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DOI: 10.1148/radiol.2402051248
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(Radiology 2006;240:411-418.)
© RSNA, 2006

Experimental Studies

Neointima Inhibition: Comparison of Effectiveness of Non–Stent-based Local Drug Delivery and a Drug-eluting Stent in Porcine Coronary Arteries1

Ulrich Speck, PhD, Bruno Scheller, MD, Claudia Abramjuk, DVM, Christoph Breitwieser, MD, Juergen Dobberstein, PhD, Michael Boehm, MD and Bernd Hamm, MD

1 From the Department of Radiology, Charité Humboldt-University Berlin, Schumannstr 20-21, D 10117 Berlin, Germany (U.S., C.A., C.B., B.H.); Department of Internal Medicine III, University Hospital, Homburg/Saar, Germany (B.S., M.B.); and Biometry and Applied Statistics, Berlin, Germany (J.D.). From the 2004 RSNA Annual Meeting. Received July 26, 2005; revision requested September 30; revision received October 13; final version accepted November 14. Supported by a grant from the Ministry of Economics and Technology. Address correspondence to U.S. (e-mail: ulrich.speck{at}charite.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Purpose: To compare the inhibition of neointimal proliferation by using non–stent-based local drug delivery and a drug-eluting stent in porcine coronary arteries.

Materials and Methods: Experiments were conducted with permission of the animal protection committee of the local government. Paclitaxel was either dissolved in a nonionic contrast medium or coated on balloons. Stents were crimped on the coated balloons. Effectiveness was tested in 22 pigs. Two coronary stents were placed in each pig, and slight overstretch was applied. The animals were treated as follows: group A (control group), uncoated balloons, bare stents, and "plain" contrast medium; group B, same treatment as group A, but with paclitaxel in the contrast medium; group C, paclitaxel-coated balloons, with premounted bare stents and plain contrast medium; and group D, sirolimus-eluting stents, noncoated balloons, and plain contrast medium. Stenosis was assessed 4 weeks later at angiography and histomorphometry. For exploratory purposes, continuous variables of quantitative coronary angiography and histomorphometry were compared by using analysis of variance.

Results: Results at follow-up angiography indicated a mean of 1.00 mm ± 0.18 (standard deviation) lumen diameter loss in the control group and 0.14 mm ± 0.18 loss in the group treated with the paclitaxel-coated balloon (group C; P < .001). Findings at histomorphometry confirmed the effectiveness of drug delivery, with the most impressive inhibition of neointimal proliferation from coated balloons—the neointimal area was 2.4 mm2 ± 0.3 (P < .01 vs all other groups), compared with 5.2 mm2 ± 0.3 in group A (control group), 4.3 mm2 ± 0.3 in group B, and 3.8 mm2 ± 0.3 in group D.

Conclusion: In spite of the short intima contact time, paclitaxel coated on the balloon inhibits neointimal formation in the porcine model of coronary stent placement.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Restenosis and occlusion after initially successful balloon angioplasty are major problems in small-diameter vessels (1). This process is to a large extent due to the excessive formation of neointimal tissue in response to the unavoidable injury that occurs during balloon dilation. The process thus initiated continues for weeks and months and may finally result in occlusion of the lumen of the artery. The mechanism driving this process after the initial phase of wound healing is not clear (2).

In coronary arteries, excessive formation of neointima has been successfully inhibited by the implantation of drug-eluting stents. Implanted stents provide a platform for sustained drug release, which is believed to be a precondition of successful restenosis inhibition (3). Drug release that is too fast has been blamed for the failure to prevent restenosis in several clinical trials (4).

Initial studies performed in a small number of patients to investigate the effectiveness of stents delivering similar doses and showing similar release kinetics as the drug-eluting stents for the coronary arteries have yielded equivocal results in peripheral vessels (5).

In the established porcine model of coronary artery overstretch and stent implantation (6), the addition of a taxane to the regular angiographic contrast medium was found to be associated with a statistically significant inhibition of neointimal proliferation 4 weeks after the intervention (7,8). Uptake of paclitaxel during the first passage of the contrast medium through the coronary arteries was measured (9). Furthermore, the drug coated on the balloons of percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal angioplasty catheters proved to inhibit neointimal hyperplasia in the same porcine model (10) and in the peripheral arteries of domestic pigs (11). The purpose of our study was to compare the inhibition of neointimal proliferation by using non–stent-based local drug delivery and a drug-eluting stent in porcine coronary arteries.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Animals
All experiments were conducted in accordance with the guidelines for animal experiments set forth by the animal protection committee of the local government.

Schering (Berlin, Germany) and Bavaria Medizin Technologie (Oberpfaffenhofen, Germany) provided financial support, contrast agents, and balloon catheters. The authors had full control of the final preparations (drug-containing contrast medium and coating), data, and information.

The study was performed in 22 healthy domestic pigs.

Stents, Catheters, and Contrast Medium
Premounted balloon-expandable coronary stent systems with a diameter of 3.0 or 3.5 mm and a length of 18 mm were used. Two stents were placed in each animal—one in the left anterior descending (LAD) artery and one in the left circumflex (CX) artery. In only the animals treated with paclitaxel (Indena, Milan, Italy) dissolved in contrast medium, the treatment method was the same in both arteries.

The control group was treated by means of bare stent implantation (premounted Bx Velocity; Cordis, Langenfeld, Germany) into the LAD (n = 5) or CX (n = 6) artery by using the conventional contrast agent (iopromide 370, Ultravist; Schering). There were 11 stents placed in 11 pigs.

One group was treated by means of premounted bare stent implantation (Bx Velocity; Cordis) into the LAD and CX arteries, with 80 mL of iopromide containing 200 µmol/L paclitaxel as a contrast agent. There were 12 stents placed in six pigs (one LAD artery and one CX artery in each pig).

The next group was treated with bare stents (MeoFlex; MeoMedical, Augsburg, Germany) mounted on a paclitaxel-coated (3 µg/mm2) PTCA balloon catheter (ie, drug-eluting balloon [DEB]) by using acetone-based coating solution technology (10); implantation into the LAD (n = 6) or CX (n = 5) artery was performed by using the conventional contrast agent (iopromide). There were 11 stents placed in 11 pigs.

The last group was treated by means of implantation of a sirolimus-eluting stent (SES) (Cypher; Cordis) into the LAD (n = 5) or CX (n = 5) artery by using the conventional contrast agent (iopromide). There were 10 stents placed in 10 pigs.

The Cypher stent was chosen instead of the paclitaxel-containing Express Taxus stent (Boston Scientific, Ratingen, Germany) because more extensive clinical experience was available for this stent at the time when the study was designed, and low late lumen loss has been demonstrated in several studies (12–14).

The MeoFlex stent (MeoMedical) differs from the Cypher and Bx Velocity stents (Cordis) in design (multicell vs closed cell) and strut thickness (0.10 mm vs 0.14 mm). No difference exists in the stent material (stainless steel, 316 L).

Animal Study and Histomorphometry
Animals were randomly subdivided into groups in two steps, as follows: step 1, animals were assigned to receive plain (conventional) contrast medium or paclitaxel in contrast medium; and step 2, animals assigned to receive plain contrast medium were treated with a bare stent and bare balloon (no drug; control group), a bare stent and a paclitaxel-coated balloon (DEB group), or an SES on a bare balloon (SES group). Whereas the animals were treated in randomized order, it was determined beforehand to perform a roughly equal number of procedures from each treatment regimen in the LAD and CX arteries and to perform two different treatments per animal to allow direct comparison. Twenty-two male domestic pigs (26–35 kg) were treated according to standard procedures (10). Stents were implanted (by B.S., with 7 years of experience with this model) in exactly the same way in all vessels by applying slight overstretch of the normal coronary arteries, which results in an oversize ratio of about 1.2 (implantation pressure, 12 atm for 60 seconds). Pigs were allowed to recover and survive for 28 days. Aspirin (100 mg/d) and ticlopidine (Sanofi-Synthelabo, Berlin, Germany) (250 mg/d; equivalent to 75 mg clopidogrel [15]) were orally administered starting 3 days before the procedure and continuing until sacrifice.

No acute reactions (eg, vasospasms, arrhythmia, or drop in blood pressure) to the injection of the paclitaxel-containing contrast medium or the use of the DEB catheters were observed. After recovery from anesthesia, the animals showed normal behavior with no signs of morbidity. All animals survived during the whole 28-day follow-up period.

After 28 days, coronary angiography was repeated; the animals were anesthetized for angiography. Immediately thereafter, the animals were sacrificed by means of an intravenously injected overdose of pentobarbital. Hearts were rapidly excised, the coronary system was flushed with 0.9% saline, and the arteries were fixed by means of perfusion with 4% buffered formalin under physiologic pressure and overnight immersion. The target segments were then dissected, and samples were obtained for histologic evaluation (Institute of Medical Technology Magdeburg).

Stent-implanted coronary arteries were dissected from the formalin-fixed hearts and immersed in methylmethacrylate (Merck, Darmstadt, Germany). For all segments with stents, three transsectional slices were prepared from the blocks with a coping saw, polished, and glued on acrylic plastic slides for histomorphologic evaluation—one at the entrance of the stent, one in the middle, and one at the end of the stent. Final specimens were stained by using the Elastica van Gieson and hematoxylin-eosin technique. After digitalizing, histomorphometric measurements were taken by using the National Institute of Health image program (Scion Image; Scion, Frederick, Maryland). The parameters evaluated were luminal diameter, external elastic lamina diameter (vessel diameter), maximal neointimal thickness, external elastic lamina area (vessel area), luminal area, neointimal area, and area stenosis, which was determined as: area stenosis = 100 – ([lumen area · 100]/vessel area). An injury score was assigned as previously described by Schwartz et al (16) and an inflammation score was assigned as described by Kornowski et al (17) (B.S., with 5 years of experience).

Quantitative Coronary Analysis
Coronary imaging was performed by using a fluoroscope (PolyArc; Philips, Hamburg, Germany) connected to a digitizer and a personal computer (Macintosh Power PC; Apple, Cork, Ireland). The CAAS II System (Pie Medical, Maastricht, the Netherlands) was used for quantitative coronary analysis by an experienced reader who was blinded to the treatment performed (B.S., with 10 years of experience).

Angiograms were evaluated by a second reader (C.B., with 2 years of experience) who was blinded to the treatment of the animals. The angiograms were interpreted in respect to thrombi and minimum vessel diameters proximal and distal to the stents as signs of edge stenosis.

Statistical Analysis
Sample sizes of about 10 vessels per treatment method were chosen according to the experience with the animal model (10,18,19). Continuous variables of quantitative coronary angiography and histomorphometry were compared by using an analysis of variance model with pigs as a random factor and treatment and vessel as fixed factors. An interaction term, treatment times vessel, was not included in the model because previous evaluations showed no improvement in the fit of the model when this term was included.

P values given for comparisons of treatments refer to the overall test for differences between the three treatments. Estimates of treatment effects were computed as least square means with the respective standard errors within the model. Treatments were compared by using linear contrasts. For exploratory reasons, these contrasts were calculated without taking into account the results of the preceding overall tests for treatment differences. The distribution of the residuals has been checked for normality by means of the Kolmogorov-Smirnov test. For all but three variables (lumen diameter, maximum thickness, and stent area), the P values for the test were not below .10. Because of the known robustness of the F statistic, no further attempts (such as data transformation) have been made to achieve normality. No correction for multiple testing was applied. The limit of statistical significance is set at P < .05; however, all P values should be interpreted exploratively. The software used for the evaluation was SAS (version 8.02; SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 
Stent Implantation
Twenty-two domestic pigs were treated, with a total of 44 stents implanted. In the LAD artery, only 3.5-mm-diameter stents were used, whereas in the CX artery, nine of the 22 stents were 3.0 mm in diameter because of the smaller size of this artery in some animals. The 3.0-mm stents were about equally distributed among the treatment groups—that is, two in each of the three groups treated with the drugs and three in the control group.

Coronary Angiography
Mean reference diameters determined at the time of the intervention did not differ significantly between the four treatment groups, although the reference diameters were slightly larger in the vessels treated with the SESs (P = .17). Stent diameters were also similar in the four groups (P = .31). No difference was found in respect to overstretch (Tables 1, 2).


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  		Table 1. Results of Quantitative Coronary Angiography in Pigs according to Treatment Method

 

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  		Table 2. P Values for Differences between Treatments at Quantitative Coronary Angiography at 4-week Follow-up

 
Coronary angiography performed at 28 days after the initial intervention yielded no signs of thrombotic events. Measurements of the reference diameters were slightly smaller than those on the images obtained during implantation. Eight of 11 vessels not treated with a drug (control group, with a bare stent and bare balloon) showed a reduced minimal lumen diameter of the stent-treated segment compared with the reference diameter. The minimal lumen diameter was significantly reduced in comparison with the stent diameter (Table 1, P < .01). Vessels treated with either paclitaxel in contrast material or an SES displayed a slightly larger minimal lumen diameter and less late loss than did the control vessels. However, only the difference in minimal lumen diameter for SES-treated vessels versus control vessels reached a P value of less than .05.

In the segments treated with an SES, the mean lumen loss resulted in an in-stent minimal lumen diameter corresponding to the reference diameter, which indicates that the lumen diameter gained through overdilation is lost after 4 weeks. Very little lumen loss occurred in arteries treated with bare stents premounted on DEBs (P < .01 vs control and SES groups). After 4 weeks, in six of 11 vessels there was no difference in comparison with the lumen diameter immediately after stent implantation, and in the remaining five vessels the diameter was still larger than the reference diameter (Fig 1). Narrowing of the arteries treated with the DEB, as measured by means of minimal lumen diameter or late loss 4 weeks after treatment, was less than in any of the other groups, although the differences in minimal lumen diameter was not statistically significant (Table 2). The SES was implanted in slightly larger vessels, which affects minimal lumen diameter more than late loss.


Figure 1
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  		Figure 1a: Left anterior oblique angiograms 4 weeks after stent placement compare SESs and stents on DEBs: (a) LAD artery DEB (left) and CX artery SES (right), (b) LAD SES (left) and CX DEB (right), (c) LAD DEB (left) and CX SES (right), (d) LAD DEB (left) and CX SES (right), and (e) LAD SES (left) and CX DEB (right). Arrows indicate the artery segments treated with stents. The remaining lumina in the stent segments treated by means of the coated DEBs are larger than or equal to the lumina in the segments treated by means of SESs.

 
Stenosis was usually diffuse along the full length of the stent and irregular in some vessels (Fig 1). Only three stenoses (≥50% narrowing in comparison with the reference diameter) were seen at the stent margins; two of them were in the control group and were nonconcentric. The mean minimum lumen diameters proximal and distal to the stent were similar in the four treatment groups, with a tendency toward a larger distal diameter in the vessels exposed to paclitaxel in contrast medium (Table 3).


Figure 1
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  		Figure 1b: Left anterior oblique angiograms 4 weeks after stent placement compare SESs and stents on DEBs: (a) LAD artery DEB (left) and CX artery SES (right), (b) LAD SES (left) and CX DEB (right), (c) LAD DEB (left) and CX SES (right), (d) LAD DEB (left) and CX SES (right), and (e) LAD SES (left) and CX DEB (right). Arrows indicate the artery segments treated with stents. The remaining lumina in the stent segments treated by means of the coated DEBs are larger than or equal to the lumina in the segments treated by means of SESs.

 

Figure 1
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  		Figure 1c: Left anterior oblique angiograms 4 weeks after stent placement compare SESs and stents on DEBs: (a) LAD artery DEB (left) and CX artery SES (right), (b) LAD SES (left) and CX DEB (right), (c) LAD DEB (left) and CX SES (right), (d) LAD DEB (left) and CX SES (right), and (e) LAD SES (left) and CX DEB (right). Arrows indicate the artery segments treated with stents. The remaining lumina in the stent segments treated by means of the coated DEBs are larger than or equal to the lumina in the segments treated by means of SESs.

 

Figure 1
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  		Figure 1d: Left anterior oblique angiograms 4 weeks after stent placement compare SESs and stents on DEBs: (a) LAD artery DEB (left) and CX artery SES (right), (b) LAD SES (left) and CX DEB (right), (c) LAD DEB (left) and CX SES (right), (d) LAD DEB (left) and CX SES (right), and (e) LAD SES (left) and CX DEB (right). Arrows indicate the artery segments treated with stents. The remaining lumina in the stent segments treated by means of the coated DEBs are larger than or equal to the lumina in the segments treated by means of SESs.

 

Figure 1
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  		Figure 1e: Left anterior oblique angiograms 4 weeks after stent placement compare SESs and stents on DEBs: (a) LAD artery DEB (left) and CX artery SES (right), (b) LAD SES (left) and CX DEB (right), (c) LAD DEB (left) and CX SES (right), (d) LAD DEB (left) and CX SES (right), and (e) LAD SES (left) and CX DEB (right). Arrows indicate the artery segments treated with stents. The remaining lumina in the stent segments treated by means of the coated DEBs are larger than or equal to the lumina in the segments treated by means of SESs.

 

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  		Table 3. Angiographically Determined Minimum Vessel Lumen Diameter Proximal and Distal to Stents according to Treatment Method

 
Histomorphometry
The outer vessel diameter was about 3 mm, with no difference between the treatment groups (Tables 4, 5). The mean total vessel area in the slices varied slightly from about 7 to 8 mm2 between the treatment groups (P > .05). The injury score, as defined by Schwartz et al (16), was also similar in all treatment groups (P > .5). The injury score of about 1.5 indicates that the internal elastic lamina is lacerated, the media is compressed or lacerated, and the external elastic lamina is intact but may be compressed.


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  		Table 4. Results at Histomorphometry for Each Treatment Method

 

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  		Table 5. P Values for Differences between Treatments at Histomorphometry at 4-week Follow-up

 
Contrary to these parameters, which characterize the state of the vessel segments at the time of stent implantation, all measures of lumen narrowing due to neointimal formation indicated differences between the different treatments:

The overexpanded lumen diameter characterized by the stent struts shrank to some extent in all groups, with shrinkage being most pronounced in the vessels not treated by means of an antiproliferative drug (P < .01 vs SES and DEB groups). The maximum thickness of the neointimal layer and the neointimal area were largest in the control group (P < .01 vs SES and DEB groups), while the luminal area was smallest (P < .001 vs SES and DEB groups). Conversely, vessels treated with a DEB displayed the largest lumen diameter and luminal area (P > .05 vs SES group), whereas the maximum neointimal thickness (P > .05 vs SES group) and the neointimal area (P < .01) were smaller in the DEB group than in the other groups. Percentage area stenosis was less (P < .01) in the vessels treated with the DEB than in any of the other groups (Fig 2).


Figure 2
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  		Figure 2: Graph of percentage area stenosis (mean ± standard error of the mean) determined at histomorphometry 4 weeks after intervention in the control group (no drug), paclitaxel in contrast medium group (CM Pac), DEB group, and SES group. The difference to the other groups in percentage area stenosis with the DEB was statistically significant (P < .001 vs the control and paclitaxel-containing contrast medium, P = .003 vs SES).

 
Although hardly any neointima could be detected in some of the vessel segments treated with the DEB, the stent struts were covered by a thin layer of endothelium (Fig 3).


Figure 3
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  		Figure 3: Examples of transverse histologic slices through arteries treated with stents. (Hematoxylin-eosin stain.) CM Pac = paclitaxel in contrast medium. Only a thin layer of neointimal tissue between the vessel lumen and the black stent struts is found in the vessel treated with the DEB, whereas neointimal proliferation resulted in substantial lumen narrowing in the control vessel.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCE IN KNOWLEDGE
 References
 
Drug delivery performed by placing the drug in contrast media or on balloon surfaces is different from that performed by using drug-eluting stents. With the drug in the contrast medium or on the balloon, somewhat higher doses and concentrations are applied for a very short time (Table 6). The concentrations of paclitaxel achieved in iopromide are about 20 times higher than in saline or other aqueous media because iopromide greatly enhances the solubility of paclitaxel (8). The lipophilic drug within the contrast medium is not enclosed in micelles or other structures that prevent it from immediate uptake into the vessel wall during the short residence time. The high concentration of paclitaxel in iopromide solution explains the improved effect of the drug in comparison with results of the study by Oberhoff et al (20), in which paclitaxel in saline was used at a far lower concentration. The balloons release about 80% of the drug coated on their surface at once (10), thus providing within a very short time a dose that is higher than the dose released by stents over the course of weeks. The drug is more evenly distributed on the vessel surface because it is not bound to the struts. Blood flow and other transport processes, as well as biotransformation, result in a rapid decrease of the antiproliferative activity in the tissue. Nevertheless, this initial inhibition of smooth muscle cell proliferation appears to be sufficient to prevent neointimal proliferation at least for some weeks, as indicated by results of several studies in pigs and in cell cultures (7,8,10).


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  		Table 6. Dose and Release Characteristics of Local Drug Delivery in Coronary Arteries

 
Effectiveness in the Animal Model
Restenosis inhibition has been tested in a variety of animal models as reviewed by Schwartz et al for coronary (6) and peripheral (21) arteries. Although there are obvious differences compared with human atherosclerotic arteries, the coronary overstretch model in young domestic pigs is the preferred model used in the development of drug-eluting stents. We have chosen this model for our study because the correlation to findings in clinical trials is best established. The design of the study followed the recommendations of Schwartz et al (6) in respect to the choice of animals, arteries, overstretch, comedication, time to repeat angiography, and measures of effectiveness. Overestimation of restenosis inhibition by new methods in animal experiments has been attributed to the use of histopathologic evaluation instead of angiography or intravascular ultrasonography. Therefore, we performed quantitative coronary angiography, in spite of the fact that it is not as precise as histomorphometry.

Our study design included a direct comparison of bare stents, drug-eluting stents (ie, SESs), and DEBs in the same animal to reduce interindividual variation. Transfer of an effective concentration of paclitaxel or rapamycin from one coronary artery to the other can be excluded on the basis of the direction of blood flow, dilution in the general circulation, and results from other studies (8,9). Surprisingly, in the five animals in which the SES and DEB treatments were compared, results at angiography suggested less narrowing of the artery treated with DEBs.

This result was confirmed at quantitative coronary angiography and histomorphometry. Area stenosis in the control group was 68%, which is slightly higher than in previous studies (7,8,10,18). Here, the control group showed mean area stenosis of 55%–59%, whereas Carter et al (19) reported lower values. Area stenosis refers not to the initial lumen area but to the total vessel area as defined by the external elastic lamina. It is overstating the degree of stenosis. Also, the neointimal area in the control group in our study, 5.1 mm2, is at the upper limit of previously published values, which range from 3.7 to 5.1 mm2. In line with the findings in the control group, area stenosis and neointimal area observed for the SES group and the paclitaxel in contrast medium group were higher than reported by Suzuki et al (18) and Scheller et al (7,8,10), respectively. Compared with all other treatments, the drug-coated balloon with instant drug release resulted in a smaller neointimal area and area stenosis (P < .01), indicating that in the porcine coronary overstretch model, sustained drug release is not a precondition for inhibition of neointimal proliferation.

The balloon coating method was adjusted to the respective balloon-stent system provided by the manufacturer (Bavaria Medizin Technologie). For technical reasons, we were not able to crimp the same type of stent on the DEB as we used in the other three groups. Thus, the stent design may have contributed to the low neointimal hyperplasia observed in the vessels treated by means of the DEB. As outlined in the Materials and Methods section, the stent on the DEB was a balloon-expandable stainless steel (316 L) stent, just as the other stents, but differed from the other stents by a slightly reduced strut thickness (0.10 mm compared with 0.14 mm) and a multicell instead of a closed-cell design. It has been proved that stent design affects restenosis rates (22), but the effect never came close to that of antiproliferative drugs such as rapamycin or paclitaxel. The main difference between the treatment groups can be assigned to the drugs.

Limitations of the Study
Differences in the structure and physiologic characteristics of coronary arteries in juvenile pigs compared with those in patients with atherosclerosis may be more relevant in case of short-time drug administration to the surface of the vessel wall compared with sustained release from stent struts implanted in the tissue. The difference may be even larger if peripheral vessels in patients are the target. However, the porcine coronary overstretch model is considered the best available model for preclinically testing the safety and effectiveness of coated stents for restenosis inhibition. Because of a lack of clinical data, no relationship between the results in this model and in patients has yet been established regarding local drug delivery by methods or carriers other than stents.

Another limitation results from the observation period of only 4 weeks. This covers the most critical time in respect to thrombotic events and healing, but it remains to be determined for how long the beneficial effect will be maintained in animals and patients. Furthermore, the study compares different treatments or devices; it does not provide a comparison between application techniques of the same drug.

Practical applications: Stents are the most widely used devices in PTCA. In coronary arteries, restenosis inhibition by drug-eluting stents is safe and efficacious (3). Nevertheless, in some procedures, such as treatment of in-stent restenosis or stenoses in bifurcations, stents are either not desirable or not applicable (23). A clinical trial of coronary in-stent restenosis has shown effectiveness of paclitaxel-coated balloons (24).

Neointimal proliferation also contributes to restenosis following percutaneous transluminal angioplasty in small extracardiac vessels. Here, stent implantation is frequently not the first treatment choice (1,25,26). Initial results with drug-eluting stents were not satisfactory (27,28). It remains to be seen whether inhibition of neointimal proliferation independent of stent implantation may contribute to vessel patency for an extended time.


   ADVANCE IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
References
 


   ACKNOWLEDGMENTS
 
The authors thank Antje Mittag and Dirk Mahnkopf, PhD, Institute of Medical Technology Magdeburg, Germany, for the excellent technical support of the study in pigs.


   FOOTNOTES
 

Abbreviations: CX = left circumflex • DEB = drug-eluting balloon • LAD = left anterior descending • PTCA = percutaneous transluminal coronary angioplasty • SES = sirolimus-eluting stent

See Materials and Methods for pertinent disclosures.

Author contributions: Guarantors of integrity of entire study, U.S., B.S., M.B., B.H.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, U.S., B.S., B.H.; experimental studies, U.S., B.S., C.A., C.B.; statistical analysis, J.D.; and manuscript editing, all authors


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCE IN KNOWLEDGE
 References
 

  1. Muradin GS, Bosch JL, Stijnen T, Hunink MG. Balloon dilatation and stent implantation for treatment of femoropopliteal arterial disease: meta-analysis. Radiology 2001;221:137–145.[Abstract/Free Full Text]
  2. Nakatani M, Takeyama Y, Shibata M, et al. Mechanisms of restenosis after coronary intervention: difference between plain old balloon angioplasty and stenting. Cardiovasc Pathol 2003;12:40–48.[CrossRef][Medline]
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