(Circulation. 1996;93:889-897.)
© 1996 American Heart Association, Inc.
Articles |
Role of Angiographically Identifiable Thrombus on Long-term Luminal Renarrowing After Coronary Angioplasty
A Quantitative Angiographic Analysis
Presented in part at the 43rd Annual Meeting of the American College of Cardiology, Atlanta, Ga, March 13-17, 1994, and the 16th Annual Congress of the European Society of Cardiology, Berlin, Germany, September 10-14, 1994.
From the Catheterization Laboratory, Thoraxcenter, Erasmus University, and the Department of Epidemiology and Biostatistics, Cardialysis (R.M.), Rotterdam, Netherlands.
Correspondence to Prof P.W. Serruys, MD, PhD, FACC, FESC, Catheterization Laboratory, Thoraxcenter, Erasmus University Rotterdam, Postbus 1738, 3000 DR Rotterdam, Netherlands.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Experimental studies suggest that mural thrombus may be involved in postangioplasty restenosis. The aim of our study was to examine the role of angiographically identifiable thrombus in the clinical situation.
Methods and Results The study population comprised 2950 patients (3583 lesions). The presence of angiographically identifiable thrombus either before or after the procedure was defined as the presence of a generalized haziness or filling defect within the arterial lumen. Restenosis was assessed by both a categorical (>50% diameter stenosis at follow-up) and a continuous approach (absolute and relative losses). The study population included 160 lesions with and 3423 lesions without angiographically identifiable thrombus. The categorical restenosis rate was significantly higher in lesions containing angiographically identifiable thrombus: 43.1% versus 34.4%, P<.01; relative risk, 1.449; CI, 1.051 to 1.997. The absolute and relative losses were also higher in lesions containing angiographically identifiable thrombus (absolute loss, 0.43±0.66 versus 0.32±0.52; relative loss, 0.16±0.26 versus 0.13±0.21; both P<.05). The higher restenosis in these lesions was due primarily to an increased incidence of occlusion at follow-up angiography in this group: 13.8% versus 5.7%, P<.001. When lesions that went on to occlude by the time of follow-up angiography were excluded from the analysis, the restenosis rate between the two groups was similar by both the categorical (34.1% versus 30.4%, P=NS; relative risk, 1.183; CI, 0.824 to 1.696) and continuous (absolute loss, 0.23±0.46 versus 0.24±0.42, P=NS; relative loss, 0.09±0.17 versus 0.09±0.16, P=NS) approaches.
Conclusions Our results indicate that the presence of angiographically identifiable thrombus at the time of the angioplasty procedure is associated with higher restenosis. The mechanism by which this occurs is through vessel occlusion at follow-up angiography. Measures aimed at improving outcome in this group of patients should be focused in this direction.
Key Words: angioplasty • thrombus • angiography • trials • meta-analysis
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Since the introduction of coronary angioplasty by Gruentzig et al1 and the subsequent refinements in equipment, the indications for the technique have been expanded to include patients with unstable angina2 3 4 and acute myocardial infarction.5 In these situations, however, angioplasty carries increased risks thought to relate, in part, to the presence of thrombus. A number of studies have demonstrated that the presence of angiographically identifiable thrombus either before or after dilatation of a coronary stenosis carries an increased risk of acute occlusion.6 7 The influence of thrombus on long-term restenosis, however, is less clear. Experimental work suggests that local platelet deposition with the subsequent release of a number of chemotactic and mitogenic factors, such as platelet-derived growth factor and thrombin,8 may mediate the fibroproliferative response. Recurrent platelet aggregation at the site of injury with associated vasoconstriction and the consequent increased frequency and severity of cyclic coronary blood flow variations may also play an important role in the subsequent development of neointimal proliferation.9 Although one study suggested that thrombus formation and incorporation into the vessel wall may play a pivotal role in restenosis,10 this has not been confirmed by other investigators.11 Few clinical studies have actually assessed the role of angiographically identifiable thrombus on subsequent restenosis. The aim of this study was to examine the role of angiographically identifiable thrombus on long-term restenosis in a large series of patients undergoing successful balloon angioplasty and routine follow-up QCA assessment.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients
The study population was taken from the 3582 patients with significant primary stenoses in native coronary arteries who were prospectively enrolled into four major restenosis trials.12 13 14 15 These demonstrated that active therapy had no effect on restenosis or clinical outcome in the first 6 months after balloon angioplasty, so for the purposes of this study, the data for the active and placebo groups were pooled. Patients, men or women, were eligible for study entry if they were symptomatic or asymptomatic, had stable or unstable angina pectoris, and showed angiographically significant narrowing in one or more major coronary arteries. Patients with recent (<1 week) or evolving myocardial infarction and those with significant left main coronary artery disease were excluded from the study.
Angioplasty Procedure and Follow-up Angiography
Coronary
angioplasty was performed with a steerable,
movable guide-wire system by the femoral route. Standard balloon
catheters were used. The choice of balloon type and brand as well as
inflation duration and inflation pressure were left to the discretion
of the operator. Patients were followed up for 6 months, at which time
a follow-up study was performed. If symptoms recurred within 6
months, coronary angiography was carried out earlier. If no
definite restenosis was present and the follow-up
time was <4 months, the patient was asked to undergo further
coronary arteriography at 6 months.
Quantitative Coronary Angiography
Three coronary angiograms,
in total, were obtained for
each patient: before and after PTCA and at angiographic follow-up.
To standardize the method of data acquisition and to ensure exact
reproducibility of the angiographic studies, measures were taken as
previously described and all angiograms were processed in a central
angiographic core
laboratory.12 13 14 15 The
angiograms were
recorded in such a manner that they were suitable for QCA by the
computer-assisted Coronary Angiography Analysis
System (CAAS), which was described and validated
earlier.16 Because the computer algorithm is unable to
measure total occlusions, a value of 0 mm was substituted for the MLD
and a value of 100% for the percent diameter stenosis before
PTCA. In these cases, the postangioplasty reference diameter was
substituted for vessel size.
Definitions
Angiographically identifiable thrombus was
defined as the
presence of a filling defect within the coronary lumen,
surrounded by contrast material, seen in multiple projections and
in the absence of calcium within the filling
defect.17 18
Alternatively, the persistence of contrast material within the lumen or
visible embolization of intraluminal material downstream was also taken
to represent intracoronary thrombus.
Total occlusion was present if no anterograde filling beyond the lesion was visible or if faint, late anterograde opacification of the distal segment was present in the absence of a discernible luminal continuity.19 Occlusion at follow-up angiography was similarly defined.
Vessel size refers to the reference diameter of the relevant coronary segment and is represented by the interpolated reference diameter before PTCA. MLD is the point of maximal luminal narrowing in the analyzed segment.
Restenosis: Many criteria have been proposed for the assessment of restenosis.20 21 For the purposes of this study, we used, first, the categorical approach with the traditional cutoff point of >50% diameter stenosis at follow-up and second, a continuous approach using absolute and relative losses.21
Absolute gain and absolute loss represent the improvement in MLD achieved at intervention and the absolute change during follow-up, respectively, measured in millimeters. Absolute gain is the MLD after PTCA minus MLD before PTCA. Absolute loss is the MLD after PTCA minus MLD at follow-up.
Relative gain and relative loss depict the improvement in MLD achieved at intervention and the change during follow-up, respectively, normalized for vessel size. Relative gain is [MLD after PTCA minus MLD before PTCA] divided by vessel size. Relative loss is [MLD after PTCA minus MLD at follow-up] divided by vessel size.
Absolute net gain is the MLD at follow-up minus MLD before PTCA.
Net gain index is the net gain normalized for the vessel size. Net gain index is [MLD at follow-up minus MLD before PTCA] divided by vessel size.
Statistical Analysis
Data were analyzed with the SAS
statistical software
package. A 
2 test was used to assess differences
in categorical variables. Student's t test was used to
assess differences in continuous variables. To test the assumption
that the variances were equal, the folded-form F statistic was
used. Whenever this assumption was violated, the Cochran and Cox
approximation of the t test was used. Differences in
variables with an ordinal scale (severity of clinical outcome) were
assessed with the Wilcoxon rank-sum test. The difference in
event-free survival time between the two groups was evaluated by
the Kaplan-Meier method with the log rank and Wilcoxon tests.
To study the relation between a binary outcome parameter
(occlusion at follow-up, the occurrence of a clinical event) and
multiple categorical and continuous determinants, multiple logistic
regression analysis was used. To study the relation between
continuous outcome parameters and multiple categorical and
continuous determinants, multiple linear regression analysis
was used. Lesion characteristics were investigated with a
lesion-based analysis and patient characteristics with a
per-patient analysis in which a single lesion was randomly
selected in patients with multivessel angioplasty. Values of
P<.05 were considered significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Baseline Patient Characteristics, Procedural Results, and Clinical Follow-up
The study population comprised the 2950 patients (3583 lesions, 1.21 lesions per patient) who successfully completed the study and had follow-up QCA. The overall QCA restudy rate was 86% of all patients undergoing successful PTCA with a residual QCA stenosis of <50%. Of 3583 lesions in 2950 patients, 160 lesions in 158 patients complied with the angiographic definition of thrombus present either before or after PTCA.
The two groups were
comparable in terms of age and sex, but patients
with angiographically identifiable thrombus at PTCA were more likely to
have sustained a previous myocardial infarction and less likely to have
had a previous PTCA (Table 1
). There were, however,
substantial differences in lesion and procedural characteristics
between the two groups (Table 2). Thrombotic lesions
were more likely to be located in the RCA than in the LAD and had a
much higher proportion of total occlusions and multiple irregularities.
They were also more likely to require a larger balloon and a greater
number and duration of inflations. After the procedure, this group of
lesions was also more likely to have a dissection (Table 2).
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Forty-four (28%) of the patients with angiographically
identifiable thrombus present and 625 (22.4%) of the patients
without thrombus had a clinical end point during follow-up
(P=.116). The individual components of death, myocardial
infarction, coronary artery bypass graft surgery, and repeat
PTCA were 0%, 8.3%, 2.6%, and 17.2%, respectively, for lesions
containing angiographically identifiable thrombus and 0.2%, 2.6%,
2.5%, and 17.0% for lesions without thrombus (P=.053). The
mean time to clinical end point was significantly less in the
angiographically identifiable thrombus group (63±63 versus
92±56 days, P<.05, Fig 1a), and when
we compared the pattern of occurrence of clinical end points by
way of the log rank test, the probability value was .051, whereas the
Wilcoxon test, which places more emphasis on early survival
times, rendered a value of P=.026, indicating the diverging
survival curves in the beginning. When lesions that went on to occlude
at the time of follow-up angiography were excluded from the
analysis, there was no significant difference in the mean time
to clinical end point (Fig 1b), and the log rank test gave a
value of
P=.209, whereas the Wilcoxon test rendered a value
of P=.159, suggesting that the excess early events were
related to the occlusions at follow-up angiography.
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To exclude the possibility of a selection bias influencing our results, we also examined the incidence of thrombus-laden lesions and clinical end points in the 14% of the population in whom full QCA measurements were not available and who were therefore excluded from the study population. The incidence of thrombus in these patients (6.7%) was comparable to that in our study population (5.4%, P=NS). Of these patients with thrombus, 22.6% and of patients without thrombus, 22.6% had a clinical end point during follow-up (P=1.000). The individual worst clinical end-point components of death, myocardial infarction, coronary artery bypass graft surgery, and repeat PTCA were 3.2%, 9.7%, 3.2%, and 6.5%, respectively, for lesions with and 3.5%, 3.2%, 5.8%, and 10.2% for lesions without thrombus (P=.403).
QCA Analysis
Satisfactory QCA was performed in a mean of 2.12
matched
angiographic projections per lesion (Table 3). The
reference diameter did not change from before to after the procedure
but was significantly larger in lesions containing angiographically
identifiable thrombus, and this difference remained at follow-up
(Table 3). Although the MLD before angioplasty was
significantly
smaller in lesions containing angiographically identifiable thrombus,
the MLD after angioplasty was similar. The residual percent
stenosis after PTCA was higher in the angiographically
identifiable thrombus group, as were the absolute and relative gains
(Table 3, Fig 2). At follow-up, although the MLD
was
similar in both groups, the percent stenosis was significantly
higher in lesions containing thrombus (Fig 2, Table
3), as were the
categorical restenosis rate (43.1% versus 34.4%,
P<.01; relative risk, 1.449; CI, 1.051 to 1.997) and the
absolute and relative losses (Table 3, Fig 3).
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The higher restenosis rate in the angiographically identifiable thrombus group was predominantly due to an increased number of occlusions at follow-up angiography (13.8% versus 5.7%, P<.001; relative risk, 2.639; 95% CI, 1.645 to 4.233). When lesions that went on to occlude at follow-up angiography were excluded from the analysis, there remained a tendency for a higher categorical restenosis rate in the thrombus group (34.1% versus 30.4%; relative risk, 1.183; CI, 0.824 to 1.696), but this was no longer statistically significant (P=.411). The absolute and relative losses were now also similar (0.23±0.46 versus 0.24±0.42 and 0.09±0.17 versus 0.09±0.16, respectively, both P=NS).
Multiple Linear Regression Analysis
We have previously
demonstrated that vessel size, MLD before PTCA,
absolute gain, and LAD location make a significant contribution to late
angiographic outcome.22 Adding thrombus to this model
significantly improved its predictive value. Least-squares means
for absolute loss were 0.404 for lesions with thrombus and 0.318 for
lesions without thrombus. The probability value of adding the
variable thrombus to the model was .037. Adding thrombus to the
model when lesions that went on to occlude at follow-up angiography
were excluded did not improve its predictive value. Least-squares
means for absolute loss were 0.222 for lesions with thrombus and 0.243
for lesions without thrombus. The probability value of adding the
variable thrombus to the model was .549.
To ascertain whether the trend toward a worse clinical outcome in patients with thrombus was related to differences in the underlying baseline characteristics, we corrected for these variables to see whether thrombus had an independent predictive value. We performed logistic regression with the above-mentioned baseline characteristics as covariates resulting in a value for the variable thrombus of P=.038, implying that thrombus has a positive relation with the probability of a clinical end point. Performing the analysis when lesions that went on to occlude at follow-up angiography were excluded gave a value of P=.183, suggesting that the positive relation with the probability of a clinical end point was related to occlusion at follow-up angiography.
Univariate and Multivariate
Analyses of Occlusions at Follow-up
Angiography
The finding that the higher restenosis in lesions
containing angiographically identifiable thrombus was predominantly due
to an increased number of occlusions at follow-up angiography
prompted us to examine the time to clinical and angiographic
follow-up and a number of variables predictive of late
occlusion in this group (Table 4). The time to clinical
and angiographic follow-up was significantly shorter in lesions
that occluded at the time of angiographic follow-up. These lesions
had a higher incidence of total occlusion, a tighter stenosis
before PTCA, a longer duration of inflation with the use of a smaller
balloon in a smaller vessel with a tighter residual MLD, and a greater
likelihood of a dissection after PTCA. Logistic regression
analysis confirmed the presence of a total occlusion before
PTCA and total inflation time (seconds) to be positively related and
the reference diameter after PTCA (millimeters) to be negatively
related to occlusion at follow-up angiography (Table 5).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Our study has specifically addressed the role of angiographically identifiable thrombus in long-term restenosis in a large patient population with a control group, a high angiographic follow-up rate, and QCA at a predetermined time interval. We have demonstrated, using both a categorical and a continuous approach, that restenosis is significantly increased by the presence of angiographically identifiable thrombus during coronary angioplasty. Furthermore, we have also shown that the mechanism for this is an increased rate of occlusion at follow-up angiography and that this is positively related to the presence of a total occlusion before PTCA and the total duration of balloon inflation and negatively related to the residual stenosis after intervention. If lesions that subsequently occlude at follow-up angiography are excluded from the analysis, then restenosis is similar in both groups. These findings support and expand our current understanding regarding the role of thrombus in long-term luminal renarrowing and occlusion after successful PTCA.
Our findings support a role for thrombus in restenosis after successful PTCA in terms of both clinical and angiographic outcomes. They suggest that the contribution thrombus makes to restenosis relates to vessel occlusion by the time of follow-up angiography. The timing of this occlusion is unclear. If it occurred early, it is likely to have been the end result of an acute thrombotic process, whereas if it occurred late, it would be the final end result of the process of restenosis itself. We do not know when the occlusion at follow-up angiography occurred in our patients, so our results must be speculative. We suspect, however, that it occurred early. In support of this is the higher incidence of previous myocardial infarction in the thrombus group (successful dilatation of the infarct-related vessel is associated with a higher rate of early silent occlusion23 ) and the Wilcoxon test indicating early divergence in the survival curves when occlusions at follow-up angiography are included. Additional evidence comes from the much earlier occurrence of clinical and angiographic end points in the thrombus-laden lesions that had occluded by the time of follow-up angiography and the fact that the excess in clinical end points is driven by a much higher incidence of acute myocardial infarction. Our hypothesis that the occlusions occurred early is also supported by evidence in the literature suggesting that 2% to 8% of elective PTCA lesions24 occlude during the first 24 hours, silently in many cases. Thus, although our data support a role for thrombus in vessel occlusion by the time of follow-up angiography and hence restenosis, they do not provide any strong evidence to support a role for angiographically identifiable thrombus in late myointimal hyperplasia. Further prospective studies are thus required to evaluate this important matter further.
Univariate regression analysis was suggestive of a number of procedural and angiographic variables related to occlusion at follow-up angiography. These included the presence of a total occlusion and a tighter stenosis before PTCA, a longer duration of inflation with the use of a smaller balloon diameter in a smaller vessel with a tighter residual MLD, and a greater likelihood of a dissection after PTCA at the dilated site. Thus, the more difficult dilatation of a more complex lesion in a smaller vessel with a less satisfactory result would be more likely to occlude by the time of follow-up angiography. Multivariate regression analysis confirmed the presence of total occlusion before PTCA and a longer total inflation time to be positively related to the risk of subsequent occlusion and the reference diameter after PTCA to be negatively related. The relation between total occlusion and subsequent risk of occlusion may be secondary to the highly thrombogenic surface generated by the successful dilatation of a total occlusion, without a preexisting endothelial lining.25 Successful dilatation of a total occlusion may also expose flowing blood to activated thrombin bound to fibrin in the internal layers of a previously formed thrombus. The prothrombotic processes stimulated by the activated thrombin would be even more severe than those associated with the deeply injured artery and would further accelerate thrombosis after PTCA in these lesions,26 27 thus contributing to both enhanced local thrombus formation after successful dilatation of these lesions and an increased likelihood of thrombotic occlusion. The total inflation time may represent the more complex dilatation of a total occlusion, multiple irregularities, or a more complicated angioplasty. This is further supported by the higher incidence of dissections requiring prolonged inflation in lesions that occlude by the time of follow-up angiography. The negative relation between increasing vessel size and subsequent occlusion is probably representative of the local flow dynamics.28
Our study has a number of limitations. First, it was a retrospective analysis of prospectively gathered data and is hence subject to the limitations inherent in any retrospective analysis. For example, there are significant differences in the baseline clinical, angiographic, and procedural characteristics between the two groups that could have been responsible for, or associated with, the outcome of the procedure, including the presence of thrombus. Patients with angiographic evidence of thrombus before or after angioplasty had a significantly greater history of previous myocardial infarction and a significantly lower proportion of previous coronary angioplasty, both of which may have had an impact on the clinical and angiographic outcomes. There is evidence for a silent early occlusion after successful acute dilatation of infarct-related vessels5 23 and evidence that after stent implantation in coronary vessels supplying an infarcted segment, the low flow makes the vessel more prone to thrombotic occlusion.29 Similar mechanisms may be operating in our study, but we do not know whether the vessel dilated was the infarct-related vessel, and we do not know the length of time since myocardial infarction, except that it was longer than 1 week. Similar arguments also apply to the history of previous PTCA. Again, we do not know whether the present procedure was performed at the same site, and it is not possible to draw conclusions about what effect it may have had on subsequent clinical and angiographic outcomes.
There were also significant differences in lesion location and lesion characteristics. There was a higher proportion of lesions containing thrombus in the RCA and less in the LAD. This may have had an impact on angiographic outcome in two ways. First, the RCA is significantly larger than the LAD, and this may explain why the reference diameter in lesions containing thrombus was significantly larger. Second, there are significant differences between the two vessels in terms of local flow dynamics, vessel geometry, and external compressive forces30 that may have a substantial influence on the subsequent risk of occlusion.31 Although lesion location was not a major risk factor in our multivariate analysis of occlusions at follow-up angiography, it is nonetheless interesting to note that the trend was for lesions that occluded to be in the RCA (P=.085). Thus, similar mechanisms may be operating in our study.
The type of lesion was also significantly different, with a greater proportion of total occlusions in the thrombus group. Successful dilatation of these may have enhanced local thrombus formation and may have contributed to the increased incidence of occlusion at follow-up angiography.23 32 It may also partly explain the smaller MLD before PTCA and greater absolute and relative gains in this group of lesions. Differences in lesion location and characteristics could also have been responsible for the significant differences in the PTCA procedure. For example, the prevalence of RCA lesions could explain the larger nominal size of the largest balloon, whereas the greater number of inflations and total duration of inflation may reflect the more complex dilatation of a total occlusion, multiple irregularities, or a more complicated angioplasty.
Although we tried to compensate for these differences in baseline characteristics by using multivariate analysis and demonstrated that thrombus has a predictive value on restenosis and clinical outcome independent of the underlying clinical and angiographic characteristics, nonetheless, we cannot exclude the possibility of covert factors not available in the study influencing outcome. For example, we do not know what proportion of the angiographically identifiable thrombus group had a successfully treated occlusive dissection, a recognized risk factor for restenosis,33 and total occlusion as a late outcome.34
Second, although the angiographic definition of thrombus we used is the standard definition found in the literature,17 18 the individual sensitivity and specificity of the three criteria have, to the best of our knowledge, never been addressed. In addition, contrast angiography, although the gold standard for randomized studies, has a poor sensitivity for intracoronary thrombus.18 When we used the above angiographic definition and coronary angioscopy as the gold standard, we found the specificity of contrast angiography to be good (100%) but the sensitivity to be poor (19.4%). This is in keeping with other evidence in the literature. Coronary angioscopy, for example, suggests a very high incidence of macroscopic mural thrombus, not identifiable by contrast angiography, after balloon angioplasty,35 36 whereas directional atherectomy suggests that thrombus may contribute to arterial narrowing in 8% to 25% of restenosis cases.37 Thus, although our results apply to angiographically identifiable thrombus, they may not apply to patients with mural thrombus not visualized by contrast angiography.
Finally, the study relies on data pooled from four separate restenosis trials.12 13 14 15 We believe that the pooling of data was justified, however, since the number of patients with angiographically identifiable thrombus present in each individual study was limited. Furthermore, the entry criteria for the studies were broadly similar, the data pooled were those common to all studies, and the angiographic criteria were standardized, with one central angiographic core laboratory performing the QCA analysis in all studies. In addition, the resulting large study population provides a unique opportunity to obtain accurate QCA data at a predetermined time interval in a field in which few such data exist to date.
Clinical Implications
Our data support previous work
suggesting that local thrombus
formation may result in acute
occlusion7 38 39 and expand
it to include late subacute occlusion and hence
restenosis. This may have important clinical implications
with regard to recent studies using monoclonal antibodies and synthetic
peptides directed against the platelet glycoprotein
IIb/IIIa receptor.40 41 42 Although
preliminary data suggest
that they reduce the need for coronary
revascularization procedures in high-risk
angioplasty patients,42 most of the reduction occurred in
the first 30 days after intervention, and the effects were not verified
at the angiographic level. Our data would suggest that perhaps some of
their improved clinical outcome may relate to eliminating subacute
occlusion in a subset of the population without necessarily affecting
the restenosis process.
Conclusions
Our results indicate that the presence of
angiographically
identifiable thrombus at the time of the angioplasty procedure is
associated with a higher rate of angiographic restenosis.
The mechanism by which this occurs is through increased vessel
occlusion at follow-up angiography. Measures aimed at improving
outcome in this group of lesions should be focused in this
direction.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Violaris is a recipient of the Wellcome Trust International Research fellowship. We gratefully acknowledge the continually high-quality QCA analyses from the staff of the angiographic core laboratory at Cardialysis, Rotterdam, and the sponsorship of Glaxo Group Research Ltd, Middlesex, UK; F. Hoffmann–La Roche Ltd, Basel, Switzerland; and Janssen Research Foundation, Beerse, Belgium. We would also like to acknowledge the work of the 31 European, 40 American, and 7 Canadian centers that participated in the CARPORT, MERCATOR, MARCATOR, and PARK studies and without whose assistance this study would not have been possible. A full list of all participating centers can be found in References 12 through 15.
Received June 9, 1995; revision received October 4, 1995; accepted October 6, 1995.
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