The
actively tested agent, atorvastatin (80 mg dose), is a more potent lipid-lowering
agent and produced both a reduction in LDL-C level approaching 50% and large
reductions in CRP. The method (intravascular ultrasound) for assessing atherosclerosis
is also relatively novel, allowing measurement of atheroma burden, not merely
luminal narrowing.11,17,18 Interestingly,
2 other studies using an ultrasound method for imaging the vessel wall (measurement
of carotid intimal medial thickness) also showed reduced progression with
intensive treatment using 80 mg of atorvastatin.19,20
Because different doses of the 2 statins were used, the potential impact
of using a higher dose of pravastatin on the trial results must be considered.
At the time of study initiation, the highest dose of pravastatin approved
by the Food and Drug Administration was 40 mg. An 80-mg dose was approved
midway through the trial. However, we deemed it undesirable to alter the dose
of either study drug during an ongoing clinical trial. Furthermore, the reduction
in LDL-C level of all statins, including pravastatin, increases only moderately
with an increased dose.21 The labeling approved
by the Food and Drug Administration indicates only a 3% greater mean LDL-C
reduction using 80 mg of pravastatin compared with the 40-mg dose. A meta-analysis
of statin trials calculated only a 4% greater effect with 80 mg of pravastatin.21 Accordingly, we think it is unlikely that the use
of the recently approved 80-mg dose of pravastatin would have significantly
affected study results.
The importance of the progression rate of atherosclerosis as a clinical
trial end point also requires additional comment. It is statistically challenging
to perform actively controlled statin trials using morbidity and mortality
end points because the differences in event rates are likely to be small.
Such studies require enrollment of approximately 10 000 patients for
5 to 6 years of follow-up. The current study design enabled comparison of
2 active drugs with a sample size of about 500 patients and a duration of
only 18 months. However, to accept this result as clinically meaningful, evidence
of a relationship between progression rate and clinical outcome is important.
Such a relationship has been demonstrated in prior angiographic trials with
a high rate of adverse clinical outcomes in patients with more rapid disease
progression.22,23 In these studies,
small differences in progression rate of atherosclerosis were associated with
significant differences in clinical outcome.
We believe that the current study has important implications for understanding
the natural history of CAD. Previously, coronary atherosclerosis has been
perceived as a progressive disease process in which most therapies are designed
to slow the inexorable advancement of the disease. The present study suggests
an impending paradigm shift, in which intensive lipid-modulating strategies
can be used to stop and potentially reverse the atherosclerotic disease process.
In some patients in the REVERSAL trial, substantial regression in atherosclerotic
disease burden was observed (Figure 3).
These observations confirm the potential of antiatherosclerotic therapies
to reverse the disease process. However, it also must be emphasized that many
patients in both groups had significant progression despite statin treatment.
The current study has limitations. Intravascular ultrasound is a relatively
new modality for assessment of atherosclerotic disease burden. Accordingly,
the clinical implications of evidence of drug benefit derived from intravascular
ultrasound remain uncertain. We also recognize that the major adverse clinical
outcomes of death and myocardial infarction are the most important end points
for secondary prevention trials. There were too few events for any meaningful
analysis because 502 patients were followed up for only 18 months (Table 6). Therefore, our findings must
be confirmed in large outcome studies comparing morbidity and mortality using
alternative lipid-lowering regimens. Several studies are under way comparing
the effect of intensive with moderate lipid-lowering regimens on clinical
events. These results will not be available for several years.
Despite these limitations, we believe the following conclusions are
warranted. For secondary prevention, intensive treatment with 80 mg of atorvastatin
in patients with moderate cholesterol elevations reduced progression of coronary
atherosclerosis compared with a more moderate lipid-lowering regimen consisting
of 40 mg of pravastatin. Compared with baseline, intensive treatment halted
progression of atherosclerosis, whereas moderate therapy was associated with
significant disease progression. The intensive regimen produced greater reductions
in atherogenic lipoproteins and CRP, which likely explain the improved outcome.
A more intensive lipid-lowering therapy is required than is currently recommended
by national and international guidelines to obtain maximal reduction in the
progression of coronary atherosclerosis.
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