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J Am Coll Cardiol, 2005; 45:1193-1200, doi:10.1016/j.jacc.2004.11.063 © 2005 by the American College of Cardiology Foundation |
* Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio
Brigham & Women’s Hospital, Boston, Massachusetts
Division of Cardiology, Washington University, School of Medicine, St. Louis, Missouri
Cardiovascular Clinical Affairs, Boston Scientific, Natick, Massachusetts
|| Mid Carolina Cardiology, Charlotte, North Carolina
¶ St. Vincent’s Hospital, Indianapolis, Indiana
# Elyria Memorial Hospital, Elyria, Ohio
** WakeMed, Raleigh, North Carolina
Washington Adventist Hospital, Tacoma Park, Maryland
St. Joseph’s Hospital, Syracuse, New York
Sacred Heart Medical Center, Eugene, Oregon
|||| Florida Hospital, Orlando, Florida
¶¶ Columbia University Medical Center, New York, New York
## Cardiovascular Research Foundation, New York, New York.
Manuscript received June 28, 2004; revised manuscript received November 1, 2004, accepted November 15, 2004.
* Reprint requests and correspondence: Dr. Stephen G. Ellis, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk F25, Cleveland, Ohio 44195. (Email: elliss{at}ccf.org).
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Abstract |
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BACKGROUND: The interrelationship between angiographic late loss, binary restenosis, and clinical recurrence (target lesion revascularization [TLR]) after coronary stent implantation has been incompletely evaluated.
METHODS: Using the angiographic substudy of the TAXUS-IV trial, in which 1,314 patients with de novo coronary lesions were randomized to either the paclitaxel-eluting TAXUS stent or to its bare-metal equivalent, we defined the relationship between in-stent and analysis segment late loss, the shape of the late loss histogram (variance and skewedness), and nine-month TLR.
RESULTS: Late loss by several measures was closely related to TLR (area under the receiver-operator curve >0.90). For individual vessels of the size in this study (2.8 ± 0.5 mm), the likelihood of TLR did not exceed 5% until analysis segment late loss was >0.5 mm, and did not exceed 10% until late loss was >0.65 mm. At greater late losses, the late loss TLR relationship was steep and nearly linear. For the overall patient cohort, the rate of TLR was related, however, not only to median late loss, but also to measures of its statistical distribution (TLR increased with lack of homogeneous biologic response [greater variance and greater right skewedness]). Similar relationships held for late loss measured within the confines of the stent itself.
CONCLUSIONS: Coronary stents result in large lumens with "room" to accommodate up to 
0.5 to 0.65 mm of tissue (angiographic analysis segment late loss) before the likelihood of clinical restenosis (TLR) exceeds 5% to 10%. These data have important implications toward understanding the absolute and relative efficacy of drug-eluting stents.
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Late loss, defined as the difference in millimeters between the MLD at the completion of the procedure and at angiographic follow-up, is commonly used to measure the degree of accumulation of tissue (4). Late loss can be calculated based on measurements within the stent, at its edges, or across the entire analysis segment, as has been done historically. Some have speculated that in-stent late loss might serve as a useful measure of biological activity of drug-eluting stents, with the implication clearly being that "less is better" (5,6). In the era of drug-eluting stents, the significance and relationship of the traditional angiographic indexes of restenosis, especially late loss, to clinical outcomes has yet to be defined.
When comparing results from the SIRIUS and TAXUS-IV trials (1,2), both drug-eluting stent systems provide significant reductions in in-stent neointimal hyperplasia compared to bare-metal stents, translating into a greatly reduced and generally similar need for repeat intervention (nine-month TLR rates of 4.1% and 3.0%, respectively) in analogous patient and lesion populations. One major difference between the Cypher (Cordis Corp., Miami, Florida) and TAXUS (Boston Scientific Corp., Natick, Massachusetts) stent systems is the absolute amount of angiographic late loss seen at late follow-up (the same angiographic core laboratory and analysis technique was utilized in both studies). For the Cypher stent, in-stent late loss was 0.17 ± 0.44 mm compared with 1.00 ± 0.70 mm for bare-metal control stents (relative reduction of 83%). For the TAXUS stent, the late loss was 0.39 ± 0.50 mm for the slow-release, polymer-based paclitaxel-eluting stent compared to 0.92 ± 0.58 mm for the EXPRESS bare-metal control (Boston Scientific Corp.) (relative reduction of 58%). The degree of late loss over the entire analysis segment, however, was similar between the Cypher and TAXUS stents (0.24 ± 0.47 mm and 0.23 ± 0.44 mm, respectively). These contrasts have raised questions about the utility of late loss as an index of clinical restenosis in the drug-eluting stent era. The objective of this substudy was, therefore, to examine the relationship between late loss and TLR.
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Methods |
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18 years of age with stable or unstable angina or provocable ischemia undergoing stenting of a single de novo lesion in a native coronary artery were considered for enrollment. Angiographic eligibility for inclusion required a target lesion with visual reference vessel diameter 2.5 to 
3.75 mm and lesion length 10 to 28 mm coverable by a single study stent. Clinical and angiographic exclusion criteria have been described (2). The institutional review board at each participating center approved the study, and consecutive, eligible patients signed informed, written consent; 559 of the 732 patients (76.4%) pre-selected for routine angiographic follow-up returned for restudy. Additionally, 150 patients had angiographic follow-up one to nine months after stent placement for clinical indications. The latter group’s data were added in some analyses to increase the number of events to be studied.
Randomization and stent implantation.
Telephone randomization was performed before pre-dilatation, stratified by the presence of medically treated diabetes and vessel size (<3.0 or 3.0 mm). Patients were equally assigned in double-blind fashion to treatment with either the slow rate-release, polymer-based, paclitaxel-eluting TAXUS stent or a visually indistinguishable bare-metal EXPRESS stent. Unfractionated heparin was administered per standard practice, and glycoprotein IIb/IIIa inhibitor use was at operator discretion. After mandatory pre-dilatation, an appropriate-sized stent (approximately 2 to 4 mm longer than the lesion, with a stent-to-distal reference vessel diameter ratio of 1 to 1.1:1) was implanted at 12 atm. Stents were available in lengths of 16, 24, and 32 mm, and in diameters of 2.5, 3.0, and 3.5 mm. Additional study stents were permitted for edge dissections greater than or equal to type B or otherwise suboptimal results, and post-dilatation was at operator discretion. Clinical follow-up was scheduled at one, four, and nine months, and yearly thereafter for five years. Angiographic follow-up was pre-specified in a prospectively identified subgroup of 732 patients at nine months (2).
End points and definitions.
Target lesion revascularization was defined as either repeat percutaneous or surgical revascularization for a lesion anywhere within the stent or the 5-mm borders proximal or distal to the stent. Target lesion revascularization was considered to be ischemia-driven if the target lesion diameter stenosis was 50% by quantitative analysis with either electrocardiographic changes at rest or a positive functional study in the distribution of the target lesion, or 70% with recurrent symptoms only. If an adverse event could not be conclusively attributed to a non-target lesion, then the event was considered a target-related event.
As previously described, the primary end point of the TAXUS-IV trial was TVR at nine months (2), defined as revascularization due to either restenosis in the target lesion, or to a new remote lesion elsewhere in the target vessel or its branches. For the present analysis, however, TLR was used as the principal clinical analysis end point, as angiographic restenosis after stent implantation (either within the stent or at its margins) is most directly correlated with TLR.
Angiographic methods.
After administration of intracoronary nitroglycerin, standard angiographic image acquisition of the coronary stenosis was performed using at least two angiographic projections that were repeated at the end of the procedure and at the time of follow-up angiography. Cineangiograms were then forwarded to the Brigham and Women’s Hospital Angiographic Core Laboratory for review by observers blinded to the treatment assignment. Baseline, postprocedural, and follow-up qualitative morphologic characteristics were characterized using standard criteria (7–9). Lesion length was defined as the axial extent of the lesion that contained a shoulder-to-shoulder lumen reduction by 20% or more (10).
Using the contrast-filled injection catheter as the calibration source, quantitative coronary angiographic (QCA) analysis was performed using a validated automated edge detection algorithm (Medis CMS, Leiden, the Netherlands) (11). Projections for image analysis were identified using views that demonstrated the stenosis in an unforeshortened view, minimized the degree of vessel overlap, and displayed the stenosis in its "sharpest and tightest" view. A 5-mm segment of reference diameter proximal and distal to the stenosis was used to calculate the average reference vessel diameter; side branches and other anatomic landmarks were used to identify and maintain the consistency of the measurement length during the follow-up period. Minimum lumen diameters were measured at these same time points within the stent (in-stent analysis) and within the 5-mm proximal and distal edges of the stent. Total occlusions were assigned an MLD = 0 mm and a 100% diameter stenosis.
Angiographic follow-up was performed nine months after the index procedure, or earlier in the event of recurrent symptoms. Binary angiographic restenosis was defined as a follow-up diameter stenosis >50%. Acute gain was defined as the MLD immediately after the procedure minus the MLD before the procedure, and late loss was defined as the MLD immediately after the procedure minus the MLD at follow-up. For the purposes of this analyses, late loss was calculated in each of three ways: 1) within the stent itself; 2) within the analysis segment itself considering the MLD anywhere within the analysis segment at the conclusion of the procedure and at follow-up; and 3) within the analysis segment itself, but separately considering the stented segment, proximal and distal edges and taking the maximum change in MLD within those three segments and applying it to this segment as a whole (maximal regional late loss) to better reflect local dimensional changes.
Statistical methods. Categorical variables were compared by the Fisher exact test. Continuous variables are presented as mean ± 1 SD or median with 25% and 75% interquartile ranges, and were compared by Student t test. Late loss data by treatment group were displayed as histograms and analyzed for variance, or the dispersion of the distribution of data around the mean value, and skewedness or the asymmetry of the data distribution and for its relation to TLR. Cumulative frequency distribution curves for each of the three measures of late loss (in-stent, in-segment, and maximal regional late loss) was plotted against TLR, and the goodness of correlation assessed using receiver operator curve analyses and the c-statistic. Separate analyses were then performed dividing the population by reference vessel size <2.5 mm, 2.5 to 3.0 mm, and >3.0 mm. To assess the TLR implications of greater and lesser heterogeneity and greater right skewedness of late loss than was actually present in the TAXUS group, simulation exercises were performed assuming: 1) the same mean late loss with a Gaussian distribution, but with 50%, 75%, 125%, or 150% of the observed variance of late loss; and 2) skewed distributions, with the same mean late loss but kurtoses of 0.37 and 0.41 representing greater right skewedness; 1,000 simulations were performed for each estimate. Finally, because not all patients with binary restenosis had TLR, similar analyses were performed with binary restenosis as the end point.
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0.3 mm and rightward 0.7 mm, respectively.
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Discussion |
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Late loss clinical implications.
The clinical translation of this finding is that the large lumens that result after coronary stent implantation in vessels of the size studied (mean 2.8 ± 0.5 mm) allow "room" to accommodate a mean late loss of up to approximately 0.75 to 1.0 mm within the stent, providing that there is a homogeneous effect across the major subpopulations of patients. When the entire analysis segment is considered, any degree of late loss 0.5 mm is sufficient to result in TLR rates below 5%. For smaller reference vessel dimensions, the amount of "room" to accommodate restenotic tissue diminishes, such that for the group with diameter <2.5 (mean 2.22 ± 0.20 mm), the probability of TLR exceeds 10% when analysis segment late loss is >0.5 mm, rather than 0.6 to 0.7 mm for the entire group. When the TLR threshold is lowered to 5% for small vessels (<2.5 mm), a late lumen loss of 0.3 to 0.4 mm or below is acceptable.
Late loss findings in paclitaxel-eluting stents. For the paclitaxel-eluting stent group as a whole, the likelihood of TLR is directly, but not linearly, related to late loss and increases with greater heterogeneity of effect (more variance) and with greater right skewedness of the late loss distribution curve compared with the bare-metal stent (2). These data have important implications for the requisite performance of drug-eluting stents. A mean analysis segment late loss of 0.5 mm (or in-stent late loss of 0.75 mm) after drug-eluting stent implantation is adequate to achieve TLR rates <5%. Greater reduction of late loss may not translate into significantly lower TLR rates, because the relatively flat portion of the TLR/late loss curve has been reached. These data provide insight as to why Cypher and TAXUS stents result in similar TLR rates despite exhibiting very different degrees of in-stent late loss. Moreover, the similar amount of late loss in the analysis segments after sirolimus-eluting and paclitaxel-eluting stent implantation (despite different degrees of in-stent hyperplasia) contribute to the near identical rates of TLR.
In addition, the homogeneity of response to the drug-eluting stent as a function of vessel size, lesion length, diabetic status, and other parameters must be considered to completely characterize drug-eluting stent performance. In this regard from the present analysis, the TAXUS stent performed slightly better in smaller compared to larger vessels, with less absolute and relative late loss. Moreover, bare-metal stents typically have a late loss of 0.8 to 1.0 mm (12–14). The present analysis suggests that changes in materials or manufacturing processes that could reduce this late loss to the 0.5- to 0.6-mm range (a reduction of only 0.2 to 0.4 mm) would have a marked impact on reducing restenosis even without a bioactive coating.
This study also demonstrates that when analysis segment late loss is <0.5 mm (or when in-stent late loss is <0.75 mm), that the homogeneity of response (variance and skew) may affect TLR rates more powerfully than any further reduction in median late loss.
Late loss findings in bare-metal stents. For bare-metal stents, a majority of patients have late loss on the steep and linear portion of the TLR/late loss curve, and, therefore, late loss itself is a good measure of clinical benefit. In contrast, for late losses in the ranges expected with drug-eluting stents, the exact amount of late loss is an insensitive determinant of clinical restenosis, with homogeneity of effect being a more important predictor of clinical benefit.
Study limitations. The principal limitations of this analysis are that much of the angiographic follow-up was per protocol rather then clinically driven, hence TLR may have been artificially exaggerated due to the "oculostenotic reflex" (despite attempts to systematically adjudicate against this) (15). Second, the results may not be generalizable to all stent platforms or other types of drug-eluting stents or other lesion types. Conversely, the strengths of the study lie in the large number of patients studied, the blinded, independent QCA process, the consistency of the TLR late loss relationship for both the paclitaxel-eluting stent and bare-metal stent groups, and of the various measures of late loss to that relationship.
Clinical implications. In conclusion, considering the salutary scaffolding effects of stents when implanted in de novo coronary artery stenoses, median analysis segment late loss of up to 0.5 to 0.65 mm (or in-stent late loss of 0.75 to 1.0 mm) may be accommodated with probability of TLR <5% to 10% provided that there is homogeneous effect across all subpopulations.
For the slow-release paclitaxel formulation stents, the median (0.15 mm) and interquartile range (–0.04 to 0.41 mm) values of analysis segment late loss fall far below the threshold where the probability of TLR increases. These findings are important in selecting drug candidates and dose thresholds for future drug-eluting stents where the antirestenotic effect needs to be balanced against adequate stent coverage consistent with a well-healed and pacified surface. Results from future drug-eluting stent studies evaluating other stent platforms and drugs, as well as a broader range of stent diameters and lengths and other lesion types, will provide more insight to prospectively determine the optimum amount of late loss combining sufficient antirestenotic properties and adequate healing after stent implantation.
Finally, these results potentially have important clinical and regulatory implications for ongoing trials in which drug-eluting stents are compared against each other, using angiographic late loss as a surrogate of clinical benefit. The present analysis suggests that a relatively broad "delta" for noninferiority in such studies would provide reasonable assurance of clinical efficacy, as long as variance of the distribution is not excessive.
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