Textbook of Interventional Cardiovascular Pharmacology - part 1 doc

Kipshidze FACC FESC FSCAI Professor of Medicine and Surgery Consultant Cardiologist Cardiovascular Research Foundation Director, Preclinical Research Lenox Hill Heart and Vascular Insti

Textbook of Interventional Cardiovascular Pharmacology

Textbook of Interventional

Cardiovascular Pharmacology

Nicholas N Kipshidze

FACC FESC FSCAI

Professor of Medicine and Surgery

Consultant Cardiologist

Cardiovascular Research Foundation

Director, Preclinical Research

Lenox Hill Heart and Vascular Institute

New York NY USA

Director and Physician in Chief

Central University Hospital Tblisi Georgia

Jawed Fareed PhD FACB

Professor of Pathology and

Pharmacology Director of Hemostasis and

Thrombosis Research Laboratories and Department of Pathology Loyola University, Stritch School

of Medicine Maywood IL USA

Jeffrey W Moses MD FACC

Professor of Medicine Director, Center for Interventional Vascular Therapy

Director, Cardiac Catheterization Laboratories

Columbia University Medical Center New York-Presbyterian Hospital New York NY USA

Patrick W Serruys MD PhD FACC FESC

Professor and Head Interventional Department Thoraxcenter

Erasmus University Medical Center Rotterdam

© 2007 Informa UK Ltd

First published in the United Kingdom in 2007 by Informa Healthcare, Telephone House, 69 -77 Paul Street, London EC2A 4LQ Informa Healthcare is a trading division of Informa UK Ltd Registered Office: 37/41 Mortimer Street, London W1T 3JH Registered in England and Wales number 1072954.

Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention.

A CIP record for this book is available from the British Library.

Data available on application

ISBN-10: 1 84184 438 1

ISBN-13: 978 184184 438 1

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Cover design concept by Cathy Kennedy

Cover image is the chemical and molecular structure of the anticoagulant heparin

Back cover illustration: electron micrographs of drug distribution

Composition by Egerton + Techset

Printed and bound in India by Replika Press Pvt Ltd

Part I Systemic and Endoluminal Therapy

Walter Jeske, Debra A Hoppensteadt, Asad Shaikh, Jeanine M Walenga, Mamdouh Bakhos, and Jawed Fareed

Raul Altman, Alejandra Scazziota, and María de Lourdes Herrera

Raphaelle Dumaine and Gilles Montalescot

Derek P Chew, Sam J Lehman, and Harvey D White

Shunji Suzuki, Hikari Watanabe, Takefumi Matsuo, and Masanori Osakabe

Brigitte Kaiser

Volker Laux and Markus Hinder

Harry I Messmore, Erwin Coyne, Meghan Businaro, Omer Iqbal, William Wehrmacher, andWalter Jeske

Freek W A Verheugt

13 Resistance to antiplatelet drugs 139Paul A Gurbel and Udaya S Tantry

Andrew M Tonkin and Omar Farouque

Clarence E Grim

Torfi F Jonasson and Hans Ohlin

Ron Waksman

Part II Local Therapy

Yanming Huang, Lan Wang, and Ivan De Scheerder

Kalpana R Kamath, Kathleen M Miller, and James J Barry

Ravi K Ramana, Ferdinand Leya, and Bruce Lewis

Robert Falotico and Jonathon Zhao

Kalpana R Kamath and James J Barry

Steven J Adelman

Ivan De Scheerder, Xiaoshun Liu, and Yanming Huang

Christodoulos Stefanadis, and Konstantinos Toutouzas

Nicholas Kipshidze, Jean-François Tanguay, Alexandre C Abizaid, and Antonio Colombo

vi Contents

30 Vascular endothelial growth factor 355Neil Swanson and Anthony Gershlick

Alok S Pachori, Luis G Melo, and Victor J Dzau

Patrick Iversen and Martin B Leon

Thomas L Wenger and Nicholas H G Yeo

Part III Cell Therapy and Therapeutic Angiogenesis

Shaker A Mousa

Munir Boodhwani, Joanna J Wykrzykowska, and Roger J Laham

Doris A Taylor, Harald Ott, and Patrick Serruys

Joanna J Wykrzykowska, Munir Boodhwani, and Roger J Laham

Part IV Adjunctive Pharmacotherapy

Basil S Lewis and Mihai Gheorghiade

John F Moran

Mitchell D Weinberg and George D Dangas

Yves L E Van Belle, M F Scholten, and Luc J Jordaens

Ioannis Iakovou

Graham Jackson

Zoran Lasic and Michael R Jaff

Waqas Ullah, Rakesh Sharma, and Carlo Di Mario

David R Holmes, Jr

Contents vii

47 Newer pharmacologic approaches targeting receptors and genes 543Omer M Iqbal, Debra Hoppensteadt, and Jawed Fareed

Part V Noncoronary Interventions

Amir Halkin, Sriram S Iyer, Gary S Roubin, and Jiri Vitek

Rajesh M Dave, Azim Shaikh, and Mubin Syed

Alexandra A MacLean and Barry T Katzen

Ralph Hein, Neil Wilson, and Horst Sievert

George Dangas, Edwin Lee, and Jeffrey W MosesE

Boston Scientific Corporation

Corporate Research and Advanced Technology

Department

Natick MA

USA

Michel E Bertrand MD FRCP FACC FAHA

Lille Heart Institute

Lille

France

Rodger L Bick MD PhD FACP

Clinical Professor of Medicine

University of Texas Southwestern Medical Center

Director, Thrombosis Hemostasis and Vascular

Medicine Clinical CenterDallas TX

Valeri S Chekanov MD PhD Heart Care Associates

Milwaukee Heart InstituteMilwaukee WI

USADerek P Chew MBBS MPH FCSANZGreen Lane Cardiovascular Research UnitFlinders University and Medical CentreAdelaide

AustraliaAntonio ColomboEMO Centro Luore Columbus and San Ran Raffaele Hospital

MilanItalyUmberto Cornelli MD PhDPresident, European Society of Biological NutritionLoyola University Medical School

Chicago ILUSAErwin CoyneHines Veteran Affairs HospitalHines IL

USAGeorge D Dangas MD PhDDepartment of Medicine

Columbia University Medical CenterProgram Director, Interventional CardiologyNew York-Presbyterian Hospital

New York NYUSA

Bayler College of Medicine

The University of Texas Health Care Center

USAClarence Grim BS MS MDClinical Professor of Medicine and EpidemiologyShared Care Research, Education and Consulting Inc.Milwaukee WI

USAPaul A Gurbel MDDirector, Sinai Center for Thrombosis ResearchSinai Hospital of Balimore

Associate Professor of MedicineDepartment of MedicineJohn Hopkins UniversityBaltimore MD

USAAmir Halkin MDLenox Hill Heart and Vascular InstituteNew York NY

USAMaría de Lourdes HerreraCentro de Trombosis de Buenos AiresBuenos Aires

ArgentinaRalph Hein MDCardiovascular Center FrankfurtFrankfurt

GermanyMarkus Hinder MDSanofi-Aventis, Science & Medical AffairsFrankfurt

GermanyDavid R Holmes, Jr MDDivision of Cardiovascular Diseases and InternalMedicine

Mayo Clinic Rochester MNUSA

x List of contributors

Departments of Cardiology and Cell Biology

The Cleveland Clinic Foundation

Cleveland OH

USA

Ioannis Iakovou MD

Department of Cardiology

Army Hospital of Thessaloniki and

Blue Cross Heart Centre

Michael R Jaff DO FACP FACC

Assistant Professor of Medicine

Harvard Medical School

Director, Vascular Medicine

Massachusetts General Hospital

Boston MA

USA

Walter JeskeCardiovascular InstituteLoyola University Medical CenterMaywood IL

USATorfi F Jonasson MD PhDDept of Cardiology

University Hospital of Iceland Reykjavik

IcelandLuc J Jordaens Erasmus UniversityThoraxcenterRotterdamThe Netherlands Brigitte Kaiser MD PhDFriedrich Schiller University JenaFaculty of Medicine

Institute for Vascular MedicineJena

GermanyKalpana R Kamath PhDBoston Scientific Corporation Corporate Research and Advanced Technology Department

Natick MA USABarry T Katzen MDFounder and Medical DirectorBaptist Cardiac and Vascular Institute Miami FL

USASanjay Kaul MDDirector, Vascular Physiology and Thrombosis LaboratoryDivision of CardiologyCedars-Sinai Medical CenterProfessor, David GeffenSchool of Medicine UCLALos Angeles CA

USA

List of contributors xi

Nicholas N Kipshidze MD PhD FACC, FESC

Cardiovascular Research Foundation

Zoran Lasic MD FACC

Department of Interventional Cardiology

Lenox Hill Hospital

Albert Einstein College of Medicine

Montefiore Medical Center

Martin B Leon MD FACC

Cardiovascular Research Foundation,

Center for Interventional Vascular Therapy

Columbia University Medical Center

New York NY

USA

Basil S Lewis MD FRCP FACC

Department of Cardiovascular Medicine

Lady Davis Carmel Medical Center

Haifa

Israel

Bruce E Lewis MDDivision of CardiologyLoyola University Medical CenterMaywood IL

USA

Ferdinand Leya MDDivision of CardiologyLoyola University Medical CenterMaywood IL

USA

Xiaoshun Liu MD PhDDepartment of CardiologyUniversity HospitalLeuven

Belgium

Alexandra A MacLean MDAssistant Professor of SurgeryDepartment of SurgeryNew York Hospital, QueensFlushing NY

Japan

Luis G Melo PhDAssociate Professor of PhysiologyDepartment of PhysiologyCollege of MedicineQueen’s UniversityKingston, OntarioCanada

xii List of contributors

Boston Scientific Corporation

Corporate Research and Advanced

Columbia University Medical Center

New York-Presbyterian Hospital

New York NY

USA

Shaker A Mousa PhD MBA FACC FACB

Pharmaceutical Research Institute

Albany College of Pharmacy

Minneapolis MNUSA

Alok S Pachori PhDInstructor in MedicineDuke University Medical CenterDurham NC

USA Ravi K Ramana DODivision of CardiologyLoyola University Medical CenterMaywood IL

USAAlfredo E Rodriguez MD PhD FACC FSCAIOtamendi Hospital - Cardiac Unit

Buenos Aires ArgentinaGary S Roubin MD PhDLenox Hill Hospital

New York NYUSA

Alejandra Scazziota PhDCentro de Trombosis de Buenos AiresBuenos Aires

Argentina

Ivan De Scheerder MD PhDGlobal Medical Services

KeeromstraatHerentBelgium

M F Scholten Erasmus UniversityThoraxcenterRotterdamThe Netherlands

List of contributors xiii

Clinical Associate Professor of Radiology

Wright State University School of Medicine

Dayton OH

USA

Jean-François Tanguay MDDepartment of Medicine

Montreal Heart InstituteMontreal QuebecCanada

Udaya S Tantry PhDSinai Center for Thrombosis ResearchSinai Hospital of Baltimore

Baltimore MDUSA

Doris A Taylor PhDScientific DirectorCenter for Cardiovascular RepairUniversity of Minnesota

Minneapolis MNUSA

Andrew M Tonkin MBBS MD FRACPHead, Cardiovascular Research Unit

Department of Epidemiology and Preventive Medicine

Monash UniversityCentral and Eastern Clinical SchoolAlfred Hospital

MelbourneAustraliaKonstantinos Toutouzas MD PhDAthens Medical School

AthensGreeceWaqas Ullah MBBSDepartment of CardiologyRoyal Brompton HospitalLondon

UKYves L E van BelleErasmus UniversityThoraxcenterRotterdamThe Netherlands

xiv List of contributors

Professor, Thoracic and Cardiovascular Surgery

Loyola University Stritch School of Medicine

New York-Presbyterian Hospital

Columbia University Medical Center

Harvey D White DSc FCSANZDirector of Coronary Care UnitGreen Lane Cardiovascular UnitAuckland City Hospital

AucklandNew Zealand

Neil Wilson MDCardiovascular CenterFrankfurt

GermanyDepartment of Paediatric CardiologyJohn Radcliffe Hospital

OxfordUK

Joanna J Wykrzykowska MDBIDMC/Harvard Medical SchoolBoston MA

USA

Nicholas H G YeoChief Executive OfficerVascular Reconditioning, Inc

Snoqualmie WA USA

Jonathon ZhaoCordis CorporationWarren NJ

I am pleased to write this introduction for the Textbook

of Interventional Cardiovascular Pharmacology This

definitive international textbook on cardiovascular

pharmacology for interventional procedures

incorpo-rates contributions from world opinion leaders and a

transatlantic perspective This textbook is a first of its

kind for practicing interventional cardiologists,

cardiol-ogists, and pharmacologists

Edited by Nicholas Kipshidze, Jawed Fareed, Jeffrey

Moses, and Patrick Serruys, the Textbook of

Interven-tional Cardiovascular Pharmacology is an outstanding

text that focuses primarily on currently used

pharma-cologic agents, interventional approaches, and the

delivery techniques available for treatment of

cardio-vascular diseases In looking forward, the book also

covers the exciting potential of various experimental

drug therapies such as angiogenetic agents to treat the

ischemic heart and limb, cardiovascular cell

transplan-tation to treat the underlying injuries associated with

cardiac and vascular disease, and the promising results

of clinical trials in these rapidly moving fields To this

end the editors have assembled an impressive roster of

international contributors who are all active in the field

of interventional cardiology and write from a hands-on

perspective They have analyzed an enormous range of

various cardiovascular pharmacological therapies in

superbly illustrated and clearly focused chapters

The book is comprised of five sections with part I

covering systemic and endoluminal therapy with an

inci-sive overview of hemostasis and thrombosis; part II

covers local therapy with several chapters devoted to

drug-eluting stents and restenosis therapies; part III

covers cell therapy and therapeutic angiogenesis and

includes chapters on cell transplantation and clinical

trials in cellular therapy; part IV covers adjunctive

pharmacotherapy with chapters devoted to various

patient populations including those with heart failure,

diabetes, atrial fibrillation, peripheral artery disease,

acute coronary syndrome, and chronic total occlusions;and part V covers non coronary interventions such ascarotid artery stenting, repair of abdominal aorticaneurysms, and alcohol septal ablation The text is writ-ten with best clinical practice in mind yet provides muchinformation that is translational in nature The finalchapter is an epilogue that provides an objective opinion

on current drug development in vascular medicine andinterventions In addition, there is a handy drug tablecomparing the pharmacokinetics of the various antico-agulants used in cardiovascular medicine

Perhaps for the next edition the editors will include

a separate section on imaging since it is a very tant development in this decade and promises tostimulate the interest of all concerned and interested incardiovascular disease, from those in basic science, tothose in the interventional and pharmacological fieldsand to those interested in clinical trials and outcomes

impor-In summary Nicholas Kipshidze, Jawed Fareed,Jeffrey Moses, and Patrick Serruys have put together

an outstanding textbook covering a broad range

of topics in cardiovascular pharmacology I wouldrecommend this book to anyone working in the field of cardiovascular disease, clinical research, andpharmacology

Valentin Fuster MD PhDDirector, Zena and Michael A Wiener CardiovascularInstitute and the Marie-Josee and Henry R Kravis

Center for Cardiovascular HealthThe Mount Sinai Medical CenterProfessor of Medicine, Mount Sinai School of

MedicineNew York NY

USAPast President, American Heart AssociationImmediate Past President, World Heart Federation

Foreword

The Textbook of Interventional Cardiovascular

Pharmacology is an excellent up-to-date text that

focuses on agents, interventional approaches, and

delivery techniques that are available for treatment of,

and to some extent prevention of, disease states arising

from vascular and intravascular pathologies Part I

focuses on hemostasis and thrombosis, including

chapters on available anticoagulant, antiplatelet, and

fibrinolytic therapies Also covered in this section are

anti-restenotic drugs and approaches at minimizing

proliferative and atherosclerotic processes The second

section, on local therapy, includes chapters on

drug-eluting stents, antiproliferative and antimigratory

drugs, and use of growth factor, gene therapy,

anti-sense, and photodynamic approaches Part III

examines current knowledge regarding cell therapy

approaches for cardiovascular repair Part IV addresses

use of adjunctive pharmacotherapy in a number of

patient populations, such as those with heart failure,

diabetes, peripheral artery disease, and erectile

dysfunction, and the final section discusses

non-coro-nary interventions and structural diseases of the heart

Each chapter in this work provides a thorough uation and concise presentation that highlights both

eval-recent advances in the field as well as the current all understanding of the topic Although written withthe best clinical practice in mind, the text provides

over-a weover-alth of informover-ation thover-at is truly trover-anslover-ationover-al innature, bridging pathogenesis and mechanism

of action with therapeutic approach I commend the editors for developing the vision of such a text, and congratulate each of the authors for the depth and clarity of their presentation I would recommendthis text to anyone working in the field of vascular and intravascular disease Basic, clinical, and transla-tional scientists, practicing clinicians, and clinical and research trainees can all benefit from the informa-tion included in indivi-dual chapters as well as from the overall scope and breadth of knowledgepresented

Richard H Kennedy, PhDSenior Associate Dean for ResearchProfessor of Physiology and Pharmacology

Loyola University Stritch School of Medicine

Chicago ILUSA

Foreword

The last quarter of a century has seen dramatic

developments in the management of cardiovascular

diseases Besides the pioneering developments in

the medical management of cardiovascular disorders

the field of interventional cardiology has also emerged

as a major discipline with a huge impact on the

clinical management of acute coronary syndrome,

chronic coronary artery disease, congestive heart

failure, and peripheral vascular and valvular diseases

Percutaneous interventions necessitated the

develop-ment of newer agents and drugs for the imaging,

anticoagulation, vascular tone control, and

post-inter-ventional proliferative control processes Drug coating

of mechanical devices posed yet another challenge in

addressing the safety issues related to these modified

devices

The last decade has witnessed a major

break-through in the use of mechanical support devices such

as stents and newer drugs, which has revolutionized

the field of interventional cardiology Moreover, novel

uses of drugs, such as drug-coated stents and grafts

have emerged While conventional drugs, such as

aspirin, heparin, and clopidrogel, are commonly used

in the short-and long-term treatment of patients who

have undergone interventions, many newer drugs and

drug combinations have been developed

The molecular and cellular understanding of the

pathogenesis of cardiovascular diseases, in particular

acute coronary syndromes, and the use of

interven-tional procedures in their management has identified

several newer targets to optimize clinical

manage-ment of patients undergoing these procedures In the

area of newer drugs developed in conjunction with

interventional procedures, progress has been

remark-able and there has been an influx of massive

information on their pharmacology and toxicology

Recognizing the importance of this developing area

and its impact on interventional cardiology practice,

the Editors identified the need of a comprehensive

reference book covering this topic Having such

infor-mation in one volume is projected to meet the need

of practicing interventional cardiologists to obtain

objective knowledge of the newer drugs used in

inter-ventional cardiology It is hoped that this book will

provide a comprehensive coverage of pharmacologicagents which are currently used and for those that are

in clinical trials and will soon become available forclinical use The use of drugs for the acute andextended indications in this area is in transition Therecommendations from peer groups undergo periodicrevisions due to the introduction of newer devicesand/or newer drugs Thus, it provides a moving target

to develop guidelines This book is intended toprovide some of the fundamental knowledge as afoundation to appreciate the ongoing developments inthe area of interventional sciences

This book is comprised of over fifty chapters, each

of which is written by an expert in the assigned topic.Assembling a multi-authored specialized pharmacol-ogy book is a major challenge for both the authorsand the editors Because of the influx of newer infor-mation, differing opinions, data interpretation andregulatory positions, the authors are challenged toprovide the most practical, unbiased and helpfulinformation on specific topics The editors are grate-ful to the authors contributing to this book for theirexcellent and objective manuscripts which are written

in an integrated fashion to provide an updated andcomprehensive account of different drugs anddevices

This book is divided into five parts comprised ofsystemic and endoluminal therapy, local therapy, ther-apeutic angiogenesis, adjunctive pharmacotherapyand non-coronary interventions The first chapter is

on hemostasis and thrombosis and is included sincemany of the new drugs target the components of thehemostatic system including cellular sites and recep-tors on platelets, endothelial cells, white cells andblood proteins The last chapter is written as anepilogue to provide an objective opinion on currentdrug development in vascular medicine and interven-tions It is hoped that the individual chapters includedwill provide updated references to practicing clini-cians and those who are involved in the development

of newer drugs

This book is also intended to serve as a hensive reference and a practical guide in theapplication of drugs and devices used for primary

compre-Preface

coronary angioplasty, coronary thrombolysis and

the correction in ST segment elevation in acute

coronary syndrome Specialized topics such as

drug coated stents, molecular therapies, cellular

ther-apies, newer pharmacologic approaches and specific

topics on non-coronary interventions are also

reported It is hoped that this book will be periodically

updated to reflect the ongoing developments in thisfast moving area

Nicholas KipshidzeJawed FareedJeffrey MosesPatrick Serruys

xxii Preface

The editors are tremendously grateful to all of the

con-tributing authors, who have voluntarily provided their

expert chapters The editors are also grateful to Ms Cathy

Kennedy, Associate Editor, who has been extremely

help-ful throughout this project and without whose help it

would have been difficult to publish this book Thepublishers, in particular Mr Oliver Walter, developmenteditor and Mr Alan Burgess, commissioning editor are to

be thanked for their commitment and support in ing this timely book on interventional pharmacology

publish-Acknowledgments

Mechanism of Thrombogenesis

TFPI

IntegrinsSelectins

Peroxide radicals

s-TM PF4 TXs 5-HT

FPA LTs P-AP PAI-1Endothelin

TAT

TF TAFI

C5a F1.2

X-Fibrin

XII XIIa Kallikrein

Prekallikrein·HMWK

HMWK Bradykinin

Protease Network in Coagulation, Fibrinolysis and Kallikrein-Kinin Systems

Anticoagulant and Antithrombotic Drugs

Ticlopidine, Clopidogrel Cyclic

GPIb/IX/V

Ca++

Mobilization Activation

”Autocrine and Paracrine Effect”

2 Activation Shape Change Granule Secretion

Activated Platelet

Fibrinogen vWF

Activated GPIIb/IIIa Receptor P-selectin

CD40L

Gr ule Secretion

Secondary Agonists ADP

TxA 2 TP Collagen

TF Thrombin

GPIa/IIa

GP VI

Primary Agonists

Prothrombotic Factors

Inflammation and Increased Thrombin Generation

Thrombotic Events Myocardial Infarction

ASA TxA2

GP IIb/I IIa Activ ation, Platelet Agg

regation

Platelet Activation Receptor

Receptor

ADP, Collagen, Thrombin

CO X-1 Indepe ndent

Activ ation of

GP IIb/III

a Receptor

AAXTxA2 COX-1

PL Release

Figure 13.2

Mechanism of action of aspirin and laboratory evaluation of

aspirin responsiveness (See p 141.)

Hydrolysis

P-selectin and CD40L Expression, Platelet-Leukocyte Aggregation

GPllb/llla Activation, Platelet Aggregation

cAMP

VASP-P

Pl3K Shape Change

?

Ca ++

Mobilization

Adenylyl Cyclase –

Granule Secretion

Rho Kinase

RAP-1b Akt

X Gi

Carboxyl Inactive Metabolite Laboratory Evaluation of Clopidogrel Responsiveness

1 Plasma unchanged dopidogrel active and inactive metabolites of dopidogrel

- LC-MS/MS assay

2 Hepatic CYP3A4 activity

- Erythromycin breath

test-3 ADP-Induced Platelet Aggregation

- LTA (PRP)

- TEG (Whole Blood)

4 P2Y 12 Reactivity Ratio

- Flow cytometry VASP-P levels

6 Point-of-Care Methods

- Thrombelastography, PFA-100 and VerifyNow P2Y12 with ADP

as agonist

5 P-selectin, activated PAC-1 expression and PLAs folllowing ex-vivo ADP stimulation-

- Flow Cytometry

Active Thiol Metabolite AZD-6140, Cangrelor

CYP3A4 Conversion

85%

15%

Intestinal Absorption Clopidogrel

Bisulfate/

Prasugrel

TxA2 Collagen Thrombin

Toxic concentration

Sub-optimal concentration Dose

60 days porcine 56 days canine

Bare metal stent Low coat weight polymer-coated stent High coat weight polymer-coated stent

0.2 0

Figure 22.5

Strut-associated inflammation in response to the polyethylene-co-vinyl acetate — poly-n-butyl methacrylate polymers in porcine and canine models at two months (See p 273.)

xxvi

Cryomicrotomed Stent

0

100µm EHT=10.00w Signal A = SE1

WD = 11 mm 0.2

80 70 60

Time (Days)

18

35% PTx 25% PTx 8.8% PTx

12

Lumen area

10 8 6

mm24 2 0 Bare metal stent SIBS-coated stent

28 Days

90 Days

Figure 22.8

Vascular compatibility of poly(styrene-b-isobutylene-b-styrene) (SIBS) as examined in the porcine coronary model (See p 274.)

xxvii

1.0 0.9 0.8 0.7

Time

Control 2.5 ug

10 ug

Figure 25.3

Event-free survival at six months in the ACTinomycin-eluting stent improves outcomes by reduction of neointimal hyperplasia trial of the actinomycin-eluting stent (See p 304.)

Diseased artery pre-stent Atherosclerotic Plaque with Resident Macros

Immediate post-stent Endothelial denudation, platelet/fibrinogen deposition

Leukocyte recruitment Cytokine release

Macros Cytokines Neutros (MCP-1, IL-6, IL-8)

Restenotic lesion More ECM rich over time

Neointimal growth Continued SMC proliferation and macro recruitment

Leukocyte infiltration SMC proliferation/migration

Platelets/fibrinogen

Growth factors (FGF, PDGF, IGF, TGF-β, VEGF)

Pathophysiology of restenosis (See p 300.)

Double balloon (blue-environment, Cordia)

Diffusion Pressure-driven Mechanical

Porous balloon (Wolinsky, Bard/USCI)

Iontophoretic balloon (CorTrak)

Needle catheter (BMT Ltd)

Microporous balloon

Macroporous balloon

Balloon with a balloon (Transport TM , Endosonics)

Channeled balloon (Mansfield Boston Scientific)

Infusion sleeve (LocalMed)

Multichamber balloon, Dispatch TM , SciMed)

Hydrogel balance (Slider TM with Hydrogel Plum TM Mansfield Boston Scientific)

Coated stent (Johnson & Johnson)

Figure 25.2

Types of catheter-based local delivery devices (See p 302.)

xxviii

– ––

– ––

+ + + +

––

– ––

– ––

+ + + +

––

– ––

– ––

+ + + +

––

– ––

– ––

0.1 ng/ml PTXL

1 ng/ml PTXL 0.1 ng/ml SRL

xxix

TAXUS VI (MR)

100

70 100

70 100

70 100

270

31

30

TAXUS IV (SR)

TAXUS II (SR/MR)

TAXUS I (SR)

Figure 25.12

Sustained freedom from target lesion revascularization in TAXUS clinical trials.(See p 309.)

28 21 14 7 0

28 21 14 7 0

28 21 14 7 0

28 21 14 7 0

Tissue Monocytes

Migration & Proliferation

Figure 32.2

Polymer-coated stent delivery of c-myc antisense

phosphorodiamidate morpholino oligomers into swine vessels.

Activating light

Molecular oxygen Photoreactive agent

Autologous myotissue viability at 4 weeks post implantation

In addition to surgical management of thrombotic disorders,

in particular those involving the arterial system including Acute

Coronary Syndrome (ACS), atrial fibrillation, thrombotic and

ischemic stroke, and other ischemic and occlusive disorders,

advanced interventional methods including stenting and

molecular/cellular approaches involving genes and stem

cell-based approaches are now used Each year in the United

States myocardial infarction contributes to over 600,000

deaths and an additional 800,000 deaths are attributed to this

syndrome in hospital discharged patients Thus, almost 1.5

million deaths are related to myocardial infarction and its

manifestations Percutaneous Interventions (PCI) have

signifi-cantly contributed to the management of acute coronary

syndrome and improved the clinical outcome in this

syndrome Similarly, interventional procedures have also

been used in the management of atrial fibrillation and embolic

stroke Although the interventional methods have been

extremely valuable, there are several specific

pathophysio-logic and pharmacopathophysio-logic problems, which require a continual

review and assessment to optimize patient care Coronary

Interventions represent a controlled injury to the vessel wall

resulting in the generation of tissue factor that initially

promotes thrombogenesis at the site of injury Regardless of

the extent of this injury, both the acute and late occlusive

process are often associated with PCI, necessitating

pharma-cological and mechanical measures to avoid occlusive events

Many of the fateful events occur in patients free of coronary

artery diseases, with almost an equal number of events

occuring in those with known coronary artery diseases

already receiving therapy, including PCI and aggressive

medical therapy with statins, antiplatelet drugs, and

anticoag-ulants A great number of these infarctions result from the

rupture of high-risk unstable plaque that in most cases did notimpede flow before the acute events Therefore, it is quiteclear that newer approaches must be developed to under-stand the pathogenesis of occlusive coronary events and todevelop methods for their optimal management Risk assess-ment involving newer approaches based on geneticpredisposition, lifestyle, and other contributing factors may beimportant Other problems related to the management ofvascular injury, the patency of the stents, and the role ofdifferent drugs used in the control and mediation of thethrombotic and bleeding complications observed during andafter PCI require serious considerations Interventionalapproaches have been in an evolutionary phase for the pasttwo decades Besides the proper understanding of pathogen-esis of the lesions requiring interventions, post-interventionalmonitoring and additional control of the pathogenesis ofthrombotic and fibrotic complications is equally important.Excessive bleeding with the use of newer anticoagulants,thrombotic complications with drug-coated stents and mole-cular and cellular abberations due to gene and stem cellapproaches will require further understanding of the mecha-nisms involved in these processes A firm understanding ofthe hemostasis and thrombosis is crucial in the optimalmanagement of patients undergoing interventions

Introduction to hemostasis and thrombosis

Hemostasis as defined by Virchow in the last century is a fine balance between blood flow, humoral factors, and cellu-lar elements of the vascular system Today, molecular and

1

An overview of hemostasis and thrombosis

Walter Jeske, Debra A Hoppensteadt, Asad Shaikh,

Jeanine M Walenga, Mamdouh Bakhos, and Jawed Fareed