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HANDBOOK OF COMPLEX PERCUTANEOUS CAROTID INTERVENTION
CONTEMPORARY CARDIOLOGY
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HANDBOOK OF COMPLEX
PERCUTANEOUS CAROTID
INTERVENTION
Edited by
JACQUELINE SAW, MD
Division of Cardiology, University of British Columbia,
Vancouver, BC, Canada
J. EMILIO EXAIRE, MD
Department of Interventional Cardiology, Instituto Nacional de
Cardiología “Ignacio Chávez,” Mexico City, Mexico
DAVID S. LEE, MD
Interventional Cardiology, Hillsboro Cardiology, Hillsboro, OR
JAY S. YADAV, MD
Department of Cardiovascular Medicine,
The Cleveland Clinic Foundation, Cleveland, OH
© 2007 Humana Press Inc.
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Library of Congress Cataloging-in-Publication Data
Handbook of complex percutaneous carotid intervention / edited by Jacqueline Saw ... [et al.].
p. ; cm. — (Contemporary cardiology)
Includes bibliographical references and index.
ISBN 1-58829-605-9 (alk. paper)
1. Carotid artery—Surgery. 2. Carotid artery—Stenosis. 3. Stents (Surgery) I. Saw, Jacqueline. II. Series:
Contemporary cardiology (Totowa, N.J. : Unnumbered)
[DNLM: 1. Carotid Stenosis—surgery—Case Reports. 2. Angioplasty,Balloon—methods—Case Reports.
3. Stents—Case Reports.WL 355 H2356 2007]
RD598.6.H36 2007
617.4'13—dc22 2006004982
DEDICATIONS
To my husband, David, and our son, Evan, and my family, who make my life endeavors
worthwhile. And to my mentors in Interventional and General Cardiology (Drs. Donald
Beanlands, Deepak Bhatt, Irvine Franco, John Jue, David Moliterno, Eric Topol, and Jay
Yadav), for their guidance and support through my training, and for inspiring me to excel.
Jacqueline Saw, MD
To my wife, Karin, and my parents, Cristina and Emilio, with all my love and gratitude.
This book would not be possible without the teachings of Dr. Jay Yadav and the remark-
able Peripheral Intervention Staff at the Cleveland Clinic Foundation.
J. Emilio Exaire, MD
To Megan and my family for their love, support, and encouragement, and to the
interventional cardiologists at the Cleveland Clinic (especially Drs. Yadav, Franco,
Whitlow, Topol, and Bajzer) for their mentorship, friendship, time, and investment in
me. I would not be who I am and where I am without you.
David S. Lee, MD
To my family for their unfailing support and understanding, and to the interventional
cardiology fellows at the Cleveland Clinic for their curiosity and inspiration.
Jay S. Yadav, MD
v
PREFACE
Since the first carotid angioplasty that was performed in 1980, this technique has
undergone tremendous modifications and improvements. Stents for the carotid artery
were utilized in the early 1990s, and emboli protection devices were introduced about
2000. Advances in equipment (guidewires, catheters, balloons, stents, and emboli pro-
tection devices) have improved the technical success and safety of carotid stenting. With
the recent SAPPHIRE publication revealing non-inferiority of carotid stenting compared
with carotid endarterectomy for high-risk surgical patients, this percutaneous procedure
is now considered a viable alternative to endarterectomy for these patients. In fact, the
FDA has approved carotid stenting for high-risk patients using the AccuLink™ stent and
AccuNet™ device (Guidant Corporation, Santa Clara, CA) in August 2004, and the
XactTM and EmboShieldTM system (Abbott Vascular Devices, Redwood City, CA) in
September 2005.
Increasing numbers of carotid stenting are being performed around the world, and
established interventionalists and trainees alike are seeking to be instructed in performing
this meticulous procedure. Unfortunately, there are insufficient well-established periph-
eral vascular training programs to meet this increasing demand. Only a small proportion
of current trainees are enrolled in fellowship programs with dedicated carotid interven-
tional training that perform high-volume extracranial carotid stenting; even fewer are
enrolled in programs that also partake in intracranial and acute stroke interventions. In
North America, this shortage of dedicated training programs leaves interested interven-
tionalists pursuing carotid stent training through short educational courses, and often
haphazard and limited “hands-on” experience in other institutions.
The purpose of our Handbook of Complex Percutaneous Carotid Intervention is to
provide a learning resource to complement the “hands-on” training of established inter-
ventionalists and trainees. This handbook is intended for various disciplines participating
in the management of patients with carotid and vertebral artery stenosis, including inter-
ventional cardiologists, vascular surgeons, interventional radiologists, and interventional
neurologists. The focus of this handbook is on percutaneous intervention of patients with
extracranial carotid artery stenosis. As interventionalists of the cerebrovasculature are
often faced with stenosis involving other cerebral vessels, we complemented our hand-
book with sections on percutaneous interventions of intracranial stenosis, vertebral artery
stenosis, and acute stroke.
We have provided a detailed introduction to the techniques of extracranial and intrac-
ranial, carotid, and vertebral interventions. We reviewed the indications, approaches,
equipment, and potential complications of these percutaneous interventions. As many
patients undergoing such procedures are elderly and high-risk with challenging anatomy,
we also provided some useful pearls and troubleshooting of technically difficult cases.
In addition, our section on challenging cases illustrates our approach to frequently en-
countered challenges at the Cleveland Clinic.
The Handbook of Complex Percutaneous Carotid Intervention is also meant to pro-
vide a comprehensive review of the management of carotid artery stenosis. Thus, we have
vii
viii Preface
included chapters reviewing the epidemiology and significance of carotid stenosis,

medical therapy, noninvasive and invasive imaging of the carotid artery, and carotid
endarterectomy. In this current era of evidence-based medicine, we have also included
chapters reviewing sentinel studies supporting carotid endarterectomy and carotid stent-
ing.
Carotid stenting is an exciting and burgeoning field. It is often a challenging proce-
dure, which may expose patients to life-threatening complications. Its success as the
preferred revascularization therapy of high-risk patients is contingent upon low peripro-
cedural complications, which in turn is highly dependent on operator skills. As studies
comparing carotid stenting and endarterectomy for low-risk patients are completed, we
may see a further increase in the volume of carotid stenting. We hope that our Handbook
of Complex Percutaneous Carotid Intervention will provide a useful resource to guide
interventionalists through this challenging and important revascularization procedure of
the 21st century.
Jacqueline Saw, MD
J. Emilio Exaire, MD
David S. Lee, MD
Jay S. Yadav, MD
CONTENTS
Dedications .................................................................................................................... v
Preface ................................................................................................................. vii
Contributors ................................................................................................................... xi
Companion CD ........................................................................................................... xiii
PART I CLINICAL EXPERIENCE

1 Epidemiology and Significance of Carotid Artery Stenosis ............ 3
Anthony Y. Fung and Jacqueline Saw
2 Medical Therapy for Carotid Artery Stenosis ................................ 11
David S. Lee
3 Carotid Endarterectomy:
Techniques and Evidence-Based Medicine ................................ 33
Joël Gagnon and York N. Hsiang
4 Carotid Angioplasty and Stenting Trials:
A Historical Perspective and Evidence-Based Medicine .......... 47
David S. Lee and Jay S. Yadav
5 Cerebrovascular Anatomy .............................................................. 65
Ravish Sachar and Samir Kapadia
6 Noninvasive Imaging of the Carotid Artery ................................... 83
J. Emilio Exaire, Mikhael Mazighi,
Jacqueline Saw, and Alex Abou-Chebl
7 Cerebrovascular Angiography ........................................................ 99
J. Emilio Exaire, Jacqueline Saw,
and Christopher Bajzer
8 Indications for Carotid Artery Stenting ........................................ 111
Cameron Haery, Sharat Koul, and Deepak L. Bhatt
PART II TECHNIQUES OF CAROTID AND VERTEBRAL ARTERY STENTING

9 The Approach to Extracranial Carotid Artery Stenting ............... 131
Jacqueline Saw and Jay S. Yadav
10 Equipment for Extracranial Carotid Artery Stenting ................... 147
Jacqueline Saw and J. Emilio Exaire
11 Emboli Protection Devices ........................................................... 159
Jacqueline Saw
12 Complications of Carotid Artery Stenting ................................... 175
Jacqueline Saw
ix
x Contents
13 The Approach to Intracranial Carotid Artery Intervention .......... 189

Ivan P. Casserly and Jay S. Yadav
14 The Approach to Intracranial and Extracranial Vertebral
Artery Stenting ......................................................................... 211
J. Emilio Exaire and Jacqueline Saw
15 Endovascular Treatment of Acute Ischemic Stroke ..................... 229
Mikhael Mazighi, Qashim Bashir, and Alex Abou-Chebl
PART III CHALLENGING CASE ILLUSTRATIONS AND PEARLS

16 Case: Left Carotid Artery Stenting with a Challenging
Type III Aortic Arch ................................................................. 249
Jacqueline Saw
17 Case: Stenting of a Tortuous Left Internal Carotid Artery .......... 259
J. Emilio Exaire
18 Case: Stenting of a Critical Internal Carotid Artery Stenosis
with String Sign ........................................................................ 265
Jacqueline Saw
19 Case: Stenting of a Carotid Endarterectomy Patch Restenosis
and Aneurysm ........................................................................... 275
J. Emilio Exaire
20 Case: Carotid Stenting with Slow Flow
and Distal Embolization ........................................................... 283
J. Emilio Exaire
21 Case: Acute Stroke Intervention with a Large
Thrombotic Burden................................................................... 289
Jacqueline Saw
22 Case: Left Internal Carotid Artery Stenting
in a Bovine Aortic Arch ........................................................... 295
David S. Lee
23 Case: Right Carotid Artery Stenting via Right
Brachial Artery Approach ........................................................ 305
David S. Lee
24 Case: Ostial Innominate Artery Intervention ............................... 317
David S. Lee
Index ....................................................................................................... 329
CONTRIBUTORS
ALEX ABOU-CHEBL, MD • Section of Stroke and Neurological Critical Care, Department
of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio
CHRISTOPHER BAJZER, MD • Department of Cardiovascular Medicine, Cleveland Clinic
Foundation, Cleveland, Ohio
QASIM BASHIR, MD • Neurology Fellow, Department of Neurology, Cleveland Clinic
DEEPAK L. BHATT, MD, FACC • Staff, Cardiac, Peripheral, and Carotid Intervention,
Associate Professor of Medicine, Department of Cardiovascular Medicine,
Cleveland Clinic Foundation, Cleveland, Ohio
IVAN P. CASSERLY, MB, BCH • Director of Interventional Cardiology, Denver Veterans
Affairs Medical Center, Cardiology Section, Denver, Colorado
J. EMILIO EXAIRE, MD • Department of Interventional Cardiology, Instituto Nacional de
Cardiología “Ignacio Chávez,” Tlalpan, Mexico City, Mexico
ANTHONY Y. FUNG, MBBS • Division of Cardiology, Vancouver General Hospital, Vancouver,
BC, Canada
JOËL GAGNON, MD • Vascular Surgery Fellow, Division of Vascular Surgery, University
of British Columbia, Vancouver, BC, Canada
CAMERON HAERY, MD • Director, Interventional Cardiology, Illinois Masonic Medical
Center, West Suburban Cardiologists, L.L.C., Chicago, Illinois
YORK N. HSIANG, MD • Professor of Surgery, University of British Columbia, Division
of Vascular Surgery, Vancouver General Hospital, Vancouver, BC, Canada
SAMIR KAPADIA, MD, FACC • Associate Professor of Medicine, Director, Interventional
Cardiology Fellowship, Department of Cardiovascular Medicine, Cleveland Clinic
SHARAT KOUL, DO • Cardiovascular Diseases Fellow, Illinois Masonic Medical Center,
Chicago, Illinois
DAVID S. LEE, MD • Interventional Cardiology, Hillsboro Cardiology, Hillsboro, Oregon
MIKHAEL MAZIGHI, MD • Neurology Fellow, Department of Neurology, Cleveland
Clinic Foundation, Cleveland, Ohio
RAVISH SACHAR, MD • Interventional Cardiologist, Wake Heart and Vascular, Raleigh,
North Carolina
JACQUELINE SAW, MD, FRCPC • Clinical Assistant Professor of Medicine, University of
British Columbia, Division of Cardiology, Vancouver General Hospital, Vancouver,
BC, Canada
JAY S. YADAV, MD • Director, Peripheral Vascular Intervention, Department of
Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio
xi
COMPANION CD
The accompanying CD ROM contains the movies associated with Part III, Challeng-
ing Case Illustrations and Pearls, and all color illustrations from the book.
The following hardware and software are the minimum required to use this CD-ROM:
• For Microsoft Windows: An Intel Pentium II with 64 MB of available RAM running

Windows 98, or an Intel Pentium III with 128 MB of available RAM running
Windows 2000 or Windows XP. A monitor set to 832 624 or higher resolution.
• For Macintosh OS X: A Power Macintosh G3 with 128 MB of available RAM
running Mac OS X 10.1.5, 10.2.6 or higher. A monitor set to 832 624 or higher
resolution.
• For Macintosh Classic: A Power Macintosh G3 with 64 MB of available RAM
running System 9.2. A monitor set to 832 624 or higher resolution.
xiii
I CLINICAL EXPERIENCE
1 Epidemiology and Significance
of Carotid Artery Stenosis
Anthony Y. Fung, MBBS

and Jacqueline Saw, MD
CONTENTS
INTRODUCTION
STROKE
CAROTID ARTERY STENOSIS
CONSEQUENCE OF CAROTID ARTERY STENOSIS
CONCLUSION
REFERENCES
Summary
Carotid artery stenosis is a prevalent disease, caused predominantly by atherosclerosis. The
reported prevalence is dependent on the population screened, investigative tool used, and the criteria
employed. The presence of carotid artery stenosis is associated with an increased risk of stroke and
other ischemic manifestations of systemic atherosclerosis (e.g., myocardial infarctions and vascular
deaths). Thus, carotid revascularization strategies for stroke prevention had been aggressively pur-
sued over the past five decades. This chapter reviews the epidemiology and prevalence of carotid
artery stenosis.
Key Words: Carotid artery stenosis, carotid artery stenting, carotid endarterectomy, epidemio-
logy, stroke.
INTRODUCTION
Carotid artery stenosis is a prevalent disease, caused predominantly by atherosclero-
sis. Other causes are rare and include fibromuscular dysplasia, trauma, and carotid dis-
section. The reported prevalence of carotid artery stenosis is dependent on the
population screened, investigative tool used, and criteria employed. In the Framingham
Study cohort, the prevalence of significant carotid artery stenosis (carotid ultrasound
stenosis 50%) was 7% in women and 9% in men (1). The prevalence is higher among
individuals at risk for atherosclerosis (11%), those who have underlying cardiac disease
(18%), and those presenting with acute stroke (60%) (2). It is clear that age and the
presence of atherosclerotic risk factors increase the prevalence of disease. Not surpris-
ingly, the presence of carotid artery stenosis is associated with an increased risk of
From: Contemporary Cardiology: Handbook of Complex Percutaneous Carotid Intervention

Edited by: J. Saw, J. E. Exaire, D. S. Lee, and S. Yadav © Humana Press Inc., Totowa, NJ
3
4 Fung and Saw
stroke and other ischemic manifestations of systemic atherosclerosis (e.g., myocardial

infarctions and vascular deaths). Thus, carotid revascularization strategies for stroke
prevention had been aggressively pursued over the past five decades.
STROKE
Prevalence of Stroke and Economic Burden
The primary goal of revascularization of significant carotid artery stenosis is to prevent
strokes. Strokes can have major impact on both the individual and the society, incurring
disability and draining the healthcare system and the economy. Each year, approx 750,000
Americans and 50,000 Canadians experience a new or recurrent stroke (3). Stroke is the
third leading cause of death, and the principal cause of long-term disability.
Approximately one third of patients die within 30 d, and one third are left with perma-
nent disability. The economic burden in North America is astounding, costing the
healthcare system more than 50 billion dollars annually in the United States and approx
3 billion dollars annually in Canada (3).
Stroke Etiology
More than 80% of all strokes are ischemic in origin (Fig. 1), while 20% are due to
intracerebral hemorrhage (Fig. 2). Three quarters of ischemic strokes involve the ante-
rior circulation, and one quarter involve the posterior vertebrobasilar system (4).
Overall, 20–30% of all strokes are accounted for by extracranial carotid artery stenosis
(5), whereas intracranial atherosclerosis account for roughly 5–10% of strokes (6,7).
However, most of these data are based on a predominantly Caucasian population, and
epidemiologic studies have also shown ethnicity to affect stroke etiology. For instance,
in the Northern Manhattan Stroke study, intracranial atherosclerosis was shown to
account for 6–10% of ischemic strokes of white patients, but up to 29% among African
Americans and Hispanics (8). Among patients with lacunar infarcts, the prevalence of
extracranial carotid artery disease (50% stenosis) is approx 10% (which is likely an
incidental finding). Whereas among patients with nonlacunar hemispheric stroke, 41%
had ipsilateral carotid artery disease (50% stenosis) (9).
CAROTID ARTERY STENOSIS

Location of Carotid Artery Stenosis
Atherosclerotic plaques tend to accumulate at branch ostia and bifurcations due to
the disturbance of laminar flow. Thus, in the carotid circulation, there is a predilection
of plaque accumulation at the carotid bifurcation into the internal carotid artery (ICA)
and external carotid artery (ECA). The ostium of the ICA is most often affected, invol-
ving the outer posterior wall of the carotid sinus, and often extending into the distal
common carotid artery (CCA). Atherosclerosis of the intracranial ICA and its branches
is much less common (described in Chapter 13).
Prevalence of Concomitant Intracranial Atherosclerosis

Although uncommon, a small proportion of patients with extracranial carotid steno-
sis have concomitant intracranial involvement. In a series of 100 consecutive patients
with severe extracranial carotid disease being considered for carotid endarterectomy,
cerebral angiography showed significant intracranial disease in 15% of patients (10). In
Chapter 1 / Significance of Carotid Artery Stenosis 5
Fig. 1. Schematic diagram illustrating frequent causes of ischemic strokes.

6 Fung and Saw
Fig. 2. Classification of stroke according to etiology.
the NASCET (North American Symptomatic Carotid Endarterectomy) study of sympto-

matic patients with extracranial carotid disease, mild intracranial disease was found in
33% patients. However, by protocol design, patients with severe intracranial disease
were excluded (11).
Significance of Carotid Bruit
Carotid disease may be discovered as patients are worked up for carotid bruit.
However, the presence of carotid bruit is poorly specific for carotid stenosis. In fact, the
prevalence of significant carotid stenosis in patients with asymptomatic carotid bruit is
only 10–20% (12,13). Patients with carotid bruit and documented carotid stenosis on
duplex ultrasound do have higher risk of cerebral events (14). Indeed, patients with
carotid bruit have been shown to have a two to fourfold higher risk of subsequent
strokes when compared to controls (12,13).
Carotid Intimal–Medial Thickness

There is a strong association between cerebrovascular atherosclerosis and adverse
vascular events. Measurement of the intimal–medial thickness (IMT) on carotid ultra-
sound has evolved to be a reliable method to evaluate early carotid atherosclerosis (15).
Many studies have documented the link between increased IMT and future adverse
vascular events. In a prospective study by O’Leary et al. involving more than 4400
elderly subjects without clinical evidence of cardiovascular disease, approx 25% of
patients in the fifth IMT quintile had experienced myocardial infarction or stroke at
7 yr follow-up, compared with 5% for the first quintile (Fig. 3) (16).
Concomitant Coronary Artery Disease and Peripheral Arterial Disease

Presence of severe atherosclerosis in one vascular bed may trigger screening for con-
comitant silent cerebrovascular disease. Among patients with severe coronary disease
Fig. 3. Cumulative event-free (myocardial infarction or stroke) survival rates according to quintiles
of combined intimal–medial thickness (IMT). (Adapted from ref. 16.)
being considered for cardiac surgery, 17–22% have 50% carotid stenosis, and 6–12%
have 80% carotid stenosis (17). Among patients with peripheral arterial disease,
14–34% had carotid stenosis 50% by duplex ultrasound (18,19), and 5% have carotid
occlusion (19).
CONSEQUENCE OF CAROTID ARTERY STENOSIS

Disease Progression
Similar to other vascular beds, atherosclerotic carotid disease is a dynamic process.
In a prospective study of patients with asymptomatic carotid bruit and mild carotid
stenosis, serial ultrasound studies showed that the annual rate of disease progression to
50% stenosis was 8% (12). In a recent series, among patients with moderate asymp-
tomatic carotid disease (50–79% stenosis) followed for a mean of 38 mo, 17% had evi-
dence of disease progression documented on serial ultrasound examinations, with an
estimated annual rate of progression of 4.9% (20).
Risk of Stroke
The risk of stroke is highly dependent on the severity of stenosis and symptom
status. Patients with known carotid artery stenosis who presented with a neurologic
event within the last 6 mo are more likely to have a future stroke event. For example,
in the NASCET study, the risks of ipsilateral strokes at 5 yr for patients with mild
(50%) stenosis on angiography were 18.7% and 7.8% for those with and without symp-
toms, respectively. For those with more severe (75–94%) stenosis, the rates were higher,
27.1% and 18.5% for symptomatic and asymptomatic patients, respectively (Fig. 4) (21).
Among patients studied in the asymptomatic carotid endarterectomy trials with
carotid stenosis 60%, the incidence of ipsilateral stroke at 5 yr was 11.5% in ACAS
8 Fung and Saw
Fig. 4. Risk of ipsilateral stroke at 5 yr based on severity of carotid stenosis and symptom status.
(Adapted from ref. 21.)
Table 1
Annual Percentage Risk of Cerebrovascular Events Depending on Stenosis Severity
and Symptom Status
Degree of stenosis
1–29% 30–59% 60–99% Occluded
Asymptomatic patients
Irreversible stroke 0.4 1.3 2.3 4.0
Reversible event 0.7 1.0 5.6 3.0
Symptomatic patients
Irreversible stroke 1.3 2.0 13.0 9.1
Reversible event — 4.0 14.5 2.0
Adapted from ref. 24.
(Asymptomatic Carotid Endarterectomy Study) (22), and 11.7% in ACST

(Asymptomatic Carotid Surgery Trial) (23). Table 1 provides a summary of the annual
ipsilateral cerebrovascular event based on underlying stenosis severity and symptom
status (24).
Other Predictors of Stroke

Aside from symptom status and stenosis severity, plaque characteristics could also
affect subsequent stroke risk. For example, hypoechogenic plaques as detected by high-
resolution ultrasound are associated with higher stroke risk. Presumably these plaques
have high lipid content and are more prone to rupture, with subsequent thrombosis and
embolization (25–27). Ulcerated plaques are also known to be more unstable and at
higher risk for neurologic event. For example, in the medical arm of NASCET, the 2-yr
stroke rate among patients without an ulcer was 21.3% irrespective of stenosis severity.
However, among those with an ulcer on angiography, the 2-yr stroke event increased
incrementally from 26.3% to 73.2%, as the stenosis severity increased from 75% to
95% (28).
Risks of Coronary Artery Disease

It should be noted that patients with cerebrovascular disease have a high prevalence
of silent coronary artery disease. Hertzer et al. performed coronary angiography on 200
asymptomatic patients (most of whom had carotid bruit). Eighty patients (40%) were
found to have severe coronary artery disease (defined as 70% stenosis of 1 coro-
nary artery), and 93 patients (46%) had mild or moderate disease. Only 27 patients
(14%) had normal coronary arteries. In terms of extent of disease, 22% were consid-
ered to have severe but compensated coronary artery disease, 16% had severe but sur-
gically correctable disease, and 2% had inoperable disease (29).
Risk of Stroke with Coronary Artery Bypass Surgery

High-grade carotid artery stenosis (80%) occur in roughly 8–12% of patients
scheduled for coronary artery bypass grafting, and was responsible for up to 30% of
hemispheric strokes that occur early after surgery. The incidence of perioperative stroke
is dependent on stenosis severity, being 2% when carotid stenosis is mild (50%
severity), but increasing to 10% with moderate lesions (stenosis 50–80%), and to
11–19% with severe stenosis (80%). Patients with bilateral high-grade stenosis
(80%) or occlusion have up to a 25% incidence of stroke perioperatively (30).
Therefore, screening for significant carotid stenosis is important prior to cardiac
surgery, and is routinely performed in most institutions. This allows surgeons to have
a better estimation of perioperative stroke risk.
CONCLUSION
Carotid artery stenosis is an important cause of stroke. Symptomatic patients with
severe carotid artery stenosis are at much higher risk for future strokes than are asymp-
tomatic patients. Patients with significant carotid artery stenosis are also at increased
risk for other vascular events, as atherosclerosis is a systemic disease. Management of
these patients should thus be multifaceted, and should include aggressive risk-factor
modification, medical treatment to diminish global atherothrombotic risks, and carotid
revascularization to lower cerebrovascular events, as appropriate.
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1. Fine-Edelstein JS, Wolf PA, O’Leary DH, et al. Precursors of extracranial carotid atherosclerosis in
the Framingham Study. Neurology 1994;44:1046–1050.
2. Rockman CB, Jacobowitz GR, Gagne PJ, et al. Focused screening for occult carotid artery disease:
patients with known heart disease are at high risk. J Vasc Surg 2004;39:44–51.
3. AHA. American Heart Association. Heart Disease and Stroke Statistics—2005 Update. Dallas, TX:
American Heart Association; 2004. americanheart.org 2005.
4. Cloud GC, Markus HS. Diagnosis and management of vertebral artery stenosis. QJM 2003;96:27–54.
5. Sacco RL. Extracranial carotid stenosis. N Engl J Med 2001;345:1113–1118.
6. Petty GW, Brown RD, Jr., Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO. Ischemic stroke sub-
types: a population-based study of incidence and risk factors. Stroke 1999;30:2513–2516.
10 Fung and Saw
7. White H, Boden-Albala B, Wang C, et al. Ischemic stroke subtype incidence among whites, blacks,
and Hispanics: the Northern Manhattan Study. Circulation 2005;111:1327–1331.
8. Sacco RL, Kargman DE, Gu Q, Zamanillo MC. Race-ethnicity and determinants of intracranial athero-
sclerotic cerebral infarction. The Northern Manhattan Stroke Study. Stroke 1995;26:14–20.
9. Tegeler C, Shi F, Morgan T. Carotid stenosis in lacunar stroke. Stroke 1991;22:1124–1128.
10. Griffiths PD, Worthy S, Gholkar A. Incidental intracranial vascular pathology in patients investigated
for carotid stenosis. Neuroradiology 1996;38:25–30.
11. Kappelle LJ, Eliasziw M, Fox AJ, Sharpe BL, Barnett HJ. Importance of intracranial atherosclerotic
disease in patients with symptomatic stenosis of the internal carotid artery. Stroke 1999;30:282–286.
12. Roederer G, Langlois Y, Jager K, et al. The natural history of carotid arterial disease in asymptomatic
patients with cervical bruits. Stroke 1984;15:605–613.
13. Chambers BR, Norris JW. Outcome in patients with asymptomatic neck bruits. N Engl J Med
1986;315:860–865.
14. Norris JW, Zhu CZ, Bornstein NM, Chambers BR. Vascular risks of asymptomatic carotid stenosis.
Stroke 1991;22:1485–1490.
15. Mancini GB, Dahlof B, Diez J. Surrogate markers for cardiovascular disease: structural markers.
Circulation 2004;109:IV22–30.
16. O’Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor
for myocardial infarction and stroke in older adults. N Engl J Med 1999;340:14–22.
17. Eagle K, Guyton R, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass
graft surgery: summary article. A report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Committee to Update the 1999 Guidelines for
Coronary Artery Bypass Graft Surgery). J Am Coll Cardiol 2004;44: p1146–1154, e213–310.
18. Simons PC, Algra A, Eikelboom BC, Grobbee DE, van der Graaf Y. Carotid artery stenosis in patients
with peripheral arterial disease: the SMART study. SMART study group. J Vasc Surg 1999;30:
519–525.
19. House AK, Bell R, House J, Mastaglia F, Kumar A, D’Antuono M. Asymptomatic carotid artery steno-
sis associated with peripheral vascular disease: a prospective study. Cardiovasc Surg 1999;7:44–49.
20. Rockman CB, Riles TS, Lamparello PJ, et al. Natural history and management of the asymptomatic,
moderately stenotic internal carotid artery. J Vasc Surg 1997;25:423–431.
21. NASCET Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-
grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators.
N Engl J Med 1991;325:445–453.
22. ACAS. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the
Asymptomatic Carotid Atherosclerosis Study. JAMA 1995;273:1421–1428.
23. ACST Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterec-
tomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004;363:
p1491–p1502.
24. Obuchowski NA, Modic MT, Magdinec M, Masaryk TJ. Assessment of the efficacy of noninvasive
screening for patients with asymptomatic neck bruits. Stroke 1997;28:1330–1339.
25. Barnett HJ, Eliasziw M, Meldrum H. Plaque morphology as a risk factor for stroke. JAMA 2000;
284:177.
26. Mathiesen EB, Bonaa KH, Joakimsen O. Echolucent plaques are associated with high risk of ischemic
cerebrovascular events in carotid stenosis: the Tromso Study. Circulation 2001;103:2171–2175.
27. Polak J, Shemanski L, O’Leary D, et al. Hypoechoic plaque at US of the carotid artery: an independ-
ent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study [pub-
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28. Eliasziw M, Streifler JY, Fox AJ, Hachinski VC, Ferguson GG, Barnett HJ. Significance of plaque
ulceration in symptomatic patients with high-grade carotid stenosis. North American Symptomatic
Carotid Endarterectomy Trial. Stroke 1994;25:304–308.
29. Hertzer NR, Young JR, Beven EG, et al. Coronary angiography in 506 patients with extracranial cere-
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opportunities. Circulation 2004;109:3136–3144.
2 Medical Therapy for Carotid
Artery Stenosis
David S. Lee, MD
CONTENTS
INTRODUCTION
TRADITIONAL CARDIOVASCULAR
RISK FACTORS AND CAROTID STENOSIS
ANTIPLATELET AND ANTITHROMBOTIC THERAPY
CONCLUSION
REFERENCES
Summary
Patients with carotid atherosclerotic disease are at an increased risk for stroke. This chapter
reviews the risk factors associated with carotid artery stenosis and the medical interventions that
decrease the cardiovascular risk from carotid atherosclerotic disease.
Key Words: Angiotensin-converting enzyme inhibitor, antiplatelet therapy, antithrombotic therapy,

cardiovascular risk factors, carotid artery stenosis, statin.
INTRODUCTION
Patients with carotid atherosclerotic disease are at an increased risk for stroke. The
focus of the rest of this book is on carotid arterial revascularization, which in certain
patient subsets has been shown to decrease the future risk of stroke and death (1–4).
This chapter focuses on medical interventions that decrease the risk from carotid athero-
sclerotic disease.
TRADITIONAL CARDIOVASCULAR RISK FACTORS

AND CAROTID STENOSIS
Traditional cardiovascular risk factors correlate with carotid artery stenosis. In the
Framingham Heart Study, the odds ratio of moderate carotid stenosis (25%) in men
was 2.11 (95% confidence interval [CI] 1.51–2.97) for an increase of 20 mmHg in sys-
tolic blood pressure (SBP), 1.10 (95% CI 1.03–1.16) for an increase of 10 mg/dL of
total cholesterol, and 1.08 (95% CI 1.03–1.13) for an increase of 5 pack-years of smok-
ing, with similar findings in women (5). In a study of 3998 people in Osaka, Japan, the
number of major coronary risk factors was associated with a higher likelihood of severe

11
12 Lee
Fig. 1. Correlation between cardiac risk factors (hypertension, dyslipidemia, and tobacco abuse) and
incidence of significant carotid stenosis (50%). A linear relationship exists between the number of
risk factors and the likelihood of significant carotid stenosis. This relationship was stronger in men
than in women. (Adapted from ref. 6.)
(50%) carotid stenosis (Fig. 1). Major coronary risk factors in this study were hyper-
tension (SBP 140, diastolic blood pressure [DBP] 90, or on medication), hyperlipi-
demia (total cholesterol 220 mg/dL or on medication), or tobacco abuse (current
smoker). The mean carotid arterial intimal–medial thickness (IMT) was also increased
with increasing numbers of coronary risk factors (6). Another study found that patients
with carotid stenosis had higher SBP and DBP, and higher plasma cholesterol and
triglyceride concentrations than the control groups. They had, as well, a far greater
likelihood of being cigarette smokers and a greater likelihood of having diabetes melli-
tus and previous evidence of coronary and peripheral arterial disease. Patients with
carotid stenosis were also more likely to have two or more of these common risk fac-
tors of atherosclerosis than were the control subjects (7). Other studies have suggested
diabetes mellitus, family history of stroke, low high-density lipoprotein (HDL) levels,
coronary artery disease (CAD), and peripheral arterial disease as associated risk factors
(7–12). Overall, approx 40% of the incidence of carotid stenosis can be accounted for
by traditional risk factors (10).
Thus, the focus of medical therapy for carotid atherosclerotic disease typically con-
centrates on treatment of these risk factors: hypertension, dyslipidemia, diabetes melli-
tus, and tobacco use. Importantly, disease in the carotid arteries suggests that
atherosclerotic disease may exist elsewhere in other arterial beds. The National
Cholesterol Education Program and ATP III guidelines consider the presence of carotid
disease equivalent to the presence of CAD for calculating cardiovascular risk (13).
Chapter 2 / Medical Therapy for Carotid Artery Stenosis 13
What are Useful End Points or Outcomes to Measure?

The major carotid surgical revascularization studies utilized ipsilateral stroke, all-stroke,
fatal stroke, and/or all-cause mortality as end points (1–4). The SAPPHIRE (Stenting and
Angioplasty with Protection in Patients at High Risk for Endarterectomy) trial comparing
carotid stenting to carotid endarterectomy used a composite including death, stroke, and
myocardial infarction (MI) to better reflect the totality of the risk of revascularization (14).
Unfortunately, for the purposes of our discussion, nearly all clinical trials addressing
medical therapies have not focused on patients with carotid stenosis. Major trials of
medical therapy have focused on patients with prior cardiovascular events, known
atherosclerotic disease, or with multiple cardiovascular risk factors. Trials specifically
evaluating patients with carotid stenosis are lacking and generally have been under-
powered and have enrolled small numbers of patients. All-cause mortality, cardiac
death, MI, coronary revascularization, and/or stroke have all been used as end points in
these trials. From a global perspective for the patient, these combination end points
best reflect the “real world.” The goal is to prevent any or all cardiovascular complica-
tions. To better determine the effect on carotid atherosclerotic disease, however, a more
limited end point of ischemic ipsilateral stroke would be preferable. Unfortunately,
most trials did not report the proportion of patients with carotid disease, the severity of
carotid disease, or the subtype of strokes in the outcomes. Therefore, for the most part,
the reduction in stroke risk specifically attributable to treated carotid disease cannot be
separated from the overall reduction in stroke risk for a given therapy.
Hypertension
Hypertension is a well recognized risk factor for cardiovascular disease, and is per-
haps the most important modifiable risk factor for stroke. Most evidence about the
effects of blood pressure (BP) on the risk of cardiovascular complications is obtained
from two types of data: prospective nonrandomized observational studies correlating
the relationship between BP and the incidence of stroke and other adverse outcomes,
and randomized trials of antihypertensive drug therapy.
A meta-analysis of 61 prospective observational studies including approx 1 million
adults found that each 20 mmHg SBP or 10 mmHg DBP difference was associated
with a more than twofold increase in the stroke or death rate. Men and women had
similar findings, and hypertension was found to be associated with both fatal hemor-
rhagic and ischemic stroke. The risk remained elevated until the BP reached a low of
115 mmHg systolic and 75 mmHg diastolic (12). An analysis of 18 studies on Chinese
and Japanese patients found a significant association between DBP and both hemor-
rhagic and nonhemorrhagic stroke. Each 5 mmHg reduction in DBP was associated
with a reduced odds ratio (OR) of nonhemorrhagic stroke [OR 0.61 (95% CI
0.57–0.66)] and hemorrhagic stroke [OR 0.54 (95% CI 0.50–0.58)] (15).
In the Systolic Hypertension in the Elderly Program (SHEP) study, 4736 patients
60 yr of age with isolated systolic hypertension were enrolled. The average SBP was
155 mmHg in control patients compared to 143 mmHg in treated patients, resulting in
a 36% relative risk reduction in total stroke (p 0.0003). Nonfatal and fatal MI were
reduced 27%, with a 32% reduction in cardiovascular events (16). In a meta-analysis of
37,000 patients, antihypertensive therapy resulted in a 5–6 mmHg decrease in the DBP,
which was associated with a 42% reduction in stroke (95% CI 35–50%, p 0.0001)
and a 14% reduction in cardiovascular events (95% CI 4–22%, p 0.01) with follow-
up over 2–5 yr (17).
14 Lee
In patients with a history of stroke or transient ischemic attack (TIA), BP continues

to be an important risk factor. However, concerns exist about the safety of BP reduction
in this patient cohort, especially in the presence of cerebrovascular disease. The
Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial studied the
effect of BP reduction in 6105 patients with a history of stroke or TIA within 5 yr.
Patients were treated with either perindopril or placebo. Physicians had the option of
adding indapamide (a diuretic) to perindopril at their discretion. The treatment arm
reduced BP (systolic/diastolic) by 9/4 mmHg. Notably, combination therapy reduced
the BP by 12/5 mmHg vs 5/3 mmHg with perindopril alone. Over 4 yr of follow-up,
treatment was associated with a 28% reduction in stroke (10% vs 14%, p 0.0001)
and a 26% reduction in major vascular events. Combination therapy reduced the stroke
rate by 43% whereas single-agent therapy did not produce a significant reduction in
stroke rate (18).
COMPARATIVE TRIALS
The choice of antihypertensive agent depends on the clinical presentation and other
comorbidities. While numerous trials have been performed attempting to determine
which antihypertensive agent is preferable as first-line treatment, the majority of
patients will likely need more than one agent, making this discussion less relevant.
However, these trials (ALLHAT, HOPE, EUROPA, PEACE, VALUE, and CAMELOT)
do have useful insights into which patient cohorts benefit from antihypertensive ther-
apy, the magnitude of the treatment effect, and the utility of specific medications.
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT) enrolled 33,357 patients 55 yr of age with hypertension and 1 cardiovas-
cular risk factor to therapy with an angiotensin-converting enzyme inhibitor (ACE
inhibitor), a calcium channel blocker, or a diuretic with mean follow-up of 4.9 yr. The
-blocker treatment arm was stopped prematurely because of an increased adverse event
rate with doxazocin compared to diuretic therapy. The primary end point, combined
fatal coronary heart disease or nonfatal MI, and all-cause mortality were not signifi-
cantly different between treatment groups. SBP was increased in the amlodipine-treated
group (0.8 mmHg, p 0.03) and in the lisinopril-treated group (2 mmHg, p 0.001),
compared to the chlorthalidone-treated group. Treatment with amlopidine was associ-
ated with an increased rate of heart failure (10.2% vs 7.7%, RR 1.38, 95% CI 1.25–1.52),
while treatment with lisinopril was associated with an increased rate of stroke (6.3% vs
5.6%, RR 1.15, 95% CI 1.02–1.30) (Fig. 2). The rate of combined cerebrovascular
disease and heart failure was also higher with lisinopril (19). The difference in stroke rates
between lisinopril and chlorthalidone may be attributed to the BP differences achieved
between the two therapies. However, thiazide-type diuretics should be preferred as first-
line therapy in patients who do not have a specific indication for another agent (e.g., ACE
inhibitors or -blockers in left ventricular dysfunction, -blockers after MI, etc.).
CARDIOPROTECTIVE EFFECT OF ACE INHIBITORS/ANGIOTENSIN RECEPTOR

BLOCKER (ARBS)?
The Heart Outcomes Prevention Evaluation (HOPE) study randomized 9000 high-
risk patients to treatment with ramipril or placebo. Patients were deemed high risk if
they had evidence of cardiovascular disease including coronary disease, prior MI,
stroke, or peripheral arterial disease, or if they had diabetes mellitus and 1 cardio-
vascular risk factor (dyslipidemia, hypertension, microalbuminuria, or tobacco abuse).
Fig. 2. Cumulative risk of stroke in patients treated with different antihypertensive medications
(lisinopril, amlodipine, chlorthalidone) in the ALLHAT trial. Lisinopril therapy was associated with
an increase in stroke rate compared to chlorthalidone therapy at 6 yr (6.3% vs 5.6%, RR 1.15; 95%
CI 1.02–1.30). (Reproduced with permission from the ALLHAT study [19].)
The mean BP at enrollment was 139/79 mmHg. Patients treated with ramipril had a
22% reduction in MI, stroke, or cardiovascular death, a 26% reduction in cardiovascu-
lar death, a 32% reduction in stroke, a 15% reduction in revascularization, and a 23%
reduction in heart failure. The benefit was seen within the first year and was consistent
within all subgroups. Treatment with ramipril would prevent 18 deaths per 1000
patients treated, 16 MIs, and 9 strokes (20). The magnitude of BP lowering with
ramipril was 3.3/1.4 mmHg. The benefit seen initially was thought to be much greater
than what could be attributed to BP lowering alone, suggesting that ACE inhibitor may
have cardiovascular benefit beyond just BP reduction. A subgroup of patients with
ambulatory BP monitoring, however, had much greater BP reductions than what was
recorded at office visits (21).
The EUROPA (European trial on reduction of cardiac events with perindopril in sta-
ble CAD) study also treated nearly 14,000 high-risk patients with an ACE inhibitor,
perindopril, or placebo. Patients were considered high risk if they had a prior MI,
known CAD, coronary revascularization, or a positive stress test. The mean BP at
enrollment was 137/82 mmHg. Therapy with perindopril was associated with a
5/2 mmHg decrease in BP. Patients enrolled in EUROPA were not as high risk as
patients in HOPE. The cardiovascular mortality in the placebo-treated groups was 8%
for HOPE and 4% for EUROPA. Perindopril treatment, however, was still associated
with a 20% reduction in the combined end point of cardiovascular death, MI, or cardiac
arrest. The benefit was seen at 1 yr and was consistent among subgroups (22).
The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE)
Trial treated patients with stable CAD [prior MI or coronary artery bypass graft
(CABG) or known angiographic CAD] with either trandolapril or placebo. The mean
16 Lee
baseline BP at enrollment was 133/78 mmHg. Treatment with trandolapril did not result
in any significant reduction in adverse events. The incidence of cardiovascular death,
nonfatal MI, or revascularization was 21.9% with trandolapril compared to 22.5% with
placebo. Notably, the cardiovascular risk was not as high in this patient cohort as with
patients enrolled in either HOPE or EUROPA, suggesting perhaps that the value of
therapy may be proportional to the underlying risk (23).
The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial compared
valsartan therapy to amlodipine therapy in hypertensive patients at high risk, defined as
known coronary heart disease, dyslipidemia, diabetes mellitus type 2, cerebrovascular
disease, peripheral arterial disease, left ventricular hypertrophy, reduced renal function,
proteinuria, or tobacco abuse. The mean BP at enrollment was 155/88 mmHg. After
mean follow-up of 4.2 yr, the primary composite end point of cardiac events, MI, stroke,
and death was not significantly different between the treatment arms (24).
The Comparison of amlodipine vs enalapril to limit occurrences of thrombosis
(CAMELOT) trial compared treatment with either amlodipine or enalapril to placebo
in patients with known angiographic coronary disease 20% and DBP 100 mmHg.
Mean baseline BP was 129/78 mmHg. The primary end point was a composite of car-
diovascular death, nonfatal MI, resuscitated cardiac arrest, coronary revascularization,
hospitalization for either angina or congestive heart failure, fatal or nonfatal stroke,
TIA, and new diagnosis of peripheral arterial disease. The incidence of the composite
end point was 23.1% in the placebo group compared to 16.6% in the amlodipine-treated
group and 20.2% in the enalapril-treated group. Only the amlodipine-treated arm had a
statistically significant reduction in risk (HR 0.69, 95% CI 0.54–0.88, p 0.003). The
enalapril-treated arm had a hazard ratio of 0.85 (95% CI 0.67–1.07, p 0.16). While
the BP reduction was similar with both treatment arms (4.8/2.5 mmHg with amlodipine
and 4.9/2.4 mmHg with enalapril), the once daily dosing of both drugs raises the possi-
bility that BP lowering may not have been as stable with enalapril (half-life of ~11 h)
compared to amlodipine (half-life of ~50 h). Moreover, amlodipine has antianginal
properties, which may have reduced the need for coronary revascularization and hospi-
talization for angina. The reduction in the incidence of nonfatal MI, stroke, and death
was similar between amlodipine and enalapril treatments, although not statistically sig-
nificant for either compared to placebo (25).
Overall, these trials suggest that high-risk patients with “normotensive” blood pres-
sures (baseline BP of 137–139/79–82 mmHg) still benefit from therapy. Moreover, it
seems likely that the magnitude of BP lowering achieved by therapy may be more
important than the actual agent used, although this is controversial.
GOAL OF BLOOD PRESSURE MANAGEMENT

The Seventh Report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC VII) issued new guidelines for
the treatment of BP in 2003. The recommended target BP was 140/90 mmHg in
patients with cardiovascular disease and 130/80 in patients with diabetes mellitus or
chronic kidney disease with proteinuria. They concluded that most patients will require
at least two BP medications to reach these goals (26). The 2003 European Society of
Hypertension-European Society of Cardiology (ESH-ESC) guidelines for the manage-
ment of arterial hypertension, however, recommended a goal BP 130/85 mmHg in
high-risk patients with cardiovascular disease (27). Given the results of HOPE,
EUROPA, PEACE, VALUE, and CAMELOT, several conclusions become evident.
Patients at higher risk derive greater benefit from BP reduction even if they are not
“hypertensive.” Blood pressure reduction itself may be more important than the actual
agent used. Certain classes of medications are of greater benefit in certain clinical situ-
ations, such as ACE inhibitors for patients with congestive heart failure, left ventricular
dysfunction, or diabetes mellitus, and -blockers for patients with angina, prior MI, or
congestive heart failure. Overall, however, the recommendations of ESH-ESC may bet-
ter reflect goals of therapy in high-risk patients.
CAROTID DISEASE AND BLOOD PRESSURE REDUCTION
In patients with severe carotid atherosclerotic disease, concerns exist about decreas-
ing the BP especially in the setting of severe bilateral carotid stenosis or carotid occlu-
sion. Cerebral perfusion has been hypothesized to be dependent on perfusion pressure,
and therefore systemic BP. Decreasing the BP in this setting may result in increasing
ischemia to regions of the brain that are marginally receiving sufficient blood flow at
baseline. While this hypothesis has validity in the acute stroke setting, very little clini-
cal data exists about this possibility for long-term treatment. Rothwell et al. conducted
a post hoc analysis of data from three trials, two of which were carotid revasculariza-
tion trials in symptomatic patients with carotid stenosis (NASCET and ECST) and one
in patients with stroke or TIA with low likelihood of carotid stenosis treated with
aspirin. Increased BP correlated with higher stroke risk in patients with symptomatic
carotid disease, although this relationship is blunted in comparison to other patients
presenting with TIA or stroke. Carotid occlusion did not affect this, but patients with
bilateral 70% stenosis had an increased stroke risk with decreased BP, suggesting
that aggressive BP reduction may result in worse outcomes in this cohort of patients
(28). However, it is important to note that this was a post hoc analysis looking at the
relationship of BP at time of enrollment and subsequent stroke. This was not a trial of
BP lowering, and the relatively small number of strokes in these patients with bilateral
carotid disease makes the data liable to statistical variance. However, caution is still
warranted in this cohort of patients.
Hyperlipidemia
EPIDEMIOLOGICAL PARADOX
Hyperlipidemia has been associated with carotid atherosclerotic disease. Elevated
total cholesterol was associated with an increased likelihood of moderate carotid steno-
sis in the Framingham Study. Other studies have suggested a correlation between total
cholesterol/HDL ratio and carotid stenosis and an inverse relationship between HDL
and carotid stenosis (29,30). High HDL may be associated with reduced carotid plaque
progression (31). Surprisingly, however, elevated lipid levels are not established as a
risk factor for stroke (32). Our understanding of how dyslipidemia affects stroke risk
comes from two types of data: observational studies looking at the association of plasma
lipid levels and stroke and randomized controlled trials of lipid-lowering therapy and
the effect on stroke risk. Unfortunately, unlike work on hypertension, a discordance is
seen between the epidemiological studies and the therapeutic studies. Only a weak
association between lipid levels and stroke is observed, but a significant benefit is seen
with lipid-lowering therapy, primarily statins, in reducing stroke risk.
In a large analysis of 450,000 patients, no correlation between cholesterol levels and
stroke could be found, except potentially in patients younger than 45 yr of age. This
finding was not different after adjusting for gender, DBP, history of CAD, or ethnicity.
18 Lee
Unfortunately, three quarters of the stroke events in this analysis were from studies that
recorded only fatal strokes. Moreover, the type of stroke was not recorded in any of the
trials to allow for analysis by subtype (33). In another analysis, Iso et al. studied more
than 350,000 men to determine the relationship between total cholesterol level and risk
of fatal stroke. After adjustment for age, smoking, DBP, and ethnicity, there was an
association between total cholesterol level and fatal nonhemorrhagic stroke
(p 0.007). Interestingly, however, in men with DBP 90 mmHg, a low total choles-
terol (160 mg/dL) was associated with a threefold greater risk of fatal hemorrhagic
stroke (p 0.05) (34). In a case control study, separating patients into quintiles based
on total and HDL cholesterol values, the highest quintile of total cholesterol compared
to the lowest quintile had an increased risk for nonhemorrhagic stroke (OR 1.6 [95%
CI 1.3–2.0]). Atherosclerotic stroke (OR 3.2) and lacunar stroke (OR 2.4) had the
strongest associations. The lowest quintile of total cholesterol had an increased risk of
hemorrhagic stroke (35).
Similar findings were seen in different ethnic cohorts. The Copenhagen City Heart
Study found that total cholesterol only correlated with nonhemorrhagic strokes in
patients with serum total cholesterol levels of 309 mg/dL (8 mmol/L). The risk
associated with lower cholesterol levels remained fairly constant. An association
between plasma triglycerides and nonhemorrhagic strokes (RR 1.12 [95% CI
1.07–1.16]) and an inverse relationship between HDL levels and nonhemorrhagic
strokes were found. Notably, however, the lipid studies were performed on nonfasting
samples (36). People in eastern Asia tend to have higher incidence of hemorrhagic
stroke than Western populations. An analysis of 18 studies studying Chinese and
Japanese patients found that total cholesterol levels were only weakly correlated with
strokes. Each 0.6 mmol/L reduction in total cholesterol was associated with a trend to a
reduced risk of nonhemorrhagic stroke (OR 0.77 [95% CI 0.57–1.06]), and an increased
risk of hemorrhagic stroke (OR 1.27 [95% CI 0.84–1.91]) (15).
Overall, elevated cholesterol levels correlated with ischemic stroke, albeit weakly,
and an association was found between low cholesterol levels and hemorrhagic stroke.
STATIN THERAPY
Amarenco et al. performed a meta-analysis on more than 90,000 patients treated
with statin therapy enrolled into randomized clinical trials published before August
2003. Statin therapy was found to reduce the stroke rate significantly (risk reduction of
21% [OR 0.79 {95% CI 0.73–0.85}]) (Fig. 3). After trials for which stroke was not a
specified end point were excluded, the OR was 0.80 (95% CI 0.74–0.87). A nonsignifi-
cant reduction in fatal strokes of 9% was also found (OR 0.91 [95% CI 0.76–1.10]).
Statin therapy also did not affect the likelihood of hemorrhagic stroke. The pooled OR
was 0.90 (95% CI 0.65–1.22). Overall, each 10% low-density lipoprotein (LDL) reduc-
tion reduced the risk of stroke by 15.6% (95% CI 6.7–23.6%). Approximately 33–80%
of the stroke reduction could be attributed to the LDL reduction. Each 10% reduction
in LDL also reduced the carotid IMT by 0.73% per year (95% CI 0.27–1.19%). The
correlation between LDL reduction and IMT reduction was significant (r 0.65,
p 0.004) (37).
Patients with “normal” cholesterol levels also benefit from statin therapy to reduce
stroke. The Cholesterol and Recurrent Events (CARE) trial treated 4159 patients with
a history of MI with average cholesterol (mean 209 mg/dL) and LDL levels (mean
139 mg/dL) with either pravastatin or placebo. The pravastatin-treated group had an
Fig. 3. Effects of statin therapy on fatal and nonfatal stroke risk from the study by Amarenco et al.
Odds ratios for stroke reduction with statin therapy are shown for individual trials. The small trials
included in the meta-analysis were grouped together. (Reproduced with permission from ref. 37.)
average reduction of 20% total cholesterol and 32% LDL. Patients treated with pravas-
tatin had a 32% reduction in all-cause stroke (95% CI 4–52%, p 0.03) and a 27%
reduction in stroke or TIA (95% CI 4–44%, p 0.02). No increase in hemorrhagic
strokes was observed (38). A subgroup analysis of the Anglo-Scandinavian Cardiac
Outcomes Trial focused on hypertensive patients with multiple cardiac risk factors
with normal total cholesterol values (6.5 mmol/L). Patients in this cohort treated
with atorvastatin had decreased nonfatal MI and cardiac death. Fatal and nonfatal
stroke was also reduced by 27% (95% CI 4–44%, p 0.024). The benefit of statin
therapy was observed in the first year of treatment (39).
Aggressive treatment with statin therapy also reduced the stroke risk. The Treating
to New Targets (TNT) trial enrolled 10,0001 patients with stable coronary disease with
LDL levels 130 mg/dL and treated them with either low- (10 mg daily) or high-dose
(80 mg daily) atorvastatin therapy. High-dose atorvastatin therapy significantly reduced
LDL more than low-dose atorvastatin (average LDL of 77 mg/dL vs 101 mg/dL) and
was associated with a significant 25% reduction in fatal and nonfatal stroke (95% CI
4–41%). Cardiovascular events were also reduced (40).
The Heart Protection Study (HPS) deserves special mention because it was the only
large statin trial that included a significant number of patients with prior stroke and
TIA. HPS studied 20,536 patients with known arterial occlusive disease or diabetes
mellitus and treated them with either simvastatin 40 mg daily or placebo. The average
LDL level at the time of enrollment was 131 mg/dL, of whom about one third had LDL
levels of 116 mg/dL. The magnitude of reduction of LDL by simvastatin was
39 mg/dL. In all patients, there was a 25% relative risk reduction for stroke (95% CI
15–34%, p 0.0001). The rate of ischemic strokes was decreased 28% (95% CI
19–37%, p 0.0001) with no increase in hemorrhagic strokes. Moreover, the rate of
TIA was decreased (2.0% vs 2.4%, p 0.02) and the need for carotid revascularization
was also reduced (0.4% vs 0.8%, p 0.0003). Notably, the benefit was found by the
end of the second year of therapy. The reduction in stroke was found in patients with
CAD, diabetics, and patients with low LDL (116 mg/dL) at enrollment (41).
Of all the patients enrolled, 3280 had a history of cerebrovascular disease defined
as prior nondisabling ischemic stroke or TIA, and/or prior carotid endarterectomy or
20 Lee
angioplasty. In this subgroup analysis, no reduction was found in the stroke rate,
although a 20% relative risk reduction was found in the rate of any vascular event
(95% CI 8–29%, p 0.001). Notably, patients who had a stroke within 6 mo were
excluded, and on average the cerebrovascular event occurred 4.3 yr before enroll-
ment. Stroke events were not subtyped although this was typical for most medical
therapy trials. The reason for this lack of benefit in this subgroup is unclear and
somewhat perplexing (41).
NONSTATIN THERAPY
Nonstatin lipid-lowering therapy has not consistently shown to decrease stroke risk.
A meta-analysis of lipid-lowering therapy revealed a relative risk reduction of 17% for
strokes. Statin therapy had a more pronounced effect compared to other treatments
(RRR of 26%). The effect was primarily seen when the total cholesterol was reduced to
232 mg/dL (42). Another meta-analysis revealed only a benefit for statin therapy but
not for other medication and lifestyle therapies for decreasing LDL. Some of the lack
of benefit of these other therapies has been attributed to their relative lack of efficacy in
reducing LDL compared to statin therapy. However, in the VA-HIT trial, patients with
low HDL cholesterol ( 40 mg/dL) treated with gemfibrozil had a decreased rate of
stroke compared to placebo (31% RRR [95% CI 2% to 52%, p 0.036]). The rate of
TIA and carotid endarterectomy were also reduced with gemfibrozil. The benefit was
evident after just 6–12 mo (43).
ACUTE STROKE TREATMENT WITH STATINS
Statin therapy has multiple effects beyond just lipid lowering and may provide neuro-
protective effects in the setting of acute stroke. In an occlusion–reperfusion model of
stroke in mice, treatment with atorvastatin for 14 d before the stroke reduced stroke
volume by 40%. This protective effect was lost when the statin therapy was stopped
abruptly, with complete loss of protection after 4 d. The authors concluded in this study
that the neuroprotective mechanism may be due at least in part to upregulation of
endothelial nitric oxide synthase (44). In humans, a small retrospective study of 167
patients suggested that being on prior statin therapy at the time of acute ischemic stroke
improved neurologic outcomes at 3 mo (using the modified Rankin score and the
Barthel Index), although the initial stroke severity and risk of progression were not dif-
ferent than in patients not on statin therapy (45). In a slightly larger retrospective study
of 650 patients, those on lipid lowering therapy at the time of an acute ischemic stroke
had a reduced risk of stroke progression and a lower 90-d mortality rate than those not
on therapy. More than 90% of patients on lipid-lowering therapy were on statin therapy
(46). Although these findings are preliminary, they are provocative about the benefit of
statins in this setting, and will hopefully lead to clinical trials assessing the value of
statin therapy in acute stroke.
Diabetes Mellitus
Diabetic patients have an increased risk of cardiovascular events including ischemic
stroke. The ATP III guidelines consider diabetes mellitus to be the equivalent of known
coronary atherosclerotic disease for future risk, and advocates aggressive secondary pre-
vention. Diabetic control, however, has not been as convincingly associated with reduced
risk of macrovascular events including ischemic stroke. The Diabetes Control and
Complications Trial (DCCT) found conclusively that aggressive diabetic control was
associated with reduced microvascular events (retinopathy, nephropathy, neuropathy).

However, there was only a trend to reduction of macrovascular or cardiovascular events
(3.2% vs 5.4%, p 0.08) (47). This trial, however, focused on young type 1 diabetic
patients, who likely did not have as high a likelihood of having ischemic events.
However, in type 2 diabetic patients, the UK Prospective Diabetes Study (UKPDS) trial
found no difference in cardiovascular events between intensive therapy and conventional
therapy (48). A subgroup analysis suggested that there might be a reduction in MI and
stroke with improved diabetic control.
Overall, diabetic control should be advocated for reduction in microvascular compli-
cations. There may be a benefit in reducing macrovascular complications, although this
has not been convincingly borne out in either type 1 or 2 diabetic patients. However,
aggressive control of other risk factors especially in type 2 diabetic patients including
hypertension, dyslipidemia, and smoking cessation are of great importance in reducing
the cardiovascular risk, including the risk of ischemic stroke. In the UK Prospective
Diabetes Study 38 Trial, intensive BP control, primarily with the use of an ACE
inhibitor or -blocker, resulted in significant BP lowering. The mean BP at baseline
was 160/94 and decreased to 144/82 mmHg with intensive treatment vs 154/87 mmHg
with standard treatment. Improved BP control was associated with a 32% reduction in
diabetes-related death (95% CI 6–51%, p 0.019), 44% reduction in strokes (95% CI
11–65%, p 0.013), and 37% reduction in microvascular complications (95% CI
11–56%, p 0.0092) (49).
Smoking Cessation
Tobacco abuse has a known association with carotid atherosclerosis as well as
adverse cardiovascular events. Smoking cessation reduces this risk eventually over
time, although the risk likely does not fully normalize. One observational study in
British men found that current smokers had a 3.7-fold relative risk (95% CI 2.0–6.9)
for stroke compared to men who had never smoked. Men who quit had a decreased
risk compared to men who were smoking, but the risk is still elevated compared
to men who never smoked although not significantly (RR 1.7; 95% CI 0.9–3.3,
p 0.11). The reduced risk seen in men who quit smoking was seen within 5 yr. The
amount of tobacco used determined the risk reduction. Light smokers (20 ciga-
rettes/d) had a risk similar to men who never smoked, while heavy smokers (20
cigarettes/d) were not able to eliminate the risk entirely (RR 2.2; 95% CI 1.1–4.3).
Hypertensive men had a greater benefit from smoking cessation compared to nor-
motensive men (50). Women had similar outcomes, with a 2.6-fold risk of stroke
(95% CI 2.08–3.19) compared to women who had never smoked. Women who quit
smoking still had an elevated risk, although not as great as current smokers (RR 1.34,
95% CI 1.04–1.73). The risk of all stroke and ischemic stroke was reduced to similar
levels as women who never smoked within 2–4 yr. Unlike the study in men, the
number of cigarettes smoked did not influence the reduction in risk associated with
smoking cessation (51).
ANTIPLATELET AND ANTITHROMBOTIC THERAPY

Antiplatelet therapy and antithrombotic therapy continue to be important weapons in
the armamentarium to decrease cardiovascular death and adverse vascular events. The
value of therapy depends on both the agent and the clinical situation.
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Acute Stroke
For acute treatment of ischemic events, unequivocal evidence supports the use of
aspirin to treat acute ST-segment elevation MI. The value of intravenous fibrinolytic
therapy has also been demonstrated in these patients, although it has been displaced by
primary percutaneous coronary intervention. For acute ischemic stroke, both aspirin
and fibrinolytic therapy are beneficial, but to a lesser degree and with a narrower thera-
peutic index than for MI.
The International Stroke Trial and the Chinese Acute Stroke Trial studied the use of
aspirin in acute ischemic stroke. The International Stroke Trial was a large randomized,
open-label trial of 19,435 patients comparing the use of up to 14 d of treatment with
either subcutaneous unfractionated heparin (5000 or 12,500 IU bid) or aspirin 300 mg
daily in a factorial design. No significant difference was seen in death at 14 d with
unfractionated heparin (9.0% for heparin vs 9.3% for placebo). Notably, the recurrent
ischemic stroke rate was significantly lower for the heparin group (2.9% vs 3.8%) but
this was offset by an increase in the risk of hemorrhagic stroke (1.2% vs 0.4%).
Therefore the rate of death or nonfatal recurrent stroke at 14 d was not significantly dif-
ferent (11.7% vs 12.0%). Aspirin also did not significantly reduce death at 14 d (9.0%
vs 9.4%). Aspirin-treated patients, however, did have a reduced rate of recurrent
ischemic strokes within 14 d (2.8% vs 3.9%) with no significant increase in the rate of
hemorrhagic strokes (0.9% vs 0.8%). Aspirin therapy resulted in a significantly lower
rate of death or nonfatal recurrent stroke at 14 d (11.3% vs 12.4%) (52).
The Chinese Acute Stroke Trial (CAST) was a large randomized, placebo-controlled,
clinical trial of 21,106 patients with acute ischemic stroke comparing aspirin 160 mg
daily with placebo, started within 48 h of symptoms and continued for up to 4 wk. Aspirin-
treated patients had a significant reduction in death at 4 wk (3.3% vs 3.9%, p 0.04).
Aspirin therapy was also associated with a decreased recurrent ischemic stroke rate (1.6%
vs 2.1%, p 0.01) and a nonsignificantly increased hemorrhagic stroke rate (1.1% vs
0.9%, p 0.1). The composite end point of in-hospital death or nonfatal stroke at 4 wk
was significantly decreased with aspirin therapy (5.3% vs 5.9%, p 0.03) (53).
Overall, treatment with aspirin in acute stroke was associated with an absolute reduc-
tion of death or nonfatal stroke of 9 per 1000 treated for 3 wk. Although a small increase
was seen in extracranial bleeding, the benefits of therapy clearly outweighed the risks
(54). Although the benefit seems small compared to the magnitude of benefit seen from
aspirin therapy in other clinical settings, it is important to note that the duration of ther-
apy needed to achieve this benefit was 2–4 wk compared to the years of therapy needed
to obtain benefit in secondary prevention.
Secondary Prevention
In patients presenting with TIA or minor stroke, low-dose aspirin has been shown to
decrease the risk of stroke. The Swedish Aspirin Low-Dose Trial (SALT) enrolled 1360
patients presenting with TIA or minor stroke and randomized them to either therapy
with low-dose aspirin (75 mg daily) or placebo. Treatment with aspirin was associated
with an 18% reduction in stroke or death (RR 0.82; 95% CI 0.67–0.99, p 0.02) with
similar reductions for stroke, frequent TIA, and MI (55). Another trial compared 30 mg
of aspirin daily with 283 mg daily in patients with prior TIA or minor stroke. Low-dose
aspirin was just as efficacious as the higher dose in preventing vascular death, nonfatal
stroke, or nonfatal MI (14.7% in the low-dose group vs 15.2% in the high-dose group)
(56). However, the United Kingdom Transient Ischaemic Attack Aspiring Trial (UK-
TIA) showed discordant results. The UK-TIA was a randomized trial of 2435 patients
with presumed TIA or minor ischemic stroke treated with either 1200 mg of aspirin
daily, 300 mg of aspirin daily, or placebo. Only a trend to decreased risk of major
stroke, MI, or vascular death was found with aspirin (OR 0.85, 95% CI 0.71–1.03). No
difference was found between low-dose and high-dose aspirin (57).
In high-risk patients, a meta-analysis of six trials of low-dose aspirin ( 325 mg
daily) found that aspirin therapy was associated with a 20% reduction in stroke, 18%
reduction in death, 30% reduction in MI, and a 30% reduction in vascular events.
However, aspirin use was associated with increased gastrointestinal bleeding (58).
Overall, the efficacy of aspirin for preventing strokes seems to be relatively leveled
from a dose of 50 mg/dL to 1500 mg/dL daily (59). The Antithrombotic Trialists’
Collaboration published a meta-analysis of antiplatelet therapy in 2002. In general, in
high-risk patients, antiplatelet therapy was associated with a 25% reduction in nonfatal
strokes. In patients with prior TIA or stroke, antiplatelet therapy was associated with a
22% reduction in the composite end point of nonfatal stroke, nonfatal MI, or vascular
death. Thirty-six events would be prevented in 2 yr for every 1000 patients treated.
Aspirin was the most commonly used antiplatelet agent in this study (60).
Aspirin and Treatment for Carotid Stenosis

Few studies have assessed the benefit of aspirin therapy for secondary prevention in
patients with known carotid stenosis. Most have enrolled relatively few patients and
have been underpowered to assess the effect of aspirin. One such study by Cote et al.
evaluated 372 patients with known carotid stenosis of 50% treated with either aspirin
325 mg daily or placebo for 2 yr. Notably, these patients were asymptomatic from their
carotid disease and did not undergo revascularization. No significant difference was
found between treatment groups in the rate of death or significant ischemic event. The
multivariate analysis found an adjusted hazard ratio for aspirin of 0.99 (95% CI
0.67–1.46, p 0.95) (61). In the Antithrombotic Trialists’ Collaboration analysis, there
was a trend toward improved outcomes with aspirin therapy in patients with carotid
stenosis, similar in magnitude to that found with aspirin for secondary prevention (60).
Patients undergoing carotid endarterectomy benefit from aspirin therapy. A small
trial of 232 patients randomized to aspirin 75 mg daily or placebo starting preopera-
tively and continued for 6 mo after surgery found that intraoperative stroke and post-
operative stroke with residual defects were lower in the aspirin-treated arm (1.7% vs
9.6%, p 0.01). There was a trend toward a lower rate of any neurological event
and/or death in the aspirin treated arm (p 0.12). Notably, there was no significant
increase in bleeding complications with aspirin therapy (62). This benefit is likely the
result of decreased emboli during surgery in patients treated with aspirin. When tran-
scranial Doppler (TCD) monitoring was performed in symptomatic patients with
carotid stenosis, the absence of aspirin therapy was associated with a sevenfold
increase in microembolic events found via TCD (63). Low-dose aspirin is preferred
over high-dose aspirin in patients undergoing carotid endarterectomy. The ASA and
Carotid Endarterectomy (ACE) Trial found that patients treated with aspirin 81 mg or
325 mg daily had a lower combined rate of stroke, MI, and death compared to 650 mg
or 1300 mg daily at 3 mo (6.2% vs 8.4%, p 0.03), and a trend toward benefit at 30 d
(5.4% vs 7.0%, p 0.07) (64).
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Primary Prevention
The Physicians’ Health Study was the largest randomized clinical trial in 22,071
men evaluating the effect of low-dose aspirin on cardiovascular mortality for primary
prevention. A 44% relative risk reduction was found in the risk of MI (RR 0.56; 95%
CI 0.45–0.70, p 0.00001). A nonsignificant but slightly increased risk of stroke
was seen, primarily of hemorrhagic stroke (RR 2.14; 95% CI 0.96–4.77, p 0.06).
No reduction in cardiovascular mortality was found. Subgroup analysis revealed that
the benefit was predominantly in patients 50 yr of age. The risk of gastrointestinal
ulceration was not significantly higher (RR 1.22, 95% CI 0.98–1.53, p 0.08) (65).
Although the British Doctors’ Trial did not show any benefit for aspirin, a meta-
analysis of five major primary prevention trials including more than 55,000 patients
(11,000 women) found a 32% relative risk reduction in the risk of a first MI and
overall 15% relative risk reduction in vascular events, but no significant effect on
nonfatal stroke or vascular death (66).
Interestingly, the Nurses’ Health Study found somewhat discordant results. In this
observational study of 79,319 women, low-dose aspirin use (one to six aspirin/wk) was
associated with a decreased stroke risk while higher doses of aspirin (seven or more
aspirin/wk) led to a slightly increased stroke risk. Multivariate analysis revealed a rela-
tive risk of 0.50 (95% CI 0.29–0.85, p 0.01) for large artery ischemic stroke in
woman taking low-dose aspirin compared to women not taking aspirin. Women taking
15 or more aspirin/wk had an increased risk for subarachnoid hemorrhage (RR 2.02,
95% CI 1.04–3.91, p 0.02). Subgroup analysis suggested that women who were
older, hypertensive, and who smoked benefited most from low-dose aspirin therapy
(67). Not surprisingly, the benefit or risk of aspirin in low-risk primary prevention
cohorts will depend on their underlying risk profile.
Therefore, in patients who have a 10-yr risk of 10% for a coronary event, the US
Preventive Services Task Force recommends the use of low-dose, long-term aspirin
therapy (68). For women at increased risk of ischemic stroke, low-dose aspirin is con-
sidered beneficial.
Dipyridamole
Dipyridamole alone and in addition to aspirin has been studied extensively for sec-
ondary prevention in patients with prior stroke or TIA. Dipyridamole inhibits adeno-
sine phosphodiesterase and adenosine deaminase, resulting in an increase and
accumulation of adenosine, cyclic adenosine monophosphate (cAMP), and adenine
nucleotides, with resultant platelet inhibition and vasodilation especially of the coro-
nary circulation. The largest trial assessing the efficacy of dipyridamole was the sec-
ond European Stroke Prevention Study (ESPS-2). In this study, 6602 patients with a
history of stroke or TIA were randomized to 25 mg of aspirin, extended release dipyri-
damole 200 mg, both, or placebo, given twice daily in a factorial design. In pairwise
comparisons, treatment with aspirin resulted in a 18% reduction in stroke risk
(p 0.013) and a 13% reduction in the risk of stroke or death (p 0.016). Treatment
with dipyridamole resulted in a 16% reduction in stroke risk (p 0.039) and a
15% reduction in stroke or death (p 0.015). More importantly, the combination of
aspirin and dipyridamole was additive, leading to a 37% reduction in the stroke rate
(p 0.001) and a 24% reduction in stroke or death (p 0.001). No significant impact
on mortality was found. Similar findings were found in the rate of TIA, with a 36%
reduction for combination therapy (p 0.001). Patients treated with dipyridamole had
a higher incidence of headaches. All-site bleeding and gastrointestinal bleeding were
significantly higher in patients treated with aspirin (69).
Prior to ESPS-2, a few studies also showed a significant reduction in stroke with the
combination of aspirin and dipyridamole, compared to placebo (70). However, others
comparing the addition of dipyridamole to aspirin therapy suggested no benefit, raising
doubts about the value of dipyridamole (71,72). However, with the publication of
ESPS-2, and a subsequent meta-analysis by Leonardi-Bee et al. (revealing a 22% reduc-
tion in recurrent stroke for the combination of dipyridamole and aspirin, compared to
aspirin alone [OR 0.78, 95% CI 0.65–0.93] [73]), the combination of aspirin and dipyri-
damole has become accepted as first-line therapy in treating patients to prevent recur-
rent ischemic stroke.
Of note, dipyridamole has been used in the past as a pharmacological coronary
stressor for nuclear stress tests. There has been concern about the use of dipyri-
damole in patients with stable angina. In fact, the American College of Cardiology
has recommended against its use in this patient cohort (74). However, in the meta-
analysis by Leonardi-Bee et al. combination therapy with aspirin and dipyridamole
was associated with a significant reduction in the composite of nonfatal stroke, non-
fatal MI, and vascular death compared to aspirin alone (OR 0.84, 95% CI 0.72–
0.97) (73). In addition, a post hoc analysis of ESPS-2 did not show any increased
incidence of cardiac events in patients with a history of CAD or MI treated with
dipyridamole (75).
Ticlopidine
Ticlopidine has been used extensively in the past for the treatment of cardiovascular
disease, after coronary stent placement, and to prevent recurrent strokes or TIA.
Ticlopidine is a thienopyridine platelet antagonist that inhibits ADP-dependent platelet
aggregation. Two major studies evaluated ticlopidine for secondary stroke prevention.
The Canadian American Ticlopidine Study (CATS) randomized 1072 patients with
recent ischemic stroke to either ticlopidine 250 mg twice daily or placebo between
1 wk and 4 mo after their index event. Treatment with ticlopidine resulted in a 30.2%
relative risk reduction in stroke, MI, or vascular death (15.3% vs 10.8%, 95% CI 7.5–
48.3%, p 0.006). Intention-to-treat analysis found a 23.3% relative risk reduction of
the combined end point (p 0.02) (76). The magnitude of benefit compares favorably
to aspirin therapy. The Ticlopidine Aspirin Stroke Study compared ticlopidine therapy
(500 mg daily) to aspirin (1300 mg daily) in 3069 patients with recent TIA, amaurosis
fugax, or stroke. The risk of nonfatal stroke or death was 17% for the ticlopidine arm
and 19% for the aspirin arm at 3 yr (RRR 12%, p NS). The rate of all strokes (fatal
and nonfatal) at 3 yr was 10% for ticlopidine and 13% for aspirin (RRR 21%, 95% CI
4–38%, p 0.024) (77). Overall, ticlopidine seems to have slightly greater efficacy
compared to aspirin therapy.
Ticlopidine, however, has a significant risk profile of side effects. Patients in CATS
had a 1% incidence of severe neutropenia, and 2% incidence of skin rash and diarrhea,
all of which were found to be reversible after discontinuation of ticlopidine (76). In the
Ticlopidine Aspirin Stroke Study, patients treated with ticlopidine had a 20% incidence
of diarrhea, a 14% incidence of skin rash, and a 1% incidence of severe neutropenia
(77). Given its side-effect profile in addition to its cost, ticlopidine has not been used as
a first-line agent.
26 Lee
Fig. 4. Risk of adverse vascular events with clopidogrel and aspirin therapy in the CAPRIE trial. The
annual rate of ischemic stroke, MI, or vascular death was reduced with clopidogrel therapy compared
to aspirin therapy (5.32% vs 5.83%, RRR of 8.7%; 95% CI 0.3–16.5%, p 0.043). (Reproduced
with permission from ref. 78.)
Clopidogrel
Clopidogrel is also a thienopyridine platelet antagonist that inhibits ADP-mediated
platelet inhibition. It has a better side-effect profile than ticlopidine, without the inci-
dence of neutropenia. Clopidogrel has a once daily dosing, and has supplanted ticlopi-
dine in most settings. The largest trial of clopidogrel for secondary prevention was the
Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial,
which randomized 19,185 patients to either clopidogrel 75 mg daily or aspirin 325 mg
daily. These patients had a recent ischemic stroke, recent MI, or symptomatic peri-
pheral arterial disease. The annual rate of ischemic stroke, MI, or vascular death was
5.32% in patients treated with clopidogrel compared to 5.83% with aspirin, with a
relative risk reduction of 8.7% for clopidogrel (95% CI 0.3–16.5%, p 0.043) (Fig. 4).
Actual treatment analysis revealed a relative reduction of 9.4% (78).
In the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) study of
patients presenting with acute coronary syndromes, combination therapy with aspirin
and clopidogrel was shown to be more beneficial than aspirin therapy alone for reduc-
ing the number of cardiovascular events. For secondary stroke prevention, however, the
benefit of combination therapy is less clear. The MATCH trial treated 7599 patients
with recent ischemic stroke or TIA already on clopidogrel 75 mg daily with aspirin
75 mg daily or placebo. The primary end point was a combination of ischemic stroke,
MI, vascular death, or hospitalization for acute ischemia at 18 mo. Patients treated with
the combination of aspirin and clopidogrel had a nonsignificant reduction in the pri-
mary end point (6.4%, 95% CI 4.6 to 16.3%) compared to treatment with clopidogrel
alone. Major and life-threatening bleeding was significantly higher in the combination
therapy group, however (79). The MATCH trial has been criticized for numerous
reasons, including its entry criteria and its use of a composite end point. However, for
stroke prevention, the combination of aspirin and clopidogrel has not been proven to be
better than clopidogrel monotherapy. More recently, a study involving 100 patients
undergoing CEA who were treated with aspirin and clopidogrel showed a 10-fold
reduction in the number of patients having more than 20 emboli detected by TCD
within 3 h of surgery (OR 10.23; 95% CI 1.3–83.3, p 0.01) (80).
Warfarin
Antithrombotic therapy with warfarin has not been shown to be effective in preventing
recurrent stroke. In the Warfarin-Aspirin Recurrent Stroke Study (WARSS), 2206 patients
presenting with ischemic stroke within 30 d were randomized to either aspirin (325 mg
daily) or warfarin (INR 1.4–2.8) for 2 yr. The risk of recurrent ischemic stroke or death
was 17.8% in the warfarin-treated group and 16.0% in the aspirin-treated group (hazard
ratio 1.13, 95% CI 0.92–1.38, p 0.25). No significant differences were found in the
rates of TIA, MI, or hemorrhage (2.22 major hemorrhage/100 patient-years in the war-
farin group and 1.49/100 patient-years in the aspirin group). Importantly, patients with
operable carotid stenosis were excluded from this trial (81). Overall, aspirin is generally
preferred to warfarin for secondary prevention in patients with carotid disease. Possible
exceptions are patients with thrombus in the carotid artery, critical carotid stenosis await-
ing surgery, and carotid dissection in whom anticoagulation may be beneficial.
CONCLUSION
Patients with carotid artery stenosis likely have atherosclerotic disease elsewhere.
Overall, the goal of therapy in these patients is not only to reduce the stroke risk attributa-
ble to the carotid stenosis, but also to decrease their global risk of cardiovascular death,
MI, and stroke. To achieve this goal, therapy should focus on aggressive treatment of an
individual patient’s cardiovascular risk factors including hypertension, dyslipidemia, and
tobacco abuse. Blood pressure reduction, even in “normotensive” patients, has a substan-
tial impact in reducing the likelihood of stroke as well as cardiovascular death and MI.
Reaching target blood pressure is likely more important than the agent used to achieve it,
with notable exceptions in patients who have other indications for particular agents (e.g.,
ACE inhibitors in patients with congestive heart failure or diabetes mellitus). Caution
should be exercised in aggressively lowering blood pressure in patients with bilateral
carotid stenoses. Lipid lowering therapy, specifically statin therapy, has significant value in
reducing cardiovascular risk including stroke reduction. However, the value of statin therapy
in patients who have a history of cerebrovascular disease is uncertain for stroke reduction.
Statin therapy should still be utilized because of its impact on overall vascular risk. Patients
at high risk for vascular events will also benefit from aspirin therapy. Patients with prior
stroke or TIA definitely benefit. Depending on other comorbidities, these patients may
also benefit from either dipyridamole–aspirin combination therapy (patients with isolated
TIAs without other significant vascular disease) or clopidogrel therapy (patients with other
established vascular disease). Smoking cessation should also be advocated strongly. The
value of aggressive glucose control in diabetic patients is not entirely clear for the reduc-
tion of macrovascular events. Aggressive control should still be encouraged for its favor-
able effect on microvascular events. In summary, although carotid revascularization is
indicated for only a minority of patients with carotid atherosclerotic disease, aggressive
medical therapy is indicated for all patients with carotid atherosclerotic disease.
28 Lee
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3 Carotid Endarterectomy
Techniques and Evidence-Based Medicine
Joël Gagnon, MD and

York N. Hsiang, MB ChB, MHSc, FRCSC
CONTENTS
HISTORICAL BACKGROUND
TECHNIQUE
RESULTS OF RANDOMIZED CLINICAL TRIALS
SURGICAL INDICATIONS AND CONTRAINDICATIONS
CONCLUSION
REFERENCES
Summary
Internal carotid artery stenosis is responsible for approx 30% of ischemic strokes. Since the
beginning of the 20th century, various surgical procedures were used for the prevention of stroke.
The first successful case of carotid endarterectomy (CEA) was reported by DeBakey in 1953. Since
then, CEA has been continually refined and is now the gold standard procedure to prevent large-
artery stroke. In this chapter we describe the procedure, and discuss the benefits and risks of CEA
as compared with medical treatment.
Key Words: Carotid artery stenosis, carotid endarterectomy, ischemic stroke.
HISTORICAL BACKGROUND
Death from stroke is the third leading cause of mortality in the United States (1). For
survivors, stroke is an important cause of disability for patients, their families, and
society. Stroke may be caused by ischemia or hemorrhage. Ischemia, from thrombo-
embolic causes, accounts for stroke in 75% of patients and hemorrhage in 25% of
stroke patients. Internal carotid artery stenosis is responsible for approx 30% of
ischemic strokes (2,3).
Since the beginning of the 20th century, various procedures such as the stellate gan-
glion block, cervical sympathectomy, thrombectomy of occluded carotid arteries, and
carotid bifurcation ligation were used for the prevention of stroke. The first successful
case of carotid endarterectomy (CEA) was reported by DeBakey in 1953. Since then,
CEA has been continually refined and is now the gold standard procedure to prevent
large-artery stroke.

33
34 Gagnon and Hsiang
Over the course of the last two decades, CEA has become the most studied surgical
procedure ever (4–16). The result of this intense scrutiny have provided irrefutable evi-
dence of its safety, performance, and durability. Indications, risks, and expectations for
this procedure have also been determined. As newer procedures become available, in
particular carotid angioplasty and stenting, they will be compared to this gold standard.
In this chapter we describe the procedure, and discuss the benefits and risks of CEA as
compared with medical treatment.
TECHNIQUE
CEA is a meticulous procedure that minimizes trauma to the carotid arteries, avoids
injury to the surrounding structures, and removes the offending plaque to leave a
smooth interior vessel wall free of particulate debris. There are two well accepted tech-
niques for CEA: the classical procedure and eversion endarterectomy. The results of
both techniques are largely comparable in terms of stroke prevention. In this chapter,
only the classical technique is described.
Anesthesia
CEA can be performed safely under local, regional, or general anesthesia. The
choice of anesthesia depends on the experience of the surgeon and anesthetist, as
well as patient factors. Known patient factors influencing this decision include
comorbidities such as poor cardiac and pulmonary reserve, as well as local factors
such as a short wide neck. In approx 10% of patients, surgery cannot be performed
under local anesthesia (17). This issue of anesthetic type and outcome is discussed
further below.
Incision and Dissection

A thorough understanding of the anatomy of the neck, in particular, the relation-
ship of the carotid arteries to important nerves and other organs, is essential. A 10-
to 15-cm skin incision is made along the anterior border of the sternocleidomastoid
muscle. The skin incision is then deepened through the subcutaneous fat and
platysma muscle to expose the carotid sheath. Once the sheath is entered, the inter-
nal jugular vein is dissected and retracted to expose the carotid vessels. The com-
mon facial vein is a landmark for the carotid bifurcation where it obliquely crosses
the carotid arteries to the internal jugular vein. The surgeon will then divide this
vein, to allow for dissection of the carotid vessels. If necessary, the posterior belly
of the digastric muscle may also be divided to allow adequate exposure of the distal
internal carotid artery.
Care is taken to avoid injury to the important nerves in this area. These include
the hypoglossal, vagus, and recurrent laryngeal nerves. Damage to the recurrent
laryngeal nerve, a branch of the vagus nerve, may cause hoarseness from vocal cord
paralysis. The hypoglossal nerve passes across the internal and external carotid arter-
ies. Injury to this nerve causes lateral deviation of the tongue toward the ipsilateral
side during protrusion and can cause difficulty with chewing and swallowing. During
dissection of the carotid bifurcation, stimulation of the sinus nerve may cause a
reflex vagal response resulting in bradycardia and subsequent hypotension. This
reflex can be abolished by injecting the carotid sinus area with a local anesthetic. In
addition, care must be taken when dissecting the carotid vessels to avoid disturbing
Chapter 3 / Carotid Endarterectomy 35
Fig. 1. Anatomy of the common, internal, and external carotid arteries. (From Brewster DC, ed:
Common Problems in Vascular Surgery. Chicago: Year Book Medical, 1989.)
Fig. 2. Shunt placed in the carotid artery. (From Brewster DC, ed: Common Problems in Vascular
Surgery. Chicago: Year Book Medical, 1989.)
the atheromatous lesions causing fragmentation and subsequent embolization and

stroke.
Once the common, internal, and external carotid arteries have been dissected, iso-
lated, and controlled with vascular loop tapes, the patient is heparinized in preparation
for endarterectomy (Fig. 1).
Clamping and Shunting

Once the patient has been adequately heparinized, clamps are applied to the common,
external, and internal carotid arteries. A longitudinal arteriotomy is made in the distal
common carotid and extended distally into the internal carotid artery, beyond the steno-
sis. At this point, a decision to use a shunt is made, based on the results of intraoperative
EEG monitoring, cerebral oximetry, or carotid stump back pressures. Some surgeons
routinely shunt. A shunt is a hollow silicone tube that is secured to the common and
internal carotid arteries to allow continuous flow to the ipsilateral cerebral hemisphere
during the procedure. Total cerebral clamp time is usually monitored (Fig. 2).
Fig. 3. Endarterectomy of the atherosclerotic plaque. (From Brewster DC, ed: Common Problems in
Vascular Surgery. Chicago: Year Book Medical, 1989.)
Endarterectomy
To remove the atheromatous plaque (the endarterectomy), the optimal plane between
the diseased intima is identified and separated from the deep media layer. At the distal
extent of this plane, the plaque is progressively thinned out or divided (Fig. 3a and 3b).
Sutures to tack down the divided plaque may be required to prevent dissection
(Fig. 4). Plaque from the external carotid artery is removed using an eversion tech-
nique. When the endarterectomy has been completed, the remaining vessel wall is irri-
gated with heparin saline, and any loose debris removed to yield a smooth surface.
Closure
A fine polypropylene suture is used to close the arteriotomy. Commonly, a vein or
prosthetic patch may be used for arteriotomy closure to increase the diameter of the
vessel, thereby decreasing the risk of early vessel thrombosis and late restenosis (Fig. 5a
and 5b). If a shunt has been used, it is removed before completion of the anastomosis.
Once flow has been restored, completeness of the procedure is assessed by Doppler
ultrasound or completion angiography. Drains are commonly used to prevent hematoma
formation.
Fig. 4. Tacking stitches. (From Brewster DC, ed: Common Problems in Vascular Surgery. Chicago:
Year Book Medical, 1989.)
Fig. 5. Patch graft closure. (From Brewster DC, ed: Common Problems in Vascular Surgery. Chicago:
Year Book Medical, 1989.)
Factors Affecting Surgical Outcome

ANESTHESIA
The issue of anesthesia affecting surgical outcome was addressed using a meta-
analysis by the Cochrane database in 2004 (17). Seven randomized trials with 554
operations and 41 nonrandomized trials with 25,622 operations were reviewed. The
results from the randomized trials showed that there was no significant difference
between local anesthesia (LA) or general anesthesia (GA) use in terms of perioperative
death from all cause, any stroke, any stroke or death, or cranial nerve injury. Fewer
local hemorrhages (odds ratio [OR] 0.31 [0.12–0.79]) and fewer shunts (OR 0.68
[0.40–1.14]) were needed in the LA group compared to the GA group.
The results of the nonrandomized trials showed less death (OR 0.67 [0.46–0.97]),
perioperative stroke (OR 0.56 [0.44–0.70]), any stroke or death (OR 0.61 [0.48–0.77]),
and fewer shunts needed (OR 0.11 [0.10–0.12]), in favor of LA. There was no differ-
ence in the frequency of local hemorrhage or cranial nerve palsies.
These results must be analyzed with caution because of the heterogeneity of the
studies and the small number of patients in the randomized trials. In addition, the major-
ity of nonrandomized trials were retrospective (29/41), and the procedures were per-
formed with different closure techniques (patch or no patch), as well as different
prognostic factors (symptomatic or asymptomatic). Based on this, the authors con-
cluded that there was no reliable evidence to guide the choice of whether to use local or
general anesthesia for CEA (17).
CLOSURE/PATCH
The goal of CEA is to prevent stroke by removing the atherosclerotic plaque causing
arterial stenosis. During primary closure of the arteriotomy, a stenosis may be involun-
tarily caused from direct suture of the vessel wall. Interposing a piece of tissue (patch)
within the arteriotomy avoids this issue. Patch grafting, however, has its own minor
problems such as increasing the length of the operative procedure, rupture (for vein
patches), and infection (prosthetic patches). Bond et al. (18) reviewed the results of pri-
mary closure and patch graft closure. Their meta-analysis included 7 controlled trials,
which enrolled a total of 1127 patients. The results showed that carotid patch angio-
plasty was associated with a reduction in the risk of stroke of any type (OR 0.33
[0.15–0.70]), ipsilateral stroke (OR 0.31 [0.15–0.63]), and stroke or death not only
during the perioperative period (OR 0.39 [0.20–0.78]) but also in the long term
(OR 0.59 [0.42–0.84]). It was also associated with a reduced risk of perioperative
arterial occlusion (OR 0.15 [0.06–0.37]) and decreased restenosis during long-term
follow-up in five trials (OR 0.20 [0.13–0.29]). Overall, these results support a
recommendation in favor of routine patching.
SHUNT
To lower perioperative stroke, blood flow is often “shunted” from the common carotid
to the distal internal carotid artery while CEA is performed. This procedure allows ipsi-
lateral cerebral blood flow during the CEA. Shunting, however, may also be responsible
for causing stroke by introducing air or plaque embolism, or cause intimal wall damage
leading to dissection or acute occlusion of the internal carotid artery. In addition, intimal
injury may cause premature postoperative stenosis by initiating neointimal hyperplasia.
Selective shunting has been advocated to minimize these complications. However,
the important clinical question to decide which patients to shunt remains unresolved.
Many indirect methods of assessing intraoperative cerebral blood flow have been used,
for example, monitoring electroencephalographic activity, somatosensory evoked
potentials, measuring carotid stump back pressure, or a combination of these. Equally,
direct assessments of cerebral blood flow during the operation have also been used, for
example, intraarterial radiolabeled xenon, transcranial Doppler, or clinical assessment
for the development of new neurological signs in awake patients who undergo the pro-
cedure under local anesthesia. None of these assessments can predict late postoperative
stroke with complete certainty.
A meta-analysis by the Cochrane group (19) to analyze this issue of routine shunting
included only two randomized trials. A total of 273 patients were randomized to the
shunt group and 286 to the nonshunt group. The results of this meta-analysis showed a
trend favoring a reduction in both deaths and strokes within 30 d of surgery when rou-
tine shunting was used, although the overall result was not significant. However, both
studies were flawed. In one, the study was not truly randomized and in the other, more
patching occurred in the shunt group, introducing a major bias. The conclusion of this
meta-analysis was a lack of sufficient evidence to support the use of routine or selective
shunting in CEA.
Our group reported on a retrospective study of 305 patients, 92 of whom were rou-
tinely shunted and 213 who were selectively shunted based on EEG monitoring. The
incidence of major strokes in the routine shunt group was significantly higher than in
the selective shunt group, 4.4% vs 0.5%, p 0.05 (20).
Complications
Stroke and acute coronary events are the most feared complications after CEA. The
risk of perioperative stroke varies with the indication for surgery, age of the patient, and
skill of the surgeon. The best reported series of perioperative stroke ranges from 1% for
an asymptomatic stenosis to 9.6% for a completed stroke. Community-based surveys
show that the risk of stroke is higher than in tertiary care institutions, with rates rang-
ing from 5.6% for an asymptomatic stenosis to 21% for a completed stroke (21).
Cardiac complications (myocardial infarction [MI], arrhythmia, and congestive heart
failure) occurred in 3.9% of patients in the NASCET study (5). For older or higher-risk
patients, the incidence of cardiac complications may be even higher.
Other important complications are wound infection, hematoma, and cranial nerve
injury. The rates of these are shown in Table 1. Usually, cranial nerve injuries are tran-
sient and improve over time. In our own experience, we reported a lower incidence of
acute MI (0.7%), wound hematoma (2.3%), wound infection (0.3%), and cranial nerve
injury (6%) (20).
Recurrent (50%) stenosis following CEA is relatively frequent based on regular
carotid duplex ultrasound follow-up. At 3 years post-CEA, the incidence is approx 10%
and increases to 13% by 5 yr (22,23). However, the clinical significance of recurrent
stenosis demonstrated by ultrasound is much less. In fact, the 5-yr ipsilateral stroke-
free rate was the same in patients with or without internal carotid restenosis, 94.4% and
94.2%, respectively (23).
CEA is a durable procedure. The prognosis of future ipsilateral stroke varies accord-
ing to the age of the patient and the original indication for surgery. The annual risk of
stroke after an uncomplicated CEA for patients presenting with asymptomatic carotid
stenosis, transient ischemic attacks (TIAs), and for completed stroke is 1.0%, 2.3%,
and 4.5%, respectively (21).
Table 1
Perioperative Complications Within 30 d
of Carotid Endarterectomy
Complication Percentage
Cardiac
Myocardial infarction 0.9
Congestive heart failure 0.6
Arrhythmia 1.2
Other 1.2
Wound
Hematoma 5.5
Infection 3.4
Cranial nerve injury 7.6
RESULTS OF RANDOMIZED CLINICAL TRIALS

As CEA became refined, many authors demonstrated its safety, effectiveness, and
durability. The popularity of this procedure continued to grow as an important method
of stroke prevention, despite reports of poor results, especially when reported in larger
databases such as statewide surveys. Because of the concern that widespread applica-
tion of this technique would lead to greater harm than good, randomized controlled
clinical trials were recommended as the definitive method of addressing the value of
CEA.
The trials comparing CEA to medical treatment have focused on a patient’s original
symptoms and the degree of stenosis. Using this convention, the trials can be catego-
rized as symptomatic or asymptomatic. Regarding the degree of stenosis, there has
been no uniform method of measuring stenosis between trials. Initially, all studies
required the gold standard diagnostic test, carotid angiography. Because of the demon-
strated accuracy of ultrasound in high-quality departments, and the lack of morbidity,
more contemporary studies have occasionally used the results of ultrasound instead of
angiography. Despite these differences, trials have concentrated on the effect of CEA
on carotid stenosis, usually 50% stenosis.
Trials of Symptomatic Carotid Stenosis

The indication for CEA in symptomatic stenosis is based on the results of three
prospective randomized trials.
The first published study, the VA symptomatic trial, randomized 189 men over 5 yr
who had symptomatic internal carotid stenosis 50% to either medical treatment or
medical treatment plus CEA (4). After a median follow-up of 11.9 mo, this study
showed that the risk of stroke or further TIAs was 7.7% in the surgical and 19.4% in
the medical group (p 0.011). Further, the benefit of CEA for patients with 70%
stenosis was even greater: Patients randomized to CEA had a combined stroke and TIA
risk of 7.9% compared with 25.6% in the medical group (p 0.004). This study was
criticized because of the small number of patients enrolled; it excluded female patients;
and the composite end point of death, stroke, and TIA deviated from the more tradi-
tional end point of stroke and death.
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Title: World atavism
Author: Edmond Hamilton
Illustrator: Frank R. Paul
Release date: June 17, 2024 [eBook #73857]
Language: English
Original publication: Jamaica, NY: Experimenter Publications Inc,

1930
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*** START OF THE PROJECT GUTENBERG EBOOK WORLD ATAVISM

***
World Atavism
By Edmond Hamilton
Author of "The Universe Wreckers,"

"The Other Side of the Moon," etc.
Illustrated by PAUL
[Transcriber's Note: This etext was produced from

Amazing Stories August 1930.
Extensive research did not uncover any evidence that
the U.S. copyright on this publication was renewed.]
The sun's rays have been credited with many beneficial
powers. It is a universally conceded fact that the sun is
necessary to good health; not only because of its
warmth-giving rays, but also because of some other
element, directly a health-giving factor, which has since
been more or less successfully duplicated in the
laboratory—in the form of Alpine lamps and what not.
It is also said, however, that there are certain
properties in the rays of the sun which might be used
as life-giving rays. As far as we know, nothing definite
has been established on this score yet. Who knows
what other helpful possibilities are hidden in the various
ether vibrations produced by the sun? Edmond
Hamilton has a brand new idea, which he elaborates
and weaves into a fascinating story of scientific fiction.
Certainly it seems to us to be of absorbing interest.
FOREWORD
I write these words in a room perched high in one of New York's

highest towers. Beneath me, in the fading sunlight of late afternoon,
there stretches the vast mass of the mighty city's structures. New
York it is—but such a New York as never man looked upon before.
And it is with its familiar but infinitely strange panorama before my
eyes that I start now this record of the great change.
My name is Allan Harker. Dr. Allan Harker, I could say, for it has been
seven years since I took the degree and with it a position on the
biological staff of Manhattan University. That was a great day for me.
Manhattan was one of the most renowned of eastern universities,
and its biological department in particular was known to scientists the
world over. This was due not only to the department's unrivalled
equipment, but also in greater part to two of the scientists who
worked in it, Dr. Howard Grant, head of the department, and Dr.
Raymond Ferson, his associate. Very proud I was to have won so
soon the opportunity of working with those two world-famed
biologists. And even prouder I was when, in the next years, my work
came gradually to link my name with theirs.
Grant and Ferson and Harker—we were known to scientists across
half the world. It was Grant, of course, the eldest of us, who was
best known. A tall, saturnine-faced and dark-browed Scotsman, his
utter and undivided passion for research was a byword among us. It
used to be said, though not in his hearing, that Grant would have
vivisected his own grandmother if he thought some new principle
might be learned by it. All respected the man, or the man's
achievements, but he never had a tithe of the popularity that was
Ferson's. Ferson was in fact a complete contrast to his superior, a
short-statured man of middle age with unruly hair and beard and
warm brown, friendly eyes. As for myself, the third of the trio, I had
neither the brilliant scientific mind of Grant nor the keen vision of
Ferson, but by dint of ceaseless plodding with monotonous details, I
had built for myself a reputation that linked my name with theirs.
Aside from our professorial duties in the university's lecture-rooms,
we had each of us our separate work. I was plodding away with my
dull experiments on cell-grouping, which I expected would some day
yield a theory that would astound all cytologists. Now and then I
received help on some difficult point from Ferson, who was himself
immersed in an attempt to demolish the Snelsen-Morrs re-
vertebration theory by prying into the interior structure of
innumerable unheard-of lizards. Grant, however, never received or
gave any help, keeping his work entirely to himself. We had gathered,
from his rare references to it, that he had been working for months
on one of the broader problems of evolutionary science, but that was
all we knew, and we were as amazed as any when Grant published
the statement that touched off the sensational "evolution
controversy."
It is needless for me to give here all the details of the thing. It is
sufficient to say that Grant, in his statement, announced that he had
solved at last the greatest enigma of biological science—that he had
discovered the cause of evolution.
One can understand what an uproar that statement created, and was
bound to create. For the cause of evolutionary change has always
been the supreme problem of biology. Long ago Darwin and Wallace
and Lamarck and their fellows had laid the processes of evolution
bare. They had shown to an astonished world that life on earth was
not static in forms that had always existed and always would exist,
but that it was in constant change and movement up through
constantly changing forms. The eohippus had changed, had evolved
into the horse, and in future ages would be something different still.
The great felines that had roamed earth had evolved into smaller
forms and into tame cats. A certain branch of ape-like forms had
evolved into great hairy troglodytes and then into modern men. All
life on earth was constantly changing, evolving, forced ever upward
through the diverging channels of evolution into new and different
forms.
But what force was it that pressed earth's life thus upward through
the paths of change? What force was it that caused all this vast, slow
evolution of earth's creatures into different creatures, that had begun
with the first jelly-like life-forms on earth and had forced the tide of
life up from them to the forms of today, that still was slowly changing
them? That question none could answer. Environment did not explain
it, for though environment had certain effects on the life-forms in it,
it was not responsible for that deep, vast tide of upward evolution.
Mendelism had seemed for a time to suggest an explanation but had
failed in the end to do so. Some great force there was, all knew, that
pressed life always up the path of evolution, but none had ever
guessed what that force might be, and the thing had come to be
accepted at last as one of the insoluble problems of science. And now
Grant claimed that he had solved it!
"For long," Grant's statement said, "I have held that since
evolutionary change is unquestionably caused by some definite and
omnipresent force acting upon all life on earth, it should be possible
to discover the nature of that force. I will not recount the work of
months which I have spent in constant search for this force, but will
say that finally I have been successful, have identified the force
which my experiments show beyond all doubt to be the single force
responsible for the upward course of evolution on earth. That force is
a vibratory force, a vibration unknown to earth's physicists prior to
my discovery of it, which has as its source the sun!
"The sun, we know, is a vast mass of incandescent matter which
ceaselessly pours out part of its matter transformed into energy. The
energy thus formed, flooding out in all directions from the sun
through space, takes various forms. At a certain vibratory frequency,
it takes the form of light and illuminates our day. At another
frequency, it is radiant heat, warming our world. At still another, it is
the cosmic ray so recently discovered. There are many others, known
to us, and still more of which we know nothing as yet, a vast welter
of vibratory forces flooding endlessly outward from the sun. And it is
one of those vibrations, one which we well may call the evolution
vibration, which is responsible for the evolutionary change of all life
on earth.
"In this there is nothing astounding. The sun's various vibratory
forces affect all living things on earth profoundly, each in a different
manner. Without the light-vibrations earth's life would fade and die,
the absence of the ultra-violet waves being fatal in time. Without its
heat-radiations all life would freeze. And without this evolution
vibration playing ceaselessly upon earth, all life upon earth would no
longer be pressed upward through the paths of evolution, would slip
back swiftly down those paths, down the myriad roads up which it
has surged for so long. For not only is it this evolution vibration that
forces earth's life upward on the way of change, it is this vibration
that keeps earth's life from slipping backward!"
Thus for Grant's statement. To Ferson and me it was as astonishing
as to the rest of the scientific world, for not until then did we learn
what work it was that had occupied Grant for so long. Yet even we
two, I think, were surprised at the sensation that that statement
caused. Always the work of Dr. Grant had been accepted almost
without question, so great was his reputation and so brilliant his
achievements. But with the publication of this amazing new theory of
his, the general dislike of the man that had always lain latent, burst
forth into a storm of criticism.
It was admitted that the new vibratory force which Grant had
discovered did apparently exist, since other scientists working on his
data had corroborated his work on it. But it was denied, by Grant's
numerous critics, that this force was what he claimed it to be—the
cause of evolutionary change. It was impossible, they stated, that
such a so-called evolution vibration could in reality be responsible for
the course of evolution on earth. And it was even more absurd to
suggest as Grant had done that were that force withdrawn, were the
evolution vibration to cease to play on earth from the sun, the living
beings of earth would slip swiftly backward on the road of change.
The controversy over the thing grew, in fact, to a point of bitterness
unprecedented in scientific discussion, a bitterness intensified by the
comments of the saturnine and black-tempered Grant. In a series of
sardonic statements, he compared his critics to those who had
derided the work of Darwin and his fellows, and indulged in some
rather acrid personalities. These in turn provoked fiercer attacks, and
the whole matter grew thus quickly into an unseemly intellectual
brawl. To Ferson and myself the whole controversy seemed a useless
one, because, in the course of time, experimentation by other
scientists would definitely prove or disprove Grant's theory. Yet
neither of us ventured to suggest that to our bitter superior, and so
the wrangle grew in intensity in the next days until it suddenly came
to a head.
It was the elderly President Rogers of Manhattan University who
brought the thing to a focus. He and the university's other officials
had been growing more and more restive under the criticisms that
Grant's controversy was bringing on the school, and so at last he
suggested that a meeting be held at which Grant could lay his
theories and data before his fellow-scientists in their entirety. This
Grant accepted, and so too did most biologists of any note within
traveling distance of New York, so widely had the clamor of the
dispute spread. And on an afternoon Grant rose before several
hundred assembled scientists in one of the university's lecture-halls
to explain his discovery.
There is little need for me to tell at length of what took place at that
meeting, which both Ferson and I attended. At the first appearance
of Dr. Grant his enemies in the audience grew vocal in their criticisms,
and before he had spoken a quarter of an hour the hall was in such
an uproar as a scientific meeting has seldom heard. Twice Grant
made an effort to go on and each time his voice was drowned by a
storm of shouted cries. The President, chairman of the meeting, was
rapping vainly for order, but Grant only stood still, looking out over
the stormy meeting with a cold contempt in his eyes, yet with a
strange fire in them. Quietly he rolled up the data-sheets in his hand
and thrust them into his pocket, and as quietly stepped forward to
the platform's edge. Something in his bearing, in his expression,
quickly quieted the noisy throng before him.
His voice came out over the hall cold and clear. "You have not let me
give to you the proof for which you asked," he said.
The President stepped to his side, said something rapidly, but Grant
shook his head calmly. "No proof that I can give you here would
convince you of my theory's truth, I know," he told the silent throng
before him, "but I will give you proof of it yet! To you, and to the
world, I will give a proof such as the world has never seen before!"
Before any could move, he had walked from the platform and out of
the hall. A buzz of excited voices broke out instantly, in comment and
criticism. It was some hours later before Ferson and I got from the
meeting to Grant's laboratory. But Grant was not there.
Within twenty-four hours more we knew, and all at the university
knew, that Dr. Grant had disappeared. From the meeting he went to
his laboratory, burned some papers there and pocketed others. Then
he went to his rooms, hastily packed a few bags and departed. He
left no note, no message. His action brought to a climax the whole
sensation of the controversy he had precipitated and Grant's going
was taken by many of his critics as a confession of the falsity of his
position. He had had no close relatives to start a search for him, and
though to Ferson and me his strange departure seemed astounding,
we could explain it no better than others. The sensation subsided,
and Ferson was appointed to head the department in place of the
vanished scientist. Our own work occupied us once more. And
certainly neither Ferson nor I, any more than another, guessed what
lay behind Grant's strange action.
It was six months after Grant's departure that the great change
began.
The first intimation was brought to the public notice by a New York
newspaper. In a sensational article entitled "Is a New Crime Wave
Upon Us?" it pointed out that in the last few days an unprecedented
number of crimes of violence had taken place.
These were the more appalling in that many seemed quite without
motive. In New York alone, in those few days, there had been more
than a dozen murders, mostly clubbings and stabbings, which had
apparently been provoked by the slightest of causes. In Chicago a
respected clerk of middle age had for some annoyance turned
suddenly and fractured the skulls of three of his associates with a
heavy bar. From San Francisco and Los Angeles had come news of
half a dozen holocausts in which one member of a family had
slaughtered or attempted to slaughter all the others. From every part
of the land there were coming reports of the most horrifying crimes
of violence, the great majority of which seemed inspired by the
pettiest of causes.
And this same wave of homicidal mania seemed at work over all the
world! It was as though hundreds in earth's population had suddenly
had their reason dwarfed and their passions magnified. No less than
three solid householders in London had run amuck in bursts of
sadistic[1] fury that had cost a half-score lives. The Paris police had
taken from the Seine more human bodies, many terribly mutilated,
than had ever been found in it in a like time before. Germany was
aghast over two mass-murders of unexampled fiendishness that had
occurred in a Rhenish and a Silesian village. There was news of an
even more terrible slaying in Calcutta, and word of murders almost as
terrible from almost every country on the globe.
Nor was it murder alone that was stalking the earth, for robberies of
the utmost brutality were even more numerous. Overshadowed as
they were by the greater horror, they were as astonishing in nature.
For all, like the slayings, seemed the result of sudden brutal instincts
or desires uncontrolled by reason. Small shopkeepers in American
and English towns were struck down for trifles. In the stores of great
cities there were those who snatched childishly at desired objects and
attempted a hopeless escape to the street. That was the keynote of
all these robberies, of all these crimes—the unreasoning childishness
of them. For the great part of them were attempted under
circumstances which should have shown to even the most dull-witted
that there was no chance of success.
It was a wave of strange and terrible crime, indeed, that was
sweeping over all the earth. The newspapers concerned themselves
with it to the exclusion of all else soon. They sought for explanations.
What had caused this sudden release of the most brutal passions of
numberless people? Many were the answers. An eminent scientist
declared that the nerve-racking strain of modern civilization had
reached such a pitch that the human mind could no longer stand it,
was giving way beneath it. Many wrote serious letters to the press
denouncing the motion pictures as schools of crime. Others defended
them. And while the cause was thus argued, the great wave of crime
and utter lawlessness that had rolled across earth seemed increasing
in volume.
The number of deaths by violence that were each day recorded had
grown now to an appalling figure. Murderous attacks were common
in every one of earth's great cities. Men hurled themselves at each
other's throats, apparently for a word, a gesture. Nor was this all. A
strange erratic insanity seemed seizing more and more of earth's
millions. Numberless were those reported to the authorities as
missing, those who had wandered causelessly away from home and
family. The world's roads held an unprecedented number of vagrant
wanderers.
But in a few days more even this astounding wave of appalling crime
was dwarfed in importance by more astounding and more terrible
happenings. Accidents, a great number of them fatal to many, were
occurring in every part of earth in an amount that was all but
incredible.
More than a hundred people had gone to death in the crash of two
thundering passenger trains in Colorado, a crash that had been due
to the failure of an engineer to heed the plainest of signals. Two train
wrecks in northern England had taken a toll of life almost as great,
and there were reports of many other crashes from various parts of
earth. In every one the accident had been due to the inexplicable
failure of the human element, the failure of dispatcher or switchman
or engineer to perform the duty that habit should have made
automatic. In one case, that of the Austrian disaster, the crash had
been directly caused by the sudden craziness of a switchman, who,
for some slight grievance, had sent a long passenger-train crashing
through an open switch and down an embankment.
There was news as terrible from the seas. Wireless reports flashed
thick with word of ships that had blundered fatally on rocks or shoals
by fault of helmsman or navigating officer. The greater part of these,
fortunately, were freight-ships of medium and small size, but one
case sent a thrill of horror through earth, already steeped in horror.
That was when the great transatlantic liner Garonia, bound to
Southampton, crashed by night into the southern Irish coast with the
resulting loss of three-fourths of the thousand humans it carried. And
that wreck, like the others, was due to an utterly inexplicable failure
of the ship's personnel.
Smaller in magnitude, but taking a total of far more lives, were the
unnumbered accidents that took place in the thickly populated and
highly mechanized countries of North America and Europe. The
number of automobile deaths, always staggering America, reached a
stunning total in those last fateful days of September. Crashes took
place at every corner, and the running down of pedestrians became a
common occurrence everywhere. Many cars mowed a path of death
through street and sidewalk before they were halted, their drivers
losing apparently all faculty of control of them.
And in mill and shop and factory death's grim hand was reaping as
thickly. Men, upon whom the lives of many depended, suddenly lost
control of their machines and sent those many to death. Countless
others were mangled or crushed to death by the great mechanisms
they had operated for years without mishaps. Airplane crashes
became so numerous that many sections of the world peremptorily
forbade all further flying until the cause of it all could be ascertained.
It was as though more and more of the masses of men were
becoming incapable of handling the mechanisms, of conducting the
operations, that they had been executing for years. Was mankind
going collectively insane?
It seemed insanity, indeed, that was sweeping earth now. Riots had
taken place on a small scale here and there in those days, but it was
not until after the first of October that the first of the great outbreaks
took place in London. Crowds of wandering men and women began
the looting of shops, the breaking of windows, and the rioting swiftly
spread. So swiftly did it spread, in fact, that by the time the troops
called to suppress it appeared on the scene, unestimated thousands
were engaged in the wild search for plunder. At the order to fire, an
irregular volley from the troops killed scores, but in the pitched mob
battle that followed scores of the soldiers took the side of the looters.
The combat between mob and soldiers was forgotten, and the battle
became a wild scene of brutality and violence in which hundreds
were slain and trampled. In the end it required machine-guns to
disperse them.
A similar great outbreak in New York was curbed quickly a day later
by the use of planes and tear-bombs, but two days after there came
a huge riot of unexampled bloodiness in Chicago, which cost several
thousand lives and which resulted in the burning of a third of the city.
Beginning as a race riot and developing into a savage general battle
for loot, it was notable for the fact that the troops, called to suppress
it, broke up even before they reached the scene and occupied
themselves in brutal looting and battle of their own. And a score of
great riots in the other cities of earth had similar results.
Civilization seemed crashing, with this oncoming dissolution of its
organization and institutions. Had humanity gone insane, indeed?
Swiftly, with full realization of the peril upon it by then, a conference
of the world's most noted scientists had been called some days
before at New York, to explain and to halt, if possible, this wave of
seeming insanity that was gripping more of the masses of humanity
each day and that was disintegrating civilization.
But when those scientists met, the world learned that they had a
hundred different explanations of the thing, no two agreeing. The
famous American alienist who had voiced his opinion days before
reiterated his belief that the minds of men were giving way en masse
beneath the strain of modern civilization. A Rumanian bacteriologist
claimed that the thing was the result of a contagious new brain
disease spreading over earth, and claimed even to have isolated the
bacterium of that disease. The scientists, gripped seemingly by
something of the erratic condition of mind they were striving to
explain, argued these theories and others with utmost passion,
sometimes attacking each other. An English physicist, who suggested
that earth was passing through strange mind-affecting gases in
space, was assaulted by the proponent of another theory. And still
more furious and incredulous, the world learned, was the reception
given to the explanation of a New York biologist named Ferson, who
claimed that the whole great terror was the result of the human races
slipping backward on the road of evolution!
"World atavism! A throwback of all the world's life on the road of
evolution!" So, they learned, Ferson had cried to the assembled
scientists. "All earth's animal life is beginning to slip back, and man,
as the most recently developed animal, is slipping first, is going back
toward the savage state, toward the cave-man or troglodyte, toward
the ape! He is losing control of his passions as he goes back, which
accounts for the violence that now fills earth! And he is losing the
mental capacity of modern man, which accounts for his inability to
operate longer our modern machines! A world atavism that is
beginning with the atavism of the human races!"
"But what could cause such world atavism as that?" the incredulous
scientists had cried.
"The evolutionary theory of my former associate, Dr. Grant——"
Ferson had begun, but was interrupted by a chorus of derisive shouts
provoked by the mention of the scientist whose ridiculous theory had
been exploded.
So Ferson had been forced from the meeting by the furious scientists,
who seemed seized indeed with the erratic craziness that was
gripping the world. Another day they advanced and argued their
theories, theories that grew ever more impossible, more incoherent,
and then the meeting dissolved in a general riotous brawl of the
arguing scientists. They, in common with the rest of the races of
men, seemed incapable longer of calm thought, of cool, unpassioned
reasoning. Two were killed, throttled in the brawl that ended the
meeting, and the rest scattered. They were not followed or punished,
for now the disintegration of humanity's institutions had become such
that crime was unheeded.
Men were outrivalling each other in mad action. Those in high places
as in low were gripped by the insanity that had apparently seized
earth, and from the Cabinets and Congresses of a score of nations
came declarations of war against other nations, for the slightest of
reasons or for none at all. England, the United States, France,
Germany, Italy, Turkey, Japan and China—these and a dozen others
issued frenzied and incoherent calls to arms. But they were
unheeded! Even war now could not penetrate the unreasoning minds
of men. Armies had broken up, all discipline and organization
vanishing. A few who tried to keep their soldiers in line found that the
men could no longer handle the great guns and instruments of war,
found that most of them were incapable of the operation of rifles!
Civilization was crashing with a prolonged roar of falling laws and
institutions and customs echoing across the world. The ordinary
methods of transportation and production having completely broken
down days before, the stream of food into the great cities had
abruptly ceased. The brutal throngs that filled those cities subsisted
by looting the existing food supplies for a time, but soon these were
exhausted and then terrible battles took place between the rioters for
food which they had found. Battles they were of hordes of ragged
brutes, of savages, who fought with knives or with their bare hands
in the streets. Only occasionally was a shot heard, for almost none
there was now with sufficient dull glimmer of intelligence to
manipulate a gun.
In the shadow of the tall towers of New York, and in the brick and
stone acres of London and the boulevards of Paris, thousands and
hundreds of thousands of these savages swarmed, the ways choked
with corpses of the slain. At night they crouched fearfully in hallways
and offices and corridors, the vast cities lying dark and silent beneath
the stars. Shapes of prowling animals were being seen in some of
them by night. No wheel turned in all the world now, for none
seemed left with intelligence enough to operate the simplest
machine.
And these swarms that had been human were changing in
appearance too. The men were unshaven and hairier, it seemed.
Much clothing had been discarded, crude belts that held knives or the
like weapons being retained. They crouched now as they walked,
their step a watchful, animal-like one. From under shaggy brows they
stared at each other. Small, crude family-groups held together, the
man battling other men for the possession of food. Some managed to
kill animals, and wore the skins.
They were troglodytes, millions of them, men such as the world had
seen thousands of years before, as humanity had been then. They
were troglodytes, wandering through the cities and towns that they
themselves had built, staring in wondering fear about them at things
the purpose of which they could not understand. But most had no
wonder, only a brutal lack of interest in all save food and mating and
sleep. There were no fires, for all had lost the use of fire and feared it
now.
Driven by hunger, great masses of them were pouring out of the
cities into the countryside, to hunt roots and herbs and to kill small
animals for food. They made rude shelters for a time, then
abandoned them for caves and crannies in the rocks. They ceased to
use knives or spears, they could but throw great stones at each other
or wield chance clubs, or fight with bare hands.
Many had remained in the cities and among them was more fighting.
With each day they were changing farther, it seemed, going farther
back along the long road of change that man had ascended so slowly
through the ages, and that he was slipping back upon so swiftly.
The streets of New York and Glasgow and Constantinople and
Yokohama saw them, these animal-like, ape-like hordes that
wandered there. Ape-like they were becoming, indeed, swiftly hairier
of body, more crouching of gait, stooping occasionally in moving to
run on hands and feet. Clothing they had discarded. The
fragmentary, mumbled speech that they had kept until days before
had given way to a meaningless medley of barking shouts and cries
whose tone conveyed their crude attempt at communication. They
roamed the great cities in little groups or tribes, of each of which one
was the strongest, the tyrant, the acknowledged lord.
And now, they were changing still. Were running more on hands and
feet, walking upright less. Back from man to troglodyte, and from
troglodyte to ape had the human races gone, and now were slipping
back still into the animal races from which the apes had come! World
atavism—and it was wiping the last human-like forms from the face
of earth!
Of this great change that in days swept man back into the brutal
forms of dead ages, I, Allan Harker, was a witness from the first. For
it was at New York that the early manifestations of the change had
been first noticed, in that increasing wave of terrible crime that was
in days to rage over the whole earth.
Neither Ferson nor I, of course, had any suspicion of the thing's real
magnitude in those first days. We followed, with the same
astonishment that held most in the world, the astounding growth of
crime and violence, but it was remote from our own interests, and we
were both very much absorbed in our differing work of
experimentation. We spent more time on that work, indeed, in those
days than before, for both Ferson and I seemed to have lost a little of
our usual skill and knowledge. I know that he caught himself in
inexplicable lapses, and I know that I, usually the most patient of
biologists, forgot myself in sudden impatient rage on one or two
occasions and smashed retorts and test-tubes about me. Neither of
us dreamed, of course, that we were being affected by the same
strange forces that were releasing humanity's passions in a carnival
of crime.
But when a little later the great wave of crime that was making earth
hideous was made more terrible by the innumerable inexplicable
accidents that were occurring, Ferson became thoughtful. He
deserted his own white-tiled laboratories for the university's
psychological test-rooms with their strange recording instruments,
and spent hours there carrying out intricate tests of the reactions of
himself and others. It was after two days of such tests, when the
fatal accidents occurring everywhere were taking toll of thousands of
lives daily, and when almost all industrial activity was slowing and
stopping because of them, that Ferson came back, his countenance
as I had never seen it.
"I've found it, Allan," he said quietly. "The cause of all this terror—
these innumerable crimes and accidents and riotings."
"The cause of them?" I repeated, uncomprehendingly, and he
nodded.
"Yes, and that cause is world atavism! An atavism, a throwback, of all
the world's animal life, that is beginning with man as the most
recently developed animal and that is taking place before our eyes!
Taking place in ourselves even!"
"World atavism!" I gasped. "But, Ferson—that such a thing could be
—it's inconceivable!"
He shook his head. "Not inconceivable. You remember Grant and his
theory, that the evolution vibrations from the sun were what had
pushed earth's life up the road of evolution? And you remember that
Grant said that were those evolution vibrations to cease to reach
earth from the sun, all earth's life would slip swiftly back upon that
road?"
"I remember," I said, "but how could such a thing happen? What
could ever halt the play of the sun's evolution vibrations on earth?"
Ferson's eyes were somber. "I do not know what could," he said
slowly, "but I think I know who could!"
"Ferson!" I cried. "You don't for an instant think that Grant——"
"I do think so," he said, his voice steelly. "Grant discovered the
existence of the evolution vibrations—he alone of men knew all
concerning them. Do you remember what he said when they refused
to let him explain his theory even at that meeting? He said: 'I will
give you proof of this. I will give you proof yet of this theory, and
such a proof as the world has never seen before!'"
My mind was reeling. "Then you think that when Grant disappeared—
that he——"
"I think that that great proof that Grant promised in his rage to give
the world is the world atavism that is upon humanity now! I think
that Grant in some inconceivable way has used his knowledge and his
power to deflect or dampen the evolution vibrations coming toward
earth from the sun, and that it is because of the absence of those
vibrations that earth's life is slipping backward!"
"But where will it stop?" I exclaimed.
"It will not stop, Harker—this tremendous change has only begun.
Man, the most recently evolved of all animals, is changing first, and
will go back through troglodyte and ape to the forms before them,
back through changing beast-forms. By then the other animals of
earth will be changing also, thrown back along the evolutionary road,
and that great atavism will continue until earth's life has all changed
back into the first crude protoplasmic forms from which eons ago it
sprung!"
"But what can we do?" I cried. "There must be some way of stopping
this!"
"There is only one way," he said. "Grant is causing this great world
atavism, is shutting off the sun's evolution vibrations from earth by
projecting toward the sun, no doubt, a great dampening or
neutralizing vibration that stifles them, annihilates them, at their
source. We must find Grant's whereabouts, must destroy whatever
apparatus he is using to do that!"
"Yet if all are changing—we two also must be changing!" I exclaimed,
and he nodded.
"We two are already a little affected as all men are, more or less. Our
lapses of memory, the difficulties we have in our work now, these
things in the last days are the result of this world atavism in us, just
as the crimes and accidents filling earth are. And we two must
protect ourselves against this tremendous change, whatever we do,
for on us depends the one chance of halting Grant's terrible work.
The world will never believe that that dread work is really going on
until it is too late, so you and I must not change!"
Ferson went swiftly on to explain his idea. This was none other than
to construct two small projectors that would each automatically and
ceaselessly generate artificial evolution vibrations, vibrations affecting
a limited range as the sun's vibrations had affected all earth. These
projectors in their compact cases could be worn on our bodies by
each of us without being noticeable, and would keep each of us
always thus in the range of the vital vibrations, so that we would not
be affected by the world-wide absence of that which was causing this
world atavism. Whatever great dampening wave Grant was sending
out toward the sun to neutralize its evolution vibrations would not, of
course, affect the vibrations of our own little projectors.
The next two days saw us at work upon these projectors. The
method of producing the evolution vibrations we knew, for as I have
mentioned, they had been artificially produced in a small way by
physicists upon Grant's first announcement of his theory. The second
day, therefore, saw our projectors complete, small flat black cases
that were strapped to our belts without being noticeable, each
holding the tiny but marvelously powerful batteries that were the
current-source, and the compact little generator that automatically
and unendingly released the vital evolution vibrations for a range of
several feet. With these completed and working, and secured thus by
them from being ourselves affected by the terrible atavism that was
upon the races of man, we began our greater work of locating Grant
and the apparatus by which he was shutting off the sun's vibrations
and loosing this horror on the earth.
For horror it had now become, and the world was waking up to its
true nature as every sort of brutal passion was released in terrible
crime over it, and as the inexplicable mindlessness of men brought
on terrific accidents. Already a dozen of the greatest governments in
coöperation had called a conference of earth's greatest scientists at
New York to explain or to halt at least the horror that was sweeping
earth. To that conference they came with each a different and more
incredible explanation of the thing, and to it went Ferson and I to
give them the true explanation and to turn them toward the search
for Grant that might yet save humanity. But that explanation was
never given, for Ferson's first mention of world atavism was greeted
with incredulous cries, and when he went on to mention Grant, such
a derisive storm arose, that he was forced bodily from the meeting,
leaving the scientists disputing fiercely over the most impossible of
theories, supporting and opposing those theories by blows.
For they, like the rest of humanity, seemed incapable now of clear
and sustained thought upon any subject. Even Ferson and I, working
day and night in the isolated upper Manhattan laboratories of the
university, were able to see clearly what was happening about us. We
were living, eating, sleeping at the laboratories by this time, for all
means of transportation and all industrial activities were ceasing.
Great masses of men roamed the streets of the city, some forming
into gangs that made life terrible for the others, the rest engaged in
indiscriminate looting. The great London riot and the abortive
outbreak in lower New York had now taken place, and it was evident
to all that the last shadow of law and order in the city was vanishing,
for more and more the troops and police who maintained it were
engaging in the rioting themselves.
News came still a little, in incoherently written and erratically printed
sheets, for a few days, and it was thus we learned of the huge
Chicago riot and subsequent fire. It marked the beginning of the end.
Within a few days more utter lawlessness reigned over New York,
corpses lay in its streets and looters were everywhere. The university
buildings, deserted now by all but ourselves, were not attacked
except on a few occasions by the looting swarms, there being no
food or other desirable things in them, and Ferson and I had rifles
and pistols in our laboratory to repel the ragged and brutal gangs
that might attack us.
In those terrible days we were occupied heart and soul in the work of
locating Grant and whatever mechanism it was by which he was
casting this doom on humanity. It was Ferson's idea that the great
damping wave, which Grant must be sending toward the sun to halt
the play of its endless evolution vibrations, would affect certain
recording instruments, if the correct frequency for their circuits could
be found. Once that was found, by observing the amount by which
the instruments were affected at different locations by the waves of
the great damping vibration, we could calculate and chart that great
wave's source with some degree of accuracy. It seemed to me a very
slender chance, yet I knew as well as did Ferson that it was the one
possible way. Grant, we knew, would have protected himself, as we
had, by a small artificial projector of the vibrations.
So in those fearful days we worked with the recording instruments,
watching them at each new trial for some indication of the force
whose source we sought. The whole great mass of New York's giant
structures that stretched southward and downward from our
laboratory lay now in complete darkness each night; the last wonted
activities of civilization having ceased in it as elsewhere. Ragged
hordes of savages roamed it, savages so hairy and crouching and
brutal of face, seeming each day more prognathous of jaw and
slanting of brow and animal-like of eye, that we knew them to be
troglodytes, cave-men, men such as humanity had been ages before
and such as it was over all earth now.
We saw them occasionally prowling through the university grounds in
search of food, shambling toward us with lowering brows to attack us
when they glimpsed us, but fleeing in fear when we fired over their
heads. For none of them could manipulate so complicated a thing as
a firearm. All earth's hundreds of millions were prowling their way in
just such brutal bands, thrown back to the state that had been man's
before history's dawn. And ever more brutal and hairy and animal-like
they were becoming as they slipped back farther still, back from
troglodyte to ape! Mankind was gone, transformed into these still-
changing brutes—all except Ferson and me.
I cannot tell now in full of those terrible last days of change, those
days in which in our chance glimpses we saw men making that other
terrible step backward, from troglodyte to ape. For Ferson and I were
working with the speed of utter despair. Even were Grant's terrible
work to be halted, the sun's evolution vibrations again released on
earth, it would take them untold ages to raise the brute-like beings
about us to the status of men once more. Humanity was passing, had
passed, into the brute around us, yet for their sake, for the sake of
the humanity that might rise again in the dim future, we kept to our
efforts, sought still to halt this awful change, that would otherwise
not stop until protoplasmic slime alone was left living on earth.
We had found the correct frequency for the circuits of our recording
instruments, and in feverish haste set up those instruments at
intervals of a mile, working through the night. The weirdest of work it
was, the vast city's streets and structures silent in the night around
us, the countless hordes of brute-like beings that once had built them
now cowering in the buildings in ape-like fear of the night's
mysteries. We took our readings, hastened back to our laboratory,
and dawn found us marking those readings on the great chart-map of
the section we had ready. Somewhere in that section, somewhere
near New York, we knew, Grant lurked with his terrible mechanism,
our first readings having shown us that. And now, as with trembling
hands Ferson and I drew the graphs on the big chart, we stared for a
moment after in complete silence.
Those lines converged at a point in a midtown block of the great city
south of us, a block occupied by a single gigantic building whose
aspiring tower was in sight of our laboratory's windows!
For moments Ferson and I stared from chart to tower in silence, and
then without words we had turned, seen to the filled magazines of
the pistols at our belts, and were passing out of the laboratory into
the bright sunlight. As silent as ever, we started southward.
Never, were my existence extended a thousand years, could there be
blotted from my memory that journey southward through the silent
towers of New York that Ferson and I made then. For the great city
that lay silent about us beneath the brilliant noon sunshine, was a
city of horror unutterable. Dead lay thick in its streets and great
dogs, already strange and fierce and wolf-like, ran in packs among
them. The rusting wrecks of smashed automobiles were piled at
every corner. No window of all we passed remained intact, sidewalks
and streets were sprinkled with shivered glass. Westward across the
river a great fire was burning in the cities there, pouring a black
volume of flame-laced smoke up to the skies. But more terrible than
all of these things were the hordes, the swarms of creatures that
moved through the streets and ways about us, the countless
creatures that once had been the city's people!
Great ape-like creatures they were, not apes such as men had
known, but ape-like races such as men had sprung from eons before.
In groups and packs of scores they roamed the city's ways. Covered
with thick hair, stooped and crouching of gait, the garments that they
had worn as men torn and discarded, there was in them no
semblance to humanity. They walked stiffly toward each other,
stooping to rest hairy forearms on the ground each few steps. They
growled and barked in rage, or chattered volubly and meaninglessly.
The majority were prowling in wrecked stores for fragments of food.
Others moved along the streets in a search for small animals, for
insects even.
Growling in rage their groups came toward Ferson and me as we
moved onward, but each time a pistol-shot sent them fleeing from
us. We moved on, never speaking, Ferson's face icy calm, my own
brain reeling. We came at last to the base of the giant building that
we knew must hold whatever mechanism Grant was using to
withhold the evolution vibrations from the earth.
Ferson turned to speak to me for the first time. "Somewhere in here,"
he whispered. "We must search, Harker——to find Grant's apparatus
——"
"And if he is with it?" I asked, but his only answer was to tighten his
grip on the pistol in his hand.
We passed into the great building's marble entrance hall, a place of
dim shadows, through which we stumbled over prostrate dead. We
went quickly through the looted, wrecked rooms that had been the
luxurious shops of its first level. Then the stairs, and we were going
upward, level after level, searching through the immense building's
numberless offices and rooms. In one or two were dead, and some
had been wrecked, but in none, in no part of the building, it seemed,
were any of the ape-like throngs. That seemed encouraging,
somehow, and with beating hearts we pressed on upward.
Level after level. We were high in the immense building; its floors
here were smaller of extent because of its pyramidal form. Yet there
was no sound from the shadows about us, no sign of what we
sought. Despair was growing in us, for we were high in the great
tower that was the building's uppermost part, and had found nothing.
Through the shadowy halls we pressed still, and through the silent
rooms lit with the gold of the westward-swinging sun. But as we
moved up the narrow stair toward the last and highest level of the
great tower, something flamed in Ferson's eyes as in mine.
A sound had come from above to our ears, a steady, slow clicking as
of a great clock. Pistols in hand, we moved up, found ourselves in a
small hall at the tower's side. The unused elevator-shaft was beside
us, and the stairs that led to the roof. But before us was the single
door that gave access, apparently, to the whole space of the tower's
uppermost level. And from behind it came the slow clicking to our
ears!
As one we crossed the hall toward that door. Ferson's hand on its
knob turned slowly, and slowly, astoundingly, the door swung open.
Our pistols lowered for the moment in our amazement, we stepped
through, stopped. A dozen feet before us stood Grant, a heavy
automatic in his hand trained upon us.
Silence. In it Grant's eyes held ours. His dark-browed powerful face
was lit with unholy triumph, with sardonic exultation. I saw that
before us was the whole space of the tower's highest level, thrown
into one great room. Huge black-cased and powerful batteries were
ranged upon each other in scores at one side of the room. Armored
cables led from them through incalculable generators and
transformers to a great object at the big room's center. It was like a
giant searchlight, a dozen feet or more in diameter, swung in a frame
resembling gimbals, so that it could be turned in any direction. The
twelve-foot disk inside it glowed silently with white light, and the
great thing was turned to face exactly the sinking sun westward. It
was slowly following the descending sun, turning slowly under the
action of a great clock-mechanism, whose clicking was loud in our
ears still.
Grant, Ferson and I——we were silent there in the room, all
motionless, until Grant spoke. His voice was metallic, controlled,
mocking.
"Ferson and Harker," he was saying. "Ferson and Harker, who
believed in my theory, my power, it seems, when none else on earth

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Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

eISBN 1-59745-002-2 ISBN13 978-1-59745-002-7

included chapters reviewing the epidemiology and significance of carotid stenosis,

PART I CLINICAL EXPERIENCE

PART II TECHNIQUES OF CAROTID AND VERTEBRAL ARTERY STENTING

13 The Approach to Intracranial Carotid Artery Intervention .......... 189

PART III CHALLENGING CASE ILLUSTRATIONS AND PEARLS

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Anthony Y. Fung, MBBS

From: Contemporary Cardiology: Handbook of Complex Percutaneous Carotid Intervention

stroke and other ischemic manifestations of systemic atherosclerosis (e.g., myocardial

CAROTID ARTERY STENOSIS

Prevalence of Concomitant Intracranial Atherosclerosis

Fig. 1. Schematic diagram illustrating frequent causes of ischemic strokes.

Fig. 2. Classification of stroke according to etiology.

the NASCET (North American Symptomatic Carotid Endarterectomy) study of sympto-

Carotid Intimal–Medial Thickness

Concomitant Coronary Artery Disease and Peripheral Arterial Disease

CONSEQUENCE OF CAROTID ARTERY STENOSIS

1–29% 30–59% 60–99% Occluded

(Asymptomatic Carotid Endarterectomy Study) (22), and 11.7% in ACST

Other Predictors of Stroke

Risks of Coronary Artery Disease

Risk of Stroke with Coronary Artery Bypass Surgery

Key Words: Angiotensin-converting enzyme inhibitor, antiplatelet therapy, antithrombotic therapy,

TRADITIONAL CARDIOVASCULAR RISK FACTORS

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What are Useful End Points or Outcomes to Measure?

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CARDIOPROTECTIVE EFFECT OF ACE INHIBITORS/ANGIOTENSIN RECEPTOR

GOAL OF BLOOD PRESSURE MANAGEMENT

associated with reduced microvascular events (retinopathy, nephropathy, neuropathy).

ANTIPLATELET AND ANTITHROMBOTIC THERAPY

Aspirin and Treatment for Carotid Stenosis

Joël Gagnon, MD and

Key Words: Carotid artery stenosis, carotid endarterectomy, ischemic stroke.

From: Contemporary Cardiology: Handbook of Complex Percutaneous Carotid Intervention

Incision and Dissection

the atheromatous lesions causing fragmentation and subsequent embolization and

Clamping and Shunting

Factors Affecting Surgical Outcome

RESULTS OF RANDOMIZED CLINICAL TRIALS

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