Page 1 of 26
`
`Edwards Lifesciences v. Boston Scientific
`U.S. Patent No. 6,915,560
`IPR2017-00444 EX. 2023
`
`

`

`Coronary Stenting:
`Current Perspectives
`
`Page 2 of 26
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`Page 2 of 26
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`Stent photographs provided by Jan Tuin and Paula Delfos.
`
`Cover images courtesy of Nico Bruining PhD.
`
`Legends to cover images
`1. TWO dimensional intravascular ultrasound image of a WallstentTM obtained in
`vitro.
`
`‘fly through’ reconstruction of intravascular ultrasound
`2. Three dimensional
`images of a VVallstentTM obtained in vitro.
`3. Three dimensional
`‘fly through’ reconstruction of intravascular ultrasound
`images of a WallstentTM obtained in Vivo.
`4. TWO dimensional intravascular ultrasound image of a RadiusTM stent obtained
`in Vitro.
`
`‘fly through’ reconstruction of intravascular ultrasound
`5. Three dimensional
`images of a RadiusTM stent obtained in vitro.
`6. Three dimensional
`(fly through’ reconstruction of intravascular ultrasound
`images of a RadiusTM stent obtained in Vivo.
`7. Two dimensional intravascular ultrasound image of a Palmaz—SchatzTM PS—153
`articulated stent obtained in vitro.
`
`‘fly through’ reconstruction of intravascular ultrasound
`8. Three dimensional
`images of a Palmaz—SchatzT‘“ PS—153 articulated stent obtained in vitro.
`9. Three dimensional
`‘Clamshell’
`reconstruction of intravascular ultrasound
`
`images of a PalmaZ—SchatzTM PS—153 articulated stent obtained in Vivo.
`
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`Page 3 of 26
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`Page 3 of 26
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`

`

`I Coronary Stenting:
`
`Current Perspectives
`
`A Companion to the Handbook of Coronary Stems
`
`Michael ]B Kutryk MD PhD FRCPC
`Catheterization Laboratory
`Division of Cardiology
`Heart Center Rotterdam
`
`Academic Hospital Rotterdam-Dijkzigt
`Rotterdam
`The Netherlands
`
`Patrick W Serruys MD PhD FACC FESC
`Professor of Interventional Cardiology
`Head of the Interventional Department
`Division of Cardiology
`Heart Center Rotterdam
`
`Academic Hospital Rotterdam—Dijkzigt
`Rotterdam and
`
`Professor of Interventional Cardiology
`Interuniversity Cardiology Institute
`of the Netherlands (ICIN)
`Utrecht
`
`The Netherlands
`
`MARTIN DUNITZ
`
`Page 4 of 26
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`Page 4 of 26
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`

`

`©Martin Dunitz Ltd 1999
`
`First published in the United Kingdom in 1999 by
`
`Martin Dunitz Ltd
`
`The Livery House
`7*9 Pratt Street
`London NW1 OAE
`
`All rights reserved. No part of this publication may be reproduced, stored
`in a retrieval system, or transmitted,
`in any form or by any means,
`electronic, mechanical, photocopying, recording, or otherwise, without
`the prior permission of the publisher or in accordance with the provisions
`of the Copyright Act 1988 or under the terms of any licence permitting
`limited copying issued by the Copyright Licensing Agency, 90 Tottenham
`Court Road, London WIP OLP.
`
`A CIP record for this book is available from the British Library.
`
`ISBN 1785317—693-1
`
`Distributed in the United States by:
`Blackwell Science Inc.
`Commerce Place, 350 Main Street
`Malden, MA 02148, USA
`Tel: 1—800w2 1 5—1000
`
`Distributed in Canada by:
`Login Brothers Book Company
`324 Salteaux Crescent
`
`Winnipeg, Manitoba, R3] 3T2
`Canada
`Tel: 204—224—4068
`
`Distributed in Brazil by:
`Ernesto Reichmann Distribuidora de Livros, Ltda
`Rua Coronel Marques 335, Tatuape O3440e000
`Sao Paulo,
`Brazil
`
`Composition by Wearset, Boldon, Tyne and Wear
`
`Printed and bound in Great Britain by
`Biddles Ltd, Guildford and King's Lynn
`
`Page 5 of 26
`
`Page 5 of 26
`
`

`

`‘ CONTENTS
`
`Preface
`
`1. Historical Overview
`
`2. Stents Currently Available
`Mesh stents
`
`Magic Wallstent
`Tubular stents
`Palmaz-Schatz Stents (135453“, SpiralT‘“ and Crown“)
`ACS MULTl—LINKTM, ACS MULTI—LINK RX DUETTM
`RadiusTM
`beStentTM
`TENSUMTM and TENAXT‘“
`
`IRIS IITM , Spiral ForceTM and ZebraTM
`distioTM
`JOSTENTTM Plus, JOSTENTT“ Flex
`Balloon Expandable (BX)TM
`PURA~ATM, PURA—VARIOT‘“, PURA—VARIO—ASTM and
`PURA—VARIO—ALTM
`
`ParagonTM
`V—FlexT“, V-Flex PlusTM
`R StentTM
`
`Parallel-Serial—JangTM (PSI—3)
`lnFlow—StentTM, InFlow—Gold—StentTM
`LP—Sten’cTM
`
`Seaquencem
`CIA (Coronary Improved Architecture)
`Diamond AST“, Diamond Flex ASTM
`PRO—STENTTM
`TerumoT‘“
`
`SynthesisTM
`Medtronic Self—Expanding Nitinol Stent
`CoroflexT‘“
`CrossFlex LCTM
`Coil stents
`GR HT“
`
`V
`
`Wiktor (-GXTM and -i""’“)
`
`ix
`
`1
`
`17
`20
`
`20
`23
`23
`26
`28
`29
`30
`
`30
`33
`34
`36
`
`36
`
`38
`40
`4-0
`
`4-2
`43
`4-3
`
`4-6
`47
`4-7
`4-9
`49
`
`50
`52
`52
`5 3
`5 3
`53
`
`55
`
`V
`
`.
`
`Page 6 of 26
`
`Page 6 of 26
`
`

`

`CONTENTS
`
`CrossFlexTM
`FreedomTM and Freedom ForceTM
`
`AngioStentTM
`Ring stents
`AVE Micro Stent IITM and GFXTM
`Bard XTm
`
`Multidesign stents
`NaviusTM
`NlRTM and NlROYALTM
`
`Custom designed stents
`Randomized Clinical Trials
`
`Stenting compared with PTCA
`Native vessel de—novo stenoses
`
`Saphenous vein graft disease
`Restenotic lesions
`Total occlusions
`Acute or threatened closure after PTCA
`
`Stenting in acute myocardial infarction
`Stenting compared with directional atherectomy
`Evaluation of adjunctive therapy
`Adjunctive pharmacotherapy
`Acute and subacute thrombosis
`Restenosis
`
`Bleeding and vascular complications
`Adjunctive rotational atherectomy
`Adjunctive Doppler flow measurement
`Adjunctive radiotherapy
`Stenting compared with surgery
`Comparison of stents
`Assessment of the role of intravascular ultrasound (IVUS)
`Assessment of the role of high—pressure stent deployment
`Comparison of access site
`Treatment of in—stent restenosis
`
`Stenting in small vessels
`
`Current Indications for Stenting
`Treatment of abrupt or threatened vessel closure during angioplasty
`Primary reduction in restenosis in de—novo focal lesions in vessels greater
`than 3 .0 mm in diameter
`
`Saphenous vein graft disease
`Chronic total occlusions
`
`Acute myocardial infarction
`Restenotic lesions after previous balloon angioplasty
`Ostial and left main disease
`Bifurcation lesions
`
`57
`58
`58
`59
`59
`61
`62
`62
`63
`65
`
`87
`87
`87
`94
`94
`95
`98
`99
`102
`103
`103
`103
`110
`113
`114
`114
`114
`116
`117
`122
`125
`125
`126
`127
`
`139
`140
`
`145
`146
`147
`152
`155
`157
`159
`
`Page 7 of 26
`
`Page 7 of 26
`
`

`

`CONTENTS
`
`Myocardial bridging
`Cardiac allograft vasculopathy
`
`Stent Guidance and Adjunctive Approaches
`Coronary angiography
`Role of intravascular ultrasound
`
`Doppler flow
`Angioscopy
`Debulking devices
`Directional coronary atherectomy (DCA)
`Rotational atherectomy
`Transluminal extraction atherectomy (TEC)
`Eximer laser coronary angioplasty (ELCA)
`
`Complications of Coronary Stenting
`Subacute stent thrombosis
`
`The problem
`Factors affecting stent thrombosis
`Device related (Surface interactions, Rheological factors)
`Patient—related factors
`
`(Vessel characteristics, Haemostatic predictors)
`Technique-related factors
`Prevention
`Treatment
`Restenosis
`
`The problem
`Risk factors
`Prevention
`Treatment
`
`Bleeding and vascular injury
`Stent embolization
`Side—branch occlusion
`
`Coronary perforation
`Infection
`
`Balloon rupture
`Coronary artery aneurysms
`
`7.
`
`8.
`
`9.
`
`Long—Term Follow—Up
`Cost Considerations
`
`Future Trends
`
`Appendix A List of Abbreviations
`
`Appendix B List of Clinical Trials
`Index
`
`170
`170
`
`197
`197
`198
`203
`204
`204
`205
`205
`206
`206
`
`215
`215
`215
`216
`216
`
`220
`222
`226
`233
`234
`234
`237
`240
`247
`250
`251
`252
`252
`253
`253
`254
`
`293
`
`297
`
`301
`
`303
`
`305
`
`307
`
`vii
`
`Page 8 of 26
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`Page 8 of 26
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`

`

`ACKNOWLEDGEMENTS
`
`We are very grateful to Jan Tuin and Paula Delfos at the Thoraxcenter for
`Providing us with superb photographs, sometimes at very short notice, and Dr
`Nico Bruining of the Computer Group for the intravascular ultrasound images.
`At Martin Dunitz Ltd, it was a joy to work once again with our commissioning
`editor, Alan Burgess, whose patience and encouragement helped rather than
`hindered us in completing the manuscript. His colleague, Clive Lawson, was
`instrumental in ensuring we met our deadlines.
`
`viii
`
`Page 9 of 26
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`Page 9 of 26
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`

`

`PREFACE
`
`The use of intracoronary stents has been increasing at a rapid pace since they
`were first used in clinical practice just over a decade ago. This increase is due in a
`large part to the conviction of the interventional cardiology community that stent
`technology can be applied to progressively more complex lesion subsets and
`unstable clinical situations. The success of coronary stenting is the result of the
`introduction of improved implantation techniques, a better understanding of the
`vascular response to injury, and advances in adjunctive pharmacology. The stent
`manufacturing industry has also contributed by providing more versatile and user
`friendly stents, designed specifically to address the problems of thrombosis and
`restenosis, and a host of custom devices designed for use in particular lesion types
`and clinical situations. In response to rapid progress, and fuelling the quest for
`new applications,
`is an ever increasing amount of basic science and clinical
`literature on all aspects of coronary stent implantation. Advances such as the
`development of intravascular brachytherapy,
`local drug delivery techniques,
`novel stent coating technologies and molecular biological approaches now
`represent the cutting edge of research.
`With the enormous amount of newly published material and new advances
`in the field,
`it is becoming increasingly difficult to keep abreast of the new
`developments. Coronary Stenting: Current Perspectives was prepared as a review of
`the available literature on coronary stenting with the goal of identifying the
`indications for stent implantation and the use of adjunctive therapies which are
`supported by clinical evidence.
`It has become commonplace to provide companion editions to all great
`textbooks of cardiology. In keeping with this custom, we felt that the technical
`information found in The Handbook of Coronary Stenting (2” edition) and the
`contents of this book complemented each other so well that they be considered a
`set. We hope that these tandem publications will serve as valuable reference
`texts and provide a comprehensive overview of the current state of the practice
`of coronary stenting and coronary stent technology.
`
`Michael] B Kutryk
`Patrick W Serruys
`
`Page 10 of 26
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`Page 10 of 26
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`

`

`' 1. HISTORICAL OVERVIEW
`
`The use of percutaneously introduced prosthetic devices to maintain the luminal
`integrity of diseased blood vessels was initially proposed by Charles Dotter in
`1964, who speculated that the temporary use of a silastic endovascular splint
`might maintain an adequate lumen after the creation of a pathway across a
`previously occluded vessel.1 Dotter and colleagues were also the first to apply the
`term stent for vascular implants in their description of an experimental technique
`for the non-surgical endarterial placement of tubular coiled—wire grafts in the
`femoral and popliteal arteries of healthy dogs.2 The etymology of the word
`“stent” is unclear. It has been associated with a device to hold a skin graft in
`position, with a support for tubular structures being anastomosed, and with an
`impression of the oral cavity made from Stent’s mass. Stent’s mass was concocted
`by Charles Thomas Stent (1807—85), an English dentist who developed it to form
`an impression of the teeth and oral cavity3’4 (figure 1 . 1). Stent, as applied to
`endovascular scaffolding devices, may also have its origins from the verb “to
`stint”, which means “to restrain within certain limits”. The early stents used by
`Dotter were mounted coaxially on a guidewire and positioned with a pusher
`catheter. Since the pre— and post-implantation stent dimensions were identical,
`the graft diameter was limited by the size of the arteriotomy and the approach
`vessel, and only small coils could be passed percutaneously. Although these stents
`could be properly positioned, stent dislocations and significant narrowing within
`the stented segments occurred. These problems temporarily bridled any
`optimism that such a device might find clinical application in the treatment of
`vascular diseases.
`
`In 1983, two preliminary reports showed the feasibility of transcatheter
`arterial grafting, and rekindled interest in the non—surgical placement of
`endovascular prostheses.5’6 Using coil wire stents made of nitinol, a unique alloy
`of titanium and nickel, Dotter and colleagues5 (figure 1 .2) and Cragg and
`colleagues6 (figure 1.3) described encouraging results of their transcatheter
`endoluminal placement in canine arteries. Nitinol has a unique heat~sensitive
`“memory”, which allowed the coil stent to be compressed or straightened at
`room temperature and introduced through a catheter. When positioned
`properly, the coils were warmed to body temperature or higher. This caused the
`metal to lose its malleability, and allowed the stent to return to its initial
`configuration. These devices successfully maintained vessel patency at 4 weeks in
`
`Page 1 1 of 26
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`Page 11 of 26
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`

`

`HISTORICAL OVERVIEW
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`Figure 1.1: Charles Stent
`(1845—1901), an English dentist
`who lent his name to a tooth mould
`
`(bottom) and perhaps to
`endoluminal scaffolding devices.
`
`
`
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`
`
`non~heparinized dogs. The work established the potential for the use of such a
`device in the non—surgical treatment of vascular disease, and was the catalyst for
`experimentation with a variety of innovative devices.
`Not long after the preliminary reports on the use of nitinol coils, Maass and
`colleagues7 reported the results of implantation of expanding steel spiral springs
`in the aortae and vena cavae of dogs and calves. With the application of torque,
`the springs decreased in diameter, to allow distal delivery. On release of the
`tension the springs expanded to their predetermined dimensions (figure 1 .4).
`Although the spirals remained stable and did not cause perforation, thrombosis,
`
`2
`
`Page 12 of 26
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`Page 12 of 26
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`

`

`HISTORICAL OVERVIEW
`
`
`
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`
`
`
`
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`
`
`
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`
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`
`
`
`
`
`
`Figure 1.2: Nitinol coil Wire stent. Top: compactedfor transcatheter placement. Bottom:
`same coil after heat—induced (60 OC) reversion to initial, anatomically indicated
`cozy‘iguration. (From Dotter CT, Buschmann PAC, McKinney MK, Rosch j Transluminal
`expandable nitinol coil stent grafting: preliminary report. Radiology 1 983,- 147:
`25 9—60.)
`
`
`
`Figure 1.3: Loosely wound nitinol coil graft. Arrow indicates a threaded adapter which
`can be attached to a modified guidewire. The coil Was straightened in ice water and passed
`Via a catheter into the aorta. The coil reformed When heated to body temperature and could
`be positioned using the attached guideWire. (From Cragg A, Lund G, RysaIg/j, Casteneda
`F, Casteneda—Zuniga W, Amplatz K. Nonsurgical placement ofarterial endoprostheses: a
`new technique using nitinol wire. Radiology 1983; 147: 261—63.)
`
`Page 13 of 26
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`Page 13 of 26
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`

`

`HISTORICAL OVERVIEW
`
`
`
`
`
`
`
`Figure 1.4: Various types ofimplanted spiral Springs. The devices were made 9fcorrosion
`resistant heat—treated spring steel alloy. Application of torque to the spiral springs in the
`direction ofthe coils increased the number (yrcoils and reduced the diameter (f the spiral.
`(From Maass D, Zollilerfir CL, Largiadér F, Senning A. Radiologicalfollowup of
`transluminally inserted vascular endoprostheses: an experimental study using expanding
`spirals. Radiology 1984; 152: 659e63.)
`
`or stenosis of the treated vessel, a large diameter applicator was needed for
`introduction and placement, and this limited target lumen access. In 1985, the
`initial results of the implantation of springdoaded self-expanding stents in dogs
`were described by Gianturco and colleagues8 (figure 1.5). That research showed
`the importance of oversizing the stent in relation to the size of the target vessel to
`prevent migration of the prostheses.
`The idea of a balloon-mounted stent for simultaneous dilatation and stent
`
`delivery was introduced by Palmaz and colleagues.9 In 1985, they described
`preliminary results of the implantation of a balloon expandable stainless—steel
`wire mesh in canine peripheral arteries. The device was made from 150 um and
`200 nm diameter continuous woven stainless—steel wire. The cross—points of the
`Wire mesh were soldered with silver to give the device a relatively high resistance
`to radial collapse (figure 1 .6). The following year, Palmaz published data on a
`larger group of 18 balloon expandable stent implantations in canine femoral,
`renal, mesenteric, and carotid arteries.10 These early results foretold problems
`that would plague intravascular stent implantation over the following decade.
`
`4
`
`Page 14 of 26
`
`Page 14 of 26
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`

`

`HISTORICAL OVERVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`
`
`
`
`
`
`(a)
`
`(b)
`
`Figure 1.5: Zigzag expanding stainless steel stent. (a) Collapsed stent beginning to exit
`12 F Teflon sheath. (1)) Stentfully expanded after being pushedfrom the sheath. (From
`Wright KC, Wallace S, Charnsangavej C, Carrasco CH, Gianturco C. Percutaneous
`endovascular stents: an experimental evaluation. Radiology 1 985; 156: 69—72.)
`
`Four thrombotic occlusions occurred in the first group of treated animals, which
`showed that adequate antithrombotic and antiplatelet therapy was needed at the
`time of stent deployment. Palmaz’s group recognized that heparin therapy did
`not prevent late occlusion of stented segments with low flow, and that the best
`results were obtained in those without flow restriction. These are now axioms of
`
`contemporary stenting. Their observation of an overall patency rate of 77% at 35
`weeks was surprisingly similar to the findings of subsequent stent trials.
`With the refinement of equipment, smaller vessels could be accessed, and
`application of stent technology to the coronary system became possible. In 1987,
`Rousseau and colleagues11 tested a flexible, self—expanding stainless~steel mesh
`stent that was restrained with a protective sheath. Forty~seven devices were
`implanted in 28 dogs, 21 of these devices in coronary arteries. No anticoagulant
`or antiplatelet agents were used, and partial or total thrombotic occlusion was
`seen in eight (35%) animals. Thrombus formation occurred at points of rapid
`reduction of vessel diameter, when the end of the prosthesis impinged upon a
`side branch of a major vessel and when there was a high ratio of unconstrained
`(maximal expansion) to implant device diameter. Endothelialization and
`incorporation of the stent into the vessel wall by neo—intimalization occurred by
`
`5
`
`Page 15 of 26
`
`Page 15 of 26
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`

`

`HISTORICAL OVERVIEW
`
`
`
`'."4"""."" V
`
`
`
`’0 o’o’o‘o’o’o’o'o’o
`
`”90999900.,
`:.;.:.;.;.:.;.;.:....
`
`
`..........
`.6...A.A.0.0.0.0.0.A’A’
`
`
`
`
`
`Figure 1.6: Schematic prg‘ile of the balloon expandable Wire mesh stent ofPalmaz and
`colleagues in the collapsed (a), and expanded (b) state. The mounted stent was protected
`from being dislodged of the balloon by oversized leading and trailing retainers (c) and
`balloon inflation expanded the grcg‘t (d) (From Palmaz]C, Sibbit RR, Reuter SR, Tio F0,
`Rice W]. Expandable intraluminal graft: a preliminary study. Radiology 1985; 156:
`73_77.)
`
`the third week after implantation. This was consistent with previously reported
`results of stainless—steel stents.8’9
`
`The feasibility of the implantation of balloon expandable stents into canine
`coronary arteries was also shown in 1987. Roubin and colleagues12 described
`implantation of a balloon mounted interdigitating flexible coil stent with a novel
`design in 39 animals (figure 1 .7). Schatz and colleagues13 reported their results of
`the percutaneous implantation of a non—articulated modified Palmaz—type stent in
`the coronary circulation of 20 dogs. The stent was cut with staggered, parallel,
`rectangular slots from a stainless—steel tube, and was more streamlined than the
`wire—mesh Palmaz stent (figure 1 .8). No thrombotic events were observed in
`these animals. The publication of these two studies in the cardiovascular
`literature rather than in a radiological journal showed that coronary stenting had
`become separated from the field of vascular radiology.
`
`6
`
`Page 16 of 26
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`Page 16 of 26
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`

`

`HISTORICAL OVERVIEW
`
`
`
`Figure 1. 7: (a) Coil stent coil wrappedfirmly on standard PTCA balloon catheter.
`(b) Stentfully expanded by inflated balloon catheter demonstrated in transparentflexible
`tubing. (c) Fully expanded stent after removal (yrdeflated balloon catheter. (From Roubin
`GS, Robinson KA, King 111 SB, et al. Early and late results ofintracoronary arterial
`stenting after coronary angioplasty in dogs. Circulation 1 98 7; 76: 891—97.)
`
`The early experience of Rousseau’s group with the implantation of the self-
`expanding stent in coronary arteries was the impetus for the implantation of a
`stent in an atheromatous human coronary artery. The first human implantation
`was done by Jacques Puel (Toulouse, France) in 1986, M followed shortly by
`Ulrich Sigwart (Lausanne, Switzerland). Subsequently, Sigwart, and colleagues”
`
`7
`
`Page 17 of 26
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`Page 17 of 26
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`

`

`HISTORICAL OVERVIEW
`
`
`
`Figure 1.8: Balloon expandable intravascular stent. Collapsed, the stentfits over any
`standard coronary angioplasty catheter. inflation of the balloon results in expansion of each
`rectangular slot into a diamond configuration. (From Schatz RA, Palmasz, Tio F0,
`Garcia F, Garcia 0, Reuter SR. Balloon-expandable intracoronary stents in the adult dog.
`Circulation 1987; 76: 450—57.)
`
`reported the results of the implantation of 24 selflexpanding mesh stents
`(Medinvent SA, Lausanne, figure 1 .9) in the coronary arteries of 19 patients.
`Three conditions were considered indications for stent insertion:
`
`'
`'
`
`restenosis of a segment previously treated with angioplasty;
`stenosis of aortocoronary—bypass grafts;
`acute coronary occlusion secondary to intimal dissection following balloon
`angioplasty.
`
`
`
`Figure 1.9: The initial design thlle Wallstent used in the early clinical studies. The
`first stents were madefrom a stainless-steel alloy with a self—expanding inesli design.
`
`8
`
`Page 18 of 26
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`Page 18 of 26
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`

`

`HISTORICAL OVERVIEW
`
`Two complications related to stent thrombosis occurred (1 1%) and there were
`no cases of restenosis within the stented segment 9 weeks to 9 months after
`implantation. As a consequence of the encouraging results of this landmark study,
`the US Food and Drug Administration (FDA) gave their approval for phase I trials
`in the United States. The trials used the balloon expandable Gianturco~RoubinTM
`and Palmaz—SchatzTM intracoronary stents.
`By early 1988, 1 17 self—expanding intravascular stents, of a type subsequently
`called the WallstentTM, had been implanted in native coronary arteries (n = 94)
`or in aortocoronary—bypass grafts (n = 23) of 105 patients. ‘6 Stents were placed
`for dilation of a restenosis, acute vessel occlusion after angioplasty, chronic
`occlusion after angioplasty, and as an adjunct to primary angioplasty. The results
`of intermediate term follow—up of this first series were sobering. Four patients
`died before repeat angiography, there was complete stent occlusion of 27 stents
`in 25 (24%) patients, and a longaterm restenosis rate of 14% in those stents that
`remained patent. '6 The overall mortality rate at 1 year was 7.6%. The results also
`fuelled the controversy that surrounded the choice of a suitable anticoagulation
`regimen to minimize postprocedural complications and haemorrhagic side
`effects. Together with the comments of a daunting editorial that accompanied the
`manuscriptI 7 these results diminished the initial optimism for the future of these
`new devices.
`
`The potential benefit of intracoronary stenting for the treatment of acute and
`threatened closure complicating percutaneous transluminal coronary angioplasty
`was demonstrated by Roubin and colleagues.18 They reported on their experience
`during 1987—89 using the balloon—expandable GianturcomRoubinTM stent, which
`was designed specifically for the control of dissection and acute closure. Stents
`were successfully deployed in all of the 1 15 patients studied, and optimum
`results were obtained in 93% of the patients. Despite the emergent nature of the
`procedures, the number of complications was low, with 4.2% of cases requiring
`CABG, an overall myocardial infarction rate of 16%, a subacute thrombosis rate
`of 7.6%, and an in—hospital mortality rate of 1 .7%. These results suggested that
`stenting for acute or threatened closure limited the need for emergency CABG
`and reduced the incidence of myocardial infarction. The high incidence of'
`restenosis (41%), similar to rates seen in acute closure successfully managed by
`balloon dilatation alone, indicated that the stent gave no benefit to late outcome
`when used for the treatment of acute closure.
`
`More favorable were the results of a multicentre registry of elective stent
`placement in native coronary vessels (1987489), presented in 1991 by Schatz and
`colleagues. 19 Their study compared the implantation of balloon expandable
`intracoronary stents of two different configurations; the prototypical rigid
`Palmaz~type stent, and an articulated Palmaz—SchatzTM stent fashioned with a
`bridging strut between two shorter stainless—steel slotted tubes (figure 1 .10). In
`this study 21% of patients had total occlusion, and 69% had a previously
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`HISTORICAL OVERVIEW
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`
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`Figure 1.10: (a) Prototype Palmaz balloon expandable rigid intracoronary stem.
`(1)) Articulated Palmaz—Schatz stent.
`
`successful coronary angioplasty with clinical and angiographic restenosis.
`Successful delivery of 299 stents was accomplished in 230 lesions in 213 (93%)
`patients. Failed delivery occurred with 22 stents, 1 1 of which were successfully
`withdrawn, three partially deployed, and eight embolizecl systemically after failed
`Withdrawal. Two anticoagulation regimens were used. The first 17 stented
`patients were given procedural dextran and heparin, and discharged on aspirin
`and dipyridamole only. No episodes of abrupt closure were seen in these
`patients. Thereafter, as more patients were treated a significant number of
`thrombotic episodes occurred. Warfarin was added to the postprocedural
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`HISTORICAL OVERVIEW
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`regimen after the first 35 patients were treated. In the 174 patients stented
`thereafter, warfarin was administered and continued for 1—3 months. This
`
`procedural change brought a dramatic reduction in the incidence of occlusive
`thrombosis (0.6%). This low incidence of subacute thrombosis could not be
`confirmed in a retrospective analysis reported by Haude and colleagues20 in the
`same year, which used the same device. In the latter study, a subacute thrombosis
`rate of 14% was reported, although the studies were not directly comparable in
`terms of selection of patients. Restenosis rates determined at follow—up
`angiography were 36% in the registry series of Schatz,21 and 27% in the work of
`Haude and colleagues.20 A higher restenosis rate was seen in those lesions treated
`with multiple stentsu'22 and in those with a history of restenosis in the stented
`segment.“
`The first trial to focus specifically on stent implantation for the treatment of
`restenosis after angioplasty was published in 1992.22 In this article, de Jaegere and
`colleagues22 described their experience with the Medtronic WiktorTM stent, a
`unique coil—like prosthesis made of a single loose interdigitating tantalum wire.
`Stents were successfully implanted in 5 9 patients. Thrombotic stent occlusion
`occurred in 10% of the treated patients, all of whom subsequently suffered a
`myocardial infarction. The restenosis rate, defined as a change in diameter
`stenosis of greater than 50% at follow—up, was 29%.
`Taken together, these early observational trials highlighted problems with the
`use of stents. Subacute stent thrombosis was clearly a problem despite the very
`aggressive anticoagulation regimens used in several of the studies. Rigorous
`anticoagulation resulted in a longer hospital stay, and in bleeding complications
`that were difficult to control and occasionally serious. Restenosis of the stented
`segment was also a problem, with restenosis rates comparable to those seen with
`angioplasty alone. Nonetheless, these technical obstacles to stent deployment
`helped to define ideal stent characteristics (table 1.1).
`Several fundamental questions were raised by these and other small
`observational trials. Were the disparate results from the various stent registries
`related to the clinical circumstances that dictated stent implantation, or were
`they due to properties inherent in the particular device? Was there a clinical
`situation for which stenting could provide the solution? After these early trials,
`the utility of stenting for the treatment of obstructive coronary artery disease
`remained to be proven.
`These pioneer investigators were convinced that coronary stenting could
`become a standard therapeutic modality in interventional cardiology, through
`improved periprocedural management of patients, better selection of patients,
`and clearly defined clinical indications. Their convictions led to the initiation of
`two major important randomized trials comparing balloon angioplasty with
`elective Palmaz—Schatz coronary stenting. The European BENESTENT23 and the
`North American STRESS24 studies both began recruitment of patients in 1991. In
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`HISTORICAL OVERVIEW
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`both studies, patients were randomized to conventional balloon angioplasty or to
`implantation of a Palmaz—Schatz stent in a primary lesion of a native coronary
`artery with a length of less than 15 mm and a diameter stenosis of 50%
`(BENESTENT) or 70% (STRESS). A total of 516 patients (257 balloon, 259
`stent) all of whom had stable angina, were recruited in the BENESTENT
`study: 407 patients (202 balloon, 205 stent), of whom 47% had unstable angina
`symptoms, were randomized in the STRESS study. The incidence of restenosis,
`according to the 50% diameter stenosis criterion, was significantly lower after
`stent implantation (BENESTENT 22%, STRESS 32%) than after balloon
`dilatation alone (BENESTENT 32%, p = 0.02, STRESS 42%, p = 0.046).
`lmportantly, this difference was associated with a more favourable long—term
`clinical outcome in patients who received a stent. The 7*month event—free
`survival in the BENESTENT trial was 79.9% after stenting and 70.4% after
`balloon angioplasty (p < 0.05). In the STRESS study, the comparable figures
`were 80.5% and 76.0% respectively (difference not significant). The benefits of
`stent implantation compared with balloon angioplasty were largely due to a
`reduced need for reintervention in the stent group. The observed benefit came at
`a cost, however, with stented patients experiencing increased vascular and
`bleeding complications, and needing a longer hospital stay. One—year follow—up
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`results of the BENESTENT trial showed a continued benefit for stented patients,
`with a 1—year event—free survival of 76.8% compared with 68.5% in the balloon
`angioplasty patients.25 These two landmark trials conclusively showed that the
`elective placement of intracoronary stents significantly reduced the incidence of
`angiographic restenosis in patients with discrete, de—novo lesions in large target
`vessels. Paradoxically, the BENESTENT and STRESS trials were accepted by
`clinicians as being positive overall, despite a subacute occlusion rate of 3.7%
`(which was higher than with balloon angioplasty alone), longer hospitalization
`times, and more vascular and bleeding complications.
`With the publication of the BENESTENT and STRESS trial results and the
`resultant acceptance of coronary stenting as a promising alternative to
`angioplasty, attention was then given to improving technical aspects of stent
`implantation, optimizing adjunctive therapy, and minimizing complication rates.
`Thrombosis within the self~expanding stainless—steel Medinvent stent, as seen in
`the early animal experiments,9 prompted the use of intracoronary urokinase
`along with heparin, aspirin, dipyridamole, and coumadin in the first human
`coronary implants.15 Despite this very aggressive anticoagulation regimen,
`thrombosis remained a problem. The addition of dextran and sulphinpyrazone16
`increased the number of anticoagulation agents to seven, which led to inevitable
`bleeding and vascular complications, and a prolonged hospital stay. The high
`early occlusion rates with these devices16’17 suggested that stents were highly
`thrombogenic foreign bodies, and this discouraged investigators from using
`coronary stents as a primary treatment for coronary artery stenosis. However,
`Antonio Colombo and his groupK”28 focused attention on the modalities of stent
`deployment, and questioned the dogma of the intrinsic thrombogenic nature of
`the stents. The major contribution of these investigators was to assume that the
`normalization of the rheology inside the stent, as well as its inflow and outflow,
`would render the anticoagulation treatment superfluous. Intravascular ultrasound
`imaging had a pivotal role in revealing that most of th