Morphologic changes during follow-up after successful percutaneous transluminal coronary balloon angioplasty: quantitative angiographic analysis in 778 lesions--further evidence for the restenosis paradox. MERCATOR Study Group (Multicenter European Research trial with Cilazapril after Angioplasty to prevent Transluminal Coronary Obstruction and Restenosis).

The purpose of this study was to determine if there are any morphologic characteristics of lesions that renarrow (that is, restenotic lesions) following successful coronary balloon angioplasty that are different from their appearance pretreatment or from the appearance of nonrestenotic lesions that might provide some new insight into the restenosis phenomenon. The study population consisted of 653 patients (778 lesions) with 6 months of angiographic follow-up (94% angiographic follow-up rate) who were participating in the Multicenter European Research trial with Cilazapril after Angioplasty to prevent Transluminal coronary Obstruction and Restenosis (MERCATOR) study. Detailed quantitative angiographic measurements, including the mean diameter of the vessel segment (in millimeters) that was subjected to balloon dilation, were performed preangioplasty, postangioplasty, and at follow-up using the cardiovascular angiographic analysis system to provide some objective measurement of the actual extent of luminal changes in the months following coronary balloon angioplasty. Two different approaches for restenosis were used: (1) static criterion of > 50% diameter stenosis at follow-up and (2) dynamic criteria of > or = 0.40 or > or = 0.72 mm change in minimal lumen diameter between postangioplasty and follow-up. Both approaches identified more severe stenosis to be a typical feature for restenotic lesions before angioplasty compared with nonrestenotic lesions. No differences were observed in lesion length, balloon-inflated vessel segment, or roughness index before angioplasty between the groups. Conflicting data were found for the amount of atherosclerotic plaque, symmetry index, and curvature index. The restenotic lesion at follow-up compared with its initial appearance gave conflicting results depending on which approach was used. The dynamic criteria illustrate that the reference diameter and the mean diameter of the entire segment dilated are reduced during follow-up. Two messages emerge from the study: (1) the restenosis process clearly involves the apparent normal vessel wall adjacent to the actual lesion, probably in response to the unavoidable injury caused by balloon dilatation and (2) the use of percentage diameter stenosis measurements depending on the assumptions of normality for a reference segment will therefore underestimate the true extent of the restenosis process and should be replaced in clinical angiographic studies by absolute luminal measurements.

Quantitative angiography during coronary angioplasty with a single angiographic view: a comparison of automated edge detection and videodensitometric techniques.

Little information is available on the reliability of coronary luminal measurements obtained from quantitative analysis of a single angiographic view, an approach that is central to the practical use of on-line quantitative angiography. In the present study we investigated the contribution of two different techniques of quantitative angiography, edge detection (ED) and videodensitometry (VD), to the application of this concept during coronary angioplasty. Forty-six balloon angioplasty procedures were included in this study, all of them performed in a stenosis located in the mid right coronary segment. This coronary location was chosen to optimize data collection on luminal morphology and to minimize the number of factors that may adversely affect quantitative analysis with both techniques. In all cases two orthogonal angiographic projections were obtained before, after balloon dilatation, and at follow-up. Correlation coefficients and differences between orthogonal measurements obtained with each technique were used to evaluate the agreement between orthogonal readings at every stage of the procedure. The obtained correlation coefficients and mean differences (MD) between orthogonal measurements were as follows: before percutaneous transluminal coronary angiography (PTCA), 0.67 (MD 0.01 +/- 0.47 mm2) and 0.57 (MD 0.05 +/- 0.64 mm2) for ED and VD, respectively (Pitman's test for SD, p < 0.05); after balloon dilatation, 0.32 (MD -0.56 +/- 1.53 mm2) and 0.53 (MD -0.15 +/- 1.43 mm2) for ED and VD, respectively (paired t test for MD, p < 0.05); and at follow-up 0.79 (MD -0.15 +/- 0.97 mm2) and 0.73 (MD 0.17 +/- 1.16 mm2) for ED and VD, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Luminal narrowing after percutaneous transluminal coronary angioplasty. A study of clinical, procedural, and lesional factors related to long-term angiographic outcome. Coronary Artery Restenosis Prevention on Repeated Thromboxane Antagonism (CARPORT) Study Group.

BACKGROUND: The renarrowing process after successful percutaneous transluminal coronary angioplasty (PTCA) is now believed to be caused by a response-to-injury vessel wall reaction. The magnitude of this process can be assessed by the change in minimal lumen diameter (MLD) at follow-up angiography. The aim of the present study was to find independent patient-related, lesion-related, and procedure-related risk factors for this luminal narrowing process. A model that accurately predicts the amount of luminal narrowing could be an aid in patient or lesion selection for the procedure, and it could improve assessment of medium-term (6 months) prognosis. Modification or control of the identified risk factors could reduce overall restenosis rates, and it could assist in the selection of patients at risk for a large loss in lumen diameter. This population could then constitute the target population for pharmacological intervention studies. METHODS AND RESULTS: Quantitative angiography was performed on 666 successfully dilated lesions at angioplasty and at 6-month follow-up. Multivariate linear regression analysis was performed to obtain variables with an independent contribution to the prediction of the absolute change in minimal lumen diameter. Diabetes mellitus, duration of angina < 2.3 months, gain in MLD at angioplasty, pre-PTCA MLD, lesion length > or = 6.8 mm, and thrombus after PTCA were independently predictive of change in MLD. Overall prediction of the model was poor, however, percentage-correct classification for a predicted change between -0.1 to -0.4 mm was approximately 10%. Lesions showing no change or regression (change > -0.1 mm) and lesions showing large progression (< or = -0.4 mm) were more predictable (correct classification, 59.5% and 49.7%, respectively). CONCLUSIONS: Renarrowing after successful PTCA as determined with contrast angiography is a process that cannot be accurately predicted by simple clinical, morphological, and lesion characteristics.

Pharmacological approaches to the prevention of restenosis following angioplasty. The search for the Holy Grail? (Part II).

Part I of this article reviewed the results of studies investigating the effectiveness of antithrombotic, antiplatelet, antiproliferative, anti-inflammatory, calcium channel blocker and lipid-lowering drugs in preventing or reducing restenosis after angioplasty. However, despite 15 years of clinical experience and research in the field of restenosis prevention, this has not yet resulted in the revelation of unequivocal beneficial effects of any particular drug. Other newer approaches likely to receive more attention in the future include antibodies to growth factors, gene transfer therapy and antisense oligonucleotides. Whether there is a feasible monotherapy, whether we have to focus on a drug combination, or whether we are only searching for 'the Holy Grail' remain to be answered.

Usefulness of quantitative and qualitative angiographic lesion morphology, and clinical characteristics in predicting major adverse cardiac events during and after native coronary balloon angioplasty. CARPORT and MERCATOR Study Groups.

Major, adverse cardiac events (death, myocardial infarction, bypass surgery and reintervention) occur in 4 to 7% of all patients undergoing coronary balloon angioplasty. Prospectively collected clinical data, and angiographic quantitative and qualitative lesion morphologic assessment and procedural factors were examined to determine whether the occurrence of these events could be predicted. Of 1,442 patients undergoing balloon angioplasty for native primary coronary disease in 2 European multicenter trials, 69 had major, adverse cardiac procedural or in-hospital complications after > or = 1 balloon inflation and were randomly matched with patients who completed an uncomplicated in-hospital course after successful angioplasty. No quantitative angiographic variable was associated with major adverse cardiac events in univariate and multivariate analyses. Univariate analysis showed that major adverse cardiac events were associated with the following preprocedural variables: (1) unstable angina (odds ratio [OR] 3.11; p < 0.0001), (2) type C lesion (OR 2.53; p < 0.004), (3) lesion location at a bend > 45 degrees (OR 2.34; p < 0.004), and (4) stenosis located in the middle segment of the artery dilated (OR 1.88; p < 0.03); and with the following postprocedural variable: angiographically visible dissection (OR 5.39; p < 0.0001). Multivariate logistic analysis was performed to identify variables independently correlated with the occurrence of major adverse cardiac events. The preprocedural multivariate model entered unstable angina (OR 3.77; p < 0.0003), lesions located at a bend > 45 degrees (OR 2.87; p < 0.0005), and stenosis located in the middle portion of the artery dilated (OR 1.95; p < 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological approaches to the prevention of restenosis following angioplasty. The search for the Holy Grail? (Part I).

Luminal renarrowing after balloon angioplasty still hampers the long term vessel patency in a substantial percentage of patients. Morphologically, the restenotic lesion comprises hyperplasia of intimal tissue, which is mainly characterised by proliferation of smooth muscle cells of the synthetic type with abundant extracellular matrix production, chiefly composed of proteoglycans. Unravelling the underlying pathophysiological process enables more specific intervention in basic interactions and cell responses. Critical events in the development of restenotic tissue are platelet aggregation and thrombus formation, while the release of several mediators promotes proliferation and migration of various cell types. All of these steps give access for a diversity of pharmacological interventions. With this in mind, antithrombotic, antiplatelet, antiproliferative, antiinflammatory, calcium channel blocking and lipid-lowering drugs have been investigated in the prevention of restenosis. Part II of this article reviews newer approaches, such as antibodies to growth factors, gene transfer and antisense oligonucleotides.

Matching based on quantitative coronary angiography as a surrogate for randomized studies: comparison between stent implantation and balloon angioplasty of native coronary artery lesions.

Although intracoronary stenting has been advocated as an adjunct to balloon angioplasty to circumvent late restenosis, its effectiveness has not yet been verified. Therefore the aim of this study was to determine the differences in the immediate and long-term changes in stenosis geometry between Wallstent implantation and balloon angioplasty in native coronary artery lesions. To obtain two study populations with identical baseline stenosis characteristics, patients were matched for lesion site, vessel size, and minimal luminal diameter. Only patients undergoing elective and successful coronary intervention of a native coronary artery, in whom a control angiographic study had been performed, were included. A total of 186 patients (93 in each group) were selected. The coronary angiograms were analyzed with the computer-assisted cardiovascular angiographic analysis system. Matching was considered adequate, since there was an equal number of lesion sites in each study population and there were no differences in baseline reference diameter and minimal luminal diameter. Wallstent implantation resulted in a significantly greater increase in minimal luminal diameter (from 1.22 +/- 0.34 mm to 2.49 +/- 0.40 mm, p < 0.00001) compared with balloon angioplasty (from 1.21 +/- 0.29 mm to 1.92 +/- 0.35 mm, p < 0.00001). Despite a greater decrease in minimal luminal diameter after Wallstent implantation (0.48 +/- 0.74 mm) than after balloon angioplasty (0.20 +/- 0.46 mm), the minimal luminal diameter at follow-up was significantly greater after stent implantation (2.01 +/- 0.75 mm vs 1.72 +/- 0.54, p < 0.0001). It was concluded that Wallstent implantation results in a superior immediate and long-term increase in minimal luminal diameter compared with balloon angioplasty. The larger initial gain after stent implantation compensates for the late loss, and thus an improved initial result and not lessened neointimal hyperplasia is responsible for a reduced incidence of restenosis. Studies based on matching of angiographic variables are a surrogate for randomized studies, forecasting their results and offering insight into the effects of different interventional techniques. Moreover, these studies yield statistical information that may be helpful for the proper design of a randomized study (sample size, type II error).

Which angiographic variable best describes functional status 6 months after successful single-vessel coronary balloon angioplasty?

OBJECTIVES: The aim of this study was to determine which quantitative angiographic variable best describes functional status 6 months after coronary balloon angioplasty. BACKGROUND: Several angiographic restenosis criteria have been developed. These can be divided into those that describe the change in lesion severity and those that merely describe lesion severity at follow-up angiography. The functional significance of these criteria is unknown. METHODS: We studied 350 patients with single-vessel coronary artery disease who underwent a single-site balloon dilation. Sensitivity and specificity curves were constructed for the prediction of anginal status and exercise electrocardiography of four quantitative angiographic variables that describe restenosis. The point of highest diagnostic accuracy for the variables was determined at the intersection of the sensitivity and specificity curves. Results of exercise electrocardiography were considered indicative for ischemia 6 months after angioplasty if horizontal or downsloping ST segment depression > or = 1 mm occurred. RESULTS: The points of highest diagnostic accuracy of the angiographic variables were similar for both anginal status and exercise electrocardiography: 1.45 and 1.46 mm for the minimal lumen diameter measurements, 45.5% and 46.5% for the percent diameter stenosis measurements at follow-up, -0.30 and -0.32 mm for change in minimal lumen diameter and -10% and -10% for the change in percent diameter stenosis at follow-up. CONCLUSIONS: Angiographic variables reflecting a change in lesion severity at follow-up angiography were only slightly less accurate than variables that describe lesion severity at follow-up. The large study group and the fact that the same optimal values for diagnostic accuracy of the various quantitative angiographic variables were obtained for the prediction of two different markers of ischemia suggests that these values reflect the lesion severity or increase in lesion severity in major epicardial vessels at which coronary flow reserve is unable to meet myocardial demands.

Patient, lesion, and procedural variables as risk factors for luminal re-narrowing after successful coronary angioplasty: a quantitative analysis in 653 patients with 778 lesions. Multicenter European Research Trial with Cilazapril after Angioplasty to prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) Study Group.

Follow-up angiography at 6 months was obtained in 94% of the 693 patients (778 successfully dilated coronary lesions) enrolled in the Multicenter European Research trial with Cilazapril after Angioplasty to prevent Transluminal Coronary Obstruction and Restenosis (MERCATOR) trial--a double-blind, placebo-controlled trial--to study the effects of cilazapril 5 mg b.i.d. on restenosis [defined as the mean loss in minimal luminal diameter during follow-up, assessed by an interpolated edge detection technique (coronary angiography analysis system)] and long-term clinical outcome. No statistically significant difference could be detected between treatment and placebo groups with regard to clinical outcome or restenosis. The purpose of this ancillary study was to determine which, if any, patient, lesion, or procedural factors were predictive of restenosis. The identification of such factors could be helpful in the selection of lesions suitable for angioplasty and, if modifiable or controllable, potentially reduce restenosis. A stepwise multiple linear regression analysis was performed to identify independent predictors of restenosis. The following variables were retained in the model in order of significance: (a) relative gain (difference between the minimal luminal diameter pre- and post-percutaneous transluminal coronary angioplasty (PTCA), normalized for vessel size), (b) minimal luminal diameter post-PTCA, and (c) dilatation of another vessel than right coronary artery. The fit of the model was poor; where the predicted change in minimal luminal diameter was < 0.1 mm, 0.1-0.3 mm, > 0.3 mm, the corresponding percent correct classification was 30, 52, and 55%. The present study illustrates that the restenosis phenomenon cannot accurately be predicted by patient, lesion, and procedural variables.

Therapeutic dissection after successful coronary balloon angioplasty: no influence on restenosis or on clinical outcome in 693 patients. The MERCATOR Study Group (Multicenter European Research Trial with Cilazapril after Angioplasty to prevent Transluminal Coronary Obstruction and Restenosis).

OBJECTIVES: The objective of this study was to examine the relation between an angiographically visible coronary dissection immediately after successful coronary balloon angioplasty and a subsequent restenosis and long-term clinical outcome. BACKGROUND: The study population comprised all 693 patients who participated in the MERCATOR trial (randomized, double-blind, placebo-controlled restenosis prevention trial of cilazapril, 5 mg two times a day). METHODS: Cineangiographic films were processed and analyzed at a central angiographic core laboratory, without knowledge of clinical data, with use of an automated interpolated edge detection technique. Dissection was judged according to the National Heart, Lung, and Blood Institute classification. Angiographic follow-up was obtained in 94% of patients with 778 lesions. Two approaches were used to assess the restenosis phenomenon: 1) categoric, using the traditional cutoff criterion of greater than 50% diameter stenosis at follow-up, and 2) continuous, defined as absolute change in minimal lumen diameter (mm) between the postcoronary angioplasty and follow-up, adjusted for the vessel size (relative loss). Clinical outcome was ranked according to the most serious adverse clinical event per patient during the 6-month follow-up period, ranging from death, nonfatal myocardial infarction, coronary revascularization and recurrent angina requiring medical therapy to none of these. RESULTS: Dissection was present in 247 (32%) of the 778 dilated lesions. The restenosis rate was 29% in lesions with and 30% in lesions without dissection (relative risk 0.97; 95% confidence interval 0.77 to 1.23). The relative loss in both groups was 0.10 (mean difference 0; 95% confidence interval -0.03 to 0.03). Clinical outcome ranged from death in 4 patients (0.9%) without dissection and 1 patient (0.4%) with dissection; nonfatal myocardial infarction in 4 (0.9%) without and 8 (3.2%) with dissection; coronary revascularization in 73 (16.6%) without and 32 (12.7%) with dissection; recurrent angina requiring medical therapy in 88 (20%) without and 47 (18.7%) with dissection to no serious adverse event in 272 (61.7%) without and 114 (65.1%) with dissection. CONCLUSIONS: These data indicate that a successfully dilated coronary lesion with an angiographically visible dissection is no more likely to develop restenosis, and is not associated with a worse clinical outcome, at 6-month follow-up than is a dilated lesion without visible dissection on the post-balloon angioplasty angiogram.

Lumen narrowing after percutaneous transluminal coronary balloon angioplasty follows a near gaussian distribution: a quantitative angiographic study in 1,445 successfully dilated lesions.

To determine whether significant angiographic narrowing and restenosis after successful coronary balloon angioplasty is a specific disease entity occurring in a subset of dilated lesions or whether it is the tail end of a gaussian distributed phenomenon, 1,445 successfully dilated lesions were studied before and after coronary angioplasty and at 6-month follow-up study. The original cohort consisted of 1,353 patients of whom 1,232 underwent repeat angiography with quantitative analysis (follow-up rate 91.2%). Quantitative angiography was carried out off-line in a central core laboratory with an automated edge detection technique. Analyses were performed by analysts not involved with patient care. Distributions of minimal lumen diameter before angioplasty (1.03 +/- 0.37 mm), after angioplasty (1.78 +/- 0.36 mm) and at 6-month follow-up study (1.50 +/- 0.57 mm) as well as the percent diameter stenosis at 6-month follow-up study (44 +/- 19%) were assessed. The change in minimal lumen diameter from the post-angioplasty angiogram to the follow-up angiogram was also determined (-0.28 +/- 0.52 mm). Seventy lesions progressed toward total occlusion at follow-up. All observed distributions approximately followed a normal or gaussian distribution. Therefore, restenosis can be viewed as the tail end of an approximately gaussian distributed phenomenon, with some lesions crossing a more or less arbitrary cutoff point, rather than as a separate disease entity occurring in some lesions but not in others.

Angiographic risk factors of luminal narrowing after coronary balloon angioplasty using balloon measurements to reflect stretch and elastic recoil at the dilation site. The CARPORT Study Group.

Because many ongoing clinical restenosis prevention trials are using quantitative angiography to assess whether a drug is capable of reducing the amount of intimal hyperplasia, quantitative angiographic risk factors for angiographic luminal narrowing after balloon angioplasty were determined, including stretch and elastic recoil at the dilatation site. Quantitative analysis was performed on 666 lesions in 575 patients during angioplasty and at 6-month follow-up. Stretch was defined as balloon diameter minus minimal luminal diameter (MLD) before angioplasty/reference diameter, and recoil as balloon diameter minus MLD after angioplasty/reference diameter. Multivariate analysis was used to yield independent risk factors for luminal narrowing at follow-up. Predictors of absolute change in MLD were (1) relative gain at angioplasty (gain in millimeters normalized for reference diameter) and (2) lesion length. To allow risk stratification, logistic regression analysis was applied using the decrease in MLD as a binary outcome variable. A decrease in MLD at follow-up of greater than or equal to 0.72 mm was considered significant. Variables retained in the model were: relative gain greater than 0.3 mm (rate ratio 2.9), relative gain 0.2 to 0.3 (rate ratio 2.1), stenosis length greater than or equal to 6.8 (rate ratio 1.7), and thrombus after angioplasty (rate ratio 2.6). Although stretch was significantly related to luminal narrowing at univariate analysis, it was not retained in the multivariate models. A large gain in lumen diameter at angioplasty, dilation of long lesions, and angiographically determined thrombus after angioplasty were found to be accompanied by more severe luminal narrowing at follow-up.

Methodological problems related to the quantitative assessment of stretch, elastic recoil, and balloon-artery ratio.

The (inflated) balloon is important to determine the extent of stretch (theoretical maximal gain in diameter or area during PTCA), elastic recoil (the loss in diameter or area immediately after PTCA), and whether under- or over-sizing (balloon-artery ratio) of the dilated lesion occurred. In these assessments, the inflated balloon is used as scaling device with assumed uniformity along its entire length. In order to assess more accurately stretch, elastic recoil, and the balloon-artery ratio, the balloon diameter was measured over its entire length with edge detection and videodensitometry in 505 lesions (453 patients). With an average inflation pressure of 8.3 +/- 2.6 atm a difference between the minimal and the maximal balloon diameter of 0.59 +/- 0.23 mm was measured using edge detection and 1.70 +/- 0.90 mm2 difference in area using videodensitometry. This results in large variations in the calculated stretch, elastic recoil, and balloon-artery ratio depending on the site of the balloon chosen for assessment. The mean difference +/- SD between stretch and elastic recoil assessed by edge detection and videodensitometry (using the minimal luminal diameter or area of the balloon) are respectively 0.00 +/- 0.19 and 0.00 +/- 0.24, suggesting that both methods are appropriate.

Postangioplasty restenosis rate between segments of the major coronary arteries.

Conflicting data have been published regarding the rate of postangioplasty restenosis observed in diverse segments of the coronary tree. However, these studies may be criticized for their biased selection of patients, methods of analysis, and definitions of restenosis. In the present study, 1,353 patients underwent a successful coronary dilatation of greater than or equal to 1 site. In all, 1,234 patients (91%) had a follow-up angiogram after 6 months, or earlier when indicated by symptoms. All films were processed and analyzed at the thoraxcenter core laboratory with the coronary angiography analysis system (automated contour detection). Restenosis was considered present if the diameter stenosis at follow-up was greater than 50%. No differences in restenosis rates were observed between coronary segments using this categorical definition. A continuous approach was also used; absolute changes in minimal luminal diameter adjusted for vessel size were used in order to allow comparison between vessels of different sizes (relative loss). No significant differences were observed between the coronary segments with this continuous approach. These results suggest that restenosis is a ubiquitous phenomenon without any predilection for a particular site in the coronary tree.

Comparative quantitative angiographic analysis of directional coronary atherectomy and balloon coronary angioplasty.

An attempt to assess the "utility" of directional atherectomy was made using a new quantitative angiographic index. This index can be subdivided into an initial gain component and a restenosis component. The initial gain index is the ratio between the gain in diameter during intervention and the theoretically achievable gain (i.e., reference diameter). The restenosis index is the ratio between the decrease at follow-up and the initial gain during the procedure. The net result at long-term follow-up is characterized by the utility index, which is the ratio between the final gain in diameter at follow-up and what theoretically could have been achieved. For this purpose, 30 coronary artery lesions were selected from a consecutive series of successfully dilated primary angioplasty lesions and were matched with the initial 30 successfully treated primary atherectomy lesions. Matching by location of stenosis and reference diameter resulted in 2 comparable groups with identical preprocedural stenosis characteristics. Atherectomy resulted in an increase in minimal luminal diameter 2 times larger than angioplasty (1.53 vs 0.77 mm; p less than 0.0001). However, at follow-up there was a significant decrease in minimal luminal diameter and a significant increase in percent diameter stenosis in the groups with atherectomy and angioplasty (1.69 +/- 0.58 vs 1.57 +/- 0.58 mm, p = not significant [NS], and 37 +/- 18 vs 47 +/- 18%, p = NS, respectively). The decrease in minimal luminal gain was more pronounced in the group with atherectomy than in that with angioplasty (0.92 +/- 0.69 vs 0.35 +/- 0.51 mm; p = 0.0005).(ABSTRACT TRUNCATED AT 250 WORDS)