l.
`
`·t\-J L
`
`The
`~ew England
`Journal of Medicine
`
`Established in 181.2 as The NEW ENGLAND JOURNAL OF MEDICINE AND SURGERY
`
`Abstracts in the
`advertising
`sections
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`VOLUME 316
`
`:MARCH 19, 1987
`
`NUMBER 12
`
`Original Articles
`Intravascular Stents to Prevent Occlusion
`and Restenosis after Transluminal
`Angioplasty ......................... .
`ULRICH SIGWART, jACQUEs PuEL,
`VELIMIR MIRKOVITCH, FRANCIS JOFFRE,
`AND LuKAs KAPPENBERGER
`Risk of Ulcerative Colitis among Former
`and ~urrent Cigarette Smokers ....... .
`EDWARDcJ. BoYKO, THOMAS D. KoEPSELL,
`DAVID R. PERERA, AND THOMAS s. lNUI
`· I)ecreasing Risk of Leukemia with Prolonged
`Follow-up after Chemotherapy and
`Radiotherapy for Hod,gkin's Disease ...
`DouGLAS W. BLAYNEY, DAN L.' LoNGo,
`RoBERT C. YouNG, MARK H. GREENE,
`SusAN M. HunBARD, MARCIA G. PosTAL,
`PATRICIA L. DuFFEY,
`AND VINCENT T. DEVITA, jR.
`Hypocalciuria in Preeclampsia ..••........
`PHYLLIS A. TAUFIELD, KATHY L. ALES,
`LAWRENCE M . RESNICK, MAURICE L. DRUZIN,
`JosEPH M. GERTNER, AND joHN H. LARAGH
`Preliminary Results of a Double-Blind, Ran-
`domized, Placebo-Controlled Trial of
`Cyclosporine in Myasthenia Gravis ....
`RICHARD S.A. TINDALL, juLIA A. RoLLINs,
`J. THEODORE PHILLIPS, RALPH G. GREENLEE,
`LIESELOTTE WELLS, AND GEORGE BELENDIUK
`
`Special Article
`Current Trends in Cigarette Advertising
`and Marketing .............•...•. -....
`RoNALD M. DAVIS
`
`Medical Intelligence
`Allogeneic Bone Marrow Transplantation in
`a Patient with Chemotherapy-Resistant
`Progressive Histiocytosis X .......... .
`0LLE RINGDEN, LARS AHsTROM,
`BERIT L6NNQVIST, lNGVAR BAYRD,
`ERIK SvEDMYR, AND GosTA GAHRTON
`
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`THE NEw ENGLAND JouRNAL OF MEDICINE (ISSN 00~ .
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`Case Records of the
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`A 28-Year-Old Woman with Pain in the
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`GwiLYM S. LoDWICK AND ANDREW E. RosENBERG
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`736
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`Editorials
`Present and Future Treatment of Myasthenia
`Gravis...............................
`DANIEL B. DRACHMAN
`A Ban on the Promotion of Tobacco
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`KENNETH E. wARNER
`Langer hans Cell Histiocytosis . . . . . . . . . . . . .
`DIANE M. KoMP
`Massachusetts Medical Society......
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`More on Progress against Cancer . . . . . . . . . . . . .
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`Cigarette Counteradvertising for Children......
`Primitive Plaques and Memory Dysfunction in
`Normal and Impaired Elderly Persons.....
`Subcutaneous Emphysema as a Complication of
`Oxygen Therapy Using Nasal Cannulas....
`To the Pediatric Ophthalmologist, with Thanks .
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`Book Reviews ......................... .
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`Notices ................................ .
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`Corrections
`The Inheritance of Gilles de Ia Tourette's Syn-
`drome and Associated Behaviors: Evidence
`for Autosomal Dominant Transmission ... .
`Medicine and Health Care in South Africa .... .
`Amiodarone .............................. .
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`STJUDE1060
`IPR of Patent No. 6,821,297
`
`

`

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`STJUDE1060
`IPR of Patent No. 6,821,297
`
`

`

`The New England
`Journal of Medicine
`
`©Copyright, 1987, by the Massachusetts Medical Society
`
`Volume 316
`
`MARCH 19, 1987
`
`Number 12
`
`INTRAVASCULAR STENTS TO PREVENT OCCLUSION AND RESTENOSIS
`AFTER TRANSLUMINAL ANGIOPLASTY
`
`ULRICH SIGWART, M.D., jACQUES PuEL, M.D., VELIMIR MIRKOVITCH, M.D., FRANCis joFFRE, M.D.,
`AND LuKAs KAPPENBERGER, M.D.
`
`Abstract Occlusion and restenosis are the most com-
`mon reasons that transluminal balloon angioplasty may
`fail to provide long-term benefit. An intravascular mechani-
`cal support was therefore developed with the aim of pre-
`venting restenosis and sudden closure of diseased arter-
`ies after angioplasty. The endoprosthesis consists of a
`self-expandable stainless-steel mesh that can be implant-
`C7.d nonsurgically in the coronary or peripheral arteries. Ex-
`periments in animals showed complete intimal coverage
`within weeks and no late thrombosis during a follow-up
`period of up to one year.
`We performed 10 implantations in 6 patients for iliac or
`femoral arterial disease; 24 coronary-artery stents were
`implanted in 19 patients who presented with coronary-
`artery restenoses (n = 17) or abrupt closure (n = 4) af-
`
`ter transluminal angioplasty or deterioration of coronary-
`bypass grafts (n = 3). We observed three complications
`in the group with coronary disease. One thrombotic
`occlusion of a stent resulted in asymptomatic closure,
`a second acute thrombosis was managed successfully
`with thrombolysis, and one patient died after bypass
`surgery for a suspected but unfound occlusion. Follow-
`up in the patients has continued for nine months without
`evidence of any further restenoses within the stented
`segments.
`Our preliminary experience suggests that this vascular
`endoprosthesis may offer a useful way to prevent occlu-
`sion and restenosis after transluminal angioplasty. Long-
`term follow-up will be required to validate the early suc-
`cess of this procedure. (N Engl J Med 1987; 316:701-6.)
`
`ALTHOUGH most stenoses of coronary and pe-
`.L-\. ripheral arteries can now be traversed and dilat-
`ed by balloon angioplasty, the unpredictable problems
`of abrupt closure and late restenosis of the dilated
`segment continue to compromise the overall results of
`this promising procedure. In addition to the pharma-
`cologic, 1 mechanical,2•3 and thermal techniques4-6
`under investigation to deal with these problems, intra-
`vascular stents may provide a useful approach to pre-
`venting both acute occlusion and late restenosisJ-13
`None of the current designs of intravascular stents
`are ideal, however, especially with respect to homoge-
`neous distribution of force, ease of placement, con-
`formability, and stability. A new system has been de-
`veloped, consisting of a stainless-steel multifilament,
`self-expanding, macroporous stent and an innovative
`instrument for placing it (Medinvent SA, Lausanne,
`Switzerland). We report our preliminary experience
`with the placement of stents in peripheral and coro-
`nary arteries after transluminal balloon angioplasty of
`a diseased arterial segment.
`
`From the Division of Cardiology, Department of Medicine, Centre Hospitalier
`Universitaire Vaudois, Lausanne, Switzerland; and Centre Hospitalier Universi-
`taire Rangueuil, Toulouse, France. Address reprint requests to Dr. Sigwart at
`the Division of Cardiology, Centre Hospitalier Universitaire Vaudois, CH-1011
`Lausanne, Switzerland.
`Supported in part by a grant (3,835,083) from the Swiss National Fund.
`
`METHODS
`Description of the Stent
`The stent is woven from a surgical-grade stainless-steel alloy for-
`mulated according to the specifications of the International Stand-
`ards Organization. The prosthesis (Fig. 1) is geometrically stable,
`pliable, and self-expanding. Its elastic and pliable properties are
`such that its diameter can be substantially reduced by moderate
`elongation. It can be constrained on a small-diameter delivery cath-
`eter, and as the constraining membrane is progressively removed,
`the elastic device will return to its original (unconstrained) larger
`diameter (Fig. 1). When the prosthesis is implanted in a vessel
`whose caliber is less than that of its unconstrained diameter, the
`residual elastic radial force in the prosthesis will tend to dilate the
`artery. Dilation will continue until an equilibrium is attained be-
`tween the circumferential elastic resistance of the arterial wall and
`the dilating force of the prosthesis. The constrained wire-mesh pros-
`thesis is held at the distal end of the delivery catheter (Fig. 1A) by a
`doubled-over membrane, the outer layer of which can be progres-
`sively withdrawn. Two radiopaque metal markers on the delivery
`catheter facilitate identification of the end of the prosthesis· at the
`time of its deployment. The outer diameter of the loaded catheter
`system is 1.5 7 mm, and prostheses up to 6.5 mm in expanded diame-
`ter can be mounted on this delivery device. Prostheses larger in
`diameter for use in peripheral arteries have correspondingly larger
`delivery systems.
`
`Experiments in Animals
`Prostheses up to 6.5 mm in diameter were mounted on the deliv-
`ery catheter and were passed with conventional guiding catheters
`into the femoral, popliteal, and coronary arteries.
`
`STJUDE1060
`IPR of Patent No. 6,821,297
`
`

`

`702
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`March 19, 1987
`
`Peripheral Arteria/Implants
`In three mongrel dogs weighing 25 to 35 kg that were given
`heparin, eight transluminal implants were placed in branches of
`the femoral arteries at the level of the knee through the common
`femoral artery. The diameters of the prostheses ranged from 2 to
`6.5 mm, and the lengths ranged from 20 to 70 mm. No anticoagu-
`lants were given after placement. All the dogs were evaluated week-
`ly by Doppler-flow monitoring for four weeks and at three-month
`intervals by angiography.
`
`Coronary Arterial Implants
`In seven dogs, seven coronary prostheses wen~ implanted through
`the femoral artery with use of 8 French coronary guiding catheters.
`Under fluoroscopy, one stent was placed in the right coronary ar-
`tery, one was placed in the first marginal branch of the right coro-
`nary artery, and five were placed in the proximal left anterior de-
`scending coronary artery. One of the five last-mentioned prostheses
`extended into the left main coronary artery. The stents ranged from
`
`A
`
`8
`
`c
`Figure 1. The Self-Expanding, Elastic, Macroporous Tubular
`Prosthesis, Which Is Woven from Stainless Steel, Is Shown (Pan-
`el A) Constrained on the Delivery Catheter, (B) Half Open during
`Deployment, and (C) Unconstrained and Fully Expanded.
`
`l I
`l
`
`2.5 to 3.5 mm in diameter and 15 to 20 mm in length. Again, no anti-
`coagulants were given after implantation, but an intraoperative
`heparinized perfusion was given.
`
`Implants in Humans
`After the trials in animals, a protocol for implants in humans was
`approved by the hospital ethics committee, and informed consent
`according to the Helsinki Declaration was obtained from each pa-
`tient before the intervention.
`
`Peripheral Arterial Implants
`For peripheral arterial implantation, highly symptomatic pa-
`tients were selected who had (I) iliac or femoral arteries with long
`and complex stenoses in which balloon angioplasty had either failed
`or offered a poor prognosis, or (2) iliac or femoral restenosis after
`previous angioplasty.
`Ten stents were implanted during seven procedures in six pa-
`tients (four femoral and three iliac arteries). Stent diameters ranged
`from 6 to 12 mm, and lengths from 30 to 80 mm. Prostheses up to
`6.5 mm in expanded diameter were delivered through an 8 French
`coronary guiding catheter; larger stents were deployed with use of
`an 8 French delivery system introduced directly through an ordi-
`nary 9 French arterial introducing sheath. Drug therapy consisted
`of acetylsalicylic acid (500 mg) the day before the intervention and
`a bolus injection of 10,000 IU of heparin during the implantation,
`followed by intravenous heparin (partial thromboplastin time at
`least twice the control value) until oral acenocoumarol had pro-
`longed the prothrombin time to a therapeutic level (2V2 times con-
`trol). A fixed combination of aspirin (330 mg) plus dipyridamole
`(75 mg) once daily in addition to oral acenocoumarol was also given
`from the first postoperative day during the first three months of
`follow-up.
`In two patients, totally occluded arteries were recanalized and
`stents were placed. One patient had a left superficia!"femoral-artery
`occlusion 30 em in length, which failed to remain patent despite
`adequate balloon angioplasty followed by local infusion of uroki-
`nase. Two consecutive prostheses 6 mm in diameter and 8 em in
`length were implanted. A longstanding 8-cm occlusion of the left
`external iliac artery was mechanically recanalized and dilated,
`and since no adequate flow was attained, a stent 8 em in length and
`12 mm in diameter was placed (Fig. 2) . All the other prostheses
`were placed in stenotic arteries that had not responded satisfactorily
`to balloon angioplasty.
`
`Coronary Arterial Implants
`Three conditions were considered indications for the insertion of
`endoluminal stents in coronary vessels or coronary-bypass grafts:
`( l) restenosis of a major coronary artery after previous balloon
`angioplasty; (2) stenosis of aortocoronary-bypass grafts (in these
`patients the stents were placed in the bypass grafts themselves); and
`(3) acute coronary occlusion secondary to intimal dissection follow-
`ing balloon angioplasty (the placements of stents in these patients
`were categorized as emergency implantations).
`Twenty-four coronary stents were implanted after transluminal
`balloon angioplasty in 19 patients during 20 operative procedures.
`In one patient the deployment of the stent in the left anterior de-
`scending coronary artery failed because of mechanical problems
`with the delivery catheter; since no reserve device was available,
`implantation was abandoned, without further complications.
`After successful angioplasty, the balloon catheter was exchanged
`for the stent delivery system over a 0.014-inch (0.036-cm) exchange
`guide wire. The diameter of the stent was chosen to be about 15
`percent larger than that of the native artery. Stents 15 or 20 mm in
`length, depending on the lesion, were placed to cover the entire
`diseased segment. Finally, the inner surface was smoothed by brief
`balloon dilatation.
`The pharmacologic treatment involved inhibitors of platelet
`aggregation (1 g of aspirin the day before the procedure) and in-
`traoperative heparin (15,000 units intravenously). During stent
`implantation, 50,000 to 100,000 units of urokinase were slowly in-
`
`STJUDE1060
`IPR of Patent No. 6,821,297
`
`

`

`Vol. 316 No. 12
`
`INTRAVASCULAR STENTS AND TRANSLUMINAL ANGIOPLASTY- SIGWART ET AL.
`
`703
`
`fused through the coronary guiding catheter. Intravenous heparin
`was continued postoperatively until the oral anticoagulation with
`acenocoumarol became effective. All patients received calcium-
`channel-blocking agents, 330 mg of aspirin, and 75 mg of dipyrida-
`mole (Persantine) per day, starting four to eight hours after the
`operation.
`Eieven stents were placed in the left anterior descending coronary
`arteries, eight stents in the right coronary arteries, two in the cir-
`cumflex arteries, and three in venous coronary-artery bypass grafts.
`Two patients received a second stent at a later date, in each case for
`a new lesion, not adjacent to the original stent. There were four
`emergency implantations for acute occlusion following transluminal
`coronary angioplasty.
`
`RESULTS
`
`Experiments in Animals
`Peripheral Arterial Implants
`Two dogs were chosen to be killed after six months
`and one after nine months. Six stents were fully pat-
`ent, one demonstrated a mural thrombus with a 50
`percent reduction in luminal diameter, and one, which
`was perfused in a retrograde manner in an artery that
`had been ligated proximally, showed complete reca-
`nalization. The prostheses remained free from intimal
`
`Figure 2. Superficial Femoral Artery after Mechanical Recanaliza-
`tion of a Total Occlusion 30 em Long, Followed by Implantation of
`Two Endoprostheses.
`For better visualization of the stents, the right-hand panel shows
`contrast medium injected at a point distal to the two prostheses
`through a 4.5 French angiography catheter. Note the nonstented
`lesion 4 em below the knee. Three more prostheses were im-
`planted three months later to treat severe lesions within
`nonstented segments.
`
`hyperplasia; moreover, all the side branches leaving
`the stented segments of the main vessel remained pat-
`ent (Fig. 3). Figure 4 shows an example of a prosthesis
`firmly embedded in the arterial wall. This specimen
`was recovered from a branch of the femoral artery at
`the level of the left knee nine months after implanta-
`tion. Scanning electron microscopy showed the neoin-
`tima smoothly filling the pores between the stent fila-
`ments. The neointimallayer was about 450 J.Lm thick,
`and no signs of necrosis due to the continuous mural
`pressure of the metal filaments were seen. The endo-
`thelial surface was very similar to the original arterial
`endothelium.
`
`Coronary Arterial Implants
`Angiography performed three and six months after
`implantation showed no signs of obstruction, either
`from thrombus or hyperplasia. However, after the
`dogs were killed at nine months, one unobstructive
`mural thrombus that was considerably larger than the
`coronary artery was seen in a stent (there had been a
`mismatching of diameters). In the single case in which
`the stent extended into the left main coronary artery,
`there was no interference with blood flow in the cir-
`cumflex artery.
`
`Clinical Experience
`Peripheral Arteria/Implants in Patients
`There were no instances of restenosis as judged
`from a reappearance of symptoms, a decrease of pe-
`ripheral blood flow by Doppler measurements, or digi-
`tal subtraction angiography. No important side effects
`were reported, although one patient continued for two
`weeks to report an occasional sensation of a foreign
`body in the iliac area. Mean follow-up in this series is
`more than six months at this writing. Adequate blood
`flow and the disappearance of severe claudication
`were observed in each case. One patient's symptoms
`reappeared after three months because of high-grade
`stenoses of the nonstented femoral arterial segments
`proximal to and between the stents (Fig. 2). These
`stenoses were therefore dilated and reinforced with
`one overlapping the first
`three additional stents -
`two prostheses and two upstream of the first im-
`plants. Again, there was clinical improvement, reduc-
`tion of the pressure gradient, and an increase in pe-
`ripheral flow as demonstrated by Doppler evaluation.
`Although hemodynamically unimportant endothelial
`thickening within the stents was noted during follow-
`up angiography, the patient remained clinically well
`after nine months of follow-up .
`
`Coronary Implants in Patients
`Occlusion of the stent occurred twice when the
`myocardium perfused by the vessel was already hypo-
`kinetic from an old nontransmural infarction; how-
`ever, the prosthesis was successfully recanalized in one
`patient after local infusion of 100,000 units of uroki-
`nase. Thr_9mbolytic therapy was refused by the second
`
`STJUDE1060
`IPR of Patent No. 6,821,297
`
`

`

`704-
`
`THE NEW ENGLAND JOURNAL OF MEDICINE
`
`l\11arch 19, 1987
`
`Figure 4. Scanning Electron Micrograph of
`a Prosthesis Firmly Embedded in the Fem-
`oral Artery of a Dog at the Level of the Left
`Knee Nine Months after Implantation.
`
`patient, who now has mild angina
`with exertion, seven months after
`the procedure.
`One patient presented a special
`problem. He was a 56-year-old man
`who had a 90 percent proximal
`stenosis of the left anterior descend-
`ing coronary artery causing residu-
`al angina one week after an an tero-
`apical infarction. After angioplasty,
`symptomatic restenosis occurred
`within two months. The lesion was
`redilated and a stent was placed.
`Two days later the patient under-
`went maximal stress testing with
`no evidence of ischemia. Fifteen
`minutes afterwards, electrocardio-
`graphic signs of anterolateral ischemia developed. In
`the absence of immediately available angiographic fa-
`cilities, the patient was transferred for bypass surgery
`(internal mammary implant), at which time the signs
`of ischemia had disappeared and the prosthesis was
`found to be patent. The postoperative period was com-
`plicated by problems with hemostasis and signs of
`cardiac tamponade. The following day the patient had
`hypoxia and subsequently died. Postmortem examina-
`tion revealed a patent bypass graft and some traces of
`a recent thrombus in the prosthesis, which was cor-
`rectly situated without extension into the left-main
`bifurcation. No clear link could be established be-
`tween death and the prosthesis, although the stent
`
`may have contributed to coronary spasm soon after
`Stress testing.
`
`Emergency Implantation
`In all four patients in whom a stent was implanted
`to relieve an acute coronary occlusion after balloon
`angioplasty, adequate coronary flow was immediately
`restored. Simultaneously, the electrocardiogram be-
`came normal and symptoms of angina pectoris disap-
`peared. IVlyocardial enzyme measurements showed no
`signs of myocardial damage. Figu~e 5 shows a left
`anterior descending coronary artery before and six
`months after emergency implantation of a prosthesis
`3.5 mm in expanded diameter and 20 mm in length. A
`stent was later placed in the right
`coronary artery of the same patient
`because of restenosis.
`
`Follow-up
`The patient whose vessels are
`shown in Figure 5 had symptomatic
`restenosis of the nonstented right
`coronary artery, which had also
`been dilated at the time of the first
`procedure; this stenosis was dilat-
`ed a second time and a stent ·was
`placed that has remained patent.
`the
`A new stenosis proximal to
`stent developed in one patient four
`
`Figure 3. Scanning Electron Micrograph of
`a Stent Covering the Orifice of a Side
`Branch of a Canine Femoral Artery.
`Nine months after implantation, the metal
`wires are completely coated with a smooth
`neointimal lining, which does not compro·
`mise blood flow to the branch artery.
`
`STJUDE1060
`IPR of Patent No. 6,821,297
`
`

`

`Vol. 316 No. 12
`
`INTRAVASCULAR STENTS AND TRANSLUMINAL ANGIOPLASTY- SIGWART ET AL.
`
`705
`
`months after the first procedure; this lesion was also
`·dilated and reinforced with a separate stent.
`All the other patients recovered normally and left
`the hospital within four days of the procedure. Follow-
`up consisted of weekly and then monthly clinical
`examinations, stress tests at two-month intervals, and
`-up to now in 12 patients- coronary angiography
`within three to six months after the intervention.
`There were no clinical signs of restenosis (except in
`the patients in whom a second prosthesis was implant-
`ed because of new lesions) as judged by the clinical
`history and exercise testing. Coronary angiography
`showed the endoluminal stent smoothly embedded
`with no traces of serious luminal narrowing or sugges-
`tion of intimal hyperplasia within the stent.
`
`DISCUSSION
`Restenosis and acute occlusion following translu-
`minal angioplasty of coronary and peripheral arteries
`restrict the usefulness of this procedure. vVith resteno-
`sis rates as high as 33 percent after coronary angio-
`plasty and even higher (68 percent) in multivessel an-
`gioplasty, the overall value of balloon angioplasty is
`diminished even when one considers the low morbid-
`ity of this procedure, which is frequently repeated sev-
`eral times. The socioeconomic implications of repeat-
`ed angioplasties for restenosis are important and
`compromise the comparatively low cost of the inter-
`vention.
`The rates of early and late repeated occlusion after
`peripheral and coronary angioplasty are independent
`of the operator's skill and the quality of the equip-
`ment. Longer inflation times, high doses of calcium-
`channel blockers, steroids, and other drug regimens
`have so far failed to solve these problems. An alterna-
`tive approach is to provide a suitable endoluminal
`support for the diseased vessel wall.
`Several designs have been proposed, including ela.§.-.
`tically self-expanding spirals, memory-metal types
`(thermally expandable and relatively inelastic), and
`balloon deformable (quasi-rigid) models. Endotheli-
`alization with uniform and consistent intimal thick-
`ening and patency of side branches, such as we
`have described, has also been reported by others,9
`but with some minor differences. It appears that the
`length of time it takes to cover the stent surface de-
`pends on the thickness of the metal element. Thus,
`Wright et al. 9 reported only 30 percent covering
`after one month for wire 0.46 mm thick, whereas we
`found complete covering of 0.09-mm filaments with-
`in three weeks. As compared with inelastic devices,
`we think that the self-expanding stent, by virtue of
`its inherent pliability, provides a smooth transition
`.between the stented segment and adjacent native ar-.
`tery; this has been corroborated by histologic stud-
`ies of the junction between the stent and the non-
`stented artery. A longitudinal flexible stent, which
`is also flexible even when mounted on its delivery
`catheter, will permit easier access through tortuous
`vessels to the target site.
`
`A
`
`8
`
`c
`Figure 5. Left Coronary Artery (Panel A) before Angioplasty,
`(B) after the Development of Complete Occlusion after Angio-
`plasty, and (C) Six Months after Emergency Recanalization of,
`and Stent Implantation in, the Left Anterior Descending
`Coronary Artery.
`The stent is invisible (Panel C) because