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(Circulation. 1996;93:34-41.)
© 1996 American Heart Association, Inc.
Articles |
Progression of Coronary Artery Disease Predicts Clinical Coronary Events
Long-term Follow-up From the Cholesterol Lowering Atherosclerosis Study
From the Atherosclerosis Research Unit and Statistical Consultation and Research Center, Departments of Preventive Medicine (S.P.A., W.J.M., L.L., H.N.H.) and Medicine (L.C.-H., D.H.B., H.N.H.), University of Southern California, Los Angeles; and Jet Propulsion Laboratory (A.M.S., R.H.S.), Pasadena, Calif.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Progression of coronary artery disease is assumed to be a surrogate end point for clinical coronary events. Because no single method or measure for a coronary angiographic end point is uniformly accepted as optimal, the utility and validity of surrogate end points for predicting clinical coronary events remain unsettled.
Methods and Results The Cholesterol Lowering Atherosclerosis Study randomized 162 nonsmoking, 40- to 59-year-old men with previous coronary artery bypass graft surgery to colestipol/niacin plus diet or placebo plus diet. Atherosclerosis change on 2-year coronary angiograms was evaluated by a consensus panel and by quantitative coronary angiography (average per-subject change in percent diameter stenosis [%S] and minimum lumen diameter [MLD]). With all three end points, the benefit of colestipol/niacin treatment on coronary artery atherosclerosis has been reported. Annual follow-up for an average of 7 years (range, 6.3 months to 10 years) has been carried out on all subjects who completed the 2-year angiogram. Clinical coronary events (need for revascularization, nonfatal acute myocardial infarction, and coronary death) have been documented. Risk of clinical coronary events was positively related to coronary lesion progression for all three surrogate end points (P<.05). New lesion formation in bypass grafts (P=.02) and progression of mild/moderate lesions (<50%S) were predictive of clinical coronary events (P<.01). Change in MLD contributed significantly to the prediction of clinical coronary events beyond a model with %S alone (P<.05).
Conclusions In this population of nonsmoking men with previous bypass surgery, both the consensus panel– and quantitative coronary angiography–based end points of coronary artery disease progression predict clinical coronary events. Subjects who demonstrate greater coronary artery lesion progression have an increased risk of future clinical coronary events. Design of shorter, smaller trials of antiatherosclerotic agents is justified.
Key Words: angiography • atherosclerosis • follow-up studies • coronary disease
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The progression of CAD is generally assumed to be a surrogate end point for clinical coronary events. This has important implications because relative to morbidity/mortality end point trials, angiographic demonstration of CAD progression is possible with trials of substantially reduced duration, sample size, and expense. Although several coronary angiographic end points are available for trial outcome, no single method or measure has been uniformly accepted as optimal. Because of this, the utility and validity of CAD progression for predicting future clinical coronary events remain unsettled.
Long-term follow-up of the CLAS cohort permits examination of the appropriateness of angiographically defined coronary artery end points, assessed by both a consensus panel and by QCA, as predictors of subsequent clinical coronary events. CLAS, which randomized its first subject in 1980 and its last in 1984, tested colestipol/niacin therapy in post–coronary bypass nonsmoking men.1 Annual follow-up for an average of 7 years (range, 6.3 months to 10 years) has been carried out on all subjects who completed the 2-year angiogram.
In the present report, we explore the ability of coronary artery end points obtained from sequential coronary angiograms, acquired at baseline and at 2 years, to predict subsequent clinical coronary events. We compare indicators of atherosclerosis progression at 2 years after randomization as assessed by a consensus panel (the global change score) with QCA-derived per-subject changes in %S and MLD, as well as with the per-subject occurrence of new lesions, occurrence of progressing lesions, and occurrence of total occlusions. In addition, we contrast the lesion populations defined by location and determine which are predictive of progression of future clinical coronary events. The results are the first to conclusively demonstrate that %S and MLD based on an average per-subject change (the most commonly used end points in atherosclerosis angiographic trials) are predictive of future clinical coronary events.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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A detailed description of the CLAS trial design and methodology has been published.1 Between September 1980 and October 1984, 188 nonsmoking, 40- to 59-year-old men with previous CABG underwent baseline coronary angiography and were randomized to receive colestipol/niacin plus cholesterol-lowering diet versus placebo plus diet; 162 subjects (86%) had a repeat angiogram after 2 years of intervention. Atherosclerosis change was evaluated by both a consensus panel and QCA. In addition, a total of 138 of 162 subjects (85%) continued their randomized treatment in an optional 2-year extension of CLAS (CLAS-II), in which 103 of 138 subjects (75%) had a repeat angiogram after 4 years of intervention. Benefit of colestipol/niacin treatment on coronary artery atherosclerosis has been reported at 2 years in 162 subjects by the consensus panel,2 at 2 years in a random sample of 85 subjects by QCA,3 and at 4 years in 103 subjects by the consensus panel.4 For this follow-up study, QCA at 2 years has been completed for the entire cohort.
Panel Evaluation
All 162 film pairs, showing identical
coronary artery
views with treatment allocation and temporal order masked, were
evaluated by an expert panel of two angiographers and a
moderator.1 5 With the first film, a consensus
opinion on
lesion identification and %S was obtained and recorded by the
moderator. With the second film, a consensus opinion on the amount of
change for each lesion and the global change score was obtained. The
GCS, an overall assessment of angiographic change that integrated all
changes seen in the film pair, ranged from 0 (no demonstrable change)
to 3 (extreme change). A direction for change (- for regression and
+
for progression) was subsequently assigned by the study statistician
when the temporal blind was broken.
QCA
Of the 162 subjects with 2-year angiograms, 156 (96%) had
evaluable end points by QCA. QCA analyses were performed masked
to treatment allocation.1 6 7 Film pairs
were processed in
tandem using dual projectors to match frames for orientation and
degree of contrast filling, and arterial segments were
defined from branch to branch. Three sequential frames exposed during
end diastole were digitized when possible; if not, three
sequential frames from other phases of the cardiac cycle were
digitized.6 The angiographic view (usually the right
anterior oblique) that best demonstrated a lesion was selected. Both
%S and MLD were measured for each panel-identified lesion and for
lesions identified by the QCA analyst (which tended to be in smaller
segments and were less severe) but not by the panel. Edge coordinates
were corrected for pincushion distortion measured from the image of a
1x1-cm anteroposterior grid filmed at the beginning of each angiogram.
Each end point was averaged over three sequential frames. The QCA end
points were calculated as the average (per subject) change from
baseline in %S and MLD.
Clinical Events
Follow-up was carried out on all 162 subjects
who completed
the 2-year angiogram for an average of 7 years (range, 6.3 months to 10
years). Subjects were followed annually with either a clinic visit
(90%) or a questionnaire (10%) and evaluated for major medical
events. ECGs were routinely obtained as part of the annual examination.
Data concerning lipid-lowering therapy subsequent to the last
angiogram were also obtained. As of April 22, 1993 (the cutoff date for
this analysis), only 6 subjects (4%) were lost to
follow-up.
The following clinical coronary events were tabulated: requirement for revascularization due to recurrence or worsening of angina pectoris (PTCA, CABG), nonfatal acute MI, and coronary death. For the study, 2-year angiographically related revascularizations and silent MIs noted by ECGs obtained at annual follow-up examinations were not counted as clinical events. Hospital records were obtained to confirm all subject-reported events. Diagnosis of MI was made by a cardiologist who was masked to treatment group assignment and was defined as the presence of two of the following three criteria: typical chest pain, positive creatinine phosphokinase–MB, and presence of new Q wave on the ECG. Cause of death was determined from hospital records or from the family and verified by a death certificate.
Statistical Analysis
Although some subjects had both 2- and
4-year angiograms, all
analyses are based on angiographic changes noted at 2 years.
Two clinical coronary end points were chosen as dependent
variables: time from 2-year angiogram to first clinical
coronary event (PTCA, CABG, nonfatal MI, or coronary
death) and time from 2-year angiogram to nonfatal MI or
coronary death. For descriptive purposes, clinical
coronary event rates were calculated for categorical levels of
the three surrogate angiographic end points. The GCS was categorized as
regression (GCS<0), no change (GCS=0), or progression (GCS>0),
and
the average per-subject changes in %S and MLD determined by QCA
were stratified into quartiles (<-2.4%S, -2.4%S to <0.8%S,
0.8%S to <4.4%S, and 
4.4%S) and (0.10 mm, -0.02 to <0.10
mm,
-0.15 to <-0.02 mm, and <-0.15 mm), representing
regression to progression, respectively.
The six independent variables
were (1) the three surrogate end
points (GCS [by panel] and average change in %S and MLD [by
QCA])
and (2) three dichotomous QCA-derived variables (the occurrence of
new lesions, the occurrence of new total occlusions, and the occurrence
of progressing lesions). A new lesion was defined as not present or
<20%S at baseline, increased by 10%S, and was 20%S on the
follow-up angiogram. A new total occlusion was defined as <100%S
at baseline but increased to 100%S on the follow-up angiogram. A
progressing lesion was defined as 20%S at baseline and increased by
10%S on the follow-up angiogram. Progressing lesions excluded
new lesions but not new total occlusions.
Stratifying variables were
(1) lesion location (native arteries,
native arteries proximal to grafts, native arteries distal or unrelated
to grafts, and bypass grafts) and (2) lesion severity at
baseline—mild/moderate (<50%S) and severe (50%S).
The GCS
and QCA independent variables were tested for
predictiveness of clinical coronary event rates with the use of
Cox regression analyses. Model covariates included indicator
variables for treatment group assignment and whether the subject
continued into CLAS-II. Because the 2-year angiographic change
variables of interest were not related to the use of
lipid-lowering medication during the follow-up period, this was
not included as a covariate in the Cox regression analyses.
Estimates of the RR for clinical coronary events were
calculated for categorical levels of each surrogate end point (relative
to the lowest level). Tests for trend used GCS- or QCA-determined
average per-subject change in %S and MLD as continuous
variables. We also estimated the RRs for clinical coronary
events per 10%S change in %S and per 0.3-mm change in MLD. These
analyses were carried out for all lesions and for lesion
subpopulations defined by lesion location (native arteries, native
arteries proximal to grafts, native arteries distal or unrelated to
grafts, and bypass grafts) and lesion severity (mild/moderate and
severe). The cutoffs of 10%S change and 0.3-mm change are twice the
measurement error for %S and MLD on short-term repeat angiograms,
respectively. Likelihood ratio 
2 tests were used
for all significance tests. Finally, we estimated on a per-subject
basis the RRs for clinical coronary events on three QCA-derived
categorical variables: the occurrence of new lesions, the
occurrence of new total occlusions, and the occurrence of at least one
progressing lesion. For these analyses, each independent
variable (new lesions, new total occlusions, and progressing
lesions) was treated on a per-subject basis as a dichotomous
variable (yes or no).
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Baseline/2-Year Results by Treatment Group
In the cohort of 162 subjects with repeat angiograms at 2 years, the average±SD age at randomization was 54.1±4.5 years, the average±SD blood pressure was 122±13 mm Hg (systolic) and 80±9 mm Hg (diastolic), and 47 subjects (29%) had never smoked. The baseline average±SD lipid levels were total plasma cholesterol of 243±35 mg/dL, LDL-C of 170±31 mg/dL, HDL-C of 42±8 mg/dL, and triglycerides of 150±88 mg/dL. Eighty subjects were assigned to receive drug, and 82 were assigned to receive placebo. No significant differences were found between treatment groups in baseline characteristics. On-trial percentage changes in lipids (drug versus placebo) were -26% versus -4% for total plasma cholesterol, 37% versus 2% for HDL-C, -43% versus -5% for LDL-C, and -21% versus -5% for triglycerides (all P<.0001).
All 162 subjects had evaluable GCS end points; 156 of 162 subjects had evaluable end points by QCA. The distribution of angiographic change as determined by GCS (drug versus placebo) was regression (16% versus 4%), no change (45% versus 37%), and progression (39% versus 59%) (P=.004). The average±SD change in %S and MLD for native arteries plus grafts as determined by QCA (drug versus placebo) was 0.3±5.9%S versus 2.7±5.8%S (P=.02) and -0.01±0.22 mm versus -0.09±0.26 mm (P=.04).
Twenty-four subjects (15%) terminated CLAS after the 2-year angiogram, 103 (64%) continued their randomized treatment and terminated after the 4-year angiogram, and 35 (22%) continued their randomized treatment but terminated before the 4-year angiogram. On termination of CLAS, 57 of the subjects (73%) randomized to the drug group continued on some cholesterol-lowering medication, and 58 of the subjects (74%) randomized to the placebo group initiated some cholesterol-lowering medication (P=NS). Medications included niacin and/or colestipol/cholestyramine, lovastatin/pravastatin/simvastatin, or gemfibrozil. The average±SD change in %S for subjects continuing on lipid-lowering medication versus those who did not in the drug group were 0.4±6.1%S versus 0.1±5.2%S (P=NS). For subjects initiating lipid-lowering medication versus those who did not in the placebo group, these changes in %S were 2.7±4.9%S versus 2.7±8.0%S (P=NS).
Angiographic Results for the Combined Groups
Table
1
presents the angiographic results for
the two treatment groups combined. Shown in the left side of the table
is the panel-based outcome for the 162 subjects with the GCS end
point. According to the panel evaluation, 16 (10%) of the subjects
regressed, 66 (41%) demonstrated no clinically significant change, and
80 (49%) subjects progressed. For the 156 subjects with evaluable QCA
end points, the right side of Table 1 is a summary of the
baseline
averages and 2-year changes in %S and MLD, overall and stratified by
lesion location (all native arteries, native arteries proximal to
grafts, native arteries distal or unrelated to grafts, and bypass
grafts) and lesion severity (mild/moderate versus severe). The
average±SD number of lesions per subject was 8.2±4.2 (5.8
lesions per
subject in the native arteries compared with 2.4 lesions per subject in
the bypass grafts). The average±SD %S was 36.2±7.0%S. On
average,
lesions in bypass grafts progressed more rapidly (3.2%S) than did
lesions distal or unrelated to bypass grafts (0.3%S), with lesions
proximal to bypass grafts being intermediate (2.5%S)
(P=.03).
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Table 2 is a summary of the
numbers of new lesions
(overall and stratified by lesion location), progressing lesions
(overall and stratified by lesion location and lesion severity) and new
total occlusions (overall and stratified by lesion severity) for the
combined treatment groups. New lesions were more prevalent in bypass
grafts than they were in native arteries (10% versus 3%,
P<.001). Fifteen (1%) of all QCA-evaluable lesions became
totally occluded. Progression occurred more frequently in mild/moderate
(<50%S) lesions compared with severe (50%S) lesions (11% versus
7%, P=.06). Of the 17 severe lesions that progressed, all
were proximal to patent grafts (n=12), total occlusions at the second
angiogram (n=7), or both.
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Clinical Coronary Events
During follow-up of an average of 7
years (range, 6.3 months
to 10 years) after the 2-year angiogram, 55 of 162 subjects (34%) (22
drug versus 33 placebo) had one or more clinical coronary
events (drug versus placebo): PTCA (7 versus 14), CABG (16 versus 11),
nonfatal MI (7 versus 19), or coronary death (2 versus 6).
Subjects randomized to the drug group had lower event rates than did
subjects randomized to the placebo group: all coronary events
(RR=0.6; P=.04) and nonfatal MI or coronary death
(RR=0.4; P=.02).
In the Cox regression analyses, treatment group remained a significant predictor of MI/coronary death after adjustment for angiographic change in the QCA end points (%S and MLD). On the other hand, treatment group was not a significant predictor of MI/coronary death after adjustment for GCS or for any coronary event after adjustment for angiographic change in any of the surrogate end points (GCS, %S, or MLD). For all analyses, the interaction between treatment group and angiographic change was not found to be a significant predictor of MI/coronary death or any coronary events.
Table 3 is a
summary of the event rates per 100
man-years stratified by the GCS (regression, no change,
progression) and quartiles of average per-subject change in %S and
MLD for native arteries plus grafts. The overall rates of clinical
coronary events and nonfatal MI/coronary death were 5.8
and 2.7 per 100 man-years, respectively. Increase in event rates
was associated with progression of the surrogate end points (ie,
increasing values of GCS and %S and decreasing values of MLD). Table
3
also presents relative risks of any coronary events and
nonfatal MI/coronary death for categorical levels for each of
the surrogate end points, adjusted for treatment group and CLAS-II
status. The risk of clinical coronary events was positively
related to coronary artery lesion progression for all three
surrogate end points (P<.05).
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Table 4
presents the relative risks of any
coronary events and nonfatal MI/coronary death per
10%S change in %S and per 0.3-mm change in MLD for all lesions and
also for lesion subpopulations stratified by lesion severity and lesion
location. Coronary artery lesion progression was significantly
related to any coronary event (2.1
RR2.2,
P<0.001) and nonfatal MI/coronary death
(1.8RR2.0, P<.03). Progression of mild/moderate lesions
(<50%S), but not progression of severe lesions (50%S), was
significantly related to coronary event rates (1.7RR2.1,
P<.01 for any coronary event and nonfatal
MI/coronary death). When the 60 new lesions (Table 2
) were
excluded from the analysis of mild/moderate lesions, we found
that progression of mild/moderate lesions was still related to
coronary event rates (1.7RR1.8, P<.05).
Progression in both native arteries (1.5RR1.8, P<.05)
and bypass grafts (1.3RR1.6, P<0.05) was
significantly correlated with coronary event rates. When
stratified by lesion location relative to the bypass grafts,
progression in lesions proximal to the bypass grafts (as determined by
MLD only) was found to be significantly associated with nonfatal
MI/coronary death rates (RR=1.5; P<.05).
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Table
5 presents relative risks of any
coronary event and nonfatal MI/coronary death for the
QCA-derived categorical end points of new lesions, new total
occlusions, and progressing lesions. On a per-subject basis, the
formation of at least one new lesion was related to the risk of any
coronary event (RR=2.0; P=.03), and this risk was
associated with new lesions in the bypass grafts (RR=2.3;
P=.02) and not in the native arteries. Although the estimate
of the relative risk was equivalent for nonfatal MI/coronary
death, the association of new lesions to nonfatal MI/coronary
death was of borderline significance (RR=2.1; P=.07).
On a per-subject basis, the occurrence of new total occlusions was
not significantly related to the risk of coronary events. On a
per-subject basis, the occurrence of at least one progressing
lesion was not significantly related to the risk of coronary
events.
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The relative predictive ability of the three coronary
angiographic end points was determined from a
multivariate analysis evaluating the added
contribution of one surrogate end point above that of another surrogate
end point. GCS did not contribute significantly beyond that for %S
(12=0.41 for nonfatal MI/coronary death and
12=2.21 for any coronary event) or for MLD
(12=0.25 for nonfatal MI/coronary death and
12=1.11 for any coronary event). %S or MLD
did not contribute significantly beyond that for GCS for nonfatal
MI/coronary death (12=2.58 for %S and 3.68
for MLD). In contrast, both %S and MLD contributed significantly
beyond that for GCS for any coronary event
(12=6.05 for %S and
12=9.39
for MLD, P<.01). Finally, MLD contributed significantly
beyond that for %S for any coronary event
(12=4.49, P<.05).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The results of the present study indicate that progression of CAD determined by sequential coronary angiography separated by a 2-year interval is predictive of clinical coronary events. Assessment of CAD progression on a per-subject basis by QCA (%S or MLD) or by panel evaluation of overall angiographic change (GCS) predicts future clinical coronary events (Tables 3
and
4). For
every 10%S increase in average %S, the risk for a clinical
coronary event doubles over an average of 7 years of
follow-up (Table 4). CLAS results also demonstrate that
formation
of new lesions in bypass grafts is a precursor of poor clinical outcome
(Table 5). When stratified by lesion location, QCA-assessed
progression
in both native and bypass grafts was found to be predictive of clinical
coronary events (Table 4). When stratified by baseline lesion
severity, QCA-assessed progression of mild/moderate lesions (<50%S)
was significantly predictive of future clinical coronary events
(even after excluding new lesions), whereas progression of severe
lesions (50%S) was not (Table 4).
Panel-Read and QCA-Read Angiographic End Points as Surrogate
Outcome Measures for Subsequent Clinical Coronary
Events
The assumption that angiographic progression is predictive of
subsequent coronary events was suggested by Bemis et
al8 and validated by Moise et al.9 Moise et
al demonstrated that progression on sequential coronary
angiograms added to the predictive power for acute MI over that of
baseline status of the coronary anatomy and left
ventricular function. The Program on the Surgical Control
of the Hyperlipidemias (POSCH), which demonstrated
benefit on coronary artery lesions with cholesterol
lowering by partial ileal bypass surgery,10 has also
demonstrated that the 3-year panel-based GCS (determined using
identical methods as in CLAS) was predictive of subsequent clinical
coronary events, fatal coronary events, and
all-cause mortality.11 Average follow-up was 6.7
years after the 3-year angiogram. It is of interest, however, that CLAS
results did not confirm the treatment/GCS interaction found in
POSCH.
QCA assessment of coronary angiograms is increasingly used in coronary angiographic trials because of its enhanced reproducibility over human analysis. Numerous antiatherosclerotic trials using QCA end points have reported positive results for cholesterol-lowering drugs,3 12 13 14 15 16 cholesterol-lowering diet and other life-style changes,17 18 and calcium channel blockers.19 20 Recently, Waters et al20 presented a report from the nicardipine trial in which atherosclerosis progression, defined as a 2-year increase of at least 15%S in at least one coronary lesion, predicted coronary events and coronary death over a subsequent 4.5-year period.21 Although these results indicate that QCA change is predictive of clinical events, determination of change in individual lesions or coronary segments has not been used as a primary end point in angiographic trials.
CLAS follow-up indicates that per-subject assessment of coronary artery lesion progression by both panel (GCS) and QCA (%S and MLD) predicts subsequent clinical coronary events. In addition to validating POSCH results using the GCS end point, this is the first report to show average per-subject change in %S or MLD by QCA to be predictive of clinical coronary events. This is important because it is the average per-subject change that is commonly used as the end point in antiatherosclerosis angiographic trials with QCA and is most representative of overall CAD progression.
Examination of the Figure indicates that %S
and MLD are
highly correlated with GCS (P<.001). Consequently, we
evaluated whether each angiographic change variable provided
additional prediction of clinical coronary event rates beyond
that provided by the other variables. From our
multivariate analyses, we determined that once
%S (or MLD) was in the model, GCS was no longer predictive. On the
other hand, although the panel-based GCS is predictive of future
clinical coronary events, either QCA end point (%S or MLD)
offered additional predictive power beyond that of GCS alone. Because
GCS is a seven-point categorical variable and %S and MLD are
continuous measures of angiographic change, the range of QCA change
within each GCS category provides additional predictive ability.
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When the two QCA end points %S and MLD, were compared it was found that MLD contributed significantly beyond that for %S in predicting the rate for any clinical coronary event. This result may indicate that disease progression in normal reference segments has a greater impact on the predictability of the %S measure than does the dilation of coronary arteries (as a result of early atherosclerosis progression) on the predictability of the MLD measure.22 Alternatively, diseased reference diameters do not permit usable estimates of %S by QCA, whereas the MLD measure is available despite the lack of a nondiseased reference diameter.
Risk of Mild/Moderate Lesions
Subjects who demonstrated
greater mild/moderate lesion progression
over a 2-year interval were at increased risk for future clinical
coronary events. This is in accord with previous reports
indicating that clinical coronary events are associated with
mild/moderate lesions that episodically progress to occlusion as a
result of local anatomic factors.23 Although severe
lesions are more likely to progress to occlusion than mild/moderate
lesions, clinical coronary events more frequently occur as a
result of acute occlusion of mild/moderate lesions. This may be a
consequence of collateral vessel formation (or CABG), which may avert
clinical coronary events when severe lesions occlude. Although
there was a significant reduction in clinical coronary events
over the subsequent follow-up of CLAS subjects treated with
colestipol-niacin, we were unable to determine which specific
lesions resulted in this reduction because angiography was not obtained
when events occurred. However, it has been shown in the Familial
Atherosclerosis Treatment Study (FATS)13
that mild/moderate lesion stability induced by LDL-C lowering
significantly reduced on-trial clinical coronary
events.24
Because acute coronary events most commonly
arise from
occlusion of lesions that are of mild/moderate severity, it is not
surprising that higher rates of progression of mild/moderate lesions
without occlusion result in a greater risk of future clinical
coronary events. Our data (Table 1) confirm reports that
lesions that are initially the least severe are the most likely to
progress.25 26 Low-grade plaques become unstable,
fissure, thrombose, and ultimately occlude as they progressively
accumulate extracellular lipid within the central core.23
Therefore, reduction in the amount of lipid in the central core, as a
consequence of LDL-C reduction, should result in plaque stability with
a decrease in lesion progression and resultant clinical
coronary events.
Risk of Severe Lesions
Progression of severe lesions was not
found to be associated with
future clinical coronary events (Table 4). This lack of
association for severe lesions could be due to the fact that (1) only
17 (12%) of the 136 progressing lesions were severe (Table 2)
and (2)
all progressing severe lesions were either proximal to patent grafts
(n=12) and thus were protected from causing an event when progressing
to occlusion and/or were total occlusions at the second angiogram
(n=7), which cannot worsen to produce an event. In this study of
subjects who underwent CABG, as well as in angiographic trials of other
study populations, it is difficult to evaluate whether progression of
severe lesions is associated with future clinical coronary
events because such lesions are rarely left undisturbed when they are
detected at coronary arteriography. However, this situation
provides an interesting indirect confirmation of the hypothesis given
above as to why progressing severe lesions rarely lead to clinical
coronary events, namely, collateral vessel formation is a
natural form of coronary artery
revascularization.
Risk in Relation to Lesion Location
Progression rates, and
the factors related to progression, are
different in native arteries proximal to patent bypass grafts than in
nonbypassed arteries or segments distal to sites of graft
insertion.3 27 28 29 30
As shown in Table 1, lesions in bypass
grafts progressed more rapidly (3.2%S) than did lesions distal or
unrelated to bypass grafts (0.3%S), with lesions proximal to bypass
grafts being intermediate (2.5%S) (P=.03). In addition, as
shown in Table 4, lesion progression in both native arteries
and bypass
grafts is significantly related to the risk of any coronary
event and the risk of nonfatal MI/coronary death. Therefore,
progression of lesions per se, whether in bypass grafts or native
coronary arteries, is predictive of clinical coronary
events. Because we are unable to determine which events are due to
bypass graft disease as opposed to native vessel disease, our findings
should be extrapolated with caution to nonbypassed patients.
Implications for Future Antiatherosclerosis
Clinical Trials
One limitation of our study is that the patient
population
included only nonsmoking, middle-aged men who had previously
undergone CABG. Another limitation is that we are unable to determine
which events are due to bypass graft disease as opposed to native
vessel disease. However, taken together, findings from the 7-year CLAS
follow-up as well as other studies11 21 strongly
indicate that end points from sequential coronary angiographic
films can be used as surrogate outcome measures for clinical
coronary events, thus justifying the design of shorter and less
expensive coronary antiatherosclerosis
trials of lipid and nonlipid modifying therapies. Specifically, results
from this study indicate that all of the traditional coronary
angiographic end points—the QCA averaged per-subject end
points (%S and MLD) and the panel-based GCS assessment of CAD
progression—predict future clinical coronary events. Also,
CLAS and POSCH, two independent trials with a common end point, GCS,
indicate that lipid-lowering therapy that slows the progression of
CAD results in a significant reduction in future clinical
coronary events.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by National Heart, Lung, and Blood Institute grants RO1-HL-45005 and R01-HL-49885.
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Footnotes |
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Reprint requests to Howard N. Hodis, MD, Atherosclerosis Research Unit, Division of Cardiology, University of Southern California School of Medicine, 2250 Alcazar St, CSC 132, Los Angeles CA 90033.
Received November 22, 1994; revision received June 19, 1995; accepted August 16, 1995.
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