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(Circulation. 1996;93:423-430.)
© 1996 American Heart Association, Inc.

Articles

Reduction in Thrombotic Events With Heparin-Coated Palmaz-Schatz Stents in Normal Porcine Coronary Arteries¹

Peter A. Hårdhammar, MD; Heleen M.M. van Beusekom, PhD; Håkan U. Emanuelsson, MD; Sjoerd H. Hofma, MD; Per A. Albertsson, MD; Pieter D. Verdouw, PhD; Eric Boersma, MSc; Patrick W. Serruys, MD, PhD; Willem J. van der Giessen, MD, PhD

From the Department of Cardiology, Thoraxcenter, Erasmus University Rotterdam (The Netherlands), and Division of Cardiology, Sahlgrenska Hospital, Gothenburg, Sweden.

Correspondence to Willem J. van der Giessen, MD, Department of Cardiology, Thoraxcenter, Bd 412, Erasmus University Rotterdam, 3015 GD Rotterdam, The Netherlands.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background The use of stents improves the result after balloon coronary angioplasty. Thrombogenicity of stents is, however, a concern. In the present study, we compared stents with an antithrombotic coating with regular stents.

Methods and Results Regular stents were placed in coronary arteries of pigs receiving no aspirin (group 1; n=8) or aspirin over 4 weeks (group 2, n=10) or 12 weeks (group 3, n=9). Stents coated with heparin (antithrombin III uptake, 5 pmol/stent) were placed in 7 pigs that did not receive aspirin (group 4). The other animals received aspirin and coated stents with a heparin activity of 12 pmol antithrombin III/stent (group 5, n=10) or 20 pmol/stent (group 6, n=10; group 7, n=10). Quantitative arteriography was performed at implantation and after 4 (groups 1, 2, and 4 through 6) or 12 weeks (groups 3 and 7). In an additional 5 animals, five regular and five coated stents (20 pmol/stent) were placed and explanted after 5 days for examination of the early responses to the implants. Thrombotic occlusion of the regular stent occurred in 9 of 27 in groups 1 through 3. However, in 0 of 30 of the animals receiving high-activity heparin-coated stents (groups 5 through 7), thrombotic stent occlusion was observed (P<.001). Histological analysis at 4 weeks showed that the neointima in group 6 was thicker compared with its control group 2 (259±104 and 117±36 µm, P<.01), but at 12 weeks the thickness was similar (152±61 and 198±49 µm, respectively). Comparison at 5 days suggested delayed endothelialization of the coating.

Conclusions High-activity heparin coating of stents eliminates subacute thrombosis in porcine coronary arteries.

Key Words: stents • thrombosis • heparin

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Over the past 15 years, the operator experience and equipment involved in PTCA have improved. Nevertheless, acute or subacute occlusion of the dilated artery occurs in 3% to 8% of cases within hours to days, requiring an immediate repeat procedure or emergency coronary bypass graft surgery.¹ Another unresolved issue of PTCA is late restenosis, which occurs in 30% to 50% of cases, predominantly after 3 to 6 months.^{2 3} There is no effective pharmacological prevention of the restenosis process.^{4 5 6}

Aspirin can reduce the incidence of acute occlusion to a limited extent.⁷ High-dose systemic antiplatelet drug therapy may be more effective as it reduces early complications after PTCA by approximately 35%—at the expense, however, of more bleeding complications.⁸ This beneficial effect appears to be sustained, as a reduction in the need for later revascularization has also been observed.⁹

The only proven approach to reduction of the incidence of late restenosis (by 25% to 31%) is the use of coronary stents.^{10 11} The use of stents, however, is not free from complications because of the risk of stent thrombosis and bleeding or vascular complications, requiring both costly monitoring and a prolonged hospital stay.^{10 11 12 13 14 15 16 17 18 19} Therefore, a combination of drugs and stents has been proposed to overcome both early and late complications of PTCA.^{16 17 18 19}

Several approaches have been introduced to improve the surface properties of vascular prostheses.²⁰ Heparin coating of stents is an attractive method because the anticoagulant properties of heparin,²¹ its inhibitory effect on mesenchymal cell growth and differentiation,^{22 23 24} and extracellular matrix formation²⁵ are well established. The aim of the present study was to compare the thrombogenicity and histological features of stents with and without heparin coating after implantation in the coronary circulation in pigs.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Balloon-Expandable Intracoronary Stent
The stent used in the present study (Palmaz-Schatz coronary stent, Johnson & Johnson Interventional Systems Co) is composed of two segments (7 mm each) of slotted tubes connected by a short (1-mm) coupler, and it is mounted coaxially over the balloon of an angioplasty catheter.²⁶ When expanded, the metallic contact surface area is 10% to 15%.

Heparin Coating of Palmaz-Schatz Stent
The coating applied to the stents consists of heparin molecules that have been end point covalently coupled to an underlying polymer matrix (a modification of the CBAS²⁷ [Carmeda AB]). The efficacy of this coating is based on the continuous and repeated interaction between the active site of the immobilized heparin and circulating antithrombin III. The coating consists, in principle, of four layers. A first layer on top of the steel is a polyamine layer; a dextran sulfate layer is applied on top of that. The third base layer is polyamine. Finally, these functional amino groups are covalently coupled to the aldehyde groups of partially degraded heparin molecules (Fig 1). The heparin activity of the coated stent is measured according to its ability to bind antithrombin III with high affinity and expressed in picomoles (of antithrombin III) per stent.

View larger version (22K): [in this window] [in a new window]   Figure 1. Principle of heparin coating and mechanism of antithrombotic action of heparin-coated stent surface. A, The metal surface has been conditioned with functional amino groups that can bind covalently with the aldehyde group of fragmented heparin molecules. B, Thus, end point–attached heparin molecules form a heterogeneous population, some without and some with the epsilon-shaped antithrombin III (AT)–binding region. C, Circulating antithrombin can bind to the active site, which catalyzes the inhibition of activated coagulation factors, eg, thrombin (T). The resultant inactive antithrombin/thrombin complex (TAT) is released into the bloodstream, thereby enabling the active site on the heparin to repeat interaction with AT and TAT.

Approximately 15% of the end point–attached heparin molecules will carry the high-affinity antithrombin III–binding site, which is responsible for the anticoagulant action of the compound. Modifications of the surface chemistry and selection of heparin molecules with binding sites for antithrombin III were used to increase the antithrombin III–binding activity of three coatings of incremental activity (onefold to fourfold higher activity per surface area than the conventional CBAS). Pilot in vitro studies have shown that (1) mounting and expansion of the stent did not affect the integrity of the coating, as demonstrated with a colorimetric assay using toluidine blue²⁸ ; and (2) sterilization with heat or ethylene oxide reduced the antithrombin III–binding activity considerably (50% to 70%). Consequently, the stents used in this study were initially coated under clean room conditions but not sterilized (group 4; Table 1); coated stents for later groups were sterilized and therefore initially coated with a higher heparin content to compensate for the loss during ethylene-oxide sterilization (groups 5 through 7). At the end of the study, the remaining heparin activity at the surface of explanted stents (both coated and controls) was assessed with the use of an antithrombin III–binding assay.

View this table: [in this window] [in a new window]   Table 1. Experimental Groups, Treatment, and Size of Implanted Stents

Animal Preparation
Experiments were performed in cross-bred Landrace-Yorkshire pigs (20 to 28 kg in weight; HVC) as described previously.²⁹ The investigations were carried out according to a protocol approved by the Committee on Experimental Animals of Erasmus University. After an overnight fast, the animals were sedated with 20 mg/kg ketamine hydrochloride. After endotracheal intubation, the pigs were connected to a ventilator that administered a mixture of oxygen and nitrous oxide (1:2, v/v). Anesthesia was maintained with 1 to 4 vol% enflurane. Antibiotic prophylaxis was administered by an intramuscular injection of 1000 mg of a mixture of procaine penicillin G and benzathine penicillin G. Under sterile conditions and after additional local anesthesia of the skin with lidocaine 2%, an arteriotomy of the left carotid artery was performed, and a 9F introduction sheath was placed. Heparin sodium (10 000 IU) was administered, and a 9F guiding catheter was advanced to the ascending aorta. After measurement of arterial blood pressure and heart rate and after withdrawal of an arterial blood sample for the measurement of blood gases and acid-base balance (settings of the ventilator were corrected if necessary), coronary angiography was performed with iopamidol (Iopamiro 370) as contrast agent. Seventy-eight animals underwent the catheterization procedures. Of these, 9 animals were excluded from final analysis due to the following reasons. In 3 animals, a stent was not implanted due to a coronary artery anomaly, air embolism at baseline angiography, and spontaneous arrhythmias, respectively. Complications during stent implantation (ventricular fibrillation or arrest during balloon inflation or balloon rupture) occurred in 3 other animals. Postoperative problems (aspiration hypoxia, reanesthesia for postoperative bleeding, and a leg problem) were the reason for premature withdrawal in 3 additional animals and were considered to be unrelated to stent placement.

Final analysis was performed for 69 animals, in which stent implantation was successful and no adverse events were observed.

Stent Implantation
Based on the angiograms and with the diameter of the guiding catheter used as a reference, a segment with a diameter of 2.5 to 3.5 mm was selected in the proximal LAD using on-line quantitative coronary arteriography after intracoronary injection of 1 mg isosorbide dinitrate. Side branches were not avoided, but stents were not placed at curved coronary artery segments. Then, a heparin-coated or a regular stent (in alternate order) crimped on its deflated balloon was advanced over a 0.014-inch steerable guide wire to the preselected site for implantation. The balloon was inflated to a pressure of 6 atm for 30 seconds and then deflated, and negative pressure was maintained for 20 seconds. The catheter was then slowly withdrawn while leaving the stent in place. After repeat angiography of the stented coronary artery, the guiding catheter and the introducer sheath were removed, the arteriotomy was repaired, the skin was closed in two layers, and the animals were allowed to recover from anesthesia. Animals receiving the control stents and the three types of heparin-coated stents were assigned to seven groups (Table 1). Fifteen animals did not receive antithrombotic prophylaxis after the procedure (groups 1 and 4). Forty-nine animals received 300 mg acetylsalicylic acid/day PO, starting the day before implantation; this treatment was continued daily during the follow-up period.

Follow-up Angiography and Quantitative Analysis
The anesthesia and catheterization procedures at 4- or 12-week follow-up were similar, as described above; coronary angiography was performed in the same projection, and identical settings of the x-ray equipment were used during implantation. All coronary angiograms were measured on-line using a personal computer-based system for quantitative angiographic analysis with the edge-detection method (Cardiovascular Measurement System, Medis Inc).³⁰

Microscopic Examination
After angiography at follow-up, the thorax was opened by a midsternal split, and a lethal dose of sodium pentobarbital was injected intravenously, immediately followed by cross-clamping of the ascending aorta. After the aortic root was punctured above the coronary ostia, 300 mL saline followed by 500 mL buffered 4% formaldehyde were infused under a pressure of 150 cm H₂O. The heart was then excised, and the coronary arteries were dissected from the epicardial surface. The stented and adjacent unstented segments were placed in 4% formaldehyde in phosphate buffer, pH 7.3, for at least 48 hours in preparation for microscopy. After further fixation for at least 48 hours, the tissue was processed for light microscopic examination as described previously.²⁹ Hematoxylin and eosin was used as a routine stain, and resorcin-fuchsin was used as an elastin stain.

Morphometry
For measurement of the thickness of the various layers of the arterial wall, at least six resorcin-fuchsin–stained sections of each stented coronary segment were examined from the proximal, mid, and distal portions of the stent. With a calibrated eyepiece, the neointimal and medial thicknesses were measured on top of and between the stent struts. The distance between the endothelial lining and the stent strut or internal elastic lamina was taken as the thickness of the intima.³¹ The media was defined as the layer between the internal and external elastic laminae.

Assessment of Stent Thrombosis
Immediately after the animals were sacrificed and the arteries underwent fixation or after autopsy, the stented coronary artery was opened lengthwise using a pair of fine scissors and examined under a dissection microscope. Low-power photomicrographs were taken from each coronary artery, and the presence or absence of stent occlusion was assessed by two observers. In addition, light microscopical examination was used to confirm the thrombotic origin of the occlusion, as demonstrated by the presence of a platelet-rich, layered thrombus.

Assessment of the Early Response to Stent Implantation
In an additional group of five animals, one regular stent (in the left circumflex coronary artery) and one high-activity heparin-coated stent (in LAD) were placed per animal. These animals received procedural heparin during the implantation plus 300 mg acetylsalicylic acid during 5 days of follow-up. At 5 days, repeat angiography was performed, followed by excision of the stented coronary arteries for light microscopy and morphometry, as described. In addition, lectin cytochemistry and scanning electron microscopy were performed to study and compare the early blood and tissue responses to the regular and coated stents, by using previously described methods.³²

Statistical Analysis
All data are expressed as mean±SD. The occurrence of thrombotic events between the groups was compared by Fisher's exact test. A two-tailed P value of <.05 was considered statistically significant. The significance of the changes in the angiographic and morphometric data were evaluated by unpaired t test when ANOVA indicated that the groups belonged to different populations. Because of repeated comparisons for these two parameters, only P<.01 (two-tailed) was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Systemic Hemodynamics and Blood Gases During Angiography
During implantation, heart rate and mean arterial blood pressure were similar for all groups (99±14 beats per minute and 74±14 mm Hg, respectively). At restudy after 4 weeks (groups 1 through 5), heart rate (105±18 beats per minute) and mean arterial blood pressure (85±17 mm Hg) were comparable, but when restudied after 12 weeks, groups 6 and 7 showed an increase in these parameters (to 112±25 beats per minute and 101±22 mm Hg, respectively; P<.01). However, at no time was there any difference between the groups with coated or control stents. The oxygenation of arterial blood and acid-base balance were in the normal range during stent placement and follow-up angiography.

Follow-up Evaluation
In 64 animals, the stent could be placed successfully, and these were included in the final analysis. Eight of the animals that received a noncoated stent died suddenly within 48 hours, whereas a ninth pig survived 4 weeks with an infarction of the LAD perfused myocardium (Table 2).

View this table: [in this window] [in a new window]   Table 2. Experimental Groups, Outcome, and Size of Stents With Complications

In the animals receiving the 5 pmol/stent heparin coating without aspirin (group 4), three cases of sudden death occurred within 48 hours. However, all animals survived that received a stent with 12 or 20 pmol/stent heparin coating in combination with oral aspirin (groups 5 through 7). The data in Table 2 also show that problems were not associated with smaller-diameter stents.

Quantitative Angiographic Measurements
Quantitative analysis of the baseline coronary angiograms showed that luminal diameters of the proximal LAD were similar for all groups (range, 2.9 to 3.2 mm; Table 3). The diameters of the stent-mounted angioplasty balloons at maximal inflation pressure also did not differ between the groups (range, 2.8 to 3.2 mm). The measured balloon-to-artery ratio was 1.0, demonstrating precise matching of balloons and recipient arteries. Implantation of the stents did not change the arterial diameters of the groups (range, 2.8 to 3.2 mm).

View this table: [in this window] [in a new window]   Table 3. Quantitative Angiographically Assessed Mean Diameters of Arteries and Balloon at the Site of Stent Implantation at Baseline, Immediately After Placement, and After 4 or 12 Weeks of Follow-up

After 4 weeks of follow-up, the average luminal diameter showed no change in both control groups as well as in the groups receiving the low- or intermediate-activity heparin-coated stent. However, in the highest-activity heparin-coated stent group (group 6), the diameter had decreased by 0.7±0.6 mm (P<.01).

After 12 weeks of follow-up, the group receiving the control stents did not show a decrease in luminal diameter compared with the 4-week data for groups 1 and 3. However, the group receiving the high-activity coated stents (group 7) now showed no change in luminal diameter compared with its baseline and immediately poststent angiograms, and an actual increase occurred compared with the 4-week high-activity stented group.

Stent Thrombosis
On postmortem examination, all stents retrieved from animals that received a regular stent and died suddenly demonstrated stent occlusion (Fig 2A and 2B) in several cases accompanied by myocardial infarction of the corresponding anterior wall of the left ventricle. Major disruption of the vessel wall or incomplete expansion or marked overdilatation of the stent was not observed in these specimens. Microscopical examination confirmed the presence of a layered, platelet-rich thrombus in all occluded stents. In the group receiving the low-activity coated stents (group 4), all three cases of sudden death proved to be caused by stent thrombosis. In none of the animals receiving a stent with 12 or 20 pmol heparin/stent was partial or occlusive stent thrombosis observed.

View larger version (172K): [in this window] [in a new window]   Figure 2. A, Photomacrograph of a control stent (group 3) occluded with a platelet-rich thrombus (arrow) causing sudden death approximately 27 hours after implantation. The stent has been opened longitudinally (arrowheads indicate struts). B, Photomicrograph of the thrombosed stent shown in A. Both the stent wire (* indicates stent wire void) and the luminal border are lined with a single layer of leukocytes (arrow). The lumen (L) is obstructed by a platelet-rich thrombus, showing the typical layered appearance (arrowhead) of an in vivo thrombotic occlusion. M indicates media; A, adventitia; E, erythrocytes; F, fibrin; and bar, 50 µm.

Therefore, (sub)acute stent thrombosis was observed in 37% in the groups receiving regular noncoated stents (P<.01), and the only factor that could be identified as responsible for stent occlusion was the absence of the high-dose heparin coating.

Light Microscopy
Examination of the seven groups showed that all stents were covered by a neointima of variable thickness (Fig 3A through 3D), ranging from only several cell layers to a collagen- and elastin-rich tissue up to 500 µm in thickness. Typically, such a neointima contained a large amount of extracellular matrix with smooth muscle cells in disarray near the intimal/medial border. Toward the lumen, the tissue was more dense and cellular, containing macrophages and a few lymphocytes but mainly smooth muscle cells oriented in a circular fashion.

View larger version (131K): [in this window] [in a new window]   Figure 3. Composition of the light microscopy of the control stent (A, group 2) and the heparin-coated stent (B, group 6) at 4 weeks after implantation and of the control stent (C, group 3) and the heparin-coated stent (D, group 7) at 12 weeks after implantation. In all specimens, the tissue response consisted of a neointimal thickness containing smooth muscle cells within a collagenous matrix. Although the thickness varied among the groups, the overall reaction was limited in its nature. I indicates intima; M, media; A, adventitia; *, stent wire void; and bar, 25 µm. Hematoxylin azophloxin stain.

Medial impression by the stent struts was variable. Some metal struts lacerated only the internal elastic lamina. A minority of the struts, however, penetrated the medial layer, resulting in either a clean cut into the media or actual dissection, sometimes with damage to the external elastic lamina. Even in those cases, inflammatory changes were minimal and discrete (Fig 3). An active inflammatory reaction was rarely observed, and only in two (control stents) was a cellular response with monocytes and macrophages more prominently associated with the stents.

The only difference between the 4- and 12-week groups was an increase in neovascularization from adventitia toward the intima in the later group, in both coated and control stents. The only late features exclusively seen in some coated stents was an occasional spot of calcification (in two coated stents) and swollen appearance of the overlying endothelium (three coated stents).

Morphometry
Comparison after 4 weeks of follow-up showed that there was no difference in neointimal thickening between groups 1 and 4 (both received no aspirin after the procedure) and between groups 2 and 5 (Table 4). However, a comparison of groups 2 and 6 and of groups 5 and 6 showed that the increased thickening of the neointima in the group with the highest heparin activity was significant (P<.01). The thickness of the media under the metal struts did not differ between the groups.

View this table: [in this window] [in a new window]   Table 4. Morphometry

After 12 weeks of follow-up, the difference between coated and noncoated stents was no longer observed as the thickness in the high-activity heparin-coated group was significantly smaller after 12 weeks (group 7) compared with at 4 weeks (group 6; P<.01). Along the length of the stent, from proximal to distal, there was an observed increase in intimal thickening for both the coated and the regular stent groups. The measurements of other vessel wall layers did not differ between the groups.

Assessment of the Early Response to Stent Implantation
In the additional group of five animals, five coated stents (20 pmol antithrombin III uptake) and five regular stents were placed (balloon-to-artery ratio, 1.0±0.1). Angiographically measured coronary diameters before implantation, immediately after implantation, and after 5 days of follow-up for the heparin-coated stents were 2.9±0.2, 3.0±0.2, and 3.0±0.3 mm, respectively; and for the regular stents, diameters were 2.7±0.2, 2.9±0.2, and 2.8±0.5 mm, respectively (P=NS). Morphometrical assessment of the thickness of the layer covering the stent struts showed no differences between the two types of stents (57±17 µm for the heparin-coated stents and 62±47 µm for the regular stents). Light microscopy demonstrated that the early local reactions to both types of stent were similar, showing a proteinaceous adherent layer with adherent leukocytes. However, both the lectin cytochemical identification of endothelium and the scanning electron microscopy demonstrated a decreased endothelial cell covering of the heparin-coated stents (Fig 4A and 4B).

View larger version (154K): [in this window] [in a new window]   Figure 4. A, Scanning electron microscopy of the regular Palmaz-Schatz stent at 5 days after implantation. The photograph, taken at the level of an intersection between two stent struts (arrows), shows advanced endothelial covering but marked leukocyte adhesion. Bar indicates 57 µm. B, Scanning electron microscopy of the highest-activity heparin-coated Palmaz-Schatz stent at 5 days after implantation. The photograph, again taken at the intersection between two stent struts, clearly shows the absence of endothelial cells. Only a variable number of leukocytes and a protein layer cover the struts, whereas in-between the endothelial layer appears to be intact. Bar indicates 57 µm.

Heparin Activity of the Stents After Explantation
The control stents showed no detectable antithrombin III–binding activity after 4 weeks of follow-up (n=2). However, measurement of the coated stents explanted at the same time revealed that 20% to 50% of this activity was still detectable at 4 weeks (n=2).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Metal Stents Reduce Restenosis but Are Thrombogenic
PTCA with balloon dilatation is a good alternative treatment to aortocoronary bypass surgery for patients with symptomatic coronary heart disease. Surgery offers longer symptomatic relief but is more invasive and requires a longer rehabilitation period.³³ PTCA allows patients to regain active life earlier, but in many patients the duration of symptomatic relief is shorter due to the restenosis process. Recently, two randomized clinical trials that compared balloon angioplasty with stent implantation were completed.^{10 11} Both trials showed that stent implantation reduced the need of revascularization due to restenosis by approximately 30%. These new data will influence the choice of therapy in patients eligible for both surgery and PTCA.

The favorable outcome of stent implantation, however, has its price: a longer hospital stay and a 15% vascular complication rate, both caused by the use of an extensive anticoagulant regimen to prevent subacute thrombosis of the stent. Stent thrombosis has been recognized as a problem inherent to all metal stents in animal experiments as well as in patients with coronary heart disease.^{10 11 12 13 14 15 16 17 18 19 32 34 35 36}

Heparin Coating
Stents with improved surface characteristics may further enhance the clinical results of coronary stenting by reducing the risk of thrombotic stent occlusion. The same techniques that have been applied to improve the blood compatibility of vascular grafts may also enhance the quality of stents.²⁰ A widely used technique is coating of the cardiovascular implant surface with heparin.^{37 38} In the present study, we tested an established heparin coating (CBAS)²⁷ and subsequent modifications of this coating applied the stainless steel Palmaz-Schatz coronary stent.

Reduction in Stent Thrombosis by High-Activity Heparin Coating
In the present study, the standard CBAS coating (5 pmol/stent) did not reduce the incidence of early thrombotic complications (Table 2). Subsequently, 300 mg aspirin was administered daily to the animals to reduce the background thrombogenicity in the animal stent model. The use of stents coated with higher heparin activity subsequently groups eliminated thrombotic events compared with a new appropriate control group also receiving aspirin. The incidence of stent thrombosis in the control groups (25% to 33%) in the present study is similar to that observed earlier with a self-expanding metallic stent in the same model.³⁵ This high incidence of stent thrombosis of regular stainless steel stents is not an artificial feature of this swine model. During the initial clinical experience with the Palmaz-Schatz stent, an 18% incidence of subacute closure was observed when warfarin or Coumadin treatment was withheld.³⁹ Very recently, it has been reported that noncoated slotted tube stents show a 42% thrombotic occlusion rate in the rabbit iliac model.⁴⁰

We did not include an additional experimental group receiving the standard coating and aspirin. Therefore, we cannot exclude a significant contribution of the surface conditioning inner layers of the coating (to which the heparin molecules were attached) to the overall thromboresistance of the stent. However, evidence in favor of an active role for heparin may be provided by studies that showed that thrombin inhibitors reduced platelet and fibrinogen deposition during arterial injury or stent placement in the pig.^{41 42} However, other studies have shown that coating metal stents with only a passive polymer layer also reduces local platelet deposition or thrombotic occlusion in experimental animals.^{35 43 44} Nevertheless, the results of the present study are consistent with the antithrombotic action of the CBAS coating in extracorporeal systems.^{45 46}

Effect of Heparin Coating on Neointimal Hyperplasia
Heparin has been shown to reduce smooth muscle cell proliferation, an important component of the restenosis process, in injured arteries of experimental animals.^{22 23 24 47 48 49} This property of heparin may be unrelated to its anticoagulant effect.²³ In the present study, we did not observe a reduction in the thickness of the neointimal layer due to the heparin coating. On the contrary, a temporary increase occurred in the group with the highest activity of the coating. Results for the early-response (5-day) group of the present study showed delayed wound healing, which indicates that the well-known action of heparin to reduce endothelial cell attachment and growth⁵⁰ is most likely responsible for the reduced endothelial control of smooth muscle cell growth.

However, the increased neointimal response with the highest activity heparin coating at 4 weeks proved to be only temporary as after 12 weeks the tissue response was similar for coated and noncoated stents.

Conclusions
This study demonstrates that heparin coating of metal stents reduces thrombotic events associated with their deployment in normal coronary arteries of pigs. If confirmed in clinical studies, this coated stent may permit reduction in the systemic anticoagulation responsible for vascular complications and longer hospital stay.

	Selected Abbreviations and Acronyms

 

CBAS = Carmeda Bioactive Surface LAD = left anterior descending coronary artery PTCA = percutaneous transluminal coronary angioplasty

	Acknowledgments

 
This study was supported by Johnson & Johnson Interventional Systems, Warren, NJ. The authors thank Yvonne van der Helm and Deirdre Whelan for helping with the histological analysis. Rob van Bremen is acknowledged for expert technical assistance. We are grateful to Drs E. Scholander and J. Riesenfeld (Carmeda AB, Stockholm, Sweden) for measurement of the antithrombin III–binding activity of the explanted stents.

	Footnotes

 
¹ This manuscript is placed in "Clinical Investigations and Reports" so as to accompany the preceding manuscript.

Received August 14, 1995; revision received October 16, 1995; accepted October 18, 1995.

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