Restenosis after coronary angioplasty for rapidly progressive coronary stenosis

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1 European Heart Journal (1996) 17, Restenosis after coronary angioplasty for rapidly progressive coronary stenosis C. Bauters, F. Passart, J.-M. Lablanche, E. P. McFadden, M. Hamon and M. E. Bertrand Service de Cardiologie B et Hemodynamique, Hopital Cardiologique, Boulevard du professeur J Leclercq, Lille Cedex, France Objectives We hypothesized that percutaneous traluminal coronary angioplasty performed on coronary stenoses that have demotrated rapid angiographic progression would be associated with a high risk of restenosis. Background High rates of restenosis have been documented after percutaneous traluminal coronary angioplasty of utable lesio and of lesio that recur rapidly after a successful initial angioplasty. This suggests that the 'activity' of the plaque at the time of angioplasty may be an important factor determining the risk of restenosis. Methods In our ititution we recommend angiographic follow-up for all patients with successful percutaneous traluminal coronary angioplasty. In this way we identified 86 coecutive patients who, at the time of angiographic follow-up had not developed restenosis at the dilated site, but required a further percutaneous traluminal coronary angioplasty at a different site (which was successful). Based on quantitative angiographic measurements, 45 of these lesio (rapidly progressive lesio) had significantly increased in severity in the interval between the two angiograms (77 ± 33 months) while 41 (stable lesio) had not. Rapid progression was defined as a >O4 mm decrease in minimal lumen diameter between initial angiography and percutaneous traluminal coronary angioplasty. ll 86 patients had further angiographic follow-up 6 months later. Results Baseline clinical and angiographic variables were similar in both groups except that a higher proportion of patients in the rapid progression group had utable angina (20% vs 5%; P<005). Late loss during follow-up did not differ statistically between groups (031 mm) and minimal lumen diameter at follow-up was also similar (stable lesion group = 1-40 ± 0-48 mm; rapidly progressive lesion group=l-30 ± 0-59 mm). The loss index (late loss divided by acute gain) was also similar in both groups (0-45 ± 052 in the stable lesion group, 0-37 ± 0-76 in the rapidly progressive lesion group). strong correlation between acute gain and late loss was observed in the stable lesion group (r=0-61; P<00001); by contrast, there was no relatiohip between these two variables in the rapidly progressive lesion group (r=0-20; P-0\9). Conclusio Percutaneous traluminal coronary angioplasty in patients with utable angina or with early recurrence after a first percutaneous traluminal coronary angioplasty is associated with an increased risk of restenosis. By contrast, this study shows that angiographic itability, as evidenced by rapid stenosis progression, has no deleterious effect on the occurrence of restenosis. Percutaneous traluminal coronary angioplasty thus appears as a reasonable therapeutic option for coronary stenoses that have demotrated rapid angiographic progression in the months prior to the procedure. (Eur Heart J 1996; 17: ) Key Words: ngioplasty, coronary, circulation, restenosis. Downloaded from at Penylvania State University on March 5, 2014 Introduction High rates of restenosis have been documented after percutaneous traluminal coronary angioplasty of utable lesio' 1-2]. We have recently shown that when a Revision submitted 13 December 1995, and accepted 7 February Correspondence: M. E Bertrand, MD, Service de Cardiologie B, Hopital Cardiologique, Boulevard du Professeur J Leclercq, Lille Cedex, France. O X/96/ $25.00/0 stable and an utable lesion were dilated during the same procedure, the restenosis rate was twice as great at the utable site 131. Other than utable lesio, another lesion subgroup, in whom lesion recurrence is rapid after a successful initial angioplasty, is associated with a high recurrence rate 14 "* 1. While utable lesio are associated with plaque rupture and thrombus formation' 7 " 91, rapidly recurring stenoses after angioplasty are likely to be related to smooth muscle cell proliferation and migration, and to excessive synthesis of extracellular matrix' 101. Taken together, these studies suggest that the 1996 The European Society of Cardiology

2 1672 C. Bauters et al. 'activity' of the plaque at the time of angioplasty may be an important factor determining the risk of restenosis. We hypothesized that percutaneous traluminal coronary angioplasty performed at coronary stenoses that have demotrated rapid angiographic progression would be associated with a high risk of restenosis. We thus analysed the mid-term angiographic outcome when percutaneous traluminal coronary angioplasty is performed at such lesio. We compared, using quantitative coronary angiography, the changes in minimal lumen diameter from angioplasty to follow-up in patients in whom dilatation was carried out in rapidly progressive stenoses and in stenoses that had not progressed. Methods Patients In our ititution, all patients are asked to return for systematic repeat angiography 6 months after successful angioplasty. Between January 1986 and December 1992, 3871 patients underwent a successful percutaneous traluminal coronary angioplasty in our ititution. Systematic angiographic follow-up was performed in 73%. From this population, we identified 89 coecutive patients who at their control angiogram did not have restenosis but underwent successful balloon angioplasty of another lesion that had not previously been treated by angioplasty. ngiographic follow-up was performed in 86 (96%) of these patients 78 ± 3-8 months later. The angiographic outcome after angioplasty of these 86 lesio, divided into two groups those that had demotrated angiographic progression, and those that had not progressed is the subject of this report. Procedure and definitio ngioplasty was performed according to the standard technique in our laboratory, as previously described' 61. The procedure was coidered successful when the residual lumen narrowing in the dilated segment was <50% immediately after angioplasty, and when there was no major complication (myocardial infarction, need for bypass surgery or death). Balloon size was chosen to approximate the diameter of the adjacent normal vessel segment. During the period of this study, the choice of the inflation pressure was at the discretion of the physician performing angioplasty. ll clinical and procedural data were prospectively entered into a computerized data base at the time of angioplasty. Utable angina was defined as episodes of chest pain at rest within the 48 h immediately preceding coronary angioplasty, with diagnostic electrocardiographic changes. ngiographic analysis Lesio were classified as rapidly progressive or stable based on a comparison of quantitative angiographic measurements in the angiogram obtained at the time of angioplasty and in the angiogram performed 7-7 ± 3-3 months earlier (at the time of the previous intervention at a different site). The lesio were coidered to have progressed if the minimal lumen diameter had decreased by 0-4 mm in the interval between the two angiograms. Lesio that showed a decrease of <;0-4 mm were coidered stable. The cut-off value dividing the rapid progression group from the stable group is derived from variability (standard deviation of repeat measurements (0-2 mm) of the same site taken from separate catheterization sessio using our quantitative angiographic system 1 " 1 ). Twice the variability represents a true change in minimal lumen diameter with >95% confidence. change in minimal lumen diameter of ^ 0-4 mm was coidered to be a reliable indicator of stenosis progression. Quantitative computer-assisted angiographic measurements of the dilated lesion were performed on end-diastolic frames with the CESR (Computer ssisted Evaluation of Stenosis nd Restenosis) system. detailed description of this system has been previously reported' 121. We routinely perform angiography in at least two projectio, after intracoronary injection of isosorbide dinitrate (2 mg), just before and immediately after angioplasty. These projectio are recorded in our database and the follow-up angiogram is performed, after the intracoronary injection of isosorbide dinitrate, in the same projectio. The qualitative analyses were performed independently by two experienced interventional cardiologists. Disagreements were resolved by a further joint reading. Lesio were classified as concentric (symmetrical narrowing, with an identical or almost identical appearance in orthogonal projectio) or eccentric (asymmetrical narrowing, with the stenotic lumen appearing to lie within the outer half of the 'normal' lumen of the vessel in at least one projection). The presence of calcification or of thrombus (a discrete intraluminal filling defect) was also noted. Statistical analysis Data are presented as mean value ± SD. Compariso between groups, for continuous data, were made with use of unpaired Student t-tests. Differences between proportio were assessed by chi-square analysis. Procedural and clinical predictors of late loss were determined using stepwise multiple regression. value of f<005 was coidered to indicate statistical significance. Results t the 86 lesio studied, the mean change in minimal lumen diameter in the 7-7 ± 3-3 months preceding percutaneous traluminal coronary angioplasty was 0-49 ± 0-44 mm; the distribution of the progression in the 86 patients is shown in Fig. 1. On the basis of the Downloaded from at Penylvania State University on March 5, 2014 Eur Heart J, Vol 17, November 1996

3 Restenosis after coronary angioplasty 1673 Table 2 ngiographic characteristics Stable lesion group (n=41) Rapidly progressive lesion group (n=45) P value Progression prior to PTC (mm) Figure 1 Distribution of the progression prior to percutaneous traluminal coronary angioplasty in the study population. Table I Baseline characteristics ge (years) Men Smokers Hyperteion Cholesterol >240 mg. dl Diabetes mellitus 1-vessel disease 2-vessel disease 3-vessel disease Utable angina Treatment since previous spirin Beta-blockers Calcium antagonists Nitrates Lipid-lowenng drugs CE inhibitors Stable lesion group (n=41) 57 ±11 36 (88%) 33 (81%) 19(46%) "' 27 (66%) 5 (12%) 17 (42%) 17 (42%) 7 (16%) 2 (5%) angiogram* 39 (95%) 26 (63%) 25 (61%) 24 (59%) 11 (27%) 4 (10%) Rapidly progressive lesion group (n=45) 58 ± (87%) 32 (71%) 20 (44%) 28 (62%) 9 (20%) 28 (62%) 15 (33%) 2 (5%) 9 (20%) 41 (91%) 29 (64%) 25 (56%) 24 (53%) II (24%) 7 (16%) P value <0-05 CE=angiotein-converting enzyme. *Treatment from previous angiogram to hospital admission for percutaneous traluminal coronary angioplasty. strict quantitative angiographic criteria used to define progression, 45 patients were classified as having lesio that had demotrated significant angiographic progression (rapidly progressive lesio) whereas 41 patients had lesio that had not significantly progressed (stable lesio). The interval between the first angiogram and percutaneous traluminal coronary angioplasty was similar in both groups (stable lesio=7-3 ± 2-3 months; rapidly progressive lesio = 81 ±40 months). Sixty three lesio were located in a different vessel from the original angioplasty; 23 were located in the same vessel, 12 proximal to the previously dilated lesion and 11 distal. The baseline characteristics before percutaneous traluminal coronary angioplasty are summarized in Left anterior descending artery Right coronary artery Left circumflex artery CC/H classification* Bl B2 C Total occlusion Eccentric stenosis Thrombus Calcification Length <10mm mm >20mm Bend location <60 60*-90* >90 Modified by Ellis el al [30] 16(39%) 16(36%) 14 (34%) 11 (27%) 7 (17%) 11 (28%) 15 (36%) 8 (19%) 16(39%) 6 (14%) 3 (7%) 31 (76%) 7(17%) 3 (7%) 30 (73%) 9 (22%) 2 (5%) 17(38%) 12 (26%) 8 (18%) 15 (33%) 15 (33%) 7 (16%) 2 (4%) 21 (47%) 8 (18%) 2 (4%) 32 (71%) 9 (20%) 4 (9%) 37 (82%) 8 (18%) Table 1. There were no statistically significant differences between the two groups in age, sex, risk factors for atherosclerosis, extent of coronary artery disease, or treatment since the previous angiogram. The incidence of utable angina in the rapidly progressive lesion group (20%) was significantly (P<005) higher than that observed in the stable lesion group (5%). The angiographic characteristics of the 86 dilated lesio are shown in Table 2. Both the location and the morphology of the stenoses were similar in the two groups. Table 3 shows procedural and quantitative angiographic data. The reference diameter did not differ significantly among the groups at any of the four time points studied (the angiogram >6 months before percutaneous traluminal coronary angioplasty, the angiogram just before percutaneous traluminal coronary angioplasty, the angiogram just after percutaneous traluminal coronary angioplasty, and the follow-up angiogram). On the first angiogram, the minimal lumen diameter was significantly greater in the rapidly progressive lesion group (1-59 ±0-48 mm vs 1-18 ±0-36 mm; P<00001). By definition, stenosis progression (between the first angiogram >6 months before percutaneous traluminal coronary angioplasty and the angiogram just before percutaneous traluminal coronary angioplasty) was significantly more marked in the rapidly progressive lesion group (0-81 ± 033 mm) than in the stable lesion group (013±0-23 mm; /><00001). s a coequence, stenosis severity before percutaneous traluminal coronary angioplasty was significantly greater in the rapidly progressive lesion group (minimal lumen diameter=079±0-33 mm) than in the stable Downloaded from at Penylvania State University on March 5, 2014 Eur Heart J, Vol. 17, November 1996

4 1674 C. Bauters et al. Table 3 Quantitative angiographic and procedural variables Stable lesion group (n=41) Rapidly progressive lesion group (n=45) P value Reference diameter (mm) First angiogram Before PTC Immediately after PTC Follow-up Minimal lumen diameter (mm) First angiogram Before PTC Immediately after PTC Follow-up Percent stenosis First angiogram Before PTC Immediately after PTC Follow-up Stenosis progression from first ngiogram to before PTC (mm) cute gain (mm) Late loss (mm) Loss index Procedural variables Largest balloon size (mm) Inflation pressure (atm) Total inflation time (seconds) 2-53 ± ± ± ± ± ± ± ± ± ±7 31 ± ± ± ± ± ± ± ± ± 111 PTC = percutaneous traluminal coronary angioplasty. lesion group (minimal lumen diameter= 1-04 ± 028 mm; / > <00005). The acute gain during percutaneous traluminal coronary angioplasty (082 ± 0-34) was, however, significantly (P=005) greater in the rapidly progressive lesion group than in the stable lesion group (0-67 ± 0-29) resulting in a similar minimal lumen diameter in both groups immediately after the procedure. Maximal inflation pressure was significantly (P<005) lower in the rapidly progressive lesion group; other procedural variables were similar in the two groups. Late luminal loss during follow-up did not differ statistically between groups (0-31 mm) and the minimal lumen diameter at follow-up was also similar (stable lesion group = 1-40 ± 0-48 mm; rapidly progressive lesion group= 1-30 ± 059 mm). The loss index (late loss divided by acute gain) was also similar in both groups (0-45 ± 0-52 in the stable lesion group, 037 ± 076 in the rapidly progressive lesion group; / > =). Figure 2 demotrates that there was no relatiohip between the rate of progression of the stenosis prior to percutaneous traluminal coronary angioplasty expressed as a continuous variable and the late loss after percutaneous traluminal coronary angioplasty in the 86 patients. Clinical, angiographic (before and after percutaneous traluminal coronary angioplasty), and procedural variables listed in Tables 1-3 were included in a multivariate model to determine independent predictors of late loss. cute gain was the only determinant of late loss in the rapidly progressive lesion group, while no determinants were detected in the stable lesion group ± ± ± ± ± ±0-33 I -61 ± ± ± ± ± ± ± ± ± ± ± ± ±75 <0 000l <00005 < <00001 < <0-05 <005 Figure 3 illustrates the relatiohip between acute gain and late in the two groups. strong correlation was observed in the stable lesion group (r = 0-61; / > <00001); by contrast, there was no relatiohip between these two variables in the rapidly progressive lesion group (r=0-20; f=019). Finally, we performed a subgroup analysis to determine whether the fact that there was a greater proportion of patients with utable angina in the rapidly progressive lesion group might have influenced (UI UI) CQ en o tel I L , 1, Progression prior to PTC (mm) J Li \ * L Figure 2 Graph showing the absence of relatiohip between progression prior to percutaneous traluminal coronary angioplasty and late loss after percutaneous traluminal coronary angioplasty. 2.5 Downloaded from at Penylvania State University on March 5, 2014 Eur Heart J. Vol. 17. November 1996

5 Restenosis after coronary angioplasty v J y = 0.869x , r = 0.61, p < J, I i I i Rapidly progressive lesio - n = 45 o o o o o o Sb -0.5 r = 0.20, p = NS -1 1, I, I, cute gain (mm) Figure 3 Graphs showing the correlation of acute gain with late loss in patients with stable lesio (top) and in patients with rapidly progressive lesio (bottom). the results. The progression from the first angiogram to percutaneous traluminal coronary angioplasty was similar in patients with (n = 9; 0-80 ± 0-22 mm) and without (n = 36; 081 ± 0-36 mm) utable angina. The acute result after percutaneous traluminal coronary angioplasty was also similar (minimal lumen diameter post percutaneous traluminal coronary angioplasty = 1 62 ± 0-36 mm in those with utable angina compared to 1-60 ±0-37 mm in those with stable angina). There was a trend towards a higher late loss in patients with utable angina (0-50 ±037 mm vs 0-26 ±052 mm) that was not statistically significant. Discussion Rapidly progressive stenoses lthough the progression/regression of coronary stenoses over relatively long periods of time (2 to 3 years) has been well described' 13 ' 151, the occurrence of rapid progression is more difficult to investigate. In our ititution, we perform systematic angiographic follow-up after successful percutaneous traluminal coronary angioplasty. Our database identified patients with lesio that had demotrated significant angiographic progression over a short period. Pathological and angiographic studies show that an increase in lesion severity may be associated with utable angina and myocardial infarction but probably often occurs without clinical coequences' 161. Progression of coronary stenoses is a complex process involving lipid accumulation, cell proliferation, extracellular matrix synthesis, and plaque rupture with subsequent thrombus formation and incorporation 116 ' 171. In the present study, 80% of the patients who had rapid progression did not have utable symptoms at the time of angioplasty; this finding is in agreement with previous studies that have suggested that most fissures probably reseal with incorporation of thrombus without producing clinical symptoms 17 '' 61. We found no differences in the incidence of angiographically visible thrombus between rapidly progressive stenoses and stable stenoses. This is probably related to the low seitivity of angiography for the detection of intracoronary thrombus' 18 ' 191 ; alternate endovascular imaging techniques such as coronary angioscopy' 18 " 201 or intravascular ultrasound' 211 would provide more precise morphological information on rapidly progressive stenoses. Similarly, directional atherectomy would allow histological examination and thus a better understanding of the mechanisms leading to rapid progression. In the present study, a significantly lower maximum inflation pressure was used for dilatation of rapidly progressive stenoses; this may indicate that rapidly progressive lesio are more compliant than stable lesio. Six-month angiographic follow-up The specific aim of this study was to analyse restenosis after percutaneous traluminal coronary angioplasty of rapidly progressive stenoses. Our results clearly show that rapid disease progression prior to percutaneous traluminal coronary angioplasty is not a risk factor for restenosis. The late loss and loss index (normalized for the acute gain which was higher in the rapidly progressive lesion group) were similar in both groups. Previous studies suggest that the 'activity' of the plaque at the time of angioplasty may be an important factor determining the risk of restenosis. High rates of restenosis have been reported in utable angina and after angioplasty of infarct-related lesio' 1 " 3 ' 221. Lesio that recur rapidly after angioplasty are also associated with a high rate of recurrence when again treated by percutaneous traluminal coronary angioplasty 14^1. The exact mechanisms explaining this higher propeity to restenosis of such 'active' lesio are unknown but may be related to the composition of the lesion prior to percutaneous traluminal coronary angioplasty. The presence of already activated smooth muscle cells in the lesion has been demotrated to be a strong predictor of restenosis after directional atherectomy 1231 ; platelet Downloaded from at Penylvania State University on March 5, 2014 Eur Heart J, Vol. 17, November 1996

6 1676 C. Bauters et al. aggregation' 24 ' or thrombus formation 1251 before angioplasty, such as occur at utable lesio, and which may also increase the respoe of smooth muscle cells to injury; finally, the presence of a thrombus prior to percutaneous traluminal coronary angioplasty of utable plaques may also increase restenosis by predisposing the vessel to thrombotic occlusion' 22 ', an event that is relatively rare after percutaneous traluminal coronary angioplasty at stable lesio' 26 '. plausible explanation for the perhaps surprising observation that rapidly progressive and stable lesio have a similar propeity to restenosis is that the time interval since the rapid growth of the plaque has been long enough to allow the lesion to stabilize and to be less susceptible to restenosis. lthough we observed an impressive mean progression of rapidly progressive stenoses (0-81 ±033 mm) over a relatively short period of time (7-7 ± 3-3 months), the absence of severe symptoms in 80% of these patients makes it impossible to determine when such progression occurred; a significant proportion of these lesio may have undergone rapid progression weeks or months before angioplasty. The time interval after which an utable lesion would become less susceptible to angiographic restenosis has never been specifically investigated but, in one study' 271, the recurrence of angina in the months following the procedure was shown to be lower for patients with utable angina who were medically treated and stabilized for 2 weeks before undergoing percutaneous traluminal coronary angioplasty. The subgroup analysis performed in the rapid progression group and showing a late loss twice as high in patients with utable angina is also in agreement with this hypothesis. lthough the recurrence rate is the same in both groups, the mechanism(s) of restenosis are not necessarily similar. Numerous studies on restenosis have demotrated that the most powerful determinant of late loss during follow-up is the acute gain during the procedure' 28 '. The very significant relatiohip between acute gain and late loss in our control group with stable atherosclerosis is in agreement with these previous reports. The usual explanation for this finding is that a high acute gain is associated with a high degree of wall injury and coequently with an exacerbated restenotic process. Despite a similar number of patients, we were not able to demotrate any relatiohip between acute gain and late loss at angiographically rapidly progressive lesio; it is again conceivable that the explanation may be related to the composition of the lesio in the rapid progression group. When percutaneous traluminal coronary angioplasty is performed for stable lesio, a high acute gain is probably obtained at the expee of a high degree of stretch and injury to the fibrotic plaque and to the vessel wall; by contrast, when percutaneous traluminal coronary angioplasty is performed for rapidly progressive lesio, it is plausible that a high acute gain can be obtained with less injury by remodelling the soft components of the plaque. Whatever the explanatio for this finding may be, the absence of a relatiohip between acute gain and late loss after percutaneous traluminal coronary angioplasty of rapidly progressive stenoses suggests that the restenotic process observed in this group of patients might be qualitatively different from that observed in patients with stable lesio. Study limitatio This was a retrospective study. However, the patients were a coecutive group who underwent percutaneous traluminal coronary angioplasty in an ititution where the probability that a patient undergoes follow-up angiography is less dependent on symptomatic status after angioplasty. The high rate of angiographic follow-up (96%) coupled with the use of quantitative angiography, allowed an objective assessment of the angiographic probability of restenosis. The strict study criteria has resulted in the inclusion of too few patients to conclusively state that there are no differences in the restenosis rate between rapidly progressive lesio and stable lesio. The data presented here, however, suggest that, if such a difference exists, it would be unlikely to be of clinical significance. Finally, this is an angiographic study; in the future, coronary angioscopy and intravascular ultrasound should give us an opportunity to study more precisely the impact of plaque morphology on restenosis. However, it is very likely that, in clinical practice, coronary angiography will remain the technique of choice for determining the indicatio for, and assessing the mid-term results of, percutaneous traluminal coronary angioplasty. Clinical implicatio It has been shown that patients whose coronary disease has recently progressed are at higher risk for future coronary events than are patients whose lesio have not changed' 29 '. Whether revascularization will improve the outcome of recent progressors is not known specifically, but the acceptable rate of restenosis observed in the present study shows that percutaneous traluminal coronary angioplasty is a reasonable therapeutic option for these patients. References [1] Leimgruber PP, Roubin GS, Hollman J et al. Restenosis after successful coronary angioplasty in patients with single-vessel disease. Circulation 1986; 73: [2] Plokker HWT, Ert SMPG, Bal ET et al. 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