Role of Angiographically Identifiable Thrombus on Long-term Luminal Renarrowing After Coronary Angioplasty
A Quantitative Angiographic Analysis
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.
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.
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.
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.
Data were analyzed with the SAS statistical software package. A χ2 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.
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⇓).
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.
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).
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⇓).
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⇓).
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.
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.
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.
Selected Abbreviations and Acronyms
|LAD||=||left anterior descending coronary artery|
|MLD||=||minimum luminal diameter|
|PTCA||=||percutaneous transluminal coronary angioplasty|
|QCA||=||quantitative coronary angiography|
|RCA||=||right coronary artery|
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.
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.
- Received June 9, 1995.
- Revision received October 4, 1995.
- Accepted October 6, 1995.
- Copyright © 1996 by American Heart Association
Myler RK, Shaw RE, Stertzer SH, Bashour TT, Ryan C, Hecht HS, Cumberland DC. Unstable angina and coronary angioplasty. Circulation. 1990;82(suppl II):II-88-II-95.
Ellis SG, Roubin GS, King SB, Douglas JS Jr, Weintraub WS, Thomas RG, Cox WR. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation. 1988;77:372-379.
Ip JH, Fuster V, Israel D, Badimon L, Badimon J, Chesebro JH. The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty. J Am Coll Cardiol. 1991;17:77B-88B.
Willerson JT, Yao S-K, McNatt J, Benedict CR, Anderson HV, Golino P, Murphree SS, Buja LM. Frequency and severity of cyclic flow alterations and platelet aggregation predict the severity of neointimal proliferation following experimental coronary stenosis and endothelial injury. Proc Natl Acad Sci U S A. 1991;88:10624-10628.
Serruys PW, Rutsch W, Heyndrickx GR, Danchin N, Mast EG, Wijns W, Rensing BJ, Vos J, Stibbe J. Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade: a randomized, double-blind, placebo-controlled trial: Coronary Artery Restenosis Prevention on Repeated Thromboxane-Antagonism Study (CARPORT). Circulation. 1991;84:1568-1580.
MERCATOR Study Group. Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind, placebo-controlled trial. Circulation. 1992;86:100-110.
Serruys PW, Klein W, Tijssen JP, Rutsch W, Heyndrickx GR, Emanuelsson H, Ball SG, Decoster O, Schroeder E, Liberman H, Eichhorn E, Willerson JT, Anderson HV, Khaja F, Alexander RW, Baim D, Melkert R, van Oene JC, van Gool R. Evaluation of ketanserin in the prevention of restenosis after percutaneous transluminal coronary angioplasty: a multicenter randomized double-blind placebo-controlled trial: the Post-Angioplasty Restenosis Ketanserin (PARK) trial. Circulation. 1993;88:1588-1601.
Serruys PW, Foley DP, deFeyter PJ, eds. Quantitative Coronary Angiography in Clinical Practise. Dordrecht, Netherlands: Kluwer Academic Press; 1994.
Kuntz RE, Baim DS. Defining coronary restenosis: newer clinical and angiographic paradigms. Circulation. 1993;88:1310-1323.
Serruys PW, Foley DP, de Feyter PJ. Restenosis after coronary angioplasty: a proposal of new comparative approaches based on quantitative angiography. Br Heart J. 1992;68:417-424.
Foley DP, Melkert R, Serruys PW, on behalf of the CARPORT, MERCATOR, MARCATOR and PARK Investigators. Influence of coronary vessel size on renarrowing process and late angiographic outcome after successful balloon angioplasty. Circulation. 1994;90:1239-1251.
Nakagawa Y, Kimura T, Nosaka H, Nobuyoshi M. Predictor of acute reocclusion after angioplasty for acute myocardial infarction. Eur Heart J. 1994;15(suppl):308. Abstract.
Zimarino M, Corcos T, Favereau X, Guerin Y, Tamburino C, Toussaint M, Funck F, Eiferman C. Silent early reocclusion after successful coronary angioplasty of chronic total occlusions. Eur Heart J. 1994;15(suppl):281. Abstract.
Badimon L, Lassila R, Badimon J, Vallabhajosua S, Chesebro JH, Fuster V. Residual thrombus is more thrombogenic than severely damaged vessel wall. Circulation. 1988;78(suppl II):II-119. Abstract.
Mruk JS, Chesebro JH, Webster MWI. Platelet aggregation and interaction with the coagulation system: implications for antithrombotic therapy in arterial thrombosis. Coron Artery Dis. 1990;1:149-158.
Goldsmith HL, Turritto VT. Rheologic aspects of thrombosis and haemostasis: basic principles and applications. Thromb Haemost. 1986;56:415-435.
Carvalho H, Fajadet J, Caillard JB, Jordan C, Laurent JP, Cassagneau B, Robert G, Marco J. Predictors of thrombotic occlusion following Gianturco-Roubin stent implantation. Eur Heart J. 1994;15(suppl):536. Abstract.
Serruys PW, Di Mario C, Kern MJ. Intracoronary Doppler. In: Topol EJ, ed. Textbook of Interventional Cardiology. 2nd ed. Philadelphia, Pa: WB Saunders; 1994:1069-1121.
Bates ER, Califf RM, Stack RS, Aronson L, George BS, Candela RJ, Kereiakes DJ, Abbottsmith CW, Anderson L, Pitt B, O’Neill WW, Topol EJ, and the Thrombolysis and Angioplasty in Myocardial Infarction Study Group. Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-1) trial: influence of infarct location on arterial patency, left ventricular function and mortality. J Am Coll Cardiol. 1989;13:12-18.
Violaris AG, Melkert R, Serruys PW. Long-term luminal renarrowing following successful elective coronary angioplasty of total occlusions: a quantitative angiographic analysis. Circulation. 1995;91:2140-2150.
Tenaglia AN, Fortin DF, Frid DJ, Gardner LH, Nelson CL, Tcheng JE, Califf RM. Restenosis and long term outcome following successful treatment of abrupt closure after angioplasty. Circulation. 1991;84(suppl II):II-131. Abstract.
Baalbaki HA, Weintraub WS, Tao X, Ghazzal ZMB, Liberman HA, Douglas JS, King SB III. Restenosis after acute closure and successful reopening: implications for new devices. Circulation. 1990;82(suppl III):III-314. Abstract.
den Heijer P, van Dijk RB, Hillege HL, Pentinga ML, Serruys PW, Lie KI. Serial angioscopic and angiographic observations during the first hour after successful coronary angioplasty: a preamble to a multicenter trial addressing angioscopic markers for restenosis. Am Heart J. 1994;128:656-663.
Detre KM, Holmes DR Jr, Holubkov R, Cowley MJ, Bourassa MG, Faxon DP, Dorros GR, Bentivoglio LG, Kent KM, Myler RK. Incidence and consequences of periprocedural occlusion: the 1985-1986 National Heart, Lung, and Blood Institute Percutaneous Transluminal Coronary Angioplasty Registry. Circulation. 1990;82:739-750.
Ellis SG, Bates ER, Schaible T, Weisman HF, Pitt B, Topol EJ. Prospects for the use of antagonists to the platelet glycoprotein IIb/IIIa receptor to prevent post-angioplasty restenosis and thrombosis. J Am Coll Cardiol. 1991;17:89B-95B.
Ellis SG, Tcheng JE, Navetta FI, Muller DWM, Weisman HF, Smith C, Anderson KM, Califf RM, Topol EJ. Safety and antiplatelet effect of murine monoclonal antibody 7E3 Fab directed against platelet glycoprotein IIb/IIIa in patients undergoing elective coronary angioplasty. Coron Artery Dis. 1993;4:167-175.
Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT, on behalf of the EPIC Investigators. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at 6 months. Lancet. 1994;343:881-886.