VOL XXXIX, NO 2
`i1 PR6071
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`SEPTEMBERIOCTOBER 1996
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`No.2
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`Wflfi‘gyress m
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`Edited by
`EDMUND H. SONNENBLICK, MD
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`MICHAEL LESCH, MI.)
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`STENTS
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`Leonard Schwartz, MD
`(Rum! Editor
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`Subject US Copyrlgf': Laws
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`Medtronic Exhibit 1438
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`Progress in
`CARDIOVASCULAR DISEASES
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`EDMUND H. SONNENBLICK, MD, Editor
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`MICHAEL LESCH, MD, Editor
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`Progress in
`CARDIOVASCULAR DISEASES
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`Stents
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`VOLUME XXXIX, NO 2
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`SEPTEMBER/OCTOBER
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`Ifltroductlon
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`..............LeonardScnwartz
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`81
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`C
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`t‘
`cronary Artery Sten mg
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`: Indications and Cost Implications..................................En'cA. Cohen
`and Leonard Schwartz
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`Contemporary Stcnt Designs: Technical Considerations, Complications. Role of Intravascular
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`I
`t‘on Theta
`....Jefirey J. Popma, Alexandra J. Lansky, Shigenon' Ito,
`Ultrasound, and Anttcoagu a l
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`Gary S. Mintz, and Martin B. Leon
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`83
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`11]
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`129
`New Stcnt Technomgies......................... Yukio Ozakt', Andante G. Molar-tit, and Patrick W. Senuys
`Noncoronary Vascular Stenting Kenneth W. Snidennan 141
`E
`. Con enital Heart Disease ........................ Lee N. Benson, David Nykanen,
`ndovascular Stents m
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`and Robert M. Freedom 165
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`Nonvascular Stents ................................................................ Leslie Vanderburgh and Chin-Sing H0
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`187
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`Clinical Trials Review
`' With S ecial
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`An iotensm-Converllng Enzyme Inhibition After Acute Myocardial Infarction
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`Reference to the Fourth International Study of Infarct Survwal (ISIS-4) .......... Mushabbar Syed,
`Steven Bonak. and Syed M. Jafn' 20]
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`New Stent Technologies Yukio Ozaki, Andonis G. Violaris, and Patrick W. Serruys Coronary stents were developed to overcome the two main limitations of balloon angioplasty, acute occlu- sion and long-term restenosis. Coronary stents can tack back intimal flaps and seal the dissected vessel wall, thereby treating acute or threatened vessel clo- sure after unsuccessful balloon angioplasty. After suc- cessful balloon angioplasty, stents can prevent late vessel remodeling (chronic vessel recoil} by mechani- cally enforcing the vessel wall and resetting the vessel size, resulting in a low incidence of restenosis. All currently available stents are composed of metal, and the long-term effects of their implantation in the coronary arteries are still not clear. Because of the metallic surface, they are also thrombogenic; there- fore, rigorous antiplatelet or anticoagulant therapy is theoretically required. Furthermore, they have an im- perfect compromise between scaffolding properties and flexibility, resulting in an unfavorable interaction between stents and unstable or thrombus-laden plaque. Finally, they still induce substantial intimal hyperplasia that may result in restenosis. Future stents can be made less thrombogenic by modifying the metallic surface or coating it with an antithrombotic agent or a membrane eluting an antithrombotic drug. The unfavorable interaction with the unstable plaque and the thrombus burden can be overcome by cover- ing the stent with a biological conduit, such as a vein, or a biodegradable material that can be endogenous, such as fibrin, or exogenous, such as a polymer. Finally, the problem of persisting induction of intimal hyperplasia may be overcome with the use of either a radioactive stent or a stent eluting an antiproliferative drug. Copyright © 1996 by W.B. Saunders Company C ORONARY stents were developed to over- come the two main limitations of balloon angioplasty, acute occlusion and long-term reste- nosis. Coronary stents can tack back intimal flaps and seal the dissected vessel wall, thereby treating acute or threatened vessel closure after unsuccessful balloon angioplasty. After success- ful balloon angioplasty, stenting can prevent late vessel remodeling (chronic vessel recoil) by mechanically enforcing the vessel wall and reset- ting the vessel size, resulting in a low incidence of restenosis. These theoretical advantages of coronary stenting have been tested in two major randomized trials. 1,2 Both the Belgium Nether- lands Stent Study (Benestent) and Stent Reste- nosis Study (STRESS) confirmed the theoreti- cal advantages of coronary stenting by showing a reduction in angiographic restenosis and clini- cal events during follow-up examination. 1,2 This reduction in restenosis was achieved by a greater luminal gain despite the accommodation of a greater absolute loss in lumen diameter in the stent group, suggesting greater neointimal hyper- plasia in this group. The reduction in long-term restenosis was counterbalanced by bleeding com- plications related to the anticoagulant therapy. Therefore, a number of limitations have to be overcome before coronary stenting achieves its full potential. CURRENTLY AVAILABLE STENTS The currently available stents, a description of their design, and the year of their clinical introduction are listed in Table i and are shown in Fig 1. In the absence of prospective random- ized interstent comparative trials, it is difficult to draw conclusions on the relative merits and demerits of each stent design. However, indi- vidual experience and registry data from each stent allow preliminary impressions to be made on the advantages and limitations of each stent. Wallstent The Wallstent (Schneider, Bulach, Switzer- land) was the pioneer of stents 34 through which we learned the risk profile and indications for coronary stenting and the necessity and adverse effects of antithrombotic measures. The new less-shortening Wallstent has been developed recently with a change in the braiding angle, and results of the first clinical implantation of this second generation stent in coronary vein grafts have been promising. 6 The unique advan- tages of the Wallstent include the extensive range of diameters and lengths available, thereby allowing the Wallstent to be used for the man- agement of long spiral dissections 7 and for vessel reconstruction) The sheathed "balloon- From the Catheterization Laboratory, Thoraxcenter, Eras- mus University, Rotterdam, The Netherlands. Address reprint request to Patrick W. Serruys, MD, PhD, FACC, FESC, Catheterization Laboratory, Thoraxcenter, Eras- mus University Rotterdam, Postbus 1738, 3000 DR Rotterdam, The Netherlands'. Copyright © 1996 by W.B. Saunders Company 0033-0620/96/3902-000455. 00/0 Progress in Cardiovascu/arD[seases, Vol XXXIX, No 2 (September/October), 1996: pp 129-140 129
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`130 OZAKI, VIOLARIS, AND SERRUYS Table 1. Currently Available Stunts Undergoing Clinical Evaluation Diameter Length First Clinical Coronary Stent Design Deployment Premounted Delivery (mm) (mm) Implantation Wallstent Wire mesh Self-expanding Balloon Over-the-wire 3,5-6.0 12-42 1986 not required 1991 (less- shortening) Palmaz- Slotted tube Balloon-expandable Premounted Over-the-wire 3.0-4.0 8-18 1988 Schatz and unmounted and both 1994 (heparin- coated) Gianturco- Incomplete coil Balloon-expandable Premounted Over-the-wire 2.5-4.0 20-40 1989 (GR-I) Roubin clam-shell loop 1995 (GR-II) Wiktor Sinusoidal Balloon-expandable Premounted Over-the-wire 3.0-4.5 16 t991 helical coil or monorail 1995 (short- wave) Multi-Link Multiple rings with Balloon-expandable Premounted Over-the-wire 3.0-3.5 15 1993 multiple links Cordis Sinusoidal Balloon-expandable Premounted Over-the-wire 3.0-4.0 15 1994 helical coil AVE Micro Zigzag axial Balloomexpandable Premounted Monorail 2.5-4.0 6-36 1994(Micro-I) struts 1995 (Micro-II) Expandable uniform Balloon-expandable Unmounted 2.0-5.0 9-32 1995 cellular mesh NIR Both less" delivery system in combination with the free, unconnected wire-mesh design, render the Wallstent one of the most trackable, pushable, and flexible stents for negotiating tortuous ves- sel and passing through proximally deployed stents (Fig 2). Furthermore, recent modification of the delivery system allows recapture of the stent before final deployment and also allows Fig 1. Coronary stents that have undergone clinical evaluation are shown clockwise from the left: Wallstent, Palmaz-Schatz, Wiktor, Gianturco-Roubin, Cordis, AVE Micro, and ACS Multi-Link. (Reprinted with permission. ~)
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`NEW STENT TECHNOLOGIES 131 Fig 2. (A) Long complex stenosis in left anterior descending artery before intervention. (B) Final angiographic outcome after the deployment of the new less-shortening Wallstent, Note the smooth contour stented segment with no loss of side branches and the absence of vessel sprinting that may be obseved after the deployment of a more rigid stent. improved positioning, raising the possibility for the use of shorter Wallstents in clinical practice. Its fine cross-hatched mesh design provides excellent scaffolding properties particularly well- suited to entrap friable material in diffusely diseased vein grafts. Additionally, enforced me- chanical remodeling produced by oversizing Wallstent implantation conveys a favorable 6-month clinical and angiographic outcome in both stenosis and total occlusions in native coronary arteries. 74 Its primary limitations are the longitudinal shortening of the stent on radial expansion and motion of the stent during retraction of the rolling membrane, thus render- ing the stent less suitable for ostial lesions. Palmaz-Schatz Stent The Palmaz-Schatz stent (Johnson & Johnson Interventional Systems, Warren, N J) has been extensively investigated in a broad range of coronary lesions. 9-18 It is the only stent to date to have completed prospective randomized trials comparing the clinical and angiographic out- come with that of balloon angioplasty. 1,z The angiographic results after Palmaz-Schatz stent implantation are predictable, and the slotted- tube design allows the performance of high- pressure intrastent balloon inflations without risk of structural deformation. However, the low radiopacity of the Palmaz-Schatz stent can render the positioning of a noncompliant baI- loon for postdeployment, high-pressure, intra- stent inflations difficult. Additionally, a higher incidence of restenosis has been reported at the site of the central articulation. 19 To overcome this limitation, a recent model has been devel- oped without the central articulation (spiral articulation design). This model has a higher radiopacity compared with that of the standard single articulation design. The availability of a free, unmounted Palmaz-Schat~z stent that can be crimped by the operator on any balloon provides more procedural versatility and results in a lower profile during stent delivery. How- ever, it does increase the risk of losing the stent during deployment. Gianturco-Roubin Stent Before obtaining Food and Drug Administra- tion (FDA) approval for noninvestigational clini- cal use, most of the clinical data on the Giant- urco-Roubin stent (Cook, ]nc, Bloomington, IN) was gathered in single and multicenter registries in the United States. 2°-25 The indica- tion for the Gianturco-Roubin stent for which most data have been gathered is for the bailout of subocclusive and occlusive dissections after balloon angioplasty in native coronary arteries. The data gathered compare well with the data from historical controls treated by repeated and prolonged balloon angioplasty alone. The re- sults of the first randomized trial of the Giant- urco-Roubin stent in bailout therapy (Gianturco- Roubin stent in Acute Closure Evaluation [GRACE]) are awaited with interest. 26 The principle advantages of the Gianturco-Roubin
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`132 stent include its range of lengths and longitudi- nal flexibility. Although the relatively large interstrut intervals of 1 mm raise questions over the suitability of this stent for the management of friable vein graft lesions, the advantages of the Gianturco-Roubin stent design include mini- mal risk of "jailing" side branches and the potential to perform coronary interventional procedures in side branches through the inter- strut spaces. Whereas this stent excels in long dissections in curved coronary segments (Fig 3), its more generalized use was hindered by the high profile of the first generation. The new Fig 3. (A) Dissection after balloon angioplasty in the proxi- mal left anterior descending artery is shown. (B) After delivery of a Gianturco-Roubin Flexstent through a Superflow 8-French Judkins guiding catheter (Cordis) to the target vessel, the radiopaque markers (located 1 mm proximal and distal to the stent extremities) facilitate the final positioning of the stent before inflation of the delivery balloon. (C) Contrast angiogra- phy poststent deployment shows preservation of the vessel curvature in the stented segment. (Reprinted with permis- sion. z ) OZAKI, VIOLARIS, AND SERRUYS generation flex-II stent overcomes these prob- lems with a lower profile and a higher visibility. Wiktor Stent The available clinical data on the Wiktor stent (Medtronic, Minneapolis, MN) arises from observational studies and registry data, 273° the principle registry of which has been in the management of restenotic lesions. Similar to the Gianturco-Roubin stent, the Wiktor stent is a coil stent that offers marked flexibility and, thus, conformability with the vessel curvature. However, also similar to the Gianturco-Roubin stent, the Wiktor stent is unlikely to excel in the treatment of friable vein grafts because of the large interstrut interval and the subsequently reduced scaffolding properties. The radiopacity of the Wiktor stent allows exquisite positioning of the stent in ostial and focal lesions, and the flexibility of the stent makes it suitable for short dissections on curved coronary segments. The recent introduction of the option of a monorail delivery system improves the user-friendliness of the device. The limitations of the initial prototype of the Wiktor stent included the availability of only one length and the limited scaffolding properties with the potential for the protrusion of intimal flaps through the inter- strut intervals. These limitations have been overcome by the new generation, short-wave- form Wiktor stent, although the radiopacity of this tantalum stent can still interfere with on- line quantitative angiographic analysis of the stented segmentP 1 Multi-Link Stent At present, the ACS Multi-Link stent (Ad- vanced Cardiovascular Systems, London, UK) has the least clinical experience of the currently available stents, having just completed its first 100-patient registry conducted at five European centers. 3z The advantages of this new stent include the flexibility and low profile of the sheathed stent and delivery system. Although the Multi-Link stent design manages to provide remarkable scaffolding properties, the metallic burden to the stented vessel remains very low by virtue of the small diameter of the corrugated struts. The limitations of the stent include its radiolucency, which renders the positioning of noncompliant balloons for postdelivery, high-
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`NEW STENT TECHNOLOGIES pressure intrastent inflations very difficult. The current availability of only one length of 15 mm means that the first prototype can only be used for very focal lesions. After some minor modifi- cations, this stent may offer some significant advantages over the earlier generation of stent designs. The attachment of radiopaque tips on the stent would present a significant enhance- ment. AVE Micro Stent The AVE Micro stent (Applied Vascular Engineering, Santa Rosa, CA) is now undergo- ing clinical evaluation in a large number of countriesY The high degree of radiopacity and balloon-expandable deployment should render this stent ideal for exquisite positioning in highly focal and ostial lesions (Fig 4). However, by virtue of the longitudinal (axial) orientation of its eight struts, the 4-mm AVE Micro stent units may be prone to proximal migration and protrusion; therefore, preferably longer, welded AVE Micro stents should be deployed in ostial locations. The customized range of short lengths make the AVE Micro stent ideal as an adjunc- tive complementary device for multiple stent- ing, filling in the gaps between longer stents, and improving the inflow or outflow of longer stents. Additionally, the high flexibility and low thrombogenecity of the AVE micro stent make it an ideal stent for bailout management after failed balloon angioplasty. 33 Despite the ab- sence of a protective sheath, the low profile and longitudinal strut orientation make the AVE micro stent one of the easiest stents to pass through other proximally deployed stents. The monorail delivery system increases the user- friendliness of the device, which has a short learning curve. The strong radial support prof- fered by the thick struts should make the stent suitable for the prevention of recoil and resteno- sis. However, care should be taken to avoid the positioning of junctions between the uncon- nected 4-ram units at the site of the minimal lumen diameter of lesions to prevent intimal protrusion. Recent developments include the helicoildal welding of multiple 3-mm-length units (Micro stent-II) to provide multiple lengths of up to 36 ram. 133 Fig 4. (A) Short dissection in the origin of the left circum- flex coronary artery after balloon angioplasty is shown. (B} An AVE Micro stent is delivered to the target vessel through an 8-French Amplatz guiding catheter (Schneider Scientific, Wa- tertown, MA). The two radiopaque markers at the extremities of the stent are clearly seen. (C) After delivery of the stent, the thick radiopaque stainless-steel struts facilitate the precise positioning of a short noncompliant balloon (single marker) within the stent for subsequent high-pressure inflations and optimization of stent deployment. (Reprinted with permis- sion. 3)
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`134 Cordis Swnl The Cordis stent (Cordis, Miami, FL) contin- ues to undergo early evaluation in the clinical arena? ~ Similar to the ACS stent, the Cordis stent offers some advantages over the first generation stents by virtue of its low profile, flexibility, and comprehensive scaffolding prop- erties. However, the absence of a protective sheath on the delivery system increases the possibility of stent dislodgement or disruption during delivery. The operator should be aware of the protrusion of the delivery balloon beyond the limits of the Cordis stent if inflations of higher pressure are considered. Although the strongly radiopaque tantalum struts allow exquis- ite positioning (Fig 5) of the stent in short dissections in curved coronary segments, the radiopacity may pose problems for on-line quan- OZAKI, VIOLARIS, AND SERRUYS titative angiographic assessment, particularly during assessment of luminal renarrowing at 6-month angiographic follow-up examination. 31 The relative merits of this stent are currently being evaluated in a European multicenter registry and by Hamasaki et al in Japan. 34 NIR Stent The NIR stent (Medinol, Tel Aviv, Israel) is a recently developed balloon-expandable stent currently undergoing clinical evaluation in some centers in Israel and Europe. Although this stent has a low radiopacity, the stent has a high flexibility and comes in a wide range of custom- ized sizes (diameter, 2 to 5 ram) and lengths (9 to 32 ram). Balloon-unmounted models allow for the choice of various types of balloon for stent delivery and may spare the usage of an i ! ;; i ii~i ¸¸ii;i!! ! I Fig 5. (A) The left coronary artery tesion located at the bifurcation is shown, {B) Postballoon angioplasty dissection type C was clearly seen. (C) Positioning of the Cordis stent was facilitated by the radiopacity of the tantalum struts, which are clearly seen during inflation of the contrast-filled intrastent balloon to 10 atm. (D) Angiography after stent deployment shows the stent struts to be embedded in the vessel wall external to the contour of the contrast-filled lumen.
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`NEW STENT TECHNOLOGIES additional balloon catheter only for stent deliv- ery. A preliminary report indicates a high deploy- ment success rate despite the fact that most of the lesions were difficult to treat because of vessel tortuosity, distal location, and long lesion length. 35 The restenosis rate has not yet been determined. FUTURE STENTS All currently available stents are composed of metal, and the long-term effects of their implan- tation in the coronary arteries are still not clear. Because of the metallic surface, they are throm- bogenic; therefore, rigorous antiplatelet or anti- coagulant therapy is theoretically required. Furthermore, they represent an imperfect com- promise between scaffolding properties and flexibility, resulting in an unfavorable interac- tion between stent and unstable plaque or thrombus burden. Finally, they still induce sub- stantial intimal hyperplasia that may result in restenosis. Future stents can be made less thrombogenic by modifying the metallic surface or coating it with an antithrombotic agent or a membrane eluting an antithrombotic drug. The unfavorable interaction with the unstable plaque and the thrombus burden can be overcome by covering the stent with a biological conduit, such as a vein, or a biodegradable material that can be endogenous, such as fibrin, or exog- enous, such as a polymer. Finally, the problem of persisting induction of intimal hyperplasia may be overcome with the use of either a radioactive stent or a stent eluting an antiprolif- erative drug. Coated Stents Metal coated. In vitro work suggests that surface potential may exert a substantial effect on both the thrombogenicity and antiprolifera- tive effect of metals. High surface potential is associated with pronounced attraction of nega- tively changed particles such as platelets and plasma proteins, thus resulting in high thrombo- genicity. Conversely, however, metals with high surface potential have a substantial antiprolifer- ative effect on fibroblasts, suggesting that, by varying surface charge, we may be able to influence the thrombogenicity and neointimal hyperplasia after stent implantation. One way 135 of accomplishing this would be by modifying the base metal. 36 Metals can be modified either by galvaniza- tion or by ion bombardment. Galvanization involves the electrochemical deposition of metal 3.3 p~m in thickness on the stent and results in 100% of the stent surface being covered before stent expansion. Ion bombardment consists of spluttering a thin metal film onto the stent followed by a bombardment with argon ions. The resulting implantation of metal onto the stent surface increases the thickness by 20 nm, and 75% stent surface coverage is required before expansion. Preliminary experience suggests that coating steel stents with platinum, gold, or copper results in higher in vitro surface potentials but that the incidence of thrombosis in vivo is increased, particularly in stents coated using galvanization. 36 Thus, in contrast to the in vitro suggestion, metal charge does not seem to play a major role in stent thrombogenicity in vivo. Furthermore, a low stent charge appeared to correlate with increased neointimal formation. Therefore, modifying stainless steel stents by covering them with gold, platinum, or copper is unlikely to be the solution to increased thrombo- genicity or neointimal hyperplasia. Cell seeding of stents. Coating of metallic stents with endothelial cells, particularly geneti- cally engineered cells with increased cell sur- face fibrinolytic activity, may improve their thrombogenic nature. Preliminary work has shown the feasibility of this approach. 3v,3s More recently, in vitro work suggests that genetically engineered endothelial cells would allow in- creased fibrinolysis to be promoted by the sur- face localization of urokinase. 39 However, ques- tions remain concerning the number of cells that will remain attached under flow conditions and the legal responsibility in case of failure of endothelial cell function. Immobilized drug coatings. Coating of the stent surface with an antithrombotic agent such as heparin 4°-42 provides a novel solution to the problem of increased thrombogenicity of metal- lic stents and the subsequent need for intensive anticoagulation that results in increased morbid- ity and costs. After encouraging preliminary experience with a heparin-coated Palmaz- Schatz stent in pig coronary arteries, the Bene-
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`Medtronic Exhibit 1438
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`136 stent-II study evaluated the safety of reducing and eliminating anticoagulant therapy in pa- tients receiving a heparin-coated stent. Initial results from the pilot study suggest that sub- acute stent thrombosis does not occur using the heparin-coated stent, which virtually eliminated the bleeding complications after stent implanta- tion and reduced the in-hospital stay to 3 days. 43 The 6-month angiographic follow-up examina- tion also indicates that these coated stents do not induce excess of intimal hyperplasia. 44 The results of follow-up studies in which coumadin and heparin are replaced by ticlodipine and aspirin are awaited. Polymer-coated stents. The stent metal sur- face can be rendered less thrombogenic by coating it with a thin layer of a synthetic polymer. Initial results suggested that, although this may protect against acute thrombotic events, it does not reduce the extent of subsequent neointimal hyperplasia. 4s However, the advan- tage of a polymer-coated stent is that it can be loaded with antithrombotic or antiproliferative agents directed against the neointim